WO2003027084A1 - Improved process for the preparation of optically active phenoxazine derivatives as antidiabetic agents - Google Patents

Improved process for the preparation of optically active phenoxazine derivatives as antidiabetic agents Download PDF

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WO2003027084A1
WO2003027084A1 PCT/IB2002/003947 IB0203947W WO03027084A1 WO 2003027084 A1 WO2003027084 A1 WO 2003027084A1 IB 0203947 W IB0203947 W IB 0203947W WO 03027084 A1 WO03027084 A1 WO 03027084A1
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compound
formula
acid
solvent
range
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PCT/IB2002/003947
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French (fr)
Inventor
Rajender Kumar Potlapally
Mahender Rao Siripragada
Ramabhadra Sarma Mamillapalli
Om Reddy Gaddam
Tirupati Reddy Jangaigar
Venkata Rama Murali Krishna Reddy Velagala
Narasimha Murthy Kotra
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Dr. Reddy's Laboratories Ltd.
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Publication of WO2003027084A1 publication Critical patent/WO2003027084A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to improved process for the preparation of antidiabetic compound having the formula (1).
  • R represents alkyl group such as methyl, ethyl, propyl, isopropyl and the like.
  • the compounds of formula (I) are useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL).
  • the compound of formula (I) is also useful in reducing body weight and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders.
  • the compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
  • the present invention also relates to novel intermediate of formula (4) and their use in the preparation of compound of formula (I).
  • the present invention also describes an alternate process for the preparation of compound of formula (10).
  • the main objective of the present invention- is to provide two simple and robust processes for the preparation of the compound of formula (1) with high chemical purity.
  • Another objective of the present invention is to overcome the problem of partial racemization during the conversion of compound of formula (10) to compound of formula (11).
  • Yet another objective of the present invention is to avoid the use of highly reactive, difficult to handle and expensive chemicals replace with simple, inexpensive chemicals such as diethylsulphate and potassium carbonate.
  • the present invention provides an improved process for the preparation of compounds of the formula (1),
  • R 1 represents (C ⁇ -C6)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like, which comprises :
  • the condensation of mesylate of the formula (2) with compound of the formula (3) may be carried out in the presence of base such as sodium carbonate, potassium- carbonate, sodium hydroxide, potassium hydroxide and the like, using solvents such as toluene, xylene, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylether, dimethylsulfoxide or alcohol such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 25 to 130 °C and the duration of the reaction may range from 2 to 20 h.
  • the hydrolysis of compound of the formula (4) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K 2 C0 3 , NaHCO 3 and the like or acids such .as methane sulfonic acid, hydrochloric ⁇ acid, sulfuric acid,, trifluoiOacetic acid, p-toluene sulfonic acid and the like.
  • the hydrolysis may also be carried ' out in the presence of solvents such as alcohol selected from methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 25 to 35 °C and the duration of the reaction may range from 2 to 15 h.
  • the conversion of compound of formula (5) to obtain compound of formula (6) 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, xylene, benzene and the like or dimethylformamide, dimethylsulfoxide, MIBK, ethyl acetate, N-methyl pyrrolidone and the like or mixtures thereof, in alkali bases such as sodiupi carbonate ! , potassium carbonate, sodium methoxide, sodium hydride, n-butyl lithium, lithium diisopr ⁇ pyl amine and the like.
  • the temperature of the reaction may be in the range of -5 to 60 °C.
  • the hydrolysis of compound of formula (6) to yield compound of formula (7) may be carried out in situ or in polar solvents such as alcohol namely methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents namely acetone, methyl ethyl ketone and the like using aqueous alkali bases such as sodium hydroxide or potassium hydroxide or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like.
  • polar solvents such as alcohol namely methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents namely acetone, methyl ethyl ketone and the like
  • ketonic solvents namely acetone, methyl ethyl ketone and the like
  • acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluor
  • the reaction of compound of formula (7) with L-arginine may be carried out in the presence of solvents like alcohol such as aqueous methanol, ethanol, propanol,, isopropanol and the like or mixtures thereof, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, 1,4-dioxane and the like.
  • solvents like alcohol such as aqueous methanol, ethanol, propanol,, isopropanol and the like or mixtures thereof, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, 1,4-dioxane and the like.
  • the temperature and duration of the reaction may be in the range of 40 to 55 °C and 12 to 18 h respectively.
  • the compound of the formula (7) may be obtained in pure form using chiral amines such as R(+) ⁇ -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, ethers like tetrahydrofuran, dioxane, diisopropyl ether and the like or hydrocarbons such as benzene, toluene, xylene, cyclohexane and the like or mixtures thereof at a temperature in the
  • R 1 represents, (C ⁇ -C6)alkyl group such as methyl, ethy ⁇ , propyl, isopropyl,, butyl, isobutyl, t-butyl and the like, which comprises:
  • the esterification of compound of fo ⁇ nula (8) may be carried out may be carried' out using alkylating agent such as alcohol such as methanol, ethanol, propanol, isopropanol, t-butanol and the like or alkyl sulfates such as methyl sulfate, ethyl sulfate and the like in the presence of acids such as sulfuric acid, methane sulfonic acid, hydrochloric acid, thionyl chloride, p-toluene sulphonic acid, or acidic resins such as amberlite, amberlist, INDION 130, INDION 140 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.
  • alkylating agent such as alcohol such as methanol, ethanol, propanol
  • the debenzylation of the compound of formula (9) may be carried out using metal catalysts such as Pd/C, Pt O, Ni, Pt H 2 and the like, in the presence of solvents such as tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol- such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • metal catalysts such as Pd/C, Pt O, Ni, Pt H 2 and the like
  • solvents such as tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol- such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • reaction of compound of the formula (10) with the phenoxazinyl mesylate of the formula (11) to give compound of the formula (12) may be earned out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and the like and an organic solvent such as dimethylformamide, tetrahydrofuran, dimethylether, dimethylsulfoxide, N- methylpyrrolidone, DEA, toluene, xylene, acetone, MIBK, diethyl ketone, acetonitrile, alcohol such as methanol, ethanol, propanol, isopropanol and the like.
  • a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and the like
  • an organic solvent such as dimethylformamide, tetrahydrofuran, dimethylether, dimethylsulfoxide, N- methylpyrrolidone, DEA, toluene, xylene,
  • the hydrolysis of a compound of formula (12) to compound of formula (13) may be carried out in a polar solvent such as alcohol selected from methanol, ethanol, propanol, isopropanol and the like or a ketonic solvent such as acetone, methyl ethyl ketone and the like, using aqueous alkali bases such as sodium hydroxide or potassium hydroxide or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like.
  • a polar solvent such as alcohol selected from methanol, ethanol, propanol, isopropanol and the like or a ketonic solvent such as acetone, methyl ethyl ketone and the like
  • aqueous alkali bases such as sodium hydroxide or potassium hydroxide
  • acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like.
  • the temperature may
  • Simultaneous etherif ⁇ cation and esterification of compound of formula (13) may be carried out using alkylating agents such as diethyl sulphate or alkyl halide such as methyl halide, ethyl halide, 2-propyl halide, t-butyl halide and the like in the presence of a solvent such as hydrocarbons namely benzene, toluene, xylene and the /027084
  • the hydrolysis of compound of formula (14) may be carried out in polar solvents such as alcohol namely methanol, ethanol, propanol, isopropanol and the like or ketonic solvents namely acetone, methyl ethyl ketone and the like using aqueous alkali bases such as sodium hydroxide or potassium hydroxide or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like to yield compound of formula (15).
  • polar solvents such as alcohol namely methanol, ethanol, propanol, isopropanol and the like or ketonic solvents namely acetone, methyl ethyl ketone and the like
  • ketonic solvents namely acetone, methyl ethyl ketone and the like
  • aqueous alkali bases such as sodium hydroxide or potassium hydroxide
  • acids such as methane sulfonic acid, hydrochloric acid, sulfuric
  • the reaction of compound of formula (15) with L-arginine may be carried out in the presence of solvents like alcohol such as aqueous methanol, ethanol, propanol, isopropanol and the like; acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, 1,4-dioxane and the like.
  • solvents like alcohol such as aqueous methanol, ethanol, propanol, isopropanol and the like; acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, 1,4-dioxane and the like.
  • the temperature and duration of the reaction may be in the range of 40 to 55 °C and 12 to 18 h respectively.
  • R 3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group
  • R 2 represents hydrogen or (C ⁇ -C 6 )alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like.
  • R represents (C ⁇ -C 6 ) alkyl group such as methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, t-butyl and the like, which comprises: ⁇ > , , ,
  • the debenzylation of the compound of formula (8) may be carried out using metal catalysts such as Pd/C, Pt 2 O, Ni, Pt H 2 and the like in the p'resence'of a' solvent such as tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • metal catalysts such as Pd/C, Pt 2 O, Ni, Pt H 2 and the like in the p'resence'of a' solvent such as tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
  • the compound of formula (17) may also be prepared by diazotising the compound of the formula (16) 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, hydrochloric acid, acetic acid and the like.
  • the reaction may be carried out in the presence of an organic solvent such as CHC1 3 , 1,4-dioxane, 1 tetrahydrofuran, acetone and the like.
  • the esterification of compound of formula (17) to give compound of formula (10) may be carried out using alkylating agent such as alcohol like methanol, ethanol, propanol, isopropanol, butanol and the like or mixtures thereof (or) alkyl sulfates such as methyl sulfate, ethyl sulfate and the like in the presence of acid such as sulfuric acid, methane sulfonic acid, hydrochloric acid, thionyl chloride, p-toluene sulphonic acid, or acidic resins such as amberlite, amberlist, INDION 130, INDION 140 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.
  • alkylating agent such as alcohol like methanol, ethanol, propanol,
  • 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 tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, tetrahydropyran(THP) etc, to protect hydroxyl or phenolic hydroxy group; N-tert- butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenyl methoxy carbonyl (-N-FMOC), benzophenoneimine, propargyloxy carbonyl (POC) etc, for protection of amino or anilino group, acetal protection for aldehyde, ketal protection for ketone and the like.
