WO2003008397A1 - An improved process for the preparation of antidiabetic phenoxazine compounds - Google Patents
An improved process for the preparation of antidiabetic phenoxazine compounds Download PDFInfo
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- WO2003008397A1 WO2003008397A1 PCT/IB2002/002776 IB0202776W WO03008397A1 WO 2003008397 A1 WO2003008397 A1 WO 2003008397A1 IB 0202776 W IB0202776 W IB 0202776W WO 03008397 A1 WO03008397 A1 WO 03008397A1
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- 0 COc1ccc(C[C@@](*)O*)cc1 Chemical compound COc1ccc(C[C@@](*)O*)cc1 0.000 description 3
- ICFDTWPLDBJRBV-UHFFFAOYSA-N CN1c(cccc2)c2Oc2c1cccc2 Chemical compound CN1c(cccc2)c2Oc2c1cccc2 ICFDTWPLDBJRBV-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
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- 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 an improved process for the preparation of antidiabetic compounds having the formula (1).
- R 1 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert- butyl and the like.
- the compound of formula (I) is useful in lowering the plasma glucose, rriglyceride, 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 (lb) and their use in the preparation of compound of formula (I).
- the main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical and chiral purity. To overcome the problem of partial racemization during the conversion of compound of formula (10) to compound of formula (11).
- the present invention provides an improved process for the preparation of compounds of the formula (1),
- R 1 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert- butyl and the like, which comprises :
- the reaction of the compound of the formula (la) with alkyl haloacetates such as methyl chloroacetate, methylbromoacetate, ethylchloroacetate, ethylbromoacetate, and the like to yield glycedic ester of the formula (lb) may be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and the like.
- the reaction may also be carried out in the presence of solvents 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 -10 to 60 °C and the duration of the reaction may range from 2-12 h.
- the opening up of epoxide group of the glycedic ester of the compound of the formula (lb) may be carried out using reagents such as Raney Nickel, t ⁇ /Pd-C, borane reagents, and the like.
- the reaction may be carried out in the presence of solvents 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 0 to 50 °C and the duration of the reaction may range from 1 to 36 h.
- the hydrolysis of compound of the formula (Ic) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K 2 CO , NaHCO 3 and the like.
- the hydrolysis may also be carried out in the presence of solvents such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
- the resolution of compound of formula (Id) may be carried out using chiral amine such as R(+) ⁇ -methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like using solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or mixtures thereof.
- chiral amine such as R(+) ⁇ -methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like using solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or mixtures thereof.
- Simultaneous etherification and esterification of compound of formula (Ie) to obtain compound of formula (If) may be carried out using alkylating agents such as diethyl sulphate, ethyl iodide or ethanol, in the presence of solvents such as hydrocarbons like benzene, toluene, xylene and the like or diemthyl formamide (DMF), dimethylsulfoxide (DMSO), methyl isobutylketone (MIBK), ethyl acetate and the like or mixtures thereof in alkali such as NaH, NaOH, KOH, t-BuOK, K 2 CO 3 , NaHCO , sodium methoxide and the like.
- alkylating agents such as diethyl sulphate, ethyl iodide or ethanol
- solvents such as hydrocarbons like benzene, toluene, xylene and the like or diemthyl formamide (
- the hydrolysis of compound of formula (If) may be carried out in polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof by using aqueous an alkali base such as sodium hydroxide or potassium hydroxide to yield compound of formula (Ig).
- polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof
- ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof
- reaction of compound of formula (Ig) with L-arginine may be carried out in the presence of solvents such as (Ci-C ⁇ ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like or mixtures thereof at a temperature in the range of 10 to 40 °C, for a period in the range of 4 to 24 h.
- solvents such as (Ci-C ⁇ ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like or mixtures thereof at a temperature in the range of 10 to 40 °C, for a period in the range of 4 to 24 h.
