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Publication numberUS2597247 A
Publication typeGrant
Publication dateMay 20, 1952
Filing dateAug 2, 1948
Priority dateAug 2, 1948
Publication numberUS 2597247 A, US 2597247A, US-A-2597247, US2597247 A, US2597247A
InventorsJames F Kerwin, Glenn E Ullyot
Original AssigneeSmith Kline French Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Nu-substituted amino-ethanols
US 2597247 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

Patented May 20, 1952 N-SUBSTITUTED AMINO-ETHANOLS James F. Kerwin and Glenn. E. Ullyot, Philadelphia, Pa., assignors to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania.

NoDrawing- Application August 2, 1948,

V Serial N0.'42,148 I Claims. (Cl. 260570.8)

This invention relates to certain new chemical compounds, more particularly certain new amino alcohols and organic and inorganic salts thereof. The new chemical compounds according to this invention have utility as intermediates for the production of compounds useful as physiologically active agents and which, more particularly, have adrenolytic or sympathicolytic activity.

From the broad standpoint the new compounds according to this invention have the structure shown by the following formula:

in which:

A is a member of the group consisting of aryl, substituted ary1, cyclohexyl, cyclopentyl and aralkyl groups.

W is a member of the group consisting of hydrogen and alkyl groups containing not more than six carbon atoms.

Y is a member of the group consisting of alkyl groups having less than eight carbon atoms.

Z is a member of the group consisting of aralkyl, substituted aralkyl, ary1 and substituted aryl groups.

R, R1 and R2 are members of the group consisting of hydrogen and alkyl groups such that the sum of the carbon atoms in R, R1 and B: does not exceed six; and organic and inorganic salts thereof. a

More particularly, preferential compounds according to this invention will have the following structure:

in which: V A is a member of the group consisting of aryl, substituted ary1 in which the substitution is chosen from the group consisting of alkyl groups containing not more than 4 carbon atoms, a hydroxy group, alkoxy groups containing not more than 4 carbon atoms, chlorine, bromine, fluorine, amino, acylamino containing not more than 4 carbon atoms, alkylainino containing not I more than 8 carbon atoms, cyclohexyl and aralkyl in which the alkyl part does not contain more than 4 carbon atoms.

- W is-a member of the group consisting of z hydrogen and an alkyl group containing not more than 3 carbon atoms.

Y is a member of the group consisting of alkyl containing not more than 4 carbon atoms.

Z is a member of the group consisting of aralkyl containing not more than 4 carbon atoms in the alkyl portion, substituted aralkyl in which the substitution is chosen from the group consisting of alkyl groups containing not more than 4 carbon atoms, a hydroxy group, alkoxy groups containing not more than 4 carbon atoms, chlorine, bromine, fluorine, amino, acylamino containing not more than 4 carbon atoms, alkylamino containing not more than 8 carbon atoms.

R, R1 and R2 are members of the group consisting of hydrogen and alkyl groups such that the sum of the carbon atoms in R, R1 and R2 does not exceed six; and organic and inorganic salts of said compounds.

The compounds according to this invention will be useful as intermediates for the preparation of compounds having physiological properties, such, for example, as halogenated amines having the following structure:

1 w n J Y Y sin-tn R R1 \N '-x Z/ 1 in which:

Ais a member of the group consisting of aryl, substituted ary1, cyclohexyl, cyclopentyl, and aralkyl groups. r

W is a member of the group consisting of hydrogen and alkyl groups containing not more than six carbon atoms. a

Y is a member of the group consisting of alkyl groups having less than eight carbon-atoms.

Z is a member of the group consisting of aralkyl, substituted aralkyl, ary1 and substituted aryl groups. Y

R, R and R2 are members of the group consisting of hydrogen and alkyl groups such that the sum of the carbon atomsin R, R1 and R2 does not exceedsix.

X is a member of the group consisting of chlorine, bromine and fluorine. I And organic and inorganic saltsof said compounds.

When in the several formulae given hereinafter in connection with description of procedure for the preparation of compounds according to thisinvention andas illustrative ofspecific compoundsaccording to this invention, the radicals either known substances or being made obvious y can be prepared by well known methods.

The organic and inorganic saltscontemplated by this invention include, by way of example,

salts formed with organic acids such, for example, as tartaric, succinic, glycolic, camphor sulfonic, etc. and with inorganic acids such as, for example, sulfamic, hydrochloric, hydrobromic, sulfuric, phosphoric, etc.

