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[ CAS No. 90776-59-3 ] {[proInfo.proName]}

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Chemical Structure| 90776-59-3
Chemical Structure| 90776-59-3
Structure of 90776-59-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 90776-59-3 ]

CAS No. :90776-59-3 MDL No. :MFCD01318092
Formula : C29H27N2O10P Boiling Point : -
Linear Structure Formula :- InChI Key :STULDTCHQXVRIX-PIYXRGFCSA-N
M.W : 594.51 Pubchem ID :10304013
Synonyms :

Calculated chemistry of [ 90776-59-3 ]

Physicochemical Properties

Num. heavy atoms : 42
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.24
Num. rotatable bonds : 12
Num. H-bond acceptors : 10.0
Num. H-bond donors : 1.0
Molar Refractivity : 154.83
TPSA : 167.23 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.54 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.98
Log Po/w (XLOGP3) : 4.77
Log Po/w (WLOGP) : 4.46
Log Po/w (MLOGP) : 2.43
Log Po/w (SILICOS-IT) : 0.99
Consensus Log Po/w : 3.13

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.11

Water Solubility

Log S (ESOL) : -6.06
Solubility : 0.000522 mg/ml ; 0.000000879 mol/l
Class : Poorly soluble
Log S (Ali) : -8.01
Solubility : 0.00000577 mg/ml ; 0.0000000097 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -6.26
Solubility : 0.000326 mg/ml ; 0.000000548 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 5.85

Safety of [ 90776-59-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338-P314 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335-H373 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 90776-59-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 90776-59-3 ]

[ 90776-59-3 ] Synthesis Path-Downstream   1~19

  • 1
  • [ 93711-81-0 ]
  • 6-mercapto-6,7-dihydro-5H-pyrazolo<1,2-a><1,2,4>triazolium chloride [ No CAS ]
  • [ 120410-24-4 ]
  • 2
  • [ 93711-81-0 ]
  • [ 96034-64-9 ]
  • [ 96036-02-1 ]
YieldReaction ConditionsOperation in experiment
91.3% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at -15 - -10℃; for 5 - 8h; To the above compound (XI) of example 3 1Og ( 16.8mmol) was added acetonitrile (dry, 100 ml) and the mixture was cooled to -10 - -15 0C in ice-salt bath. Then, [2S,4S]-l-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidne (XX) 6. Ig (17.3mmol),and diisopropylethamine 2.5g (19.3mmol) were added at the same temperature and the mixture was stirred for 5-8 h. After completion of the reaction, the reaction solution was diluted by ethyl acetate (150 ml) and washed with 3.5% aqueous sodium phosphate monobasic solution. The organic phase was dried with anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue 11.2 g, quantified by HPLC containing 10.7 g of targeted compound (XXIV), (91.3% yield) was directly used in the follow step.
18% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -10℃; for 3.16667h;Product distribution / selectivity; (Example 6) ; 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 75 ml of dimethylformamide were added 24.8 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 15.5 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 (6.5 g) was added thereto over 10 minutes, and the resulting mixture was stirred at the same temperature for 3 hours. To the reaction mixture were added, at -10 to -5C, 175 ml of ethyl acetate and 125 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 125-ml portions of a 5% aqueous solution of sodium chloride and one 125-ml portion of water, whereby a water-saturated ethyl acetate solution containing the compound (3) was obtained. The concentration of the compound (3) was 18% by weight.
17% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at -10℃; for 3.16667h;Product distribution / selectivity; (Example 1); 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 120 ml of acetonitrile were added 40.0 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 25.0 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 (10.5 g) was added thereto over 10 minutes, and the resulting mixture was stirred at the same temperature for 3 hours. To the reaction mixture were added, at 0 to 7C, 240 ml of ethyl acetate and 200 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 200-ml portions of a 10% aqueous solution of sodium chloride and one 200-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.
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.
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)
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.
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.
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%).
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.
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%
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.
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.
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.