- R 1 represents alkyl group such as ethyl, ethyl, propyl, isopropyl, butyl, tert- butyl and the like, which comprises : (i) reacting the compound of formula (la) with alkyl haloacetates in the presence of a base and a solvent at a temperature in the range of -10 to 60 °C (Darzen's condensation), for 2 to 12 h, to yield the glycedic ester of compound of formula (lb), where R 2 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, ter- butyl and the like,
- the reaction of the compound of the formula (la) with alkyl haloacetates such as methyl chloroacetate, methylbromoacetate, ethylchloroacetate, ethylbromoacetate, and the like to yield glycedic ester of the formula (lb) may be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and the like.
- the reaction may also be carried out in the presence of solvents such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof, at a temperature in the range of -10 to 60 °C and the duration of the reaction may range from 2 to 12 h.
- the opening up of epoxide group of the glycedic ester of the compound of the formula (lb) may be carried out using reagents such as Raney Nickel, H 2 /Pd-C, borane reagents, and the like.
- the reaction may be carried out in the presence of solvents 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 0 to 50 °C and the duration of the reaction may range from 1 to 36 h.
- (Ih) may be carried out using alkylating agents such as diethyl sulphate, ethyl iodide or ethanol, in the presence of solvents such as hydrocarbons like benzene, toluene, xylene and the like or DMF, DMSO, MIBK, ethyl acetate and the like in alkali such as NaH, NaOH, KOH, t-BuOK, K 2 CO 3 , NaHCO 3 , sodium methoxide and the like.
- alkylating agents such as diethyl sulphate, ethyl iodide or ethanol
- solvents such as hydrocarbons like benzene, toluene, xylene and the like or DMF, DMSO, MIBK, ethyl acetate and the like in alkali such as NaH, NaOH, KOH, t-BuOK, K 2 CO 3 , NaHCO 3 , sodium methoxide
- the hydrolysis of compound of formula (Ih) may be carried out in polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof, by using an aqueous alkali base such as sodium hydroxide or potassium hydroxide, to yield a compound of formula (Ii).
- polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof
- ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof
- the resolution of compound of formula (Ii) may be carried out using chiral amine such as R(+) ⁇ -methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like using solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or mixtures thereof, to obtain a compound of formula (Ig).
- chiral amine such as R(+) ⁇ -methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like
- solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or mixtures thereof
- reaction of compound of formula (Ig) with L-arginine may be carried out in the presence of solvents like (Ci-C ⁇ ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like at a temperature in the range of 10 - 40 °C, for a period in the range of 4-24 h.
- solvents like (Ci-C ⁇ ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like at a temperature in the range of 10 - 40 °C, for a period in the range of 4-24 h.
- 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 protecting groups are those conventional methods appropriate to the molecule being protected.
- reaction mass was brought to room temperature in 18-24 h time.
- Water (25 ml) added to the reaction mass and extracted with toluene (3 x 50 ml).
- the combined organic layers were washed with water (2 x 25 ml) and concentrated to yield the title compound as thick syrup (purity >90 %).
- reaction mass was cooled to 50-55 °C and the compound was flitted, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g, 75.0 %, purity 99.27, diastereomer 0.41 %).
Abstract
The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula (1) where R1 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group and the like.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF ANTIDIABETIC PHENOXAZINE COMPOUNDS.
Field of the invention
The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula (1).
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 (lb) and their use in the preparation of compound of formula (I).
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 (1). The process described therein comprises of converting aldehyde of formula (2) where X represents hydrogen or halogen atom to a compound of formula (3) where all symbols are as defined above and R2 represents lower alkyl group, reducing the compound of formula
(3) to produce a compound of formula (4), hydrolysing the compound of formula (4) to obtain an acid of formula (5), converting the acid of formula (5) to an amide of the
formula (6) and hydrolysing the amide to produce the compound of formula (1), where X and R are as defined above. The process is shown in the scheme -1 given below
(1)
Scheme-1 While developing the improved process we observed that the process for the preparation of the compounds of the formula (1) as disclosed in our above referred application involves
• the use of exotic reactions like Wittig-Homer reaction, which is a moisture sensitive reaction, to prepare the compound of the formula (3). Moisture sensitive reactions are difficult to handle in large scale manufacturing process.
