Claims:We Claim:

1. A process for the preparation of 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I), comprising the steps of;

a) 4-hydroxy-benzaldehyde (XIII) is reacted with isopropyl bromide in presence of base and solvent to obtain 4-Isopropoxy benzaldehyde (V),

b) The compound of formula (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine and followed by reduced with reducing agent in presence of solvent to obtain Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII),

c) The compound of formula (VII) is reacted with hydrazine hydrate to obtain the compound of formula (II),

d) The compound of formula (II) is reacted with sulfonating agent in presence of base and solvent to obtain 4-(4-isopropoxybenzyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (III),

e) The compound of formula (III) is reacted with isopropyl bromide in presence of base and solvent to obtain 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (IV),

f) The compound of formula (IV) converts into 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I) in presence of base and solvent.

2. A process for the preparation of methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII), which comprises the compound of formula (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine and followed by reduced with reducing agent in presence of solvent to obtain Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII),

3. The process as claimed in claim 1 and 2, wherein the reducing agent is selected from Lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), Palladium / carbon (Pd/ C), Raney.Ni, Tin tetrachloride (SnCl4), Iron powder, Diisobutylaluminum hydride, Diborane, Sodium amalgam.

4. The process as claimed in claim 1, wherein the sulfonating agent is selected from methane sulphonyl chloride (MsCl), p-toluene sulphonyl chloride (p-TsCl), Chlorosulfuric acid (HSO3Cl), methanesulfonic anhydride.

5. The process as claimed in claim 1 and 2, wherein the wherein the organic base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethyl amine, aniline, morpholine, piperidine, N,N-dimethylaniline, pyridine, 1,8-diazabi cyclo[5.4.0]undec-7-ene (DBU),5-diazabicyclo[4.3.0]non-5-ene (DBN). Wherein the inorganic base is selected from, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, potassium iodide, sodium acetate, and potassium acetate.

6. The process as claimed in claim 1 and 2, wherein the organic solvent is selected from, water, ethanol, methanol, isopropanol, toluene, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetic acid, acetone, methyl ethyl ketone, N-methylpyrrolidone, methyl isobutyl ketone, cyclohexane, methylene dichloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.
7. The process as claimed in claim 1 is used for the preparation of Remogliflozin etabonate.

Dated this eighteenth (18th) day of December, 2020,
, Description:“PROCESS FOR THE PREPARATION OF PROCESS FOR THE PREPARATION OF 4-(4-ISOPROPOXYBENZYL)-1-ISOPPROPYL-5-METHYL-1H-PYRAZOL-3(2H)-ONE”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I)., which is a key intermediate for the preparation of Remogliflozin etabonate

BACKGROUND OF THE INVENTION

Remogliflozin etabonate is a pro-drug of Remogliflozin, the active entity that inhibits 25 the sodium dependent glucose transporter 2 (SGLT2). Remogliflozin etabonate is chemically known as 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O- (ethoxycarbonyl)-β-D-glucopyranosid is as follows.

All synthetic process of Remogliflozin etabonate utilize one of the key intermediate i.e., 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I.

Remogliflozin etabonate is first reported in US 7,084,123 B2 by Kissei Pharmaceutical Co., Ltd., The synthetic process for Remogliflozin etabonate is reported in US ‘123, which comprises, the compound of formula (i) is reacted with MsCl in presence of TEA / THF to obtain the compound of formula (ii). The compound of formula (ii) is reacted with methyl acetoacetate in presence of NaH / THF / 1,2-dimethoxyethane and followed by reacted with anhydrous hydrazine in presence of toluene to obtain the compound of formula (II). The compound of formula (II) is reacted with the compound of formula (iv) in presence of Ag2CO3 / THF to obtain the compound of formula (v). The compound of formula (v) converts into the compound of formula (vi) in presence of Aq. NaOH / EtOH. The compound of formula (vi) is reacted with 2-bromopropane in presence of Cs2CO3 / DMF to obtain Remogliflozin (vii). The compound of formula (vii) is reacted with ethylchloro formate in presence of 2,4,6-trimethylpyridine / citric acid monohydrate and water to obtain Remogliflozin etabonate.

