CA2031586A1 - Process for preparing an optically active cyclobutane nucleoside - Google Patents
Process for preparing an optically active cyclobutane nucleosideInfo
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- CA2031586A1 CA2031586A1 CA002031586A CA2031586A CA2031586A1 CA 2031586 A1 CA2031586 A1 CA 2031586A1 CA 002031586 A CA002031586 A CA 002031586A CA 2031586 A CA2031586 A CA 2031586A CA 2031586 A1 CA2031586 A1 CA 2031586A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/04—N-nitroso compounds
- C07C243/08—N-nitroso-carboxamides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Abstract A process for the preparation of the optically active compound [1R-(1.alpha.,2.beta.,3.alpha.)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one, represented by the formula:
Description
~ ~! 'J ~
PROCESS FOR PREPARING AN OPTICALLY ACTIVE
CYCLOBUTANE NUCLEOSIDE
The present invention relates to the optically active compound [lR~ ,2~,3~)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6~purin-6-one, represented by formula 1 and to a process for the preparation thereof.
uo~C ~ N ~ 2 ~ 20 The invention relates to novel intermediates : in the above process and to a process for preparing thes~ intermediates.
2 ~ s~
Compound 1 as a 1:1 mixture with its optical antipode (i.e., the racemic mixture) is an antiviral agent with activity against herpes simplex virus types 1 and 2, varicella zoster virus, human cytomegalovirus, vaccinia virus, murine leukemia virus, and human immunodeficiency virus; and are believed to be active against a variety of other DNA viruses and retroviruses.
Antiviral activity is also exhibited by the single enantiomer, compound 1, and its pharmaceutically acceptable salts. Compound 1 as a 1:1 mixture with its optical antipode has been prepared by methods described in European patent application 335,355 published on October 4, 1989.
The process of the present invention is shown in the reaction scheme below:
R2O2C ~ OR1 RO2C ~ R~
~ ~ ?~
_3_ GY16 R3~3Noc~O~ ORI Rl o~CONHR3 R3HNoC CoNHR3 5 4 \ 5 .~ ~
~0 R3a~No~o< ORl R3No~o< OR
R3aHNoc R3NoC
NO
V 8 1, NO
R3 aN0C~o<ORl HOH2 C~><
- ORI _ oP~
R3 a ~ OC HOH2 C
R4 O~I2 C~XRI ~Oe R4 OE~2 C R4 0~12 C
~3~
R4O~2C ~ ~ X
R~OH2C R4OH2C
N NH
R4OH2C~ ~ W HOH2C ~ ~ NH2 wherein R1 and R2 are lower alkyl, R3 is an alkyl or substituted alkyl group derived from a chiral primary amine of the formula R3NH2,R3a is a suitably protected form of R3, R4 is a protecting group, X is a leaving group, and W is a 9-guanyl residue or a suitably protected foDm of a 9-guanyl residue. Compounds 2 and 3 are each racemic mixtures. The relative stereochemistry of the two R2O2C groups in compound 2 is trans and the rela-tive stereochemistry of the two HO2C groups in compound 3 is al so: trans . Compo~nd 1 and compounds 4 through }4 are chiral compounds, and their absolute stereochemistry is as pictured in the figures of the above reaction schemes.
:
GY16 2 ~ 3 ~ ~
The term "lower alkyl" refers to both straight and branched chain groups which contain from l to 5 carbons. Those groups having 1 to 2 carbons are preferred. The term "alkyl" refers to both straight and branched chain groups. The groups having 1 to 10 carbons are preferred. The term "substituted alkyl" refers to alkyl groups having one or more substituents. Examples of substituents include hydroxy, alkoxy, alkoxy-carbonyl, phenyl, hydroxyphenyl, dihydroxyphenyland nitrophenyl. Preferred substituents are hydroxy and phenyl. When R3 is substituted with hydroxy, R3 should be protected with a suitable hydroxy protecting group to give R3a. Exemplary protecting groups are hindered silyl groups such a t-butyldimethylsilyl, t-butyldiphenylsilyl, tri-isopropylsilyl and the like; acyl groups such as acetyl; aroyl groups such as benzoyl; the tri-phenylmethyl (trityl) group or a lower alkoxy substituted triphenylmethyl group sush as 4'-methoxyphenyldiphenylmethyl. Preferred protecting groups are t-butyldimethylsilyl and acetyl. The protecting group R4 may be a hindered silyl group (such as t-butyldiphenylsilyl or triisopropyl-silyl~, an acyl group (such as acetyl), an aroylgroup (such as benzoyl~, a benz~l group or a substituted benzyl group (such as p-methoxybenzyl).
The leaving group X may be an alkanesulfonyloxy group (such as methanesulfonyloxy(mesyl)), a substituted alXanesulfonyloxy group (such as trifluorome~hanesulfonyloxy (triflyl)), or an arene- or substituted arenesulfonyloxy group ~such as p-toluenesulfonyloxy group (tosyl) or p-nitro-~31~
benzenesulfonyloxy group (nosyl)). The group W
includes ~he 2-amino-6-ben~yloxypurin-9-yl, 2-amino-6-methoxyethoxypurin-9-yl, 2-amino-6 chloro-purin-9-yl, and 2-acetamido-6-hydroxypurin-9-yl residues as suitably protected forms of the 9-guanyl residue. The 2-amino-6-benæyloxypurin-9-yl and 2-amino-6-methoxyethoxypurin-9-yl residues are preferred as protected forms of the group W.
The racemic compound of formula 2 wherein R1 and R2 are lower alkyl can be prepared by reacting ketene di(lower alkyl)acetal with di(lower alkyl)-fumarate (see K.C. Brannock et al., J. Org. Chem., 9, 940 (1964)). Preferentially R1 and R2 are methyl or ethyl. For example, ketene diethyl acetal is reacted with diethyl fumarate either neat or in an appropriate solvent such as acetonitrile, t-butanol, or the like, preferably t-butanol. The mixture is stirred for about 4 to 10 days, preferably for about 6 to 8 days, at a temperature of about 70C to 100C, preferably of about 80C to 90C. The resultant compound 2 can be isolated by chromatography or distillation.
Di(lower alkyl)fumarates are either commercially available (e.g., Aldrich Chemical Co.) or can be readily prepared by methods known in the art. Ketene di(lower alkyl)acetals are either co~mercially available (e.g., Wiley Organics Inc.) or can be readily prepared by known methods (see e.g., Orqanic Syntheses, Collective Volume III, p. 506; J. Amer. Chem. Soc., 62, 964 (1940)).
The racemic compound of formula 3 is prepared by treatment of the compound of formula 2 with alkali, preferably potassium hydroxide, in aqueous or mixed aqueous-organic solvent solutions, for example, water-dioxane, water-tetrahydrofuran, water tetrahydrofuran-methanol and the llke, preferably water-tetrahydrofuran-methanol. The mixture is stirred for 1 to 5days, preferably for 2 to 3 days at a temperature of lO~C to 50C, preferably of 20C to 30C. The reaction mixture is diluted with water, acidified to about p~ 2.5 with aqueous acid and extracted with an organic solvent such as dichloromethane, ethyl acetate, and the like, followed by concen-tration of the organic solvent.
The diastereomeric mixture of compounds 4 and 5 is prepared by treatment of compound 3 with a chiral primary amine (R3NH2) in the presence of a coupling agent such as 1,3-dicyclohexylcarbodi-imide, l-(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride, and the like, in a solvent such as methylene chloride or tetrahydrofuran. To this reaction mixture, additional reaction components such as l-hydroxybenzotriazole, or 1-hydroxybenzotriazole plus N-me~hylmorpholine, may optionally be added. The mixture is stirred at about 0C to 50C, preferably at about 20C to 25 30C for 1 to 48 hours, preferably for 10 to 18 hours. Water is added to the reaction mixture, and the mixture of compounds 4 and 5 is isolated ~ by extxaction.
; Examples of suitable chiral primary amines, R3NH2, include chiral alkyl amines such as (+)- or (-)-2-aminobutane and (+)- or (-)-2-aminoheptane;
chiral hydroxy-substituted alkylamines such as (+)- or (A)-2-amino-1-butanol, (+)- or (-)-2-amino-l-propanol, (~)- or (-)-2-amino-3-methyl-l-butanol, (+)- or (-) - leucinol, and (+)- iso-leucinol; chiral phenyl or naphthyl-substituted alkyl amines such as (+)- or (-)-~-methylbenzyl-amine, ~+)- or (-)-a-(1-naphthyl)ethylamine, and (+)- or (-)-~-(2-naphthyl)ethylamine; chiral alkylamines substituted with both hydroxy and phenyl such as (+)- or (-)-2-phenylglycinol, (+)-or (-)-threo-2-amino-1-phenyl-1,3-propanediol, (+)-or (-)-norephedrine, (+)- or (-)-2-amino-3-phenyl-1-propanol, and (+)- or (-)-2-amino-1,2-diphenyl-ethanol; and other substituted alkylamines such as (+)- or (-)-~-methyl-p-nitrobenzylamine, (+)- or (-)-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol, (+)- or (-)-norepinephrine, (~)-dehydroabietyl-amine, (+)-2-amino-3-methoxy-1-phenylpropanol, L-tyrosinol, and lower alkyl esters of ~-amino acids such as (+)-or (-)-alanine, (~)- or (-)~
valine, (+)- or (-) leucine, (+)- or (-)- isoleu~
cine, (+)- or (-)-phenylalanine, (+)- or (-)-tyro-sine, (+)- or (-)-serine, and (+)- or (-)-threo-nine. Preferred chiral alkylamines include those substituted with both hydroxy and phenyl groups;
most pr~ erred is (-)-2~phenyls~1ycinol.
Compounds 4 and 5 may be separated by chromatography (e.g. on silica gel), or by crystallization from various solvents and solvent mixtures such as methylene chloride, chloroform, ether, ether-methanol, water, and the like. When the chiral amine R3N~2 is (-)-2~phenylgly~inol, the resultant compound 4 is separated preferably by crystalli2;ation from methylene chloride.
_g_ When the group R3 of compound 4 is substi-tuted with a hydroxy group, the hydroxy is protect~d to afford compound 6, wherein the group R3a is tha protected form of R3. A compound of formula 6 where-in the hydroxy group of R3 has been protected witha hindered silyl group such as t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl is prepared by treating the compound of formula 4 with the appropriate silyl reagent such as the correspon-ding tri(hydrocarbon)silyl chloride. Compound 4 isreacted with the silyl reagent in a sol~ent such as dimethylformamide, tetrahydrofuran, acetonitrile, and the like, preferably dimethylformamide, at -10C to 30C, prefeIably at 0C to 20C for 1/4 hour to 2 hours, preferably for 1/2 hour to 1 hour.
The reaction is run in the presence of a base such as triethylamine, pyridine, or imidazole, preferably imidazole. The compound of formula 6 is extracted and optionally purified by, e.g. chromatography on silica gel.
The compound of formula 6 wherein the hydroxy group has been protected with an acyl or aroyl group such as acetyl or benzoyl is prepared by treating the compound of formula 4 with the corresponding acyl or aroyl chloride or with the corresponding acyl or aroyl anhydride in a solvent such a pyridine or tetrahydrofuran. When te~ra-hydro~uran is used as solvent, a base such as triethylamine is added.
A compound of formula 6 wherein the hydroxy group has been protected with a trityl or a lower alkoxy substituted trityl group is prepared by treating the compound of formula 4 with trityl chloride or the lower alkoxy substituted trityl chloride in a solvent such as pyridine.
A compound of formula 7 is prepared by reacting a compound of formula 6 with a suitable nitrosating agent such as nitrosyl chloride, nitronium tetrafluoroborate, nitrogen tetroxide (N2O~), and the like, preferably nitrogen tetroxide. (See e.g., E. H. White, J. Amer.
