WO2014016852A1

WO2014016852A1 - Asymmetric synthesis of (-)-venlafaxine using organocatalyst

Info

Publication number: WO2014016852A1
Application number: PCT/IN2013/000464
Authority: WO
Inventors: Subhash Prataprao Chavan; Sumanta GARAI; Kailash Pralhad PAWAR
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2012-07-25
Filing date: 2013-07-25
Publication date: 2014-01-30
Anticipated expiration: 2015-01-25
Also published as: IN2012DE02300A; US9409855B2; US20150175524A1

Description

ASYMMETRIC SYNTHESIS OF (-)-VENLAFAXINE USING ORGANOCATALYST Technical field of invention:

The invention relates to the asymmetric synthesis of (-)-venlafaxine using an organo catalyst. Particularly, the invention relates to the selective synthesis of one enantiomer of venlafaxine using the organocatalyst.

Background and prior art:

Venlafaxine is a new generation antidepression drug, first introduced in 1993. It is used for the treatment of major depressive disorder (MDD), as a treatment for generalized anxiety disorder, and co-morbid indications in certain anxiety disorders with depression. In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions. Although venlafaxine is sold as a racemate, (-)-venlafaxine is a more potent inhibitor , of norepinephrine synaptosomal uptake while (+)-venlafaxine is more selective in serotonin uptake. It is different from other antidepressants in that it has no or little activity on a variety of neuroreceptors, (e.g. a or ^-adrenergic receptors, muscarinic receptors, cholinergic receptors, histaminic receptors etc.).

There are number of racemic syntheses reported for venlafaxine, including those by the inventors. These synthetic routes for racemic venlafaxine mainly involve the condensation of cyclohexanones with 4-methoxyphenyl acetic acids or 4- methoxyphenyl acetonitriles followed by functional group manipulationr

As both enantiomers posses^' different biological activities, therefore asymmetric synthesis of Venlafaxine is a subject matter of interest.

Nanda et al in Tetrahedron Letters 53 (2012) 1990- 1992 reported an enzyme based resolution for asymmetric synthesis of venlafaxine. Their strategy included (S)-HNL catalyzed synthesis of cyanohydrins from cyclic ketones and lipase-PS catalyzed kinetic resolution for creation of the stereocenter.

Chem. Commun. , 2006, 3110-3112 disclose β -Amino esters which are readily formed from rhodium(II) prolinate-catalyzed intermolecular OH insertion between methyl aryldiazoacetates and a bis— silyl protected inethylamine. This was applied for effective synthesis of venlafaxine with enantiomers obtained with moderate yields moderate % ee.

But prior art methods suffer from the main drawback of having to resolve the enantiomers in a separate dedicated step, and yet result in only moderate yield. Also, these processes employ hazardous and potentially explosive reagents. They need dry, inert conditions during use of Grignard s reagent and many processes need cryogenic conditions. Also, these prior art processes use metal based catalyst which are not environmentally friendly.

Objects of invention:

The main object of the invention is to provide a process for asymmetric synthesis of (-)-venlafaxine, wherein one enantiomer is obtained in high enantiomeric purity.

Another object of the invention is to provide a process to those results selectively in one enantiomer of venlafaxine, without the need for a step of resolution.

Summary of Invention:

Accordingly, the present invention provides a process for asymmetric synthesis of enantiomerically pure venlafaxine with ee > 99% comprising the steps of: a. reacting anisaldehyde with nitromethane in mole ratio 1 : 11.8 in presence of ammonium acetate in acetic acid under sonication condition at room temperature ranging between 25 - 35° C for a period ranging between 2-4 hrs to obtain nitro styrene;

b. michael addition of nitrostyrene as obtained in step (a) with

- cyclohexanone in mole ratio 1 :5 in presence of proline based

organocatalyst under stirring at room temperature ranging between 25 - 35° C for a period ranging between 23-25 hrs in the presence of p- toluene sulphonic acid to obtain nitro ketone;

