SK287537B6 - Method of producing N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenylpropylamine in its racemic or optically active form - Google Patents

Abstract

Disclosed is a process for preparing N,N-diisopropyl-3-(2- hydroxy-5-methylphenyl)-3-phenylpropyl amine (tolterodine) of formula (I) in racemic or optically active form thereof wherein the preparation process comprises synthesis of enantiomerically enriched compounds (R)- and (S)-3,4-dihydro-6-methyl-4-phenyl-2H- benzopyran-2-one of the general formulae (II-R) and (II-S) and preparation of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol in racemic or enantiomerically enriched form of formulae (VIII) or (VIII-R) and (VIII-S), protected on both oxygen atoms with sulfoester group.

Description

The present invention relates to a novel process for the preparation of N, N -diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine of formula (I)

in its racemic or optically active form.

BACKGROUND OF THE INVENTION

The optically active compound of formula (I), namely (R, N - N, N, N -diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine, often called tolterodine, is in the form of an acid salt. tartrate, such as (R) -tolterodine L-tartrate, used to treat overactive bladder associated with urgency and numerous urination including incontinence.

Tolterodine was first described in U.S. Pat. No. 5,382,600, which also describes a process for its preparation. This process starts from 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of formula (II)

This compound is reacted with methyl iodide and potassium carbonate in refluxing acetone to give methyl 3- (2-methoxy-5-methylphenyl) -3-phenylpropionate of formula (III)

which is reduced with lithium aluminum hydride to give 3- (2-methoxy-5-methylphenyl) -3-phenylpropanol of formula (IV)

The hydroxy group of the compound of formula (IV) is reacted with p-toluenesulfonyl chloride to convert the hydroxy group to a toluenesulfonyl group. This conversion allows further nucleophilic substitution with diisopropylamine in hot acetonitrile to give a methoxy analog of tolterodine of formula (V)

Further, to form the racemic compound of formula (I), it is necessary to remove the methyl protecting group, which is carried out with boron tribromide (boron tribromide) in dichloromethane. The final step is cleavage with tartaric acid.

This procedure is relatively lengthy and uneconomical. Its significant disadvantage is also the use of hazardous methyl iodide, lithium aluminum hydride and boron tribromide.

An alternative procedure is described in U.S. Pat. No. 5,922,914. The same starting compound, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of formula (II), is reduced according to this patent by a metal hydride, preferably diisobutylaluminium hydride (DIBAL) at less than -20 ° C. At this temperature, the keto group is reduced without opening the lactone cycle to give 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol. In the last step, a reductive amination of the product with diisopropylamine is carried out under elevated hydrogen pressure and catalysis of palladium on activated carbon. This procedure removes the shortcomings of the previous procedure. The inconvenience here is the low reduction temperatures and the use of the self-igniting catalyst in pressure reductive amination.

A third method is described in patent application WO 03/014060. This is an improvement to the process of the basic patent US 5382600. Compound II in this case reacts with dimethyl sulfate in the presence of sodium hydroxide and a phase transfer catalyst to form a compound of formula (III). The reduction of the compound of formula (III) is carried out with sodium borohydride in the presence of Lewis base (aluminum chloride). The resulting compound of formula (IV) is further processed by a known method.

The process of the invention combines the simplicity of the second process of US 5922914 with less demanding reaction conditions according to WO 03/014060.

WO 01/49649 describes the preparation of (R) - and (S) -3,4-dihydro-6-methyl-4-phenyl-2 H -benzopyran-2-one of formula (Π-R), respectively. (II-S)

(II-R)

by 5-step synthesis from 2-bromo-4-methylacetophenone using chiral catalysts in 54% yield with an optical purity of 89% ee.

According to our earlier results (not yet published), for the production of tolterodine, it is possible to use a process starting from (7R) -3- (2-alkyloxy-5-methylphenyl) -3-phenylpropanoic acid which is converted to tolterodine by amination, reduction and finally deprotection. . The application opens the possibility of applying these synthetic methods to optically active intermediates of tolterodine.

The present invention follows the possibility of processing optically active intermediates of tolterodine, but introduces completely new synthetic methods, also applicable to racemic mixtures followed by resolution.