  • 3
  • [ 90776-59-3 ]
  • [ 153851-71-9 ]
  • [ 155835-09-9 ]
YieldReaction ConditionsOperation in experiment
91% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide; acetone; acetonitrile at 0℃; for 2h;
  • 4
  • [ 202467-69-4 ]
  • [ 93711-81-0 ]
  • [ 202467-70-7 ]
YieldReaction ConditionsOperation in experiment
98.5% Example 1: Preparation of compound 2a wherein Np repesents [Show Image] and P1 and P2 are both PNB 36.0g (0.0605mmol) of carbapenem parent nucleus 3 (P1 is PNB) was dissolved in 300ml DMF, then 26.7g (0.0599mol) of the side chain of Ertapenem 4a (P2 is PNB) was added. To the reaction mixture, 9.4g (0.0727mol) of N,N-diisopropylethylamine was added slowly at-35C. The reaction was performed under stirring. Upon completion of reaction, the reaction mixture was poured into aqueous HCl solution (pH=4), filtered, 46.6g of solid was obtained as white or off-white powder. Purity: 98.2% (by HPLC). Yield: 98.5%. The obtained solid was analyzed by powder x-ray diffraction and the results showed the solid was in amorphous form. Figure 1 is powder X-ray diffraction pattern of the product. H-NMR (DMSO-d6) : delta1.18 (d, 3H) ; 1.20 (d, 3H) ; 1.95 (m, 1H) ; 2.81 (m, 1H) ; 3.18-3.47 (m, 3H) ; 3.60-4.50 (m, 6H) ; 5.04-5.44 (m, 5H) ; 7.30-8.30 (m, 12H) ; 10.27 (d, 1H) MS : 788.9 (M-1) , 812.7 (M+Na) .
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -30℃;Product distribution / selectivity; Example- I; Preparation of diprotected Ertapenem of formula (IV); To 3-[[[(2S,4S)-4-mercapto-2-pyrrolidinyl-l-(4-nitrobenzyloxy)carbonyl] carbonyl]amino]benzoic acid (8.3 g) in DMF (30 mL), p-nitrobenzyl (lR,5R,6S)-6-[(lR)- l-hydroxyethyl]-2-[(diphenylphosphono)oxy]-l-methylcarbapen-2-em-3-carboxylate (IO <n="10"/>g) was added. To the reaction mass, N,N-diisopropylethylamine (5.4 g) was added at -30 C and stirred. After completion of reaction, the reaction mass was diluted with THF (60 mL) and poured into mixture of buffer solution (pH=7) and ethyl acetate (300 mL). The layers obtained were separated and the filtrate washed with brine solution. The organic layer was subjected to carbon treatment and the filtrate distilled out at 40 0C under vacuum to remove the solvent. The residue was stirred with ethyl acetate (50 mL) to yield title compound of formula (IV) (11 g).; Example-2; Preparation of diprotected Ertapenem of formula (IV); To 3-[[[ (2S,4S)-4-mercapto-l-(4-nitrobenzyloxy)carbonyl-2-pyrrolidinyl] carbonyl]amino]benzoic acid (7.68g) in DMF (30 mL), /Miitrobenzyl (l R,5R,6S)-6-[(l R)- l-hydroxyethyl]-2-[(diphenylphosphono)oxy]-l-methylcarbapen-2em-3-carboxylate (10 g) was added. To the reaction mixture N,N-diisopropylethylamine (4.78g) was added at - 30 C and stirred. After completion of reaction, the reaction mass was poured into water and ethyl acetate mixture at 1O0C. The layers were separated and organic layer washed with brine solution. The organic layer was subjected to carbon treatment and taken for subsequent step.; Example- 3; Preparation of diprotected Ertapenem of formula (IV); To 3-[[[(2S,4S)-4-mercapto-2-pyrrolidinyl- 1 -(4-nitrobenzy loxy)carbonyl] carbonyl]amino]benzoic acid (8.3 g) in DMF (30 mL), p-nitrobenzyl (lR,5R,6S)-6-[(l R)- 1 -hydroxyethyl]-2-[(diphenylphosphono)oxy]- 1 -methylcarbapen-2-em-3-carboxy late ( 10 g) was added. To the reaction mass nu,nu-diisopropylethylamine (5.4 g) was added at -30 C and stirred. After completion of reaction, the reaction mass poured into buffer solution (pH=7) or water. The reaction mass stirred, the solid obtained was filtered and washed with water to yield title compound of formula (IV).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -30℃;Product distribution / selectivity; Example-1Preparation of Diprotected Ertapenem of Formula (IV); To 3-[[[(2S,4S)-4-mercapto-2-pyrrolidinyl-1-(4-nitrobenzyloxy)carbonyl]carbonyl]amino]benzoic acid (8.3 g) in DMF (30 mL), p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(diphenylphosphono)oxy]-1-methylcarbapen-2-em-3-carboxylate (10 g) was added. To the reaction mass, N,N-diisopropylethylamine (5.4 g) was added at -30 C. and stirred. After completion of reaction, the reaction mass was diluted with THF (60 mL) and poured into mixture of buffer solution (pH=7) and ethyl acetate (300 mL). The layers obtained were separated and the filtrate washed with brine solution. The organic layer was subjected to carbon treatment and the filtrate distilled out at 40 C. under vacuum to remove the solvent. The residue was stirred with ethyl acetate (50 mL) to yield title compound of formula (IV) (11 g).
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at -10℃;Product distribution / selectivity; B) Preparation of a compound of formula VI from formula Ib To provide p-nitrobenzyl(1R,5S,6S)-6-[(IR)-1-hydroxyethyl]-2-[(di- phenylphosphono)oxy]-1-methylcarbapen-2-em-3-carboxylate of formula Ib (119 g) obtained from Example 1B in acetonitrile (560 g) at -5C, 3-([[(2S,4S)-mercapto-2- pyrrolidinyl-1-(4-nitrobenzyloxy) carbonyl] carbonyl]amino]benzoic acid (90 g) was added. To the reaction mixture, diisopropylethylamine (72 g) was added at -10C and stirred. After completion of reaction, the reaction solution was distilled to remove acetonitrile. Water (1.8 kg) and dichloromethane (1.6 kg) were added to resulting mixture into, stirred, and separated. The organic layer was obtained to yield the compound of formula VI and taken for subsequent step described in Example 3C.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at -10 - -5℃; B) Preparation of a Compound of Formula VI from formula Ib To provide p-nitrobenzyl(1R,5S,6S)-6-[(IR)-1-hydroxyethyl]-2-[(di-phenylphosphono)oxy]-1-methylcarbapen-2-em-3-carboxylate of formula Ib (119 g) obtained from Example 1B in acetonitrile (560 g) at -5 C., 3-([[(2S,4S)-mercapto-2-pyrrolidinyl-1-(4-nitrobenzyloxy) carbonyl]carbonyl]amino]benzoic acid (90 g) was added. To the reaction mixture, diisopropylethylamine (72 g) was added at -10 C. and stirred. After completion of reaction the reaction solution was distilled to remove acetonitrile. Water (1.8 kg) and dichloromethane (1.6 kg) were added to resulting mixture into, stirred, and separated. The organic layer was obtained to yield the compound of formula VI and taken for subsequent step described in Example 3B.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -30 - 0℃; for 4.0h; (4-Nitrophenyl)methyl(4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy-6-[(l R)- l- hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50 g, 0.084 moles) was added to a mixture of 3-[[[(2S,4S)-4-Mercapto- l -(4- nitrobenzyloxy)carbonyl-2-pyrrolidinyl]carbonyl]amino]benzoic acid (39.33 g, 0.088 moles), N-ethyldiisopropylamine (32.6 g, 0.252 moles) and N,N- dimethylformamide (300 ml) at 0 to -30C and stirred for 4 h at -20 to -30C. After completion of the reaction, water (750 ml) was added, adjusted the pH to 3- 5 with diluted hydrochloric acid, extracted the title compound with ethyl acetate (500 ml) and taken for hydrogenation in the next step
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; Under the condition of -10 C, the side chain of formula I with a protective group of penem parent core MAP and formula II of ertapenem side chain in the solvent diisopropylethylamine and dichloromethane to form the intermediate product. The above intermediate product is subjected to hydrogenation and deprotection using 20% Raney nickel as a catalyst and sodium bicarbonate as an alkalizing agent to obtain crude ertapenem monosodium salt, which is then subjected to crystallization purification method can be refined to obtain ertapenem monosodium salt. That is, [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-carboxyphenyl)amino]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt with a yield of 75.1%.