• tedious reaction steps employing expensive, tedious and time consuming column chromatographic methods
• the overall yield of the compounds of the formula (1) is only -2.5% and time cycle required for the completion of the reaction sequence resulting in the compounds of the formula (1) is very long which makes the process very expensive for commercial application .
In our PCT application no. IB99/00684 (publication no. WO 00/26200) we have described process for preparing the compound of formula (1). The reaction schemes are shown below:
Scheme-2 Though it is convergent synthetic method, the compound of formula (10) is produced in racemic mixture, which has to be resolved to get the optically pure material.
Schemes 3 and 4 also disclose an alternate process for the preparation of compound of formula (10).
Scheme-3
In this process also the resolution has to be carried out for compound of formula (10).
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 (1).
Objective of present invention The main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical and chiral purity. To overcome the problem of partial racemization during the conversion of compound of formula (10) to compound of formula (11).
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),
where R1 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert- butyl and the like, which comprises :
(i) reacting the compound of formula (la) with alkyl haloacetates in the presence of a base and a solvent at a temperature in the range of -10 to 60 °C (Darzen's condensation) for 2 to 12 h, to yield the glycedic ester of compound of formula (lb), where R2 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert- butyl and the like,
(ii) opening the epoxide group of the glycedic ester of the compound of the formula (lb) using reducing agent in the presence of a solvent at a temperature in the range of 0 to 50 °C (Darzen's condensation) for 1 to 36 h, to yield a compound of the formula (Ic) where R2 is as defined above, (iii) hydrolysing the compound of the formula (Ic) by conventional methods to yield compound of the formula (Id),
(iv) resolving the compound of formula (Id) using chiral amines in the presence of solvent to produce compound of (Ie)
(v) simultaneous etherification and esterification of compound of formula (Ie) using alkylating agent in the presence of a base and a solvent to obtain crude compound of formula (If) where R and R are as defined above,
(vi) hydrolysing the compound of formula (If) to yield pure (S)-alkoxy compound of the formula (Ig) where R1 is as defined above in the presence of a base and solvent, (vii) reacting the compound of formula (Ig) with L-arginine in the presence of a solvent at a temperature in the range of 10 to 40 °C, for 4 to 24 h, to yield compound of formula (1) where R1 is as defined above and
(viii) isolating the compound of formula (I) formed by conventional methods.
The reaction scheme is shown in scheme-5 below:
Scheme - 5
The reaction of the compound of the formula (la) with alkyl haloacetates such as methyl chloroacetate, methylbromoacetate, ethylchloroacetate, ethylbromoacetate, and the like to yield glycedic ester of the formula (lb) may be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and the like. The reaction may also be carried out in the presence of solvents 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 -10 to 60 °C and the duration of the reaction may range from 2-12 h.
The opening up of epoxide group of the glycedic ester of the compound of the formula (lb) may be carried out using reagents such as Raney Nickel, t^/Pd-C, borane reagents, and the like. The reaction may be carried out in the presence of solvents 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 0 to 50 °C and the duration of the reaction may range from 1 to 36 h.
The hydrolysis of compound of the formula (Ic) may be carried out in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K2CO , NaHCO3 and the like. The hydrolysis may also be carried out in the presence of solvents such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.
The resolution of compound of formula (Id) may be carried out using chiral amine such as R(+) α-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like using solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or mixtures thereof.
