Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF BENZOTHIAZINE AND BENZOOXAZINE CLASS OF COMPOUNDS

Abstract Abstract The present invention relates to an improved process for the preparation of ant diabetic compounds having the formula (1). where R represents (C|-C6)alkyl group, X represents sulphuric or oxygen atom
Full Text

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

In our US Patent numbers 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 aldehydes of formula (2) where X represents sulphuric or oxygen atom to a compound of formula (3) where R1 and R2 represent lower alkyl group, reducing the compound of formulae (3) to produce a compound of formula (4), hydrolyzing 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 R are as defined above. The process is shown in the scheme -1 given below


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 exotic reactions like Witting-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 (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 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 (9) where R and R are as described therein, 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, Na2C03, NaH and the like or mixtures thereof to produce ester of formula (10) and hydrolyzing the compound of the formula (10) by conventional methods to yield the compound of the formula (11) where R' is as described therein, reacting the compound of formula (10) with arginine to produce arginine salt of compound of formula (1). The reaction is shown in scheme-2 below :


The process has the following disadvantages:
• The condensation of mesylate with compound of formula (9) in DMF and
potassium carbonate results into highly impure product, which could not be purified
by conventional methods like distillation '
• Column chromatography was employed for purification of 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.
Objecth'es of the present invention
The main objective of the present invention is therefore to provide a convergent synthesis of the compounds of the formula (1), without employing exotic and expensive chemicals, thereby making the process commercially viable.
Yet another objective of the present invention is to provide a simple and efficient process for the preparation of the compounds of the formula (1), which would be friendly to a manufacturing chemist v/ith 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 R represents (Ci-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 t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group, R1 represents (Ci-C6)alkyl group in the presence of a base and organic solvent at a temperature in the range of 30 to 150 °C for 2 to 30 h, to give compound of the formula (13) where R2 represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R1' represents (Ci-C6)alkyl group as defined above,

(ii) hydrolysing the compound of formula (13) to yield the compound of the
formula (14) in the presence of p-toluene sufonic acid, 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) to a compound of formula (11) using
sodium hydride, an alkylating agent such as R-halide or (R)2-sulfate, where R is as
defined above, in the presence of a base and a solvent at a temperature in the range of 5
to 35 °C for a period of 0.5 to 25 h,
(iv) converting the compound of formula (11) to a compound of formula (15) by
reacting 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, >
(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 is as
defined above and
(vi) isolating the compound of formula (1) formed by conventional methods.
The process explained above is shown in scheme-3 below :


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 DMF, THF, DME, DMSO, N-methyl pyrrolidone (NMP), DBA, toltiene, xylene, acetone, MIBK, diethyl ketone, acetonitrile, alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or mixtures 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 p-tolunesulfonic acid, a solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or ketonic solvents such as acetone, methyl ethyl ketone and the like or mixtures thereof, using aqueous alkali base such as sodium hydroxide or potassium hydroxide or an acid such as methane sulfonic acid, HCl, H2SO4, trifluoroacetic acid and the like. The reaction may be carried out at a temperature in the range of 5 to 75 °C for a period in the range of 0.5 to25h.
Etherification of compound of formula (14) may be carried out using sodium hydride, an alkylating agent selected from (R)2-sulfate such as diethyl sulfate, dimethyl sulfate and the like; or R-halide such as methyl halide, ethyl halide, 2-propyl halide, t-butyl halide and the like, where R is as defined earlier, in the presence of a solvent such as hydrocarbons namely benzene, toluene, xylene and the like or DMF, DMSO, MIBK, ethyl acetate, NMP and the like or mixmres thereof, a base such as sodium carbonate, potassium carbonate, NaH, NaOH, KOH and the like. The reaction may be carried out 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 a-phenyl ethylamine in the presence of a solvent such as alkyl ester such as methyl acetate, ethyl acetate, ethyl propanoate, n-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 and the like or acetonitrile, ethers like THF, 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 (C1-C6) alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and th6 like; acetonitrile, DMF, DM-SO, acetone, 1,4-dioxane and the like or mixture thereof The reaction may be carried out 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.
According to yet another embodiment of the present invention there is provided an alternate process for the preparation of compounds of the formula (1)

