WO2007009354A1 - Pyrrolidine derivative intermediates,preparation and usage thereof - Google Patents

Abstract

The present invention discloses a kind of compounds of general formula (I), in which PNZ is p-nitrobenzyl-oxycarbonyl, R is Ac or H, as well as the preparation method of the compounds and their usage as intermediate in the preparation of novel 1β-methylcarbapenem antibiotic-doripenem and the preparation method of doripenem. The pyrrolidine derivative intermediates do not have Boc-protecting group and avoid side reaction caused by acidolysis , so the present method is simple and it is convenient for purifying the product and is cost-efficient.

Description

 Pyrrolidine derivative intermediate, preparation method and use thereof

 The invention relates to a novel pyrrolidine derivative intermediate and a preparation method thereof, and belongs to the field of chemical synthesis. Background technique

 Carbapenem antibiotics have received attention due to their extensive antibacterial activity. The drugs that have been marketed include imipenem, meropenem, etc. From the formula ( Π ), doripenem is a new 1 β -methyl carbapenem antibiotic, and the 2-position side chain is aminosulfonate. Amide substituted tetrahydropyrrole ring. The structure-activity relationship study showed that the acylation or sulfonylation of the side chain amino group of doripenem was beneficial to the increase of antibacterial activity, and the inhibitory activity against Gram-positive bacteria was higher than that of meropenem, against Gram-negative bacteria. The inhibitory activity is higher than that of imipenem, and it is also effective against imipenem-resistant bacteria. It is stable to serine (3-lactamase and renal dehydropeptidase, and can be used for the treatment of severe infections in the brain, kidneys and lungs). [Chinese Journal of New Drugs 2003, Vol. 12, No. 9, 700-703].

 ( Π )

There are currently two production routes for doripenem. Route 1 is based on (lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1- Methyl-1-carbo-2-penemene-3-carboxylic acid benzhydryl ester and (2S,4S)-1-tert-butoxy-oxyl-2-(N-tert-butoxycarbonyl-N- Reaction of sulfamoylamino)methyl-4-mercaptopyrrolidine to form protected pyrrolidinyl carbapenem, followed by deprotection with Lewis acid aluminum trichloride to prepare doripenem (Organic Process Research & Development 2003, 7,846 -850; CN1032257 ), the process route is as follows:

AlCl ₃ / PhoMe

 The diphenyl phthalate intermediate used in this route has no raw material supply in China, and the cost is very high. After deprotection with Lewis acid aluminum chloride, it needs to be purified by using divinyl benzene type macroporous resin column for industrial production. The inconvenience is caused, and at the same time, the residual aluminum ions in the product are difficult to be removed, and the purification of the product is very difficult.

Another route 2, using (2S, 4S) small p-nitrobenzyloxycarbonyl-2-(N-tert-butoxycarbonyl-N-sulfamoylamino)methyl-4-acetylthiopyrrolidine with sulfuric acid In addition to tert-butoxycarbonyl and acetyl, (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-sulfamoylamino)indolyl-4-mercaptopyrrolidine is used, followed by (lR, 5R ,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1-indenyl-1-carbo-2-penem-3-carboxylic acid The benzyl ester reacts to form a protected pyrrolidinyl carbapenem, which is then subjected to hydrogen deprotection using palladium/carbon as a catalyst to prepare doripenem (Organic Process Research & Development 2003, 7, 846-850; CN1032257). as follows:

 This route uses sulfuric acid to remove tert-butoxycarbonyl and acetyl to prepare (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-sulfamoylamino)indolyl-4-hydrazinopyrrolidine. The produced carbon cations bring more side reactions, and the generated impurities are difficult to remove. If the carbon cation trapping agent is added, the production cost is increased, and the intermediate obtained by desulfurization of sulfuric acid is an oil at normal temperature, and is industrially produced. Measuring and feeding brings difficulties. Summary of the invention

 The technical proposal of the present invention is to provide a novel pyrrolidine derivative intermediate, and another technical solution of the present invention is to provide a preparation method of the intermediate and to apply the same to the preparation of 1 β-mercaptocarbapene antibiotic-multiple Niperan.

The pyrrolidine derivative intermediate provided by the invention has the structure of formula (I):

 (I)

 Wherein PNZ represents p-nitrobenzyloxycarbonyl and R is -H or a thiol protecting group. The thiol protecting group generally includes an acyl group, an aryl-substituted lower alkyl group such as a benzyl group, a phenethyl group, a triphenylsulfonyl group, a diphenylfluorenyl group and the like.