c. reducing nitro ketone of step (b) using NaBH₄ in THF:H20 (9: 1) to obtain crude alcohol (25)-2-((/t)-l-(4-methoxyphenyl)-2- nitroethyl)cyclohexan-l-ol which on subjecting to nitro reduction by NiCl₂.6H₂0 and sodium borohydride in MeOH as a solvent, afforded the resultant amine (25)-2-((/¾-2-amino-l-(4- methoxyphenyl)ethyl)cyclohexan-l-ol which on in situ protection by benzylchloroformate in presence of Et₃N as a base furnished Cbz protected amino alcohol benzyl ((2/¾-2-((l $-2-hydroxycyclohexyl)-2- (4-methoxyphenyl)ethyl)carbamate;

d. treating amino alcohol of step (c) with mesyl chloride in presence of Et₃N as a base in DCM solvent under reflux condition at temperature ranging berween 40-45 ⁰ C for a period ranging 14-25 hrs to give the crude mesylated reaction mixture which further on treatment with DBU in acetonitrile solvent furnished selectively more substituted double bond product benzyl (/¾-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)carbamate;

e. subjecting compound (v?)-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)carbamate of step(d) with NaH and Mel in dry THF to obtain benzyl ($-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)(methyl)carbamate ; f. epoxidation of benzyl (RM2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)(methyl)carbamate of step (e) by treating with irr CPBA in presence of NaHC0₃ in DCM under stirring at temperature ranging between 25-35 °C for a period ranging between 1-3 hrs to afford crude epoxide benzyl ((2R)-2-(7-oxabicyclo[4.1.0]heptan-l-yl)-2-(4 methoxyphenyl)ethyl)(methyl)carbamate; g. subjecting the crude epoxide of step (f) to selective epoxide opening as well as carbamate reduction in one pot using lithium aluminum hydride at reflux condition at temperature ranging berween 65-70 ° C for a period ranging 4-5 hrs in THF to afford (-)-venlafaxine.

In one embodiment of the present invention the overall yield of enantiomerically pure (-)-venlafaxine is in the range of 21-22%.

In an embodiment of the present invention the enantioselectivity of (-)-venlafaxine is in the range of 99- 99.9%.

In another embodiment of the present invention proline based organocatalyst used in step (b) is (S)-N1, V/-dimethyl-N_?-(pyrrolidin-2-ylrnethyl)ethane-l ,2-diamine

Brief Description of figures:

Figure 1 : Chromatogram for racemic venlafaxine Figure 2: Chromatogram for optically pure venlafaxine Figure 3 Scheme I indicates Retrosynthetic analysis of (-)-venlafaxine. Figure 4: Scheme 2 indicates synthesis of venlafaxine Detailed description of invention: Abbreviations used: PTSA:_. para-Toluene sulphonic acid.

THF: Tetrahydrofuran.

Cbz: Carbobenzyloxy.

Ms: Methanesulphonyl

DBU: 1, 8-Diazabicyclo[5.4.0]undec-7-ene. m-CPBA: meia-Chloroperoxybenzoic acid.

DCM: Dichloromethane

LAH: Lithium aluminium hydride.

The process of the invention is outlined in Scheme 1.

According to retrosynthetic analysis, synthesis of (-)-venlafaxine began with Henry reaction of commercially cheap, easily available starting material anisaldehyde 6 with nitromethane in presence of ammonium acetate in acetic acid under sonication condition at room temperature to furnish nitro styrene 5 in 95% yield. Michael addition of nitro styrene 5 with cyclohexanone in presence of proline based organocatalyst 11 gives nitro keto compound 4 in 79% with > 99% ee after stirring 24 hours at room temperature in presence of p-toluene sulphonic acid (PTSA) as an additive in DMF solvent. Selective reduction of keto 4 using NaBH₄ in THF:H₂0 (9: 1) as solvent system afforded alcohol. The crude alcohol was subjected to nitro reduction by NiCl₂.6H₂0 and sodium borohydride in MeOH as a solvent, then the resultant amine was in situ protected by benzylchloroformate in presence Et₃N as a base to furnish

Cbz protected amino alcohol 7 in 75% yield.