wherein R represents (Ci-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 compound of the formula (16) with mesylate of the formula (8) in the presence of a base and an organic solvent at a temperature in the range of 25 to 150 °C for a period in the range of 2 to 30 h to give compound of the formula (17) where R' represents (C1-C6) alkyl group as defined above,
(ii) hydrolysing the compound of formula (17) to a compound of formula (14), in the presence of a base or an acid and a solvent, at a temperature in the range of 5 to 60 °C for 0.5 to 12 h,
(iii) etherifying the compound of formula (14) using sodium hydride, an alkylating agent such as R-halide or (R)2-sulfate, where R is as defined above, in the presence of a base and a solvent to obtain compound of formula (11) where R represent (Ci-Ce) alkyl group at a temperature in the range of 5 to 30 °C for a period of in the range of 0.5 to
24 h,
(iv) converting the compound of formula (11) to a compound of formula (15) by
reacting 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,
(v) reacting the compound of formula (15) with L-arginine in the presence of a
solvent to yield compound of formula (1) where R represents (Ci-Ce) alkyl group
7

defined above at a temperature in the range of 20 °C to the reflux temperature of the
solvent used for 1 to 24 h and
(vi) isolating the compound of formula (1) formed by conventional methods.
The process explained above is shown in scheme-3 below : * '

Sfheme-3
The condensation of the mesyli^te of formula (8) with compound of formula (16) 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 DMF, THF, DME, DMSO, N-methyl pyrrolidone (NMP), DEA, toluene, xylene, acetone, MIBK, diethyl ketone, acetonitrile, alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or mixtures thereof The reaction may be carried out at a temperature in the range of 25 to 150 °C for a period in the range of 2 to 30 h.
The hydrolysis of compound of formula (17) to compound of formula (14) may be carried out in the presence of a solvent selected from alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol and the like or ketonic solvent such as acetone, methyl ethyl ketone and the like or mixtures thereof, using aqueous alkali base
8

such as sodium hydroxide or potassiura hydroxide or an acid such as methane sulfonic acid, HCl, H2SO4, trifluoroacetic acid and the like. The reaction may be carried out at a temperature in the range of 5 to 60 °C for a period in the range of 0.5 to 12 h.
Etherification of compound of formula (14) may be carried out" using sodium hydride, an alkylating agent is selected from (R)2-sulfate such as diethyl sulfate, dimethyl sulfate and the like; or R-halide such as methyl halide, ethyl halide, 2-propyl halide, t-butyl halide and the like where R is as defined earlier, in the presence of a solvent such as hydrocarbons namely benzene, toluene, xylene and the like or DMF, DMSO, MIBK, ethyl acetate, NMP and the like or mixtures thereof, a base such as sodium carbonate, potassium carbonate, NaH, NaOH, KOH and the like. The reaction may be carried out at a temperature in the range of 5 to 30 °C for a period in the range of0.5to24h.
The conversion of compound of the formula (11) to phenyl ethyl amine salt of compound of formula (14) may be carried out using phenyl ethylamine in the presence of a solvent such as alkyl ester such as methyl acetate, ethyl acetate, ethyl propanoate, n-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 and the like or acetonitrile, ethers like THE, dioxane, diisopropyl ether and the like or hydrocarbon 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 (Ci-Ce) alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol and the like; acetonitrile, DMF, DMSO, acetone, in 1,4-dioxane and the like or mixture thereof The reaction may be carried out at a temperature in the range of 20 °C to reflux temperature, for a period in the range of 2-
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)
Preparation of (-) methvl-3-K-(2-(3.4-dihvdro-2H-benzorbiri.41thiazin-4-
yl)ethoxv)phenyl1-2-tertiarv butyl dimethyl silyloxy propanoate * '
In a I L four necked round bottom flask, fitted with a Dean Stark apparatus, reflux condenser and efficient stirrer, powdered K2CO3 (74 g, 0.534 M) and toluene (300 ml) was added at 30 to 35 °C under stirring. The reaction mixture was heated t6 110 to 120 °C and maintained at reflux temperature of toluene for 2 to 3 h. The water was removed azeotropically till no more water droplets were observed. After azeotropic removal of water, the reaction mixture was 'brought to 70 to 80 °C and (-) methyl 3-(4-hydroxyphenyl)-2-(t-butyldimethyl silyloxy)propanoate (30 g) and 2-(3,4-dihydro-2H-benz6[b][l,4]thiazin-4-yl)ethyl methane sulfonate (25 g) were added at the same temperature under stirring. The reaction mixture was heated to 110 to 120 °C and maintained the reflux condition of toluene. The water was removed azeotropically and maintained the reaction mixture under reflux for 15
tol8 h. The reaction mixture was brought to 30 to 35 °C and cooled tolO to 15 °C and sufficient amount of water was added and separated the organic toluene layer. The aqueous layer was extracted with toluene. The organic layer was combined and washed with DM water till pH becomes neutral. The organic layer was 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"'^ 3060, 2922, 1740.
'H NMR (200 MHz, CDCI3) 8: 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, IH), 4.10-4.22 (m, IH), 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). Massm/z(CI):508(M+ + l). Step (ii)
Preparation of (-) 3-[4-r2-(3.4-dihvdro-2H-benzorbiri,41thiazin-4-vl) ethoxylphenyll-2-hvdroxvpropanoic acid
In a 2 L four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, (-) methyl-3-[4-(2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy)phenyl]-2-
10

