WO2002024625A2

WO2002024625A2 - Process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives

Info

Publication number: WO2002024625A2
Application number: PCT/IB2001/001699
Authority: WO
Inventors: Rajender Kumar Potlapally; Mahender Rao Siripragada; Narasimha Murthy Kotra; Raju Sirisilla; Ramabhadra Sarma Mamillapalli; Om Reddy Gaddam
Original assignee: Dr. Reddy's Research Foundation
Priority date: 2000-09-22
Filing date: 2001-09-17
Publication date: 2002-03-28
Also published as: AU2001286163A1; WO2002024625A3

Abstract

The present invention relates to an improved process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives of formula (1) where R1 represents hydrogen atom or (C¿1?-C6)alkyl group and R?2¿ represents (C¿1?-C6)alkyl group which comprises: (i) selectively benzylating L-tyrosine to yield compound of formula (15); (ii). diazotising the compound of formula (15) to produce compound of formula (8); (iii) simultaneous etherification and esterification of compound of formula (8) to obtain crude compound of formula (9) with ee>90 %; (iv) hydrolysing the crude compound of formula (9) to produce compound of formula (9a) acid; (v) treating the compound of formula (9a) with chiral base to produce pure salt of formula (16); (vi) converting the compound of formula (16) to pure compound of formula (9a); (vii) esterifying pure compound of formula (9a) to produce pure compound of formula (9); (viii) debenzylating the compound of formula (9) to yield pure compound of formula (1).

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF 3-ARY -2- HYDROXY PROPANOIC ACID DERTVATIVES

Field of the invention

The present invention relates to an improved process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1)

wherein R represents hydrogen atom or (C]-C₆)alkyl group and R² represents (Cι-C₆)alkyl group.

The compound of formula (1) is useful as an intennediate for the preparation of many pharmaceutically active compounds.

Background of invention The process for the preparation of 3-aryl-2-hydroxy propanoic acid, its derivatives and analogs exhibiting various pharmacological actives have been described in US 5,232,945, US 5,306^726, WO 91/11999, DE 1,948,373, DE. 2,033,959, DE 2,014,479, DE 1,668,938, WO 91/19702, WO 92/0252, WO 96/04260, WO 96/0426, WO 95/17394. In addition, these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with eating such as anorexia nervosa and disorders associated with overeating such as obesity and anorexia bulimia.

3-Aryl-2-hydroxy propanoic acid derivatives are also used as sweetening agent (Gries etal. EP 55,689 (1982)), also in photosensitive materials (Komamura etal. JP 6022850) and also in liquid crystals (Grey et.al.

WO 88/02390). It is also a part of sesquiterpene lactone glycoside isolated from Crepis tectorium (Kisiel Wanda etal. Phytochemistry, 2403, 28 (9) (1989)]. It is also part of Aeruginorins 102 A and B, a new class of Thrombin inhibitors from the Cyanobacterium Microcystis vindis.

3-Aryl-2-hydroxy propanoic acid is prepared by several methods reported in the literature. Hisashi Matruda. etal., Tet. 52 (46) 14501 (1996)

_HzN

(2) (3) Scheme-1

In our WO publication No. 00/26200 we have described process for preparing the compound of formula (1). The reaction schemes are shown below :

(1) (9) (8)

Scheme-2 u^'

Though it is convergent synthetic method, the compound of formula (7) is produced in racemic mixture, which has to be resolved to get the optically pure material.

ScSιeme-3 In this process too the resolution has to be carried out for compound of formula (7).

(9)

Scheme-4

WO 99/62872 and WO01/40159 describes a process for the preparation of. compound of formula (I), wherein R² is OH or the group OR^p, where in R^p is protecting group consisting of H, benzyl or (CrC₃)alkyl, which comprises reacting a racemic compound of the formula II where Q is a protecting group or H, with a chiral amine forming a salt of the formula ' III, subsequently separating the diastereomers by crystallization followed by removal of the amine and deprotecting the Q group of the resulting compound with a deprotecting agents and optionally protecting a free carboxylic acid function with the group R . The reaction is shown in scheme 5 below :

Scheme-5

Objective of present invention The main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical and chiral purity. Another objective of the present invention is to produce pure and stable compound of formula (9) acid salt with respect to chemical and chiral purities.

To convert the crude compound of formula (9) (partially racemised) to compound of formula (9) acid and to get pure compound of formula (9) acid, which is back esterifϊed to get pure compound of formula (9). To overcome the problem of partial racemisation during the conversion of compound of formula (8) to compound of formula (9).

