WO2003099800A1 - An improved process for the preparation of bicyclic antidiabetic agents - Google Patents

An improved process for the preparation of bicyclic antidiabetic agents Download PDF

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WO2003099800A1
WO2003099800A1 PCT/IB2003/001978 IB0301978W WO03099800A1 WO 2003099800 A1 WO2003099800 A1 WO 2003099800A1 IB 0301978 W IB0301978 W IB 0301978W WO 03099800 A1 WO03099800 A1 WO 03099800A1
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formula
compound
methyl
ketone
ethyl
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PCT/IB2003/001978
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French (fr)
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Om Reddy Gaddam
Chandra Sekhar Batchu
Siva Rama Prasad Addanki
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Dr. Reddy's Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to a process for the preparation of antidiabetic compounds having the formula (1)
  • R represents (C ⁇ -C 6 )alkyl group
  • X represents sulphur or oxygen atom
  • the present invention provides a process for the synthesis of compounds of the formula (1).
  • the present invention provides a process for the preparation of compounds of the formula (1)
  • R represents (C ⁇ -C 6 )alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like;
  • X represents sulphur or oxygen atom, which comprises: (i) condensing the mesylate of formula (8) where X represents sulphur or oxygen atom with compound of formula (12) where R 2 represents hydrogen or t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group, R 1 represents (C ⁇ -C 6 )alkyl group in the presence of a base and organic solvent at a temperature in the range of 25 to 150 °C for 2 to 30 h, to give compound of the formula (13) where R 2 represents hydrogen, t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R 1 represents (C ⁇ -Ce)alkyl group as defined above, (ii) hydrolyzing the compound of
  • the condensation of the mesylate of formula (8) with compound of formula (12) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and the like and a solvent such as dimethyl formamide, tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl sulfoxide, N-methyl pyrrolidone, N,N-diethyl aniline, toluene, xylene, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, acetonitrile, alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 30 to 150 °C for a period in the range of 2 to 30 h.
  • the hydrolysis of compound of formula (13) to compound of formula (14) may be carried out in the presence of aqueous alkali base such as sodium hydroxide or potassium hydroxide or an acid such as (-toluene sulfonic acid, methane sulfonic acid, HC1, H 2 S0 4 , trifluoroacetic acid and the like, a solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or ketone such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and the like or a mixture thereof, at a temperature in the range of 5 to 75 °C for a period in the range of 0.5 to 25 h.
  • aqueous alkali base such as sodium hydroxide or potassium hydroxide or an acid such as (-toluene sulfonic acid, methane sulfonic
  • Etherification of compound of formula (14) maybe carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, an alkylating agent selected from (R) 2 -sulfate such as diethyl sulfate, dimethyl sulfate and the like; or R-halide such as methyl halide like methyl iodide; ethyl halide like ethyl chloride, ethyl iodide, ethyl bromide; 2-propyl halide like 2-propyl bromide, 2-propyl chloride; t-butyl halide like t-butyl chloride, t-butyl bromide and the like, where R and halide are as defined earlier, in the presence of a solvent such as hydrocarbons namely benzene, toluene, xylene and the like or dimethyl formamide, dimethyl sulfoxide
  • the conversion of compound of the formula (11) to phenyl ethyl amine salt of compound of formula (15) may be carried out using ⁇ -phenyl ethylamine in the presence of a solvent selected from an ester such as methyl acetate, ethyl acetate, ethyl propanoate, ri-butyl acetate and the like or alcohol such as methanol, ethanol, propanol, isopropanol, n- butanol and the like or ketone such as acetone, methyl isobutyl ketone, diethyl ketone, methyl ethyl ketone and the like or acetonitrile, ethers like tetrahydro furan, 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
  • the reaction of compound of formula (15) with L-arginine may be carried out in the presence of a solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and the like; acetonitrile, dimethyl formamide, dimethyl sulfoxide, acetone, 1,4-dioxane and the like or a mixture thereof.
  • a solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and the like; acetonitrile, dimethyl formamide, dimethyl sulfoxide, acetone, 1,4-dioxane and the like or a mixture thereof.
  • the reaction may be carried out at a temperature in the range of 20 °C to 150 °C, for a period in the range of 1 to 24 h.
  • reaction mixture was further refluxed for 15 to 18 h.
  • the reaction mixture was cooled to 10 to 15 °C, water was added to separate the toluene layer.
  • the aqueous layer was extracted with toluene.
  • the combined toluene layer was washed with water till pH becomes neutral and concentrated to yield (-) methyl-3-[4-(2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy)phenyl]-2-tertiarybutyl dimethyl silyloxy propanoate as an oily liquid (weighs about 36.5 g, yield 75 %, purity 96%).