  • the methods of formation and removal of such prptecting, groups are tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbony
  • the reaction mixture was brought t ⁇ 70-80 °C and isopropyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- hydroxyphenyl)propanoate (30 g) and phenoxazine mesylate (27.15 g) were added at the same temperature under stirring. The reaction mixture was maintained for stirring. The reaction mixture was heated to 110-120 °C and maintained the reflux condition of toluene. Water was removed azeotropically and maintained the reaction mixture under reflux for 15-18 h. The reaction mixture was brought to 30-35 °C and cooled to 10-15 °C. Water (210 ml) was added and separated the toluene layer.
  • Step (iii) Preparation of ethyl (S)-3-r4-[2-(phenoxazin-10-yl)ethoxylphenyll-2-ethoxy propanoate To a stmed suspension of 60 % sodium hydride (16.3 g) in dimethylformamide (150 ml) at -5 to 5 °C, ethyl iodide (78.5 g) was added drop wise in about 10-15 min time.
  • the reaction mixture was brought to 70-80 °C and isopropyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- hydroxyphenyl)propanoate (30 g) and phenoxazine mesylate (27 ⁇ ..l5 g) were added at, the same temperature under stirring. The reaction mixture was maintained for stirring'. The reaction mixture was heated to 110-120 °C and maintained the reflux condition of toluene. Water was removed azeotropically and maintained the reaction mixture under reflux for 15-18 h. The reaction mixture was brought to 30-35 °C and cooled to 10-15 °C. Water (210 ml) was added and separated the toluene layer.
  • reaction mixture was cooled to 20 - 25 °C and 20 % sodium hydroxide solution (75 ml) was added slowly under stirring. After complete addition the reaction mixture was brought to 30-35 °C and maintained at that temperature for 6-8 under stirring. The reaction mixture was washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined ethyl acetates layers were washed with water (2 x 100 ml) and concentrated below 50 -60 °C till no more vapors of ethyl acetate were observed. Pet.
  • the reaction mixture was brought to 70-80 °C and isopropyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- ⁇ hydroxyphenyl)propanoate (30 g) and phenoxazine mesylate (27.15 g) were added at the same temperature under stirring. The reaction mixture was maintained for stirring. The reaction mixture was heated to 110-120 °C and maintained the reflux condition of toluene. Water was removed azeotropically and maintained the reaction mixture under reflux for 15-18 h. The reaction mixture was brought to 30-35 °C and cooled to 10-15 °C. Water (210 ml) was added and separated the toluene layer. The aqueous layer was extracted with toluene.
  • reaction mixture was cooled to 20 - 25 °C and 20 % sodium hydroxide solution (75 ml) was added slowly under stirring. After complete addition the reaction mixture was brought to 30-35 °C and maintained at that temperature for 6-8 under stirring. The reaction mixture was washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid. The aqueous layer was extracted with ' ethyl acetate. The combined ethyl acetates layers were washed with water (2 x 100 ml) and concentrated below 50 -60 °C till no more vapors of ethyl acetate were observed. Pet.
  • the analogues compound of formula (9) are also prepared using the solvents and acid given below following the procedure as described above:
  • the analogues compound of formula (10) are also prepared using the solvents given below following the procedure described above:
  • the analogues compound of formula (13) are also prepared using the solvents and base given below following the procedure described above:
  • the analogues compound of formula (9) are also prepared using the solvents and acidic resin given below following the procedure described above:
  • reaction mass was stirred for.further 10-12 h and brought to room temperature. After completion of the reaction, the reaction mass was added portion wise to chilled water (1.0 L). The two layers "were allowed to separate and the aqueous layer was washed with toluene (500 ml), acidified with 25 % sulphuric acid (100 ml) at 15-20 °C. The residue was extracted with toluene. The combined organic layers were washed with water (1.0 L) and concentrated to yield the title compound as thick syrup under vacuum below 100 °C (yield : Quantitative, purity 93-96 %). Step (vi)
  • analogues compounds of formula (10) are also prepared using the solvents and reagents given below following the procedure described above:

Abstract

The present invention relates to improved process for the preparation of antidiabetic compound having the formula (1). where R1 represents alkyl group such as methyl, ethyl, propyl, isopropyl and the like.

Description

IMPROVED PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE PHENOXAZINE DERIVATIVES AS ANTIDIABETIC AGENTS
Field of the invention
The present invention relates to improved process for the preparation of antidiabetic compound having the formula (1).
Figure imgf000002_0001
i ' '■ i . i where R represents alkyl group such as methyl, ethyl, propyl, isopropyl and the like.
The compounds of formula (I) are useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL).
The compound of formula (I) is also useful in reducing body weight and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
The present invention also relates to novel intermediate of formula (4) and their use in the preparation of compound of formula (I).
The present invention also describes an alternate process for the preparation of compound of formula (10).
Background of invention
In our WTO application No. 2416/MAS/97 we have described a process for the preparation of a novel antidiabetic compound having the formula (la). The process described therein comprises of converting aldehyde of formula (2a) where X represents hydrogen or halogen atom to a compound of formula (3 a) where all symbols are as defined above and R2 represents lower alkyl group, reducing the compound of formula (3a) to produce a compound of formula (4a), hydrolysing the compound of formula (4a) to obtain an acid of formula (5a), converting the acid of foπnula (5a) to an amide of the formula (6a) and hydrolysing trie amidέ to produce' the compound of foπnula (la), where X and R1 are as defined above. The process is shown in the scheme- 1 given below:
Figure imgf000003_0001
(la)
Scheme-1 While developing the improved process we observed that the process for the preparation of the cornpounds of the formula (la) as disclosed in our above referred, application involves
• the use of reactions like Wittig-Horner's, which is a moisture sensitive reaction, to prepare the compound of the formula (3 a). Moisture sensitive reactions are difficult to handle in large scale manufacturing process.
• tedious reaction steps employing expensive, time consuming column chromatographic methods
• the overall yield of the compounds of the formula (la) is only -2.5% and time cycle required for the completion of the reaction sequence resulting in the compounds of the formula (la) is very long which makes the process very
' expensive for commercial application .
In our copending application No. 2431/MAS/98 we have described .process, for preparing the compound of formula (la). The reaction schemes are shown below:
Figure imgf000004_0001
Scheme-2
' Though this is convergent synthetic method, the compound of formula (10a) is produced as racemic mixture, which has to be resolved to get the optically pure material.
Figure imgf000005_0001
Scheme-3
The process described above also required resolution of compound of formula (10a).
C02H C02H C02H C02R
HO' NH2
BnO' NH2 " OR' _
Bπθ' OR1
BnO'
(21) (22) (11a') (12a)
Figure imgf000005_0002
Scheme-4 Recognizing the importance of the new antidiabetic compound, we continued the research to develop a more efficient, simple and commercially viable stereoselective process for the preparation of the said novel compounds of the formula (la).
Objective of the present invention The main objective of the present invention- is to provide two simple and robust processes for the preparation of the compound of formula (1) with high chemical purity.
!■ I l Another objective of the present invention is to overcome the problem of partial racemization during the conversion of compound of formula (10) to compound of formula (11).
Yet another objective of the present invention is to avoid the use of highly reactive, difficult to handle and expensive chemicals replace 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 of compounds of the formula (1),
Figure imgf000006_0001
where . R1 represents (Cι-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like, which comprises :
(i) condensing the phenoxazine mesylate of the formula (2) with compound of formula (3) where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R2 represents hydrogen or (Cι-Ce)alkyl group defined above, in the presence of a base and an organic solvent at a temperature in the range of 20 to 150 °C, for a period in the range of 2 to 30 h, to give a compound of the formula (4) where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R represents hydrogen or (Cι-C6)alkyl group defined above, '' ' (ii) hydrolysing the compound of formula (4) to yield the compound of the formula (5) in the presence of a base or an acid and a solvent at a temperature in the range of 20 to 50 °C for 2 to 20 h,
(iii) converting the compound of formula (5) to a compound of formula (6) wherein R1 and R2 represent (Cι-C6)alkyl group > defined above, using alkylating
1 l' i , i agent in the presence of a base and a solvent at a temperature and duration in the range of .-10 to 70 °C and 1 to 24 h respectively, followed by hydrolysis to give compound of formula (7)
(iv) reacting the compound of formula (7) with L-arginine in the presence of a solvent at a temperature in the range of 10 to 80 °C, for a period in the range of 4 to
24 h, to yield compound of formula (1) where R1 is as defined above and
(v) isolating the compound of formula (1) formed by conventional methods.
The process explained above is shown in scheme-5 below:
Figure imgf000007_0001
Scheme-5
The condensation of mesylate of the formula (2) with compound of the formula (3) may be carried out in the presence of base such as sodium carbonate, potassium- carbonate, sodium hydroxide, potassium hydroxide and the like, using solvents such as toluene, xylene, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethylether, dimethylsulfoxide or alcohol such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 25 to 130 °C and the duration of the reaction may range from 2 to 20 h.
The hydrolysis of compound of the formula (4) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2C03, NaHCO3 and the like or acids such .as methane sulfonic acid, hydrochloric ιacid, sulfuric acid,, trifluoiOacetic acid, p-toluene sulfonic acid and the like. The hydrolysis may also be carried ' out in the presence of solvents such as alcohol selected from methanol, ethanol, propanol, isopropanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of 25 to 35 °C and the duration of the reaction may range from 2 to 15 h.
The conversion of compound of formula (5) to obtain compound of formula (6) 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, xylene, benzene and the like or dimethylformamide, dimethylsulfoxide, MIBK, ethyl acetate, N-methyl pyrrolidone and the like or mixtures thereof, in alkali bases such as sodiupi carbonate!, potassium carbonate, sodium methoxide, sodium hydride, n-butyl lithium, lithium diisoprόpyl amine and the like. The temperature of the reaction may be in the range of -5 to 60 °C.
The hydrolysis of compound of formula (6) to yield compound of formula (7) may be carried out in situ or in polar solvents such as alcohol namely methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents namely acetone, methyl ethyl ketone and the like using aqueous alkali bases such as sodium hydroxide or potassium hydroxide or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like.