Scheme 2. Reagents and conditions: a) Nitromethane, NH₄OAc, glacial acetic acid, ))), 3 hrs, 95%; b) Cyclohexanone, 11, PTSA, DMF, 24 hrs, 79%, >99% ee; c) i) NaBH₄, THF:H₂0 (9: 1), 2 hrs.; ii) NiCl₂. 6H₂0, NaBH₄, MeOH, 1.5 hrs., 0 ⁰ C then CbzCl, Et₃N, rt, overnight, 75% (over two steps); d) i) sCl, Et₃N, reflux, 14 hrs; ii) DBU, CH₃CN, 24 hrs, reflux, 68% (over two steps); e) Mel, NaH, THF, overnight, rt, 92%; f) i) m-CPBA, NaHC0₃, DCM, 2 hrs. , rt. ii) LiAlH₄, THF, 5 hrs, reflux, 60% , >99% ee. The hydroxyl group of compound 7 was converted into corresponding mesyl derivative by using mesyl chloride in presence of Et₃N as a base in DCM solvent under reflux condition. The crude mesylated reaction mixture on treatment with DBU in acetonitrile solvent furnished selectively more substituted double bond product 8 in 68% yield. After introduction of double bond dihydroxylation reaction condition was tried for installation of tertiary hydroxyl group. After successful installation of diol through dihydroxylation (Os0₄, NMO), selective removal of secondary hydroxyl group failed. So it was decided to install tertiary hydroxyl group through epoxidation and followed by epoxide opening. Thus the compound 8 was subjected with NaH and Mel in dry THF to afford compound 9 in 92%- yield. For epoxidation compound 9 was treated with /TT-CPBA in presence of NaHC0₃ in DCM to afford epoxide. The crude epoxide 10 was subjected to selective epoxide opening as well as carbamate reduction in one pot using lithium aluminum hydride at reflux condition in THF to afford (-)-venlafaxine 1 in 60% yield with >99% ee. Spectral data and optical rotation for (-)-Venlafaxine 1 is provided herein in the form of examples. This strategy of asymmetric synthesis of venlafaxine 1 by using organocatalyst can be extended to the synthesis of both enantiomers by switching the stereocentre of the catalyst with no loss in the optical activity of desired product. Derivatives of venlafaxine can be prepared in the same manner.

The invention is now explained with reference to embodiments and preferred embodiments, which in no way should be construed to be restrictive. Examples:

Example 1: Synthesis of (-)-Venlafaxine.