  • the reaction mixture was heated to 65 to 75 °C and maintained for 10 to 15 h, cooled to 5 to 10 °C and 20% NaOH solution (180 ml) was added to it slowly under stirring. After addition, the reaction mixture was brought to 25 to 35 °C and maintained for 9 to 10 h under stirring.
  • the reaction mixture was diluted with water (250 ml) and washed with toluene.
  • the aqueous layer was acidified with cone. HCl at 5 to 10 °C and maintained at the same temperature for 1 h.
  • the aqueous layer was extracted with toluene, washed with water till pH became neutral.
  • the toluene layer was concentrated below 50 to 60 °C under vacuum.
  • Step (iii) (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy]phenyl]-2- ethoxypropanoic acid.
  • Step (iv) ⁇ -Phenyl ethylamine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
  • Step (v) L-arginine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy]phenyl]-2-ethoxypropanoic acid.
  • Isopropanol 140 ml was added to the reaction mixture and further refluxed for 2 h, cooled to 25 to 35 °C and maintained for 10 min under stirring and further cooled to 10 to 15 °C for 2 to 3 h for complete precipitation.
  • Step (i) (-) Isopropyl 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]- 2-hydroxypropanoate.
  • the reaction mixture was brought to room temperature and cooled to 10 to 15 °C and water was added to separate the toluene layer.
  • the organic layer was washed with water till pH becomes neutral.
  • the toluene layer was washed with 10% HCl and water, concentrated under vacuum to yield the title compound as light to dark brown clear liquid (weighs about 7.6 g; yield 80%; purity 97%).
  • the aqueous layer was acidified with 25 % sulphuric acid at 15 to 20 °.
  • the aqueous layer was extracted with toluene.
  • the combined toluene extracts were washed with water and concentrated under vacuum to afford pure (-) 3-[4-[2-(3,4-dihydro-2H- benzo[b] [1 ,4]thiazin-4-yl)ethoxy]phenyl]-2-hydroxy propanoic acid as dark brown, glassy, sticky mass (weighs about 25 g, yield 82 %, purity 97 %).
  • Step (iii) (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
  • the aqueous layer was acidified with cone. HCl at 10 to 15 °C and maintained at the same temperature for 30 min.
  • the aqueous layer was extracted with toluene.
  • the combined toluene extract were washed with water till pH becomes neutral, concentrated under vacuum to afford the title compound as dark brown, glassy, sticky mass (weighs about 22 g, yield 80%, purity 95%).
  • Step (iv) ⁇ -Phenyl ethylamine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
  • the reaction mixture was cooled to 25 to 35 °C and maintained for 2 to 3 h under stirring.
  • the reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation.
  • the precipitated product was filtered, washed with water (150 ml) and dried to yield pure title compound as off white to cream colored crystalline solid (weighs about 15 g, yield 63%, mp: 121 °C, purity 98.0% (Chemical)).
  • Step (v) L-arginine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)eth ⁇ xy]phenyl]-2-ethoxypropanoic acid.
  • ⁇ -Phenyl ethyl amine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid (14 g) and methanol (70 ml) were added to a flask at 25 to 35 °C, fitted with a mechanical stirrer and reflux condenser.
  • the reaction mixture was heated to 60 to 70 °C for complete dissolution of the mass.
  • L-arginine (4.79 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring.
  • the reaction mixture was heated and maintained the gentle reflux for 1 h.
  • Isopropanol 140 ml was added to the reaction medium and refluxed for 2 h, cooled to 25 to 35 °C and maintained for 10 min under stirring and further cooled to 10 to 15 °C for 2 to 3 h for complete precipitation.
  • the invention thus provides an improved process for preparing the compounds of formula (1) which is economic as the overall yields have been enhanced and obviates the need to use expensive chemicals as well column chromatographic techniques. .

Abstract

The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula (1). where R represents (C1-C6)alkyl group, X represents sulphur or oxygen atom

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF BICYCLIC ANTIDIABETIC AGENTS
Field of the invention
The present invention relates to a process for the preparation of antidiabetic compounds having the formula (1)
Figure imgf000002_0001
where R represents (Cι-C6)alkyl group, X represents sulphur or oxygen atom.
In our US Patent number 6,265,401 we have described a process for the preparation of free acid of arginine salt of formula (1). The process described therein comprises of converting aldehyde of formula (2) where X represents sulphur or oxygen atom to a compound of formula (3) where R1 and R2 represent 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 hydrolyzing the amide to produce the compound of formula (7), where X and R1 are as defined above. The process is shown in the scheme -1 given below
Figure imgf000002_0002
Scheme-1
The above described process makes use of reactions like Wittig-Horner reaction, which is a moisture sensitive reaction, to prepare the compound of the formula (3). Overall yield of the compounds of the formula (7) is only -2.5% and time cycle required for the completion of the reaction sequence resulting in the compounds of the formula (7) is very long.