tertiary butyl dimethyl silyloxy propancate (87.5 g) and methanol (437 ml 1:15 w/v) were added at 25 to 35 °C under stirring. p-Toluenesulfonic acid (7 g, 0.0368 M) was added to the reaction mixture at 30 to 35 °C. After complete addition, tlje reaction mixture was heated to 65 to 75 °C for 10 to 15 h under stirring for com])letion. After completion of the reaction, the reaction mixture was cooled to 5 to 10 °C and 20% NaOH solution (0.898 M, 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 for completion. The reaction mixture was diluted with DM water (250 ml) and washed with toluene. The aqueous layer was acidified with cone. HCl at 5 to 10 °C to pH 1.5 to 2.0 and maintained at the same temperature for 1 h. The aqueous layer was extracted with toluene, washed with DM water till pH became neutral. The toluene layer was concentrated below 50 to 60 °C using plant vacuum till no more vapours of toluene were observed. 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 (60 ml) 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 liolid (weighs about 61 g, yield 95%, purity 92-95%).
IR (neat) cm' : 3400-3300, 3120, 2970,1710.
'H NMR (200 MHz, DMSO-do) 5 : 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), 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). Massm/z(CI):360(M^+l). Step (iii)
Preparation of (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b1fl,41thiazin-4-yl) ethoxylphenyll-2-ethoxvpropanoic acid
In a 500 ml four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, DMF (50 ml) and 60% sodium hydride (11.5 g) were added and cooled the room temperature to 10 to 15 °C under stirring. Diethyl sulfate (23 ml, 27 g) was added slowly maintaining the temperature at 10 to 15 °C in about 10 to 15 min under stirring. After complete addition, the reaction mixture was brought to 25 to 35 °C
11