METHOD A A mixture of a ketone of the type and-an-amin'o alcohol of the type:

ram-d-d-on is reduced with hydrogen in the presence of a suitable hydrogenation catalyst, as, for example,

platinum, palladium or Raney nickel with the production of an amino alcohol having the formula:

If desired, the ketone and-amino alcohol may be first reacted to form a ketimine and such catalytically reduced. However, proceeding as first outlined above "will'generally be most convenient. Y

The amino alcohol so produced is reacted with a halogenated compound corresponding to the radical Z in the general formula above, such, for example, as benzyl chloride, which will introduce the group Z shown in the general formula above. The reaction will be accomplished by heating together the secondary amine and the alkylating agent, the temperature employed depending upon the reactivity of the halide chosen. In most cases,the reaction is conveniently carried out in alcohol solution in the presence of an acid binding agent such as potassium carbonate.

When used as an intermediate for the production of the halogen containing amine indicated above, the hydroxylgroup of the amino alcohol-is replaced by a halogen radical X in the general formula given above by reacting the amino alcohol with a halogenating agent such as. for example, with thionyl chloride, thionyl bromide, hydrochloric, or hydrobromic acid. The product will be obtained in the form of its hydrohalide salt.

METHOD B A mixture of a ketone of the type indicated in connection with Method A above and a primary amine of the type ZNH2-are catalytically reduced to-form a secondaryamine' of the type:

iii

The same secondary-amine can be prepared by reduction of 'an aldehyde or ketone in which the group Z is included, such as benzaldehyde or benzyl methyl ketone, etc., in the presence of a a primary amine of the type The secondary amine so produced is then reacted withan alkylene halohydrin, such as ethyl- I ene bromhydrin, l-bromo-2-propanol, or the like.

or with an alkylene oxide, such as ethylene oxide, propylene oxide, or the like, to form an amino alcohol having the structure:

NAB-tam z R H When used as an intermediate the amino alcohol is treated as above for replacement of the hydroxyl group by a halogen group as X in the gen- .eral formulagiven above.

The following examples will be illustrative of the various types of compounds and of specific compounds in accordance with this invention and procedure for their preparation and will, it is believed, serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof, respectively, it being noted that the utility indicated for the several compounds flows from the elements of the general structure common to all of them.

Example 1 N 8 phenylisopropyl) N -'benzylaminoethanol will be prepared by Method A above as follows:

Step 1.A solution of 122 g. of ethanolamine, 268 g. of benzyl methyl ketone and 300 cc. of alcohol is shaken in an atmosphere of hydrogen in'the presence of platinum catalyst. After removal of the catalyst and alcohol, the remainder was distilled in vacuo and the fraction boiling-at 118-122/3 mm. has the formula:

To form a salt of this base, it is added to aqueous hydrochloric acid to give the'hydrochlorlde salt. melting. at.201.5.-203.5 C. Similarly, any

organic or inorganic acid salt may be prepared.

The above compound will be used as an intermediate for the preparation of a halogenated amine salt as follows: A solution of 17 g. of the hydrochloride salt, N-(fl-phenylisopropyD-N- benzyl-aminoethanol hydrochloride, and 13 g. of thionyl chloride in 100 cc. of chloroform is heated at 50-60 for an hour. Removal of the solvent and recrystallization of the residue from alcohol and ether gives N-(p-phenylisopropyD- N-benzyl-B-chlorethylamine hydrochloride, a solid, M. P. 144-147" C. corresponding to the formula:

Example 2 N ,9 -phenylisopropyl) N benzylaminoethanol will be prepared by Method B above as follows:

Step 1.Fifty-three grams of benzaldehyde and 67 g. of fi-phenylisopropylamine are mixed, the water formed in the reaction is separated and the residue hydrogenated in alcohol solution in the presence of platinum catalyst. Catalyst and solvent are removed and the product, N-benzyl-p-phenylisopropylamine, distilled, B. P. 190- 195 C./22 mm.

Step 2.Eighty-five grams of N-benzyl-flphenylisopropylamine, 24 g. of ethylene bromohydrin and 100 cc. of toluene are refluxed for four hours. The reaction mixture is filtered and the filtrate distilled. The fraction boiling at 178-182" C. at 2 mm. corresponds to the formula:

This base may be converted to a salt. Thus, added to aqueous hydrochloric, it will give the hydrochloride salt melting at 201-204 C., or added to other organic or inorganic acids will give the salt corresponding to the acid selected.

As illustrative of use of the abov compound as an intermediate, 2. solution of 17 g. of the hydrochloric salt, N- (B-phenylisopropyl) -N-benzylaminoethanol hydrochloride, and 13 g. of thionyl chloride in 100 cc. of chloroform is heated at 50-60 for an hour. Removal of the solvent and recrystallization of the residue from alcohol and ether gives N-(fl-phenylisopropyl)-N-benzyl-,8- chlorethylamine hydrochloride, a solid, M. P. 144-147 C. corresponding to the formula:

Following the above procedure using optically active fi-phenylisopropylamine, the product compound will be optically active. Thus, where the d-isomer of B-phenylisopropylamine is used in step 1, dextrorotatory N-(p-phenylisopropyD- N-benzylaminoethanol, M. P. 137-139 C., [c] =+34.4= (0:8.00 in ethanol) is formed as the end product.