The reaction of compound of formula (7) with L-arginine may be carried out in the presence of solvents like alcohol such as aqueous methanol, ethanol, propanol,, isopropanol and the like or mixtures thereof, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, 1,4-dioxane and the like. The temperature and duration of the reaction may be in the range of 40 to 55 °C and 12 to 18 h respectively. The compound of the formula (7) may be obtained in pure form using chiral amines 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, ethers like tetrahydrofuran, dioxane, diisopropyl ether and the like or hydrocarbons such as benzene, toluene, xylene, cyclohexane and the like or mixtures thereof at a temperature in the range of 25 °C to reflux temperature of the solvent used.
According to another embodiment of the present invention, there is provided an alternate process for the preparation of antidiabetic compound of formula (I)
Figure imgf000009_0001
where R1 represents, (Cι-C6)alkyl group such as methyl, ethy}, propyl, isopropyl,, butyl, isobutyl, t-butyl and the like, which comprises:
(i) -esterifying the pure compound of formula (8) using an alkylating agent in the presence of base or acid or acidic resin and a solvent at a temperature in the range of 30 °C to reflux temperature of the solvent for a period in the range of 2 to 20 h to produce pure compound of formula (9) where R represents (Ci-Cβ) alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like, (ii) debenzylating the compound of formula (9) using a metal catalyst in the presence of a solvent at a pressure in the range of 40 to 80 psi, to yield pure compound of foπnula (10) where R represents (Cι-C6) alkyl, (iii) reacting the compound of the formula (10) with phenoxazinyl mesylate of the fonmila (11) in the presence of a base and a solvent at a temperature m the range of 5 to 130 °C for a period in the range of 5 to 30 h to give a compound of the formula (12) where R represents (Ci-Cβ) alkyl group defined above, followed by hydrolysing the compound of formula (12) to a compound of foπnula (13), (iv) simultaneous etherification and esterification of the compound of formula (13) using an alkylating agent in the presence of a base and a solvent at a temperature and duration in the range of -5 to 60 °C and 1 to 24 h respectively, to obtain a compound of formula (14) where R and R1 represent (Cι-C6) alkyl group, (v) hydrolysing the compound of formula (14) to yield compound of the formula , (15) where R1 represents (Ci-Cg) alkyl group defined above in the presence of a base or an acid and a solvent at a temperature and duration in the range of 0 to 40 °C and 1 to 10 h,
(vi) reacting the compound of formula (15) with L-arginine in the presence of a solvent at a temperature and duration in the range of 10 to 80 °C and 4 to 24 h, to yield compound of formula (I) where R1 represents ( -Cβ) alkyl group 'defined' above and,
(vii) isolating the compound of formula (I) formed by conventional methods. . • The reaction scheme is shown in scheme-5 below:
Figure imgf000010_0001
Scheme-5 The esterification of compound of foπnula (8) may be carried out may be carried' out using alkylating agent such as alcohol such as methanol, ethanol, propanol, isopropanol, t-butanol and the like or alkyl sulfates such as methyl sulfate, ethyl sulfate and the like in the presence of acids such as sulfuric acid, methane sulfonic acid, hydrochloric acid, thionyl chloride, p-toluene sulphonic acid, or acidic resins such as amberlite, amberlist, INDION 130, INDION 140 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. The debenzylation of the compound of formula (9) may be carried out using metal catalysts such as Pd/C, Pt O, Ni, Pt H2 and the like, in the presence of solvents such as tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol- such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof. The reaction of compound of the formula (10) with the phenoxazinyl mesylate of the formula (11) to give compound of the formula (12) may be earned out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and the like and an organic solvent such as dimethylformamide, tetrahydrofuran, dimethylether, dimethylsulfoxide, N- methylpyrrolidone, DEA, toluene, xylene, acetone, MIBK, diethyl ketone, acetonitrile, alcohol such as methanol, ethanol, propanol, isopropanol and the like. The hydrolysis of a compound of formula (12) to compound of formula (13) may be carried out in a polar solvent such as alcohol selected from methanol, ethanol, propanol, isopropanol and the like or a ketonic solvent such as acetone, methyl ethyl ketone and the like, using aqueous alkali bases such as sodium hydroxide or potassium hydroxide or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like. The temperature may be in the range of 0 to reflux temperature of the solvent.
Simultaneous etherifϊcation and esterification of compound of formula (13) may be carried out using alkylating agents such as diethyl sulphate or alkyl halide such as methyl halide, ethyl halide, 2-propyl halide, t-butyl halide and the like in the presence of a solvent such as hydrocarbons namely benzene, toluene, xylene and the /027084
11 like or dimethylformamide, dimethylsulfoxide, MIBK, ethyl acetate, N'-methyl' pyrrolidorie and the like or a base such as sodium carbonate, potassium carbonate, NaH, NaOH, KOH, sodium methoxide, n-butyl lithium, lithium diisopropyl amine and the like. The temperature and duration may be in the range of -5 to 60 °C and 1 to 24 h respectively.
The hydrolysis of compound of formula (14) may be carried out in polar solvents such as alcohol namely methanol, ethanol, propanol, isopropanol and the like or ketonic solvents namely acetone, methyl ethyl ketone and the like using aqueous alkali bases such as sodium hydroxide or potassium hydroxide or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like to yield compound of formula (15). The duration of the reaction may be in the range of 6 to 8 h respectively.
The reaction of compound of formula (15) with L-arginine may be carried out in the presence of solvents like alcohol such as aqueous methanol, ethanol, propanol, isopropanol and the like; acetonitrile, dimethylformamide, dimethylsulfoxide, acetone, 1,4-dioxane and the like. The temperature and duration of the reaction may be in the range of 40 to 55 °C and 12 to 18 h respectively.
According to yet another embodiment of the present invention there is provided a novel intermediate of formula (4)
Figure imgf000012_0001
where R3 'represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R 2 represents hydrogen or (Cι-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like.
According to still yet another embodiment of the present invention there is provided a novel intermediate of formula (10)
Figure imgf000013_0001
where R represents (Cι-C6) alkyl group such as methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, t-butyl and the like, which comprises: \> , , ,
(i) (a) debenzylation of the compound of formula (8) to a compound of formula
(17) in 'the presence of a catalyst and a solvent at a pressure of 40 to 80 psi, to obtain a compound of formula (17) (or)
(b) diazotizing the compound of formula (16) by using a diazotizing agent, an acid and a solvent at a temperature and duration in the range of 0 to 40 °C and 15 min to
12 h respectively and
(ii) esterifying the compound of formula (17) in the presence of an alkylating agent or an alkyl sulfate, an acid or an acid resin or a base, to obtain a compound of formula (10).
The processes described in scheme-6 below:
Figure imgf000013_0002
The debenzylation of the compound of formula (8) may be carried out using metal catalysts such as Pd/C, Pt2O, Ni, Pt H2 and the like in the p'resence'of a' solvent such as tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof. Alternatively, the compound of formula (17) may also be prepared by diazotising the compound of the formula (16) 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, hydrochloric acid, acetic acid and the like. The reaction may be carried out in the presence of an organic solvent such as CHC13, 1,4-dioxane,1 tetrahydrofuran, acetone and the like. (Y. Kotake . Hoppe;> Seylers Z; Physiol. Chem 65 (1910) 397; Bernhard Wunsch; Liebagsd; Ann. Client. (1992) 39-45).
The esterification of compound of formula (17) to give compound of formula (10) may be carried out using alkylating agent such as alcohol like methanol, ethanol, propanol, isopropanol, butanol and the like or mixtures thereof (or) alkyl sulfates such as methyl sulfate, ethyl sulfate and the like in the presence of acid such as sulfuric acid, methane sulfonic acid, hydrochloric acid, thionyl chloride, p-toluene sulphonic acid, or acidic resins such as amberlite, amberlist, INDION 130, INDION 140 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. The (temperature, and duration in the range of reflux temperature of the solvent and 10 to 18 h respectively. 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 tertiarybutyldimethylsilyl, methoxymethyl, triphenyl methyl, benzyloxycarbonyl, tetrahydropyran(THP) etc, to protect hydroxyl or phenolic hydroxy group; N-tert- butoxycarbonyl (N-Boc), N-benzyloxycarbonyl (N-Cbz), N-9-fluorenyl methoxy carbonyl (-N-FMOC), benzophenoneimine, propargyloxy carbonyl (POC) etc, for protection of amino or anilino group, acetal protection for aldehyde, ketal protection for ketone and the like. The methods of formation and removal of such prptecting, 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.
Exaniple-l
Step (i)
Preparation of isopropyl S(-)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2- tertiarybutyl dimethyl silyloxy propanoate
Figure imgf000015_0001
In a 1 L four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and efficient stirrer, powdered K2C03 (74 g) and toluene (300 ml) was added at 30-35 °C under stirring. The reaction mixture was heated to 110-120 °C and maintained at reflux temperature of toluene for 2-3 h. Water was removed azeotropically till no more water droplets were observed. The reaction mixture was brought tø 70-80 °C and isopropyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- hydroxyphenyl)propanoate (30 g) and phenoxazine mesylate (27.15 g) were added at the same temperature under stirring. The reaction mixture was maintained for stirring. The reaction mixture was heated to 110-120 °C and maintained the reflux condition of toluene. Water was removed azeotropically and maintained the reaction mixture under reflux for 15-18 h. The reaction mixture was brought to 30-35 °C and cooled to 10-15 °C. Water (210 ml) was added and separated the toluene layer. The aqueous layer was extracted with toluene. The combined toluene layers were washed with DM water till pH becomes neutral. The toluene layer was concentrated on rotavapor bath at temperature <100 °C under vacuum till no more drops of toluene were observed. Methanol (150 ml) was added to the oily crude at room temperature, under stirring. The solution was allowed to stir at room temperature for 10-15 min, followed by cooling at 5-10 °C under stirring for 2 h. The precipitated product was filtered, washed with chilled methanol (60 ml) and dried under vacuum at 30-35 °C to yield the title compound as off-white to cream colour solid (34-36.5 g). Step (ii)
Preparation of (S)-3-[4-f2-(phenoxazin-10-yl)ethoxylphenyll-2-hydroxy propanoic acid
Figure imgf000016_0001
In a 2 L four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, isopropyl S(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- tertiarybutyl dimethyl silyloxy propanoate (35 g) and methanol (525 ml) were added at 30-35 °C under stirring, hydrochloric acid (58 ml) was added to the reaction mixture at 30- 35 °C. After complete addition, the reaction mixture was maintained at 30 - 35 °C for 12-15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 20 - 25 °C and 20 % sodium hydroxide solution (75 ml) was added slowly under stirring. After complete addition the reaction mixture was
I. , , . brought to 30-35 °C and maintained at that temperature for 6-8 under stirring. The reaction mixture was washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetates layers were washed with water (2 x 100 ml) and concentrated below 50 -60 °C till no more vapors of ethyl acetate were observed. Pet. ether (70 ml) was added to the residue at 30-35 °C under stirring. The reaction mixture was cooled to 5 - 10 °C. The precipitated product was filtered and dried to yield the title compound as light yellow to cream colored solid (18-20 g). Step (iii) Preparation of ethyl (S)-3-r4-[2-(phenoxazin-10-yl)ethoxylphenyll-2-ethoxy propanoate
Figure imgf000017_0001
To a stmed suspension of 60 % sodium hydride (16.3 g) in dimethylformamide (150 ml) at -5 to 5 °C, ethyl iodide (78.5 g) was added drop wise in about 10-15 min time. A solution of (S)-3,-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2r;hydroxγ propanoic, acid (40 g) in dimethylformamide (250 ml) was added drop wise at -5 °C to 0 °C. The reaction mass was brought to room temperature in 18-24 h time. Toluene (300 ml) was added to the reaction mass, cooled to 0 - 5 °C and water (800 ml) was added slowly. The reaction mass was stirred for about 10-15 min and the two layers were separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with water (400 ml) and concentrated to yield the title compound as thick symp. Step (iv)
Preparation of (S)-3-r4-[2-(phenoxazin-10-yl)ethoxy1phenyl"l-2-efhoxy propanoic acid
.