and maintained under stirring for 60 min. (-) 3-[4-[2-(3,4-Dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid (25 g) in DMF (50 ml) was add to the reaction mixture at 10 to 15 °C in about 3 to 4 h. After complete addition the room temperature was maintained at 10 to 15 °C for 16 tO '24 h under stirring. After completion of the reaction, the reaction mixture was quenched slowly with methanol (20ml) and poured into ice cold water (200 ml) 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 slowly with cone. HCl (50 ml) at 10 to 15 °C in about 30 min to pH 2.0-2.5 and maintained at same temperature for 30 min. The aqueous layer was extracted with toluene and the combined organic extracts were washed with DM water to make pH neutral. The toluene layer was concentrated below 100 °C using plant vacuum till no more drops of toluene were observed 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 (neat) cm' : 3400-3300, 3060, 2922, 1720).
'H NMR (200 MHz, CDCb) 5 : 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. The Mass m/z (CI): 388(M*+1). Step (iv)
Preparation of g-phenylethylamine salt of (-) 3-[4-[2-(3,4-dihvdro-2H-benzofblf 1,41thiazin-4-yl)ethoxy1phenyl1-2-ethoxypropanoic acid In a 250 ml four necked round bottom flask, fitted with a mechanical 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 slowly heated to 60 to 70 °C and maintained for 1 h for complete dissolution of the glassy sticky mass. a-Phenyl ethyl amine (5.62 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring. DM (120 ml) water was added to the reaction mixture and stirred for 1 hr. 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
12

precipitation. The precipitated product was filtered, washed with DM water by stirring
and dried to yield pure a-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"' : 3300-3200, 3120, 2935, 1637.
'H NMR (200 MHz, MeOD) 5 : 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 (CgH,|N), 105 (CsHg).
Step (V)
Preparation of L-arginine salt of (->3-[4-r2-(3,4-dihvdro-2H-benzo[biri,41thiazin-4-vl)
ethoxy1phenyl1-2-ethoxypropanoic acid
In a 250 ml four necked round bottom flask fitted with a mechanical stirrer and reflux
condenser a-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. The reaction mixture was slowly 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 of reaction mixture at 60 to 70 °C for 1 h.
Isopropanol (140 ml) was added to the room temperature and re fluxed for 2 h. The
reaction mixture was 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-dihydio-2H-benzo[b][l,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' : 3300-3250, 3120, 2935, 1705, 1585.
'H NMR (200 MHz, DMSO-do + TFA) 5 : 1.0 (t, 3H), 2.4-3.4 (m, 9H), 3.45-4.0 (m,
lOH), 4.05 (t, 2H), 6.5 (t, IH), 6.7-7.4 (m, 8H aromatic).
Mass m/z (CI): 388 (M^ + 1), 174 (C6H,4N402), 147 (C6H,3N03).
Example 2
Step (i)
Preparation of (-) isopropyl 3-[4-[2-(3,4-dihydro-2H-benzo[b|fl,41thiazin-4-
vl)ethoxy1phenyn-2-hydroxypropanoate
13

In a 500 ml four necked round bottom flask, fitted with a dean stark apparatus, reflux condenser and efficient stirrer, powdered K2CO3 (20.7 g) and toluene (540 ml) was added at 25 to 35 °C under stirring. The reaction mixture was heated to 1IQ to 120 °C and maintained reflux temperature of toluene for 2 to 3 h. Water vvas removed azeotropically now After azeotropic removal of water, the reaction mixture was 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 propandate (5.57 g, 0.024 M) were added sequentially in one lot. The reaction mixture was heated to 110 to 120 °C and maintained the gentle reflux condition of toluene. Water was removed azeotropically now and then. The'reaction mixture was refluxed for 4 to 5 h. The reaction mixture was brought to room temperature and cooled to 10 to 15 °C and water (200 ml) was added and separated the organic toluene layer. The organic layer was washed with DM water till pH becomes neutral. The toluene layer was washed with 10% HCl (100 ml X 2) and DM wate. The organic layer toluene was 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"' : 3300, 3060, 2922, 1740,
'H NMR (200 MHz, CDCI3): 5 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, 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). Massm/z(CI):402(M*+l). Step (ii)
Preparation of (-) 3-r4-[2-(3,4-dihYdro-2H-bcnzofbiri,41thiazin-4-vl)ethoxv1phenyn-2-hydroxypropanoic acid
In a 1 L four necked round bottom flask, fitted with a plain aerial condenser and mechanical (-) 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 slowly maintaining the temperature below 20 °C in about 20 to 30 min. After complete addition, the reaction mixture was brought to 25 to 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 to 20 °C to pH
14