Simultaneous etherification and esterification of compound of formula (Ie) to obtain compound of formula (If) may be carried out using alkylating agents such as diethyl sulphate, ethyl iodide or ethanol, in the presence of solvents such as hydrocarbons like benzene, toluene, xylene and the like or diemthyl formamide (DMF), dimethylsulfoxide (DMSO), methyl isobutylketone (MIBK), ethyl acetate and the like or mixtures thereof in alkali such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCO , sodium methoxide and the like.
The hydrolysis of compound of formula (If) may be carried out in polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof by using aqueous an alkali base such as sodium hydroxide or potassium hydroxide to yield compound of formula (Ig).
The reaction of compound of formula (Ig) with L-arginine may be carried out in the presence of solvents such as (Ci-Cό) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like or mixtures thereof at a temperature in the range of 10 to 40 °C, for a period in the range of 4 to 24 h.
According to another embodiment of the present invention there is provided a process for the preparation of compounds'of the formula (1),
where R1 represents alkyl group such as ethyl, ethyl, propyl, isopropyl, butyl, tert- butyl and the like, which comprises :
(i) reacting the compound of formula (la) with alkyl haloacetates in the presence of a base and a solvent at a temperature in the range of -10 to 60 °C (Darzen's condensation), for 2 to 12 h, to yield the glycedic ester of compound of formula (lb), where R2 represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, ter- butyl and the like,
(ii) opening the epoxide group of the glycedic ester of the compound of the formula (lb) using reducing agent in the presence of a solvent, at a temperature in the range of 0 to 50 °C and the duration of the reaction may range from 1 to 36 h, to yield a compound of the formula (Ic) where R2 is as defined above, (iii) alkylating the compound of the formula (Ic) using alkylating agent in the presence of a solvent and a base to yield compound of the formula (Ih) where R1 and R2 are as defined above,
(iv) hydrolysing the compound of formula (Ih) to yield acid of the formula (Ii) where R1 is as defined above in the presence of a base and a solvent, (v) resolving the compound of formula (Ii) using chiral amines in the presence of solvent to produce compound of (Ig) where R1 is as defined above, (vi) reacting the compound of formula (Ig) with L-arginine in the presence of a solvent to yield compound of formula (1) where R1 is as defined above and (vii) isolating the compound of formula (I) formed by conventional methods.
The reaction scheme is shown in scheme-6 below:
The reaction of the compound of the formula (la) with alkyl haloacetates such as methyl chloroacetate, methylbromoacetate, ethylchloroacetate, ethylbromoacetate, and the like to yield glycedic ester of the formula (lb) may be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and the like. The reaction may also be carried out in the presence of solvents such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof, at a temperature in the range of -10 to 60 °C and the duration of the reaction may range from 2 to 12 h.
The opening up of epoxide group of the glycedic ester of the compound of the formula (lb) may be carried out using reagents such as Raney Nickel, H2/Pd-C, borane reagents, and the like. The reaction may be carried out in the presence of solvents 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 0 to 50 °C and the duration of the reaction may range from 1 to 36 h.
The alkylation of compound of formula (Ic) to obtain compound of formula
(Ih) may be carried out using alkylating agents such as diethyl sulphate, ethyl iodide or ethanol, in the presence of solvents such as hydrocarbons like benzene, toluene, xylene and the like or DMF, DMSO, MIBK, ethyl acetate and the like in alkali such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCO3, sodium methoxide and the like.
The hydrolysis of compound of formula (Ih) may be carried out in polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof (or) ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof, by using an aqueous alkali base such as sodium hydroxide or potassium hydroxide, to yield a compound of formula (Ii).
The resolution of compound of formula (Ii) may be carried out using chiral amine such as R(+) α-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like using solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or mixtures thereof, to obtain a compound of formula (Ig).
The reaction of compound of formula (Ig) with L-arginine may be carried out in the presence of solvents like (Ci-Cβ) alcohols such as aqueous methanol, ethanol, propanol, isopropanol and the like at a temperature in the range of 10 - 40 °C, for a period in the range of 4-24 h.