The above process is schematically shown as below:

US 2011/0224413 of GlaxoSmithKline reported a process for the preparation of 4-(4-Isopro poxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I, which comprises the compound of formula (II) is reacted with MsCl in presence of pyridine and MeCN to obtain the compound of formula (III). The compound of formula (III) is reacted with isopropyl iodide in presence of LiOH / NMP to obtain the compound of formula (IV), which is followed by converts into the compound of formula (I) in presence of 2-amino ethanol, NaOH and HCl.

The above process is schematically shown as below:

IN 201927017911 of Glenmark reported a process for the preparation of 4-(4-Isopropoxy benzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I, which comprises the compound of formula (XI) is reacted with isopropyl bromide in presence of DMF / potassium t-butanoate / H2O and EtOAc to obtain the compound of formula (i). The compound of formula (i) is reacted with oxalyl chloride in presence of MeCN / DMF / toluene and H2O to obtain the compound of formula (XII). The compound of formula (XII) is reacted with methyl aceto acetate in presence of H2O / K2CO3 / DMF and toluene to obtain the compound of formula (VII). The compound of formula (VII) is reacted with NH2NH2.H2O in presence of toluene to obtain the compound of formula (II). The compound of formula (II) is reacted with MsCl in presence of MeCN / pyridine and H2O to obtain the compound of formula (III). The compound of formula (III) is reacted with isopropyl bromide in presence of LiOH.H2O / TEA / HCl / NMP / NaOH and MeOH to obtain the compound of formula (I).

The above process is schematically shown as below:

WO 2012133783 of Kissei Pharmaceutical., reported process for the preparation of 4-(4-Iso propoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I, which comprises the compound of formula (V) is reacted with methyl acetoacetate in presence of AcOH and piperidine and the reaction carried out 115 hours (~5 days) to obtain the compound of formula (VI). The compound of formula (VI) undergoes reduction in presence of 10% Pd/C / 2-propanol / EtOAc and H2O to obtain the compound of formula (VII). The compound of formula (VII) converts into the compound of formula (VIII) in presence of p-TsOH.H2O / methyl acid in toluene / NaHCO3 and water. The compound of formula (VIII) undergoes hydrogenation in presence of Aq. NaOH / methyl propanoate in MeOH / MTBE / H2O and HCl to obtain the compound of formula (IX). The compound of formula (IX) is reacted with isopropyl hydrazine hydrochloride in presence of imidazole / pyridine / SOCl2 / THF / DMF and TEA to obtain the compound of formula (X). The compound of formula (X) converts into the compound of formula (X) in presence of HCl / baking soda toluene / MeCN and H2O.

The above process is schematically shown as below:

The main drawback of the prior art is time consuming (115 hours/~5 days) process for the preparation of 4-(4-Iso propoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I. Conversion of the compound of formula (V) is reacted with methyl acetoacetate to the compound of formula (VI) in presence of Piperidine and the reaction carried out 115 hours (~5 days). The present invention process for the preparation of 4-(4-Iso propoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I is carried out less span of time. Conversion of the compound of formula (V) is reacted with methyl acetoacetate to the compound of formula (VI) in presence of Morpholine and the reaction is carried out 10-12 hours.

To overcome the prior-art problems the present inventors have now developed an improved process for the preparation of 4-(4-Iso propoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula I using industrially friendly solvents and reagents.
SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I).

In one aspect of the present invention, provides a process for the preparation of 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I), comprising the steps of;

a) 4-hydroxy-benzaldehyde (XIII) is reacted with isopropyl bromide in presence of base and solvent to obtain 4-Isopropoxy benzaldehyde (V),

b) The compound of formula (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine and followed by reduced with reducing agent in presence of solvent to obtain Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII),

c) The compound of formula (VII) is reacted with hydrazine hydrate to obtain the compound of formula (II),

d) The compound of formula (II) is reacted with sulfonating agent in presence of base and solvent to obtain 4-(4-isopropoxybenzyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (III),

e) The compound of formula (III) is reacted with isopropyl bromide in presence of base and solvent to obtain 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (IV),

f) The compound of formula (IV) converts into 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I) in presence of base and solvent.

In another aspect of the present invention, provides 4-isopropoxy benzaldehyde (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine and followed by reduced with reducing agent in presence of solvent to obtain Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I).