  • 5
  • [ 90776-59-3 ]
  • [ 179337-57-6 ]
  • [ 161715-20-4 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine; acetonitrile at -20℃; for 2h;
88.5% With N-ethyl-N,N-diisopropylamine at -20℃; for 3.5h; 2 Preparation of intermediate I The 1-(4,5-Dihydro-2-thiazolyl)-3-azetidinethiol hydrochloride 274.0g(1.3mol) and 1β-Methyl vinyl phosphate 594.5g(1mol)added to 1783ml of Diisopropylethylamine and stirred the reaction at -20°C for 3.5h. After the end of the reaction, 900 ml of pure water was added and the temperature was raised to 0 ° C in 30 minutes. The filter cake was washed with 297 ml of acetonitrile water (V acetonitrile: Vwater = 2: 3) and dried to give I 458.4 g of intermediate. the calculated yield was 88.5% and the purity was 99.2%.
With N-ethyl-N,N-diisopropylamine In acetonitrile
  • 6
  • [ 93711-81-0 ]
  • [ 120410-24-4 ]
  • 7
  • [ 93711-81-0 ]
  • [ 96034-64-9 ]
  • meropenem trihydrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 1 : Synthesis of Meropenem; 4-nitrobenzyl (4/?,5i?,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(li?)-l -hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (enol-phosphate of Formula III, 50 gm) and 4-nitrobenzyl (21S',45)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-1-carboxylate (thiopyrrolidine of Formula IV, 30 gm) was dissolved in a mixture of N,N-dimethylformamide (200 ml) at ambient temperature. The solution was then cooled to -450C and to it was added diisopropylamine (11 gm) dropwise under stirring while maintaining the temperature between -50 to -450C. After stirring the reaction mass for about 1 hour, it was poured in to a mixture of ethyl acetate (500 ml) and water (300 ml). The organic layer was separated and added to a mixture of 5% palladium on carbon (50 gm) in aqueous buffer (500 ml) containing N-methylmorpholine and acetic acid (pH about 7.0). The above biphasic reaction mass was hydrogenated for 3 hours under pressure at 20-250C. After completion of the reaction, the mixture was filtered and aqueous layer was separated. The aqueous layer was concentrated by reverse osmosis and to the condensate was added tetrahydrofuran at a temperature of about 5-1O0C. The resultant mixture was stirred for about 5 hours to get crystalline meropenem trihydrate in a yield of 21.6 gm.
  • 8
  • [ 93711-81-0 ]
  • [ 96034-64-9 ]
  • [ 141818-52-2 ]
YieldReaction ConditionsOperation in experiment
With diisopropylamine; In N,N-dimethyl-formamide; at -50 - 20℃; for 1h; Example 2: Synthesis of Meropenem; Step a); Preparation of 4-Nitrobenzyl (4R,5S,6S)-3-({(3S,5S)-5- [(dimethylamino)carbonyl]-l-[(4-nitrophenoxy)carbonxyl] pyrroIidin-3-yl}thio)-6- [(lphi-l-hydorxyethyl^-methyl-T-oxo-l-azabicclobetaJ.Olhept-Z-ene-Z-carboxylate; 4-nitrobenzyl (4Lambda,5i?,65)-3-[(diphenoxyphosphoryl)oxy]-6-[(li?)-l -hydroxyethyl]-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (enol-phosphate of Formula III, 100 gm) and 4-nitrobenzyl (25,45)-2-[(dimethylamino)carbonyl]-4- mercaptopyrrolidine-1-carboxylate (thiopyrrolidine of Formula IV, 60 gm) was dissolved in a mixture of N,N-dimethylformamide (800 ml) at ambient temperature. The solution was then cooled to -450C and to it was added diisopropylamine (22 gm) drop-wise under stirring while maintaining the temperature between -50 to -450C. After stirring the EPO <DP n="11"/>reaction mass for about 1 hour, it was poured in to a mixture of ethyl acetate (1 L) and water (1 L). The organic layer was separated and under vacuum concentrated to dryness to get the title compound in a yield of 100 gm.
  • 9
  • [ 148017-03-2 ]
  • [ 90776-59-3 ]
  • [ 491878-07-0 ]
YieldReaction ConditionsOperation in experiment
83% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; Inert atmosphere; Large scale; 1.2 Step 2: Condensation reaction In a 100L reactor under nitrogen atmosphere, MAP (7.2kg) and DMF (33.6kg) were added, stirred and dissolved; cooling to 0 ~ 5°C, start dropping diisopropylethylamine 2.64 kg, approximately 0.5h dropping was completed, the reaction the system was kept overnight at 0 ~ 5°C reaction, TLC (chloroform: methanol = 10: 1) to monitor progress of the reaction; after completion of the reaction, the reaction solution was transferred into 200L extraction tank 54kg of pure water and a mixed solvent of containing 48kg ethyl acetate, the stirring, layers were separated and the organic layer was separated; the organic layer was washed with 0.7% HCl solution, once with 40kg and 20kg with a 5% NaHCO3 solution and washed once with 5% NaCl solution was washed with 26kg × 2; the organic layer was separated, added to 0.8kg charcoal and dried over anhydrous sodium sulfate 4 ~ 5kg, stirred 0.5h, filtered; the filtrate was transferred into 200L autoclave, 45°C dry off the solvent under reduced pressure, the residue was added 120L (94.9kg) in methanol, with vigorous stirring; 1 ~ 2h residue cured, until large amount of solid formed and became powdery, the solid was collected by centrifugation, and washed with a small amount of methanol, and dried under reduced pressure of not less than 40°C 6h, to give the crude condensation product of about 8.18kg.100L reactor by adding 8.1 kg condensate and 24.3L (21.6 kg) tetrahydrofuran (w/v = 1/3), stirred and heated up to 35-40°C, solid dissolves very quickly, then adding 0.81 kg active carbon, preserving heat and stirring 0.5h, filtering, the filtrate into 500L in the reaction kettle, add 72.9L (57.7 kg) (w/v = 1/9) methanol, stirring crystallization, after the solid is separated out stirring 2h rear, filtering, 40 °C reduced-pressure drying not less than 6h, receive condensates about refined product 7.29 kg. The reaction yield is range 80-83% (to MAP meter). Intermediate condensation product quality, consistent with its internal control is used for the reaction of the next standard.
