SK2072004A3 - Method of producing N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenylpropylamine in its racemic or optically active form - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl amine (tolterodine) in racemic or optically active form thereof wherein the preparation process comprises synthesis of enantiomerically enriched compounds of (R)- and (S)-3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-onone of the general formulae II-R and II-S and preparation of 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanol of the general formula VIII in racemic or enantiomerically enriched form, protected on both oxygen atoms with a sulfa ester group. Further claimed are compounds of the general formulae VII and IX, in which X represents a protecting group being selected from the group consisting of toluene sulfonyl, methane sulfonyl and camphor sulfonyl, as well as optically active forms thereof.

Description

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

(D in its racemic or optically active form.

BACKGROUND OF THE INVENTION

An optically active compound of formula I, namely (R) - (+) - N, N -diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine. often called tolterodine, is in the form of a tartaric acid salt, i.e. as (R) -tolterodine L-tartrate, used to treat overactive bladder associated with urgent manifestations and numerous urination including incontinence.

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

(II)

This material reacts with methyl iodide and potassium carbonate in refluxing acetone to give methyl 3- (2-methoxy-5-methylphenyl) -3-phenylpropionate of formula

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 makes it possible to carry out nucleophilic substitution with diisopropylamine in hot acetonitrile to give the methoxy analog of tolterodine of the formula V

Further, to give 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 material. The 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 diisobutylaluminum hydride (DIBAL), at a temperature of less than -20 ° C. At this temperature the keto group is reduced without opening the lactone cycle and is formed

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 on the process of the basic U.S. Pat. No. 5,382,600. 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-2H-benzopyran-2-one of formula II-R. respectively. II-S

(H-S) by a five-step synthesis from 2-bromo-4-methylacetophenone using chiral catalysts in a yield of 54% with an optical purity of 89% ee.

According to our earlier results (not yet published), a process based on (P) -3- (2-alkyloxy-5-methylphenyl) -3-phenylpropanoic acid, which is amination by starting, can be used to produce tolterodine. reduction and finally deprotection is converted to tolterodine. 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 brand new synthetic methods, also applicable to racemic mixtures followed by resolution.

SUMMARY OF THE INVENTION

The preparation of N, N -disopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpentine of the lamine in its racemic or optically active form according to the invention is shown in Scheme I and includes (a) improved synthesis of enantiomerically enriched (R) - and (S) -3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one compounds from (R) - and (S) -3- (2-alkyloxy-5-methyl-phenyl) -

3-phenylpropanoic acid of formula VI-R and VI-S

(VI-R).

wherein R 1 is C 1-6 alkyl to C 1 or benzyl.

(b) reduction of racemic or enantiomerically enriched (R) - or (S) -3,4-

of dihydro-6-methyl-2H-benzopyran-2-one of formula II. respectively. II-R or II-S

(II-R)

to give the racemic or enantiomerically enriched (R) - or (S) -3- (2-hydroxy-5-methylphenyl) -3-phenylpropanol of formula VII, respectively. VI-R or VII-S

(c) reacting the compounds of Formula VI 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 formulas VIII, VIII-R and VIII-S

(d) reacting a compound of formula VIII, or an optically active form of formula VIII or VIII-R-S with diisopropylamine to form the Λ ', ^N diisopropyl-3- (2-X-oxy-5-rnetylfenyl) -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 the corresponding enantiomeric form.

The sequence of reactions utilizes selective reductive opening of the lactone cycle instead of the carbonyl reduction described above. Reductive opening of the lactone cycle occurs with a compound of formula II or II-R or II-S by reaction with a metal hydride, preferably bis- (2-methoxyethoxy) aluminum dihydride. For esterification of the hydroxy groups in 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 is a good leaving group for the reaction with the secondary amine on the aliphatic chain. By using the same functional group as both a protective and an activating process, it will simplify 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 another embodiment, the nucleophilic substitution is carried out in a manner known per se, 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 racemic or (R) - or (S) -tolterodine formed is then reacted with L (+) - tartaric acid in a known manner. In the case of racemic tolterodine, the diastereomeric 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 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. It is in particular 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. S-IX.