Our WO publication No. 00/66572 describes an alternate process for the preparation of compounds of formula (1). The process described therein is shown in scheme-2 below:
Figure imgf000003_0001
Scheme-2
The above described process involves the condensation of mesylate of formula (8) with compound of formula (9) in DMF and potassium carbonate which results into highly impure product that could not be purified by conventional methods like distillation. Column chromatography was employed for purification, which is difficult to practice in scale up trials. DMF is used as medium, the recovery and recycling of DMF in bulk quantities poses a problem.
Summary of the present invention
The present invention provides a process for the synthesis of compounds of the formula (1).
Detailed description of the invention Accordingly, the present invention provides a process for the preparation of compounds of the formula (1)
Figure imgf000003_0002
where R represents (Cι-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like; X represents sulphur or oxygen atom, which comprises: (i) condensing the mesylate of formula (8) where X represents sulphur or oxygen atom with compound of formula (12) where R2 represents hydrogen or t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group, R1 represents (Cι-C6)alkyl group in the presence of a base and organic solvent at a temperature in the range of 25 to 150 °C for 2 to 30 h, to give compound of the formula (13) where R2 represents hydrogen, t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1 represents (Cι-Ce)alkyl group as defined above, (ii) hydrolyzing the compound of formula (13) to yield the compound of the formula (14) in the presence of a base or an acid and a solvent at a temperature in the range of 5 to 75 °C for 0.5 to 25 h,
(iii) etherifying the compound of formula (14) using an alkylating agent such as R- halide or (R)2-sulfate, where R represent (Cι-C6) alkyl group and halide selected from fluorine, chlorine, bromine or iodine, in the presence of a base and a solvent to obtain compound of formula (11) where R represent (Ci-Cβ) alkyl group at a temperature in the range of 5 to 35 °C for a period of in the range of 0.5 to 25 h,
(iv) reacting the compound of formula (11) with phenyl ethylamine in the presence of a solvent at a temperature in the range of 10 to 70 °C for 1 to 12 h to obtain a compound of formula (15) where R represent (Cι-C6) alkyl group,
(v) reacting the compound of formula (15) with L-arginine in the presence of a solvent at a temperature in the range of 20 °C to reflux temperature of the solvent used, for a period in the range of 1 to 24 h, to yield compound of formula (1) where R represent (Ci- C6) alkyl group and (vi) isolating the compound of formula (1).
The process explained above is shown in scheme-3 below:
Figure imgf000005_0001
(1)
Scheme-3
- The condensation of the mesylate of formula (8) with compound of formula (12) may be carried out in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and the like and a solvent such as dimethyl formamide, tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl sulfoxide, N-methyl pyrrolidone, N,N-diethyl aniline, toluene, xylene, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, acetonitrile, alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 30 to 150 °C for a period in the range of 2 to 30 h.
The hydrolysis of compound of formula (13) to compound of formula (14) may be carried out in the presence of aqueous alkali base such as sodium hydroxide or potassium hydroxide or an acid such as (-toluene sulfonic acid, methane sulfonic acid, HC1, H2S04, trifluoroacetic acid and the like, a solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or ketone such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone and the like or a mixture thereof, at a temperature in the range of 5 to 75 °C for a period in the range of 0.5 to 25 h. Etherification of compound of formula (14) maybe carried out in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, an alkylating agent selected from (R)2-sulfate such as diethyl sulfate, dimethyl sulfate and the like; or R-halide such as methyl halide like methyl iodide; ethyl halide like ethyl chloride, ethyl iodide, ethyl bromide; 2-propyl halide like 2-propyl bromide, 2-propyl chloride; t-butyl halide like t-butyl chloride, t-butyl bromide and the like, where R and halide are as defined earlier, in the presence of a solvent such as hydrocarbons namely benzene, toluene, xylene and the like or dimethyl formamide, dimethyl sulfoxide, methyl isobutyl ketone, acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate, N-methyl pyrrolidone and the like or a mixture thereof, at a temperature in the range of 5 to 35 °C for a period in the range of 0.5 to 25 h.