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -40 - -35℃; for 1h; 1 EXAMPLE l: Preparation of DoripenemA mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-[(aminosulfonyl)(tert- butoxy carbony^aminojmethyljpyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) was refluxed for 3 hours, followed by cooling to about 25°C. A mixture of ethylacetate (400 ml) and water (400 ml) was added to the reaction mixture. The organic layer was separated and the aqueous layer was re-extracted with ethylacetate (200 ml). The combined organic layer was washed twice with 5% w/v aqueous sodium chloride solution and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l- carboxylate. N,N-dimethylformamide (250 ml) was added to the concentrate followed by the addition of enolphosphate (50 g) at about 25°C. The resulting solution was cooled to - 400C and diisopropylamine (11 g) was added to this solution drop wise under stirring while maintaining the temperature at -40° to -35°C. After stirring for 1 hour at the same temperature, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The organic layer was separated and added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (500 ml) containing N-methylmorpholine and acetic acid (pH 6.5 to 7.0). The biphasic reaction mass was then hydrogenated for 3 hours under pressure at about 25°C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer was separated. The analysis of the aqueous layer by HPLC showed the formation of doripenem in 85% yield.
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; for 18h; 2; 3; 4 EXAMPLE 2: Preparation of Amorphous DoripenemA mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{ [(aminosulfonyl)(tert- butoxy carbonyl)amino]methyl}pyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to about 25°C. The reaction mixture was poured into a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was separated and washed with water (2 X 500 ml) and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l-carboxylate. The concentrate so obtained was dissolved in N,N-dimethylformamide (50 ml) and added to EPO enolphosphate (50 g) dissolved in N,N-dimethylformamide (200 ml), at 00C to 5°C, followed by drop wise addition of diisopropylethylamine (15.1 g) at the same temperature. After stirring for 18 hours at 00C to 5°C, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0 and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 100C to 200C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated. The aqueous layer was then added to absolute ethanol (3.5 L) at 200C to 25°C in 15 to 20 minutes. After stirring at 00C to 5°C for 60 minutes, the reaction mixture was filtered and washed with absolute ethanol followed by acetone to yield the title compound.Yield: 2O g Purity (HPLC): 95%EXAMPLE 3: Preparation of Amorphous DoripenemA mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{ [(aminosulfonyl)(tert- butoxy carbonyl)amino]methyl}pyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to about 25°C. The reaction mixture was poured into a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was separated and washed with water (2 X 500 ml) and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l-carboxylate. The concentrate so obtained was dissolved in N,N-dimethylformamide (50 ml) and added to enolphosphate (50 g) dissolved in N,N-dimethylformamide (200 ml) at 0° to 5°C, followed by drop wise addition of diisopropylethylamine (15.1 g) at the same temperature. After stirring for 18 hours at 0° to 5°C, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0 and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to EPO 4 hours under pressure at 10° to 200C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated. The aqueous layer was then added to isopropyl alcohol (3.5 L) at 20° to 25°C in 15 to 20 minutes. After stirring at 0° to 5°C for 60 minutes, the reaction mixture was filtered and washed with isopropyl alcohol followed by acetone to yield the title compound.Yield: 2O gEXAMPLE 4: Preparation of Amorphous DoripenemA mixture of 4-nitrobenzyl(2S,4S)-4-(acetylthio)-2-{ [(aminosulfonyl)(tert- butoxy carbonyl)amino]methyl}pyrrolidine-l-carboxylate (53.5 g) and concentrated sulfuric acid (25 g) in methanol (250 ml) were refluxed for 3 hours, followed by cooling to about 25°C. Into the reaction mixture was poured a mixture of methylene chloride (500 ml) and water (500 ml). The organic layer was separated and washed with water (2 X 500 ml) and concentrated under reduced pressure to give a concentrate containing 4-nitrobenzyl (2S,4S)-2-{ [(aminosulfonyl)amino]methyl}-4-mercaptopyrrolidine-l-carboxylate. The concentrate so obtained was dissolved in N,N-dimethylformamide (50 ml) and added to enolphosphate (50 g) dissolved in N,N-dimethylformamide (200 ml) at 0° to 5°C, followed by drop wise addition of diisopropylethylamine (15.1 g) at the same temperature. After stirring for 18 hours at 0° to 5°C, the reaction mixture was poured into a mixture of ethylacetate (500 ml) and water (300 ml). The pH was adjusted to 2.5 to 3.0, and the organic layer was separated. The organic layer so obtained was added to a mixture of 5% palladium on carbon (50 g) in aqueous buffer (300 ml) containing N-methylmorpholine and acetic acid (pH 6.0 to 7.0). The biphasic reaction mass was then hydrogenated for 3 to 4 hours under pressure at 10° to 200C. After the completion of the reaction, the reaction mixture was filtered and the aqueous layer (350 ml) was separated. The aqueous layer was then added to methanol (3.5 L) at 20° to 25°C in 15 to 20 minutes. After stirring at 0° to 5°C for 60 minutes, the reaction mixture was filtered and washed with methanol followed by acetone to yield the title compound.
32.5 kg With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; for 18h; Large scale;
Stage #1: (2S,4S)-4-mercapto-2-(N-sulfamoyl-aminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine; (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate In N,N-dimethyl-formamide at -30℃; for 0.166667h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 20h; Inert atmosphere; 1 Synthesis of Doripenem (I) [0231] Under the protection of nitrogen, 5.94 g (10 mmol) compound (II) was added into 50 ml dry N,N-dimethylformamide (DMF), and the mixture was cooled to -30° C. while stirring, then added with 11 mmol side-chain compound (VI) and stirred for 10 minutes, then added with 1.80 g (14.2 mmol) N,N-diisopropylethylamine, and then continued to be stirred for 20 hours after completion of addition, and the reaction finished; then the reaction mixture was poured into a mixture of 200 ml ice water and 200 ml ethyl acetate and stirred for 30 minutes, then the ethyl acetate layer was separated, and the water layer extracted twice with ethyl acetate (200 ml each time), the organic layers were combined, and washed with 200 ml dilute hydrochloric acid (0.7%), 200 ml sodium bicarbonate solution (5%) and 200 ml saturated brine once respectively, all of the water layers were combined and back-washed once with 200 ml ethyl acetate, and the organic layers were combined and anhydrous sodium sulfate was added to dry for 2 hours, and then ethyl acetate was recovered under reduced pressure, the resulting product (VII) was directly used for the next step of reaction without further purification. [0232] The above product (VII), 45 ml tetrahydrofuran, 30 ml water, 1.02 g magnesium chloride and 3.8 g palladium/ carbon were added into a 1 L hydrogenation reactor. The mixture was vigorously stirred for 2 hours at room temperature and hydrogen pressure of 0.5 MPa, and filtered to remove palladium/carbon, and palladium/carbon was washed with a mixed solvent of 15 ml tetrahydrofuran/8 ml water. The resulting filtrate was added with 0.5 g magnesium chloride and 220 ml tetrahydrofuran and the water layer was separated. The above operation was repeated twice, the water layers were combined and cooled to 05° C., the filtrate was added with 150 ml methanol while stirring, and then stirred at -10° C. for 1 hour and filtered, the resulting solid was washed with 100 ml methanol and dried under vacuum, then 2.76 g powder of pale yellow crystalline doripenem (I) was obtained with yield of 63% (calculated based on the compound (II)).
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at -40 - -20℃; for 10h; A mixture of (2S, 4S)-4-(acetylthio)-2-(((tert-butoxycarbonyl)(sulfamoyl)amino) methyl)pyrrolidine-1-carboxylic 4-nitrobenzoic anhydride (1b,17.1kg, 32.1mol) and valerylchloride (1.7 kg, 14.09 mol) in methanol (75 L) was heated to 50C and stirred at 48-50C for 18 h. After completion of reaction, the reaction mixture was diluted withdichloromethane (150 L) and water (150 L). The separated organic layer was washed withdemineralised water (150 L), followed by 1% w/v aqueous NaCl solution (150 L). Afterwashings the organic layer was concentrated to oil which was dissolved in N, N-dimethylformamide(30 L). The solution was added to (4R,5R,6S)-4-nitrobenzyl3-((diphenoxyphosphoryl)oxy)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate(3b, 15kg, 25.23 mol) in N,N-dimethylformamide (45 L) at -40C. Later N-ethyldiisopropylamine (4.53 kg, 35.05 mol) was added to reaction mass and stirred for 4 h at40C. The temperature of reaction was then raised to 20C and stirred for 6 h. Thereaction mixture was diluted with ethylacetate (150 L), water (90 L) and acidified topH 2.8 with 1N aqueous hydrochloric acid (12.45 L) at 5C. The two layers were separated,and the aqueous layer extracted with ethyl acetate (90 L). The combined organiclayers washed with 0.25% w/v aqueous NaCl solution (2£150 L) at 15C and concentratedto a sticky mass which was dissolved in tetrahydrofuran (195 L) at 20C. A buffersolution (pH 7.1), prepared by mixing N-methylmorpoline (2.55 kg, 25.21 mol), aceticacid (1.095 kg, 18.25 mol) and water (82.5 L) at 20C, which was added to the abovereaction mass. The solution was added to pre-reduced Pd/C, obtained by stirring 10% w/wPd/C (22.5 kg, 50% w/w wet) in DM water (82.5 L) for 1 h under hydrogen atmosphere(0.3 Mpa) at 20C. The reaction mixture was stirred for 2.5 h under hydrogen atmosphere(0.8 Mpa) at 20C. The reaction mass was filtered through a Celite bed and the filtrate waswashed with a mixture of water (15 L) and tetrahydrofuran (15 L). The aqueous filtrateobtained was extracted with ethyl acetate (210 L) at 20C. After addition of seed crystalsof doripenem (0.03 Kg) at 18C and slow addition of of isopropanol (507 L) over a periodof 5 h, the slurry mass was cooled to 0-5C and stirred for 8 h. The slurried mass wasfiltered at 0-5C to give the wet product which was washed with 20% v/v aqueous isopropanol(30 L, 0-5C) and dried under vacuum at 45-50C for 8 h to give doripenem hydrate5 (7.89 kg with 71% yield and 99.68% a/a HPLC purity).

