WO2003024944A1

WO2003024944A1 - An improved process for the preparation of bicyclic antidiabetic compounds

Info

Publication number: WO2003024944A1
Application number: PCT/IB2002/003875
Authority: WO
Inventors: Chandrasekhar Batchu; Sivarama Prasad Addanki; Ramabhadra Sarma Mamillapalli; Om Reddy Gaddam
Original assignee: Dr. Reddy's Laboratories Ltd.
Priority date: 2001-09-20
Filing date: 2002-09-20
Publication date: 2003-03-27

Abstract

The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula (1), where R1 represents (C¿1?-C6)alkyl group, X represents sulphur or oxygen atom.

Description

AN IMPROVED PROCESS FOR THE PREPARATION, OF BiςYCLIC ANTIDIABETIC COMPOUNDS

Field of the invention

The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula (1).

where R represents (Cι-Ce)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 compounds of formula (1). The process described therein comprises of converting aldehyde of formula (2) to a compound of formula (3) where' all symbols' are as defined above and R 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 R¹ are as defined above. The process is shown in the scheme -1 given below:

(1)

Scheme-1

By recognizing the importance of the antidiabetic compound, we continued our research efforts to develop a more efficient, simple and commercially viable stereoselective process for the preparation of the said novel compounds of the formula (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, patent involves

> the use of reactions like Wittig-Horner, 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 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 WO publication No. 00/66572 we have described^an alternate process for the preparation of compounds of formula (1). The process described therein comprises' the condensation of compound of the formula (7), with mesylate of the formula (8) in the presence of solvents such as THF, DMF, DMSO, DME and the like or mixtures thereof and base such as K₂CO₃, Na₂CO_3; NaH and the like to produce ester of formula (9) and hydrolysing the compound of the formula (9) by conventional methods to yield the compound of the general formula (1). The reaction is shown in scheme-2 below:

(1)

Scheme-2 The above process has the following disadvantages:

> the condensation of mesylate with compound of formula (7) in DMF and potassium carbonate results into highly impure product, which could not be purified by conventional methods like distillation column chrortiatography was employed for the isolatiorl' and purification of¹ the product, 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 as it absorbs moisture and decomposes during distillation.

Objectives of the present invention

The main objective of the present invention is therefore to provide an improved process for the preparation of the compounds of the formula (1), thereby making the process commercially viable. Yet another objective of the present invention is to provide a simple and efficient process for¹ the preparation of the compounds of the^formula (1), which' would be easy to handle for a manufacturing chemist with simple and safe operations even in scale up of the process for commercial applications.

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, ( -C_ό^lkyl 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 compound of the formula (7) where R¹ and R² represent (Ci- C₆)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, with mesylate of the formula (8) where X represents sulphur or oxygen atom in the presence of a base and a solvent at a temperature and duration in the range of 20 to

150 °C and 1.5 to 30 h respectively, to give the ester of the formula (9) where R¹ represents (Cι-C6)alkyl group, R represents propyl, isopropyl, butyl, isobutyl or t- butyl, X represents sulphur or oxygen atom,

(ii) hydrolysing the compound of the formula (9) by conventional methods to yield the compound of the formula (1) defined above, by using a solverit and a base' at a temperature and duration in the range of 10 to 40 °C and 20 min to 12 h respectively and

(iii) isolating the compound of formula (I) by conventional methods.

The process explained above is shown in scheme-3 below:

(1)

Scheme-3

The condensation of compound of formula (7) with mesylate of compound of formula (8) may be carried in the presence of base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, using solvents such as toluene, xylene and the like or mixtures thereof or alcohols such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.

The hydrolysis of compound of formula (9) may be carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and the like using solvent such as toluene, xylene and the like or mixtures thereof or alcohols such as methanol,¹' ethanol, propanol,' isopropanol and the like or mixtures thereof. The reaction may be carried out at a temperature in the range of preferably at 25 to 35 °C. The reaction time preferably may range from 20 min to 8 h. The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 Step (i)

Preparation of (-)ethyl-3-[4-[2-(3,4-dihydro-2H-benzo b]ri ,41thiazin-4-yl) ethoxylphenyll-2-ethoxypropanoate