In one embodiment of the present invention, provides a process for the preparation of 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I), comprising the steps of;

a) 4-hydroxy-benzaldehyde (XIII) is reacted with isopropyl bromide in presence of base and solvent to obtain 4-Isopropoxy benzaldehyde (V),

b) The compound of formula (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine and followed by reduced with reducing agent in presence of solvent to obtain Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII),

c) The compound of formula (VII) is reacted with hydrazine hydrate to obtain the compound of formula (II),

d) The compound of formula (II) is reacted with sulfonating agent in presence of base and solvent to obtain 4-(4-isopropoxybenzyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (III),

e) The compound of formula (III) is reacted with isopropyl bromide in presence of base and solvent to obtain 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (IV),

f) The compound of formula (IV) converts into 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I) in presence of base and solvent.

In an embodiment of the present invention, wherein the compound of formula (XIII) is reacted with isopropyl bromide in presence of K2CO3 / KI and DMF and the reaction is carried out at ambient temperature to obtain the compound of formula (V). The compound of formula (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine, acetic acid and cyclohexane the reaction is carried out at ambient temperature for 10-12 hours to obtain the compound of formula (VI). The compound of formula (VI) undergoes reduction in presence of 5% Pd/C, IPA and toluene to obtain the compound of formula (VII). The compound of formula (VII) is reacted with hydrazine hydrate in presence of methanol at ambient temperature for 4 hours to obtain the compound of formula (II). The compound of formula (II) is reacted with MsCl in presence of pyridine / MeCN at below 15ºC to obtain the compound of formula (III). The compound of formula (III) is reacted with isopropyl bromide in presence of LiOH. H2O / NMP at 25-30ºC for 12 hours to obtain the compound of formula (IV). The compound of formula (IV) converts into 4-(4-Isopropoxybenzyl)-1-isoppropyl-5-methyl-1H-pyrazol-3(2H)-one of formula (I) in presence of NaOH / MeOH / water at 35-40ºC for 12 hours and the reaction mass pH adjusted to 7.5-8.0 with conc. hydrochloric acid.

According to an embodiment of the present invention, wherein the reducing agent is selected from Lithium aluminium hydride (LiAlH4), sodium borohydride (NaBH4), Palladium / carbon (Pd/C), Raney.Ni, Tin tetrachloride (SnCl4), Iron powder, diisobutylaluminum hydride, diborane, Sodium amalgam.

According to an embodiment of the present invention, wherein the sulfonating agent is selected from methane sulphonyl chloride (MsCl), p-toluene sulphonyl chloride (p-TsCl), Chlorosulfuric acid (HSO3Cl), methanesulfonic anhydride.

According to an embodiment of the present invention, wherein the organic base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, aniline, morpholine, piperidine, N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),5-diazabicyclo[4.3.0]non-5-ene (DBN). Wherein the inorganic base is selected from, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, potassium iodide, sodium acetate, and potassium acetate.

According to an embodiment of the present invention, wherein the organic solvent is selected from, water, ethanol, methanol, isopropanol, toluene, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetic acid, acetone, methyl ethyl ketone, N-methylpyrrolidone, methyl isobutyl ketone, cyclohexane, methylene dichloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.

In another aspect of the present invention, provides 4-isopropoxy benzaldehyde (V) is reacted with methyl acetoacetate in presence of catalytic amount of morpholine and followed by reduced with reducing agent in presence of solvent to obtain Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (VII).

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example - 1:

Preparation of 4-Isopropoxybenzaldehyde:

To a stirred solution of N,N’-Dimethylformamide (1500 mL), 4-hydroxybenzaldehyde (300 g), potassium carbonate (508.5 g) and potassium iodide (40.8 g) was added 2-bromopropane (453.2 g) at ambient temperature. The resulted reaction mass was heated to 50-55°C and maintained for about 6 hours. After completion of reaction, water (600 mL) was added at below 30°C and filtered the unwanted solid. Product was extracted into ethyl acetate (1800 mL) from the filtrate and washed the ethyl acetate layer with 10% w/v aqueous sodium chloride solution (300 mL) at 25-30°C. The organic layer was concentrated under vacuum to obtain 4-isopropoxybenzaldehyde.