  • 10
  • [ 202467-69-4 ]
  • [ 93711-81-0 ]
  • sodium 2-ethylhexanoic acid [ No CAS ]
  • sodium salt of (4R,5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-1-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 2-[(4-nitrophenyl)methyl] ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example-4; Preparation of sodium salt of di-protected Ertapenem (IV):;To a solution of /?-nitrobenzyl (lR,5R,6S)-6-[(lR)-l-hydroxyethyl]-2-[(diphenylphosphono)oxy]-l -methylcarbapen-2-em-3-carboxylate of formula (II) (100 g) <n="11"/>and 3-[[[ (2S,4S)-4-mercapto-l-(4-nitrobenzyloxy)carbonyl-2-pyrrolidinyl] carbonyl]amino]benzoic acid of formula (III) (73.8 g) in DMF, solution of DBU (60 mL) in DMF was added at -50 C, and the reaction mass stirred till completion of reaction. After completion of reaction, the reaction mass quenched into mixture of ethyl acetate and buffer solution (potassium dihydrogen phosphate (175 g) in water or di potassium hydrogen phosphate buffer solution). The pH of biphasic system was adjusted to 4.5 and layers separated. To the organic layer, a solution of sodium-2-ethylhexanoate in ethyl acetate was added (32 g) was added. A pasty mass was obtained. The organic layer was decanted, and the pasty mass dissolved in methanol. The methanol solution was added in IPE to yield the sodium salt of di-protected Ertapenem (IV) (125 g).
  • 11
  • [ 202467-69-4 ]
  • [ 93711-81-0 ]
  • sodium salt of (4R,5S,6S)-3-[[(3S,5S)-5-[[(3-carboxyphenyl)amino]carbonyl]-1-[[(4-nitrophenyl)methoxy]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 2-[(4-nitrophenyl)methyl] ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example-4Preparation of Sodium Salt of Di-Protected Ertapenem (IV); To a solution of p-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[(diphenylphosphono)oxy]-1-methylcarbapen-2-em-3-carboxylate of formula (II) (100 g) and <strong>[202467-69-4]3-[[[(2S,4S)-4-mercapto-1-(4-nitrobenzyloxy)carbonyl-2-pyrrolidinyl]carbonyl]amino]benzoic acid</strong> of formula (III) (73.8 g) in DMF, solution of DBU (60 mL) in DMF was added at -50 C., and the reaction mass stirred till completion of reaction. After completion of reaction, the reaction mass quenched into mixture of ethyl acetate and buffer solution (potassium dihydrogen phosphate (175 g) in water or di potassium hydrogen phosphate buffer solution). The pH of biphasic system was adjusted to 4.5 and layers separated. To the organic layer, a solution of sodium-2-ethylhexanoate in ethyl acetate was added (32 g) was added. A pasty mass was obtained. The organic layer was decanted, and the pasty mass dissolved in methanol. The methanol solution was added in IPE to yield the sodium salt of di-protected Ertapenem (IV) (125 g).
To a stirred solution of p-nitrobenzyl (4R,5S,6S)-3-(diphenyloxy)phosphoryloxy-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate (compound II) (100 g) and (2S,4S)-2-[[(3-carboxyphenyl)amino]carbonyl]-4-mercapto-1-(4-nitrobenzyl)pyrrolidinecarboxylate (compound III) (75 g) in N,N-dimethylformamide was added N,N-diisopropylethylamine at -30 to -40 C. and stirred. The reaction mass, after completion of the reaction, was quenched with a mixture of phosphate buffer solution-ethyl acetate and the pH was adjusted to 5-6 with phosphoric acid. The organic layer was separated, washed with water and subjected to carbon treatment. To the organic layer containing the compound of formula (IV) (wherein P? and P? refers to p-nitrobenzyl), a solution of sodium 2-ethylhexanoate (42 g in 500 mL methanol) was added and taken to next step as such. (If required the compound of formula (IV) is isolated either as sodium salt or as free acid by following the process reported in prior art and taken further)
  • 12
  • [ 93711-81-0 ]
  • [ 96034-64-9 ]
  • [ 96036-03-2 ]
YieldReaction ConditionsOperation in experiment
REFERENCE EXAMPLE Preparation of Meropenem: 4-nitrobenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1-R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3 2.0]hept-2-ene-2-carboxylate (Formula VIIIA; 20 g) was dissolved in N-methyl-2-pyrrolidone (100 mL) and cooled to -20 to -150C. 4-Nitrobenzyl (25',4S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-l-carboxylate (12 g) was added to the reaction mixture followed by the drop-wise addition of diisopropylethylamine (5.6 g) at -15 to -50C and the reaction mixture was stirred. The reaction mixture was subsequently added to a buffer containing 5% palladium-carbon (30 g) and hydrogenated for 3 to 4 hours at about 250C. (The buffer was prepared using N-methylmorpholine (3.4 g) and appropriate quantity of hydrochloric acid so as to obtain a pH of 6.5 to 7.0 in distilled water (120 mL)). The catalyst was filtered after the completion of hydrogenation and washed with water (100 mL). The filtrate was treated with activated charcoal and acetone (1.6 L) was added to the filtrate at 0 to 50C. The reaction mixture was stirred for 6 hours at 0 to 50C and filtered to obtain the title compound.Yield: 9.8 g Purity: 98% (HPLC)