Figure imgf000017_0002
To a stirred solution of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoate (54 g) in methanol (200 ml) at 0 °C, 10 % aqueous NaOH solution (200 ml) was added slowly in about 15-20 min and then the reaction mixture was brought to room temperature and maintained at that temperature for 8 h. Water was added and the aqueous layer was washed with toluene, acidified with dilute sulfuric acid and extracted with toluene. The organic layer was washed with water and concentrated to yield the title compound as pale yellow to pale brown color solid (20 g)- . , , Step (v)
Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy]ρhenyl1-2-ethoxy propanoic acid L-arginine salt
Figure imgf000018_0001
A solution of L-arginine (2.07 g) in warm water (6.6 ml) was added' to a stirred' solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (5 g) in isopropanol (125 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound as white solid (5.25 g).
Example 2
Step (i)
Preparation of isopropyl S(-)-3-r4-r2-(phenoxazin-10-yl)ethoxylphenyll-2- tertiarybutyl dimethyl silyloxy propanoate
Figure imgf000018_0002
In a 1 L four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and efficient stirrer, powdered K2CO3 (74 g) and toluene (300 ml) was added at 30-35 °C under stirring. The reaction mixture was heated to 110-120 °C and maintained at reflux temperature of toluene for 2-3 h. Water was removed azeotropically till no more water droplets were observed. The reaction mixture was brought to 70-80 °C and isopropyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- hydroxyphenyl)propanoate (30 g) and phenoxazine mesylate (27ι..l5 g) were added at, the same temperature under stirring. The reaction mixture was maintained for stirring'. The reaction mixture was heated to 110-120 °C and maintained the reflux condition of toluene. Water was removed azeotropically and maintained the reaction mixture under reflux for 15-18 h. The reaction mixture was brought to 30-35 °C and cooled to 10-15 °C. Water (210 ml) was added and separated the toluene layer. The aqueous layer was extracted with toluene (90 ml x 2). The combined toluene layers were washed with DM water till pH becomes neutral. The toluene layer was concentrated on rotavapor bath at temperature <100 °C under vacuum till no more drops of toluene were observed. Methanol (150 ml) was added to the oily crude at RT, under stirring. The solution was allowed to stir at RT 'for 10-'l 5 minutes,' followed by cooling at 5-10 °C under stirring for 2 h. The precipitated product was filtered, washed with chilled methanol (60 ml) and dried under vacuum at 30-35 °C to yield the title compound as off-white to cream colour solid (34-36.5 g). Step (ii)
Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyll-2-hydroxy propanoic acid
Figure imgf000019_0001
In a 2 L four necked round bottom flask, fitted with a plain condenser and' - mechanical stirrer, isopropyl S(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- tertiarybutyl dimethyl silyloxy propanoate (35 g) and methanol (525 ml) were added at 30-35 °C under stirring, hydrochloric acid (58 ml) was added to the reaction mixture at 30- 35 °C. After complete addition, the reaction mixture was maintained at 30 - 35 °C for 12-15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 20 - 25 °C and 20 % sodium hydroxide solution (75 ml) was added slowly under stirring. After complete addition the reaction mixture was brought to 30-35 °C and maintained at that temperature for 6-8 under stirring. The reaction mixture was washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined ethyl acetates layers were washed with water (2 x 100 ml) and concentrated below 50 -60 °C till no more vapors of ethyl acetate were observed. Pet. ether (70 ml) was added to the residue at 30-35 °C under stirring. The reaction mixture was cooled to 5 - 10 °C. The precipitated product was filtered and dried to yield the title compound as light yellow to cream colored solid (18-20 g). Step (iii) Preparation of ethyl (S)-3-[4-r2-(phenoxazin-10-yl)ethoxy1pheιτyl1-2-ethoxy propanoate
Figure imgf000020_0001
To a stirred suspension of potassium carbonate (14 g) and dimethyl formamide (50 ml) (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propanoic acid (10 g) was added and temperature was raised to 50-60 °C, and diethylsulfate (11.5 g) was added slowly. The reaction mass was maintained at 50-60 °C for 12-14 h. After completion of the reaction, the reaction mass was dumped into water (200 ml) and extracted with ethylacetate. The combined organic layers were evaporated to yield title compound (10 g). Step (iv)
Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid
Figure imgf000020_0002
To a stirred solution of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoate (54 g) in methanol (200 ml) at 0 °C, 10 % aqueous NaOH solution (200 ml) was added slowly in about 15-20 min and then the reaction mixture was brought to room temperature and maintained at that temperature for 8 h. Water was added and the aqueous layer was washed with toluene, acidified with dilute sulfuric acid and extracted with toluene. The organic . layer was washed with water and concentrated to yield the title compound as pale yellow to pale brown color solid (20 g).
Step (v)
Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxylphenyll-2-ethoxy propanoic acid L-arginine salt
Figure imgf000021_0001
A solution of L-arginine (2.07 g) in warm water (6.6 ml) was added to a stiπed solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (5 g) in isopropanol (125 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound as white solid (5.25 g).
Example 3 Step (i)
Preparation of isopropyl S(-)-3-r4-[2-(phenoxazin-10-yl)ethoxy1phenyl"|-2- tertiarybutyl dimethyl silyloxy propanoate " ' '
Figure imgf000021_0002
In a 1 L four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and efficient stirrer, powdered K2CO3 (74 g) and toluene (300 ml) was added at 30-35 °C under stirring. The reaction mixture was heated to 110-120 °C and maintained at reflux temperature of toluene for 2-3 h. Water was removed azeotropically till no more water droplets were observed. The reaction mixture was brought to 70-80 °C and isopropyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4-< hydroxyphenyl)propanoate (30 g) and phenoxazine mesylate (27.15 g) were added at the same temperature under stirring. The reaction mixture was maintained for stirring. The reaction mixture was heated to 110-120 °C and maintained the reflux condition of toluene. Water was removed azeotropically and maintained the reaction mixture under reflux for 15-18 h. The reaction mixture was brought to 30-35 °C and cooled to 10-15 °C. Water (210 ml) was added and separated the toluene layer. The aqueous layer was extracted with toluene. The combined toluene layers were washed with DM water till pH becomes neutral. The toluene layer was concentrated on rotavapor bath at temperature <100 °C under vacuum till no more drops of toluene were observed. Methanol (150 ml) was added to the oily crude at RT, under .stirring. i The solution was allowed to stir at RT for 10-15 minutes, followed by cooling at 5- 10 °C under stirring for 2 h. The precipitated product was filtered, washed with chilled methanol (60 ml) and dried under vacuum at 30-35 °C to yield the title compound as off-white to cream colour solid (34-36.5 g). Step (ii) Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxylphenyll-2-hydroxy propanoic acid
Figure imgf000022_0001
In a 2 L four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, isopropyl S(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- tertiarybutyl dimethyl silyloxy propanoate (35 g) and methanol (525 ml) were added at 30-35 °C under stirring, hydrochloric acid (58 ml) was added to the reaction mixture at 30- 35 °C. After complete addition, the reaction mixture was maintained at 30 - 35 °C for 12-15 h under stirring. After completion of the reaction, the reaction mixture was cooled to 20 - 25 °C and 20 % sodium hydroxide solution (75 ml) was added slowly under stirring. After complete addition the reaction mixture was brought to 30-35 °C and maintained at that temperature for 6-8 under stirring. The reaction mixture was washed with toluene. The aqueous layer was acidified with cone, hydrochloric acid. The aqueous layer was extracted with' ethyl acetate. The combined ethyl acetates layers were washed with water (2 x 100 ml) and concentrated below 50 -60 °C till no more vapors of ethyl acetate were observed. Pet. ether (70 ml) was added to the residue at 30-35 °C under stirring. The reaction mixture was cooled to 5 - 10 °C. The precipitated product was filtered and dried to yield the title compound as light yellow to cream colored solid (18-20 g). Step (iii)
Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxylphenyll-2-ethoxy propanoic acid
Figure imgf000023_0001
To a stirred suspension of 60 % sodium hydride (16.3 g) in dimethylformamide (150 ml) at -5 to 5 °C, ethyl iodide (78.5 g) was added drop wise in about 10-15 min time. A solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propanoic acid (40 g) in dimethylformamide (250 ml) was added drop wise at -5 °C to 0 °C. The reaction mass was brought to room temperature in 18-24 h time. Toluene (300 ml) was added to the reaction mass, cooled to 0 to 5 °C and water (800 ml) was added slowly. The reaction mass was stirred for about 10-15 min and the two layers were separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with water (400 ml) and concentrated to obtain thick syrup. To the solution of thick syrup in methanol (200 ml) at 0 °C, 10 % aqueous NaOH solution (200 ml) was added slowly in about 15-20 min and then the reaction mixture was brought to room temperature and maintained at that temperature for 8 h. Water was added and the aqueous layer was washed with toluene, acidified with dilute sulfuric acid and extracted with toluene. The organic layer was washed with water and concentrated to yield the title compound as pale yellow to pale brown color solid (20 g). Step (iv)
Preparation of (S)-3-r4-[2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy propanoic acid L-arginine salt i. i ,
23
Figure imgf000024_0001
A solution of L-arginine (2.07 g) in warm water (6.6 ml) was added to a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (5 g) in isopropanol (125 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound as white solid (5.25 g). '■ ι ■
Example 4 Step (i)
Preparation of methyl S(-)-3-r4-r2-(phenoxazin-10-yl)ethoxylphenyl]-2 -tertiarybutyl dimethyl silyloxy propanoate
Figure imgf000024_0002
To a stnred suspension of methyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- hydroxyphenyl)propanoate (100 g), phenoxazine mesylate (108.2 g) and potassium carbonate.(111.2 g) in xylene (1.3 L), were added and heated under reflux with Dean-Stark apparatus for 6-9 h. After completion of the reaction, the reaction mass was cooled, water was added (500 ml), stirred for 15-30 min and separated. The aqueous layer was extracted with xylene (300 ml). The combined organic layer was washed with 1 % aqueous sulphuric acid solution (500 ml) and the organic layer was concentrated under vacuum below 100 °C to yield the title compound thick syrup (155 g). Step (ii) Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyll-2-hydroxy propanoic acid . 24 "• , . .