According to another embodiment of the present invention there is provided a novel intermediate of formula (lb)
wherein R represents alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, ter- butyl and the like,
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 protecting groups are those conventional methods appropriate to the molecule being protected.
The invention is described in the examples given below which are provided by way of illustration only and therefore should not construed to limit the scope of the invention.
Example-1
Step (i) Preparation of ethyl-3-[4-f2-(phenoxazin-10-yl)ethoxy1phenyl1-2,3-epoxy propanoate
To a freshly prepared sodium ethoxide (prepared by dissolving 6.95 g of sodium metal in 350 ml of absolute ethanol), 4-[2-(phenoxazin-10-yl)ethoxy]benzaldehyde
(50 g, 0.015 M) was added. To this mixture ethyl chloro acetate (27.7 g, 0.22 M) was added while stirring at 25-30 °C in about 30 min time. The reaction was maintained at same temperature for 12 h. Cold water was added to the reaction mass, filtered and dried the product to yield the title compound, (yield 56 g).
Η NMR (200 MHz, CDCh): δ 7.0-6.5 (bm, 12H), 4.35-4.10 (m, 4H), 4.0-3.8 (m,
3H), 3.6 (d, IH).
Mass m/z: 418, 346, 332, 210.
Step (ii) Preparation of ethyl 3-f4-r2-(phenoxazin-10-yl)ethoxylphenyl1-2-hydroxy propanoate
A solution of ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2,3-epoxy propanoate
(15 g) in methanol (150 ml) was hydrogenated over 5 % Pd-C (3 g) at 60 psi pressure for 12 h at room temperature. The catalyst was filtered and the solution was concentrated to yield the title compound as thick syrup ( yield 12 g).
Η NMR (200 MHz, CDC13): δ 7.2 (d, 2H), 6.9-6.5 (m, 10H), 4.45 (q, IH), 4.25 (q,
2H), 4.15 (t, 2H), 3.95 (t, 2H), 3.1 (dd, IH), 2.9 (dd, IH), 1.25 (t, 3H).
Step (iii)
Preparation of 3-r4-r2-(phenoxazin-10-yl)ethoxylphenyl1-2-hydroxy propanoic acid To a solution of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propanoate (11.0 g, 0.026 M) in methanol (110 ml), 10 % aqueous NaOH solution
(110 ml) was added at room temperature and stirred for 4 h. Water (100 ml) was added and the aqueous solution was washed with toluene (3 x 100 ml), acidified with sulphuric acid and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water (2 x 100 ml) and concentrated to yield the title compound as thick syrup (yield 4.0 g, 39.2 %).
Η NMR (200 MHz, CDCh): δ 7.2 (d, 2H), 6.9-6.5 (m, 10H), 4.45 (q, IH), 4.15 (t,
2H), 3.95 (t, 2H), 3.1 (dd, IH), 2.9 (dd, IH).
Step (iv) Preparation of (S)-3-r4-f2-(phenoxazin-10-yl)ethoxy1phenyll-2-hydroxy propanoic acid
To a stirred solution of racemic 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- hydroxy propanoic acid (10 g, 0.025 M) in ethyl acetate (50 ml) at room temperature,
(S)-phenyl glycinol (3.5 g, 0.25 M) was added and stirred for 2 h and filtered. The mother liquor was washed with 10 % aqueous HCl (100 ml) and the organic layer was washed with water (2 x 100 ml). To the ethyl acetate layer (-) α-methyl benzyl
amine (1.5 g, 0.0125 M) was added and stirred for 4 h. The precipitate obtained was filtered and washed with ethyl acetate (2 x 25 ml). The precipitate was dissolved in a mixture of ethyl acetate (50 ml) and dilute HCl (50 ml). The organic layer was washed with water (2 x 25 ml) and concentrated to yield the title compound as off white solid (yield 2.6 g, 25 %, purity 99 2 % and diastereomer 0.8 % by HPLC).