In a 1 L four necked round bottom flask, fitted with a Dean-Stark apparatus, reflux condenser and efficient stirrer, powdered K₂C0₃ (55 g) and toluene (540 ml) were added at 25-35 °C under stirring. The reaction mixture was heated to 110-120 °C and maintained reflux temperature of toluene for 2-3 h. Water was removed azeotropically till no more water droplets were observed. After azeotropic removal of water, the reaction mixture was cooled to 75-85 °C and added 2-(3,4-dihydro-2H- benzo[b][l,4]thiazin-4-yl)ethylmethane sulphonate (27.8 g), (-)ethyl 2-ethoxy-3-(4- hydroxyphenyl)propanoate (23.8 g) sequentially in one lot. The reaction mixture was heated to 110-120 °C and maintained the gentle reflux of toluene. Then water was removed azeotropically and maintained the reaction mixture under reflux for 4-5 h. The reaction mixture was brought to room temperature and cooled tol0-15 °C and water (200 ml) was added and separated the toluene layer. The toluene layer was washed with DM water till pH becomes neutral. The toluene layer was washed with 10 %^" HC1 and DM water till pH becomes neutral. The toluene layer was concentrated at temperature <100 °C under vacuum till no more drops of toluene were observed. High vacuum was applied at that temperature for 20-30 min to afford pure (-) ethyl 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2- ethoxy propanoate as light to dark brown clear liquid (weighs about 88 g, yield 92 %, purity 97 %).

IR (neat) cm^"1: 3060 (-C-H aromatic stretch), 2922 (-C-H aliphatic stretch), 1740 (- COOEt stretch).

1H NMR (200 MHz, CDC1₃): δl.1-1.30 (m, 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, IH), 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): 416 (M⁺ + l). Step (ii) Preparation of (-)-3-r4-[2-(3,4-dihydro-2H-benzorbiri,41thiazin-4-yl)ethoxyl phenyll-2-ethoxypropanoic acid

In a 1 L four necked round bottom flask, fitted with a plain aerial condenser and mechanical stirrer (-)ethyl 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy}phenyl]-2-ethoxypropanoate (33 g) and methanol (153 ml) were added at 25- 35 °C under stirring. The reaction mixture was cooled to 10-15 °C and 10 % NaOH solution (170 ml) was added slowly maintaining the temperature below 20 °C in about 20-30 min. After complete addition, the reaction mixture was brought to 25-35 °C and maintained under stirring for completion of the reaction. After completion of the reaction, water (75 ml) was added to the reaction mixture and washed with toluene. The aqueous layer was acidified with 25 % sulphuric acid (101 ml) at 15-20 °C to pH 2.5-3.0. The aqueous layer was extracted with toluene. The combined toluene extracts were washed with DM water and concentrated below 100 °C using 100-150 mm vacuum till no more drops of toluene were observed. High vacuum wasi applied below <100 °C for removal of traces of toluene to afford pure (-)-3-[4-[2- (3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-ethoxy propanoic acid as dark brown, glassy, sticky mass (weighs about 25 g, yield 82 %, purity 97 % by HPLC.

IR (neat) cm^"1 : 3400-3300 (-OH stretch), 3060 (-C-H aromatic stretch), 2922 (-C-H aliphatic stretch), 1720 (-COOH stretch). 1H NMR (200 MHz, CDC1₃): δ 1.18 (t, J=7.0Hz, 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 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): 388 (M⁺ + 1). Example 2

Step (i)

Preparation of (-)isopropyl 3-r4-r2-(3,4-dihydro-2H-benzorbiri,41thiazm-4-yl) ethoxylphenyll-2-ethoxypropanoate In a 5L four necked round bottom flask, fitted with a dean stark apparatus, reflux condenser and efficient stirrer, powdered K₂C0₃ (565 g) and toluene (3 L) were added at 25-35 °C under stirring. The reaction mixture was heated to 110-120 °C and maintained reflux of toluene for 2-3 h. Water was removed azeotropically till no more water droplets were observed. After azeotropic removal of water, the reaction mixture was cooled to 75-85 °C and added 2-(3, 4-dihydro-2H-benzo[ό][l,4]thiazin- 4-yl)ethylmethane sulphonate (250 g), (-)isopropyl 2-ethoxy-3-(4- hydroxyphenyl)propanoate (207 g) sequentially in one lot. The reaction mixture was heated to 110-120 °C and maintained the gentle reflux of toluene. The water was removed azeotropically maintained the reaction mixture under reflux for 4-5 h. The reaction mixture was brought to room temperature and cooled tol0-15 °C, water (1.5 L) was added and separated the toluene layer. The toluene layer was washed with DM water till pH becomes neutral. The toluene layer was washed with 10 % HC1 and washed with DM water till pH becomes neutral. The toluene layer was

' I' ι _ , > concentrated at temperature <100 °C under vacuum till no more drops of toluene were observed. High vacuum was applied at that temperature for 20-30 min to afford pure (-)isopropyl 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazm-4-yl)ethoxy]phenyl]- 2-ethoxypropanoate as light to dark brown clear liquid (weighs 354 g, yield 93 %, purity 97 %).