Chem. Soc., 77 6008 (1955) and J. Vilarrasa, J. Orq. Chem., 54, 3209 (1989) for a discussion of various nitrosating agents). For example, a compound of formula 6 is treated with nitrogen tetroxide in a solvent such as carbon tetra-chloride, methylene chloride and the like, preferably carbon tetrachloride, in the presence of a base such as sodium acetate, pyridine, and the like, preferably sodium acetate. The reaction mixture is stirred for 1/4 hour to 4 hours, preferably 1/2 hour to 1 1/2 hours at -10C to 20C, preferably at ~5C to 10C. The mixture is poured into ice water and extracted.
A compound of formula 8 is prepared from a compound of formula 4 when the group R~ does not contain a hydroxy substituent. The preparation of a compound of formula 8 from a compound of formula 4 is accomplished in the same manner as described for the preparation of a compound of formula 7 from a compound of formula 6.
A compound of formula 9 is prepared by treating a compound oE formula 7 or a compound of formula 8 with a suitable reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride and the like, preferably lithium borohydride. For example, a compound of formula 7 or a compound of formula 8 is treated with lithium borohydride in a solvent such as tetrahydrofuran, ether, dimethoxyethane (glyme) and the like, preferably tetrahydrofuran, at -20C to 20C, preferably at -lO~C to 10C for 1/4 hour to 2 hours, preferably 1/2 hour to 1 hour.
The reaction mixture is ~uenched with water and the product is extracted and purified by e.g.
chromatography.
A compound of formula 10 wherein R4 is a suitable protecting gxoup is prepared by reacting a compound of formula 9 with the corresponding protecting group precursor. Suitable protecting groups R4 include hindered silyl groups (such as t-butyldiphenylsilyl or triisopropylsilyl), benzyl or substituted benzyl groups (such as p-methoxy-benzyl), aroyl groups (quch as benzoyl) and acyl (such as acetyl). Benzyl and benzoyl are preferred for R4. A compound of formula 10 wherein R4 is a hindered silyl group is prepared by treating a compound o~ formula 9 with tha appropriate silyl reagent e.g., the corresponding silyl chloride, using reaction conditions described previously. A
2 ¢1 ~ 3~
G~16 compound of formula 10 wherein R~ is a benzyl or substituted benzyl i5 prepared by treating a compound of formula 9 with a benzyl halide or a substituted ben7yl halide in a solvent such as tetrahydrofuran or dimethylformamide in the presence of a suitable base such as sodium hydride.
A compound of formula 10 wherein R4 is an acyl or aroyl group is prepared by treating a compound of formula 9 with the corresponding acyl- or aroyl-anhydride or halide, preferably ben~oyl chloride, in a solvent such as pyridine or tetrahydrofuran/triethy~amine, preferably pyridine.
The benzoylation reaction is carried out at -10C
to 20C, preferably at -5C to 5C, for 1/4 hour to 2 hours, preferably for 1~2 hour to 1 1/2 hours.
Water is added to the reaction mixture, the mixture is stirred overnight, and the product is extracted and optionally purified e.g. by chromatography.
A compound of formula 11 is prepared by treatment of a compound of formula 10 with an acid catalyst such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and the like, preferably sulfuric acid, in a solvent or solvent mixture such as water, water-acetonitrile, water-dioxane, acetone, and the like, preferably water-acetoni-trile. The reaction mixture is stirred at 0C to 60C~ preferably at 15C to 30C: for 1/2 hour to 2 days, preferably for 2 hours to ~ hours. The reaction mixture is neutralized, and the product is extracted and optionally purified ~y e.g.
chromatography.
~3~
A compound of formula 12 is prepared by reaction of a compound of formula 11 with a suitable reducing agent. Reducing agents may include hindered hydride reagents such as lithium tri-sec-butylborohydride, lithium trisiamylboro-hydride, diisobutylaluminum hydride and the like, preferably lithium trisiamylborohydride and hin-dered borane reducing agents such as dicyclohexyl-borane, disiamylborane, and the like. The rsaction is run in a solvent such as ether, tetrahydrofuran, glyme, and the like, preferably tetrahydrofuran.
When a hindered borohydride reducing agent is employed the reaction mixture is stirred at 90C
to -60C, preferably -80C to -70C for 5 minutes to l hour, preferably for 1/4 hour to l/2 hour and the mixture is allowed to warm to 0C to 30C, preferably 20C to 25C. The reaction is worked up with aqueous sodium bicarbonate-hydrogen peroxide and the product is isolated by extraction and optionally purified by e.g. chromatography.
A compound of formula 13 wherein X is a leaving group such as an alkanesulfonyloxy group (e.g., mesyl), a substituted alkanesulfonyloxy group (e.g., triflyl), or an arene- or substituted arenesulfonyloxy group (e.g., tosyl or nosyl), may be prepared by treatment of a compound of formula 12 with the appropriate sulfonylating reagent such as the corresponding sulfonic anhydride or sulfonyl chloride, preferably tosyl chloride, in a solvent such as pyridine, tetrahydrofuran, methylene : :
-14- GYl6 chloride, and the like, preferably pyridine. When non-basic solvents such as tetrahydrofuran, methylene chloride and the like are employed for the reaction, a base such as triethylamine is added to the mixture. Depending on the solvent and the sulfo-nating reagent, the reaction mixture is stirred at 0C to 60C, for 1 hour to 48 hours. For example, a mixture of a compound of formula 12 and tosyl chloride in pyridine is stirred at 60C overnight.
The product is isolated by extraction and option-ally purified by, e.g., chromatography.
A compound of formula 14, wherein W is a 9-guanyl residue or a protected form of ~he 9-guanyl residue is prepared by reaction of a compound of formula 13 with guanine or the corresponding protected guanine. Protected forms of guanine include 2-amino-6-benzyloxypurine, 2-amino-6-methoxyethoxypurine, 2-amino-6-chloropurine, and 2-acetamido-6-hydroxypurine.
Preferred protected forms of guanine are 2-amino-6-benzyloxypurine and 2-amino-6-meth-oxyethoxypurine. A mixture of the compound of formula 13 and guanine or a protected guanine, and a base such as potassium carbonate, sodium hydride, and the like, preferably potassium carbonate, is stirred in a solvent such as dimethylformamide, dimethylsulfoxide, sulfolane, ~nd the like, prefer-ably dimethylformamide. The mixture is heated to 40C to 150C, preferably 100c to 120C for 4 . . ~
-15- GYl6 hours to 48 hours, preferably for 12 hours to 24 hours. Crown ethers such as 18-crown-6 when the base is potassium ca{bonate, or 15-crown-5 when the base is sodium hydride, may optionally be added to the reaction mixture. The product is purified e.g.
by chromatography.
The compound of formula 1 is prepared by deprotecting a compound of formula 14. For a compound of formula 14 wherein W is a 9-guanyl residue, the protecting groups R4 are removed.
For a compound of formula 14 wherein W is a protected 9-guanyl residue, the protecting groups R4 may be removed first, followed by deprotection of the 9-guanyl residue, or the 9-guanyl residue may be deprotected first followed by removal of the R4 groups, or all protecting groups may be removed simultaneously. The method of deprotection depends on the particular protecting groups employed. For a compound of formula 14 wherein W is a 9-guanyl residue and R4 is a hindered silyl group, R4 is removed by treatment with a fluoride reagent such as tetra-n-butylam-monium fluoride, pyridinium fluoride, and the like or by hydrolysis with acid or base. (See T. W.
Green, Protective Groups in Organic Synthesis, Wiley-Interscience, 1981, for a detailed discus-sion of such deprotection procedures~. For a compound of formula 14 wherein W is a 9-guanyl residue and R4 is a benzyl or substituted benzyl group, R4 is removed under reductive conditions GYl6 such as by treatment with dissolving metal reagent (e.g. sodium in liquid ammonia), by hydrogenolysis (e.g. hydrogen gas in the presence of a catalyst such as palladium on carbon, or cyclohexene in the prese~ce of a catalyst such as palladium hydroxide on carbon), or by treatment with a reagent such as boron trichloride. For a compound of formula 14 wherein W is a 9-guanyl residue and R4 is an acyl group such as acetyl or an aroyl group such as benzoyl, R4 is removed by basic hydrolysis, for example, by treatment with an aqueous metal hydrox-ide such as potassium hydroxide, or by treatment with a metal alkoxide in an alcohol solvent such as sodium metho~ide in methanol.
For a compound OI formula 14 wherein W is a 6-benzyloxy-2-aminopurin-9-yl residue and R4 is a hindered silyl group, R4 may be removed first using a fluoride reagent and the W group may then be deprotected by aci~ic hydrolysis, by reduction either by a dissolving metal agent or by hydro-genolysis, or by treatment with a reagent such as boron trichloride. Alternatively, the W group may be first deprotected e.g. by reduction with a dissolving metal reagent or by hydrogenolysis, followed by removal of the silyl R4 group by treatment with a fluoride reagent. Alternatively, simultaneous deprotection of both the W and R~
groups can be accomplished by acidic hydrolysis.
For a compound of formula 14 wherein W is a 6-benzyloxy-2-aminopurin-9-yl residue and R~ is a .
~3~
benæyl or substituted benzyl group, deprotection of the W group can be accomplished first by acidic hydrolysis, followed by reductive removal of the R4 groups. Alternatively, all of the protecting S groups can be removed simultaneously under, for example, reductive conditions or by treatment with a reagent such as boron trichloride. For a compound of formula 14 wherein W is a 6~benzyloxy-2-aminopurin-9-yl residue and R4 is an acyl group such as acetyl or an aroyl group such as benzoyl, the aroyl groups may be removed first by basic hydrolysis, followed by deprotection of the W
group e.g. by reduction, by acidic hydrolysis, or by treatment with a reagent such as boron tri-lS chloride. For example, for a compound of formula 14 wherein W is a 6-benzyloxy-2-aminopurin-9-yl residue and R4 is benzoyl, the benzoyl groups are preferentially removed first by treatment with a solution of sodium methoxide in methanol at 20C to 60C, preferably at 30C to 50C for 1/4 hour to 6 hours preferably for 1/2 hour to 2 hours. The mixture is neutralized, concentrated and treated with hydrochloric acid in water-methanol at 30C to 60C, preferably at 45C to 55C for l/2 hour to 12 hours, preferably for 1 hour to 3 hours. The reaction mixture is neutralized, and the product, compound 1 is purified by e.g. chromatography.
For a compound of formula 14 wherein W is a 2-amino-6-methoxyethoxypurin-9-yl residue and R~
is a hindered silyl group, the silyl group may first be removed with a fluoride reagent followed by deprotection of the W residue by acidic hydrolysis. Alternatively, all protecting groups may be removed simultaneously by acidic hydrolysis. For a compound of formula 14 wherein W is a 2-amino-6-methoxyethoxypurin-9-yl residue and R4 is a benzyl or substituted benzyl group, the W residue may be first deprotected by acidic hydrolysis, followed by removal of the R9 groups under reductive conditions (e.g. with a dissolving metal reagent or by hydrogenolysis) or by treatment with a reagent such as boron trichloride. For a compound of formula 14 wherein W is a 2-amino-6-methoxyethoxypurin-9-yl residue and R4 is an acyl group such as acetyl or an aroyl group such as a benzoyl, the R4 groups may be removed by basic hydrolysis, followed by deprotection of the W residue by acidic hydrolysis. Alternatively, all of the protecting groups may be removed simultaneously by acidic hydrolysis.