To avoid use of highly reactive, difficult to handle and expensive chemicals such as sodium hydride and ethyl iodide and replaced with simple, inexpensive chemicals such as diethylsulphate and potassium carbonate.

Detailed description of the invention

Accordingly, the present invention provides an improved process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1)

wherein R¹ represents hydrogen atom or (C_rC₆)alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and the like, and R represents (Cj- C₆)alkyl group such as methyl, ethyl, propyl, isopropyl and the like which comprises:

(i). selectively benzylating L-tyrosine of the formula (14) using benzyl halide, CuSO and sodium hydroxide in a solvent to yield a compound of the formula (15),

(ii). diazotising the compound of the formula (15) using diazotizing agent in the presence of an acidic reagent and an organic solvent to produce compound of the formula (8a), (iii). simultaneous etheriiϊcation and esterifϊcation of compound of formula (8a) using allcylating agent in the presence of a base and a solvent to obtain crude compound of formula (9) with ee >90 % wherein R¹ represents hydrogen or lower alkyl group and R represents lower alkyl group., (iv). hydrolysing the crude compound of formula (9) obtained in step (iii) above in polar solvents using aqueous alkali to produce compound of formula (9a) acid wherein R¹ represents hydrogen or lower alkyl group,

(v). treating the compound of formula (9a) acid where R¹ represents hydrogen and lower alkyl group with chiral base in the presence of solvent to produce chemical and chiral pure (ee >99 %) salt of formula (16) where R¹ represents hydrogen or lower alkyl group and X represents chiral bases such as R(+)-α-methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrine, N- octylglucaramine, N-methylglucaramine and the like,

(vi). if desired, recrystallizing the compound of formula (16) obtained above in. a solvent to produce highly pure compound of formula (16) where R¹ represents hydrogen or lower alkyl group, (vii). converting the compound of formula (16) defined above using a solvent and an acid to pure compound of formula (9a) where R¹ represents hydrogen or lower alkyl group,

(viii). esterifying the pure compound of formula (9a) defined above using alkylating agent in the presence of base or acid or acidic resin to produce pure compound of formula (9) where R¹ represents hydrogen or lower alkyl group and R² represents lower alkyl group and

(ix). debenzylating the compound of formula (9) using solvents in the presence of metal catalysts to yield pure compound of formula (1) where R¹ represents hydrogen or lower alkyl group and R² represents lower alkyl group.

The process explained above is shown in scheme-6 below

Scheme-6 The process of the present invention starts with benzylating the compound formula (14) using benzyl halide such as benzyl chloride, benzyl bromide and the like, CuSO , sodium hydroxide in the presence of solvents such as aqueous methanol, ethanol and the like to afford compound of the formula (15). Diazotization of the compound of the formula (15) using diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under acidic conditions using acids such as sulfuric acid, HC1, acetic acid and the like, in an organic solvent such as CHC1₃, 1,4-dioxane, THF, acetone and the like, gives the compound of the formula (8a). Simultaneous etherification and esterification of compound of formula (8a) to obtain crude compound of formula (9) may be carried out using alkyl sulfates such as diethyl sulphate, dimethylsulphate and the like or alkyl halides such as ethyl iodide, methyliodide and the like, in the presence of solvents such as hydrocarbons like toluene, benzene and the like or DMF, DMSO, methyl isobutyl ketone (MIBK) and the like, in alkali bases such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride and the like. Alternatively, the compound of formula (9) may also be prepared by slow addition of compound of formula (8a) to a solution of DMF, sodium hydride, and alkali halides such as methyl iodide, ethyl iodide and the like at a temperature ranging from 0 to 80 °C. The compound of formula (9) upon hydrolysis in polar solvents like alcohols such as methanol, ethanol, propanol, isopropanol and the like or ketonic solvents such as acetone, methyl ethyl ketone and the like using aqueous alkali base such as sodium hydroxide or potassium hydroxide yields compound of formula (9a). The resolution of compound of formula (9a) with chiral base such as R(+)-α- methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrine, N- octylglucaramine, N-methylglucaramine and the like using solvents such as alkyl ester such as methyl acetate, ethyl acetate, ethyl propanoate, n- butylacetate and the like or alcohol such as methanol, ethanol, propanol, isopropanol and the like or ketone such as acetone, methyl isobutyl ketone and the like or acetonitrile produces the chemical and chiral pure compound of formula (16) where ^" X represents chiral base such as R(+)-α- methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrin, N- octylglucaramine, N-methylglucaramine and the like. The compound of formula (16) defined above may further purified by recrystallization from solvents such as alkyl ester such as methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or alcohol such as methanol, ethanol, propanol, isopropanol and the like or ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like or acetonitrile to obtain highly pure compound of formula (16). The pure compound of formula (9a) is obtained from the compound of formula (16) by treating with acid such as hydrochloric acid, sulfuric acid and the like in the presence of solvent such as toluene, xylene, ethyl acetate, diethyl ether, methyl tertiary butyl ether and the like. The pure compound of formula (9a) obtained above is esterified with suitable alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like or alkyl sulfates such as methyl sulfate, ethyl sulfate and the like in the presence of acids such as hydrochloric acid, sulfuric acid and the like or acidic resins such as amberlite, amberlist and the like or bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate or organic bases such as alkoxides like sodium ethoxide, potassium tertiary butoxide or triethyl amine and the like to produce pure compound of formula (9). The debenzylation of the compound of formula (9) using THF, aqueous acetic acid, ethyl acetate, aqueous or non aqueous (Cι-C ) alcohols such as methanol, ethanol, propanol, isopropanol and the like in the presence of metal catalysts such as Pd/C produces pure compound of formula (1).