Η NMR (200 MHz, CDC13): δ 7.2 (d, 2H), 6.9-6.5 (m, 10H), 4.45 (q, IH), 4.15 (t,
2H), 3.95 (t, 2H), 3.1 (dd, IH), 2.9 (dd, IH).
Mass m/z : 391, 322, 196, 182.
Chemical Purity: 99 2% (HPLC). Step (v)
Preparation of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy propanoate
To a stirred suspension of 60 % sodium hydride (1.02 g, 0.052 M) in DMF (25 ml) at
-5 to 0 °C, ethyl iodide (9.84 g, 0.0637 M) was added dropwise 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, 0.012 M) in DMF (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 (3 x 50 ml). The combined organic layers were washed with water (2 x 25 ml) and concentrated to yield the title compound as thick syrup (purity >90 %).
Η NMR (200 MHz, CDCI3): δ 7.15 (d, 2H), 6.9-6.5 (m, 10H), 4.2 (m, 4H), 4.0 (m,
3H), 3.6 (q, IH), 3.35 (q, IH), 2.95 (d, 2H), 1.3-1.1 (m, 6H).
Mass m/z : 447, 196, 182, 91.
Step (vi) Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxylphenyl1-2-ethoxy propanoic acid
To a stirred solution of ethyl (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoate (5.0 g) 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 %, purity 98.5 %, diastereomer: 1.1 %). Step (vii) Preparation of (S)-3-[4-f2-(phenoxazin-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid L-arginine salt
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, 6.6 mmol) 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, 75.0 %, purity 99.27, diastereomer 0.41 %).
Example 2
Step (i)
Preparation of ethyl-3-r4-[2-(phenoxazin-10-yl)ethoxylphenyl1-2,3-epoxy propanoate
To a freshly prepared sodium ethoxide (prepared by dissolving 6.95g of sodium metal in 350 ml of absolute ethanol) 4-[2-(phenoxazin-10-yl)ethoxy]benzaldehyde
(50 g, 0.015 M) was added. To this mixture ethyl chloro acetate (27.7 g, 0.22 M) was added while stirring at 25-30 °C in about 30 min time. The reaction was maintained at same temperature for 12 h. Cold water was added to the reaction mass, filtered and dried the product to yield the title compound (yield 56 g), Step (ii)
Preparation of ethyl 3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2-hydroxy propanoate
A solution of ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2,3-epoxy propanoate
(15 g) in methanol (150 ml) was hydrogenated over 5 % Pd-C (3 g) at 60 psi pressure for 12 h at room temperature. The catalyst was filtered and the solution was concentrated to yield the title compound as thick syrup (yield 12 g).
Step (iii)
Preparation of ethyl 3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyll-2-ethoxy propanoate To a stirred solution of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propanoate (5 g, 0.012 M) in xylene (50 ml), potassium carbonate (4.1 g, 0.03M) and diethyl sulphate (2.75 g, 0.018M) were added and heated under reflux for 10 h. The reaction mass was cooled to room temperature, water was added, stirred for 1 h and the two layers were separated. The organic layer was washed with water and concentrated to yield the title compound as thick syrup, 4.76 g, 91.2 %. Step (iv) 3-r4-[2-(phenoxazin-10-yl)ethoxylphenyll-2-ethoxy propanoic acid
To a stirred solution of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoate (15.0 g) in methanol (150 ml) at 0 °C, 10 % aqueous NaOH solution (150 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 10 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 15.5 g, 96.4 %, purity 97.2 %). Step (v) Preparation of (S)-3-[4-r2-(phenoxazin-10-yl)ethoxylphenyl1-2-ethoxy propanoic acid
To a stirred solution of racemic 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (5.0 g, 0.012 M) in toluene (100 ml) at room temperature, (-) ephedrine (2.09 g, 0.012 M) was added and stirred for 12 h. The precipitate was filtered and washed with toluene (25 ml). The precipitate was taken in a round- bottomed flask, stirred with toluene (20 ml) and diluted with sulphuric acid (15 ml). The organic layer was washed with water. To the organic layer (-) ephedrine (1.0 g, 6.0 mmol) was added and stirred for 12 h. The precipitate was filtered and washed with toluene. The precipitate was treated with toluene (15 ml) and dilute sulfuric acid (10 ml). The organic layer was washed with water and concentrated to yield the title
compound as thick syrup, which was triturated with n-heptane to a fine free flowing solid (yield 1.45 g, 29 %, purity 99.08 %, diastereomer 0.42 %). Step (vi)
Preparation of (S)-3-r4-r2-(phenoxazin-10-yl)ethoxy1phenyl1-2-ethoxy propanoic acid L-arginine salt
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, 6.6 mmol) 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 flitted, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g, 75.0 %, purity 99.27, diastereomer 0.41 %).