Figure imgf000025_0001
To a solution of methyl S(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- tertiarybutyl dimethyl silyloxy propanoate (100 g) in methanol (500 ml), p-toluene sulphonic acid (3.6 g) was added and refluxed until the starting material disappears (3-5 h). After completion of the reaction, the reaction mass was cooled and sodium hydroxide solution (155 ml of 10 % sol) was added slowly between 0-5 °C. After complete addition, the reaction mass was brought to room temperature and stirred
" I 1 • until the starting material disappears. After completion of the reaction, water (345 ml) was added and washed with toluene. The aqueous layer was acidified with dil. sulphuric acid (120 ml of 10 % sol) and the residue was extracted with ethyl acetate. The combined organic layers were washed with the water (2 x 300 ml), concentrated and pet-ether (1.0 L) was added while stirring and cooled to room temperature. The residue was filtered and dried at 60-70 °C under vacuum for 6-8 h to yield the title compound (45-47g). Step (iii)
Preparation of (S)-3-r4-[2-(phenoxazin-10-yl)ethoxy1phenyl'|-2-efhoxy propanoic acid
Figure imgf000025_0002
To a stirred suspension of NaH- (60 % suspension in mineral oil, 40.92 g) in toluene (700 ml) at 15-20 °C, diethylsulfate (98.46 g) was added slowly and stirred for 15-30 min. followed by the addition of a solution of (S)-3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-hydroxy propanoic acid (100 g) dissolved in N- methylpyrrolidone (200 ml) and diluted with toluene (.100 ml) in about 2-3 h at the same temperature. After complete addition, the reaction mass was stirred for further 10-12 h and brought to room temperature. After completion of the reaction, the reaction mass was added portion wise to chilled water (1.0 L). The two layers were allowed to separate and the aqueous layer was washed with toluene (500 ml), acidified with 25 % sulphuric acid (100 ml) at 15-20 °C. The residue was extracted with toluene. The combined organic layers were washed with water (1.0 L) and concentrated to yield the title compound as thick syrup under vacuum below 100 °C (yield: Quantitative, purity 93-96 %). Step (iv)
Preparation of (S)-3- 4- 2-(phenoxazin-10-yl)ethoxy]phenyll-2-ethoxy propanoic acid L-arginine salt
Figure imgf000026_0001
To a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (10 g) in isopropanol (250 ml) at 50-55 °C, a solution of L-Arginine in water (4.1 g in about 15 ml of water) was added in about 10-15 min time. After complete addition, the reaction mass was heated under reflux for about 12-18 h. The reaction mass was cooled to 50-55 °C and the product was filtered, washed with cold isopropanol (10 ml). The residue was dried under vacuum at 55-65 °C for 12-20 h to give the title compound as white to off white free flowing solid (10.5 g).
Example 5
Step (i) ' ii i Preparation of methyl S(-)-3-[4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2-tertiarybutyl dimethyl silyloxy propanoate
Figure imgf000026_0002
To a stirred suspension of methyl 2(S)-tertiary butyl dimethyl silyloxy-3-(4- hydroxyphenyl)propanoate (100 g), phenoxazine mesylate (108.2 g) and potassium carbonate (111.2 g) in xylene (1.3 L), were added and heated under reflux with Dean-Stark apparatus for 6-9 h. After completion of the reaction, the reaction mass was coole'd, water was added (500 ml), stirred for 15-30 min and separated. The aqueous layer was extracted with xylene. The combined organic layer was washed with 1 % aqueous sulphuric acid solution (500 ml) and the organic layer was concentrated under vacuum below 100 °C to yield the title compound thick syrup (155 g). Step (ii)
Preparation of (S)-3-r4-|"2-(phenoxazin-10-yl)ethoxy]phenyl1-2-hydroxy propanoic acid
Figure imgf000027_0001
To a solution of methyl S(-)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- tertiarybutyl dimethyl silyloxy propanoate (100 g) in methanol (500 ml), p-toluene sulphonic acid (3.6 g) was added and refiuxed until the starting material disappears
(3-5 h). After completion of the reaction, the reaction mass was cooled and sodium hydroxide solution (155 ml of 10 % sol) was added slowly between 0-5 °C. After complete addition, the reaction mass was brought to room temperature and stirred until the starting material disappears. After completion of the reaction, water (345 ml) was added and washed with toluene. The aqueous layer was acidified with dil. sulphuric acid (120 ml of 10 % sol) and the residue was extracted with ethyl acetate. The combined organic layers were washed with the water (2 x 300 ml), concentrated and pet-ether (1.0 L) was added while stirring and cooled to room temperature. The residue was filtered and dried at 60-70 °C under vacuum for 6-8 h to yield the title compound (45-47g). Step (iii) Preparation of (S)-3-[4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid
Figure imgf000028_0001
To a stirred suspension of NaH (60 % suspension in mineral oil, 40.92 g) in toluene
(700 ml) at 15-20 °C, diethylsulfate (98.46 g) was added slowly and stirred for 15-30 min and followed by the addition of a solution of (S)-3-[4-[2-(phenoxazin-iθ- yl)ethoxy]phenyl]-2-hydroxy propanoic acid (100 g) dissolved in dimethylformamide (500 ml) and diluted with toluene (100 ml) in about 2-3 h at the same temperature. After complete addition, the reaction mass was stiπed for further 10-12 h and brought to room temperature. After completion of the reaction, the reaction mass was added portion wise to chilled water (1.0 L). The two'layέrs were1 allowed to separate and the aqueous layer was washed with toluene (500 ml), acidified with 25 % sulphuric acid (100 ml) at 15-20 °C. The residue was extracted with toluene. The combined organic layers were washed with water (1.0 L) and concentrated to yield the title compound as thick syrup under vacuum below 100 °C. Step (iv) Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyl"|-2-efhoxy propanoic acid L-arginine salt
Figure imgf000028_0002
To a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (10 g) in isopropanol (250 ml) at 50-55 °C, a solution of L-Arginine in water (4.1 g in about 15 ml of water) was added in about 10-15 min time. After complete addition, the reaction mass was heated under reflux for about 12-18 h. The reaction mass was cooled to 50-55 °C and the product was filtered, washed with cold isopropanol (10 ml). The residue was dried under vacuum at 55-65 °C for 12-20 h to give the title compound as white to off white free flowing solid (10.5 g). Example-6 ■ ι, ,
Step (i)
Prepara'tion of isopropyl 2(S)-hydroxy-3 -(4-benzyloxyphenyl)propanoate
Figure imgf000029_0001
In a 50 ml 3 neck round bottom flask, fitted with a mechanical stirrer and reflux condenser 3-(4-benzyloxyphenyl)-2-hydroxypropanoic acid (3 g) isopropanol (30 ml) and sulfuric acid (0.3 ml) were taken and refluxed for 16 h. Refluxing was continued, till the starting material has disappeared on TLC. The reaction mass was cooled to room temperature and transfeπed into a distillation flask and concentrated on a rotavapour. The concentrated mixture was diluted with ethyl acetate (30 ml),, neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were washed with water (30 ml) and concentrated on a rotavapour under reduced pressure to yield the title compound, yield 90-97 %.
The analogues compound of formula (9) are also prepared using the solvents and acid given below following the procedure as described above:
Figure imgf000029_0002
Figure imgf000030_0003
Step (ii-) "
Preparation of isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate
Figure imgf000030_0001
In a 2 L parr hydrogenation flask isopropyl 3-(4-benzyloxyphenyl)-2(S)-hydroxy propanoate (200 g) obtained in step (i) above, isopropanol (1 L) and palladium carbon (5 %) were added and hydrogenated at 40-60 psi hydrogen pressure. After completion of the reaction, the catalyst was filtered and concentrated to give the title compound (135 g). > \- . , , .
The analogues compound of formula (10) are also prepared using the solvents given below following the procedure described above:
Figure imgf000030_0004
Step (iii)
Preparation of (S)-3-[4- (2-phenoxazin-10-yl)ethoxy1phenyl1-2-lιydroxy propanoic acid
Figure imgf000030_0002
In 500 ml RB flask isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate (10 g) obtained in step (ii) 'above, isopropanol (100 ml), potassium carbonate' (15 g) and' phenoxazin-10-yl ethyl methane sulfonate (15 g) were added and heated to reflux temperature with constant stirring. After completion of the reaction, the reaction mass was cooled to 5 - 10 °C and aqueous sodium hydroxide (10 %, 100 ml) was added slowly with constant stirring, then the reaction mass was allowed to reach to a temperature of 25 °C. After completion of the reaction, the aqueous layer was acidified with dil. hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate layers were evaporated to yield the title compound (12 g).
