WO2012114280A1 - An improved process for the preparation of pyrrolidine thiol derivatives useful in the synthesis of carbapenem compounds - Google Patents

Abstract

The present invention relates to an improved process for the preparation of the compound of formula (III) which is used in the synthesis of carbapenem antibiotics. wherein R³ is hydrogen or an amine protecting group.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF

PYRROLIDINE THIOL DERIVATIVES USEFUL IN THE SYNTHESIS OF CARBAPENEM COMPOUNDS FIELD OF THE INVENTION

This specification is patent of addition to Indian patent application IN 424/CHE/2009. The present invention provides an improved process for the preparation of Thiol compound of general formula (III), which is an important key raw material in the preparation of Doripenem.

(Ill)

wherein R represents hydrogen or amino protecting group such as p-nitrobenzyloxy carbonyl, tert-butyloxy carbonyl (BOC), allyoxy carbonyl, p-methoxy benzyloxy carbonyl.

BACKGROUND OF THE INVENTION

Doripenem, is a synthetic broad-spectrum carbapenem antibiotic structurally related to β-lactam antibiotics. Doripenem in the form of monohydrate is marketed in United States of America as DORIBAX^™

Various methods are reported in the prior art for the preparation of Doripenem compound of formula (I) which includes the condensation of compound of formula (II) with compound of formula (III) and subsequent deprotection of the protecting group as shown in scheme- 1.

wherein R¹ is hydrogen or hydroxy protecting group such as tert-butyl dimethyl silyl and the like, R² is hydrogen or carboxyl protecting group such as p-nitrobenzyl, p- methoxy benzyl, allyl and the like, A is an activating group such as P(0)(OR)₂, SO₂R and the like wherein R is selected from substituted or unsubstituted Ci_6 alkyl, aralkyl or aryl to form the compound of formula (II). R³ is hydrogen or amino protecting group such as p-nitrobenzyloxy carbonyl, tert-butyloxy carbonyl (BOC), allyoxy carbonyl, p- methoxybenzyloxy carbonyl and the like to form the compound of formula (III).

Doripenem was first disclosed in US 5,317,016 which also discloses a process for the preparation of same. This patent discloses various methods for the preparation of compound of general formula (III) followed by condensation with compound of general formula (II) using base such as N-ethyldiisopropylamine and subsequent deprotection yields Doripenem which was isolated by lyophilization technique. This patent utilizes column chromatographic technique for the isolation of compound of general formula (III).

JP 2003/026680 discloses process for the preparation of Doripenem without isolating the thiol compound of general formula (III) by condensing with compound of general formula (II) thereby isolating the Doripenem in lower yield which contains impurities. Additional purification is required to remove the unwanted impurities thereby increasing the cost of production which in turn not viable in large scale production. IN 1 104/DEL/2005 and its equivalent WO 2006/1 17763 discloses a process for the preparation of Doripenem by condensing compound of formula (II) and (III) to produce compound of formula (IV) followed by deprotection with out isolating the compound of formula (IV).

IN 2370/DEL/2005 and its equivalent WO 2007/029084 discloses the use of acetyl chloride, silica chloride, thionyl chloride or oxalyl chloride for the preparation of thiol compound of general formula (III) from compound of general formula (V). Further this patent does not involve the isolation of compound of general formula (III) as solid and used it as an oily residue for further reaction.

(V) wherein R and R are same or different and selected from hydrogen or amino protecting group. Since the said application uses oily residue with out purification, the impurities and by-products formed during the reaction carried forward to the next stage leading to the production of less pure Doripenem in lower yield. This patent utilizes acetyl chloride for the deacetylation to prepare the compound of formula (III).

All the above said prior arts utilizes compound of formula (III) as a pasty mass or requires column purification method for the isolation of compound of formula (III). Applicant observed that the compound of formula (III) obtained after deacetylation contain various impurities particularly dimer (disulphide of compound of formula (III)), because of which the purity of compound of formula (III) was affected and resulted as pasty mass.

With our continued intensive and diligent research for developing a process for the preparation of compound of formula (III) with high purity thereby producing Doripenem in good yield and high purity, we have identified an improved process which is commercially viable and eliminates the issues associated with purity.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide a simple and commercially viable, industrially scalable process for the isolation of compound of general formula (III) with high purity and good yield. Yet another objective of the present invention is to provide a simple and commercially suitable process for the preparation of compound of general formula (III) with high purity and good yield thereby producing Doripenem Compound of Formula (I) with high purity. SUMMARY OF THE INVENTION

Accordingly the primary aspect of the present invention is to provide an improved process for the preparation of compound of formula (III)

with high purity, the said p ound of formula (V),

(V)

wherein R and R is same or different and independently represents hydrogen or an amino protecting group; using deacetylating reagent in a solvent in the presence of triphenylphosphine, wherein the improvement consists in the use of triphenylphosphine. DETAILED DESCRIPTION

In an embodiment of the present invention the amine protecting group represented by R³ and R⁴ is same or different and are independently selected from a group consisting of p-nitrobenzyloxy carbonyl, tert-butyloxy carbonyl (BOC), allyoxy carbonyl, p-methoxybenzyloxy carbonyl and the like, preferably p-nitrobenzyloxy carbonyl for R3 and tert-butyloxy carbonyl (BOC) for R4.

In another embodiment of the present invention the deacetylating reagent is selected from phosphorous oxychloride, acetyl chloride, silica chloride, thionyl chloride, oxalyl chloride sulphuric acid, sodium methoxide, sodium hydroxide and resins like Lewatit® K 2649, Diaion UBK 530, Diaion UBK 535, Diaion UBK 550, Diaion UBK 555, Diaion SK 104, Diaion SK IB, Diaion SKL 10, Diaion PK 208, Diaion PK 220, Relite RPS, Relite CFZ, Relite CND and the like or mixtures thereof, preferably phosphorous oxychloride and Lewatit® K 2649. Lewatit(R) K 2649 is a strongly acidic, macroporous, polymer-based catalyst in spherical bead form, with sulfonic acid groups. Details can be viewed at http://www.sybronchemicals.net /products/organic/k2649.pdf. Use of phosphorous oxychloride even in catalytic amount gave good product formation.

In still another embodiment of the present invention, the solvent(s) employed in deacetylation is selected from methanol, ethanol, isopropanol, tetrahydrofuran and the like or mixtures thereof. In yet another embodiment of the present invention, the compound of formula

(III) is isolated from the reaction mass by quenching the reaction mass into water followed by extraction into a water immiscible solvent and optionally removing the water immiscible solvent to get the compound of formula (III) or by adding anti-solvent or by any other conventional techniques.

In another embodiment of the present invention, the organic solvent employed in the extraction is selected from ethyl acetate, dichloromethane, chloroform and the like; the said organic solvent is optionally removed by conventional technique like distillation, evaporation and the like.

In one more embodiment of the present invention, the anti solvent used for the isolation of compound of general formula (III) is selected from the group comprising toluene, diisopropyl ether, cyclohexane, heptane, hexane, pentane and the like or mixtures thereof.

It should be noted that in all the reported prior arts the compound of formula (III) is isolated only as an oily residue form which contains impurities and the said residue form is inconvenient to store, whereas our earlier application provides compound of formula (III) as a crystalline solid which possess good stability. Accordingly the present invention provides an improved process for the preparation of compound of formula (III) as a crystalline form, which comprises the steps of

f formula (V),

(V)

wherein R³ and R⁴ is same or different and independently represents hydrogen or an amine protecting group; using deacetylating reagent in a solvent in the presence or absence oftriphenylphosphine;

b) extracting the compound of formula (III) in a water immiscible solvent;

c) optionally concentrating the step (b) solution;

d) adding anti- solvent; and

e) isolating the compound of formula (III) by filtration.

Deacetylation of compound of formula (V) without the use of triphenylphosphine (TPP) results in the formation of impurities in particular disulfide impurity (or dimer impurity) of formula (D) in higher content and leads to inferior quality of compound of formula (III) which in turn affect the quality of final product Doripenem. The prior art process reported so far yields the compound of formula (III) with purity less than 99% and contain the compound of formula (D) to an extent greater than 1.5%. Surprisingly, applicant found that use of triphenylphosphine during deacetylation minimizes the said impurity of formula (D) drastically and produces the compound of formula (III) having purity greater than 99.00% and desired yield which constitutes the novelty

Formula (D)

wherein R³ and R⁴ represents hydrogen or amino protecting group

In this present invention compound of formula (III) is obtained as crystalline solid with improved purity and good stability. The high purity of compound of formula (III) achieved in the present invention results in improved purity of the final compound (i.e) Doripenem.

In one more embodiment of the present invention, compound of formula (III) is used in the preparation of Doripenem of formula (I).

Accordingly the present invention can also be extended to the process for the preparation of compound of general formula (Y), which comprising the steps of:

A) deacetylating the compound of general formula (X) using phosphorus oxychloride or a resin with triphenylphosphine in a solvent

hue.

(X)

olating compound of general formula (Y)

(wherein R is hydrogen or tert-butoxycarbonyl), and R³ represents p-nitrobenzylo or) a chemical formula

The following examples are provided by way of illustration only and should not be construed to limit the scope of the invention. Preparation of (2S,4S)-l-p-nitrobenzyloxycarbonyl-2-sulfamoylamino methyl-4- mercaptopyrrolidine compound of formula (III):

Example -1 :

To a slurry of (2S,4S)-4-Acetylthio-2-(N-sulfamoyl-tert-butoxycarbonyl aminomethyl)- l-(4-nitrobenzyloxycarbonyl)p rrolidine (50g) and triphenyl phosphine (2.5 g) in methanol (150 ml), phosphorous oxychloride (3.8 g) was added at 25-30°C. The resultant mixture was heated to 63-67°C and maintained for 4-8 hours and cooled to 25-30°C. To the reaction mixture ethyl acetate (250 ml), purified water and saturated sodium chloride solution were added and the layers were separated. The organic layer was washed with saturated sodium chloride solution and concentrated to get a thick mass which was dissolved in tetrahydrofuran (50 ml). The tetrahydrofuran layer containing the product was charged slowly into purified water containing diisopropyl ether. The resultant mass was stirred and cooled. The solid product formed was filtered and washed with purified water. The wet material was suck dried under vacuum and unloaded. The wet product was stirred with toluene (100 ml) at 25-30°C and filtered. The product was washed with toluene (50 ml) and dried under vacuum.

Yield: 31.2 g Purity by HP LC: 99.1% Reference example -1;

To a slurry of (2S,4S)-4-Acetylthio-2-(N-sulfamoyl-tert-butoxycarbonyl aminomethyl)- l-(4-nitrobenzyloxycarbonyl)pyrrolidine (50g) in methanol (150 ml), phosphorous oxychloride (3.8 g) was added at 25-30°C. The resultant mixture was heated to 63- 67 °C and maintained for 4-8 hours and cooled to 25-30°C. To the reaction mixture ethyl acetate (250 ml), purified water and saturated sodium chloride solution were added and the layers were separated. The organic layer was washed with saturated sodium chloride solution and concentrated to get a thick mass which was dissolved in tetrahydrofuran (50 ml). The tetrahydrofuran layer containing the product was charged slowly into purified water containing diisopropyl ether. The resultant mass was stirred and cooled. The solid product formed was filtered and washed with purified water. Drying the product under vacuum afforded the title compound

Yield: 30 g Purity by HPLC: 96.61 % Use of triphenylphosphine reduced the unwanted impurities. The level of impurities which is formed during the deacetylation process is reduced considerably. The said fact can be evidenced by the comparative table presented below:

Table-1 :

Comparative Data:

Example-2:

To a slurry of (2S,4S)-4-Acetylthio-2-(N-sulfamoyl-tert- butoxycarbonylaminomethyl)-l -(4-nitrobenzyloxycarbonyl)pyrrolidine (5 g) and triphenylphosphine in methanol (30 mL), phosphorous oxychloride (2 g) was added. The resultant mixture was heated to reflux till completion of the reaction. To the cooled reaction a mixture of ethyl acetate (25 mL), purified water (10 mL) and saturated sodium chloride solution (15 mL) were added and separated the organic layer. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed successively with purified water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate was concentrated to get a thick mass and toluene (20 mL) was added. The solid formed was filtered and washed with diisopropyl ether. Drying the product afforded pure crystalline title compound.

Example-3:

To a slurry of (2S,4S)-4-Acetylthio-2-(N-sulfamoyl-tert- butoxycarbonylaminomethyl)-l -(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) in methanol (20 mL) and triphenylphosphine, Diaion UBK-530 resin (10 g) was added and heated to 50-55 °C and maintained till completion of the reaction. The resin was removed by filtration and the filtrate was concentrated to thick mass. To the residue was added diisopropyl ether. The solid obtained was filtered and washed with diisopropyl ether. Drying the product under vacuum afforded pure title compound.

