GB2305171A

GB2305171A - Diester intermediates

Info

Publication number: GB2305171A
Application number: GB9611512A
Authority: GB
Inventors: Mark Anthony Ashwell
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1992-10-17
Filing date: 1993-10-08
Publication date: 1997-04-02
Anticipated expiration: 2013-10-08
Also published as: GB2305171B; GB9611512D0

Abstract

Diesters of formula: where R 1 is aryl or heteroaryl; R 2 is hydrogen or lower alkyl; R 3 is hydrogen, C 1-10 alkyl, C 3-12 cycloalkyl, cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; or R 2 and R 3 together with the adjacent N atom form a saturated heterocyclic ring optionally containing a further hetero atom; and R 4 and R 5 are C 3-6 alkyl, are intermediates in the production of heterocyclic amides.

Description

AMIDE DERIVATIVES This invention relates to a novel asymmetric synthesis for preparing amide derivatives and to intermediates useful in the synthesis.

The invention particularly relates to a process for preparing optically active amides of the general formula

and the pharmaceutically acceptable salts thereof.

In formula A, X represents

R represents a mono or bicyclic aryl or heteroaryl group, R1 is an aryl or heteroaryl radical, R is hydrogen or lower alkyl1 3.

R is hydrogen, an alkyl group of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl (lower)alkyl, aryl or aryl(lower)alkyl or R2 and R together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom [eg an azetidino, pyrrolidino, piperidino, hexahydroazepino, heptamethyleneimino, morpholino or piperazino ring which may be optionally substituted by, for example, lower alkyl, aryl, aryl(lower)alkyl, lower alkoxy, halogen or halo(lower)alkyl].

The term lower as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl and isopentyl.

When R is an alkyl group a particularly preferred radical is a tertiary alkyl radical such as tert.butyl.

A cycloalkyl group can contain 3 to 12 carbon atoms.

Preferably a cycloalkyl group is cyclopentyl, cyclohexyl or cycloheptyl, most preferably cyclohexyl.

Cycloalkyl groups also include bicyclic, tricyclic and tetracyclic groups, eg adamantyl.

When used herein aryl means an aromatic radical having 6 to 12 carbon atoms (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents commonly used in medical chemistry, eg substituents such as lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), loweralkylthio, halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, cyano, carboxamido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino substituents. Two substituents on the aromatic ring may be connected together to form another ring system.

For example R may be a bicyclic oxygen-containing radical such as a optionally substituted radical of the formula

The term "heteroaryl" refers to an aromatic radical containing one or more hetero atoms (eg oxygen, nitrogen, sulphur) and which may be optionally substituted by one or more substituents. Some examples of suitable substituents are given above in connection with aryl radicals. The heteroaryl radical may, for example, contain up to 10 ring atoms; for example the heteroaryl radical may be a monocyclic radical containing 5 to 7 ring atoms. Preferably the hetero ring contains a nitrogen hetero atom with or without one or more further hetero atoms.

When R is a heteroaryl radical it is preferably an optionally substituted pyrimidyl (particularly 2-pyrimidyl), quinolinyl or indolyl [particularly indol-4-yl which may be optionally substituted eg by (lower)alkoxycarbonyl] radical.

When R is a heteroaryl or heteroaryl-lower alkyl the heteroaryl group is preferably a nitrogen containing heteroaryl radical (eg an optionally substituted pyridinyl, pyrimidinyl or pyrazinyl radical) or a heteroaryl radical containing an oxygen or sulphur atom as a hetero atom eg an optionally substituted thienyl or furyl group.

Preferred compounds of formula A have the following characteristics either singly or in any possible combination: (a) X is

(b) R is optionally substituted phenyl, eg o-alkoxy-phenyl (particularly o-methoxyphenyl) (c) R1is phenyl (d) R and R together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring, particularly hexahydroazepino.

Compounds of formula (A) are useful because of their pharmacological activity, eg as 5-HTlA-antagonists.

The compounds and their uses are disclosed, for example, in GB 2230780 A, GB 2230781 A, GB 2248836 A, GB 2254324 A, GB 2262093 A and WO-GB 93/01542. The prior specifications refer to the preparation of enantiomers by, for example1 resolution of the racemates. The process of the present invention avoids the inconvenient resolution step.

The invention particularly relates to a process for preparing (-)-(R)-2,3,4,5,6,7-hexahydro- -1-[4-[4- (2-methoxyphenyl)piperazin-l-yl]-2-phenyl)-butanoyl-lH azepine and the pharmaceutically acceptable acid addition salts thereof. The compound, in its free base form, has the formula

The compound and its use as a 5-HTlA-antagonist is disclosed in GB-A-2248836. Example 2(a) of GB-A-2248836 describes the preparation of the compound and its salts by resolution of a corresponding racemate.

It has now been found that compound (I) can be prepared in good yield by an asymmetric synthesis from readily available starting materials thus avoiding an inconvenient resolution step.

An essential step in the synthesis of the present invention which forms the first aspect of the present invention, is a process which comprises condensation of an aldehyde of formula

(where R, R and R are as defined above) with an amine of formula

(where X and R are as defined above) to give the compound of formula (A). For example an amine of formula

may be condensed with a piperazine derivative of formula

to give the compound of formula (I). We have found that the stereochemisty of the aldehyde is retained during the condensation to give the desired enantiomeric form of the product in good yield. In contrast if for example the piperizine (III) is condensed with an entantiomeric form of an alkylating agent of formula

where X is halogen, racemisation occurs during the reaction.

The condensation of the aldehyde of formula (B) with the piperazine of formula (C) may be carried out, for example, in presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.

The aldehyde of formula (B) may be prepared by a process which comprises hydrolysing a diester of formula

(where R, R and R are as defined above and R4 and R5 are each lower alkyl groups of 3 to 6 carbon atoms) to give a diacid amide of formula

(where R, R and R are as defined above), decarboxylating the diacid amide of formula (E) to give the monoacid amide of formula

(where R1, R2 and R3 are as defined above) and reducing the monacid amide of formula (F) to the aldehyde of formula (B).

Preferably R and R5 are both branched chain alkyl groups such as isopropyl or, more preferably, tertiary butyl.

The hydrolysis of the diester can be effected with an acid, e.g. formic acid, trifluoroacetic acid.

The diacid amide need not be isolated before carrying out the decarboxylation process. The decarboxylation may be carried out by heating the diacid amide in an inert solvent, e.g. acetonitrile, optionally in presence of a catalytic amount of Cm20.

The monacid amide (F) may be reduced directly to the aldehyde (B) with, for example, an aminoalane, but it is prefered to reduce the monoacid amide to the alcohol of formula

and then oxidise the alcohol (G) to the aldehyde (B).

The reduction to the alcohol may be effected by using a reducing agent that does not reduce the amide group, e.g. reduction with Me2S.BH3, preferably in the presence of BF3.Et2O, or alternatively activation of the monoacid amide by reaction with bis-succinimido carbonate followed by reduction with NaBH4. The oxidation of the alcohol (G) to the aldehyde (B) may be effected with, for example, tetra-n-propylammonium per-ruthenate, DMSO, oxalyl chloride triethylamine.

The diesters of formula (D) are novel compounds provided by the invention. Particularly preferred are the diesters of formula

(where R4 and R5 are as defined above). These are used as intermediates for the compound of formula (I).

The diesters of formula (D) may be prepared by a novel process which comprises reacting an activated hydroxy amide of formula

(where R, R and R are as defined above and R6 is an activating group which maintains chirality such as an arylsuphonyl group, e.g. p-toluenesulphonyl) with a dialkylmalonate of formula

where R4 and R5 are as defined above. The dialkylmalonate is preferably reacted in the form of its sodium or potassium salt. It has been found that the reaction is stereospecific with inversion of the centre at the benzylic position to give the desired stereochemistry in the diester (D).The stereospecificity of the process is surprising since the compound of formula (H) has an aryl or heteroaryl group and an amide group which would be expected to produce a much more acidic proton (in the benzylic position) than the corresponding proton in the prior art compound in which equivalent groups are respectively alkyl and ester (M. Larcheveque et al, Synthesis, February 1991, 162-164). The more labile proton would have been expected to give rise to a racemic product.

The activated a-hydroxy amides of formula (H) can be prepared from the S-(+)-mandelic acid derivatives of formula

(where R is as defined above) for example the hydroxy groups of S-(+)-mandelic acid of formula

may be protected to give a protected derivative of formula

(where R7 is a protecting group such that OR7 is stable when -COOR is converted to -COhalogen), halogenating the protected derivative (VI) to give an acyl halide of formula (VII)

(where R7 is as defined above and Z is chlorine or bromine), reacting the acyl halide (VII) with an amine of formula NHR2R3 (where R2 and R3 are as defined in claim 1) to give the protected hydroxy amide

(where R2, R3 and R7 are as defined above), removing the protecting group from the protected hydroxy amide (VIII) to give the hydroxy amide (IX)

(where R, and R are as defined above), and activating the hydroxy amide (IX) to give the a-activated hydroxy amide (H).

The prefered protecting groups, R7, for S-(+)-mandelic acid are trimethysilyl or tertbutyldimethylsilyl. The mandelic acid may, for example, be reacted with 1,3-bis(trimethylsilyl)urea or with tert.butyldimethylsilyl chloride.

The protected derivative (VI) may be halogenated with, for example, oxalyl chloride to give an acyl halide (VII) where Z is chlorine or, more preferably with triphenyl phosphine/bromine to give an acyl halide (VII) where Z is bromine. The acyl halide (VII) need not be isolated before reaction with the amine (eg hexamethyleneimine).

The protecting group R7 may be removed from the protected hydroxy amide (VIII) with an acid e.g. citric acid.

The hydroxyamide (VIII) may be activated with a reagent that does not destroy the chirality of the compound.

Suitable reagents include arylsulphonic anhydrides (e.g. p-toluenesulphonic anhydride) and methanesulphonic anhydride.

The processes desribed above may be carried out to give a product in the form of a free base or as an acid addition salt. If the product is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt.

Conversely, if the product of the process is a free base an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, p-toluenesulphonic, oxalic and succinic acids.

The following examples illustrate the invention.

Example 1 (S)-Bis(trimethylsilyl)mandelic acid To a solution of (S)-(+)-mandelic acid (62.49g, 0.41mol) in dry dichloromethane (250ml) was added l,3-bis(trimethylsilyl)urea (88.40g, 0.41mol). The reaction mixture was stirred for twenty four hours at room temperature under argon. The suspension was refluxed for twelve hours.

The suspension was allowed to cool. Celite was added and the suspended urea removed by suction through a bed of Celite. The dichloromethane solution was filtered directly into the suspension of triphenyl phosphine dibromide prepared in Example 2.

Example 2 (S)-2,3,4,5,6,7-Hexahydro-1-(2-trimethylsilyloxy- 2-phenyl )ethanoyl-lH-azepine To a stirred, ice cooled solution of triphenyl phosphine (107.54g, 0.41mol) in dry dichloromethane (400ml) was added dropwise bromine (21.lml, 0.41ml) under argon. Following the addition the cooling bath was removed and the reaction mixture obtained in Example 1 filtered directly into the freshly prepared triphenyl phosphine dibromide suspension.

The reaction mixture was stirred under argon at room temperature until it became homogeneous. The cooling bath was returned and hexamethyleneimine (143ml, 1.27mol) added dropwise over forty five minutes. Following addition the cooling bath was removed and the reaction mixture allowed to attain room temperature.

After a further hour the solvent was removed and the solid extracted with hexane (2 x 1.51). This was filtered by suction through Celite. The solvent was removed and the residue distilled under vacuum.

At 0.5m bar: 125-1550C discarded 155-1650C main fraction (86.77g, 69%) Example 3 (S)-2,3,4,5,6,7-Hexahydro-1-(2-hydroxy-2- phenyl)ethanoyl-lH-azepine The OTMS ether obtained in Example 2 (86.77g, 0.284mol) was dissolved in methanol (200ml) and catalytic citric acid added. The solvent was removed and the residue dissolved in dichloromethane. This was washed with sodium bicarbonate, saturated sodium chloride solution, dried (MgS04)and reduced under vacuum. The colourless oil was distilled under vacuum.

At 0.35m bar: 134-1380C (62.9g,95%) Example 4 (S)-2,3,4,5,6,7-Hexahydro-1-(2-p-toluenesulphonylOxy- 2-phenyl)ethanoyl-1H-azepine The a-hydroxy amide from Example 3 (34.88g, 150mmol) was stirred in dry dichloromethane (250ml) under argon. To this solution was added p-toluenesulphonic anhydride (50.31g, 150mmol).

Pyridine (12.lml, 156mmol) was added over one hour.

The reaction mixture was stirred for eighteen hours at room temperature.

The dichloromethane solution was washed with cold HC1 (1N), saturated sodium chloride solution and dried (MgSO4). Removal of the solvent gave a solid which was recrystallised from acetone. The supernatant was taken to dryness and recrystallised from acetone/hexane. A combined mass of 47.0g (81%) was obtained.

Example 5 (R)-2,3,4,5,6, 7-Hexahydro-l- (3-di-tert- butylcarboxylate)propanoyl-1H-azepine To a stirred solution of di-tert-butyl malonate (9.53m1, 45.6mmol) in dry N,N-dimethylformamide (80ml) under argon was added sodium hydride (1.21g, 40.3mmol, 80% suspension in oil) in two portions over a period of ninety minutes. After complete reaction of the sodium hydride had taken place the solution was warmed to 80oC and the tosylate from Example 4 (15.0g, 38.7mmol) added immediately as a hot solution in dry N,Ndimethyformamide (20ml).

The reaction was stirred at this temperature for a further two hours. The solution was allowed to cool to room temperature. Water was added followed by hexane. The hexane was removed and the aqueous layer extracted with two further portions of hexane. The organic layers were combined, washed with saturated sodium chloride solution, dried (MgSO4) and reduced under vacuum.

The solid residue was recrystallised from hexane to afford 5.93g. The supernatant was purified by pressure silica gel column chromatography eluting with hexane/diethyl ether (2/1) to give after recrystallisation a further 3.3g. A total of 9.23g (55%) was thus obtained.

Example 6 (R)-2,3,4,5,6,7-Hexahydro-1-(3-carboxy-2- phenyl)propanoyl-lH-azepine The di-tert-butyl ester from Example 5 (9.64g, 22.3mmol) was added to formic acid (75ml) cooled to OoC with stirring. The cooling bath was removed and stirring continued for three hours. The solvent was removed under reduced pressure (bath temperature less than 400C). Dichloromethane was used to co-evaporate the formic acid and a stable white foam was obtained.

The foam was dissolved in dry acetonitrile and refluxed under argon for three hours. The solution was allowed to cool overnight.

The solvent was removed and the oily residue taken up in dichloromethane. The acid was removed by extraction with sodium hydroxide (10%) (2Oml) The aqueous layer was washed with ether and then taken to pH6 by the careful addition of cold HC1 (1N). The mono-acid was extracted with ether, washed with saturated sodium chloride solution, dried (MgS04)and reduced under vacuum to a colourless oil (4.95g, 81%).

Example 7 (R)-2 ,3,4,5,6, 7-Hexahydro-1- ( 4-hydroxy-2- phenyl)butanoyl-lH-azepine To a solution of the acid from Example 6 (approx.

80% chemically pure, > 95% (R) (315mg,1.15mmol) in dry THF at room temperature under argon was added BF3 Et20(183ul, 1.5mmol). The solution was stirred for ten minutes before adding Me2S.BH3 in THF (2M) (744m1, 15mmol). The reaction mixture was stirred at room temperature for four hours. Water was added cautiously and the volatiles removed.

The residue was partitioned between ether and saturated sodium bicarbonate solution. The ether layer was further washed with saturated sodium chloride solution and dried (MgS04). Removal of the solvent following filtration gave the alcohol (200mg, 67%).

Example 8 (R)-2,3,4,5,6,7-Hexahydro-l-(3-carboxaldehyde 2-phenyl )propanoyl-lH-azepine The alcohol from Example 7 (226mg, 0.86mmol) was dissolved in dry dichloromethane (8ml) at room temperature under argon, N-methylmorpholine N-oxide (152mg, 1.29mmol) and 4 -molecular sieves added with stirring. After ten minutes tetra-n-propylammonium per-ruthenate (15mg, 0.043mmol) was added.

Stirring was continued for four hours. The reaction was diluted with dichloromethane (30ml) and washed successively with saturated sodium sulphite solution (10ml) saturated sodium chloride solution (lOml) and saturated copper (II) sulphate (lOml). The organic layer was dried (MgS04),filtered and used without further purification in Example 9.

Example 9 (-)-R-2,3,4,5,6,7-Hexahydro-3-[4-[4-(2-methoxyphenyl)- piperazin-l-yl]-2-phenylgbutanoyl-lH-azepine To the solution of aldehyde produced in Example 8 maintained at room temperature under argon was added l-(2-methoxyphenyl)piperazine (165mg, 0.86mmol) and sodium triacetoxyborohydride (182mg, 0.86mmol) followed by acetic acid (98u1, 1.72mmol).

The reaction mixture was stirred for three hours.

The reaction mixture was washed with saturated sodium bicarbonate (10ml), saturated sodium chloride solution (lOml), dried (MgSO4), and reduced in vacuo. The resulting oil was purified by flash chromatrography eluting with dichloromethane/methanol (20/1) to give the title compound.

The material was shown to be identical to an authentic sample by H, C NMR, IR and chiral stationary phase HPLC.

Claims

1. A process for preparing a diester of general formula (D)

wherein: R1 is an aryl or heteroaryl radical, R2 is hydrogen or lower alkyl, R3 is hydrogen, an alkyl group of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl- (lower)alkyl, aryl or aryl(lower)alkyl or R2 and R3 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom and R4 and R5 are each lower alkyl groups of 3 to 6 carbon atoms) which comprises reacting an activated alpha-hydroxy amide of formula

(where R11 R2 and R3 are as defined above and R6 is an activating group which maintains chirality) with a dialkylmalonate of formula

(where R4 and R5 are as defined above).

2. A process according to claim 1 in which the activated alpha-hydroxy amide of formula (H) where R1 is phenyl is prepared by protecting the hydroxy groups of S-(+)-mandelic acid of formula

to give a protected derivative of formula

(where R7 is a protecting group), halogenating the protected derivative (VI) to give an acyl halide of formula (VII)

(where R7 is as defined above and Z is chlorine or bromine), reacting the acyl halide (VII) with an amine of formula NHR2R3 (where R2 and R3 are as defined in claim 1) to give a protected hydroxy amide of formula

(where R2, R3 and R7 ae as defined above), removing the protecting group from the protected hydroxy amide (VIII) to give the hydroxy amide (IX).

(where R2, and R3 are as defined above), and activating the hydroxy amide (IX) to give the alpha-activated hydroxy amide of formula (H).

3.. A process as claimed in claim 1 or claim 2 in which X is

4. A process as claimed in any one of claims 1 to 3 in which R is o-methoxyphenyl.

5. A process as claimed in any one of claims 1 to 4 in which R1 is phenyl.

6. A process as claimed in any one of claims 1 to 5 in which R2 and R3 together with the nitrogen atom to which they are both attached represent hexahydroazepino.

7. A diester of formula (D)

(where R1, R2 and R3 are as defined in claim 1 and R4 and R5 are each lower alkyl groups of 3 to 6 carbon atoms).

8. A diester when prepared by the process claimed in any one of claims 1 to 4 and 7.

8. A diester as claimed in claim 7 of formula

(where R4 and R5 are as claimed in claim 7).

9. A process for preparing a diester of formula (D) as defined in claim 1 substantially as herein before described with reference to Example 5.

10. A diester when prepared by the process claimed in any one of claims 1 to 6 and

9.

Amendments to the claims have been filed as follows 1. A process for preparing a diester of general formula (D)

wherein: R1 is an aryl or heteroaryl radical; R2 is hydrogen or lower alkyl; R3 is hydrogen, an alkyl group of 1 to 10 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, cycloalkyl- (lower)alkyl, aryl or aryl(lower)alkyl; or R2 and R3 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom; and R4 and R5 are each alkyl groups of 3 to 6 carbon atoms; which comprises reacting an activated alpha-hydroxy amide of formula

(where R1, R2 and R3 are as defined above and R6 is an activating group which maintains chirality) with a dialkylmalonate of formula

(where R4 and R5 are as defined above).

to give a protected derivative of formula

(where R7 is as defined above and-Z is chlorine or bromine), reacting the acyl halide (VII) with an amine of formula NHR2R3 (where R2 and R3 are as defined in claim 1) to give a protected hydroxy amide of formula

(where R2, R3 and R7 are as defined above), removing the protecting group from the protected hydroxy amide (VIII) to give the hydroxy amide (IX).

3. A process as claimed in claim 1 or claim 2 in which R1 is phenyl.

4. A process as claimed in any one of claims 1 to 3 in which R2 and R3 together with the nitrogen atom to which they are both attached represent hexahydroazepino.

5. A diester of formula (D)

(where R1, R2 and R3 are as defined in claim 1 and R4 and R5 are each alkyl groups of 3 to 6 carbon atoms).

6. A diester as claimed in claim 5 of formula

(where R1 R4 and R5 are as defined in claim 5).

7. A process for preparing a diester of formula (D) as defined in claim 1 substantially as herein before described with reference to Example 5.