The analogues compound of formula (13) are also prepared using the solvents and base given below following the procedure described above:
Figure imgf000031_0002
Step (iy) -
Preparation of ethyl (S)-3-r4- 2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy propanoate
Figure imgf000031_0001
To a stirred suspension of potassium carbonate (14 g) and dimethyl fomiamide (50 ml) (S)-3-[4-[2-(phenoxaziιι-10-yl)ethoxy]phenyl]-2-hydroxy pr,<ppanoic(acid (10 g), obtained in step (iii) above, was added and temperature was raised to 50-60 °C, and diethylsulfate (11.5 g) was added slowly. The reaction mass was maintained at 50-60 °C for 12-14 h. After completion of the reaction, the reaction mass was dumped into water (200 ml) and extracted with ethylacetate. The combined organic layers were evaporated to yield title compound (10 g). Step (v)
Preparation of (S)-3-r4-F2-(phenoxazin-10-yl)ethoxy1phenyl"l-2-ethoxy propanoic acid
Figure imgf000032_0001
To a -stirred solution of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoate (5.0 g) obtained in step (iv) above in methanol (50 ml) at 0 °C, 10 % aqueous NaOH solution (50 ml) was added slowly in about 15-20 min and then the reaction mixture was brought to room temperature and maintained at that temperature for 8 h. Water was added and the aqueous layer was washed with toluene, acidified with dilute sulfuric acid and extracted with toluene. The organic layer was washed with water and concentrated to yield the title compound as thick symp (yield 4.8 g). Step (vi)
Preparation of (S)-,3- 4-r2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy, propanoic, acid L-arginine salt
Figure imgf000032_0002
A solution of L-arginine (1.16 g, 6.6 mmol) in warm water (3.7 ml) was added to a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (2.8 g) obtained in step (v) above in isopropanol (70 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction
' 1' i , i mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g).
ExampIe-7
Step (i)
Preparation of isopropyl 2(S)-hydroxy-3 -(4-benzyloxyphenyl)propanoate
Figure imgf000033_0001
In a 50 ml 3 neck round bottom flask, fitted with a mechanical stirrer and reflux condenser 3-(4-benzyloxyphenyl)-2-hydroxypropanoic acid (3 g) isopropanol (30 ml) and ajtnberlite resin (1.5 g) were taken and refluxed for 16 h. Refluxing was continued, till the starting material has disappeared on TLC. The reaction mass was cooled to room temperature and filtered the resin and transfeixed the filtrate into a distillation flask and concentrated on a rotavapour. The concentrated mixture was diluted with ethyl acetate, neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (30 ml) and concentrated on a rotavapour under reduced pressure to yield the title compound, yield 80-84 %.
The analogues compound of formula (9) are also prepared using the solvents and acidic resin given below following the procedure described above:
Figure imgf000033_0002
Figure imgf000034_0003
Step (ii)
Preparation of isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate
Figure imgf000034_0001
In a 2 L parr hydrogenation flask isopropyl 3-(4-benzyloxyphenyl)-2(S)-hydroxy propanoate (200 g) obtained in step (i) above, isopropyl alcohol (1000 ml) and palladium carbon (5 %, 20 g) were added and hydrogenated at 40-60 psi hydrogen pressure. After completion of the reaction, the catalyst was filtered and concentrated to give the title compound (135 g, yield 96 %).
Step (iii)
Preparation of isopropyl (S)-3-r4-r(2-phenoxazin-10-yl)ethoxy11ph'enyl"l-2- hydroxypnopanoate
Figure imgf000034_0002
In 500 ml RB flask isopropyl 3-(4-hydroxy phenyl)-2(S)-hydroxy propanoate (10 g, 0.04 M), dimethylformamide (100 ml), potassium carbonate (15 g, 0.11 M) and phenoxazin-10-yl ethyl methane sulfonate (15 g, 0.049M) were added and warmed to 70-80 °C with constant stirring. After completion of the reaction, the reaction mass was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water and concentrated to yield the title compound as a gummy material, which was taken for the next step with out purification. Part the gummy material was precipitated in cold methanol and characterized as isopropyl (S)-3-[4-[(2-phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxypropanoate.
The analogues compounds of formula (12) are also prepared using the solvents and base given below following the procedure described above:
Figure imgf000035_0002
Step (iv)
Preparation of (S)-3-[4-[(2-phenoxazin-10-yl)ethoxylphenyl1-2-hydroxy propanoic acid
Figure imgf000035_0001
Isopropyl (S)-3-[4-[(2-phenoxazin-10-yl)ethoxy]]phenyl]-2-hydroxy propanoate obtained in step (ii) above obtained in step (iii) above was dissolved in methanol (250 ml) and cooled to 0-5 °C. To this aqueous sodium hydroxide (10 %, 250 ml) was added slowly with constant stirring. The reaction was allowed to reach to a temperature of 20-30 °C and the reaction was monitored with TLC. After completion of the reaction, the reaction mixture was extracted with toluene and discarded. The aqueous layer was acidified with dil. hydrochloric acid and extracted with •toluene.' The toluene layer was evaporated and the gummy material was precipitated from ethyl acetate and hexane mixture to yield the title compound (yield 90 %).
The analogues compounds of formula (13) are also prepared using the solvents given below following the procedure described above:
Figure imgf000036_0002
Step (v)
I' i ,
Preparation of (S)-3-r4-r2-(phenoxazm-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid
Figure imgf000036_0001
To a stirred suspension of NaH (60 % suspension in mineral oil, 40.92 g) in toluene (700 ml) at 15-20 °C, diethylsulfate (98.46 g) was added slowly and stirred for 15-30 min and followed by the addition of a solution of (S)-3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-hydroxy propanoic acid (100 g) obtained in step (iv) above dissolved in N-methyl pyπolidone (200 ml) and diluted with toluene (100 ml) in about 2-3 h at the same temperature. After complete addition, the reaction mass was stirred for.further 10-12 h and brought to room temperature. After completion of the reaction, the reaction mass was added portion wise to chilled water (1.0 L). The two layers "were allowed to separate and the aqueous layer was washed with toluene (500 ml), acidified with 25 % sulphuric acid (100 ml) at 15-20 °C. The residue was extracted with toluene. The combined organic layers were washed with water (1.0 L) and concentrated to yield the title compound as thick syrup under vacuum below 100 °C (yield : Quantitative, purity 93-96 %). Step (vi)
Preparation of (S)-3-[4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid L-arginine salt
Figure imgf000037_0001
A solution of L-arginine (1.16 g, 6.6 mmol) in warm water (3.7 ml) was added to a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (2.8 g) obtained in step (v) above in isopropanol (70 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g, yield 75.0).
Example-8
Step (i)
Preparation of 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoic acid
Figure imgf000037_0002
In a 500 ml round bottomed flask, L-tyrosine (25 g), acetone (150 ml) and sulfiiric acid (21.2 g, in 150 ml of H2O) were place and stirred at RT to get clear solution. Then the reaction mass was cooled to 0 - 5 °C and NaN02 solution (32.3 g in 50 ml. H20) was added slowly over a period of 15 to 20 min. After complete addition of NaNO2, the reaction mixture was maintained at room temperature and allowed to stir for a period of 10 - 12 h. After completion of the reaction, the precipitated salts were filtered and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was 37 washed with water and concentrated to yield 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoic acid as dark reddish brown syrupy liquid (16 g, 15 %, purity 24 %). Step (ii) Preparation of isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate
Figure imgf000038_0001
A mixture of 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoic acid (14 g) obtained in step (i) above, isopropyl alcohol (140 ml), and sulfuric acid (1.4 ml) was taken in a 250 ml round bottom flask fitted with reflux condenser and refluxed for 16 - 18 h. After completion of the reaction, the reaction mass was diluted with ethyl acetate and washed with water and 5 % bicarbonate solution. The organic layer was evaporated to give the crude compound as brown colored liquid. The crude compound was purified with column chromatography using pet. ether and ethyl acetate to yield pure title compound (2.5 g, 15 %).
' I. I , ,
The analogues compounds of formula (10) are also prepared using the solvents and reagents given below following the procedure described above:
Figure imgf000038_0003
Step (iii)
Preparation of (S)-3-r4-|"(2-phenoxazin-10-yl)ethoxy1phenyl1-2-hydroxy propanoic acid
Figure imgf000038_0002
In 500 ml RB flask isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate (10 g) obtained in step (ii) above, isopropanol (100 ml), potassium carbonate (15 g) and phenoxazin-10-yl ethyl methane sulfonate (15 g) were added and heated to reflux temperature with constant stirring. After completion of the reaction, the reaction mass was cooled to 5 - 10 °C and aqueous sodium hydroxide (10 %, 100 ml) was added slowly with constant stirring. After complete addition, the reaction mass was allowed to reach to a temperature of 25 °C. After completion of the reaction, the aqueous layer was acidified with dil. hydrochloric acid and extracted with ethyl, . acetate. The combined ethyl acetate layers were evaporated to yield the title compound (12 g, yield 70 %, purity 95 %). Step (iv)
Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxylphenyl1-2-ethoxy propanoic acid
Figure imgf000039_0001
To a stored suspension of NaH (60 % suspension in mineral oil, 40.92 g) in toluene (700 ml) at 15-20 °C, diethylsulfate (98.46 g) was added slowly and stirrpd for 15-30, min and followed by the addition of a solution of (S)-3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-hydroxy propanoic acid (100 g) obtained in step (iii) above dissolved in dimethylformamide (500 ml) and diluted with toluene (100 ml) in about 2-3 h at the same temperature. After complete addition, the reaction mass was stirred for further 10-12 h and brought to room temperature. After completion of the reaction, the reaction mass was added portion wise to chilled water (1.0 L). The two layers were allowed to separate and the aqueous layer was washed with toluene, acidified with 25 % sulphuric acid (100 ml) at 15-20 °C. The residue was extracted with toluene. The combined organic layers were washed with water (1.0 L) and concentrated to yield the title compound as thick syrup under vacuum below 100 °C. Step (v) ' i' i , i Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy propanoic acid L-arginine salt
Figure imgf000040_0001
A solution of L-arginine (1.16 g, 6.6 mmol) in warm water (3.7 ml) was added to a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic' acid (2.8 g) obtained in step (iv) above in isopropanol (70 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g, yield 75.0).