For a compound of formula 14 wherein W is a 2-amino-6-chloropurin-9-yl resiclue and R4 is a hindered silyl group, the silyl group may firs~ be removed with a fluoride reagent followed by deprotection of the W residue by acidic hydrolysis. Alternatively, all protecting groups may be removed simultaneously by vigorous acidic hydrolysis. For a compound of formula 14 wherein w is a 2-amino-6-chloropyrin-9-yl residue and R4 is a benzyl or substituted benzyl group, the W
residue may be first deprotected by acidic hydrolysis, followed by removal of the R4 groups under reductive conditions or by treatment with a reagent such as boron trichloride or trimethylsilyl iodide. For a compound of formula 14 wherein W is a 2-amino-6-chloropurin-9-yl residue and R4 is an aroyl group such as a benzoyl, the W residue may be first deprotected by acidic hydrolysis, followed by xemoval of the R4 groups by basic hydrolysis. Alternatively, all of the protecting groups may be removed simultaneously by aqueous basic hydrolysis.
For a compound of formula 14 wherein W is a 2-acylamino-6-hydroxypurin-9-yl residue and R4 is a hindered silyl group, the silyl group may first be removed with a fluoride reagent followed by deprotection of the W residue by basic hydrolysis. Alternatively, all protecting groups may be removed simultaneously be aqueous basic hydrolysis. For a compound of formula 14 wherein W is a 2-acylamino-6-hydroxypurin-9-yl residue and R4 is a ben2yl or substituted benzyl group, the W
residue may first be deprotected by basic or acidic hydrolysis, followed by removal of the R4 group under reductive conditions ~e.g., with a dissolving metal reagent or by hydrogenolysis) or by treatment w~th a reagent such as boron tri-chloride. For a compound of formula 14 wherein W
2~3~c?~6 is a 2-acylamino-6-hydroxypurin-9-yl residue and R4 is an acyl group such as acetyl or an aroyl group such as a benzoyl all of the protecting groups may be removed simultaneously by basic or acidic hydrolysis.
The following examples are specific embodiments of the invention.
:
Example 1 ~lR~ , 2,B, 3~ 2-Amino-9- [2, 3-bis-(hydroxymethyl)-cyclobutyl]-6H-~urin-6-one Example la trans-3, 3-Diethoxy-1,2-cyclobutanedicarboxYlic acid, diethyl ester (racemic mixture) A mixture of diethylketene acetal (38.35 g) and diethylfumarate (53.5 ml) in t~butanol (90 ml) was heated at 84C for 72 hours. Distillation of the reaction mixture (113-125C, 0.6-1.6 mm Elg) afforded 50.4 g of product.
Example lb tran~-3,3-Dletho~v 1,2-cvclobutanedicarboxYlic acid (racemic mixture) A solution of trans-3,3-diethoxy 1,2-cyclo-butanedicarboxylic acid, diethyl ester (100 g) in 1400 ml of tetrahydrofuran uncler argon was treated with 1400 ml of methanol and 1400 ml of lN potas-sium hydroxide solution. The resulting mixture wasallowed to stand for 3 days at room temperature and then was evaporated in vacuo to an aqueous solution.
The pH was adjusted to 2.3 with 3N hydrochloric acid and the solution was saturated with sodium chloride. The resulting s~spension was extracted with ethyl acetate (3 x 1000 ml). The combined extracts were washed with 250 ml of water and 250 ml of brine, dried over sodium sulfate, and eva-porated to afford the product as solid, 78.8 g, m.p. 118 - 120C.
$
Exam~le lc rlS-[la(S*~,2~(S*)l~-3,3-Die_h xy-N,N'-bis(2-hydroxy-l-~henvlethyl)-1,2-cyclobutanedicarboxamide A suspension of 60.0 g of trans-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid in 500 ml of methylene chloride under argon was treated with 92.4 g of R-(-)-2-phenylglycinol. The resulting solution was cooled in an ice bath and treated 10 with 120 g of 1,3-dicyclohexylcarbodiimide. The mixture was stirred overnight at ambient te~perature and then was diluted with 1500 ml of diethyl ether and filtered. The filtrate was washed with 10% sodium bisulfate (twice3, saturated sodium bicarbonate (twice) and brine (twice). The organic phase was dried over sodium sulfate and evaporated to a semi-solid which was chromatographed on a column of silica gel (2.5 L), eluting with ethyl aceta~e-hexane followed by methanol~ethyl acetate. Combination of appropriate fractions gave a mixture of the two isomers, tlS-[la(S*),2~(S*)]]-3,3-diethoxy-N,N'-bis(2-hydroxy-1-phenylethyl)-1,2-cyclobutanedicarboxamide and ~lR-~la(R*),2~(R*)]]-3,3-dilsthoxy-N,N'-bis-(2-hydroxy-1-phenylethyl)-1,2-cyclobutane-dicarbo~amide as a foam (88.7 g). This mixture was dissolved almost completely in 600 ml of methylene chloride with heating. This solution was chilled at 5C for 4 hours and the resulting solid was filtered and washed with 150 mi of cold methylene chloride. Drying in vacuo gave 31 g of solid.
~Q3~
Concentration of the mother liquors and chillins at -30C for 12 hours gave a second crop of solid.
Similar solid from several preparations (98.1 g) was heated with 2500 ml of methylene chloride until nearly completely dissolved. The solution was chilled at 5C overnight and filtered, and the solid was washed with 500 Ml of cold methylene chloride. Drying in vac~o gave 83 g of the desired product, which was completely free of the other isomer, [lR-[l~(R*j, 2~(R*)]]-3,3-diethoxy-N,N'-bis(2-hydroxy-1-phenylethyl)-1,2-cyclobutane-dicarboxamide, as judged by ~PLC. The mother liguor was concentrated to 150 ml, heated to partially dissolve solids, and then cooled in an ice bath for 1 hour. The resulting solid was filtered and washed with 50 ml of cold methylene chloride and dried in ~acuo to give an additional 11.8 g of the product, isomerically pure. An analytical sample was obtained by recrystallization from ethyl acetate, m.p. 128 - 129C, [~]D ~ 16.8 (c = 1.00, methanol). The absolute stereoche~istry of the product was ascertained by X-ray crystallo-graphic analysis (crystals obtained by recrystal-lization form water).
Example ld [lS-[~a~ 2~(S*~l~N,N'-Bis~2-[
dim~th21ethyl)dimethYlsilylloxyl-l-phenyleth 3,3-diethoxy-1,2-cyclobutanedicarboxamide A slurry of 23.5 g of [lS-[1~(5*),2~(S*)]]-3,3-diethoxy-N,N'-bis(2-hydroxy-1-phenylethyl)-1,2-cyclobutanedicarboxamide and 13.6 g of imidazole GYl6 in 100 ml dry dimethylformamide under nitrogen was cooled to oC and treated with 15.8 g of solid t-butyldimethylsilyl chloride. After stirring at oC for 1.5 hours, the mixture was diluted to 600 ml with ethyl acetate and washed with 3% hydro-chloric acid (thrice), water (once), and brine (twice). Drying over sodium sulfate and evaporation gave an oily solid. This was taken up in 50 ml of ethyl acetate and diluted with 200 ml of hexane. The resulting slurry was filtered and the cake was washed with 100 ml of 20% e~hyl acetate in hexane. Evaporation of the filtrate in vacuo afforded the product as a clear glass, 33.6 g Example le [ls-[l~l(s*),2~3(s*)]]-N,N'-BisL2~
dimethylethvl)dimethylsilyl]-oxy]-1-Phenylethyl1-3,3-diethoxy-N,N'-dinitroso-1,2-cyclo-butanedicarboxamide A solution of 33.6 g of lS-[l~(S*),2~(S*)]]-N,N'-bis[2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-l-phenylethyl]-3,3-d~ethoxy-1,2-cyclobutane-dicarboxamide in 250 ml of dry carbon tetrachloridewas treated with 35 g of fresh ~mhydrous sodium acetate. The resulting slurry was chilled in an ice bath and treated with stirr:ing over 15 minutes with 75 ml of a 2.76 M solution of nitrogen tetrox-ide in carbon tetrachloride. The resulting yellowmixture was stirred for another 15 minutes at 0C
2 ~ 3 A~ ~ ~
GYl6 and then was poured into a mixture of ice (500 ml), water (200 ml), sodium acetate trihydrate (100 g), and methylene chloride (500 ml). The mixture was shaken for a few minutes and the resulting yellow organic layer was separated and washed with brine.
Drying over magnesium sulfate and evaporation in vacuo at <15C gave 46.6 g of the product as a thick yellow oil.
Example l (lS-trans )-3,3-diethoxy-1!2-cyclobutane dimethanol 46.6 g of [lS-[la~S*),2~(S*)]~-N;N'-Bis[2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy-l-phenylethyl]-3,3-diethoxy-N,N'-dinitroso-1,2-cyclobutanedicarboxamide, was dissolved in 200 ml of dry tetrahydrofuran and the resulting solu-tion was chilled at 0C and cannulated into a 0C
solution of lithium borohydride in tetrahydrofuran (150 ml of a 2M solution). The addition took 15 minutes after which the cooling bath was removed and the clear orange mixture waæ allowed to stir at ambient temperature overnight. The resulting nearly colorless solution was chilled in an ice bath while being treated with 25 ml of water drop~ise. ~he resulting slurry was diluted with 500 ml of diethyl ether and water was added to dissolve most of the solid (100 ml). The layers were separated and the aqueous layer was extracted with more ether and finally with ethyl acetate.
$
The organic layexs were combined, dried over sodium sulfate, and concentrated to afford 33.8 g of an oil. Chromatography on a column of silica gel eluting with ethyl acetate-hexane followed by ethyl acetate, afforded 8.0 g of the product as a colorless oil. An analytical sample was obtained by semi-preparative HPLC, [~]D ~ 17.3 (c = 1.06, chloroform).
Example lg (lS-trans)-3,3-Diethoxy-1,2-cyclobutanedi-methanol,dibenzoa~e ester (lS-trans)-3,3-Diethoxy-1,2~cyclobutanedi-me~hanol (35.1 g) was dissolved in 250 ml of dry pyridine, cooled to 0C under argon, and treated over 0.5 hours with benzoyl chloride (59.7 ml).
The cooling bath was removed and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was then cooled to 0C and treated over 5 minutes with 125 ml of water. The cooling bath was removed and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo and the residue was co-distilled with water (x 3) and with toluene (x 2) iR vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 10X sodium bisulfate (2 x 250 ml), .
~3~
GYl ~r water (4 x 250 ml), saturated sodium bicarbonate (2 x 250 ml), and water (3 x 250 ml). Drying over sodium sulfate, concentration in vacuo and azetroping with carbon tetrachloride gave 83 g of the title compound as a semi-solid.
Example lh (2S-trans)-2,3-Bis[benzoyloxymethyl]-cyclobutanone The above sample of (lS-trans)-3,3-Diethoxy-1,2-cyclobutanedimethanol, dibenzoate ester (83 g) was dissolved in acetonitrile (1.75 L) under argon and treated with 660 ml of 0.5 N sulfuric acid.
The mixture was stirred at ambient temperature for 17 hours and then was diluted with 5L of ethyl acetate. This solution was washed with water (2 x 1 L), saturated sodium bicarbonate (lL), water (2 x 1 L~, and brine (1 L). The organic phase was dried over sodium sulfate and evaporated to a white solid in vacuo. Partial dissolution in 400 ml of ether and cooling at -30C for 2 hours gave a solid which was filteredr washed with cold ethar and dried in air to give 46.4 g of the title 25 compound, m.p. 93 - 94C, [~]D :: +22.8 (c = 1.0, CHC13)-Another 8 g of slightly impure title compound was obtained by evaporation of the filtrate to a solid residue.