Reacting anisaldehyde (20 gm, 0.147 mol) with nitromethane (94 mL, 1.741 mol) in presence of ammonium acetate in acetic acid (24 mL, 0.419 mol ) under sonication condition at room temperature (25 ° C) for a period of 3 hrs to furnish 24.7 gm nitro styrene 5 in 95% yield. Michael addition , of nitro styrene 5 (3 gm, 16.8 mmol) with cyclohexanone (8.2 gm, 84 mmol) in presence of proline based organocatalyst (5)- yV/,/Vi-dimethyl-N-?-(pyrrolidin-2-ylmethyl)ethane-l ,2-diamine (115 mg, 0.67 mmol ) gives 6.1 gm of (S)-2-((R)-l-(4-methoxyphenyl)-2-nitroethyl)cyclohexan-l-one 4 in 79% with > 99% ee after stirring 24 hours at room temperature (25 ⁰ C) in presence of p-toluene sulphonic acid (PTSA) (127 mg, 0.67 mmol ) as an additive in DMF solvent. Selective reduction of keto 4 (2 gm, 7.2 mmol )using NaBH₄ (0.816 gm, 21.6 mmol ) in THF:H₂0 (9: 1) (20 ml), as solvent system afforded (^-2-((/¾-l-(4-methoxyphenyl)- 2-nitroethyl)cyclohexan-l-ol. The crude alcohol (2.06 gm, 7.4 mmol) was subjected to nitro reduction by NiCl₂.6H₂0 (4.4 gm, 18.5 mmol) and sodium borohydride (7.03 gm, 0.185 mol) in MeOH (20 mL) as a solvent, then the resultant amine was in situ protected by benzylchloroformate (3.7 ml, 22.2 mmol) in presence Et₃ (4 mL, 29.6 mmol) as a base to furnish 2.07 gm Cbz protected amino alcohol benzyl ((_?A -2-((/,5)- 2-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)carbamate in 75% yield. The hydroxyl group of Cbz protected amino alcohol (100 mg, 0.26 mmol) was converted into corresponding mesyl derivative by using mesyl chloride (0.06 mL, 0.78 mmol) in presence of Et₃N(0.22 mL, 1.56 mmol) as a base in DCM solvent under reflux condition (40 ° C) for 14 hrs The crude mesylated reaction mixture (120 mg) on treatment with DBU (1 mL) in acetonitrile solvent (3 mL) furnished 64.6 mg of selectively more substituted double bond product 8 benzyl ( ?)-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)carbamate in 68% yield. After introduction of double bond dihydroxylation reaction condition was tried for installation of tertiary hydroxyl group. After successful installation of diol through dihydroxylation (Os0₄, NMO), selective removal of secondary hydroxyl group failed. So it was decided to install tertiary hydroxyl group through epoxidation and followed by epoxide opening. Thus the compound 8 (100 mg, 0.274 mmol) was subjected with NaH (22 mg, 0.55 mmol, 60%) and Mel (0.034 mL, 0.55mmol) in dry THF(5 mL) to afford 95 mg compound 9 benzyl (/¾-(2-(cyclohex-l-en-l-yl)-2-(4-methoxyphenyl)ethyl)(methyl)carbamate in 92% yield. To a cold (0 °C), magnetically stirred solution of /V-methylCbz compound 9 (235 mg, 0.6 mmol) in distilled DCM (5 ml), NaHCO_s (126 mg, 1.5 mmol) was added followed by 60% m-CPBA (348 mg, 1.2 mmol) was added portion wise and stirred for 2hrs at rt (25 ⁰ C) The reaction was quenched with solid NaHC0₃ (300 mg) and stirred for further 15 min. The reaction mixture was extracted with DCM (3 X 5 ml) and the combined organic layer was washed with brine (7 mL) and dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude reaction mixture was used as such in the next reaction without further purification. To a cold (0 °C), magnetically stirred solution of lithium aluminum hydride (100 mg, 2.5 mmol) in dry THF (5 ml), crude epoxide 10 (100 mg, 0.25 mmol) was added dropwise and refluxed (66 ⁰ C) for 5 hrs. The reaction mixture was cooled to 0 ⁰ C and excess LAH was quenched with ethyl acetate and then by addition of water, stirred for 2 hrs. Evaporation of the solvent furnished a residue which was extracted with ethyl acetate (3 X 20 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. Purification of the residue on a silica gel column using ethyl acetate as eluent furnished the (-)- venlafaxine 1 (103 mg, 60%) as a white solid.

Example 2: Characterization data of (-)-Venlafaxine. The product of the process enlisted in example 1 was . characterized by IR and Ή and ¹³C NMR and results are as follows: R_f (100% EtOAc) 0.2 (long tail); IR (CHC1₃): 3164, 2982, 2938, 2860, 2782, 1610, 1512 cm^-1; ^lH NMR (200 MHz, CDC1₃+CC1₄,): Ή NMR (200 MHz, CDC1₃+CC1₄₎): 0.83-1.00 (m, 2H), 1.23-1.76 (m, 8H), 2.28 (dd, 7=12.2, 2.9 Hz, 1H), 2.33 (s, 6H), 2.93 (dd, J= 12.2, 2.9 Hz, 1H), 3.28 (t, 7=12.2 Hz, 1H), 3.79 (s, 3H), 6.79 (d, 7=8.8 Hz, 2H), 7.03 (d, 7=8.79 Hz, 2H).¹³C NMR (50 MHz, CDC1₃ + CC1₄): 20.70, 21.05, 25.55, 30.72, 37.53, 44.89, 51.20, 54.36, 60.74, 73.48, 112.75, 129.43, 132.00, 157.72.