ExampIe-9
Step (i)
Preparation of 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoic acid
Figure imgf000040_0002
In a 500 ml parr hydrogenation flask 3-(4-benzyloxyphenyι)-2(S)-hydroxy propanoic acid (20 g), isopropyl alcohol (100 ml) and palladium carbon (5 %, 20 g) were added and hydrogenated at 40-60 psi hydrogen pressure. After completion of the reaction, the catalyst was filtered and concentrated to give the title compound (12.4 g).
Step (ii)
Preparation of isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate
Figure imgf000040_0003
In a 500 ml RB flask 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoic acid (10 g), isopropyl alcohol (100 ml) obtained in step (i) above, and ion exchange resin
(INDION'- 140, 5 g) were added and heated to reflux temperature with constant stirring. After completion of the reaction, the resin was filtered off and the filtrate was evaporated to yield the title compound as dark brown colored syrupy liquid (85 %).
Step (iii)
Preparation of (S)-3-["4-r(2-phenoxazin-10-yl)ethoxylphenyl]-2-hydroxy propanoic acid
Figure imgf000041_0001
In 500 ml RB flask isopropyl 3-(4-hydroxyphenyl)-2(S)-hydroxy propanoate (10 g) obtained in step (ii) above, isopropanol (100 ml), potassium carbonate (15 g) and phenoxazin-10-yl ethyl methane sulfonate (15 g) were added and heated to reflux temperature with constant stirring. After completion of the reaction, the reaction mass was cooled to 5 - 10 °C and aqueous sodium hydroxide (10 %, 100 ml) was added slowly with constant stirring. After complete addition, the reaction mass was allowed to reach to a temperature of 25 °C. After completion of the reaction, the aqueous layer was acidified with dil. hydrochloric acid and extracted with ethyl' acetate. The combined ethyl acetate layers were evaporated to yield the title compound (12 g, yield 70 %, purity 95 %). Step ( v) Preparation of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy propanoate
Figure imgf000041_0002
To a stirred suspension of 60 % sodium hydride (1.02 g) in dimethylformamide (25 ml) at -5 to 0 C, ethyl iodide (9.84 g) was added drop wise in about 10-15 min time.. A solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propanoic acid (5'0 g) obtained in step (iii) above in dimethylformamide (25 ml) was added drop wise at -5 to 0 °C. The reaction mass was brought to room temperature in 18-24 h time. Water (25 ml) added to the reaction mass and extracted with toluene. The combined organic layers were washed with water (2 x 25 ml) and concentrated to yield the title compound as thick syrup (purity >90 %). Step (v)
Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid
Figure imgf000042_0001
To a stiπed solution of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoate (5.0 g) obtained in step (iv) above in methanol (50 ml) at 0 °C, 10 % aqueous NaOH solution (50 ml) was added slowly in about 15-20 min and then the reaction mixture was brought to room temperature and maintained at that temperature for 8 h. Water was added and the aqueous layer was washed with toluene, acidified with dilute sulfuric acid and extracted with toluene. The organic layer was washed with water and concentrated to yield the title compound as thick syrup (yield 4.8 g, 90.0 %). Step (vi)
Preparation of (S)-3-[4-r2-(phenoxazin-10-yl)ethoxylphenyl1-2-ethoxy propanoic acid L-arginine salt
Figure imgf000042_0002
A solution of L-arginine (1.16 g, 6.6 mmol) in warm water (3.7 ml) was added to a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (2.8 g) obtained in step (v) above in isopropanol (70 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was filtered, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g, yield 75.0). Advantages of the present process
• A new process for the preparation of the compound of foπnula (1) has been developed without employing exotic and expensive chemicals, which is commercially viable, simple and efficient with safe operations even in scale-up reactions. I, , , , .
• An easy resolution method has been developed by preparing the chiral amine salts instead of the round about procedure of preparing the diastereomeric amide of the formula (6) followed by its tedious hydrolysis.
• Wherever possible resolution has b>een avoided thereby reducing the number of steps and loss of compound.

Claims

We claim:
1. An improved process for the preparation of compounds of the formula (1),
Figure imgf000044_0001
wherein R represents (Cι-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like, which comprises :
(i) -condensing the phenoxazine mesylate of the formula (2)
Figure imgf000044_0002
with compound of foπnula (3)
Figure imgf000044_0003
where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R2 represents hydrogen or (C1-C6)alkyl group, in the presence of a base and an organic solvent-at'a temperature in the range of 20 to 150 °C, for a period in the range of 2 to 30 h, to give compound of the formula (4)
Figure imgf000044_0004
where R represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R" represents hydrogen or (Cι-C6)alkyl group, (ii) hydrolysing the compound of foπnula (4) to yield a compound of the foπrmla
(5) • ' .
Figure imgf000045_0001
of a base or an acid and a solvent at a temperature in the range of 20 to 50 °C for 2 to 20 h, (iii) converting the compound of formula (5) to a compound of formula (6) using alkylating agent in the presence of a base and a solvent
Figure imgf000045_0002
wherein R1 and R2 represent (Cι-C6)alkyl group, using an alkylating agent in the presence of a base and a solvent at a temperature and duration in the range of -10 to 70 °C and 1 to 24 h respectively, followed by hydrolysis to give compound of formula (7)
Figure imgf000045_0003
(iv) Teacting the compound of formula (7) with L-arginine, to yield compound of formula (1) where R is as defined above, in the presence of a solvent at a temperature in the range of 10 to 80 °C, for a period in the range of 4 to 24 h and (v) isolating the compound of formula (1) formed by conventional methods.
2. The process as claimed in claim 1, wherein the base used in step (i) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
3. The process as claimed in claims 1 and 2, wherein the solvent used in step (i) is selected from toluene, xylene, tetrahydrofuran, dimethylforaiamide, dimethylether, dimethylsulfoxide or, alcohol selected from methanol, ethanol, pr,opanol,(isopropanol, or mixtures thereof.
4. The process as claimed in claims 1 to 3, wherein the base used in step (ii) is selected from NaH, NaOH, KOH, t-BuOK or K2C03 or NaHC03.
5. The process as claimed in claims 1 to 4, wherein the acid used in step (ii) is selected from methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid or p-toluene sulfonic.
6. The process as claimed in claims 1 to 5, wherein the solvent used in step (ii) is selected from alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof. ' '' ' • ' '
7. The process as claimed in claims 1 to 6, wherein the temperature and duration in step (ii) of the reaction are in the range of 25 to 35 °C and 2 to 15 h respectively.
8. • The process as claimed in claims 1 to 7, wherein the alkylating agent used in step (iii) is selected from alkyl sulfates selected from diethyl sulphate or dimethylsulphate or alkyl halides selected from ethyl iodide or methyliodide.
9. The process as claimed in claims 1 to 8, wherein the solvent used in step (iii) is selected from toluene, xylene, benzene, dimethylformamide, dimethylsulfoxide, MIBK, ethyl acetate, N-methyl pyrrolidone or mixtures thereof.
10. The process as claimed in claims 1 to 9, wherein the base used in step (iii) is selected from as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, n-butyl lithium or lithium diisopropyl amine. '' ' '
11. The process as claimed in claims 1 to 10, wherein the temperature in step (iii) is in the range of -5 to 60 °C.
12. - The process as claimed in claims 1 to 11, wherein the hydrolysis in step (iii) is carried out in the presence of solvent selected from methanol, ethanol, propanol, isopropanol or mixtures thereof (or) methyl ethyl ketone.
13. The process as claimed in claims 1 to 12, wherein the hydrolysis in step (iii) is caπied out in the presence of alkali base selected from sodium hydroxide or potassium hydroxide or acid selected from methane sulfonic acid, hydrochloric acid, sulfuric acid or trifluoroacetic acid.
14. The process as claimed in claims 1 to 13, wherein the solvent used in step (iv) is selected from alcohol such as aqueous methanol, ethanol, propanol, isopropanol or' mixtures thereof, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone or 1 ,4-dioxane.
15. The process as claimed in claims 1 to 14, wherein the temperature and duration of the reaction in step (iv) are in the range of 40 to 55 °C and 12 to 18 h respectively.
16. The process as claimed in claims 1 to 15, wherein the reaction in step (iii) can also be carried out in the presence of a chiral amine selected from R(+)α- methylbenzylamine, , S(+) phenylglycinol, cinchonidine,, ephidrine, N- octylglucaramine, or N-methylglucaramine.
17. -The process as claimed in claims 1 to 16, wherein the reaction in step (iii) can also be carried out in the presence of a solvent selected from methyl acetate, ethyl acetate, ethyl propanoate or n-butylacetate (or) alcohol selected from methanol, ethanol, propanol or isopropanol (or) ketone selected from acetone or methyl isobutyl ketone (or) acetonitrile, ethers selected from tetrahydrofuran, dioxane or diisopropyl ether (or) hydrocarbons selected from benzene, toluene, xylene, cyclohexane or mixtures thereof.
18. An improved process for the preparation of compounds of the fonmila ( 1 ) ,
Figure imgf000047_0001
where R1 represents (Ci-Cδ) alkyl group, which comprises: (i) . esterifying the pure compound of formula (8)
Figure imgf000047_0002
using an alkylating agent in the presence of a base or an acid or acidic resin and a solvent at a temperature in the range of 30 °C to reflux temperature of the solvent for a period in the range of 2 to 20 h to produce compound of formula (9)
Figure imgf000048_0001
where R represents (Ci-Cβ) alkyl group,
(ii) debenzylating the compound of formula (9) using metal catalysts in the presence of a solvent at 40 to 80 psi, to yield a pure compound of formula ( 10)
Figure imgf000048_0002
where R represents (C]-C6) alkyl,
(iii) - reacting the compound of the formula (10) with phenoxazinyl mesylate of the foπnula (11)
Figure imgf000048_0003
s in the presence of a base and a solvent, at a temperature in the range of 5 to 130 °C for a period in the range of 5 to 30 h, to give compound of the formula (12)
Figure imgf000048_0004
where R represents (Ci-Ce) alkyl group, followed by hydrolysing the compound of formula (12) to a compound of formula (13),
Figure imgf000048_0005
(iv) simultaneous etherifying and esterifying the compound of formula (13) using an alkylating agent in the presence of a base and a solvent at a temperature in the range of -5 to 60 °C for a period in the range of 1 to 24 h to obtain compound of foπnula (14)
Figure imgf000049_0001
where R and R represent (Ci-Cβ) alkyl group,
(v) hydrolysing the compound of formula (14) to yield compound of the formula
(15)
Figure imgf000049_0002
where R represents (Cι-C6) alkyl group in the presence of a base or an acid and a solvent at a temperature and duration in the range of 0 to 40 °C and 1 to 10 h, (vi) reacting the compound of formula (15) with L-arginine in the presence of a solvent at a temperature and duration in the range of 10 to 80 °C, for a period in the range of 4 to 24 h, to yield compound of formula (I) where R1 represents (Cι-C6) alkyl group and (vii) isolating the compound of formula (I) formed by conventional methods.