2~3~
GYl6 Example li [lS-(1~,2~,3~ 3-hYdroxy~ 2-cyclobutane dimethanol,1,2-dibenzoate ester (2S-trans)-2,3-Bis[benzoyloxymethyl]cyclo-butanone (33.81 g) in 440 ml of dry tetrahydro-furan at -78C under argon was treated with lO0 ml of 1~ lithium trisiamylborohydride in tatrahydro-furan over 20 minutes. After stirring another lO
minutes at -78C, the mixture was warmed to room temperature, and lO0 ml of saturated sodium bi-carbonate was added over 5 minutes. The resultant mixture was cooled in an ice-acetone bath and treated with 36.5 ml of 30% hydrogen peroxide at a rate so as to maintain the temperature at 25-30C. After the addition, the mixture was diluted with 300 ml of water and extracted with 1.1 L of ethyl acetate. The organic phase was washed with water (x 3), dried over sodium sulfate, and concentrated to a colorless oil (35 g). The oil was taken up in 100 ml of hexane/ethyl acetate (2/1) and filtered through a lL pad of silica gel(K-60), eluting with the same solvent mixtuxe. Evaporation o~E the pure fractions gave 27 g of pure title compound as a colorless oil. Another 4.4 g of slightly impure material gave 3.4 g o pure title compound after column chromatography in the same solv~nt mixture.
~:
:
.
::: : ::
2~3~
Example lj [lS-(la,2~,3~)1-3[[(4-MethylphenYl)sulfonYll-oxy]-1,2-cyclobutanedimethanol, dibenzoate ester lS~ ,2~,3~)]-3-hydroxy-1,2-cyclobutane-dimethanol, 1,2-dibenzoate ester (27 g~ was dissolved in 110 ml of dry pyridine under argon and treated with p-toluenesulfonyl chloride (16.7 g). The mixture was heated and stirred at 60 for 16 hours, cooled to 40C and treated with 2 ml of water. After stirring for 2 hours at 40C the mixture was concentrated in vacuo to an oil.
After azetroping with 2 x 150 ml of water in vacuo, the residue was partitioned between water and ethyl acetate. The organic phase was washed with water (x 2), saturated sodium bicarbonate (x 2), and brine. Drying over sodium sulfate and evaporation in vacuo gave 32.2 g of an oil.
Trituration with pentane gave 28.3 g of a solid.
Crystallization from ethyl acetate/pentane gave 18.4 g of pure title compound as a solid, m.p.
91-92C, [~]D = +13.8 (c = 1.3, C~C13). Another 4 g of title compound was obtained by chromato-graphy of the mother liquors on silica gel usinghexane/ethyl acetate (3/1).
~3~
Example lk [lS-(la,2~,3a)]-3-[2-~mino-6-~phenylmethoxy)-9H-purin-9-yl]-1,2-cYclobutanedimethanol,_ dibenzoate ester A mixture of dry 2-amino-6-benzyloxyguanine (13.4 g), [lS-(la,2~,3~)]-3[[(4-methylphenyl)sul-fonyl]-oxy]-1,2-cyclobutanedimethanol, dibenzoate ester, (18.33 g), powdered anhydrous potassium carbonate (10.22 g, dried over phosphorus pentoxide in vac~o at 130C for 72 hours~, and 18 crown-6 (9.8 g) in 495 ml of dry dimethyl-formamide was stirred and heated at 110C under argon for 21 hours. The mixture was cooled to room temperature and filtered, ar.d the filtrate was ~vaporated in vacuo to an oil which was partitioned between ethyl acetate and water. The organic phase was washed twice with water, dried over sodium sulfate, and evaporated to a foam (24.4 g). Chromatography on silica gel in hexane/-ethyl acetate (1/1) gave 10.7 g of the title compound as a foam with [a3D = -9.0 (c = 0.67, CEIcl3 ) -25Example lL
[lR-(la,2~,3a)l-2-Amino-9-r2,3-bis~hydroxymethyl)-cvclobutyl]-6H-purin-6-one A solution of [lS-(la,2~,3a)]-3-[2-amino-306-(phenylmethoxy)-9~-purin-9-yl]-1,2-cyclobutane-dimethanol, dibenzoate ester S20.0 g) in 550 ml of methanol under argon was treated with 5 ml of 25%
293~5~6 -31- ~Y16 sodium methoxide in methanol and heated at 40C
for 2 hours. A~ueous hydrochloric acid (3N, 275 ml) was then added to the reaction mixture, and heating was continued at 50C for 2 hours. This mixture was concentrated to 100 ml and the solution was transferred to a separatory funnel, with addition of another 100 ml of water. The solution was extracted with ether (3 x 100 ml) and the pH of the aqueous layer was adjusted to 8.5 with the 510w addition of 360 ml of 2N potassium hydroxide. The resulting thick precipitate was filtered and the damp solid was recrystallized by dissolving in 200 ml of hot water, filtering while hot, and chilling at 5C overnight. Drying in 15 vacuo over phosphorus pentoxide gave 7.~5 g of an impure white solid. Chromatography on 750 ml of CHP-20P resin with gradient elution using acetonitrile and water, concentration of the pertinent product fractions until turbid, and chilling this turbid solution for 1 hour at 0C
gave crystals which were filtered. Drying in vacuo at room temperature over phosphorus pentoxide gave 6.3 g of the title compound as a white crystalline solid, m.p. >270C, [~]D = -27 (c = 1.0, DMSO).
PROCESS FOR PREPARING AN OPTICALLY ACTIVE
CYCLOBUTANE NUCLEOSIDE
The present invention relates to the optically active compound [lR~ ,2~,3~)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6~purin-6-one, represented by formula 1 and to a process for the preparation thereof.
uo~C ~ N ~ 2 ~ 20 The invention relates to novel intermediates : in the above process and to a process for preparing thes~ intermediates.
2 ~ s~
Compound 1 as a 1:1 mixture with its optical antipode (i.e., the racemic mixture) is an antiviral agent with activity against herpes simplex virus types 1 and 2, varicella zoster virus, human cytomegalovirus, vaccinia virus, murine leukemia virus, and human immunodeficiency virus; and are believed to be active against a variety of other DNA viruses and retroviruses.
Antiviral activity is also exhibited by the single enantiomer, compound 1, and its pharmaceutically acceptable salts. Compound 1 as a 1:1 mixture with its optical antipode has been prepared by methods described in European patent application 335,355 published on October 4, 1989.
The process of the present invention is shown in the reaction scheme below:
R2O2C ~ OR1 RO2C ~ R~
~ ~ ?~
_3_ GY16 R3~3Noc~O~ ORI Rl o~CONHR3 R3HNoC CoNHR3 5 4 \ 5 .~ ~
~0 R3a~No~o< ORl R3No~o< OR
R3aHNoc R3NoC
NO
V 8 1, NO
R3 aN0C~o<ORl HOH2 C~><
- ORI _ oP~
R3 a ~ OC HOH2 C
R4 O~I2 C~XRI ~Oe R4 OE~2 C R4 0~12 C
~3~
R4O~2C ~ ~ X
R~OH2C R4OH2C
N NH
R4OH2C~ ~ W HOH2C ~ ~ NH2 wherein R1 and R2 are lower alkyl, R3 is an alkyl or substituted alkyl group derived from a chiral primary amine of the formula R3NH2,R3a is a suitably protected form of R3, R4 is a protecting group, X is a leaving group, and W is a 9-guanyl residue or a suitably protected foDm of a 9-guanyl residue. Compounds 2 and 3 are each racemic mixtures. The relative stereochemistry of the two R2O2C groups in compound 2 is trans and the rela-tive stereochemistry of the two HO2C groups in compound 3 is al so: trans . Compo~nd 1 and compounds 4 through }4 are chiral compounds, and their absolute stereochemistry is as pictured in the figures of the above reaction schemes.
:
GY16 2 ~ 3 ~ ~
The term "lower alkyl" refers to both straight and branched chain groups which contain from l to 5 carbons. Those groups having 1 to 2 carbons are preferred. The term "alkyl" refers to both straight and branched chain groups. The groups having 1 to 10 carbons are preferred. The term "substituted alkyl" refers to alkyl groups having one or more substituents. Examples of substituents include hydroxy, alkoxy, alkoxy-carbonyl, phenyl, hydroxyphenyl, dihydroxyphenyland nitrophenyl. Preferred substituents are hydroxy and phenyl. When R3 is substituted with hydroxy, R3 should be protected with a suitable hydroxy protecting group to give R3a. Exemplary protecting groups are hindered silyl groups such a t-butyldimethylsilyl, t-butyldiphenylsilyl, tri-isopropylsilyl and the like; acyl groups such as acetyl; aroyl groups such as benzoyl; the tri-phenylmethyl (trityl) group or a lower alkoxy substituted triphenylmethyl group sush as 4'-methoxyphenyldiphenylmethyl. Preferred protecting groups are t-butyldimethylsilyl and acetyl. The protecting group R4 may be a hindered silyl group (such as t-butyldiphenylsilyl or triisopropyl-silyl~, an acyl group (such as acetyl), an aroylgroup (such as benzoyl~, a benz~l group or a substituted benzyl group (such as p-methoxybenzyl).
The leaving group X may be an alkanesulfonyloxy group (such as methanesulfonyloxy(mesyl)), a substituted alXanesulfonyloxy group (such as trifluorome~hanesulfonyloxy (triflyl)), or an arene- or substituted arenesulfonyloxy group ~such as p-toluenesulfonyloxy group (tosyl) or p-nitro-~31~
benzenesulfonyloxy group (nosyl)). The group W
includes ~he 2-amino-6-ben~yloxypurin-9-yl, 2-amino-6-methoxyethoxypurin-9-yl, 2-amino-6 chloro-purin-9-yl, and 2-acetamido-6-hydroxypurin-9-yl residues as suitably protected forms of the 9-guanyl residue. The 2-amino-6-benæyloxypurin-9-yl and 2-amino-6-methoxyethoxypurin-9-yl residues are preferred as protected forms of the group W.
The racemic compound of formula 2 wherein R1 and R2 are lower alkyl can be prepared by reacting ketene di(lower alkyl)acetal with di(lower alkyl)-fumarate (see K.C. Brannock et al., J. Org. Chem., 9, 940 (1964)). Preferentially R1 and R2 are methyl or ethyl. For example, ketene diethyl acetal is reacted with diethyl fumarate either neat or in an appropriate solvent such as acetonitrile, t-butanol, or the like, preferably t-butanol. The mixture is stirred for about 4 to 10 days, preferably for about 6 to 8 days, at a temperature of about 70C to 100C, preferably of about 80C to 90C. The resultant compound 2 can be isolated by chromatography or distillation.
Di(lower alkyl)fumarates are either commercially available (e.g., Aldrich Chemical Co.) or can be readily prepared by methods known in the art. Ketene di(lower alkyl)acetals are either co~mercially available (e.g., Wiley Organics Inc.) or can be readily prepared by known methods (see e.g., Orqanic Syntheses, Collective Volume III, p. 506; J. Amer. Chem. Soc., 62, 964 (1940)).
The racemic compound of formula 3 is prepared by treatment of the compound of formula 2 with alkali, preferably potassium hydroxide, in aqueous or mixed aqueous-organic solvent solutions, for example, water-dioxane, water-tetrahydrofuran, water tetrahydrofuran-methanol and the llke, preferably water-tetrahydrofuran-methanol. The mixture is stirred for 1 to 5days, preferably for 2 to 3 days at a temperature of lO~C to 50C, preferably of 20C to 30C. The reaction mixture is diluted with water, acidified to about p~ 2.5 with aqueous acid and extracted with an organic solvent such as dichloromethane, ethyl acetate, and the like, followed by concen-tration of the organic solvent.
The diastereomeric mixture of compounds 4 and 5 is prepared by treatment of compound 3 with a chiral primary amine (R3NH2) in the presence of a coupling agent such as 1,3-dicyclohexylcarbodi-imide, l-(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride, and the like, in a solvent such as methylene chloride or tetrahydrofuran. To this reaction mixture, additional reaction components such as l-hydroxybenzotriazole, or 1-hydroxybenzotriazole plus N-me~hylmorpholine, may optionally be added. The mixture is stirred at about 0C to 50C, preferably at about 20C to 25 30C for 1 to 48 hours, preferably for 10 to 18 hours. Water is added to the reaction mixture, and the mixture of compounds 4 and 5 is isolated ~ by extxaction.