Advantages of the present process
• A convergent synthesis of the compound of the formula (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.
• 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 been avoided thereby reducing the number of steps and loss of compound.
Claims
1. An improved process for the preparation of compound of the formula (1),
where R1 represents alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group,
(i) reacting the compound of formula (la)
(iv) resolving the compound of formula (Id) using chiral amines in the presence of solvent to produce compound of (Ie)
(v) simultaneous etherification and esterification of compound of formula (Ie) using alkylating agent in the presence of a base and a solvent to obtain crude compound of formula (If)
(vi) hydrolysing the compound of formula (If) to yield pure (S)-alkoxy compound of the formula (Ig)
(vii) reacting the compound of formula (Ig) with L-arginine in the presence of a solvent at a temperature in the range of 10 to 40 °C, for 4 to 24 h, to yield compound of formula (1), where R1 is as defined above and (viii) isolating the compound of formula (I) formed by conventional methods.
2. The process as claimed in claim 1, wherein the alkylhaloacetate used in step
(i) is selected from methylchloroacetate, methylbromoacetate, ethylchloroacetate or ethylbromoacetate.
3. The process as claimed in claims 1 and 2, wherein the base used in step (i) is selected from sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide.
4. The process as claimed in claims 1 to 3, wherein the solvent used in step (i) is selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
5. The process as claimed in claims 1 to 4, wherein the reducing agent used in step (ii) is selected from Raney Nickel, H2/Pd-C or borane reagents.
6. The process as claimed in claims 1 to 5, wherein the solvent used in step (ii) is selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
7. The process as claimed in claims 1 to 6, wherein the base used in step (iii) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3 or NaHCO3.
8. The process as claimed in claims 1 to 7, wherein the solvent used in step (iii) is selected from methanol, ethanol, propanol, isopropanal or mixtures thereof.
9. The process as claimed in claims 1 to 8, wherein the chiral amine used in step (iv) is selected from R(+)-α-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine or n-octylglucosamine.
10. The process as claimed in claims 1 to 9, wherein the solvent used in step (iv) is alkyl ester, which is selected from methyl acetate, ethyl acetate, ethyl propanoate or n-butylacetate.
11. The process as claimed in claims 1 to 10, wherein the alkylating agent used in step (v) is selected from diethyl sulphate, ethyl iodide or ethanol.
12. The process as claimed in claims 1 to 11, wherein the solvent used in step (v) is selected from hydrocarbons like benzene, toluene or xylene (or) DMF, DMSO, MIBK or ethyl acetate.
13. The process as claimed in claims 1 to 12, wherein the base used in step (v) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCO3 or sodium methoxide.
14. The process as claimed in claims 1 to 13, wherein the solvent used in step (vi) is selected from an alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof (or) ketonic solvent selected from acetone, methyl ethyl ketone or mixtures thereof.
15. The process as claimed in claims 1 to 14, wherein the base used in step (vi) is selected from sodium hydroxide or potassium hydroxide.
16. The process as claimed in claims 1 to 15, wherein the solvent used in step (vii) is (Cι-C6) alcohol selected from aqueous methanol, ethanol, propanol, isopropanol or mixtures thereof.