1 . . . '' I 1, 1
19. The process as claimed m claim 18, wherein the alkylating agent used in step (i) is selected from alcohol selected from methanol, ethanol, propanol, isopropanol, t- butanol or an alkyl sulfate selected from methyl sulfate or ethyl sulfate.
20. " The process as claimed in claims 18 and 19, wherein the acid used in step (i) is selected from sulfuric acid, methane sulfonic acid, hydrochloric acid, thionyl chloride or p-tolune sulfonic acid.
21. The process as claimed in claims 18 to 20, wherein the acidic resin used in step (i) is selected from amberlite, amberlist, INDION 130 or INDION 140.
22. The process as claimed in claims 18 to 21, wherein the base used in step (i) 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 '
49
23. The process as claimed in claims 18 to 22, wherein the metal catalyst used in step (ii) is selected from Pd/C Pd/C, Pt20, Ni or Pt/H2.
24. The process as claimed in claims 18 to 23, wherein the solvent used in step (ii) is selected from tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol such as methanol, ethanol, propanol, isopropanol or mixtures thereof.
25. The process as claimed in claims 18 to 24, wherein the base used in step (iii) is selected from sodium carbonate, potassium carbonate, cesium carbonate or potassium bicarbonate.
26. The process as claimed in claims 18 to 25, wherein the solvent used in s ep' (iii) is __ selected from dimethylformamide, tetrahydrofuran, dimethylether, dimethylsulfoxide, N-methyl pyrrolidone, diethylamine, toluene, xylene, acetone, MIBK, diethyl ketone, acetonitrile, alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
27. The process as claimed in claims 18 to 26, wherein the hydrolysis in step (iii) is carried out in the presence of a polar solvent selected from alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof (or) a ketonic solvent selected from acetone or methyl ethyl ketone.
28. The process as claimed in claims 18 to 27, wherein the hydrolysis in step (iii) is carried out in the presence of an aqueous alkali base selected from sodium hydroxide or potassium hydroxide or an acid selected from methane sulfonic acid,' hydrochloric acid, sulfuric acid or trifluoroacetic acid.
29. The process as claimed in claims 18 to 28, wherein the hydrolysis in step (iii) is carried out at a temperature in the range of 0 to reflux temperature of the solvent used.
30. The process as claimed in claims 18 to 29, wherein the alkylating agent used in step (iv) is selected from diethyl sulphate or dimethylsulphate (or) an alkyl halide selected from methyl halide, ethyl halide, 2-propyl h'alide or t-butyl halide.
31. The process as claimed in claims 18 to 30, wherein the solvent used in step (iv) is selected from alcohol selected from methanol, ethanol, propanol, isopropanol or t-butanol or mixtures thereof (or) a hydrocarbon selected from benzene, toluene, ' i' i , i
50 xylene,' dimethylformamide, dimethylsulfoxide, MIBK, ethyl acetate or N-methyl pyrrolidone.
32. The process as claimed in claims 18 to 31, wherein the base used in step (iv) is selected from sodium carbonate, potassium carbonate, NaH, NaOH, KOH, sodium methoxide, n-butyl lithium or lithium diisopropyl amine.
33. The process as claimed in claims 18 to 32, wherein the temperature and duration in step (iv) are in the range of -5 to 60 °C and 1 to 24 h respectively
34. The process as claimed in claims 18 to 33, wherein the solvent used in step (v) is selected from alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures there of '(or) a ketonic solvent selected from acetone or methyl ethyL ketone
35. 'The process as claimed in claims 18 to 34, wherein the base used in step (v) is selected from sodium hydroxide or potassium hydroxide.
36. The process as claimed in claims 18 to 35, wherein the acid used in step (v) is selected from methane sulfonic acid, hydrochloric acid, sulfuric acid or trifluoroacetic acid.
37. The process as claimed in claims 18 to 36, wherein the duration of the reaction in step (v) of the reaction is in the range of 6 to 8 h.
38. The process as claimed in claims 18 to 37, wherein the solvent used in step (vi) is selected from alcohol selected from aqueous methanol, ethanol, propanol, isopropanol or mixtures thereof, acetonitrile, dimethylforaiamide,, dimethylsulfoxide, acetone or 1,4-dioxane.
39. The process as claimed in claims 18 to 38, wherein the temperature and duration of the reaction in step (vi) are in the range of 40 to 55 °C and 12 to 18 h respectively.
40. A process for the preparation of compound of formula (10)
Figure imgf000051_0001
where R represents (Cι-C6) alkyl group such as methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, t-butyl and the like, which comprises: (i) (a)- debenzylation of the compound of formula (8)
Figure imgf000052_0001
to a compound of formula (17) in the presence of a catalyst and a solvent at a pressure in the range of 40 to 80 psi, to obtain a compound of formula (17)
Figure imgf000052_0002
(or)
(b) diazotizing the compound of formula (16)
Figure imgf000052_0003
by using a diazotizing agent, an acid and a solvent at a temperature and duration in the range of 0 to 40 °C and 15 min to 12 h respectively, to obtain a compound of fonmila (17) and
(ii) esterifying the compound of foπnula (17), in the presence of an alkylating agent or an alkyl sulfate, an acid or an acid resin and a base, to obtain a compound of formula (10).
41. The process as claimed in claim 40, wherein, the catalyst used in step (i)(a) of the reaction is carried out in the presence of the catalyst selected from Pd/C Pd/C,
Pt20, Ni or Pt/H2.
42. The process as claimed in claim 40 and 41, wherein the solvent used in step
(i)(a) of the reaction is selected from tetrahydrofuran, aqueous acetic acid, ethyl acetate, aqueous or non aqueous alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
43. The process as claimed in claim 40 to 42, wherein the diazotizing agent used in step (i)(b) of the reaction is selected from sodium nitrite, isoamyl nitrite, potassium nitrite or ammonium nitrite. i' i i •
44. The process as claimed in claim 40 to 43, wherein the acid used in step (i)(b) of the reaction is selected from sulfuric acid, hydrochloric acid or acetic acid.
45. The process as claimed in claim 40 to 44, wherein the acid used in step (i)(b) of the reaction is selected from CHC1 , 1,4-dioxane, tettahydrofuran or acetone.
46. The process as claimed in claim 40 to 45, wherein the alkylating agent used in step (ii) is chosen from alcohol selected from methanol, ethanol, propanol, isopropanol, butanol and the like or mixtures thereof (or) an alkyl sulfate selected from methyl sulfate or ethyl sulfate.
47. The process as claimed in claim 40 to 46, wherein the acid used in step (ii) is selected from acid, methane sulfonic acid, hydrochloric acid, thionyl chloride or p- toluene sulphonic acid. ι, , , ,
48. The process as claimed in claim 40 to 47, wherein the acid resin used in step (ii) of the reaction is selected from amberlite, amberlist, INDION 130 or INDION 140.
49. The process as claimed in claim 40 to 48, wherein the base used in step (ii) of the reaction is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkoxides selected from sodium ethoxide or potassium tertiary butoxide (or) triethyl amine.
50. The process as claimed in claim 40 to 49, wherein the temperature and duration in step (ii) of the reaction is maintained at the reflux temperature of the solvent used and 10 to 18 h respectively.
51. A process for, the preparation of compound of the formula (I) as described in, claims 1-50, substantially as herein described with reference to examples 1-9.
52. 'Arϊ intermediate of formula (4)
Figure imgf000053_0001
where R3 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R2 represents hydrogen or (Cι-C6)alkyl group.
PCT/IB2002/003947 2001-09-25 2002-09-25 Improved process for the preparation of optically active phenoxazine derivatives as antidiabetic agents WO2003027084A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019152A2 (en) * 2003-06-06 2005-03-03 Cadila Healthcare Limited Process for preparing 3-aryl-2-hydroxy propanoic acid derivatives without resolution
WO2013072915A1 (en) * 2011-11-15 2013-05-23 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Tricyclic compounds, compositions comprising them and uses thereof
WO2014181362A1 (en) 2013-05-09 2014-11-13 Council Of Scientific & Industrial Research A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

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Publication number Priority date Publication date Assignee Title
WO2000026200A1 (en) * 1998-10-29 2000-05-11 Dr. Reddy's Research Foundation An improved process for the preparation of new antidiabetic agents
WO2000066572A1 (en) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents

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Publication number Priority date Publication date Assignee Title
WO2000026200A1 (en) * 1998-10-29 2000-05-11 Dr. Reddy's Research Foundation An improved process for the preparation of new antidiabetic agents
WO2000066572A1 (en) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Substituted bicyclic heterocycles, process for their preparation and their use as antiobesity and hypocholesterolemic agents

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019152A2 (en) * 2003-06-06 2005-03-03 Cadila Healthcare Limited Process for preparing 3-aryl-2-hydroxy propanoic acid derivatives without resolution
WO2005019152A3 (en) * 2003-06-06 2005-08-11 Cadila Healthcare Ltd Process for preparing 3-aryl-2-hydroxy propanoic acid derivatives without resolution
WO2013072915A1 (en) * 2011-11-15 2013-05-23 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Tricyclic compounds, compositions comprising them and uses thereof
US9447040B2 (en) 2011-11-15 2016-09-20 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Tricyclic compounds, compositions comprising them and uses thereof
WO2014181362A1 (en) 2013-05-09 2014-11-13 Council Of Scientific & Industrial Research A process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds
US9550719B2 (en) 2013-05-09 2017-01-24 Council Of Scientific And Industrial Research Process for the preparation of 3-aryl-2-hydroxy propanoic acid compounds

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