The conversion of compound of the formula (11) to phenyl ethyl amine salt of compound of formula (15) may be carried out using α-phenyl ethylamine in the presence of a solvent selected from an ester such as methyl acetate, ethyl acetate, ethyl propanoate, ri-butyl acetate and the like or alcohol such as methanol, ethanol, propanol, isopropanol, n- butanol and the like or ketone such as acetone, methyl isobutyl ketone, diethyl ketone, methyl ethyl ketone and the like or acetonitrile, ethers like tetrahydro furan, 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 range of 10 to 70 °C. The duration of the reaction may range from 1 to 12 h.
The reaction of compound of formula (15) with L-arginine may be carried out in the presence of a solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and the like; acetonitrile, dimethyl formamide, dimethyl sulfoxide, acetone, 1,4-dioxane and the like or a mixture thereof. The reaction may be carried out at a temperature in the range of 20 °C to 150 °C, for a period in the range of 1 to 24 h.
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) (-) Methyl-3-[4-(2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy)phenyl]-2- tertiary butyl dimethyl silyloxy propanoate.
In a flask, fitted with a Dean Stark apparatus, reflux condenser and a stirrer, K2CO3 (74 g, 0.534 M) and toluene (300 ml) was added at 30 to 35 °C under stirring. The reaction mixture was refluxed for 2 to 3 h, cooled to 70 to 80 °C and (-) methyl 3-(4- hydroxyphenyl)-2-(t-butyldimethyl silyloxy)propanoate (30 g) and 2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethyl methane sulfonate (25 g) were added under stirring. The reaction mixture was further refluxed for 15 to 18 h. The reaction mixture was cooled to 10 to 15 °C, water was added to separate the toluene layer. The aqueous layer was extracted with toluene. The combined toluene layer was washed with water till pH becomes neutral and concentrated to yield (-) methyl-3-[4-(2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy)phenyl]-2-tertiarybutyl dimethyl silyloxy propanoate as an oily liquid (weighs about 36.5 g, yield 75 %, purity 96%). IR (neat) cm"1: 3060, 2922, 1740. !H NMR (200 MHz, CDC13) δ: 0.89 (s, 9H), 2.94(d, J=6.42Hz, 2H), 3.01-3.10 (m, 2H), 3.28-3.68 (m, 2H), 3.70-3.80 (m, 4H), 3.95 (t, J=6.42Hz, 1H), 4.10-4.22 (m, 1H), 4.01 (s, 3H), 6.55-6.74 (m, 2H), 6.80 (d, J=8.63Hz, 2H), 6.98-7.10 (m, 2H), 7.14 (d, J=8.63Hz, 2H). Mass m/z (CI): 508 (M+ + l). Step (ii) (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy]phenyl]-2- hydroxypropanoic acid.
To a flask, fitted with a condenser and a stirrer, (-) methyl-3-[4-(2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethoxy)phenyl]-2-tertiary butyl dimethyl silyloxy propanoate (87.5 g) and methanol (437 ml 1:15 w/v) were added at 25 to 35 °C under stirring followed by p-Toluene sulfonic acid (7 g, 0.0368 M). The reaction mixture was heated to 65 to 75 °C and maintained for 10 to 15 h, cooled to 5 to 10 °C and 20% NaOH solution (180 ml) was added to it slowly under stirring. After addition, the reaction mixture was brought to 25 to 35 °C and maintained for 9 to 10 h under stirring. The reaction mixture was diluted with water (250 ml) and washed with toluene. The aqueous layer was acidified with cone. HCl at 5 to 10 °C and maintained at the same temperature for 1 h. The aqueous layer was extracted with toluene, washed with water till pH became neutral. The toluene layer was concentrated below 50 to 60 °C under vacuum. Methanol (150 ml) was added to the oily crude at room temperature, under stirring. The solution was stirred at room temperature for 10 to 15 min, followed by cooling at 5 to 10 °C under stirring for 2 h. The precipitated product was filtered, washed with chilled methanol and dried under vacuum at 30 to 35 °C to yield (-) 3-[4-(2-(3,4-dihydro-2Hbenzo[b][l,4]thiazin-4-yl)ethoxy)phenyl]- 2-hydroxy propanoic acid as cream color solid (weighs about 61 g, yield 95%, purity 92- 95%). IR (neat) cm"1: 3400-3300, 3120, 2970, 1710.
1H NMR (200 MHz, DMSO-d6) δ : 2.94 (d, J=6.42Hz, 2H), 3.01-3.10 (m, 2H), 3.28-3.68 (m, 2H), 3.70-3.80 (m, 4H), 3.95 (t, J=6.42Hz, 1H), 6.55-6.74 (m, 2H), 6.80 (d, J=8.63Hz, 2H), 6.98-7.10 (m, 2H), 7.14 (d, J=8.63Hz, 2H). Mass m/z (CI): 360 (M+ + l).
Step (iii) (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy]phenyl]-2- ethoxypropanoic acid.