Example} p N-(fl cyclohexylisopropyl) N benzylamino. ethanol will be prepared byMethod A above as follows:

Step 1.Seventy grams of cyclohexylacetone are added to 30 g. of ethanolamine in cc. of alcohol and the solution shaken with hydrogen in the presence of platinum catalyst. The solution is filtered from the catalyst, the alcohol removed and the residue distilled in vacuo. The fraction boiling at 154-158/20 mm., fl-cyclohexylisopropylaminoethanol, has the formula:

Step 2.-A mixture of 114 g. of fl-cyclohexylisopropylaminoethanol, '78 g. of benzyl chloride, 69 g. of anhydrous potassium carbonateand cc. of alcohol are stirred and refluxed for six hours.

The reaction mixture is diluted with water and extracted with ether., The ether solution is dried and distilled; the product, N-(p-cyclohexylisopropyl)-N-benzylaminoethanol, boils at 170- 179/4 mm.

The distillate is converted into a salt by the addition of an acid, for example, hydrochloric, which gives it hydrochloride salt which melts at 121.5-123 C.

Using the above compound as an intermediate, twenty-eight grams of N-(p-cyclohexylisopropyD-N-benzylaminoethanol hydrochloride are added to 21 g. of thionyl chloride in 50 cc. of chloroform and the solution heated to 55-60 for an hour. The solvent is removed and the product, N (,8 cyclohexylisopropyl) N benzyl chlorethylamine hydrochloride, recrystallized from a mixture of alcohol and ether, M. P. 145-147 C.

Example 4 N-(p methoxyphenylisopropyl) N benzylaminoethanol will be prepared by Method A above as follows:

Step 1.--A mixture of 82' g. *of p-methoxyphenylacetone and 31 g. of ethanolamine is reduced as in Example 1 above to obtain p-methoxyphenylisopropylaminoethanol, anoil boiling at 154-157/2 mm. and having the formula:

Step 2. g. of p-methoxyphenylisopropylaminoethanol with 63 g. of benzyl chloride are then reacted in the presence of potassium carbonate as described in Example 1 above to obtain N (p methoxyphenylisopropyl) N benzylaminoethanol, an oil boiling at l90-195/1 mm. and corresponding to the formula:

ciao-Genet?! N-CH -CHgOH 7 and recrystallization of the residue, the N-(pmethoxyphenylisopropyl) N benzyl c chlorethylamine hydrochloride, a white'solid, melts at 122123 C. and corresponds to the formula:

cedure described in Examplee above using 3,4- dimethoxyphenylacetone' in place of p-methoxyphenylacetone in step 1.

This compound will be prepared by the procedure described in Example 1 above using benzyl ethyl ketone in place of benzyl methyl ketone in step 1. 7 7

Eatample 7 This compound will'be prepared by the procedure described in connection with Example 1 above using isopropanolaminein place of ethanolamine in step l.

Example 8 This compound will be prepared by the procedure described in Example 2 above using benzyl methyl ketone and fi-phenylisopropylamine in step 1. The hydrochloride salt melts at 158.5- 160 C.

Example 9 This compound will be prepared according to the procedure described in'Example 1 above using p-methylphenylacetone in place of benzyl methyl ketone in step 1.

Example 1 0 This compound will be prepared according to the procedure described in Example 1 above using p-chlorophenylacetone in place of benzyl methyl ketone in step 1.

Example 11 CHaOQ-Cz This compound will be prepared according to the procedure described in Example 1 above using p-methoxybenzyl chloride in place of benzyl chloride in step 2.

Example 12 N-CHz-CHr-OH This compound will be prepared according to the procedure described in Example 1 above using p-bromobenzyl chloride in place of benzyl chloride in step 2.

Example 13 This compound will be prepared according to the procedure described in Example 4 above using p-methoxybenzyl chloride in place of benzyl chloride in step 2.

Example 14 This compound will be prepared according to the procedure described in Example 1 above using benzylacetone in place of benzylmethyl ketone in step 1. Example 15 This compound will be prepared according to the procedure described in Example 1 above using 3-amino-2-butanol in place of ethanolamine in step 1.

Example 16 9 This compound wil1 ;beprepared according to the procedure described in Example 1 above using 2-amino-2-methyl-1-propanol in place of ethanolamine in step 1.