; Examples of suitable chiral primary amines, R3NH2, include chiral alkyl amines such as (+)- or (-)-2-aminobutane and (+)- or (-)-2-aminoheptane;
chiral hydroxy-substituted alkylamines such as (+)- or (A)-2-amino-1-butanol, (+)- or (-)-2-amino-l-propanol, (~)- or (-)-2-amino-3-methyl-l-butanol, (+)- or (-) - leucinol, and (+)- iso-leucinol; chiral phenyl or naphthyl-substituted alkyl amines such as (+)- or (-)-~-methylbenzyl-amine, ~+)- or (-)-a-(1-naphthyl)ethylamine, and (+)- or (-)-~-(2-naphthyl)ethylamine; chiral alkylamines substituted with both hydroxy and phenyl such as (+)- or (-)-2-phenylglycinol, (+)-or (-)-threo-2-amino-1-phenyl-1,3-propanediol, (+)-or (-)-norephedrine, (+)- or (-)-2-amino-3-phenyl-1-propanol, and (+)- or (-)-2-amino-1,2-diphenyl-ethanol; and other substituted alkylamines such as (+)- or (-)-~-methyl-p-nitrobenzylamine, (+)- or (-)-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol, (+)- or (-)-norepinephrine, (~)-dehydroabietyl-amine, (+)-2-amino-3-methoxy-1-phenylpropanol, L-tyrosinol, and lower alkyl esters of ~-amino acids such as (+)-or (-)-alanine, (~)- or (-)~
valine, (+)- or (-) leucine, (+)- or (-)- isoleu~
cine, (+)- or (-)-phenylalanine, (+)- or (-)-tyro-sine, (+)- or (-)-serine, and (+)- or (-)-threo-nine. Preferred chiral alkylamines include those substituted with both hydroxy and phenyl groups;
most pr~ erred is (-)-2~phenyls~1ycinol.
Compounds 4 and 5 may be separated by chromatography (e.g. on silica gel), or by crystallization from various solvents and solvent mixtures such as methylene chloride, chloroform, ether, ether-methanol, water, and the like. When the chiral amine R3N~2 is (-)-2~phenylgly~inol, the resultant compound 4 is separated preferably by crystalli2;ation from methylene chloride.
_g_ When the group R3 of compound 4 is substi-tuted with a hydroxy group, the hydroxy is protect~d to afford compound 6, wherein the group R3a is tha protected form of R3. A compound of formula 6 where-in the hydroxy group of R3 has been protected witha hindered silyl group such as t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl is prepared by treating the compound of formula 4 with the appropriate silyl reagent such as the correspon-ding tri(hydrocarbon)silyl chloride. Compound 4 isreacted with the silyl reagent in a sol~ent such as dimethylformamide, tetrahydrofuran, acetonitrile, and the like, preferably dimethylformamide, at -10C to 30C, prefeIably at 0C to 20C for 1/4 hour to 2 hours, preferably for 1/2 hour to 1 hour.
The reaction is run in the presence of a base such as triethylamine, pyridine, or imidazole, preferably imidazole. The compound of formula 6 is extracted and optionally purified by, e.g. chromatography on silica gel.
The compound of formula 6 wherein the hydroxy group has been protected with an acyl or aroyl group such as acetyl or benzoyl is prepared by treating the compound of formula 4 with the corresponding acyl or aroyl chloride or with the corresponding acyl or aroyl anhydride in a solvent such a pyridine or tetrahydrofuran. When te~ra-hydro~uran is used as solvent, a base such as triethylamine is added.
A compound of formula 6 wherein the hydroxy group has been protected with a trityl or a lower alkoxy substituted trityl group is prepared by treating the compound of formula 4 with trityl chloride or the lower alkoxy substituted trityl chloride in a solvent such as pyridine.
A compound of formula 7 is prepared by reacting a compound of formula 6 with a suitable nitrosating agent such as nitrosyl chloride, nitronium tetrafluoroborate, nitrogen tetroxide (N2O~), and the like, preferably nitrogen tetroxide. (See e.g., E. H. White, J. Amer.
Chem. Soc., 77 6008 (1955) and J. Vilarrasa, J. Orq. Chem., 54, 3209 (1989) for a discussion of various nitrosating agents). For example, a compound of formula 6 is treated with nitrogen tetroxide in a solvent such as carbon tetra-chloride, methylene chloride and the like, preferably carbon tetrachloride, in the presence of a base such as sodium acetate, pyridine, and the like, preferably sodium acetate. The reaction mixture is stirred for 1/4 hour to 4 hours, preferably 1/2 hour to 1 1/2 hours at -10C to 20C, preferably at ~5C to 10C. The mixture is poured into ice water and extracted.
A compound of formula 8 is prepared from a compound of formula 4 when the group R~ does not contain a hydroxy substituent. The preparation of a compound of formula 8 from a compound of formula 4 is accomplished in the same manner as described for the preparation of a compound of formula 7 from a compound of formula 6.
A compound of formula 9 is prepared by treating a compound oE formula 7 or a compound of formula 8 with a suitable reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride and the like, preferably lithium borohydride. For example, a compound of formula 7 or a compound of formula 8 is treated with lithium borohydride in a solvent such as tetrahydrofuran, ether, dimethoxyethane (glyme) and the like, preferably tetrahydrofuran, at -20C to 20C, preferably at -lO~C to 10C for 1/4 hour to 2 hours, preferably 1/2 hour to 1 hour.
The reaction mixture is ~uenched with water and the product is extracted and purified by e.g.
chromatography.
A compound of formula 10 wherein R4 is a suitable protecting gxoup is prepared by reacting a compound of formula 9 with the corresponding protecting group precursor. Suitable protecting groups R4 include hindered silyl groups (such as t-butyldiphenylsilyl or triisopropylsilyl), benzyl or substituted benzyl groups (such as p-methoxy-benzyl), aroyl groups (quch as benzoyl) and acyl (such as acetyl). Benzyl and benzoyl are preferred for R4. A compound of formula 10 wherein R4 is a hindered silyl group is prepared by treating a compound o~ formula 9 with tha appropriate silyl reagent e.g., the corresponding silyl chloride, using reaction conditions described previously. A
2 ¢1 ~ 3~
G~16 compound of formula 10 wherein R~ is a benzyl or substituted benzyl i5 prepared by treating a compound of formula 9 with a benzyl halide or a substituted ben7yl halide in a solvent such as tetrahydrofuran or dimethylformamide in the presence of a suitable base such as sodium hydride.
A compound of formula 10 wherein R4 is an acyl or aroyl group is prepared by treating a compound of formula 9 with the corresponding acyl- or aroyl-anhydride or halide, preferably ben~oyl chloride, in a solvent such as pyridine or tetrahydrofuran/triethy~amine, preferably pyridine.
The benzoylation reaction is carried out at -10C
to 20C, preferably at -5C to 5C, for 1/4 hour to 2 hours, preferably for 1~2 hour to 1 1/2 hours.
Water is added to the reaction mixture, the mixture is stirred overnight, and the product is extracted and optionally purified e.g. by chromatography.
A compound of formula 11 is prepared by treatment of a compound of formula 10 with an acid catalyst such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and the like, preferably sulfuric acid, in a solvent or solvent mixture such as water, water-acetonitrile, water-dioxane, acetone, and the like, preferably water-acetoni-trile. The reaction mixture is stirred at 0C to 60C~ preferably at 15C to 30C: for 1/2 hour to 2 days, preferably for 2 hours to ~ hours. The reaction mixture is neutralized, and the product is extracted and optionally purified ~y e.g.
chromatography.
~3~
A compound of formula 12 is prepared by reaction of a compound of formula 11 with a suitable reducing agent. Reducing agents may include hindered hydride reagents such as lithium tri-sec-butylborohydride, lithium trisiamylboro-hydride, diisobutylaluminum hydride and the like, preferably lithium trisiamylborohydride and hin-dered borane reducing agents such as dicyclohexyl-borane, disiamylborane, and the like. The rsaction is run in a solvent such as ether, tetrahydrofuran, glyme, and the like, preferably tetrahydrofuran.
When a hindered borohydride reducing agent is employed the reaction mixture is stirred at 90C
to -60C, preferably -80C to -70C for 5 minutes to l hour, preferably for 1/4 hour to l/2 hour and the mixture is allowed to warm to 0C to 30C, preferably 20C to 25C. The reaction is worked up with aqueous sodium bicarbonate-hydrogen peroxide and the product is isolated by extraction and optionally purified by e.g. chromatography.
A compound of formula 13 wherein X is a leaving group such as an alkanesulfonyloxy group (e.g., mesyl), a substituted alkanesulfonyloxy group (e.g., triflyl), or an arene- or substituted arenesulfonyloxy group (e.g., tosyl or nosyl), may be prepared by treatment of a compound of formula 12 with the appropriate sulfonylating reagent such as the corresponding sulfonic anhydride or sulfonyl chloride, preferably tosyl chloride, in a solvent such as pyridine, tetrahydrofuran, methylene : :
-14- GYl6 chloride, and the like, preferably pyridine. When non-basic solvents such as tetrahydrofuran, methylene chloride and the like are employed for the reaction, a base such as triethylamine is added to the mixture. Depending on the solvent and the sulfo-nating reagent, the reaction mixture is stirred at 0C to 60C, for 1 hour to 48 hours. For example, a mixture of a compound of formula 12 and tosyl chloride in pyridine is stirred at 60C overnight.
The product is isolated by extraction and option-ally purified by, e.g., chromatography.
A compound of formula 14, wherein W is a 9-guanyl residue or a protected form of ~he 9-guanyl residue is prepared by reaction of a compound of formula 13 with guanine or the corresponding protected guanine. Protected forms of guanine include 2-amino-6-benzyloxypurine, 2-amino-6-methoxyethoxypurine, 2-amino-6-chloropurine, and 2-acetamido-6-hydroxypurine.
Preferred protected forms of guanine are 2-amino-6-benzyloxypurine and 2-amino-6-meth-oxyethoxypurine. A mixture of the compound of formula 13 and guanine or a protected guanine, and a base such as potassium carbonate, sodium hydride, and the like, preferably potassium carbonate, is stirred in a solvent such as dimethylformamide, dimethylsulfoxide, sulfolane, ~nd the like, prefer-ably dimethylformamide. The mixture is heated to 40C to 150C, preferably 100c to 120C for 4 . . ~
-15- GYl6 hours to 48 hours, preferably for 12 hours to 24 hours. Crown ethers such as 18-crown-6 when the base is potassium ca{bonate, or 15-crown-5 when the base is sodium hydride, may optionally be added to the reaction mixture. The product is purified e.g.
by chromatography.
The compound of formula 1 is prepared by deprotecting a compound of formula 14. For a compound of formula 14 wherein W is a 9-guanyl residue, the protecting groups R4 are removed.
For a compound of formula 14 wherein W is a protected 9-guanyl residue, the protecting groups R4 may be removed first, followed by deprotection of the 9-guanyl residue, or the 9-guanyl residue may be deprotected first followed by removal of the R4 groups, or all protecting groups may be removed simultaneously. The method of deprotection depends on the particular protecting groups employed. For a compound of formula 14 wherein W is a 9-guanyl residue and R4 is a hindered silyl group, R4 is removed by treatment with a fluoride reagent such as tetra-n-butylam-monium fluoride, pyridinium fluoride, and the like or by hydrolysis with acid or base. (See T. W.
