GB1590903A

GB1590903A - 1,2-disubstituted-1-phenyl-cyclopropane derivatives

Info

Publication number: GB1590903A
Application number: GB179280A
Authority: GB
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 1977-06-23
Filing date: 1977-08-11
Publication date: 1981-06-10
Also published as: IE46235B1

Description

(54) NOVEL 1 ,2-DISUBSTITUTED- 1 -PHENYL- CYCLOPROPANE DERIVATIVES (71) We, AMERICAN CYANAMID COMPANY, a company organised and existing under the laws of the State of Maine, United States of America, of Berdan Avenue, Township of Wayne, State of New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel 1,2-di-substituted - 1 - phenyl - cyclopropane compounds which are useful as intermediates in the preparation of certain therapeutically useful azabicyclohexanes which form the subject of our co-pending Application No. 33818/77 (Serial No. 1,590,901) from which the present Application is divided.

The novel compounds of the present invention are represented by the formula:

wherein the phenyl moiety is unsubstituted or is mono-substituted by halogen, straight chain C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, nitro, amino, acetamido or hydroxy; and W is selected from methanesulfonyloxy, paratoluenesulfonyloxy, chlorine, iodine and bromine.

A preferred embodiment of the invention consists of those compounds wherein the phenyl moiety is mono-substituted at the paraposition by methyl, ethyl, chloro, fluoro, bromo or trifluoromethyl; and W is methanesul fonyloxy.

The invention includes the (+) and (-) isomers of the compounds of formula (I).

Compounds of formula (I) may be prepared by the reaction of diols of the formula:

wherein the phenyl moiety is as defined above, with phosphorous pentabromide, hydrogen bromide, hydrogen iodide, hydrogen chloride-zinc chloride, thionyl chloride, phos phorous pentachloride, methanesulfonyl chloride, or p-toluenesulfonyl chloride.

The above diols of formula (II) may in .tum be prepared from compounds of the formula:

wherein the phenyl moiety is as defined above and R is selected from hydrogen and C1-C alkyl, by reaction with diborane, lithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminum hydride in an aprotic solvent such as diethyl ether, benzene or tetra hvdrofuran at a temnerature of from 0" to 80 C for a period of from one to six hours.

The reaction mixture is cooled and the product is liberated by hydrolysis of the reaction product using acids or bases in a manner known to those skilled in the art.

The diesters above, wherein R is C,CG alkyl, may be prepared by reaction of a bromoester of the formula:

wherein the phenyl moiety is as defined above and R is as defined above, with an acrylic ester of the formula: CH2=CHCOOR (V) wherein R is as defined above, using a base such as lithium hydride, sodium hydride, sodium methoxide, or potassium tert-butoxide in an aprotic solvent such as diethyl ether, benzene, or tetrahydrofuran, as described in U.S. Patent No. 3,344,026. The desired cis isomers are the predominant products of this reaction.

cis-Diacids of the formula:

wherein the phenyl moiety is as defined above, may also be prepared by heating the following compounds with a base such as sodium hydroxide or potassium hydroxide in a solvent such as methanol, ethanol or water at a temperature of from 30 to 1000C, from 3 to 18 hours, followed by liberation of the free diacid with a mineral acid such as hydrochloric acid or sulfuric acid:

wherein U and V are the same or different and are selected from -CO2R1, where R1 is selected from C1-C6 alkyl, and cyano.

As noted, the novel compounds of this invention exist as optical isomers which comprise racemic dextrorotatory and levorotatory forms. This invention contemplates all such isomeric forms. The optical isomers of the compounds of this invention may be prepared by a variety of resolution procedures.

By one method, a cis-diacid of the formula:

wherein the phenyl moiety is as defined above, may be combined with an optically active amine such as ( - ) -a- (1 -naphthyl) ethylamine in a solvent such as methanol, ethanol, acetone, tetrahydrofuran, or acetonitrile to give a salt comprised of one molecular equivalent of the above ( - )-amine. In some cases, and particularly when the phenyl moiety is substituted with an alkyl group, and specifically where the aryl moiety is the p-tolyl group, it is advantageous to use a tetrahydrofuran-ether mixture as the solvent.