Example 3: Optical purity of (-)-Venlafaxine.

G^-venlafaxine [ a ]= - 24.285 (c = 1.04, EtOH). Column: Kromasil 5-Amy Coat (250 X 4.6 mm)

Mobile Phase: EtOH: Pet ether: Diethylamine (05: 95: 0.5)

Wave length: 254 nm

Racemic: Chiral

Retention time Area% Retention time Area%

12.075 47.587

15. 158 100.000 -

15.283 52.413

Advantages of invention:

1. Use of cheap and easily available raw materials

2. Use of cheap and environmentally friendly catalyst

3. Avoidance of expensive and metal based catalyst

4. Avoidance of additional steps involving resolution of enantiomers 5. High % ee purity of product obtained

Claims

We claim:

1. A process for asymmetric synthesis of enantiomerically pure venlafaxine with ee > 99% comprising the steps of: a. reacting anisaldehyde with nitromethane in mole ratio 1 : 11.8 in presence of ammonium acetate in acetic acid under sonication condition at room temperature ranging between 25 - 35° C for a period ranging between 2-4 hrs to obtain nitro styrene;

b. michael addition of nitrostyrene as obtained in step (a) with cyclohexanone in mole ratio 1 :5 in presence of proline based organocatalyst under stirring at room temperature ranging¹ between 25 - 35° C for a period ranging between 23-25 hrs in the presence of p- toluene sulphonic acid to obtain nitro ketone;

c. reducing nitro ketone of step (b) using NaBH₄ in THF:H20 (9: 1) to obtain crude alcohol (25)-2-((v¾-l-(4-methoxyphenyD-2-nitroethyl)cyclohexan-

1- ol which on subjecting to nitro reduction by NiCl₂.6H₂0 and sodium borohydride in MeOH as a solvent, afforded the resultant amine (25)-2- (( ?)-2-amino-l-(4-methoxyphenyl)ethyl)cyclohexan-l-ol which on in situ protection by benzylchloroformate in presence of Et₃N as a base furnished

^ Cbz protected amino alcohol benzyl ((2/¾-2-((l 5)-2-hydroxycyclohexyl)-

2- (4-methoxyphenyl)ethyl)carbamate;

d. treating amino alcohol of step (c) with mesyl chloride in presence of Et₃N as a base in DCM solvent under reflux condition at temperature ranging berween 40-45 ° C for a period ranging 14-25 hrs to give the crude mesylated reaction mixture which further on treatment with DBU in acetonitrile solvent furnished selectively more substituted double bond product benzyl (/?)-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyOethyDcarbamate; e. subjecting compound (/¾-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)carbamate of step(d) with NaH and Mel in dry THF to obtain benzyl (/¾-(2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)(methyl)carbamate ; f. epoxidation of benzyl (/£H2-(cyclohex-l-en-l-yl)-2-(4- methoxyphenyl)ethyl)(methyl)carbamate of step (e) by treating with zn-CPBA in presence of NaHC0₃ in DCM under stirring at temperature ranging between 25-35 °C for a period ranging between 1-3 hrs to afford crude epoxide benzyl ((2R)-2-(7-oxabicyclo[4.1.0]heptan-l-yl)-2-(4 methoxyphenyl)ethyl)(methyl)carbamate; g. subjecting the crude epoxide of step (f) to selective epoxide opening as well as carbamate reduction in one pot using lithium aluminum hydride at reflux condition at temperature ranging berween 65-70 ° C for a period ranging 4-5 hrs in THF to afford (-)-venlafaxine.

2. The process according to claim 1 , wherein the yield of enantiomerically pure (-)-venlafaxine is in the range of21^~58%.

3. The process according to claim 1 , wherein the enantioselectivity of (-)- venlafaxine is in the range of 97- 99%.

4. The process according to claim 1, wherein proline based organocatalyst used in step (b) is (^-/V/,N -dimethyl-N-?-(pyrrolidin-2-ylmethyl)ethane-l ,2-diainine.