To a flask, fitted with a condenser and a stirrer, dimethyl formamide (50 ml) and sodium hydride (11.5 g) were added and cooled to 10 to 15 °C under stirring. Diethyl sulfate (23 ml, 27 g) was added slowly maintaining the temperature at 10 to 15 °C under stirring. The reaction mixture was brought to 25 to 35 °C and maintained under stirring for 1 h. (-) 3-[4- [2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-hydrox5 ropanoic acid (25 g) in dimethyl formamide (50 ml) was added to the reaction mixture at 10 to 15 °C in about 3 to 4 h and was maintained at the same temperature for 16 to 24 h under stirring. The reaction mixture was quenched with methanol (20ml), poured into ice cold water and stirred for 30 min. The organic layer was separated and the aqueous layer was washed with toluene and pooled the toluene extracts. The aqueous layer was acidified with cone. HCl (50 ml) at 10 to 15 °C and maintained at same temperature for 30 min. The aqueous layer was extracted with toluene and the combined organic extracts were washed with water .to make pH neutral. The toluene layer was concentrated below 100 °C under vacuum to afford (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid as dark brown, glassy, sticky mass (weighs about 22 g, yield 80%, purity 95%). IR (neaf) cm"1 : 3400-3300, 3060, 2922, 1720). !H NMR (200 MHz, CDC13) δ : 1.18 (t, J=7Hz, 3H), 2.82-3.15 (complex, 4H), 3.40-3.68 (complex, 4H), 3.7-3.81 (complex, 4H), 4.05 (dd, J=7.29, 4.33Hz, 1H), 4.16 (t, J=5.72Hz, 2H), 6.68-6.74 (complex, 2H), 6.81 (d, J=8.5Hz, 2H), 6.94-7.06 (complex, 2H), 7.14 (d, J=8.5Hz, 2H), COOH proton is too broad to observe. The Mass m/z (CI): 388 (M+ + 1). Step (iv) α-Phenyl ethylamine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
To a .flask, fitted with a stirrer and reflux condenser (-) 3-[4-[2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethoxy] phenyl]-2-ethoxypropanoic acid (18 g) and methanol (60 ml) were added at 25 to 35 °C. The reaction mixture was heated to 60 to 70 °C and maintained for 1 h. α-Phenyl ethyl amine (5.62 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring. Water (120 ml) was added to the reaction mixture and stirred for 1 h, cooled to 25 to 35 °C and maintained for 2 to 3 h under stirring. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with water and dried to yield pure α-phenylethylamine salt (-) 3-[4-[2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid as off white to cream coloured crystalline solid (weighs about 15 g, yield 63%, mp : 121 °C, purity 98.0%). IR (neat) cm"1: 3300-3200, 3120, 2935, 1637. !H NMR (200 MHz, MeOD) δ : 1.1 (t, 3H), 1.6 (d, 3H), 2.6-3.4 (m, 5H), 3.45-4.0 (m, 7H), 4.05 (9, 2H), 6.5 (t, 1H), 6.7-7.4 (m, 13H). Mass m z (CI): 388 (M+ + 1), 121 (C8HnN), 105 (CSH8).
Step (v) L-arginine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy]phenyl]-2-ethoxypropanoic acid. To a flask fitted with a stirrer and reflux condenser -phenyl ethyl amine salt of (-) 3-[4- [2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (14 g, 0.0275 M) and methanol (70 ml) were added at 25 to 35 °C and heated to 60 to 70 °C. L-arginine (4.79 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring. The reaction mixture was heated and maintained at 60 to 70 °C for 1 h. Isopropanol (140 ml) was added to the reaction mixture and further refluxed for 2 h, cooled to 25 to 35 °C and maintained for 10 min under stirring and further cooled to 10 to 15 °C for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with chilled isopropanol (10 ml) and dried to yield pure L-arginine salt of (-) 3-[4- [2-(3 ,4-dihydro-2H-benzo [b] [ 1 ,4]thiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid as off white crystalline solid (weighs about 14 g, yield 91%, mp : 174 to 178 °C, purity 98.98% (Chiral)).
IR (neat) cm"1: 3300-3250, 3120, 2935, 1705, 1585.
*H NMR (200 MHz, DMSO-d6 + TFA) δ : 1.0 (t, 3H), 2.4-3.4 (m, 9H), 3.45-4.0 (m, 10H), 4.05 (t, 2H), 6.5 (t, 1H), 6.7-7.4 (m, 8H aromatic). Mass m/z (CI): 388 (M+ + 1), 174 (C6Hι4N4O2), 147 (C6Hι3NO3). Example 2
Step (i) (-) Isopropyl 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]- 2-hydroxypropanoate.