Scheme 1

The scheme applies to both racemic and enantiomerically enriched forms

EXAMPLES

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-2H-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 is introduced at atmospheric pressure at 70 ° C for 5 h with a gentle stream. The mixture was purged briefly with nitrogen, filtered, the filter cake was washed with acetic acid and the filtrate was evaporated. The crude product was recrystallized from 2-propanol. Yield 43 g (91%). 92% ee (ChiralCel OD-H, hexane / 2-propanol 95/5). t. t. 101-103 Of 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 funnel and chlorocalcium cool to -5 ° C with a stopper. 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%. crystalline white; b. t. 11 2.8-113.4 ° 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. 9.5 g (0.05 mol) of toluenesulfonyl chloride dissolved in 50 ml of tetrahydrofuran are added dropwise with cooling. 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 nrol) 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 was separated and extracted with 3 x 50 mL IM HCl and 3 x 50 mL distilled water. Evaporation of the solvent gave an oily product in 94% yield.

Example 4: 3- (2-tosyloxy-5-methylphenyl) -3-phenyl-O- (1 R) - (-) - camphor-10-sulfonylpropanol (VII, 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 The 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. After evaporation of the solvent, an oily product is obtained

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 N, N -diisopropyl-3- (2-tosyloxy-5-methylphenyl) -3-phenylpropylamine (IX-R) are dissolved in 50 ml of ethanol and 50 ml of 5M NaOH are added. 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 µl of ethanol. After standing for 16 h at 4 ° C, the precipitated crystals are sucked off and washed with cold ethanol. 6.6 g (70.2% on 1X-R) of (R) -tolterodine (L) -tartrate are obtained. mp 210-211 C ^J, [to] ^{0 =} +27.4 (c = l, methanol).

Claims (6)

A process for the preparation of N, N -diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropyl amine in its racemic form of formula 1 or an optically active form of formula I-R, respectively. I-S characterized by comprising (a) synthesis of enantiomerically enriched (R) - and (S) -3,4-dihydro-6-methyl-4-phenyl-2 H -benzopyran-2-one compounds of formula II-R, respectively; and II-S. or a racemic mixture of formula II thereof from (R) - and (S) -3- (2-alkyloxy-5-methylphenyl) -3-phenylpropanoic acid of formula VI-R. respectively. VI-S. optionally from a racemic mixture of the formula VI (VI) (VI-R) (VI-S) wherein R 1 | is alkyl C, to C _4, or benzyl. O-dealkylation and subsequent in situ cyclization. b) reduction of 3,4-dihydro-6-methyl-2 H -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 (VII) 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 formula VIII. respectively. VIII-R or VIII-S x wherein X is selected from the group consisting of toluenesulfonyl, methanesulfonyl and camphorsulfonyl. d) reacting the thus formed compounds in racemic or optically active form of formula VIII. respectively. VIII-R or VIII-S (VIII) (VIII-R) (VIII-S). wherein X is the same as in 1c, with diisopropylamine to form the compounds in racemic or optically active form of formula IX. respectively. 1X-R or 1X-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 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. 10. The method of claim 1, wherein the reduction is as in point (b) carried out with a metal hydride selected from the group consisting of lithium aluminum hydride, bis- (2-methoxyethoxy) aluminum dihydride and di isobutyl-aluminum hydride. Method according to claim 1, characterized in that. wherein 3- (2-tosyloxy- 5-methyl-phenyl) -3-phenyl-O-tosylpropanol. The method of claim 1, wherein the nucleophilic substitution according to d) is carried out in an organic polar aprotic solvent at elevated pressure at a temperature of 50 to 200 ° C. 6. 3- (2-Hydroxy-5-methylphenyl) -3-phenylpropanol in racemic form VII or in enantiomerically enriched forms of formula VII-R and VII, respectively. 7th 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.