17. A process for the preparation of compound of the formula (1),
where R represents alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group, which comprises: (i) reacting the compound of formula (la)
(iii) alkylating the compound of the formula (Ic) using alkylating agent in the presence of a solvent and a base to yield compound of the formula (Ih)
(iv) hydrolysing the compound of formula (Ih) to yield acid of the formula (Ii)
(vi) reacting the compound of formula (Ig) with L-arginine in the presence of a solvent to yield compound of formula (1), where R1 is as defined above and (vii) isolating the compound of formula (I) formed by conventional methods.
18. The process as claimed in claim 17, wherein the alkylhaloacetate used in step (i) is selected from methylchloroacetate, methylbromoacetate, ethylchloroacetate or ethylbromoacetate.
19. The process as claimed in claims 17 and 18, wherein the base used in step (i) is selected from sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide.
20. The process as claimed in claims 17 to 19, wherein the solvent used in step (i) is selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
21. The process as claimed in claims 17 to 20, wherein the reducing agent used in step (ii) is selected from Raney Nickel, H2/Pd-C or borane reagents.
22. The process as claimed in claims 17 to 21, wherein the solvent used in step (ii) is selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.
23. The process as claimed in claims 17 to 22, wherein the alkylating agent used in step (iii) is selected from diethyl sulphate, ethyl iodide or ethanol.
24. The process as claimed in claims 17 to 23, wherein the solvent used in step (iii), is hydrocarbon selected from toluene, xylene, benzene or mixtures thereof (or) DMF, DMSO, MIBK, ethyl acetate or mixtures thereof.
25. The process as claimed in claims 17 to 24, wherein the base used in step (iii) is selected - from NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCO3 or sodium methoxide.
26. The process as claimed in claims 17 to 25, wherein the solvent used in step (iv) is selected from an alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof (or) a ketonic solvent selected from acetone, methyl ethyl ketone or mixtures thereof.
27. The process as claimed in claims 17 to 26, wherein the base used in step (iv) is alkali base selected from sodium hydroxide or potassium hydroxide.
28. The process as claimed in claims 17 to 27, wherein the chiral amine used in step (v) is selected from R(+) α-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine or n-octylglucosamine.
29. The process as claimed in claims 17 to 28, wherein the solvent used in step (v) is alkyl ester selected from methyl acetate, ethyl acetate, ethyl propanoate or n- butylacetate.
30. The process as claimed in claims 17 to 29, wherein the solvent used in step (vi) is (Cι-C6) alcohol selected from aqueous methanol, ethanol, propanol, isopropanol or mixtures thereof.
31. An intermediate of formula (lb)
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| Application Number | Priority Date | Filing Date | Title |
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| IN585/MAS/2001 | 2001-07-18 | ||
| IN585CH2001 | 2001-07-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1533300B1 (en) * | 2003-11-21 | 2012-05-09 | Ajinomoto Co., Inc. | Organic amine salts of glutamic acid derivatives and their application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999019313A1 (en) * | 1997-10-27 | 1999-04-22 | Dr. Reddy's Research Foundation | Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them |
| WO2000026200A1 (en) * | 1998-10-29 | 2000-05-11 | Dr. Reddy's Research Foundation | An improved process for the preparation of new antidiabetic agents |
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2002
- 2002-07-16 WO PCT/IB2002/002776 patent/WO2003008397A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999019313A1 (en) * | 1997-10-27 | 1999-04-22 | Dr. Reddy's Research Foundation | Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them |
| WO2000026200A1 (en) * | 1998-10-29 | 2000-05-11 | Dr. Reddy's Research Foundation | An improved process for the preparation of new antidiabetic agents |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1533300B1 (en) * | 2003-11-21 | 2012-05-09 | Ajinomoto Co., Inc. | Organic amine salts of glutamic acid derivatives and their application |
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