The above racemic diacid can also be combined with ( - )-2-amino-1-butanol in a solvent, as previously described, to give a salt wherein the acid moiety is the (+ ) - diacid. The above salts can be converted to the corresponding (+ )-diacid by combination of the shove salts with a base such as sodium hydroxide or potassium hydroxide, ammonium hydroxide or potassium carbonate followed by acidification of the aqueous solution with an acid such as hydrochloric acid or sulfuric acid. For the ( - )-diacid, a cis-diacid of the formula:

may be combined with an optically active amine such as brucine, or (+ )-a-(l- naphtyl) - ethylamine or (+) - 2 - amino- 1-butanol in a solvent, as described above, to give salts wherein the acid moiety is the ( - )-diacid. These salts can be converted to the corresponding (- ) -diacid in the manner described above.

The parent specification contains examples illustrating the resolution procedures described above.

The invention is illustrated by the Example which follows.

EXAMPLE.

A solution of 9.00 g of cis-1-phenyl-1,2- cyclopropanedicarboxylic acid in 100 ml of tetrahydrofuran is added to 180 ml of 1M borane-tetrahydrofuran at 0 C., under nitrogen over 15 minutes. The solution is kept at room temperature for 30 minutes and then is refluxed for 4 hours. After cooling the reaction mixture in ice, 60 ml of 6N hydrochloric acid is added and the tetrahydrofuran is removed under reduced pressure. The aqueous residue is made basic with sodium hydroixde and extracted with ether. The extract is dried over potassium carbonate and the filtered solution is evaporated to give 7.7 g of cis-l-phenyl-l ,2-cyclopropanedimethanol.

A solution of 6.00 g of the above diol in 335 ml of dichloromethane and 14 ml of triethylamine is cooled to - 100C and to this is added 8.45 g of methanesulfonyl chloride over 15 minutes. This is stirred at room temperature for 30 minutes and is then washed with cold dilute hydrochloric acid, then with cold water and finally with 10% sodium bicarbonate solution. The organic solution is dried over magnesium sulfate, and the filtered solution is evaporated to give 8.40 g of the dimethanesulfonate as a pale yellow oil.

WHAT WE CLAIM IS: 1. A compound of the formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. wherein R is as defined above, using a base such as lithium hydride, sodium hydride, sodium methoxide, or potassium tert-butoxide in an aprotic solvent such as diethyl ether, benzene, or tetrahydrofuran, as described in U.S. Patent No. 3,344,026. The desired cis isomers are the predominant products of this reaction. cis-Diacids of the formula: wherein the phenyl moiety is as defined above, may also be prepared by heating the following compounds with a base such as sodium hydroxide or potassium hydroxide in a solvent such as methanol, ethanol or water at a temperature of from 30 to 1000C, from 3 to 18 hours, followed by liberation of the free diacid with a mineral acid such as hydrochloric acid or sulfuric acid: wherein U and V are the same or different and are selected from -CO2R1, where R1 is selected from C1-C6 alkyl, and cyano. As noted, the novel compounds of this invention exist as optical isomers which comprise racemic dextrorotatory and levorotatory forms. This invention contemplates all such isomeric forms. The optical isomers of the compounds of this invention may be prepared by a variety of resolution procedures. By one method, a cis-diacid of the formula: wherein the phenyl moiety is as defined above, may be combined with an optically active amine such as ( - ) -a- (1 -naphthyl) ethylamine in a solvent such as methanol, ethanol, acetone, tetrahydrofuran, or acetonitrile to give a salt comprised of one molecular equivalent of the above ( - )-amine. In some cases, and particularly when the phenyl moiety is substituted with an alkyl group, and specifically where the aryl moiety is the p-tolyl group, it is advantageous to use a tetrahydrofuran-ether mixture as the solvent. The above racemic diacid can also be combined with ( - )-2-amino-1-butanol in a solvent, as previously described, to give a salt wherein the acid moiety is the (+ ) - diacid. The above salts can be converted to the corresponding (+ )-diacid by combination of the shove salts with a base such as sodium hydroxide or potassium hydroxide, ammonium hydroxide or potassium carbonate followed by acidification of the aqueous solution with an acid such as hydrochloric acid or sulfuric acid. For the ( - )-diacid, a cis-diacid of the formula: may be combined with an optically active amine such as brucine, or (+ )-a-(l- naphtyl) - ethylamine or (+) - 2 - amino- 1-butanol in a solvent, as described above, to give salts wherein the acid moiety is the ( - )-diacid. These salts can be converted to the corresponding (- ) -diacid in the manner described above. The parent specification contains examples illustrating the resolution procedures described above. The invention is illustrated by the Example which follows. EXAMPLE. A solution of 9.00 g of cis-1-phenyl-1,2- cyclopropanedicarboxylic acid in 100 ml of tetrahydrofuran is added to 180 ml of 1M borane-tetrahydrofuran at 0 C., under nitrogen over 15 minutes. The solution is kept at room temperature for 30 minutes and then is refluxed for 4 hours. After cooling the reaction mixture in ice, 60 ml of 6N hydrochloric acid is added and the tetrahydrofuran is removed under reduced pressure. The aqueous residue is made basic with sodium hydroixde and extracted with ether. The extract is dried over potassium carbonate and the filtered solution is evaporated to give 7.7 g of cis-l-phenyl-l ,2-cyclopropanedimethanol. A solution of 6.00 g of the above diol in 335 ml of dichloromethane and 14 ml of triethylamine is cooled to - 100C and to this is added 8.45 g of methanesulfonyl chloride over 15 minutes. This is stirred at room temperature for 30 minutes and is then washed with cold dilute hydrochloric acid, then with cold water and finally with 10% sodium bicarbonate solution. The organic solution is dried over magnesium sulfate, and the filtered solution is evaporated to give 8.40 g of the dimethanesulfonate as a pale yellow oil. WHAT WE CLAIM IS:

1. A compound of the formula:

wherein the phenyl moiety is unsubstituted or is mono-substituted by halogen, straight chain C1-C, alkyl, Cl C,. alkoxy, trifluoromethyl, nitro, acetamido or hydroxy; and W is selected from methanesulfonyloxy, para-toluene-sulfonyloxy, chlorine, iodine and bromine.

2. A compound according to Claim 1 wherein the phenyl moiety is unsubstituted or is mono-substituted at the para-position by methyl, ethyl, chloro, fluoro, bromo, or trifluoromethyl, and W is methanesulfonyloxy.

3. An optically active form of a compound according to Claim 1 or Claim 2.

4. A method of preparing a compound as defined in Claim 1, which comprises reacting a diol of the formula:

wherein the phenyl moiety is as defined in Claim 1 with phosphorus pentabromide, hydrogen bromide, hydrogen iodide, hydrogen chloride-zinc chloride, thionyl chloride, phosphorus pentachloride, methanesulfonyl chloride or p-toluenesulfonyl chloride.

5. A method according to Claim 4, wherein said diol is prepared by reacting an acid or ester of the formula:

wherein the phenyl moiety is as defined in Claim 1, and R is selected from hydrogen and C1C, alkyl, with diborane, lithium aluminium hydride or sodium bis(2-methoxyethoxy) aluminium hydride in an aprotic solvent at a temperature of from 0 to 80"C for from one to six hours; cooling the thusobtained reaction mixture; and hydrolysing the reaction product with an acid or a base.

6. A method according to Claim 5, wherein R is hydrogen and wherein said acid is in the form of a ( + )- or (- )-optical isomer obtained by (+)- or (-)a(1-naphthyl)- ethylamine in an organic solvent, to produce a solid; collecting said solid and slurrying it in water; basifying; extracting with diethyl ether; and acidifying.

7. A method according to Claim 6, wherein said organic solvent comprises tetrahydrofuran.

8. A method according to Claim 6 or Claim 7, wherein said acid is (+)- or ( - )-cis l-p-tolyl-1,2-cyclo-propane-dicarboxylic acid.

9. A method of preparing a compound as defined in Claim 1, substantially as described in the Example herein.

10. A compound as defined in Claim 1, whenever prepared by a method according to any one of Claims 4-9.