This compound will be prepared according to the procedure described in Example 1 above using cyclopentylacetone in place of benzyl methyl ketone in step 1.

Example 18 This compound will be prepared according to the procedure described in Example 2 above using benzyl methyl ketone and aniline in step 1.

Example 19 This compound will be prepared according to the procedure described in Example 2 above using benzyl methyl ketone and p-anisidine in step 1 and reacting with ethylene bromohydrin in step 2.

Example 20 cm on:

This compound will be prepared according to the procedure described in Example 1 above using s-methyl-e-phenylacetone in place of benzyl methyl ketone in step 1.

In the foregoing examples aminoethanols and aminoethanol hydrochlorides according to this invention have been exemplified. It will, however, be understood that all of the several aminoethanols embraced within the scope of this invention as defined by the general formula given herein will be readily prepared by the general methods herein described ,as exemplified by the specific examples given. herein and such, We believe, will be evident to those skilled in chemistry. Further, it will be understood that organic and inorganic salts of the several aminoethanols, as Well as those more specifically mentioned herein, will be formed as generally described herein and as specifically described for the production of hydrochlorides and such, we believe, will be obvious to anyone skilled in chemistry, it being made apparent from the foregoing disclosure that the several aminoethanols will react with organic and inorganic acids generally under known procedure.

It will be appreciated with reference to the foregoing examples that the aminoethanol product may be recovered in step 2 as the free base or in the form of a salt,

Specific examples of aminoethanols and of organic and inorganic salts thereof and of those organic and' inorganic salts specifically mentioned herein will be had by reference to the structural formulae, given herein by substituting therein the several specific s'ubstituents given in connection with the general formula and, in the case of organic and inorganic salts of the aminoethanols, by the addition of the radical of any organic or inorganic acid to the amino group.

The compounds contemplated by this invention will be variously optically inactive or optically active and it will be understood that the optically active and optically inactive forms of the compounds contemplated by this invention are all included within the scope of this invention.

As has been indicated, the starting material for the preparation of any given compound having the structure contemplated by this invention will be found among known compounds or, the structure being obvious from the foregoing disclosure with reference to any given compound, will be readily prepared by known methods.

What we claim and desire to protect by Letters Patent is:

1. Compounds having the formula:

OHO- on JJH a Q m 3. The compound having the formula:

CHsO

I CH3 omo-Gcm-dn 4. The compound having the formula:

OEnO-Q-Cm 5. The compound having the formula:

JAMES F. KERWIN. GLENN E. ULLYOT.

(References on following page) The following references are of record inthe REFERENCES CITED Number Name Date Peyer Jan.-21, 1941 .Number FOREIGN PATENTS Country Date Germany Nov. 13, 1931 France Jan. 23, 1932 Great Britain May 26, 1932 Germany Aug. 20, 1940 Great Britain May 30, 1941

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2229187 *Jul 18, 1938Jan 21, 1941Sandoz LtdAmino-alcohol and a process for its production
DE538456C *Jun 11, 1930Nov 13, 1931Ig Farbenindustrie AgVerfahren zur Darstellung von ‰-[Di-(arylmethyl-)]aminoaethanolen
DE695217C *Mar 5, 1938Aug 20, 1940Alexis TschitschibabinVerfahren zur Herstellung von Polyaminen bzw. ihren quaternaeren Ammoniumverbindungen
FR718398A * Title not available
GB373440A * Title not available
GB536881A * Title not available
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3215738 *Jan 16, 1963Nov 2, 1965Hoffmann La RocheN-(substituted-phenethyl)-1-hydroxy-1-cycloalkyl-ethylamines
US3225098 *Jul 17, 1962Dec 21, 1965Hoechst AgN-substituted phenylalkylamines
US3320319 *Aug 6, 1965May 16, 1967Degussa1-(aryl)-2-methyl-2-aliphatic amino-propanes
US3489801 *May 5, 1966Jan 13, 1970Kalle AgN - mono - hydroxyalkylated tertiary aminobenzene compounds and process for the preparation thereof
US4608391 *Apr 16, 1979Aug 26, 1986Cornell Research Foundation Inc.Catecholamine derivatives, a process for their preparation and pharmaceutical compositions thereof
US5220068 *Jan 29, 1991Jun 15, 1993Chinoin Gyogyszer - Es Vegyeszeti Termekek Gyara Rt.Psychostimulant agent
US20100317853 *Feb 1, 2008Dec 16, 2010Yoon Seok OhNovel imatinib camsylate and method for preparing thereof
Classifications
U.S. Classification564/381, 564/454, 564/374
International ClassificationC07C215/08
Cooperative ClassificationC07C215/08
European ClassificationC07C215/08