Preparation of (2S,4S)-l-p-nitrobenzyloxycarbonyl-2-dimethylamino carbonyl -4- mercaptopyrrolidine:

Example- (a):

To a slurry of (2S,4S)-4-Acetylthio-2-(dimethylaminocarbonyl)- l -(4- nitrobenzyloxycarbonyl)pyrrolidine and triphenylphosphine (lOg) in methanol (100 ml), Lewatit® K 2649 - ion exchange resin was added at 25-30°C. The resultant mixture was heated to 60-67°C then cooled to 25-30°C. The reaction mixture was filtered and washed with methanol. To the reaction mixture ethyl acetate, purified water and saturated sodium chloride solution were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. Organic layer was concentrated to thick mass and the product was crystallized using toluene. Example- (b):

To a slurry of (2S,4S)-4-Acetylthio-2-(dimethylaminocarbonyl)- l -(4- nitrobenzyloxycarbonyl)pyrrolidine (l Og) and triphenylphosphine in methanol , phosphorous oxychloride (0.96 g) was added at 25-30°C. The resultant mixture was heated to 60-67°C and then cooled to 25-30°C. To the reaction mixture ethyl acetate, purified water and saturated sodium chloride solution were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the organic layers were combined. Organic layer was concentrated to thick mass and the product was crystallized using n-hexane.

Claims

We Claim:

1. An improved process for the preparation of compound of formula (III) having purity greater than 99.00% by HPLC

which comprises deace (V)

(V)

wherein R³ and R⁴ is same or different and are independently selected from hydrogen or an amine protecting group, using deacetylating reagent in a solvent in the presence of triphenylphosphine; wherein the improvement consists in the use of triphenylphosphine.

2. A process as claimed in claim 1, wherein the deacetylating reagent employed is selected from group comprising phosphorous oxychloride, acetyl chloride, silica chloride, thionyl chloride, oxalyl chloride sulphuric acid, sodium methoxide, sodium hydroxide, Lewatit® K 2649, Diaion UBK 530, Diaion UBK 535, Diaion UBK 550, Diaion UBK 555, Diaion SK 104, Diaion SK IB, Diaion SKL 10, Diaion PK 208, Diaion PK 220, Relite RPS, Relite CFZ, Relite CND or mixtures thereof, preferably phosphorous oxychloride and Lewatit® K 2649.

3. A process as claimed in claim 1, wherein the solvent employed is selected from a group comprising methanol, ethanol, isopropanol, tetrahydrofuran or mixtures thereof.

4. A process as claimed in claim 1 , wherein amine protecting group represented by R³ and R⁴ is same or different and are independently selected from a group consisting of p-nitrobenzyloxy carbonyl, tert-butyloxy carbonyl (BOC), allyoxy carbonyl and p-methoxybenzyloxy carbonyl.

5. An improved process for the preparation of compound of formula (III) as a crystalline form, which comprises the steps of

a. deacetylation

(V)

wherein R³ and R⁴ is same or different and are independently selected from hydrogen or an amine protecting group; using deacetylating reagent in a solvent in the presence or absence of triphenylphosphine;

b. extracting the compound of formula (III) in a water immiscible solvent; c. optionally concentrating the step (b) solution;

d. adding anti-solvent; and

e. isolating the compound of formula (III) by filtration.

6. A process as claimed in claim 5, wherein the water immiscible solvent is selected from ethyl acetate, dichloromethane and chloroform or the mixtures thereof.

7. A process as claimed in claim 5, wherein the anti-solvent is selected from toluene, diisopropyl ether, cyclohexane, heptane, hexane, pentane or the mixtures thereof. i. A process for the preparation of compound of general formula (Y),

(Y)

wherein G represents hydrogen or a group of formula,

-CONMe₂, ^R4

wherein R⁴ is Hydrogen or tert-butoxycarbonyl,

and R³ represents p-nitrobenzyloxycarbonyl OR a chemical formula

which comprising the steps of:

(i) deacetylating the compound of general formula (X) using phosphorus oxychloride or a resin selected from Lewatit® K 2649 , Diaion UBK 530, Diaion UBK 535 preferably Lewatit® K 2649 in the presence of triphenylphosphine

(ii) isolating compound of general formula (Y).