Green, Protective Groups in Organic Synthesis, Wiley-Interscience, 1981, for a detailed discus-sion of such deprotection procedures~. For a compound of formula 14 wherein W is a 9-guanyl residue and R4 is a benzyl or substituted benzyl group, R4 is removed under reductive conditions GYl6 such as by treatment with dissolving metal reagent (e.g. sodium in liquid ammonia), by hydrogenolysis (e.g. hydrogen gas in the presence of a catalyst such as palladium on carbon, or cyclohexene in the prese~ce of a catalyst such as palladium hydroxide on carbon), or by treatment with a reagent such as boron trichloride. For a compound of formula 14 wherein W is a 9-guanyl residue and R4 is an acyl group such as acetyl or an aroyl group such as benzoyl, R4 is removed by basic hydrolysis, for example, by treatment with an aqueous metal hydrox-ide such as potassium hydroxide, or by treatment with a metal alkoxide in an alcohol solvent such as sodium metho~ide in methanol.
For a compound OI formula 14 wherein W is a 6-benzyloxy-2-aminopurin-9-yl residue and R4 is a hindered silyl group, R4 may be removed first using a fluoride reagent and the W group may then be deprotected by aci~ic hydrolysis, by reduction either by a dissolving metal agent or by hydro-genolysis, or by treatment with a reagent such as boron trichloride. Alternatively, the W group may be first deprotected e.g. by reduction with a dissolving metal reagent or by hydrogenolysis, followed by removal of the silyl R4 group by treatment with a fluoride reagent. Alternatively, simultaneous deprotection of both the W and R~
groups can be accomplished by acidic hydrolysis.
For a compound of formula 14 wherein W is a 6-benzyloxy-2-aminopurin-9-yl residue and R~ is a .
~3~
benæyl or substituted benzyl group, deprotection of the W group can be accomplished first by acidic hydrolysis, followed by reductive removal of the R4 groups. Alternatively, all of the protecting S groups can be removed simultaneously under, for example, reductive conditions or by treatment with a reagent such as boron trichloride. For a compound of formula 14 wherein W is a 6~benzyloxy-2-aminopurin-9-yl residue and R4 is an acyl group such as acetyl or an aroyl group such as benzoyl, the aroyl groups may be removed first by basic hydrolysis, followed by deprotection of the W
group e.g. by reduction, by acidic hydrolysis, or by treatment with a reagent such as boron tri-lS chloride. For example, for a compound of formula 14 wherein W is a 6-benzyloxy-2-aminopurin-9-yl residue and R4 is benzoyl, the benzoyl groups are preferentially removed first by treatment with a solution of sodium methoxide in methanol at 20C to 60C, preferably at 30C to 50C for 1/4 hour to 6 hours preferably for 1/2 hour to 2 hours. The mixture is neutralized, concentrated and treated with hydrochloric acid in water-methanol at 30C to 60C, preferably at 45C to 55C for l/2 hour to 12 hours, preferably for 1 hour to 3 hours. The reaction mixture is neutralized, and the product, compound 1 is purified by e.g. chromatography.
For a compound of formula 14 wherein W is a 2-amino-6-methoxyethoxypurin-9-yl residue and R~
is a hindered silyl group, the silyl group may first be removed with a fluoride reagent followed by deprotection of the W residue by acidic hydrolysis. Alternatively, all protecting groups may be removed simultaneously by acidic hydrolysis. For a compound of formula 14 wherein W is a 2-amino-6-methoxyethoxypurin-9-yl residue and R4 is a benzyl or substituted benzyl group, the W residue may be first deprotected by acidic hydrolysis, followed by removal of the R9 groups under reductive conditions (e.g. with a dissolving metal reagent or by hydrogenolysis) or by treatment with a reagent such as boron trichloride. For a compound of formula 14 wherein W is a 2-amino-6-methoxyethoxypurin-9-yl residue and R4 is an acyl group such as acetyl or an aroyl group such as a benzoyl, the R4 groups may be removed by basic hydrolysis, followed by deprotection of the W residue by acidic hydrolysis. Alternatively, all of the protecting groups may be removed simultaneously by acidic hydrolysis.
For a compound of formula 14 wherein W is a 2-amino-6-chloropurin-9-yl resiclue and R4 is a hindered silyl group, the silyl group may firs~ be removed with a fluoride reagent followed by deprotection of the W residue by acidic hydrolysis. Alternatively, all protecting groups may be removed simultaneously by vigorous acidic hydrolysis. For a compound of formula 14 wherein w is a 2-amino-6-chloropyrin-9-yl residue and R4 is a benzyl or substituted benzyl group, the W
residue may be first deprotected by acidic hydrolysis, followed by removal of the R4 groups under reductive conditions or by treatment with a reagent such as boron trichloride or trimethylsilyl iodide. For a compound of formula 14 wherein W is a 2-amino-6-chloropurin-9-yl residue and R4 is an aroyl group such as a benzoyl, the W residue may be first deprotected by acidic hydrolysis, followed by xemoval of the R4 groups by basic hydrolysis. Alternatively, all of the protecting groups may be removed simultaneously by aqueous basic hydrolysis.
For a compound of formula 14 wherein W is a 2-acylamino-6-hydroxypurin-9-yl residue and R4 is a hindered silyl group, the silyl group may first be removed with a fluoride reagent followed by deprotection of the W residue by basic hydrolysis. Alternatively, all protecting groups may be removed simultaneously be aqueous basic hydrolysis. For a compound of formula 14 wherein W is a 2-acylamino-6-hydroxypurin-9-yl residue and R4 is a ben2yl or substituted benzyl group, the W
residue may first be deprotected by basic or acidic hydrolysis, followed by removal of the R4 group under reductive conditions ~e.g., with a dissolving metal reagent or by hydrogenolysis) or by treatment w~th a reagent such as boron tri-chloride. For a compound of formula 14 wherein W
2~3~c?~6 is a 2-acylamino-6-hydroxypurin-9-yl residue and R4 is an acyl group such as acetyl or an aroyl group such as a benzoyl all of the protecting groups may be removed simultaneously by basic or acidic hydrolysis.
The following examples are specific embodiments of the invention.
:
Example 1 ~lR~ , 2,B, 3~ 2-Amino-9- [2, 3-bis-(hydroxymethyl)-cyclobutyl]-6H-~urin-6-one Example la trans-3, 3-Diethoxy-1,2-cyclobutanedicarboxYlic acid, diethyl ester (racemic mixture) A mixture of diethylketene acetal (38.35 g) and diethylfumarate (53.5 ml) in t~butanol (90 ml) was heated at 84C for 72 hours. Distillation of the reaction mixture (113-125C, 0.6-1.6 mm Elg) afforded 50.4 g of product.
Example lb tran~-3,3-Dletho~v 1,2-cvclobutanedicarboxYlic acid (racemic mixture) A solution of trans-3,3-diethoxy 1,2-cyclo-butanedicarboxylic acid, diethyl ester (100 g) in 1400 ml of tetrahydrofuran uncler argon was treated with 1400 ml of methanol and 1400 ml of lN potas-sium hydroxide solution. The resulting mixture wasallowed to stand for 3 days at room temperature and then was evaporated in vacuo to an aqueous solution.
The pH was adjusted to 2.3 with 3N hydrochloric acid and the solution was saturated with sodium chloride. The resulting s~spension was extracted with ethyl acetate (3 x 1000 ml). The combined extracts were washed with 250 ml of water and 250 ml of brine, dried over sodium sulfate, and eva-porated to afford the product as solid, 78.8 g, m.p. 118 - 120C.
$
Exam~le lc rlS-[la(S*~,2~(S*)l~-3,3-Die_h xy-N,N'-bis(2-hydroxy-l-~henvlethyl)-1,2-cyclobutanedicarboxamide A suspension of 60.0 g of trans-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid in 500 ml of methylene chloride under argon was treated with 92.4 g of R-(-)-2-phenylglycinol. The resulting solution was cooled in an ice bath and treated 10 with 120 g of 1,3-dicyclohexylcarbodiimide. The mixture was stirred overnight at ambient te~perature and then was diluted with 1500 ml of diethyl ether and filtered. The filtrate was washed with 10% sodium bisulfate (twice3, saturated sodium bicarbonate (twice) and brine (twice). The organic phase was dried over sodium sulfate and evaporated to a semi-solid which was chromatographed on a column of silica gel (2.5 L), eluting with ethyl aceta~e-hexane followed by methanol~ethyl acetate. Combination of appropriate fractions gave a mixture of the two isomers, tlS-[la(S*),2~(S*)]]-3,3-diethoxy-N,N'-bis(2-hydroxy-1-phenylethyl)-1,2-cyclobutanedicarboxamide and ~lR-~la(R*),2~(R*)]]-3,3-dilsthoxy-N,N'-bis-(2-hydroxy-1-phenylethyl)-1,2-cyclobutane-dicarbo~amide as a foam (88.7 g). This mixture was dissolved almost completely in 600 ml of methylene chloride with heating. This solution was chilled at 5C for 4 hours and the resulting solid was filtered and washed with 150 mi of cold methylene chloride. Drying in vacuo gave 31 g of solid.
~Q3~
Concentration of the mother liquors and chillins at -30C for 12 hours gave a second crop of solid.
Similar solid from several preparations (98.1 g) was heated with 2500 ml of methylene chloride until nearly completely dissolved. The solution was chilled at 5C overnight and filtered, and the solid was washed with 500 Ml of cold methylene chloride. Drying in vac~o gave 83 g of the desired product, which was completely free of the other isomer, [lR-[l~(R*j, 2~(R*)]]-3,3-diethoxy-N,N'-bis(2-hydroxy-1-phenylethyl)-1,2-cyclobutane-dicarboxamide, as judged by ~PLC. The mother liguor was concentrated to 150 ml, heated to partially dissolve solids, and then cooled in an ice bath for 1 hour. The resulting solid was filtered and washed with 50 ml of cold methylene chloride and dried in ~acuo to give an additional 11.8 g of the product, isomerically pure. An analytical sample was obtained by recrystallization from ethyl acetate, m.p. 128 - 129C, [~]D ~ 16.8 (c = 1.00, methanol). The absolute stereoche~istry of the product was ascertained by X-ray crystallo-graphic analysis (crystals obtained by recrystal-lization form water).
Example ld [lS-[~a~ 2~(S*~l~N,N'-Bis~2-[
dim~th21ethyl)dimethYlsilylloxyl-l-phenyleth 3,3-diethoxy-1,2-cyclobutanedicarboxamide A slurry of 23.5 g of [lS-[1~(5*),2~(S*)]]-3,3-diethoxy-N,N'-bis(2-hydroxy-1-phenylethyl)-1,2-cyclobutanedicarboxamide and 13.6 g of imidazole GYl6 in 100 ml dry dimethylformamide under nitrogen was cooled to oC and treated with 15.8 g of solid t-butyldimethylsilyl chloride. After stirring at oC for 1.5 hours, the mixture was diluted to 600 ml with ethyl acetate and washed with 3% hydro-chloric acid (thrice), water (once), and brine (twice). Drying over sodium sulfate and evaporation gave an oily solid. This was taken up in 50 ml of ethyl acetate and diluted with 200 ml of hexane. The resulting slurry was filtered and the cake was washed with 100 ml of 20% e~hyl acetate in hexane. Evaporation of the filtrate in vacuo afforded the product as a clear glass, 33.6 g Example le [ls-[l~l(s*),2~3(s*)]]-N,N'-BisL2~
dimethylethvl)dimethylsilyl]-oxy]-1-Phenylethyl1-3,3-diethoxy-N,N'-dinitroso-1,2-cyclo-butanedicarboxamide A solution of 33.6 g of lS-[l~(S*),2~(S*)]]-N,N'-bis[2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-l-phenylethyl]-3,3-d~ethoxy-1,2-cyclobutane-dicarboxamide in 250 ml of dry carbon tetrachloridewas treated with 35 g of fresh ~mhydrous sodium acetate. The resulting slurry was chilled in an ice bath and treated with stirr:ing over 15 minutes with 75 ml of a 2.76 M solution of nitrogen tetrox-ide in carbon tetrachloride. The resulting yellowmixture was stirred for another 15 minutes at 0C
2 ~ 3 A~ ~ ~
GYl6 and then was poured into a mixture of ice (500 ml), water (200 ml), sodium acetate trihydrate (100 g), and methylene chloride (500 ml). The mixture was shaken for a few minutes and the resulting yellow organic layer was separated and washed with brine.