SUMMARY OF THE INVENTION

The preparation of N, N -diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine in its racemic or optically active form according to the invention is shown in Scheme I and involves (a) improved synthesis of enantiomerically enriched (R) - and (S) -3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one from (R) - and (S) -3- (2-alkyloxy-5-methylphenyl) - 3-phenylpropanoic acid of formula (VI-R) and (VI-S)

wherein R 1 is C 1 -C ₄ alkyl or benzyl, (b) reducing the racemic or enantiomerically enriched (R) - or (S) -3,4-dihydro-6-methyl-2H-benzopyran-2-one of formula ( II), respectively. (II-R) or (II-S)

(H) II-R

to form a racemic or enantiomerically enriched (R) - or (Sy-5- (2-hydroxy-5-methylphenyl) -3-phenyl propanol of formula (VII), respectively (VII-R) or (VII-S)

(c) reacting compounds of formula (VII) or (VII-R), or (VII-S) with sulfonic acid derivatives thereby introducing protective groups X selected from the group consisting of toluenesulfonyl, methanesulfonyl, camphorsulfonyl to form derivatives of the general formulas (VIII), (VIII-R) and (VIII-S)

(d) reacting a compound of formula (VIII) or optically active forms of formula (VIII-R) or (VIII-S) with diisopropylamine to give N, N -diisopropyl-3- (2-X-oxy-5-methylphenyl) -3 -phenylpropylamine of formula (IX), respectively; (IX-R) or (IX-S)

(IX) (IX-R) (IX-S), wherein X is the same as in formula (VIII), (e) and subsequent deprotection to give the compound of formula (I) in racemic or corresponding enantiomeric form.

The sequence of reactions utilizes selective reductive opening of the lactone cycle, instead of the previously described reduction of 10 carbonyl. The reductive opening of the lactone cycle occurs with a compound of formula (II) or (II-R), or (Π-S) by reaction with a metal hydride, preferably bis- (2-methoxyethoxy) -aluminium dihydride. For esterification of the hydroxy groups in the compound of formula (VII) or its enantiomers of formulas (VII-R) and (VII-S), a sulfoester group is used which acts as a protecting group on the aromatic ring and a good leaving group for the aliphatic chain for reaction with the secondary amine. Using the same functional group 15 as both a protective and an activating process simplifies the complex work of introducing and removing the methyl group on the aromatic ring according to previous work (a variant is shown in Scheme 1). In a further embodiment of this variant, the nucleophilic substitution is carried out in a known manner, i.e. under pressure at a temperature of about 100 ° C for about 24 to 72 hours. This substitution is completely selective for the aliphatic hydroxy group. The sulfo protecting group is removed by acidic or alkaline hydrolysis to give phenol. The resulting racemic or (R) - or (S) -tolterodine is then reacted with L (+) - tartaric acid in a known manner. In the case of racemic tolterodine, the diastereoisomeric salt formed is separated by crystallization.

The reaction of (a) is preferably carried out in a solvent such as a lower C 1 -C ₄ carboxylic acid, in the case where R is benzyl, preferably in acetic acid; or in lower alcohols C 1 to C ₄ , or in another solvent using catalysts such as noble metals, preferably palladium, at a temperature of 20 to 100 ° C 25 and a hydrogen pressure of 1 to 10 MPa. The reduction according to b) is preferably carried out with a metal hydride selected from the group consisting of lithium aluminum hydride, bis- (2-methoxyethoxy) aluminum dihydride and diisobutylaluminium hydride. 3- (2-tosyloxy-5-methylphenyl) -3-phenyl-O-tosylpropanol is preferably used as the compound of formula (VIII).

The invention also relates to key intermediates of the disclosed method not yet described. This is primarily the product of the reductive opening of the lactone cycle - 3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol, both in the racemic form of formula (VII) and in the enantiomerically enriched forms of formula (VII-R), respectively. (VII-S). Further, the products of its reaction with sulfonic acid derivatives of formula (IX) or in enantiomerically enriched forms of formula (IX-R), respectively. (IX-S).

Scheme 1

The scheme applies to both racemic and enantiomerically enriched forms

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention sufficiently, but do not limit it in any way.

Example 1: (R, 3,4-Dihydro-6-methyl-4-phenyl-2 H -benzopyran-2-one (II-R)

A stirred solution of 69 g of (R) -3- (2-benzyloxy-5-methylphenyl) -3-phenylpropanoic acid (VI-R) in 300 ml of acetic acid is bubbled with nitrogen, then 14 g of catalyst (5% Pd / C) and then hydrogen gas at atmospheric pressure was bubbled through a gentle stream at 70 ° C for 5 h, the mixture was bubbled briefly with nitrogen, filtered, the filter cake was washed with acetic acid and the filtrate was evaporated. g (91%), 92% ee (ChiralCel OD-H, hexane / 2-propanol 95/5), mp 101-103 ° C.