To a flask, fitted with a dean stark apparatus, reflux condenser and a stirrer, K2CO3 (20.7 g) and toluene (540 ml) were added at 25 to 35 °C under stirring. The reaction mixture was refluxed for 2 to 3 h, cooled to 65 to 75 °C and 2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethylmethane sulfonate (6.8 g, 0.024 M), isopropyl 3-(4- hydroxyphenyl)-2(S)-hydroxy propanoate (5.57 g, 0.024 M) were added sequentially in one lot and further refluxed for 4 to 5 h. The reaction mixture was brought to room temperature and cooled to 10 to 15 °C and water was added to separate the toluene layer. The organic layer was washed with water till pH becomes neutral. The toluene layer was washed with 10% HCl and water, concentrated under vacuum to yield the title compound as light to dark brown clear liquid (weighs about 7.6 g; yield 80%; purity 97%). IR (neat) cm"1: 3300, 3060, 2922, 1740. Η NMR (200 MHz, CDC13): δ 1.1-1.30 (d, 6H); 2.94(d, J=6.42Hz, 2H), 3.01-3.10 (m, 2H), 3.28-3.68 (m, 2H), 3.70-3.80 (m, 4H), 3.95 (t, J=6.42Hz, 1H), 4.10-4.22 (m, 2H), 6.55-6.74 (m, 2H), 6.80 (d, J=8.63Hz, 2H), 6.98-7.10 (m, 2H), 7.14 (d, J=8.63Hz, 2H). Mass m/z (CI): 402 (M+ + l). Step (ii) (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2- hydroxypropanoic acid.
To a flask, fitted with a condenser and a stirrer (-) isopropyl 3-[4-[2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoate (33 g) and methanol (153 ml) were added at 25 to 35 °C under stirring. The reaction mixture was cooled to 10 to 15 °C and 10 % NaOH solution (170 ml) was added maintaining the temperature below 20 °C. After complete addition, the reaction mixture was brought to 25 to 35 °C and maintained under stirring. Water (75 ml) was added to the reaction mixture and washed with toluene. The aqueous layer was acidified with 25 % sulphuric acid at 15 to 20 °. The aqueous layer was extracted with toluene. The combined toluene extracts were washed with water and concentrated under vacuum to afford pure (-) 3-[4-[2-(3,4-dihydro-2H- benzo[b] [1 ,4]thiazin-4-yl)ethoxy]phenyl]-2-hydroxy propanoic acid as dark brown, glassy, sticky mass (weighs about 25 g, yield 82 %, purity 97 %). IR (neat) cm"1: 3400-3300, 3060, 2922, 1720. Η NMR (200 MHz, CDC13): δ 2.82-3.15 (complex, 4H), 3.40-3.68 (complex, 4H), 3.7- 3.81 (complex, 2H), 4.05 (dd, J=7.29 and 4.33Hz, IH), 4.16 (t, J=5.72Hz, 2H), 6.68-6.74 (complex, 2H), 6.81 (d, J=8.5Hz, 2H), 6.94-7.06 (complex, 2H), 7.14 (d, J=8.5Hz, 2H), COOH proton is too broad to observe. Mass m/z (CI): 360 (M+ + 1).
Step (iii) (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid.
