KR20120007331A - An improved process for the preparation of carbapenem compounds - Google Patents

Abstract

PURPOSE: An improved method for preparing 2-(substituted mercapto)-1beta-methyl-carbapenem-based antibiotics is provided to crystallize derivatives in the water and to prevent yield loss. CONSTITUTION: A method for preparing carbapenem compounds comprises: a step of condensing protected mercapto compound HR_2 with a compound of chemical formula III to isolate a compound of chemical formula II in the water in an amorphous form; and a step of deprotecting the compound of chemical formula II. The reaction solvent is dimethyl formamide, dimethyl aceteamide, or acetonitrile.

Description

Improved manufacturing method of carbapenem compounds {AN IMPROVED PROCESS FOR THE PREPARATION OF CARBAPENEM COMPOUNDS}

The present invention provides an amorphous protected carbapenem-based compound in water after condensation of a protected mercapto compound at the C-2 position of the general formula (III), which is an enol phosphate compound, without drying it and without purification. The present invention relates to a novel process for preparing 2- (substituted mercapto) -1β-methyl-carbapenem-based compounds in high yield and high purity by performing dehydrogenation under a palladium hydroxide-carbon metal catalyst.

Since the discovery of thienamycin in 1976, carbapenem-based antibiotics have been actively researched, and carbapenem-based compounds having many excellent antimicrobial activities, including imipenem, have been developed. However, many of these carbapenem compounds have the disadvantage of being easily metabolized by dehydropeptase-1 (DHP-1).

As a result, research aimed at improving the stability of DHP-1 has been actively conducted, and in 11984, 1β-methyl- having chemical and physical stability and excellent resistance to DHP-1 while maintaining excellent antimicrobial activity by Merck. Carbapenem compounds (imipenem) have been developed.

Since then, several companies have condensed the protected mercapto compound HR2 with the enolphosphate compound of formula III to prepare a substituted mercapto compound of formula II, followed by deprotection to produce 2- (substituted mercapto) -1β-. Compounds of formula (I), a methyl-carbapenem antibiotic, have been developed and commercialized.

[Formula III]

[Formula II]

Formula I

PNB is a paranitrobenzyl group.

R ₂ is

(2S, 4S) -4-mercapto-2-[[[3- (2-propenyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid 2-propenyl ester, ( 2S, 4S) -4-mercapto-2-[[[3- (p-nitrobenzyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid p-nitrobenzyl ester, 6- Thio-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazoletrifluoroacetic acid salt, 2-sulfamoylaminomethyl-1-p-nitrobenzyloxycarbo Nyl-4-mercaptopyrrolidin, or 4-nitrobenzyl (2S, 4S) -2-[(dimethylamino) carbonyl] -4-mercaptopyrrolidine-1-carboxylate.

R ₃ is

(2S, 4S) -4-mercapto-2-[[(3-carboxyphenyl) amino] carbonyl] -3-pyrrolidine, 6-thio-6,7-dihydro-5H-pyrazolo [1 , 2-a] [1,2,4] triazole, 4-thio-2-sulfamoylaminomethylpyrrolidine, or 4-thio- (2S), (4S) -2-[(dimethylamino) carbo Nil] pyrrolidine.

As the compound of formula (I), ertafenem represented by formula (Ia)

Viapenem represented by the following formula (Ib),

Doripenem, represented by Formula Ic,

Meropenem and the like represented by the following formula Id have been developed.

Looking at the preparation method of these 2- (substituted mercapto) -1β-methyl-carbapenem compounds, Formula III, which is an enol phosphate compound used as a starting material, is described in Tetrahedron Letter 2293 (1982); It was prepared and used in the same manner as in Scheme 1 in Tetrahedron 48, 55 (1992); US 4,888,344 (1987).

Scheme 1

In Scheme 1, TBS represents a t-butyldimethylsilyl group, and PNB represents a p-nitrobenzyl group.

R ₂ is

(2S, 4S) -4-mercapto-2-[[[3- (2-propenyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid 2-propenyl ester, ( 2S, 4S) -4-mercapto-2-[[[3- (p-nitrobenzyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid p-nitrobenzyl ester, 6- Thio-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazoletrifluoroacetic acid salt, 2-sulfamoylaminomethyl-1-p-nitrobenzyloxycarbo Nyl-4-mercaptopyrrolidin, or 4-nitrobenzyl (2S, 4S) -2-[(dimethylamino) carbonyl] -4-mercaptopyrrolidine-1-carboxylate.

R ₃ is

(2S, 4S) -4-mercapto-2-[[(3-carboxyphenyl) amino] carbonyl] -3-pyrrolidine, 6-thio-6,7-dihydro-5H-pyrazolo [1 , 2-a] [1,2,4] triazole, 4-thio-2-sulfamoylaminomethylpyrrolidine, or 4-thio- (2S), (4S) -2-[(dimethylamino) carbo Nil] pyrrolidine.

In Scheme 1, a condensation reaction of a compound of formula III, which is a conventional enol phosphate compound, and HR ₂ , which is a protected mercapto compound, is used to prepare a protected 2- (substituted mercapto) -1β-methyl-carbapenem antibiotic. In the manufacturing method, US 5,478,820 (1995), US 4,888344 (1987), JP 35366 (1992), EP480100 (1992), JP35366 (1992), and JP272426 (1996) were extracted with an organic solvent and then column By chromatographic method, protected 2- (substituted mercapto) -1β-methyl-carbapenem (formulas IIa, IIb, IIc, and IId) were isolated in low yields of 60% to 80%.

Also in US2007 / 0249827A1, the compound of formula IId, which is protected 2- (substituted mercapto) -1β-methyl-carbapenem, was crystallized in an organic solvent, obtained in a yield of 87%, and registered as crystalline form.

Deprotection of the second reaction, protected 2- (substituted mercapto) -1β-methyl-carbapenem, is described in WO2006 / 035300 (2005), EP0528678 (2001), US 4,888344 (1987), EP289801 ( In 1990, an expensive 5-10% palladium-carbon was used as the metal catalyst, but the yield was only 40-75%.

The reason for this is that when deprotection is carried out using palladium-carbon, a large amount of impurities are generated, which causes a decrease in yield.

In order to solve this problem, the researchers have developed a breakthrough method that can be widely applied to the production of carbapenem antibiotics, is economical by minimizing yield loss, and minimizes impurities.

US 5,478,820 (1995) US 4,888344 (1987) JP 35366 (1992) EP480100 (1992) JP35366 (1992) JP272426 (1996) US2007 / 0249827A1 WO2006 / 035300 (2005) EP0528678 (2001) US 4,888344 (1987) EP289801 (1990)

Tetrahedron Letter 2293 (1982); Tetrahedron 48, 55 (1992); US 4,888,344 (1987)

Problems of the conventional carbapenem antibiotic manufacturing process,

First, the cost of separating the protected 2- (substituted mercapto) -1β-methyl-carbapenem compounds such as formula (II) after reacting the enol phosphate compound (III) with the protected mercapto compound (HR ₂ ) There is a problem in that the column chromatography method which is expensive and difficult to use at the production site should be used.

In another method, crystallization and separation in an organic solvent, the IId compound, which is a precursor of meropenem, cannot be avoided due to crystallization in an organic solvent. Therefore, there is an urgent need for an economic method to maximize yield.

Second, the use of an expensive metal catalyst, palladium-carbon, for deprotection from protected 2- (substituted mercapto) -1β-methyl-carbapenem can minimize the formation of impurities, which can be minimized. The purpose is to develop a method for preparing 2- (substituted mercapto) -1β-methyl-carbapenem suitable for industrial application by increasing yield using other metal catalysts and simplifying the manufacturing process.

In order to achieve the above object, an improved preparation method of formula (I), which is a 2- (substituted mercapto) -1β-methyl-carbapenem-based compound,

i) Condensation reaction of an enol phosphate compound represented by the following general formula (III) with HR ₂ , a protected mercapto compound, in the presence of a base to give a protected 2- (substituted mercapto) -1β-methyl-carbapenem compound of Separating the compound by solidifying it amorphously in water;

ii) preparing a compound of formula (I) by deprotecting a compound of formula (II) which is a protected 2- (substituted mercapto) -1β-methyl-carbapenem compound in the presence of palladium hydroxide-carbon as a catalyst; Characterized in that it comprises a step.

[Scheme 2]

In Scheme 2, PNB represents a p-nitrobenzyl group

R ₂ is

(2S, 4S) -4-mercapto-2-[[[3- (2-propenyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid 2-propenyl ester, ( 2S, 4S) -4-mercapto-2-[[[3- (p-nitrobenzyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid p-nitrobenzyl ester, 6- Thio-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazoletrifluoroacetic acid salt, 2-sulfamoylaminomethyl-1-p-nitrobenzyloxycarbo Nyl-4-mercaptopyrrolidine, or 4-nitorobenzyl (2S, 4S) -2-[(dimethylamino) carbonyl] -4-mercaptopyrrolidine-1-carboxylate.

R ₃ is

(2S, 4S) -4-mercapto-2-[[(3-carboxyphenyl) amino] carbonyl] -3-pyrrolidine, 6-thio-6,7-dihydro-5H-pyrazolo [1 , 2-a] [1,2,4] triazole, 4-thio-2-sulfamoylaminomethylpyrrolidine, or 4-thio- (2S), (4S) -2-[(dimethylamino) car Carbonyl] pyrrolidine.

According to one aspect of the invention, the amorphous compounds of formula II prepared in step i) can be deprotected without further purification and drying.

Compounds of formula II are protected 2- (substituted mercapto) -1β-methyl-carbapenem derivatives represented by the formulas IIa, IIa-1, IIb, IIc, and / or IId.

[Formula IIa]

[Formula IIa-1]

[Formula IIb]

Formula IIc]

[Formula IId]

Looking at the process of Scheme 2,

Condensation reaction of the enol phosphate compound represented by Chemical Formula III in step i) with HR ₂ , which is a protected mercapto compound, and the reaction solution is added to cooling water to separate an amorphous solid, followed by step ii). In addition, the separated amorphous solid may no longer be subjected to purification and drying.

Therefore, step i) yield is more than 98%, almost no loss, and it is an economical method that can be manufactured with high purity of 99% with efficiency.

On the other hand, step ii) of Scheme 2 is a method of deprotecting the general formula (II), which is a protected 2- (substituted mercapto) -1β-methyl-carbapenem compound, and palladium hydride instead of palladium-carbon. Efficient preparation for economical and mass production to produce formula (I), 2- (substituted mercapto) -1β-methyl-carbapenem derivative, in high purity and high yield by minimizing impurities by using roxide-carbon It is a way.

According to the present invention, since the protected 2- (substituted mercapto) -1β-methyl-carbapenem derivatives are crystallized in water, the yield is more than 98%, and there is almost no loss of yield, and without drying the obtained product of the wet body. The next step, deprotection, can be carried out, making it an industrially very efficient method.

In addition, by using palladium hydroxide-carbon instead of palladium-carbon in the deprotection reaction, a very economical method for producing impurities with high purity and high yield was minimized.

1 is an XRD graph of a compound of formula IIc prepared according to an embodiment of the present invention, which shows that it is amorphous.

A method for preparing 2- (substituted mercapto) -1β-methyl-carbapenem according to the present invention will be described in more detail based on Scheme 2 as follows.

The reaction process of step i), the first reaction, is carried out by condensation reaction of the enol phosphate compound of formula III with HR ₂ , a mercapto compound protected in the presence of a base, and then added to cooling water And / or amorphous separation of the IId compounds.

The reactant HR ₂ is used in an amount of 1 to 1.2 equivalents based on the chemical formula III of the enol phosphate compound, and a reaction solvent selected from acetonitrile, dimethylformamide, and dimethylacetamide, which are polar solvents, or a mixed solvent thereof may be used. .

As the base, a tertiary amine compound, for example, an aromatic amine of N, N-dimethylaminopyridine, diisopropylethylamine, triethylamine, or trimethylamine can be used, and preferably diisopropylethylamine is used. use. The use amount of base is 1-10 equivalents, preferably 1-3 equivalents to the general formula (III) which is an enol phosphate compound. The reaction is carried out at 25 to 50 ° C, preferably at -15 to 20 ° C for 1 to 3 hours. In the case of crystallization after completion of the reaction, the reaction solution is slowly added dropwise to the cooled water of 4 to 10 times the volume of the solvent used to separate it into an amorphous solid. At this time, the reaction solution was added dropwise to the cooling water while adjusting with 1N HCl so that the pH does not exceed 7. Preferably it is adjusted between pH 4-7.

The compounds of formulas IIa, IIa-1, IIb, IIc, and / or IId, which are amorphous crude products obtained in step i), can be used in the second reaction deprotection reaction without drying and further purification.

The reaction process of the second reaction step ii) is a deprotected by hydrogenation of the compounds of the amorphous crude product (IIa, IIa-1, IIb, IIc, and / or IId) of the general formula Ia, Preparing compounds of Ib, Ic, and / or Id.

The above deprotection reaction can be carried out under 0.2 to 20 mole% palladium hydroxide-carbon metal catalyst for the crude product of formulas IIa, IIa-1, IIb, IIc, and / or IId.

As the reaction solvent, a single solvent selected from the group consisting of purified water, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, and ethyl acetate or a mixed solvent thereof may be used.

Reaction temperature is 0-25 degreeC, Preferably it is 15 degreeC. After reacting for 2 to 8 hours at a pressure of 2 ~ 10kg / m ² and then extracted with ethyl acetate to remove impurities, the pH of the aqueous layer is adjusted to 3-6. Acetone, tetrahydrofuran, methanol, propanol, or isopropanol was added to the aqueous layer and crystallized at 0-5 ° C. for 3 to 24 hours, followed by filtration and drying, yielding a high yield of 76-80% and a yield of at least 98%. Made to high purity.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of the claims by the appended claims.

EXAMPLE

A. Preparation of crude product of compound of formula II from compound of formula III

Example 1

(4R, 5S, 6S) -p-nitrobenzyl-3-[[(3S, 5S) -5-[(dimethylamino) carbonyl] -1-[[4-nitrobenzyl) oxy] carbonyl] -3 -Pyrrolidinyl] thio-6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-carboxylate Preparation of (Compound of Formula IId)

120 g (201.9 mmol) of the compound of formula III and 4-nitrobenzyl- (2S, 4S) -2-[(dimethylamino) carbonyl] -4-mercaptopyrrolidine-1 in 500 ml of dimethylformamide 74 g (209.4 mmol) of carboxylate was added to dissolve and cooled to -20 ° C. 40 ml of diisopropylethylamine was slowly added dropwise thereto, and then stirred at the same temperature for 1 hour. The reaction solution was slowly added dropwise to 2 L of cooling water to crystallize. At this time, the pH was adjusted to 1 N hydrochloric acid so as not to exceed 7 and the final pH was adjusted to 6.5.

After stirring for 1 hour at 0-5 [deg.] C., filtration gave 450 g (wet product) of the crude product of the compound of formula IId.

Drying yield: 138g (98%)

Purity (HPLC): 99.4%

Example 2

(1R, 5S, 6S) -2-[(3S, 5S) -1-p-nitrobenzyl-5- (N-sulfamoylamino) methylpyrrolidin-3-yl] thio-6 [(1R)- Preparation of 1-hydroxyethyl-1-methyl-1-carba-2-phenem-3-carboxylic acid p-nitrobenzyl ester (compound of formula IIc)

12 g (20.2 mmol) of the compound of formula III and (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercap in 50 ml of dimethylacetamide 8.16 g (20.9. Mmol) of torrolidine was added and dissolved, followed by cooling to -20 ° C. 4 ml (23 mmol) of diisopropylethylamines were slowly added dropwise thereto, followed by stirring at the same temperature for 1 hour.

The reaction solution was slowly added dropwise to 300 ml of cooling water to crystallize. At this time, the pH was adjusted to 6.0 by adding dropwise with 1N HCl so as not to exceed pH 7.

After stirring for 1 hour at 0-5 ° C., filtration gave 55 g (wet product) of the crude product of the compound of formula IIc.

Drying yield: 14.57 g (98.2%)

Purity: 99.2%

Example 3

6-[[2 (4R, 5S, 6S) -carboxy-6-[(1R) -hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2- Preparation of En-3-yl] thio] -6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazole p-nitrobenzylester (compound of Formula IIb)

12 g (20.2 mmol) of the compound of formula III and 6-thio-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazoletri in 50 ml of acetonitrile 5.37 g (20.9. Mmol) of fluoroacetic acid was added to dissolve and cooled to -20 ° C. 5 ml of diisopropylethylamine was slowly added dropwise thereto, followed by stirring at the same temperature for 1 hour.

The reaction solution was slowly added dropwise to 400 ml of cooling water to crystallize. At this time, the pH was adjusted to 6.8 by dropwise addition with 1N HCl so as not to exceed pH 7.

After stirring for 1 hour at 0-5 ° C., filtration gave 30 g (wet product) of the crude product of the compound of formula IIb.

Drying yield: 9.73 g (99%)

Purity: 99.1%

Example 4

[4R- [3 (3S *, 5S *), 4α, 5β, 6β (R *)]]-6- (1-hydroxyethyl) -4-methyl-3-[[[1-[(2- Propenyloxy) carbonyl] -5-[[3-[(2-propenyloxy) carbonyl] phenyl] amino] carbonyl-3-pyrrolidinyl] thio] -7-oxo-1-azabicyclo Preparation of [3,2,0] hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (compound of formula IIa)

12 g (20.2 mmol) of the compound of formula III and (2S, cis) -4-mercapto-2-[[[3- (2-propenyloxy) carbonyl in 40 ml of acetonitrile and 10 ml of dimethylformamide ] Phenyl] amino] carbonyl] -1-pyrrolidinecarboxylic acid 2-propenyl ester 7.57 g (20.9. Mmol) was added and dissolved, and it cooled to -20 degreeC. 10 ml of diisopropylethylamine was slowly added dropwise thereto, followed by stirring at the same temperature for 1 hour.

The reaction solution was slowly added dropwise to 400 ml of cooling water to crystallize. At this time, the pH was adjusted to 6.8 by dropwise addition with 1N HCl so as not to exceed pH 7.

After stirring for 1 hour at 0-5 ° C., filtration gave 35 g (wet product) of the crude product of the compound of formula IIa.

Drying yield: 14.34 g (98.5%)

Purity: 99.3%

Example 5

[4R- [3 (3S *, 5S *), 4α, 5β, 6β (R *)]]-6- (1-hydroxyethyl) -4-methyll-3-[[[1-[(2 -p-nitrobenzyloxy) carbonyl] phenyl] amino] carbonyl-3-pyrrolidinyl] thio-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-car Preparation of the acid p-nitrobenzyl ester (compound of formula IIa-1)

12 g (20.2 mmol) of the compound of formula III and (2S, cis) -4-mercapto-2-[[[3- (2-p-nitrobenzyloxy) in 40 ml of acetonitrile and 10 ml of dimethylacetamide Carbonyl] phenyl] amino] carbonyl] -1-pyrrolidinecarboxylic acid p-nitrobenzyl ester 12.13g (20.9.mmol) was added, melt | dissolved, and it cooled to -20 degreeC. 8 ml of diisopropylethylamine was slowly added dropwise thereto, followed by stirring at the same temperature for 1 hour.

The reaction solution was slowly added dropwise to 400 ml of cooling water to crystallize. At this time, the pH was adjusted to 6.8 by dropwise addition with 1N HCl so as not to exceed pH 7.

After stirring for 1 hour at 0-5 ° C., filtration was performed to obtain 40 g (wet product) of the crude product of the compound of formula IIa-1.

Drying yield: 18.31 g (98%)

Purity: 99.3%

B. Preparation of Compounds of Formula (I) from Compounds of Formula (II)

Example 6

(4R, 5S, 6S) -3-[[(3S, 5S) -5-[(dimethylamino) carbonyl] -3-pyrrolidinyl] thio] -6-[(1R) -1-hydroxyethyl ] -4-Methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-carboxylic acid (compound of Formula Id)

After dissolving 450 g (wet product) of the compound of formula IId obtained in Example 1 in 1.4 L of THF, 1.1 L of buffered solution (20 ml of N-morpholine was added to 1.08 L of purified water and adjusted to pH 7 with acetic acid) 28 g of 5% palladium hydroxide-carbon was added thereto, followed by dehydrogenation at a pressure of 5 kg / m ² by adding hydrogen at room temperature for 6 hours.

The reaction solution was filtered, washed with 50 ml of water, and then separated into layers by adding 1 L of ethyl acetate. The aqueous layer was cooled to 0-5 [deg.] C., and 6L of acetone was added thereto, followed by overnight stirring and filtering. The solid was washed with cold acetone and dried to give 58.8 g of compound of formula Id.

Two-step total yield: 76%

Purity: 99.3% (HPLC)

¹ H-NMR (D ₂ O) δ 1.24 (3H, d), 1.32 (3H, d), 1.92 (1H, m), 3.02 (3H, s), 3.08 (3H, s), 3.31 ~ 3.50 (3H , m), 3.68 (1H, m), 4.07 (1H, m), 4.22-4.30 (2H, m)

Example 7

(1R, 5S, 6S) -6 [(1R) -1-hydroxyethyl] -2- [5-sulamidomethylpyrrolidin-3-yl] thio-1-methyl-1-carba-2 Preparation of Penem-3-carboxylic Acid (Compound of Compound Ic)

After dissolving 55 g (wet) of the crude product of formula IIc obtained in Example 2 in 140 ml of THF, 110 ml of buffer solution (2 ml of N-morpholine was added to 108 ml of purified water and adjusted to pH 7 with acetic acid) and 5% palladium 5.6 g of hydroxide-carbon was added and hydrogen was added at room temperature for 6 hours to effect deprotection under a pressure of 5 kg / m ² .

The reaction solution was filtered, washed with 10 ml of water, 100 ml of ethyl acetate was added, the mixture was stirred for 30 minutes, and the layers were separated. The aqueous layer was cooled to 0-5 [deg.] C., the pH was adjusted to 5.5, and 600 ml of acetone was added, followed by overnight stirring and filtering. The solid was washed with cold acetone and dried to give 6.8 g of compound Ic.

Two stage total yield: 80.3%

Purity: 99.1% (HPLC)

¹ H-NMR (D ₂ O) δ1.23 (3H, d), 1.28 (3H, d), 1.65 ~ 1.84 (1H, m), 2.63 ~ 2.82 (1H, m), 3.26 ~ 3.60 (5H, m ), 3.64-3.77 (1H, m), 3.85-4.22 (2H, m), 4.16-4.30 (2H, m)

Example 8

(1R, 5S, 6S) -2- [6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl ) ] thio-6-[( R) -1-hydroxyethyl-1-methyl-carbapenem-3-carboxylate (compound of Formula Ib)

30 g (wet) of the crude product, a compound of Formula IIb obtained in Example 3, was added with 140 ml of THF and 110 ml of aqueous acetate buffer solution (2 ml of N-morpholine was added to 108 ml of purified water and adjusted to pH 7 with acetic acid), followed by 5% palladium hydroxide. 2.8 g of loxide-carbon was added and hydrogen was added at room temperature for 2 hours to effect deprotection under a pressure of 5 kg / m ² .

The reaction solution was filtered, washed with 10 ml of water, 100 ml of ethyl acetate was added, the mixture was stirred for 30 minutes, and the layers were separated. The aqueous layer was cooled to 0˜5 ° C., the pH was adjusted to 5.5, and 600 ml of isopropyl alcohol was added, stirred overnight, and filtered. The solid was washed with cold isopropyl alcohol and dried to give 5.44 g of compound of formula Ib.

Two stage total yield: 77%

Purity: 99.03% (HPLC)

¹ H-NMR (D ₂ O) δ: 1.28 (3H, d), 1.32 (3H, d), 3.45 (1H, dd), 3.57 (1H, dd), 4.32 (1H, q), 4.36 (1H, dd), 4.74 to 4.85 (2H, m), 4.97 to 5.06 (1H, m), 5.07 to 5.18 (2H, m), 9.07 (1H, s), 9.08 (1H, s)

Example 9

(4R, 5S, 6S) -3-[[(3S, 5S) -5-[[(3-carboxyphenyl) amino] carbonyl-3-pyrrolidinyl] thio-6-[(1R) -1- Preparation of Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3,2,0] hept-2-ene-2-carboxylic acid (compound of Formula Ia)

40 g (wet) of the crude product of Formula IIa-1 obtained in Example 5 was added to 140 ml of THF and 110 ml of an aqueous buffer buffer solution (2 ml of N-morpholine was added to 108 ml of purified water and adjusted to pH 7 with acetic acid), and 5% 5.6 g of palladium hydroxide-carbon was added and deprotected by hydrogenation under a pressure of 5 kg / m ² for 6 hours at room temperature.

The reaction solution was filtered, washed with 10 ml of water, 100 ml of ethyl acetate was added, the mixture was stirred for 30 minutes, and the layers were separated. The aqueous layer was cooled to 0-5 ° C., the pH was adjusted to 4.5, and 600 ml of isopropyl alcohol was added, stirred overnight, and filtered. The solid was washed with cold isopropyl alcohol to give 7.5 g of compound of formula Ia.

Two stage total yield: 78%

Purity: 98.5% (HPLC)

¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (6H, d), 1.95 (1H, m), 2.84 (1H, m), 3.11 (1H, dd), 3.23 (1H, dd), 3.41 (1H , q), 3.67 (1H, dd), 3.90 (1H, q), 3.40 (1H, t), 4.22 (1H, dd), 4.27 (1H, t), 7.48 (1H, t), 7.71 (1H, d), 7.87 (1 H, d), 8.26 (1 H, s)

As in the above examples, the two-step overall yield for preparing 2- (substituted mercapto) -1β-methyl-carbapenem derivatives, i.e., Formulas Ia, Ib, Ic, and / or Id, respectively, was 78, 77. The yield is high as 80, and 76%, the purity can be prepared to 98% or more, and the next deprotection reaction can be carried out without purifying IIa, IIa-1, IIb, IIc, and / or IId without drying. It was able and was efficient.

Claims (7)

i) condensation of the compound represented by the following formula (III) with the protected mercapto compound HR ₂ to form an amorphous separation of the compound represented by the following formula (II) in water; And
ii) a method for preparing a carbapenem-based compound, comprising the step of deprotecting the compound represented by the following formula (II) to produce a compound represented by the following formula (I):

[Formula III]

[Formula II]

Formula I

Wherein PNB is a paranitrobenzyl group,
R ₂ is
(2S, 4S) -4-mercapto-2-[[[3- (2-propenyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid 2-propenyl ester, ( 2S, 4S) -4-mercapto-2-[[[3- (p-nitrobenzyloxy) carbonyl] phenyl] amino] carbonyl-1-pyrrolidinecarboxylic acid p-nitrobenzyl ester, 6- Thio-6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazoletrifluoroacetic acid salt, 2-sulfamoylaminomethyl-1-p-nitrobenzyloxycarbo Nyl-4-mercaptopyrrolidine, or 4-nitrobenzyl (2S, 4S) -2-[(dimethylamino) carbonyl] -4-mercaptopyrrolidine-1-carboxylate,
R ₃ is
(2S, 4S) -4-mercapto-2-[[(3-carboxyphenyl) amino] carbonyl] -3-pyrrolidine, 6-thio-6,7-dihydro-5H-pyrazolo [1 , 2-a] [1,2,4] triazole, 4-thio-2-sulfamoylaminomethylpyrrolidine, or 4-thio- (2S), (4S) -2-[(dimethylamino) carbo Nil] pyrrolidine.
The method of claim 1,
The compound represented by Formula II is a compound of Formula IIa, IIa-1, IIb, IIc, or IId,
Wherein the compound represented by Formula I is a compound of Formula Ia, Ib, Ic, or Id:

[Formula IIa]

[Formula IIa-1]

[Formula IIb]

Formula IIc]

IIc

[Formula IId]

Formula Ia

Formula Ib

Formula Ic

[Formula Id]

. The method according to claim 1 or 2,
Method of using a solvent selected from the group consisting of dimethylformamide, dimethylacetamide and acetonitrile or a mixed solvent thereof as the reaction solvent of step i). The method according to claim 1 or 2,
The separation step of step i) is characterized in that the reaction solution is added to cooling water to separate the amorphous compound of formula II between pH 4-7. The method of claim 4, wherein
A process for carrying out the deprotection reaction without further purification and drying of the isolated amorphous compound of formula II. The method according to claim 1 or 2,
The deprotection reaction of step ii) is carried out in the presence of palladium hydroxide-carbon as a metal catalyst. The method according to claim 1 or 2,
Method of using a single solvent or a mixed solvent thereof selected from the group consisting of purified water, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol and ethyl acetate as the reaction solvent of step ii).

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