2.5-3.0. The aqueous layer was extracted with toluene. The combined toluene extracts were washed with DM water and concentrated under vacuum. High vacuum was applied below 'H NMR (200 MHz, CDCI3): 5 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. Massm/z(CI):360(M^+l). Step (iii)
Preparation of (-) 3-r4-[2-(3,4-dihydro-2H-benzorb1[1.41thiazin-4-vl)ethoxy1phenyl1-2-ethoxypropanoic acid
In a 500 ml four necked round bottom flask, fitted with a plain condenser and mechanical stirrer, DMF (50 ml) and 60% 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 in about 10 to 15 min under stirring. After complete addition, the reaction mixture was brought to 25 to 35 °C and maintained under stirring for 60 min. (-) 3-[4-[2-(3,4-dihydro-2H-benzo[b][l,4]thiazin-4-yl)ethoxy]phenyl]-2-hydroxypropanoic acid (25 g) dissolved in DMF (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 slowly with methanol (20 ml) and poured into ice cold water (200 ml) 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 slowly with cone. HCl (50 ml) at 10 to 15 °C in about 30 min to pH 2.0 to 2.5 and maintained at the same temperature for 30 min. The aqueous layer was extracted with toluene. The combined toluene extract were washed with DM water till pH becomes neutral. Concentrated the toluene layer using plant vacuum to afford the title compound as dark brown, glassy, sticky mass (weighs about 22 g, yield 80%, purity 95%). IR (neat) cm"' : 3400-3300, 3060, 2922, 1720.
15

'H NMR (200 MHz, CDCI3): 8 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. Massm/z(CI):388(M+ + l). Step (iv)
Preparation of a-phenylethylamine salt of (-) 3-K-[2-(3,4-dihvdro-2H-
benzo[bl[ 1,41thiazin-4-yl)ethoxv1phenyl1-2-ethoxvpropanoic 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 the 250 ml four necked round bottom flask, fitted with a mechanical stirrer and reflux condenser at 25 to 35 °C. The reaction mixture was slowly heated to 60 to 70 °C and maintained for 1 h for complete dissolution of the glassy sticky mass. 1 !-Phenyl ethylamine (5.62 g) was added to the reaction mixture at 55 to 65 °C in a single lot under stirring. DM 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 DM 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' : 3300-3200, 3120, 2935, 1637.
'H NMR (200 MHz, MeOD): 5 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 (CgHnN), 105 (CgHg). Step (v)
Preparation of L-arainine salt of (-) 3-[4-[2-(3,4-dihydro-2H-benzorbiri,41thiazin-4-yl)ethoxv1phenyl1-2-ethoxypropanoic acid
a-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 the 250 ml four necked round bottom flask at 25-35 °C, fitted with a mechanical stirrer and reflux condenser. The reaction mixture was slowly 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 medium remains as a
16

clear solution at this stage. The reaction mixture was heated and maintained the gentle
reflux of reaction mixture at 60 to 70 °C for 1 hr. Isopropanol (140 ml) was added to
the reaction medium and refluxed for 2 h. The reaction mixture was 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-': 3300-3250,3120,2935, 1705, 1585.
'H NMR (200 MHz, DMS0-d6 + TFA): 6 1.0 (t, 3H), 2.4-3.4 (m, 9H), 3.45-4.0 (m,
lOH), 4.05 (t, 2H), 6.5 (t, IH), 6.7-7.4 (m, 8H aromatic).
Mass m/z (CI): 388 (M* + 1), 174 (C6H,4N402), 147 (C6H13NO3).
Advantages of the present process
• A convergent synthesis of the compound of the formula (1), has been developed without employing exotic and expeitsive chemicals, which is commercially viable, simple and efficient with safe operations even in scale-up reactions.
• The use of column chromatography has been avoided completely thereby making the process cost and time effective .
• The overall yield of the process has been improved and the time required for the production of the compound of the formula (1) has been reduced drastically, which makes the process commercially very attractive.