Yield: 363 g (90.2%)

Example - 2:

Preparation of Methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate:

To a mixture of 4-isopropoxybenzaldehyde (500 g), cyclohexane (2500 mL) and catalytic amount of morpholine (26.5 g) was added acetic acid (127.9 g) at ambient temperature. The reaction mass was heated to reflux temperature and collected the byproduct water by azeotropic distillation for about 10-12 hours. Alter completion of the reaction, concentrated the reaction mass under vacuum to get the residue of methyl 2-(4-isopropoxybenzylidene)-3-oxobutanoate.

To the above obtained residue of methyl 2-(4-isopropoxy benzyl idene)-3-oxobutanoate was dissolved in isopropyl alcohol (2500 mL) at 25-30°C and hydrogenated in the presence of 5% palladium on carbon (75 g) under 5-6 kg/cm2 hydrogen gas at ambient temperature for about 6 hours. Removed the palladium on carbon by filtration through hyflo bed after completion of the reaction at 25-30°C. The filtrate was concentrated under vacuum and dissolved in toluene (3000 mL) then washed with 5% w/v aqueous sodium bicarbonate solution (1500 mL) followed by water (1500 mL) at 25-30°C. The organic layer was concentrated under vacuum to obtain methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate.

Yield: 800 g (100%)

Example - 3:

Preparation of 4-(4-isopropoxybenzyl)-5-methyl-1H-pyrazol-3(2H)-one:

To a stirred solution of methanol (800 mL) and methyl 2-(4-isopropoxybenzyl)-3-oxobutanoate (400 g) was added hydrazine hydrate (104.6 g, 75% assay) at 25-30°C and maintained the reaction mass for about 4 hours. After completion of the reaction, water (6000 mL) was added to the reaction mass at below 30°C and maintained for 5 hours. Filtered the precipitated solid and dried the solid under vacuum at 50-55°C to obtain 4-(4-isopropoxybenzyl)-5-methyl-1H-pyrazol-3(2H)-one.

Yield: 310 g (83.33%)

Example - 4:

Preparation of 4-(4-isopropoxybenzyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate:

To a stirred solution of 4-(4-isopropoxybenzyl)-5-methyl-1H-pyrazol-3(2H)-one (300 g), acetonitrile (1500 mL) and pyridine (125.1 g) was added Methanesulfonyl chloride (167.4 g) at below 15°C. Water (4500 mL) was added after completion of the reaction at below 30°C and maintained for 2 hours at 25-30°C. The obtained solid was filtered and dried under vacuum at 50-55°C. To the dried solid, toluene (450 mL) was added and heated to 50-55°C then maintained for 30 min. Cooled the slurry mass to 10-15°C, maintained for 2 hours, filtered and dried under vacuum to obtain pure 4-(4-isopropoxybenzyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate.

Yield: 265 g (67.43%)
tr), 1169, 1084, 1013 (C-O);
Example - 5:

Preparation of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate:

To the mixture of 4-(4-isopropoxybenzyl)-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methane sulfonate (170 g), N-methyl-2-pyrrolidone (850 mL) and lithium hydroxide monohydrate (72.6 g) was added 2-bromopropane (148.2 g) at 10-15°C and maintained for about 12 hours at 25-30°C. After completion of the reaction, water (1700 mL) was added at below 30°C and adjusted the reaction mass pH 7.5-8.0 with concentrated hydrochloric acid (~165 mL). The precipitated solid was filtered and dried under vacuum at 50-55°C to obtain 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate.

Yield: 153 g (80.35%)

Example - 6:

Preparation of 4-(4-Isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3(2H)-one:

To a stirred solution of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-2,3-dihydro-1H-pyrazol -3-yl methanesulfonate (100 g) and methanol (500 mL) was added 4M solution of sodium hydroxide (200 mL) at 25-30°C. The reaction mass was heated to 35-40°C for about 12 hours. After completion of the reaction, cooled the reaction mass to 25-30°C and adjusted the reaction mass pH to 7.5-8.0 with concentrated hydrochloric acid (~52 mL). The precipitated solid was filtered and purified from methanol (300 mL) to obtain pure 4-(4-Isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3(2H)-one.

Yield: 53 g (67.94%)