WO2008087021A1 - Synthesis of 4-amino-pyrimidines - Google Patents
Synthesis of 4-amino-pyrimidines Download PDFInfo
- Publication number
- WO2008087021A1 WO2008087021A1 PCT/EP2008/000320 EP2008000320W WO2008087021A1 WO 2008087021 A1 WO2008087021 A1 WO 2008087021A1 EP 2008000320 W EP2008000320 W EP 2008000320W WO 2008087021 A1 WO2008087021 A1 WO 2008087021A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- solvent
- acetamidine
- salt
- formyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Definitions
- the present invention relates to the direct transformation of an ⁇ -formyl-propionitrile salt (Li-, Na- or K-salt) to substituted 4-amino-pyrimidines.
- ⁇ -formyl-propionitrile salt Li-, Na- or K-salt
- acetamidine hydrochloride 2- methyl-4-amino-5-formylaminomethylpyrimidine by a cyclization reaction of an ⁇ -formyl- ⁇ - formylaminopropionitrile salt (Li-, Na- or K-salt) and acetamidine hydrochloride.
- 4-aminopyrimidines and the aminosubstituted derivatives can be found as structural elements in several antibiotic substances, in herbicides as well as in vitamin B1.
- trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoWellcome under trade names including Proloprim®, Monotrim® and Triprim®.
- Amprolium (sold as CORID ®), thiamine analog, competitively inhibits the active transport of thiamine.
- the coccidia are 50 times as sensitive to this inhibition as is the host. It can prevent costly coccidial infection in exposed cattle and treat clinical outbreaks when they do occur. By stopping coccidia in the small intestine, CORID ® prevents more damaging coccidiosis in the large intestine.
- Vitamin B1 (thiamin) is used chiefly in the form of chloride hydrochloride (1) and nitrate.
- vitamin B 1 in the human being is associated with the disease beriberi, with imbalances in carbohydrate status and deleterious effects on nerve functions.
- a human being needs 20 - 30 ⁇ g/kg body weight, which corresponds to 0.3 - 1.5 mg/d daily allowance. Since extraction of thiamin from natural sources would not be economically profitable, it has to be manufactured by chemical synthesis. Industrial production of vitamin B 1 started in 1937 by Hoffmann-La Roche in Switzerland and Merck in the United States. Commercially available forms of thiamin are the chloride hydrochloride and the mononitrate.
- 4-amino-5-aminomethyl-2-methylpyrimidine is a key-intermediate in the synthesis of thiamin which contains a thiazole and a pyrimidine ring.
- One main approach towards the synthesis of thiamin is the pyrimidine synthesis and subsequent formation of the thiazole ring attached to the pyrimidine moiety from 4-amino-5-aminomethyl-2-methylpyrimidine and 3-chloro-5-hydroxy- pentan-2-one, the 3-mercaptoketone or the corresponding acetates.
- Several procedures have been published for the synthesis of 4-amino-5-aminomethyl-2-methylpyrimidine.
- the building blocks are based on a C2-unit, e.g. acetamidine, and a C1-unit, usually from CO. Acrylonitrile can be used as C2-unit as a cheap starting material for the synthesis.
- JP 39022009 and JP 39022010 describe the synthesis of 2-methyl-4-amino-5-formylamino- methylpyrimidine by reacting formamidine hydrochloride with sodium and ethanol to liberate the amidine followed by an addition of 2-(ethoxymethoxymethyl)-3-ethoxypropionitrile.
- This procedure is disadvantageous as it necessitates an extra reaction step, the liberation of form- amidine from the hydrochloride and the synthesis of the enol ethyl ether.
- the UBE-Takeda procedure for over seven steps [EP-055 108-A1 ; EP-279 556-A1 ; DE-33 03 815-A1 ; EP-124 780-A1 ; EP-290 888-A2; DE-32 22 519-A1] includes in the first step the transformation of acrylonitrile to cyanoacetaldehyde-dimethylacetal. This step is very complex and requires major investigations because the oxidation of acrylonitrile with methyl nitrite leads to the formation of nitrous gases which have to be reoxidized to nitrite [EP-055 108-A1].
- the 5 step procedure from BASF [EP-172 515-A1] uses o-chloroaniline for the synthesis of the corresponding enamine.
- o-Chloroaniline is suspected to provoke cancer.
- the enamine is used in the following step for the cyclization with acetamidine. After the formation of 4-amino-5- aminomethyl-2-methylpyrimidine the o-chloroaniline has to be separated and re-used in a complex process.
- APN aminopropionitrile
- the key-step in this approach is the cyclization of derivatives of ⁇ -formyl- ⁇ -formylaminopropio- nitrile sodium salt with acetamidine.
- These derivatives can be for example the enamines, acetates or methylenolethers of ⁇ -formyl- ⁇ -formylaminopropionitrile sodium salt [see for example EP-001 760-A2, DE-28 18 156-A1, DE-23 23 845].
- the acetamidine has to be liberated from its hydrochloride. Severe drawbacks of this procedure are the formation of a salt, additional costs for the base and additional reaction steps including work-up, e.g. by filtration of the salts.
- the process consists of reacting ⁇ -forrnyl- ⁇ -formylaminopropionitrile sodium salt having a minimal purity of 92 % with acetamidine hydrochloride in a solvent like isopropanol, methylisobutylcarbinol, open chain- or cyclic ethers during 4 to 6 hours at reflux yielding 2- methyl-4-amino-5-formylaminomethylpyrimidine and subsequent hydrolysis leading to 4-amino- 5-aminomethyl-2-methylpyrimidine.
- the reported yield is 57 %. Unfortunately it was not possible to obtain the reported yield under the reported conditions. The highest yield obtainable under the reported conditions was in fact 35 %.
- R 1 hydrogen, alkyl (C1 - C10, linear, cyclic or branched, aliphatic or aromatic), NR'R"
- R' and R" are independently selected from H, alkyl [C1 - C10, linear, cyclic or branched, aliphatic or aromatic] and
- the starting materials can be added in any order to the reaction vessel.
- acetamidine salts can be used as starting material.
- an ⁇ -formyl- ⁇ -formylaminopropionitrile salt (Li-, Na- or K-salt) is reacted with an acetamidine salt to 2-methyl-4-amino-5-formylamino- methylpyrimidine.
- 2-methyl-4-amino-5-formylaminomethyl- pyrimidine can be purified as described in patent application WO 2006/079504 A2, i.e. after the hydrolysis of 2-methyl-4-amino-5-formylaminomethylpyrimidine to 4-amino-5-aminomethyl-2- methylpyrimidine an easy liquid/liquid purification of the crude reaction mixture is carried out to obtain 4-amino-5-aminomethyl-2-methylpyrimidine in high yield and high purity.
- the process of the present invention therefore preferably comprises the following additional step(s): i) hydrolysis of the 2-methyl-4-amino-5-formylaminomethylpyrimidine to 4-amino-5- aminomethyl-2-methylpyrimidine; ii) phase separating the reaction mixture in an aqueous and an organic phase; iii) optionally extracting the aqueous phase with the organic solvent (mixture) used in the previous steps and combining the organic phases.
- Steps i) to iii) may be performed in any way known to the person skilled in the art.
- the Lewis acids are selected from salts of alkaline earth metals (especially Be, Mg, Ca), transition metals (especially Fe, Co, Ni, Ru, Rh, Pd, Cu, Ag, Au, Zn 1 ), poor metals (especially Al, Ga, In) and/or lanthanides; preferred are salts of transition metals; especially preferred are iron (II)-, cobalt(ll)-, ruthenium(ll)-, copper(l) and/or zinc(ll) salts.
- alkaline earth metals especially Be, Mg, Ca
- transition metals especially Fe, Co, Ni, Ru, Rh, Pd, Cu, Ag, Au, Zn 1
- poor metals especially Al, Ga, In
- lanthanides especially preferred are salts of transition metals; especially preferred are iron (II)-, cobalt(ll)-, ruthenium(ll)-, copper(l) and/or zinc(ll) salts.
- additives which e.g. further enhance the yield of the desired product.
- additives are MgSO 4 and/or NaSO 4 .
- solvents or mixtures of solvents which do not have a primary alcohol function like hydrocarbons, aromatic compounds, ethers, ketones, esters, carbonates, alkohols, tertiary amines, nitriles, amides, acetonitrile and so on.
- aromatic compounds, ketones, carbonates, tertiary amines or any mixtures of these solvents especially preferred are 3-pentanone, triethylamine and/or toluene or any mixtures of these solvents. 3-pentanone is most preferred.
- An example of a preferred mixture of solvents is a mixture of 3-pentanone and isopropanol in a volume ratio of from 9 : 1 to 1 : 9, preferred in a volume ratio of from 8 : 2 to 2 : 8, especially preferred in a volume ratio of from 7.5 : 2.5 to 6 : 4.
- traces of water and/or another polar solvent can be advantageous. It is preferred if the amount of water and/or another polar solvent is in the range of 0.005 to 1 equivalents, more preferred in the range of 0.05 to 0.5 equivalents.
- ⁇ a pressure in the range of 1 to 10 bar, preferred of 1 to 6 bar;
- ⁇ a reaction time in the range of 0.5 to 20 hours, preferred of 1 to 10 hours, more preferred of 2.5 to 4 hours;
- NMR spectra were recorded on a Bruker Avance 300 MHz spectrometer. 1 H-NMR were recorded at 300 MHz, 13 C spectra were recorded at 75 MHz, respectively. The quantitative spectra were recorded in DMSO-d 6 using p-dimethoxyhydroquinone as internal standard. The delay between two pulses was set to 30 s. 12 - 25 mg samples were used.
- the mixture was stirred at 300 rpm under argon at 88° C (internal temperature). After 14 hours, the solvent was removed at reduced pressure at 40° C bath temperature and the crude reaction mixture was analyzed by HPLC and NMR. The yield was 90 % based on ⁇ -formyl- ⁇ - formylaminopropionitrile sodium salt.
- the mixture was stirred at 300 rpm under argon at 88° C (internal temperature). After 6 hours, the solvent was removed at reduced pressure at 40° C bath temperature and the crude reaction mixture was analyzed by HPLC and NMR. The yield of 4-amino-5-formylaminomethylpyrimidine was 34 % based on ⁇ -formyl- ⁇ -formylaminopropionitrile sodium salt.
- Comparative example 1 (without Lewis acid): 1.67 g of ⁇ -formyl- ⁇ -formylaminopropionitrile sodium salt (84%, 9.5 mmol) were placed in a three-necked, round bottom 25 mL flask, fitted with a reflux-condenser, a magnetic stirrer and an argon supply. Acetamidine hydrochloride (1.09 g, 11.6 mmol, 1.15 eq.) and finally 2.5 mL of toluene and 6.6 mL of triethylamine were added.
- the mixture was stirred at 300 rpm under argon at 88° C (internal temperature). After 19 hours, the solvent was removed at reduced pressure at 40° C bath temperature and the crude reaction mixture was analyzed by HPLC and NMR. The yield was 22 % based on ⁇ -formyl- ⁇ - formylaminopropionitrile sodium salt.
- Comparative example 2 (without Lewis acid): 998 mg of ⁇ -formyl- ⁇ -formylaminopropionitrile sodium salt (84%, 5.7 mmol) were placed in a three-necked, round bottom 25 mL flask, fitted with a reflux-condenser, a magnetic stirrer and an argon supply. Acetamidine hydrochloride (670 mg, 6.8 mmol, 1.19 eq.) and 5.4 mL of 3- pentanone were added.
- the mixture was stirred at 300 rpm under argon at 88° C (internal temperature). After 19 hours, the solvent was removed at reduced pressure at 40° C bath temperature and the crude reaction mixture was analyzed by HPLC and NMR. The yield was 45 % based on ⁇ -formyl- ⁇ - formylaminopropionitrile sodium salt.
Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/522,929 US8198443B2 (en) | 2007-01-19 | 2008-01-07 | Synthesis of 4-amino-pyrimidines scaffolds |
CN2008800026343A CN101583604B (en) | 2007-01-19 | 2008-01-17 | Synthesis of 4-amino-pyrimidines |
KR1020097014982A KR101428123B1 (en) | 2007-01-19 | 2008-01-17 | Synthesis of 4-amino-pyrimidines |
EP08707086.8A EP2102172B1 (en) | 2007-01-19 | 2008-01-17 | Synthesis of 4-amino-pyrimidines |
JP2009545869A JP5289331B2 (en) | 2007-01-19 | 2008-01-17 | Synthesis of 4-amino-pyrimidine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07001136.6 | 2007-01-19 | ||
EP20070001136 EP1972620A1 (en) | 2007-01-19 | 2007-01-19 | Synthesis of 4-amino-pyrimidines |
Publications (1)
Publication Number | Publication Date |
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WO2008087021A1 true WO2008087021A1 (en) | 2008-07-24 |
Family
ID=38224299
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/000320 WO2008087021A1 (en) | 2007-01-19 | 2008-01-17 | Synthesis of 4-amino-pyrimidines |
Country Status (6)
Country | Link |
---|---|
US (1) | US8198443B2 (en) |
EP (2) | EP1972620A1 (en) |
JP (1) | JP5289331B2 (en) |
KR (1) | KR101428123B1 (en) |
CN (1) | CN101583604B (en) |
WO (1) | WO2008087021A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103420918A (en) * | 2013-07-22 | 2013-12-04 | 新发药业有限公司 | Simple and convenient preparation method of key intermediate (2-methyl-4-amino-5-amino methyl pyrimidine) for vitamin B1 |
CN103435556A (en) * | 2013-08-26 | 2013-12-11 | 新发药业有限公司 | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine |
CN107602481A (en) * | 2017-09-05 | 2018-01-19 | 常州大学 | A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process |
CN107602482A (en) * | 2017-09-05 | 2018-01-19 | 常州大学 | A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process |
CN113252829A (en) * | 2021-05-07 | 2021-08-13 | 镇江高等职业技术学校 | Method for determining acetamidine hydrochloride in irrigation water |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE789815A (en) * | 1970-03-27 | 1973-04-06 | Stauffer Chemical Co | VINYLPHOSPHONATES COPOLYCONDENSES AND THEIR USE AS INFLAMMATION-DELAYING AGENTS |
JPS5518702B2 (en) * | 1972-05-12 | 1980-05-21 | ||
DE3431270A1 (en) * | 1984-08-25 | 1986-03-06 | Basf Ag, 6700 Ludwigshafen | ALPHA- (O-CHLORPHENYL) -AMINOMETHYLENE-BETA-FORMYLAMINOPROPIONITRILE, METHOD FOR THE PRODUCTION THEREOF AND USE FOR THE PRODUCTION OF 2-METHYL-4-AMINO-5-FORMYLAMINOMETHYLP |
US5461075A (en) * | 1988-06-17 | 1995-10-24 | The Procter & Gamble Company | Use of vanilloids for the prevention of lesions due to herpes simplex infections |
US4942085A (en) * | 1989-01-23 | 1990-07-17 | American Cyanamid Company | Method of manufacturing a sag-resistant bonded particulate article |
US5140047A (en) * | 1991-05-03 | 1992-08-18 | Smithkline Beecham Corporation | Lipoxygenase inhibitors |
-
2007
- 2007-01-19 EP EP20070001136 patent/EP1972620A1/en not_active Withdrawn
-
2008
- 2008-01-07 US US12/522,929 patent/US8198443B2/en active Active
- 2008-01-17 KR KR1020097014982A patent/KR101428123B1/en active IP Right Grant
- 2008-01-17 WO PCT/EP2008/000320 patent/WO2008087021A1/en active Application Filing
- 2008-01-17 CN CN2008800026343A patent/CN101583604B/en active Active
- 2008-01-17 EP EP08707086.8A patent/EP2102172B1/en active Active
- 2008-01-17 JP JP2009545869A patent/JP5289331B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103420918A (en) * | 2013-07-22 | 2013-12-04 | 新发药业有限公司 | Simple and convenient preparation method of key intermediate (2-methyl-4-amino-5-amino methyl pyrimidine) for vitamin B1 |
CN103435556A (en) * | 2013-08-26 | 2013-12-11 | 新发药业有限公司 | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine |
CN107602481A (en) * | 2017-09-05 | 2018-01-19 | 常州大学 | A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process |
CN107602482A (en) * | 2017-09-05 | 2018-01-19 | 常州大学 | A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process |
CN113252829A (en) * | 2021-05-07 | 2021-08-13 | 镇江高等职业技术学校 | Method for determining acetamidine hydrochloride in irrigation water |
CN113252829B (en) * | 2021-05-07 | 2023-09-22 | 镇江高等职业技术学校 | Determination method of acetamidine hydrochloride in irrigation water |
Also Published As
Publication number | Publication date |
---|---|
EP1972620A1 (en) | 2008-09-24 |
KR20090101254A (en) | 2009-09-24 |
JP2010516644A (en) | 2010-05-20 |
EP2102172A1 (en) | 2009-09-23 |
CN101583604A (en) | 2009-11-18 |
CN101583604B (en) | 2013-03-06 |
KR101428123B1 (en) | 2014-08-07 |
EP2102172B1 (en) | 2015-08-12 |
JP5289331B2 (en) | 2013-09-11 |
US20100016591A1 (en) | 2010-01-21 |
US8198443B2 (en) | 2012-06-12 |
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