We claim:
1. An improved process for the preparation of compounds of the formula (I)

where R represents (C1-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like; X represents sulphuric or oxygen atom, which comprises: (i) condensing the mesylate of formula (8)
(8) where X represents sulphuric or oxygen atom with compound of formula (12)

where R2 represents t-butyldimethyl silyl, trim ethyl silyl or alkoxyalkyl group, R1 represents (C1-C6)alkyl 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)

where R2 represents t-butyldimethyl silyl, trim ethyl silyl or alkoxyalkyl group; R1 represents (C|-C6)alkyl group and X is as defined above,
(ii) hydrolyzing the compound of formula (13) to yield the compound of the formula (14)
in the presence of p-toluene sulfuric acid, 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)

using sodium hydride, an alkyl ting 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) converting the compound of formula (11) to a compound of formula (15)

by reacting with a-phenyl ethylamine in the presence of a solvent at a temperature in
the range of 10 to 70 °C for 1 to 12 h,
(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 is as
defined above and
(vi) isolating the compound of formula (1) formed by conventional methods.
2. The process as claimed in claim 1, wherein the base used in step (i) is selected from sodium carbonate, potassium carbonate, cesium carbonate or potassium bicarbonate.
3. The process as claimed in claims 1 to 2, wherein the organic solvent used in step (i) is select from DMF, THF, DME, DMSO, N-methyl pyrrolidone (NMP), DEA, toluene, xylene, acetone, MIBK, diethyl ketene, acetonitrile or alcohol selected from methanol, ethanol, propane, isopropanol, n-butane or mixtures thereof

5. The process as claimed in claims 1 to 4, wherein the solvent used in step (ii) is alcohol selected from methanol, ethanol, propane, isopropanol, n-butane or mixtures; or kenotic solvent selected from acetone or methyl ethyl ketene; or mixtures thereof
6. The process as claimed in claims 1 to 5, wherein the aqueous alkali base used in step (ii) is selected from sodium hydroxide or potassium hydroxide.
7. The process as claimed in claims 1 to 6, wherein the acid used in step (ii) is selected from methane sulfonic acid,^ HCl, H2SO4 or trifluoroacetic acid.

8. The process as claimed in claims 1 to 7, wherein the alkylating agent used in step (iii) is (R)2-sulfate selected from diethyl sulfate or dimethyl sulfate; or R-halide, where R is as defined in claim 1.
9. The process as claimed in claims 1 to 8, wherein the solvent usedSn step (iii) is selected from hydrocarbon, DMF, DMSO, MIBK, ethyl acetate, NMP or mixtures thereof
10. The process as claimed in claims 1 to 9, wherein the base used in step (iii) is selected from sodium carbonate, potassium carbonate, NaH, NaOH or KOH.
11. The process as claimed in claims 1 to 10, 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, propane, isopropanol or n-butanol; ketone selected from acetone or methyl ethyl ketone; acetonitrile, ether selected from THF, dioxane or isopropyl ether; hydrocarbon selected from benzene, toluene, xylene or cyclohexane; or mixtures thereof.
12. The process as claimed in claims 1 to 11, wherein the solvent used in step (v) is selected from alcohol, acetonitrile, DMF, DMSO, acetone, 1,4-dioxane or mixture thereof
13. An improved process for the preparation of compounds of the formula (1)

wherein R represents (Ci-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 compound of the formula (16)

with mesylate of the formula (8)

in the presence of a base and an organic solvent at a temperature in the range of 25 to 150 °C for a period in the range of 2 to 30 h to give compound of the formula (17)


where R' represents (C1-C6) alkyl group defined above,
(ii) hydrolysing the compound of formula (17) to a compound of formula (14),

in the presence of a base or an acid and a solvent at a temperature in the range of 5 to 60 °C for a period in the range of 0.5 to 12 h,
(iii) etherifying the compound of formula (14) using sodium hydride, an alkylating agent in the presence of a base and a solvent to obtain compound of formula (11)