Example 2: 3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol (VII)

23.8 g (0.1 mol) of 3,4 dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (II) dissolved in 100 ml of dried toluene in a 500 ml three-necked flask equipped with a thermometer separating Cool to -5 ° C via funnel and chlorocalcium plug. While cooling, 100 ml of a 3.5M solution of Red-Al (bis- (2-methoxyethoxy) aluminum dihydride) in toluene is added dropwise and stirred for 1 hour. The excess reducing agent was then quenched with hydrochloric acid, the toluene layer was separated, washed with water and the solvent was evaporated. The product is obtained in a yield of 90%, a crystalline white solid, b. t. 112.8-113.4 ° C.

Example 3: 3- (2-tosyloxy-5-methylphenyl) -3-phenyl-O-tosylpropanol (VIII. X = tosyl)

12.1 g (0.05 mol) of 3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol (VII) are dissolved in 40 ml of tetrahydrofuran, 50 ml of 1M NaOH solution are added and the mixture is cooled to -5 ° C. C. While cooling, 9.5 g (0.05 mol) of toluenesulfonyl chloride dissolved in 50 ml of tetrahydrofuran was added dropwise. The mixture is stirred for 1 hour, then diluted with 100 ml of distilled water and the product is extracted into dichloromethane. The dichloromethane solution was concentrated to a volume of 50 mL, cooled to -5 ° C and 12 mL of pyridine was added. While cooling, 11.3 g (0.06 mol) of toluenesulfonyl chloride dissolved in 50 ml of dichloromethane are added dropwise. Store the solution in the refrigerator the next day. The reaction mixture was then diluted with 200 mL of distilled water. The organic phase is separated and extracted with 3 x 50 ml of 1M HCl and 3 x 50 ml of distilled water. Evaporation of the solvent gave an oily product in 94% yield.

Example 4: 3- (2-tosyloxy-5-methylphenyl) -3-phenyl-O- (1 H) - (-) - camphor-10-sulfonylpropanol (VIII, X = camphor-10-sulfonyl)

12.1 g (0.05 mol) of 3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol (VII) are dissolved in 40 ml of tetrahydrofuran, 50 ml of 1M NaOH solution are added and the mixture is cooled to -5 ° C. C. While cooling, 9.5 g (0.05 mol) of toluenesulfonyl chloride dissolved in 50 ml of tetrahydrofuran was added dropwise. The mixture is stirred for 1 hour, then diluted with 100 ml of distilled water and the product is extracted into dichloromethane. The dichloromethane solution was concentrated to a volume of 50 mL, cooled to -5 ° C and 12 mL of pyridine was added. While cooling, 15.0 g (0.06 mol) of (17 R) - (-) - camphor-10-sulfonyl chloride dissolved in 50 ml of dichloromethane are added dropwise. Store the solution in the refrigerator the next day. The reaction mixture was then diluted with 200 mL of distilled water. The organic phase is separated and extracted with 3 x 50 ml of 1M HCl and 3 x 50 ml of distilled water. After evaporation of the solvent, the product is obtained in a yield of 81%. The material was crystallized from methanol.

Example 5: N, N -diisopropyl-3- (2-tosyloxy-5-methylphenyl) -3-phenylpropylamine (IX) g (0.047 mol) 3- (2-tosyloxy-5-methylphenyl) -3-phenyl-O- tosylpropanol is dissolved in 40 ml of acetonitrile and 47.8 g (0.47 mol) of diisopropylamine are added. The solution was placed in an autoclave and heated at 110 ° C for 50 hours. The precipitated toluenesulfonic acid salt was filtered off and the solvent was evaporated. The residue is dissolved in 150 ml of dichloromethane and extracted with 3 x 100 ml of 1M HCl and 3 x 100 ml of distilled water. Evaporation of the solvent gave oily product IX in 85% yield.