It is appreciated that in any of the above mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are tertiarybutyl dimethyl silylchloride, methoxymethyl chloride and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. The invention is described in the examples given below which are provided by way of illustration only and therefore should not construed to limit the scope of the invention. Example 1 Step (i) Preparation of (S)-2-amino-3-(4-bβnzyIoxyphenyl)propanoic acid of the formula (15)

To a solution of L-tyrosine of the formula (14) (250 g) in 2N NaOH solution (552 ml), copper sulphate solution (172 g of CuSO₄ in 600 ml of water) was added and heated at 60 °C for 2 h. The reaction mixture was cooled to room temperature and methanol (2.5 L) and 2N NaOH (83 ml) was added and then benzyl chloride (15 ml) was added drop wise. The reaction mass was allowed to warm to room temperature. The precipitate was filtered and washed to give the title compound as white to off-white solid (260 g, 70 %) (Ref. The practice ofpeptide synthesis, M. Bodansz y & A. Bodanszky pp50).

Step (ii)

Preparation of S(-)-2-hydroxy-3-(4-benzyϊoxyphenyl)propanoic acid of the formula (8a) To a stirred solution of (S)-2-amino-3-(4-benzyloxyphenyl)propanoic acid of the formula (15) (300 g) obtained in step (i) above, in acetone (1.8 L) and dilute H₂SO₄ (75 ml in 1.2 L of H₂O) at 0 °C, a solution of NaNO₂ (210 g in 400 ml H₂O) was added slowly between 0 °C to 15 °C. After complete addition of NaNO₂ the reaction mixture was maintained below 25 °C for a period of 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The organic extracts were concentrated and the residue was purified by washing with diisopropyl ether to give the title compound of the formula (8a) as off white to yellowish solid (159 g, 52.8 %).

Step (iii)

Preparation of crude S(-) ethyl 2-ethoxy-3-(4- bβnzyloxypheny!)propanoate of the formula (9) A mixture of S(-)-2-hydroxy-3-(4-benzyloxyphenyl)propanoic acid of the formula (8a) (50 g), potassium carbonate (152 g), diethyl sulfate (113 g), and toluene (750 ml) was taken in a round bottom flask and refluxed for 24 to 36 h. The completion of the reaction was monitored by TLC. After completion of the reaction, water (500 ml) was added and stirred to dissolve inorganic salts. The organic layer was concentrated to yield crude ethyl 2-ethoxy-3-(4- benzyloxyphenyl)propanoate of the formula (9) (56 g, 93 %).

The other compounds of formula (9) are also prepared using the solvents given below following the procedure as described above :

Preparation of S(-) 2-ethoxy-3-(4-benzy!oxyphenyl)propanoic acid the formula (9a)

To a solution of crude S(-) ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propanoate (180 g) of the formula (9) obtained in step (iii), in methanol (900 ml) cooled to 10-20 °C, sodium hydroxide solution (900 ml) was added slowly. The reaction temperature was raised to 25-30 °C and stirred for 4-6 h. Completion of the reaction was monitored by TLC. After completion of the reaction, water (900 ml) was added and extracted with toluene (2 X 900 ml) to remove impurities. Aqueous layer was removed and pH was adjusted to 2 and extracted with toluene (2 X 900 ml). Combined organic layers were washed with water and concentrated to afford the title compound of the formula (9a) (139 g, 84 %).