where R represents (C1-C6) alkyl group, at a temperature in the range of 5 to 30 °C for a
period in the range of 0.5 to 24 h,
(iv) converting the compound of formula (11) to a compound of formula (15)

by reacting with phenyl ethylamine in the presence of a solvent at a temperature in the
range of 10 to 70 °C for a period in the range of 1 to 12 h,
(v) reacting the compound of formula (15) with L-arginine in the presence of a
solvent to yield compound of formula (1) where R represents (Ci-Co) alkyl group
defined above 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, and
(vi) isolating the compound of formula (1) formed by conventional methods.
14. The process as claimed in claim 13, wherein the base used in step (i) is selected
from sodium carbonate, potassium carbonate, cesium carbonate or potassium
bicarbonate.

15. The process as claimed in claims 13 and 14, wherein the organic solvent used in step (i) is DMF, THF, DME, DMSO, N-methyl pyrrolidone (NMP), DEA, toluene, xylene, acetone, MIBK, diethyl ketone, acetonitrile or alcohol selected from methanol, ethanol, propanol, isopropanol or n-butanol; or mixtures thereof.
16. The process as claimed in claims 13 to 15, wherein the solvent used in step (ii) is alcohol selected from methanol, ethanol, propanol, isopropanol, n-butanol or mixtures; or ketonic solvent such as acetone or methylethyl ketone; or mixtures thereof
17. The process as claimed in claims 13 to 16, wherein the base used in step (ii) is selected from sodium hydroxide or potassium hydroxide.
18. The process as claimed in claims 13 to 17, wherein the acid used in step (ii) is selected from methane sulfonic acid, HCl, H2SO4 or trifluoroacetic acid.
19. The process as claimed in claims 13 to 18, wherein the alkylating agent used in step (iii) is (R)2-sulfate selected from diethyl sulfate or dimethyl sulfate; or R-halide, where R is as defined in claim 22.
20. The process as claimed in claims 13 to 19, wherein the solvent used in step (iii) is selected from hydrocarbon, DMF, DMSO, MIBK, ethyl acetate, NMP or mixtures thereof
21. The process as claimed in claims 13 to 20, wherein the base used in step (iii) is selected from sodium carbonate, potassium carbonate, NaH, NaOH or KOH.
22. The process as claimed in claims 13 to 21, wherein the solvent used in step (iv) is selected from 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 or methyl ethyl ketene; acetonitrile, ether selected from THF, dioxane or isopropyl ether; hydrocarbon selected from benzene, toluene, xylene or cyclohexane or mixtures thereof.
23. The process as claimed in claims 13 to 22, wherein the solvent used in step (v) is selected from alcohol, acetonitrile, DMF, DMSO, acetone, 1,4-dioxane or mixture thereof.
24. A process for the preparation of compound of the formula (1) as described in claims 1-23, substantially as herein described with reference to examples 1-2.


Documents:

398-mas-2002 abstract duplicate.pdf

398-mas-2002 abstract.pdf

398-mas-2002 claims duplicate.pdf

398-mas-2002 claims.pdf

398-mas-2002 correspondence others.pdf

398-mas-2002 correspondence po.pdf

398-mas-2002 description (complete) duplicate.pdf

398-mas-2002 description (complete).pdf

398-mas-2002 form-1.pdf

398-mas-2002 form-13.pdf

398-mas-2002 form-19.pdf

398-mas-2002 form-3.pdf


Patent Number 198926
Indian Patent Application Number 398/MAS/2002
PG Journal Number 23/2006
Publication Date 09-Jun-2006
Grant Date 21-Feb-2006
Date of Filing 23-May-2002
Name of Patentee DR. REDDY’S LABORATORIES LTD
Applicant Address 7-1-27 AMEERPET, HYDERABAD 500 016
Inventors:
# Inventor's Name Inventor's Address
1 GADDAM OM REDDY DR. REDDY’S LABORATORIES LTD, 7-1-27 AMEERPET, HYDERABAD 500 016
PCT International Classification Number A61K33/14
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA