| 17% |
With N-ethyl-N,N-diisopropylamine; In ethyl acetate; acetonitrile; at -10℃; for 5.16667h;Product distribution / selectivity; |
(Example 7); Production of p-nitrobenzyl (4R,5S,6S)-3-[[(3S,5S)-1-(p-nitrobenzyloxycarbonyl)-5-(dime thylaminocarbonyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyet hyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxy late (3); [Show Image] To a mixed solvent containing 20 ml of acetonitrile and 10 ml of ethyl acetate were added 10.0 g of p-nitrobenzyl (4R,5R,6S)-3-diphenyloxyphosphoryloxy-6-[(1R)-1-hydroxyethy 1]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxyla te and 6.2 g of (2S,4S)-2-dimethylaminocarbonyl-4-mercapto-1-(p-nitrobenzyl oxycarbonyl)-pyrrolidine, and the mixture was cooled to -10C with stirring. N,N-Diisopropylethylamine (2.6 g) was added thereto over 10 minutes, and the resulting mixture was stirred at the same temperature for 5 hours. To the reaction mixture were added, at 0 to 7C, 50 ml of ethyl acetate and 50 ml of water, and the mixture was stirred for 10 minutes. The aqueous layer was removed, and the organic layer obtained was washed, at 0 to 10C, with two 50-ml portions of a 5% aqueous solution of sodium chloride and one 50-ml portion of water, whereby a water-saturated ethyl acetate solution containing the compound (3) was obtained. The concentration of the compound (3) was 17% by weight. |
| 12% |
With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at -10℃; for 1.25h;Product distribution / selectivity; |
(Example 5); Production of p-nitrobenzyl (4R,5S,6S)-3-[[(3S,5S)-1-(p-nitrobenzyloxycarbonyl)-5-(dime thylaminocarbonyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyet hyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxy late (3) ; [Show Image] [Show Image] To 40 ml of dimethylacetamide were added 10.0 g of p-nitrobenzyl (4R,5R,6S)-3-diphenyloxyphosphoryloxy-6-[(1R)-1-hydroxyethy 1]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxyla te and 6.2 g of (2S,4S)-2-dimethylaminocarbonyl-4-mercapto-1-(p-nitrobenzyl oxycarbonyl)pyrrolidine, and the mixture was cooled to -10C with stirring. N,N-Diisopropylethylamine (6.9 g) was added thereto over 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added, at -10 to -5C, 120 ml of ethyl acetate and 85 ml of water, and the mixture was stirred for 10 minutes. The aqueous layer was removed, and the organic layer obtained was washed, at 0 to 10C, twice with a mixture of 36 ml of a 5% aqueous solution of sodium chloride and 9 ml of 2 N hydrochloric acid and once with 45 ml of water, whereby a water-saturated ethyl acetate solution containing the compound (3) was obtained. The concentration of the compound (3) was 12% by weight. |
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With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at -10 - -7℃; for 1.2h; |
Example 1: Crystalline (4R,5S,6S)-(p-nitrobenzyl) 3-ff(3S,5S)-1(-p-nitrobenzyloxycarbonyl)- 5-( dimethvlaminocarbonvl)-3-pvrrolidinvllthiol-6-r( 1 R)-1-hvdroxvethvll-4-methvl-7 -oxo-1- azabicyclof3.2.Olhept-2-ene-2-carboxylate; p-nitrobenzyl-( 1 R, 5R, 6S)-6-[( 1R)-1-hydroxyethyl]-2-[(diphenylphosphono)oxy]-1- methylcarbapen-2-em-3-carboxylic acid ester (23.5g, 39.5mmols) and (2S,4S)-2- dimethylaminocarbonyl-4-mercapto-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (14.8g, 41.9mmols) are dissolved in 100 ml of dimethylacetamide and cooled to -10C. Over the course of 15 mins, 22 ml of diisopropylethyl amine are added dropwise in such a way that the temperature does not exceed-7C. The mixture is stirred for 1 hour at -10C. Then, 300 ml of cold ethyl acetate are added over 30 mins at a temperature of < -7C and finally 200 ml of ice water are added at <-5C over 30 mins. The aqueous phase is separated and extracted with 150 ml of ethyl acetate. The combined organic phases are extracted twice, each time with a cold mixture of 80 ml of 6% aqueous NaCl solution and 20 ml of 2N hydrochloric acid, and once with 100 ml of phosphate buffer solution pH 7.0. The organic phase is separated, filtered and the filter washed with 10 ml of ethyl acetate. The filtrate is concentrated to 90 g at 40C and made up to 110 g with ethyl acetate and stirred for 72 h at 20C. The product crystallises. In order to complete crystallisation, 35 ml of heptane are added dropwise and the crystal suspension is stirred for 30 mins. The crystalline product is isolated by filtration, washed twice, each time with 50 ml of heptane, and dried for 16 h at 40C in a vacuum. Weighed product: 25.45g (36.5mmols) purity (HPLC) : 98.6% Melting point: 156-159C IR (Golden gate) cm-1: 1762.6, 1702.6, 1638.4, 1519.3, 1444.0,1402.4, 1341.2, 1317.0, 1273.4, 1205.6, 1179.2, 1138.2, 1111.9, 1045.4, 1017.1, 985.1, 860.0, 841.1, 767.1, 739.4 'H-NMR (d6-DMSO) No. 8.24 (m, 4H), 7.73 (d, J = 9.00 , 2H), 7.66&7.54 (d, J = 9.0,2H), 5.47&5.30(ABq, 2H,J=14.1 Hz), 5.25-5.04 (m,3H), 4.80(m,1 H), 4.26(m,1 H), 4.15(m, 1 H), 3.99(m,1 H), 3.86(m,1 H), 3.61 (m,1 H), 3.29(m,1 H), 3.20(m,1 H), 3.03&2.97(2s,3H), 2.87(m,1 H), 2.83&2.83(2s,3H), 1.63(m,1 H), 1.17 (2t, 6H,J=6.0Hz) |
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Step (ii) To a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester in acetonitrile (1660 mL) were added (2S,4S)-l-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonylamino-4-mercaptopyrrolidine (66 g) and N- ethyldiisopropylamine (36 mL) at -15 0C and stirred under nitrogen atmosphere. After completion of the reaction, the resultant mass was quenched into ethyl acetate containing dipotassium hydrogen orthophosphate and stirred for 15 min. The ethyl acetate layer was distilled out completely under vacuum. The residue was dissolved in ethyl acetate and stirred. To the precipitated mass was added diisopropylether and stirred for an hour. The solid v/as filtered and dried to yield the title compound (110 g, Purity: 98%).Example 4(a). Preparation of Meropenem trihydrate:To a solution of (4R,5R,6S)-3-[(di?henoxyphosphoryloxy]-6-[(R)-l-hydroxyet'hyl]-4- methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 niL) was added (2S,4S)-l-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonylamino-4-mercaptopyrrolidine (33 g) and N- diisopropylethylamine (14 g) at -15 0C and stirred. After the reaction was over, the reaction mixture was quenched in phosphate buffer solution. The product was extracted into ethyl acetate and washed with water. The organic layer was subjected to carbon treatment, filtered off and evaporated under vacuum to get thick paste (foam nature)(b). Preparation of Meropenem trihydrate:To a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 mL) was added (2S,4S)-l-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonylamino-4-mercaptopyrrolidine (33 g) and N- ethyldiisopropylamine (14 g) at -15 0C and stirred. After the reaction was over, the reaction mixture was quenched in phosphate buffer solution. The product was extracted into ethyl acetate and washed with water. The organic layer was subjected to carbon treatment, filtered off and evaporated by vacuum to get the thick paste.c). Preparation of Meropenem Trihydrate:To a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 mL) were added (2S,4S)-l-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonylamino-4-mercaptopyrrolidine (33 g) and N- ethyldiisopropylamine (14 g) at -15 C and stirred. After the reaction was over, the reaction mixture was quenched in phosphate buffer solution. (d). Preparation of Meropenem trihydrate:To a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) in acetonitrile (500 niL) was added (2S,4S)-l-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonylamino-4-mercaptopyrrolidine (32 g) and N- ethyldiisopropylamine (14 g) at -15 0C and stirred. After the reaction was over, the reaction mixture was quenched in phosphate buffer solution. The product was extracted with ethyl acetate and washed with water. The organic layer was subjected to carbon treatment, filtered off and evaporated under vacuum to get thick paste. |
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Example 5 (a). Preparation of Meropenem trihydrateTo a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo- l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) and (2S,4S)-l-p-ni1?obenzyloxycarbonyl-2-dimethylaminocarbonylarnino-4- mercaptopyrrolidine (33 g) in N,N-dimethylformamide (250 mL) was added slowly diisopropylethylamine (14 g) at - 40 to -10 C and stirred for 2-3 h. The reaction mass was then added slowly to the phosphate buffer to isolate the solid product. The pH was then adjusted to 3.8 to 4.0 using sulphuric acid at 5-10 0C then stirred for an hour. The isolated (4R,5S,6S,8R,2lS,4'S)-p-nitrobenzyl-3-[4-(l-p-nitrobenzyloxycarbonyl-2- dimethylaminocarbonyl) pvrrolidinylthio]-4-methyl-6-(l-hydroxyethyl)-l- azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (V) was filtered and washed with water.b). Preparation of Meropenem trihydrateTo a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) and (2S,4S)-l-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4- mercaptopyrrolidine (33 g) in N,N-dimethylformamide (250 mL) was added slowly diisopropylethylamine (14 g) at - 40 to -10 0C then stirred for 2-3 h. The reaction mass was then added sloly to the phosphate buffer to isolate the solid product. The pH was adjusted 3.8 to 4.0 using sulphuric acid at 5-10 C and stirred for an hour. The product was filtered and washed with water. The product was then dried to result in amorphous diprotected meropenem of compound formula (V) (Figure 1).(c). Preparation of Meropenem trihydrateTo a solution of (4R,5R,6S)-3~[(diphenoxyphosphotyloxy]-6-[(R)-l-hydroxyethyl]-4- methyl-7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester (50 g) and (2S,4S)-l-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4- mercaptopyrrolidine (33 g) in N,N-dimethylformamide (250 niL) was added slowly diisopropylethylamine (14 g) at - 40 to -10 0C and stirred for 2-3 h. The reaction mass was added slowly to the water at 3 to 10 0C to isolate the solid product. The pH was then adjusted to 3.8 to 4.0 using sulphuric acid at 5 to 10 0C and stirred for an hour. The product was filtered and washed with water. |
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Step (ii) Preparation of (4R,5S,6S,8R,2'S,4'S)-p-Nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]-hept-2-en-7-one-2-carboxylate (V) To a solution of (4R,5R,6S)-3-[(diphenoxyphosphoryloxy]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (4-nitrophenyl)methyl ester in acetonitrile (1660 mL) were added (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylamino-4-mercaptopyrrolidine (66 g) and N-ethyldiisopropylamine (36 mL) at -15 C. and stirred under nitrogen atmosphere. After completion of the reaction, the resultant mass was quenched into ethyl acetate containing dipotassium hydrogen orthophosphate and stirred for 15 min. The ethyl acetate layer was distilled out completely under vacuum. The residue was dissolved in ethyl acetate and stirred. To the precipitated mass was added diisopropylether and stirred for an hour. The solid was filtered and dried to yield the title compound (110 g, Purity: 98%). |
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With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; acetonitrile; at -10 - 20℃; |
EXAMPLE 1; Preparation of Protected Meropenem4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10 gm) Formula-A and 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-1-carboxylate (6.122 gm) Formula-B was dissolved in 60 ml acetonitrile and 3 ml dimethyl acetamide at ambient temperature. The solution was stirred under same condition for 10 minutes to get clear solution and cool to a temperature of minus -10 C. Di-isopropylethyl amine (9.15 ml) was added dropwise under stirring conditions to the above solution at -10 C. and continued the reaction for 90 minutes at the same reaction parameters. After completion of the reaction, 150 ml ethyl acetate was added in said reaction mass, the ethyl acetate layer was extracted by acidic water till to get pH 6-7 of the extracted acidic water, then dried over sodium sulphate and distilled off up to free solid. Next a 1:1 mixture of 50 ml methyl ethyl ketone and acetone was added and allowed to keep for 14 hours for crystallization at 0-5 C., finally 30 ml cold water with a small amount of seeding was added for complete crystallization. The solid was filtered and washed with 10 ml mixture of diethyl ether and ethyl acetate to obtain pure 4-Nitrobenzyl (4R,5S,6S)-3-({(3S,5S)-5-[(dimethylamino)carbonyl]-1-[(4-nitrophenoxy)carbonxyl]pyrrolidin-3-yl}thio)-6-[(1R)-1-hydorxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0].hept-2-ene-2-carboxylate (referred as protected meropenem)Yield=10.20 gm. purity=99% above. |
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With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at -50 - -40℃; for 1h; |
4-Nitrobenzyl (2S,4S)-4-(acetylthio)-2-[(dimethylamino)carbonyl]pyrrolidine-1-carboxylate (30 g) was dissolved in dichloromethane (90 ml) and cooled to -10 to 0 C., followed by drop-wise addition of pyrrolidine (8.0 g) at the same temperature. The reaction mixture was stirred at -5 to 0 C. for 30 minutes and poured into 5% hydrochloric acid (150 ml), followed by separation of the organic layer. 4-Nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (Enolphosphate; 30 g) was dissolved in dimethylformamide (150 ml) and cooled to -40 to -50 C., followed by the addition of dichloromethane solution containing 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-1-carboxylate. Diisopropylethylamine (8.4 g) was added drop-wise to the reaction mixture so obtained and stirred for 60 minutes at -40 to -30 C. The reaction mixture was then poured into a mixture of ethyl acetate (300 ml) and water (300 ml). The ethyl acetate layer was separated and hydrogenated at pH 7.0 over palladium-carbon and the aqueous layer was separated after hydrogenation, followed by treatment with activated carbon. The solution so obtained was filtered and acetone (2 L) was added at 0-5 C. and stirred for 3 h at the same temperature. The reaction mixture was filtered, washed with acetone and dried to obtain the title compound. Yield: 11 g HPLC Purity: 98% |
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With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at -25℃; |
To a stirred solution of (4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(lR)-l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (XIII) and (2S,4S)-2-dimethylaminocarbonyl-4-mercapto-l-p-nitrobenzyloxycarbonyl pyrrolidine (VII) in N-Methylpyrrolidone ( or a mixture of N-Methylpyrrolidone and acetonitrile) was added Nu,Nu-Diisopropylethylamine at -25 C and stirred till the completion of the reaction. The mass was quenched in phosphate buffer and ethyl acetate and the pH was adjusted to 4 with phosphoric acid. The ethyl acetate layer containing compound (XIV) was treated with carbon and filtered. The ethyl acetate layer containing compound (XIV) was hydrogenated with Palladium on carbon using aqueous solution of 3-(N-morpholino)propanesulfonic acid buffer. The ethyl acetate layer was separated and the aqueous phase containing Meropenem (XV) was treated with carbon and filtered. The filtrate was cooled to 5C and pH was adjusted using dilute hydrochloric acid (or other organic acids like formic acid, acetic acid etc.) to 3-4 and crystallized the product by adding acetone (or solvents like methanol, ethanol, isopropyl alcohol, 1-propanol or mixtures therof). The solid was filtered and dried under vacuum to get Meropenem. |
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With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 0 - 5℃; for 5h; |
20 g of MAP was dissolved in 80mL of dimethylacetamide, and 12.5 g of the side chain compound was added thereto. After cooling to 0 to 5 C. 6.5mL of diisopropylethylamine was added dropwise. After stirring at 0 to 5 Cfor 5 hours, 120 mL of ethyl acetate and 200 mL of water were added, and the reaction mixture was stirred and then phase-separated. 80 mL of 0.5N HCl was added to the ethyl acetate layer to remove the remaining base, and the resultant mixture was washed with 200 mL of saturated salt water. The remaining water and color were removed by using anhydrous magnesium sulfate and activated carbon. The ethyl acetate solution which was the filtrate was stirred to generate crystal. After stirring at room temperature for 8 hours, cooling to 0 to 5 C. and stirring for 2 hours and filtering, 18.78 g of meropenem-PNB was obtained. |
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Example 1 1-1) Preparation of meropenem-PNB 20g of MAP was dissolved in 80mL of dimethylacetamide, and 12.5g of the side chain compound was added thereto. After cooling to 0 to 5, 6.5mL of diisopropylethylamine was added dropwise. After stirring at 0 to 5 for 5 hours, 120mL of ethyl acetate and 200mL of water were added, and the reaction mixture was stirred and then phase-separated. 80mL of 0.5N HCl was added to the ethyl acetate layer to remove the remaining base, and the resultant mixture was washed with 200mL of saturated salt water. The remaining water and color were removed by using anhydrous magnesium sulfate and activated carbon. The ethyl acetate solution which was the filtrate was stirred to generate crystal. After stirring at room temperature for 8 hours, cooling to 0 to 5, and stirring for 2 hours and filtering, 18.78g of meropenem-PNB was obtained. |
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