To a flask, fitted with a condenser and a stirrer, dimethyl formamide (50 ml) and sodium hydride (11.5 g) were added and cooled to 10 to 15 °C under stirring. Diethyl sulfate (23 ml, 27 g) was added maintaining the temperature at 10 to 15 °C under stirring. After complete addition, the reaction mixture was brought to 25 to 35 °C and maintained under stirring for 1 h. (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2- hydroxypropanoic acid (25 g) dissolved in dimethyl formamide (50 ml) was added to the reaction mixture at 10 to 15 °C in about 3 to 4 h. After complete addition the reaction mixture was maintained at 10 to 15 °C for 16 to 24 h under stirring. After completion of the reaction, the reaction mixture was quenched with methanol (20 ml) and poured into ice cold water and stirred for 30 min. The organic layer was separated and the aqueous layer was washed with toluene and pooled the toluene extracts. The aqueous layer was acidified with cone. HCl at 10 to 15 °C and maintained at the same temperature for 30 min. The aqueous layer was extracted with toluene. The combined toluene extract were washed with water till pH becomes neutral, concentrated under vacuum to afford the title compound as dark brown, glassy, sticky mass (weighs about 22 g, yield 80%, purity 95%). IR (neat) cm"1'' 3400-3300, 3060, 2922, 1720. !H NMR (200 MHz, CDCI3): δ 1.18 (t, J=7Hz, 3H); 2.82-3.15 (complex, 4H), 3.40-3.68 (complex, 4H), 3.7-3.81 (complex, 4H), 4.05 (dd, J=7.29, 4.33Hz, IH), 4.16 (t, J=5.72Hz, 2H), 6.68-6.74 (complex, 2H), 6.81 (d, J=8.5Hz, 2H), 6.94-7.06 (complex, 2H), 7.14 (d, J=8.5Hz, 2H), COOH proton is too broad to observe. Mass m/z (CI): 388 (M+ + l). Step (iv) α-Phenyl ethylamine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
(.) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (18 g) and methanol (60 ml) were added to a flask, fitted with a mechanical stirrer and reflux condenser at 25 to 35 °C. The reaction mixture was heated to 60 to 70 °C and maintained for 1 h. α-Phenyl ethylamine (5.62 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring. Water (120 ml) was added to the reaction mixture and stirred for 1 h. The reaction mixture was cooled to 25 to 35 °C and maintained for 2 to 3 h under stirring. The reaction mixture was further cooled to 10 to 15 °C under stirring and maintained for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with water (150 ml) and dried to yield pure title compound as off white to cream colored crystalline solid (weighs about 15 g, yield 63%, mp: 121 °C, purity 98.0% (Chemical)). IR (neat) cm"1: 3300-3200, 3120, 2935, 1637. Η NMR (200 MHz, MeOD): δ 1.1 (t, 3H), 1.6 (d, 3H), 2.6-3.4 (m, 5H), 3.45-4.0 (m, 7H), 4.05 (9, 2H), 6.5 (t, IH), 6.7-7.4 (m, 13H). Mass m/z (CI): 388 (M+ + 1), 121 (C8HUN), 105 (C8H8).
Step (v) L-arginine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethσxy]phenyl]-2-ethoxypropanoic acid. α-Phenyl ethyl amine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid (14 g) and methanol (70 ml) were added to a flask at 25 to 35 °C, fitted with a mechanical stirrer and reflux condenser. The reaction mixture was heated to 60 to 70 °C for complete dissolution of the mass. L-arginine (4.79 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring. The reaction mixture was heated and maintained the gentle reflux for 1 h. Isopropanol (140 ml) was added to the reaction medium and refluxed for 2 h, cooled to 25 to 35 °C and maintained for 10 min under stirring and further cooled to 10 to 15 °C for 2 to 3 h for complete precipitation. The precipitated product was filtered, washed with chilled isopropanol (10 ml) and dried to yield the pure title compound as off white crystalline solid (weighs about 14 g, yield 91%, mp: 174 to 178 °C, purity 98.98% (Chiral)). IR (neat) cm"1: 3300-3250, 3120, 2935, 1705, 1585. lU NMR (200 MHz, DMSO-d6 + TFA): δ 1.0 (t, 3H), 2.4-3.4 (m, 9H), 3.45-4.0 (m, 10H), 4.05 (t, 2H), 6.5 (t, IH), 6.7-7.4 (m, 8H aromatic). Mass m/z (CI): 388 (M+ + 1), 174 (C6Hι4N402), 147 (C6Hι3N03).
The invention thus provides an improved process for preparing the compounds of formula (1) which is economic as the overall yields have been enhanced and obviates the need to use expensive chemicals as well column chromatographic techniques. .

Claims

We claim:
1. A process for the preparation of compound of the formula ( 1 )
Figure imgf000013_0001
where R represents (Ci-C6)alkyl group selected methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; X represents sulphur or oxygen atom, which comprises: (i) condensing the mesylate of formula (8)
Figure imgf000013_0002
where X represents sulphur or oxygen atom with compound of formula (12)
Figure imgf000013_0003
where R2 represents hydrogen or t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group, R1 represents (Cι-C6)all yl group in the presence of a base and a solvent at a temperature in the range of 30 to 150 °C for 2 to 30 h, to give compound of the formula (13)
Figure imgf000013_0004
where R2 represents hydrogen or t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1 represents (Cι-C6)alkyl group and X is as defined above, (ii) hydrolysing the compound of formula (13) to yield the compound of the formula
(14)
Figure imgf000013_0005
in the presence of a base or an acid and a solvent at a temperature in the range of 5 to 75 °C for 0.5 to 24 h, (iii) etherifying the compound of formula (14) to a compound of formula (11)
Figure imgf000014_0001
using an alkylating agent in the presence of a base and a solvent at a temperature in the range of 5 to 35 °C for 0.5 to 25 h,
(iv) reacting the compound of formula (11) with phenyl ethylamine in the presence of a solvent at a temperature in the range of 10 to 70 °C for 1 to 12 h to obtain a compound of formula (15) where R represent (Cι-C6) alkyl group,
OS)
Figure imgf000014_0002
(v) reacting the compound of formula (15) with L-arginine in the presence of a solvent at a temperature in the range of 20 °C to 150 °C, for a period in the range of 1 to 24 h, to yield compound of formula (1) where R represent (Cι-C6) alkyl group and (vi) isolating the compound of formula (1).