Step (v)

Preparation of (S)-2-ethoxy-3-(4-benzyϊoxyphenyl)propanoic acid α- methyl benzyl amine salt of the formula (16)

To S(-) 2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid (141 g) the formula (9a) dissolved in ethylacetate (1.4 L), R(+)-α-methylbenzylamine (57 g) was added slowly and stirred for 3-4 h. The precipitated white solid was filtered (recrystalhsed from ethylacetate 1.5 L if required, to the desired purity) to yield pure (S)-2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid α-methyl benzyl amine salt of the formula (16) (125g, 63 %).

The other compounds of formula (16) are also prepared from S(-) 2-ethoxy-3- (4-benzyloxyphenyl)propanoic acid or S(-) 2-methoxy-3-(4- benzyloxyphenyl)propanoic acid using the chiral bases and solvents given below following the procedure as described above :

Step (vi)

Preparation of (S)-methyϊ 2-ethoxy-3-(4-benzyϊoxyphenyl)propanoate of the formula (9)

A mixture of (S)-2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid α-methyl benzyl amine salt " of the formula (16) or (S)-2-ethoxy-3-(4- benzyloxyphenyl)propanoic acid phenyl glycinol salt of the formula (16), (6.7 g) water (70 ml) and toluene (35 ml) was taken in a reaction flask and stirred for 5-10 min. The reaction mass was cooled to 10-15 °C and 25% cold sulfuric acid was added slowly to adjust pH of the reaction mass to 2. Aqueous and organic layers were separated. Aqueous layer was extracted with toluene (35 ml). The combined toluene layers were washed with water (20 ml) and evaporated to yield (S) 2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid the formula (9a) (4 g).

The pure compound of formula (9a) obtained above was dissolved in methanol (35 ml), sulfuric acid (0.4 ml) was added and stirred at refluxing temperature for 12-24 h. Completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (35 ml) and extracted with toluene (2 X 35 ml). The combined organic layers were washed with 0.5 % sodium hydroxide solution (30 ml) and water (50 ml) and concentrated to afford pure tile compound of the formula (9) (3.5 g, 83 %).

The other compounds of formula (9) from compounds of formula (9a) are also prepared using the solvents given below following the procedure as described above :

Step (vii)

Preparation of (S)-methyl 2-ethoxy-3-(4-hydroxypheny!)propanoate of

A mixture of (S)-methyl 2-ethoxy-3-(4-benzyloxyphenyl)propanoate of the formula (9) (56 g) in aqueous methanol (300 ml) and slurry of 5% palladium carbon (6 g in 60 ml water) was taken in hydrogenation flask and hydrogenated on Parr shake flask at 60 psi pressure for 6-8 h at room temperature. Completion of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered and the filtrate was evaporated to yield tile compound of the formula (1) (39 g, 96 %).

The other compounds of formula (1) are also prepared using the solvents given below following the procedure as described above :

Advantages of the present process

^β An efficient synthesis for the production of compounds of formula (I) with high chiral and chemical purity. « The overall yield of the process has been improved.

• Pyrophoirc and exotic reagents like NaH are replaced with simple, inexpensive chemicals such as diethylsulphate and potassium carbonate.

Claims

Claims :

1. An improved process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1)

where R¹ represents hydrogen atom or (Cι-C₆)alkyl group and R² represents (Cι-C₆)alkyl group which comprises: (i). selectively benzylating L-tyrosine of the formula (14)

using benzyl halide, CuSO₄ and sodium hydroxide in a solvent to yield a compound of the formula (15),

(ii). diazotising the compound of the formula (15) using diazotizing agent in the presence of an acidic reagent and an organic solvent to produce compound of the formula (8 a),

(iii). simultaneous etherification and esteriflcation of compound of formula (8a) using alkylating agent in the presence of a base and a solvent to obtain crude compound of formula (9) with ee >90 %

wherein R¹ represents hydrogen or lower alkyl group and R² represents lower alkyl group.,