Drying over magnesium sulfate and evaporation in vacuo at <15C gave 46.6 g of the product as a thick yellow oil.
Example l (lS-trans )-3,3-diethoxy-1!2-cyclobutane dimethanol 46.6 g of [lS-[la~S*),2~(S*)]~-N;N'-Bis[2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy-l-phenylethyl]-3,3-diethoxy-N,N'-dinitroso-1,2-cyclobutanedicarboxamide, was dissolved in 200 ml of dry tetrahydrofuran and the resulting solu-tion was chilled at 0C and cannulated into a 0C
solution of lithium borohydride in tetrahydrofuran (150 ml of a 2M solution). The addition took 15 minutes after which the cooling bath was removed and the clear orange mixture waæ allowed to stir at ambient temperature overnight. The resulting nearly colorless solution was chilled in an ice bath while being treated with 25 ml of water drop~ise. ~he resulting slurry was diluted with 500 ml of diethyl ether and water was added to dissolve most of the solid (100 ml). The layers were separated and the aqueous layer was extracted with more ether and finally with ethyl acetate.
$
The organic layexs were combined, dried over sodium sulfate, and concentrated to afford 33.8 g of an oil. Chromatography on a column of silica gel eluting with ethyl acetate-hexane followed by ethyl acetate, afforded 8.0 g of the product as a colorless oil. An analytical sample was obtained by semi-preparative HPLC, [~]D ~ 17.3 (c = 1.06, chloroform).
Example lg (lS-trans)-3,3-Diethoxy-1,2-cyclobutanedi-methanol,dibenzoa~e ester (lS-trans)-3,3-Diethoxy-1,2~cyclobutanedi-me~hanol (35.1 g) was dissolved in 250 ml of dry pyridine, cooled to 0C under argon, and treated over 0.5 hours with benzoyl chloride (59.7 ml).
The cooling bath was removed and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was then cooled to 0C and treated over 5 minutes with 125 ml of water. The cooling bath was removed and the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo and the residue was co-distilled with water (x 3) and with toluene (x 2) iR vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 10X sodium bisulfate (2 x 250 ml), .
~3~
GYl ~r water (4 x 250 ml), saturated sodium bicarbonate (2 x 250 ml), and water (3 x 250 ml). Drying over sodium sulfate, concentration in vacuo and azetroping with carbon tetrachloride gave 83 g of the title compound as a semi-solid.
Example lh (2S-trans)-2,3-Bis[benzoyloxymethyl]-cyclobutanone The above sample of (lS-trans)-3,3-Diethoxy-1,2-cyclobutanedimethanol, dibenzoate ester (83 g) was dissolved in acetonitrile (1.75 L) under argon and treated with 660 ml of 0.5 N sulfuric acid.
The mixture was stirred at ambient temperature for 17 hours and then was diluted with 5L of ethyl acetate. This solution was washed with water (2 x 1 L), saturated sodium bicarbonate (lL), water (2 x 1 L~, and brine (1 L). The organic phase was dried over sodium sulfate and evaporated to a white solid in vacuo. Partial dissolution in 400 ml of ether and cooling at -30C for 2 hours gave a solid which was filteredr washed with cold ethar and dried in air to give 46.4 g of the title 25 compound, m.p. 93 - 94C, [~]D :: +22.8 (c = 1.0, CHC13)-Another 8 g of slightly impure title compound was obtained by evaporation of the filtrate to a solid residue.
2~3~
GYl6 Example li [lS-(1~,2~,3~ 3-hYdroxy~ 2-cyclobutane dimethanol,1,2-dibenzoate ester (2S-trans)-2,3-Bis[benzoyloxymethyl]cyclo-butanone (33.81 g) in 440 ml of dry tetrahydro-furan at -78C under argon was treated with lO0 ml of 1~ lithium trisiamylborohydride in tatrahydro-furan over 20 minutes. After stirring another lO
minutes at -78C, the mixture was warmed to room temperature, and lO0 ml of saturated sodium bi-carbonate was added over 5 minutes. The resultant mixture was cooled in an ice-acetone bath and treated with 36.5 ml of 30% hydrogen peroxide at a rate so as to maintain the temperature at 25-30C. After the addition, the mixture was diluted with 300 ml of water and extracted with 1.1 L of ethyl acetate. The organic phase was washed with water (x 3), dried over sodium sulfate, and concentrated to a colorless oil (35 g). The oil was taken up in 100 ml of hexane/ethyl acetate (2/1) and filtered through a lL pad of silica gel(K-60), eluting with the same solvent mixtuxe. Evaporation o~E the pure fractions gave 27 g of pure title compound as a colorless oil. Another 4.4 g of slightly impure material gave 3.4 g o pure title compound after column chromatography in the same solv~nt mixture.
~:
:
.
::: : ::
2~3~
Example lj [lS-(la,2~,3~)1-3[[(4-MethylphenYl)sulfonYll-oxy]-1,2-cyclobutanedimethanol, dibenzoate ester lS~ ,2~,3~)]-3-hydroxy-1,2-cyclobutane-dimethanol, 1,2-dibenzoate ester (27 g~ was dissolved in 110 ml of dry pyridine under argon and treated with p-toluenesulfonyl chloride (16.7 g). The mixture was heated and stirred at 60 for 16 hours, cooled to 40C and treated with 2 ml of water. After stirring for 2 hours at 40C the mixture was concentrated in vacuo to an oil.
After azetroping with 2 x 150 ml of water in vacuo, the residue was partitioned between water and ethyl acetate. The organic phase was washed with water (x 2), saturated sodium bicarbonate (x 2), and brine. Drying over sodium sulfate and evaporation in vacuo gave 32.2 g of an oil.
Trituration with pentane gave 28.3 g of a solid.
Crystallization from ethyl acetate/pentane gave 18.4 g of pure title compound as a solid, m.p.
91-92C, [~]D = +13.8 (c = 1.3, C~C13). Another 4 g of title compound was obtained by chromato-graphy of the mother liquors on silica gel usinghexane/ethyl acetate (3/1).
~3~
Example lk [lS-(la,2~,3a)]-3-[2-~mino-6-~phenylmethoxy)-9H-purin-9-yl]-1,2-cYclobutanedimethanol,_ dibenzoate ester A mixture of dry 2-amino-6-benzyloxyguanine (13.4 g), [lS-(la,2~,3~)]-3[[(4-methylphenyl)sul-fonyl]-oxy]-1,2-cyclobutanedimethanol, dibenzoate ester, (18.33 g), powdered anhydrous potassium carbonate (10.22 g, dried over phosphorus pentoxide in vac~o at 130C for 72 hours~, and 18 crown-6 (9.8 g) in 495 ml of dry dimethyl-formamide was stirred and heated at 110C under argon for 21 hours. The mixture was cooled to room temperature and filtered, ar.d the filtrate was ~vaporated in vacuo to an oil which was partitioned between ethyl acetate and water. The organic phase was washed twice with water, dried over sodium sulfate, and evaporated to a foam (24.4 g). Chromatography on silica gel in hexane/-ethyl acetate (1/1) gave 10.7 g of the title compound as a foam with [a3D = -9.0 (c = 0.67, CEIcl3 ) -25Example lL
[lR-(la,2~,3a)l-2-Amino-9-r2,3-bis~hydroxymethyl)-cvclobutyl]-6H-purin-6-one A solution of [lS-(la,2~,3a)]-3-[2-amino-306-(phenylmethoxy)-9~-purin-9-yl]-1,2-cyclobutane-dimethanol, dibenzoate ester S20.0 g) in 550 ml of methanol under argon was treated with 5 ml of 25%
293~5~6 -31- ~Y16 sodium methoxide in methanol and heated at 40C
for 2 hours. A~ueous hydrochloric acid (3N, 275 ml) was then added to the reaction mixture, and heating was continued at 50C for 2 hours. This mixture was concentrated to 100 ml and the solution was transferred to a separatory funnel, with addition of another 100 ml of water. The solution was extracted with ether (3 x 100 ml) and the pH of the aqueous layer was adjusted to 8.5 with the 510w addition of 360 ml of 2N potassium hydroxide. The resulting thick precipitate was filtered and the damp solid was recrystallized by dissolving in 200 ml of hot water, filtering while hot, and chilling at 5C overnight. Drying in 15 vacuo over phosphorus pentoxide gave 7.~5 g of an impure white solid. Chromatography on 750 ml of CHP-20P resin with gradient elution using acetonitrile and water, concentration of the pertinent product fractions until turbid, and chilling this turbid solution for 1 hour at 0C
gave crystals which were filtered. Drying in vacuo at room temperature over phosphorus pentoxide gave 6.3 g of the title compound as a white crystalline solid, m.p. >270C, [~]D = -27 (c = 1.0, DMSO).
Claims (13)
1. A process for the preparation of the optically active compound [1R-(1.alpha.,2.beta.,3.alpha.)]-2-amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-6H-purin-6-one, represented by the formula which comprises (1) reacting a racemic compound of the formula wherein R1 and R2 are lower alkyl with alkali to yield the racemic compound of the formula wherein R1 is as defined above;
(2) reacting a compound of formula 3 with a chiral primary amine of the formula wherein R3 is an alkyl or substituted alkyl group in the presence of a coupling agent to yield a mixture of compounds having the formulae wherein R1 and R3 are as defined above;
(3) separating the diastereomeric compounds of formulae 4 and 5;
(4) protecting hydroxy groups substituted on the moiety R3 in a compound of formula 4 to afford a compound having the formula wherein R3a is a suitably protected form of R3 and R1 is as defined above;
(5) reacting a compound of formula 6 with a nitro-sating agent to yield a compound having the formula wherein R3a and R1 are as defined above;
(6) treating a compound of formula 7 with a reducing agent to yield a compound of the formula wherein R1 is as defined above;
(7) reacting a compound of formula 9 with a pro-tecting group to yield a compound of the formula wherein R4 is a protecting group and R1 is as defined above;
(8) reacting a compound of formula 10 with an acid catalyst to yield a compound of the formula wherein R4 is as defined above;
(9) reacting a compound of formula 11 with a reducing agent to yield a compound of the formula wherein R4 is as defined above;
(10) reacting a compound of formula 12 with a sulfonylating reagent to yield a compound of the formula wherein X is a leaving group and R4 is as defined above;
(11) reacting a compound of formula 13 with guanine or a protected guanine to yield a compound of the formula wherein W is a 9-guanyl residue or a protected 9-guanyl residue and R4 is as defined above;
(12) deprotecting a compound of formula 14 to yield the compound of formula 1.