Reference ExamplePreparation of 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 (Formula VIIIA; 20 g) was dissolved in N-methyl-2-pyrrolidone (100 mL) and cooled to -20 to -15 C. 4-Nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-mercaptopyrrolidine-1-carboxylate (12 g) was added to the reaction mixture followed by the drop-wise addition of diisopropylethylamine (5.6 g) at -15 to -5 C. and the reaction mixture was stirred. The reaction mixture was subsequently added to a buffer containing 5% palladium-carbon (30 g) and hydrogenated for 3 to 4 hours at about 25 C. (The buffer was prepared using N-methylmorpholine (3.4 g) and appropriate quantity of hydrochloric acid so as to obtain a pH of 6.5 to 7.0 in distilled water (120 mL)). The catalyst was filtered after the completion of hydrogenation and washed with water (100 mL). The filtrate was treated with activated charcoal and acetone (1.6 L) was added to the filtrate at 0 to 5 C. The reaction mixture was stirred for 6 hours at 0 to 5 C. and filtered to obtain the title compound.Yield: 9.8 gPurity: 98% (HPLC)
20 g of MAP was dissolved in 80 mL 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 for 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. Without the solvent concentration procedure after filtration, the next step was carried out directly in the state of ethyl acetate solution. 60 g of potassium phosphate monobasic (KH2PO4) dissolved in 400 mL of water was added to the ethyl acetate solution and heated to 30 C. or higher. 80 g of zinc powder was added thereto and stirred between 25 and 35 C. for 1 hour. After completion of the reaction, zinc powder was filtered and the filtrate was washed with a mixture solution of tetrahydrofuran/water. The aqueous layer was separated, washed 4 times with 100 mL of methylene chloride and developed in a column filled with adsorption resin SP-207 for adsorption. The resin column was washed with 2 L of water to remove potassium phosphate monobasic used in the reaction and impurities, and developed with 2 L of 60% methanol to elute meropenem completely. The fractions containing meropenem were collected, a buffer solution of N-methylmorpholine/acetic acid (pH 6.5) was added thereto, and concentration was conducted to a volume 10 times greater than the weight of meropenem-PNB. 1100 mL of acetone was added to generate crystal and stirred at room temperature for 1 hour. After filtration and drying, 10.30 g of meropenem trihydrate was obtained.
Example 4 Synthesis of meropenem trihydrate (in situ process) 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 5C, 6.5mL of diisopropylethylamine was added dropwise. After stirring 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. Without the solvent concentration procedure after filtration, the next step was carried out directly in the state of ethyl acetate solution. 60g of potassium phosphate monobasic (KH2PO4) dissolved in 400mL of water was added to the ethyl acetate solution and heated to 30C or higher. 80g of zinc powder was added thereto and stirred between 25 and 35C for 1 hour. After completion of the reaction, zinc powder was filtered and the filtrate was washed with a mixture solution of tetrahydrofuran/water. The aqueous layer was separated, washed 4 times with 100mL of methylene chloride and developed in a column filled with adsorption resin SP-207 for adsorption. The resin column was washed with 2L of water to remove potassium phosphate monobasic used in the reaction and impurities, and developed with 2L of 60% methanol to elute meropenem completely. The fractions containing meropenem were collected, a buffer solution of N-methylmorpholine/acetic acid (pH 6.5) was added thereto, and concentration was conducted to a volume 10 times greater than the weight of meropenem-PNB. 1100mL of acetone was added to generate crystal and stirred at room temperature for 1 hour. After filtration and drying, 10.30g of meropenem trihydrate was obtained.

  • 13
  • [ 202467-69-4 ]
  • [ 93711-81-0 ]
  • ertapenem [ No CAS ]
  • 14
  • [ 202467-69-4 ]
  • [ 93711-81-0 ]
  • [4R-[3(3S,5S)-4α,5β,6β(R)]]-3-[[5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0.]hept-2-ene-2-carboxylic acid monosodium [ No CAS ]
  • 15
  • [ 90776-59-3 ]
  • [ 153851-71-9 ]
  • [ 141499-38-9 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide; acetonitrile at 0 - 5℃; 1.1 Step-I: Preparation of p-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H- Pyrazolo[l,2-al [l,2,41triazol-8-ium-6-ylsulfanyl)-6-(l-hvdroxyethyl)-4- methyl-7-oxo-l-azabicvclo[3.2.01hept-2-ene-2-carboxylate [Compound of formula (IV) Preparation of Biapenem (Non-Sterile) Step-I: Preparation of p-Nitrobenzyl (4R,5S,6S)-3-(6,7-dihydro-5H- Pyrazolo[l,2-al [l,2,41triazol-8-ium-6-ylsulfanyl)-6-(l-hvdroxyethyl)-4- methyl-7-oxo-l-azabicvclo[3.2.01hept-2-ene-2-carboxylate [Compound of formula (IV)1 To a mixture of acetonitrile and DMF, P-Nitrobenzyl (4R,5S,6S)-3- (diphenyloxy)phosphoryloxy-6-[(lR)-l-hydroxyethyl]-4-methyl-7-oxo-l- azabicyclo[3,2,0]hept-2-ene-2-carboxylate (compound of formula II) and 6,7- dihydro-6-mercapto-5H-pyrazolo[l,2-a] [1,2,4] triazole chloride (compound of formula III) were added and cooled to 0-5° C. To this mixture, N- ethyldiisopropyl amine was added and stirred till the completion of the reaction, followed by the addition of dichloromethane to crystallize the p-Nitrobenzyl (4R,5 S ,6 S)-3 - (6 ,7 -dihydro-5 H-pyrazolo [ 1 ,2 -a] [ 1 ,2 ,4]triazol-8 - ium-6-ylsulfanyl)-6-(l -hydro xyethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylate which was filtered and dried under nitrogen.
  • 16
  • [ 202467-69-4 ]
  • [ 93711-81-0 ]
  • [ 100-11-8 ]
  • [ 1262305-54-3 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 35℃; for 3.0h; A solution of (Ilia) (1.09 eq) and (lla) (1eq) in DMAc (0.4M) was cooled to -20C and DIPEA (4.4eq) is added. After 2h a solution of p-nitrobenzylbromide (1.3eq) in DMAc (2M) was added. The reaction was warmed to 35C and stirred for 3h. DMAc was added to reach0.16M. Excess base was quenched by the addition of AcOH (2.5eq). Isopropyl alcohol and water were added, followed by seeding crystals. The mixture was stirred for another 20h at 35C. The suspension was cooled to room temperature, filtered and washed with isopropyl alcohol. The crystalline product was dried in vacuo. H-NMR (500 MHz, d6-DMSO): delta = 10.32 (s, 1 H), 8.30 (bs, 0.4H), 8.24 (d, J = 8.51 Hz, 2H), 8.26 (bs, 0.6H), 8.19 (bd, J = 8.51 Hz, 3H), 7.91 (bt, J = 6.94Hz, 1 H), 7.87 (d, J = 8.51 Hz, 1 H), 7.72 (bd, J = 8.51 Hz, 3H), 7.69 (d, J = 8.51 Hz, 2H), 7.66 (d, J = 8.51 Hz, 1 H), 7.47 (d, J = 7.88Hz, 1 H), 7.46 (d, J = 8.51 Hz, 1 H), 5.50 (s, 2H), 5.41 (d, J = 14.19Hz, 1 H), 5.30 (d, J = 13.87Hz, 0.6H), 5.29 (d, J = 14.02Hz, 1 H), 5.24 (s, 0.8H), 5.08 (d, J = 5.04Hz, 1 H), 5.04 (d, J= 13.87Hz, 0.6H), 4.50 (t, J = 7.72Hz, 0.6H), 4.43 (t, J = 7.72Hz, 0.4H), 4.27 (dt, J = 9.65, 0.70Hz, 1 H), 4.22 (dd, J = 9.95, 7.39 Hz, 0.4H), 4.15 (dd, J = 10.40, 7.25Hz, 0.6H), 3.99 (m, 2H), 3.61 (m, 1 H), 3.39 (t, J = 9.30HZ, 0.4H), 3.34 (t, J = 9.30Hz, 0.6H), 3.30 (dd, J = 6.30, 2.52Hz, 1 H), 2.81 (m, 1 H), 1 .93 (m, 1 H), 1.19 (d, J = 7.25Hz, 3H), 1.16 (d, J = 6.30Hz, 3H)
  • 17
  • [ 1240894-02-3 ]
  • [ 90776-59-3 ]
  • [ 491878-07-0 ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: C15H20N4O7S2 With sulfuric acid In methanol at 60 - 65℃; for 3h; Stage #2: (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 5℃; for 10h; Preparation of Doripenem -PNB Doripenem -PNB was prepared to according to Scheme 2 .98 g of a compound represented by the formula (3) in methanol 490 After slow addition of sulfuric acid, 25 ,and the internal temperature was allowed to react for 3 hours while maintaining the 60 ~ 65°C . After completion of the reaction a sense Pressure and concentrated to remove methanol and extracted with 100 , ethyl acetate 100 water . The organic layer was collected , washed with water and 5% and washed with brine . Over anhydrous magnesium sulfate and concentrated to remove the water remaining in the organic layer under reduced pressure , The solution represented by the formula (4) in 100 g of dimethylformamide was added to the melted and , after cooling to 0 ~ 5°C and diisopropylethylamine added dropwise . At the same temperature Stand stirring over 10 hours after the reaction solution was agitated by the addition of ethyl acetate and 100ml water and delamination .Removing the remaining base was added 1N HCl in 100 ethyl acetate layer was washed with saturated salt water . It may remove the remaining water by using magnesium sulfate, and concentrated under a reduced pressure of the ethyl acetate solution . Concentrated the solution was added slowly to the toluene , and filtered after stirring for 1 hour at room temperature, represented by the formula 2 -PNB To give a 132.51 g ( 98% yield).
  • 18
  • [ 90776-59-3 ]
  • [ 161715-21-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 3.5 h / -20 °C 2: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / acetonitrile 2: hydrogen; water; palladium on activated charcoal / butan-1-ol
  • 19
  • [ 90776-59-3 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 3.5 h / -20 °C 2.1: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr 3.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 35 °C 3.2: 7 - 8 °C 4.1: sodium hydrogencarbonate / water; ethyl acetate / 2.5 h
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile 2.1: hydrogen; water; palladium on activated charcoal / butan-1-ol 3.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 25 °C / Large scale 3.2: 5 h / 45 °C / Large scale
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