(iv). hydrolysing the crude compound of formula (9) obtained in step (iii) above in polar solvents using aqueous alkali to produce compound of formula 5 (9a) acid

wherein R¹ represents hydrogen or lower alkyl group,

(v). treating the compound of formula (9a) acid where R¹ represents hydrogen or lower alkyl group with chiral base in the presence of solvent to l o produce chemically and chirally pure (ee >99 %) salt of formula (16)

where R represents hydrogen or lower alkyl group and X represents chiral bases such as R(+)-α-methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrine, N-octylglucaramine or N-methylglucaramine, 15 (vi). if desired, recrystallising the compound of formula (16) obtained above in a solvent to produce highly pure compound of formula (16) where R¹ represents hydrogen or lower alkyl group,

(vii). converting the compound of formula (16) defined above using a solvent and an acid to pure compound of formula (9a),

where R¹ represents hydrogen or lower alkyl group, (viii). esterifying the pure compound of formula (9a) defined above using alkylating agent in the presence of base or acid or acidic resin to produce pure compound of formula (9)

where R represents hydrogen or lower alkyl group and R represents lower alkyl group and

(ix). debenzylating the compound of formula (9) using solvents in the presence of metal catalysts to yield pure compound of formula (1) where R¹ represents hydrogen or lower alkyl group and R represents lower alkyl group.

2., The process as claimed in claim 1, wherein the solvent used in step (i) is selected from aqueous methanol or ethanol.

3. The process as claimed in claims 1 and 2, wherein the diazotizing agent used in step (ii) is selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite.

4. The process as claimed in claims 1 to 3, wherein the acidic reagent used in step (ii) is selected from acids such as sulfuric acid, HC1 or acetic acid.

5. The process as claimed in claims 1 to 4, wherein the organic solvent used in step (ii) is selected from CHC1₃, 1,4-dioxane, THF or acetone

6. The process as claimed in claims 1 to 5, wherein the allcylating agent used in ste . (iii) is selected from dimethyl sulfate, diethyl sulfate, methyliodide or ethyliodide.

7. The process as claimed in claims 1 to 6, wherein the solvent used in step (iii) is selected from toluene, benzene, DMF, DMSO or MIBK.

8. The process as claimed in claims 1 to 7, wherein the base used in step (iii) is selected from sodium carbonate, potassium carbonate, sodium methoxide or sodium hydride.

9. The process as claimed in claims 1 to 8, wherein the polar solvent used in step (iv) is selected from methanol, ethanol, propanol, isopropanol, acetone or' methyl ethyl ketone.

10. The process as claimed in claims 1 to 9, wherein the alkali used in step (iv) is selected from sodium hydroxide or potassium hydroxide.

11. The process as claimed in claims 1 to 10, wherein the chiral base used in step (v) is selected from R(+)α-methylbenzylamine, S(+)~phenylglycinol, cinchonidine, ephidrine, N-octylglucaramine or N-methylglucaramine.

12. The process as claimed in claims 1 to 11, wherein the solvent used in step (v) is selected from methyl acetate, ethyl acetate, ethyl propanoate, n- butylacetate, methanol, ethanol, propanol, isopropanol, acetone, methyl isobutyl ketone or acetonitrile.

13. The process as claimed in claims 1 to 12, wherein the recrystallization in step (vi) is effected using solvent such as methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate, methanol, ethanol, propanol, isopropanol, acetone, methyl isobutyl ketone or acetonitrile.

14. The process as claimed in claims 1 to 13, wherein the acid used in step (vii) is selected from hydrochloric acid or sulfuric acid.

15. The process as claimed in claims 1 to 14, wherein the solvent used in step (vii) is selected from toluene, xylene, ethyl acetate, diethyl ether or methyl tertiary butyl ether.

16. The process as claimed in claims .1 to 15, wherein the allcylating agent used in step (viii) is selected from methanol, ethanol, propanol, isopropanol, butanol, dimethyl sulfate or diethyl sulfate.

17. The process as claimed in claims 1 to 16, wherein the acid used in step (viii) is selected from sulfuric acid or hydrochloric acid.

18. The process as claimed in claims 1 to 17, wherein the acidic resin used in step (viii) is selected from amberlite or amberlist.

19. The process as claimed in claims 1 to 18, wherein the base used in step (viii) is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate or organic bases such as alkoxides like sodium ethoxide, potassium tertiary butoxide or triethyl amine.

20. The process as claimed in claims 1 to 19, wherein the solvent used in step (ix) is selected from THF, aqueous acetic acid, ethyl acetate, aqueous or non aqueous (Cι-C₆) alcohols such as methanol, ethanol, propanol or isopropanol.

21. The process as claimed in claims 1 to 20, wherein the metal catalysts used in step (ix) is Pd/C.

22. An improved process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1) substantially as herein described with reference to the Examples.