(2) reacting a compound of formula 3 with a chiral primary amine of the formula wherein R3 is an alkyl or substituted alkyl group in the presence of a coupling agent to yield a mixture of compounds having the formulae wherein R1 and R3 are as defined above;
(3) separating the diastereomeric compounds of formulae 4 and 5;
(4) protecting hydroxy groups substituted on the moiety R3 in a compound of formula 4 to afford a compound having the formula wherein R3a is a suitably protected form of R3 and R1 is as defined above;
(5) reacting a compound of formula 6 with a nitro-sating agent to yield a compound having the formula wherein R3a and R1 are as defined above;
(6) treating a compound of formula 7 with a reducing agent to yield a compound of the formula wherein R1 is as defined above;
(7) reacting a compound of formula 9 with a pro-tecting group to yield a compound of the formula wherein R4 is a protecting group and R1 is as defined above;
(8) reacting a compound of formula 10 with an acid catalyst to yield a compound of the formula wherein R4 is as defined above;
(9) reacting a compound of formula 11 with a reducing agent to yield a compound of the formula wherein R4 is as defined above;
(10) reacting a compound of formula 12 with a sulfonylating reagent to yield a compound of the formula wherein X is a leaving group and R4 is as defined above;
(11) reacting a compound of formula 13 with guanine or a protected guanine to yield a compound of the formula wherein W is a 9-guanyl residue or a protected 9-guanyl residue and R4 is as defined above;
(12) deprotecting a compound of formula 14 to yield the compound of formula 1.
2. A process according to claim 1 wherein a compound of formula 9 is prepared from a compound of formula 4 wherein R3 does not have hydroxy groups by reacting said compound 4 with a nitrosating agent to form a compound having the formula wherein R1 and R3 are as defined above and reducing a compound of formula 8 to yield a compound of formula 9.
3. A process according to claim 1 wherein the chiral primary amine is selected from the group consisting of chiral alkyl amines, chiral hydroxy-substituted alkyl amines, chiral phenyl or naph-thyl-substituted alkyl amines, chiral alkylamines substituted with both hydroxy and phenyl; and chiral primary substituted alkylamines selected from the group consisting of (+)- or (-)-.alpha.-methyl-p-nitrobenzylamine, (+)- or (-)-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol, (+)- or (-)-nore-pinephrine, (+)-dehydroabietylamine, (+)-2-amino-3-methoxy-1-phenylpropanol L-tyrosinol, and lower alkyl esters of (+)- or (-)-alanine, (+)- or (-)-valine, (+)- or (-)- leucine, (+)- or (-)-iso-leucine, (+)- or (-)-phenylalanine, (+)- or (-)-tyrosine, (+)- or (-)-serine, and (+)- or (-)-threonine.
4. A process according to claim 3 wherein the chiral primary amine is a chiral alkylamine substituted with both hydroxy and phenyl.
5. A process according to claim 3 wherein the selected amine is R-(-)-2-phenylglycinol.
6. The optically active compound, [1R-(1.alpha.,2.beta.,3.alpha.)]-2-amino-9-[2,3-bis(hydroxymethyl)-cyclobutyl]-6H-purin-6-one.
7. The compound having the formula wherein R1 is lower alkyl and R3 is an alkyl or substituted alkyl group derived from a chiral primary amine of the formula R3NH2.
8. The compound according to claim 7 wherein R1 is lower alkyl and R3 is
9. The compound having the formula wherein R1 is lower alkyl and R3a is a suitably protected form of R3.
10. The compound according to claim 9 wherein R1 is lower alkyl and R3a is
11. The compound having the formula wherein R1 is lower alkyl and R3a is a protected protected form of R3.
12. The compound according to claim 11 wherein R1 is lower alkyl and R3a is
13. The compound having the formula wherein R1 is lower alkyl and R3 is an alkyl or substituted alkyl group derived from a primary chiral amine of formula R3NH2 when R3 does not have protectable hydroxyl groups.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/451,664 US5064961A (en) | 1989-12-18 | 1989-12-18 | Process for preparing an optically active cyclobutane nucleoside |
| US451,664 | 1989-12-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2031586A1 true CA2031586A1 (en) | 1991-06-19 |
Family
ID=23793189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002031586A Abandoned CA2031586A1 (en) | 1989-12-18 | 1990-12-05 | Process for preparing an optically active cyclobutane nucleoside |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US5064961A (en) |
| EP (1) | EP0433897B1 (en) |
| JP (1) | JPH05178857A (en) |
| AT (1) | ATE158798T1 (en) |
| CA (1) | CA2031586A1 (en) |
| DE (1) | DE69031534T2 (en) |
| DK (1) | DK0433897T3 (en) |
| ES (1) | ES2106726T3 (en) |
| GR (1) | GR3025694T3 (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5130462A (en) * | 1988-03-30 | 1992-07-14 | E. R. Squibb & Sons, Inc. | Cyclobutane derivatives |
| US5126345A (en) * | 1988-03-30 | 1992-06-30 | E. R. Squibb & Sons, Inc. | Bis (hydroxymethyl) cyclobutyl triazolopyrimidines |
| US5185459A (en) * | 1988-03-30 | 1993-02-09 | E. R. Squibb & Sons Inc. | Bis protected (hydroxymethyl)cyclobutanols |
| US5723609A (en) * | 1988-03-30 | 1998-03-03 | E. R. Squibb & Sons, Inc. | Bis (hydroxymethyl) cyclobutyl purines |
| US5064961A (en) * | 1989-12-18 | 1991-11-12 | E. R. Squibb & Sons, Inc. | Process for preparing an optically active cyclobutane nucleoside |
| GB9004881D0 (en) * | 1990-03-05 | 1990-05-02 | Biocompatibles Ltd | Method of improving the ocular of synthetic polymers haemo and biocompatibility |
| US5235052A (en) * | 1990-04-16 | 1993-08-10 | Bristol-Myers Squibb Company | Process for preparing substituted cyclobutane purines |
| US5233076A (en) * | 1990-05-24 | 1993-08-03 | E. R. Squibb & Sons, Inc. | Process for preparing an optically active cyclobutanone, an intermediate in the synthesis of an optically active cyclobutane nucleoside |
| US5344962A (en) * | 1990-05-24 | 1994-09-06 | E. R. Squibb & Sons, Inc. | Intermediates in the synthesis of an optically active cyclobutane nucleoside |
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| US5340816A (en) * | 1990-10-18 | 1994-08-23 | E. R. Squibb & Sons, Inc. | Hydroxymethyl(methylenecyclopentyl) purines and pyrimidines |
| USH1142H (en) | 1990-11-05 | 1993-02-02 | Optically active cyclobutyl pyrimidine | |
| DE69230349T2 (en) * | 1991-03-05 | 2000-07-27 | Ajinomoto Kk | Cyclopropane derivative |
| US5218142A (en) * | 1991-10-02 | 1993-06-08 | E. R. Squibb & Sons, Inc. | Process for the preparation of an antiviral agent |
| US5237096A (en) * | 1991-10-02 | 1993-08-17 | E. R. Squibb & Sons, Inc. | Process for the preparation of an antiviral agent |
| US5233086A (en) * | 1991-10-02 | 1993-08-03 | E. R. Squibb & Sons, Inc. | Intermediates for the preparation of an antiviral agent |
| US5185463A (en) * | 1991-10-02 | 1993-02-09 | E. R. Squibb & Sons, Inc. | Process for the preparation of an antiviral agent |
| US5237095A (en) * | 1991-10-02 | 1993-08-17 | E. R. Squibb & Sons, Inc. | Process for the preparation of an antiviral agent |
| US5525726A (en) * | 1991-10-02 | 1996-06-11 | E. R. Squibb & Sons, Inc. | Process for the preparation of an antiviral agent |
| EP0554025A3 (en) * | 1992-01-27 | 1993-11-18 | Squibb & Sons Inc | Fluorinated cyclobutyl purines and pyrimidines |
| US5412134A (en) * | 1992-05-26 | 1995-05-02 | E. R. Squibb & Sons, Inc. | Process for preparing diprotected 2,3-hydroxymethyl cyclobutanol |
| US5821357A (en) * | 1992-06-22 | 1998-10-13 | Eli Lilly And Company | Stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoropurine and triazole nucleosides |
| US5874578A (en) * | 1992-07-13 | 1999-02-23 | Bristol-Myers Squibb | Process for preparing guanine-containing antiviral agents and purinyl salts useful in such process |
| US5783593A (en) * | 1993-11-04 | 1998-07-21 | Abbott Laboratories | Inhibitors of squalene synthetase and protein farnesyltransferase |
| IL117574A0 (en) * | 1995-04-03 | 1996-07-23 | Bristol Myers Squibb Co | Processes for the preparation of cyclobutanone derivatives |
| US6353122B1 (en) | 1997-02-26 | 2002-03-05 | Bristol-Myers Squibb Company | Method for epoxidation of 3-methylenecyclopropanes |
| EP1102765B1 (en) * | 1998-08-03 | 2003-09-17 | Applied Research Systems ARS Holding N.V. | PROCESS FOR THE SYNTHESIS OF (1$i(H))-BENZO C]QUINOLIZIN-3-ONES DERIVATIVES |
| CN111848423B (en) * | 2019-04-30 | 2022-10-14 | 尚科生物医药（上海）有限公司 | Preparation method of tert-butyl 3-oxocyclobutylcarbamate |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855466A (en) * | 1987-12-28 | 1989-08-08 | E. R. Squibb & Sons, Inc. | Purinyl cyclobutanes |
| US5723609A (en) * | 1988-03-30 | 1998-03-03 | E. R. Squibb & Sons, Inc. | Bis (hydroxymethyl) cyclobutyl purines |
| AU622926B2 (en) * | 1988-09-09 | 1992-04-30 | Nippon Kayaku Kabushiki Kaisha | Pyrimidine or purine cyclobutane derivatives |
| IL92096A0 (en) * | 1988-10-25 | 1990-07-12 | Abbott Lab | Carboxylic nucleoside analogs |
| US4918075A (en) * | 1988-12-20 | 1990-04-17 | E. R. Squibb & Sons, Inc. | Purinyl and pyrimidinyl cyclobutanes and their use as antiviral agents |
| US5241064A (en) * | 1989-10-02 | 1993-08-31 | Fujisawa Pharmaceutical Co., Ltd. | Enzymatic process for preparing optically active 3-substituted azetidinones |
| US5256806A (en) * | 1989-12-18 | 1993-10-26 | E. R. Squibb & Sons, Inc. | Intermediates for the preparation of optically active cyclobutane nucleoside |
| US5064961A (en) * | 1989-12-18 | 1991-11-12 | E. R. Squibb & Sons, Inc. | Process for preparing an optically active cyclobutane nucleoside |
| US5198583A (en) * | 1989-12-18 | 1993-03-30 | E. R. Squibb & Sons, Inc. | Optically active cyclobutane nucleoside and intermediates, therefor |
-
1989
- 1989-12-18 US US07/451,664 patent/US5064961A/en not_active Expired - Fee Related
-
1990
- 1990-12-05 CA CA002031586A patent/CA2031586A1/en not_active Abandoned
- 1990-12-13 DK DK90124123.2T patent/DK0433897T3/en active
- 1990-12-13 AT AT90124123T patent/ATE158798T1/en active
- 1990-12-13 DE DE69031534T patent/DE69031534T2/en not_active Expired - Fee Related
- 1990-12-13 ES ES90124123T patent/ES2106726T3/en not_active Expired - Lifetime
- 1990-12-13 EP EP90124123A patent/EP0433897B1/en not_active Expired - Lifetime
- 1990-12-18 JP JP2412010A patent/JPH05178857A/en active Pending
-
1993
- 1993-07-15 US US08/091,389 patent/US5306837A/en not_active Expired - Fee Related
-
1997
- 1997-12-17 GR GR970403345T patent/GR3025694T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2106726T3 (en) | 1997-11-16 |
| DK0433897T3 (en) | 1997-10-27 |
| EP0433897A2 (en) | 1991-06-26 |
| US5064961A (en) | 1991-11-12 |
| DE69031534T2 (en) | 1998-04-02 |
| EP0433897A3 (en) | 1992-08-05 |
| JPH05178857A (en) | 1993-07-20 |
| ATE158798T1 (en) | 1997-10-15 |
| US5306837A (en) | 1994-04-26 |
| GR3025694T3 (en) | 1998-03-31 |
| DE69031534D1 (en) | 1997-11-06 |
| EP0433897B1 (en) | 1997-10-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20001205 |