2. The process as claimed in claim 1, wherein the base used in step (i) is selected from sodium carbonate, potassium carbonate, cesium carbonate or potassium bicarbonate. 3. The process as claimed in claim 1, wherein the solvent used in step (i) is select from dimethyl formamide, tetrahydrofuran, ethylene glycol dimethyl ether, dimethyl sulfoxide, N-methyl pyrrolidone, N,N-diethyl aniline, toluene, xylene, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, acetonitrile, alcohol selected from methanol, ethanol, propanol, isopropanol, n-butanol or a mixture thereof. 5. The process as claimed in claim 1, wherein the solvent used in step (ii) is alcohol selected from methanol, ethanol, propanol, isopropanol, n-butanol or a mixture thereof; or a ketone selected from acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone or a mixture thereof.
6. The process as claimed in claim 1, wherein the aqueous alkali base used in step (ii) is selected from sodium hydroxide or potassium hydroxide.
7. The process as claimed in claim 1, wherein the acid used in step (ii) is selected from jr toluene sulfonic acid, methane sulfonic acid, HCl, H2S0 or trifluoroacetic acid.
8. The process as claimed in claim 1, wherein the alkylating agent used in step (iii) is (R)2-sulfate selected from diethyl sulfate or dimethyl sulfate; or R-halide selected from methyl halide like methyl iodide, ethyl halide like ethyl chloride, ethyl iodide, ethyl bromide, 2-propyl halide like 2-propyl bromide, 2-propyl chloride or t-butyl halide like t- butyl chloride, t-butyl bromide, where R represent (Cι-C6) alkyl group and halide is defined as fluorine, chlorine, bromine or iodine. 9. . The process as claimed in claim 1, wherein the solvent used in step (iii) is selected from hydrocarbons like benzene, toluene or xylene or dimethyl formamide, dimethyl sulfoxide, methyl isobutyl ketone, acetone, methyl ethyl ketone, diethyl ketone, ethyl acetate, N-methyl pyrrolidone or a mixture thereof.
10. The process as claimed in claim 1, wherein the base used in step (iii) is selected from sodium carbonate, potassium carbonate, sodium hydride, sodium hydroxide or potassium hydroxide.
11. The process as claimed in claim 1 , wherein the solvent used in step (iv) is alkyl ester selected from methyl acetate, ethyl acetate, ethyl propanoate or n-butyl acetate; alcohol selected from methanol, ethanol, propanol, isopropanol or n-butanol; ketone selected from acetone, methyl isobutyl ketone, diethyl ketone or methyl ethyl ketone; acetonitrile, ether selected from tetrahydrp furan, dioxane or isopropyl ether;- hydrocarbon selected from benzene, toluene, xylene or cyclohexane; or a mixture thereof.
12. The process as claimed in claim 1, wherein the solvent used in step (v) is selected from alcohol like methanol, ethanol, propanol, isopropanol or n-butanol; acetonitrile, dimethyl formamide, dimethyl sulfoxide, acetone, 1,4-dioxane or a mixture thereof.
13. A process for the preparation of compound of the formula (1) as described in claims 1-12, substantially as herein described with reference to examples 1-2.
PCT/IB2003/001978 2002-05-23 2003-05-23 An improved process for the preparation of bicyclic antidiabetic agents WO2003099800A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020614A1 (en) * 1998-05-27 1999-04-29 Dr. Reddy's Research Foundation Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them
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
WO2002030914A1 (en) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Salts of benzothiazine and benzoxazine derivatives and pharmaceutical compositions containing them
WO2003024944A1 (en) * 2001-09-20 2003-03-27 Dr. Reddy's Laboratories Ltd. An improved process for the preparation of bicyclic antidiabetic compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999020614A1 (en) * 1998-05-27 1999-04-29 Dr. Reddy's Research Foundation Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them
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
WO2002030914A1 (en) * 2000-10-12 2002-04-18 Dr. Reddy's Research Foundation Salts of benzothiazine and benzoxazine derivatives and pharmaceutical compositions containing them
WO2003024944A1 (en) * 2001-09-20 2003-03-27 Dr. Reddy's Laboratories Ltd. An improved process for the preparation of bicyclic antidiabetic compounds

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