IR (neat) cm^"1 : 3060 (-C-H aromatic stretch), 2922 (-C-H aliphatic stretch), 1740 (- COOCH(CH₃)₂ stretch).

1H NMR (200 MHz, CDC1₃): δ 1.1-1.30 (m, 12H), 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, IH), 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): 430 (M⁺ + l). Step (ii)

Preparation of (-)-3-r4-r2-(3,4-dihydro-2H-benzo[bl [1 ,41thiazin-4-yl) ethoxylphenyl] -2-ethoxypropanoic acid

In a 10 L four necked round bottom flask, fitted with a plain aerial condenser and mechanical stirrer (-)isopropyl 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl) ethoxy]phenyl]-2-ethoxypropanoate (330 g) and methanol (2.4 L) were added at 25- 35 °C under stirring. The reaction mixture was cooled to 10-15 °C and 20 % NaOH solution (800 ml) was added slowly maintaining the temperature below 20 °C in about 20-30 min. After complete addition, the reaction mixture was brought to 25-35 °C and maintained under stirring. After completion of the reaction, water (750 ml) was added and washed with toluene. The aqueous layer was acidified with 15-16 % hydrochloric acid (1.3 L) at 15-20 °C and extracted with toluene. The combined toluene extracts were washed with DM water and concentrated the toluene layer below 100 °C using 100-150 mm vacuum till no more drops of toluene were observed. High vacuum was applied below <100 °C for removal of traces of toluene to afford (-)-3-[4-[2-(3,4-dihydro-2H-benzo[b] [1 ,4]thiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid as light brown, glass, sticky mass (weighs about 251 g, yield 85 %, purity 97 % by HPLC). IR (neat) cm^"1 : 3400,-3300 (-OH stretch), 3060 (-C-H aromatic stretch), ₍ 2922 (-C-H, aliphatic stretch), 1720 (-COOH stretch).

TI NMR (200 MHz, CDC1₃): δ 1.18 (t, J=7.0Hz, 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 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): 388 (M* + 1).

Advantages of the present invention

• The compound of the formula (1) has been developed without employing expensive chemicals, which is commercially viable, simple and efficient with safe operations eyen in scale-up reactions. The use of column chromatography has been avoided completely thereby, making, the process cost and time effective.

The use of new solvent has improved the overall yield of the compound of fonnula (I) and the time cycle required for the production of the compound of the formula (1) has been reduced drastically, which makes the process commercially viable.

Claims

We claim:

1. A process for the preparation of compounds of the formula ( 1 )

where R represents (Cι-C₆)alkyl group; X represents sulphur or oxygen atom, which comprises:

(i) condensing th,e compound of the formula (7)

where R¹ and R² represent (C₁-C₆)alkyl group, with mesylate of the formula (8)

where X represents sulphur or oxygen atom in the presence of a base and a solvent at a temperature and duration in the range of 10 to 150 °C and 2 to 30 h respectively, to give the ester of the formula (9)

where R , 1 , R r>2 and X are as defined above, (ii) hydrolysing the compound of the formula (9) by conventional methods to yield the compound of the formula (1) defined above, by using a base and a solvent at a temperature and duration in the range of 10 to 40 °C and 20 min to 12 h respectively and (iii) isolating the compound of formula (1) by conventional methods.

2. The process as claimed in claim 1, where 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, where the solvents used in step (i) is selected from toluene, xylene or alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.

4. The process as claimed in claims 1 to 3, where the base used in step (ii) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

5. The process as claimed in claims 1 to 4, where the solvent used in step (ii) is selected fr.om toluene, xylene or alcohol selected from methanol, ethanol, propanol, isopropanol or mixtures thereof.

6. ^■ The process as claimed in claims 1 to 5, where the hydrolysis in step (ii) carried out at a temperature in the range of 25 to 35 °C and duration in the range of 20 min to 8 h.

7. A process for the preparation of compound of the formula (1) as claimed in claims 1-6, substantially as herein described with reference to example 1.