Example 6: N, N-Diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine I

19.2 g (0.04 mol) of N, N -diisopropyl-3- (2-tosyloxy-5-methylphenyl) -3-phenylpropylamine (IX) are dissolved in 100 ml of ethanol and 100 ml of 5M NaOH are added. The reaction mixture was refluxed for 2 hours. The ethanol is evaporated and the residue is diluted with 100 ml of distilled water and extracted 3 times with dichloromethane. After evaporation of the solvent, an oily product is obtained in a yield of 80%.

Example 7: (R) -N, N-Diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine (I-R) L-hydrogen tartrate

9.6 g (0.02 mol) of (R) - N, N -diisopropyl-3- (2-tosyloxy-5-methylphenyl) -3-phenylpropylamine (IX-R) are dissolved in 50 ml of ethanol and 50 ml of ethanol are added. mL of 5M NaOH. The reaction mixture was refluxed for 2 hours. The ethanol is evaporated and the residue is diluted with 50 ml of distilled water and extracted with 3 x 50 ml of dichloromethane. After evaporation of the solvent, the residue was dissolved in 25 ml of ethanol and slowly added to a solution of 2.4 g (0.016 mol) of L-tartaric acid in 60 ml of ethanol. After standing for 16 h at 4 ° C, the precipitated crystals are sucked off and washed with cold ethanol. It will be obtained

6.6 g (70.2% on 1X-R) of (R) -tolterodine (L) -tartrate, 1.1. Mp 210-211 ° C, [α _D ] = + 27.4 ° (c = 1, methanol).

PATENT CLAIMS

Claims (7)

A process for the preparation of N, N -diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine in its racemic (D (I-R) (1-S)), characterized in that it comprises a) synthesis of enantiomerically enriched compounds (R) - and (S) -3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one of formula (II-R), respectively; and (II-S), optionally a racemic mixture of formula (II) (HR) (II-S) of (R) - and (S) -3- (2-alkyloxy-5-methylphenyl) -3-phenylpropanoic acid of general formula of formula (VI-R), respectively. (VI-S), optionally from a racemic mixture of formula (VI) wherein R 1 is C 1 -C ₄ alkyl or benzyl, O-dealkylation and subsequent in situ cyclization, Ί b) reduction of 3,4-dihydro-6-methyl-2H-benzopyran-2-one of formula (II), respectively. (II-R) or (II-S) to give 3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol of formula (VII), respectively. (VII-R) or (VII-S) c) reacting 3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol of formula (VII), respectively; (VII-R) or (VII-S) with sulfonic acid derivatives to form compounds of formulas (VIII), respectively. (VIII-R) or (VIII-S) wherein X represents a group selected from the group consisting of toluenesulfonyl, methanesulfonyl and camphorsulfonyl, d) reacting the compounds thus obtained in racemic or optically active form of the general formula (VIII), respectively; (VIII-R) or (VIII-S) (VIII) (VIII-R) wherein X is the same as in 1c with diisopropylamine to give the compounds in racemic or optically active form of formula (IX), respectively. (IX-R) or (IX-S) (IX) (IX-R) (IX-S), wherein X is the same as in 1c, followed by deprotection to give the compound of formula (I) in racemic or an optically active form. Process according to claim 1, characterized in that the reaction according to a) is carried out in a solvent such as lower carboxylic acids C 1 to C ₄ , in the case where R is benzyl, preferably in acetic acid; or in lower alcohols C 1 to C ₄ , or in another solvent using catalysts such as noble metals, preferably palladium, at a temperature of 20 to 100 ° C and a hydrogen pressure of 1 to 10 MPa. 3. The process according to claim 1, wherein the reduction according to b) is carried out with a metal hydride selected from the group consisting of lithium aluminum hydride, bis- (2-methoxyethoxy) aluminum dihydride and diisobutylaluminium hydride. Process according to claim 1, characterized in that 3- (2-tosyloxy-5-methylphenyl) -3-phenyl-O-tosylpropanol is used as the compound of formula (VIII) 5. 5. The process according to claim 1, wherein the nucleophase substitution according to d) is carried out in an organic polar aprotic solvent at elevated pressure at a temperature of 50 to 200 [deg.] C. 6. 3- (2-Hydroxy-5-methylphenyl) -3-phenylpropanol in racemic form of formula (VII) or in enantiomerically enriched forms of formula (VII-R), respectively. (VII-S). 7. Sulfonic acid esters in racemic form of formula (IX) or in enantiomerically enriched forms of formula (IX-R), respectively. (IX-S) wherein X is as defined in claim 1.