 The invention provides a method for preparing a pyrrolidine derivative intermediate of the formula (I), which comprises (2S,4S)-4-acetylthio-1-pyridyloxycarbonylpyrrolidine-2-methanol and N- The reaction of p-nitrobenzyloxycarbonylsulfonamide is carried out, and the process route is as follows:

 Specifically it includes:

 Preparation of a, N-p-nitrobenzyloxycarbonyl amide

 The p-nitrobenzyl alcohol is firstly reacted with chlorosulfonyl isocyanate to form N-p-nitrobenzyloxycarbonylaminosulfonyl chloride, and then subjected to N-acylation reaction to obtain N-p-nitrobenzyloxycarbonyl group. Sulfonamide, acidified with acid, solvent extracted and recrystallized to obtain N-p-nitrobenzyloxy sulfonamide flaky crystal;

 b. Preparation of acetylthiopyrrolidine derivatives

(2S,4S)-4-acetylthio-1- 1-p-nitrobenzyloxypyrrolidino-2-nonanol, N-p-nitrobenzyloxycarbonyl The sulfonamide and triphenylphosphine are dissolved, and diisopropyl azodicarboxylate (formed as a condensing agent with triphenylphosphine) is added dropwise under ice cooling. After the addition is completed, the reaction is continued to room temperature and the reaction is continued 30 - After 240 minutes, the reaction solution was concentrated under reduced pressure, and then dissolved in anhydrous ethanol. The precipitate was precipitated to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N- Sulfonamide aminomethyl-4-acetylthiopyrrolidine.

 (2S,4S)- 1-p-Nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indolyl-4-acetylthiopyrrolidine deacetylation to give mercaptopyrrole Alkane derivative.

 The preparation method of doripenem provided by the invention is prepared by using the above pyrrolidine derivative intermediate as a raw material, and comprises:

 a. Deacetylation of an acetylthiopyrrolidine derivative to prepare a mercaptopyrrolidine derivative;

 b. Preparation of (lR,5R,6S)-2-[(3S,5S)-1- 1-p-nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxycarbonyl) by nucleophilic substitution reaction -N-sulfamoylamino)nonylpyrrolidin-3-yl]thio-6-

[(1R)-1-hydroxyethyl]small methyl-1-carbo-2-penemene-3-carboxylic acid p-nitrobenzyl ester;

 c, (lR,5R,6S)-2- [(3S,5S) small p-nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)decylpyrrolidine- Deprotection of p-nitrobenzyl ester of 3-yl]thio-6-[(1R)oxyhydroxyethyl] benzhydryl-1-carbo-2-phenylpenicene-3-carboxylic acid.

 The method for deacetylating in the step a is: (2S, 4S) small p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indolyl-4- Acetylthiopyrrolidine is dissolved in an organic solvent such as tetrahydrofuran, and an aqueous solution of an inorganic base (sodium hydroxide, potassium hydroxide or lithium hydroxide) is added in a water bath to hydrolyze the acetyl group to obtain (2S, 4S)-1-p-nitro group. a salt of benzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)methyl-4-mercaptopyrrolidine, acidified with an acid to precipitate a solid viscous material, which is dissolved in a small amount of solvent Adding another solvent to precipitate, filtering and drying to obtain (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)hydrazine Base 4-mercaptopyrrolidine.

 The nucleophilic substitution reaction in step b is: (lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryl group having a molar ratio of 1:1-1.5 Oxy-1-inden-1-carbo-2-penem-2-carboxylic acid p-nitrobenzyl ester and (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N- p-Nitrobenzyloxycarbonyl-N-sulfamoylamino)methyl-4-mercaptopyrrolidine is dissolved in DMF (N,N-dimethylformamide), and a tertiary amine (diisopropylethylamine) is added under cooling in a water bath. Or triethylamine, etc.) for 1 to 4 hours, the reaction mixture is diluted with ethyl acetate, washed successively with hydrochloric acid, saturated sodium hydrogencarbonate and saturated brine to wash off the tertiary amine, DMF, and the resulting diphenyl phosphate, anhydrous After drying over sodium sulfate, it is concentrated to a small volume, and a precipitate is added to the solvent to precipitate, which is filtered and dried.

The method of deprotection described in step c is: (lR,5R,6S)-2-[(3S,5S)-1- 1-p-Nitrobenzyloxy 5-(N-p-nitrobenzyloxytt-N-sulfamoylamino)decylpyrrolidine-3 -yl]thio-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbo-2-penems-3-carboxylic acid p-nitrobenzyl ester dissolution, hydrogenolysis reduction (lR,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-sulfamoylaminomethylpyrrolidin-3-yl]thio- 1-Methyl-1-carbo-2-penem-3-carboxylic acid.

 The process route is as follows:

本发明提供的新型的吡咯烷衍生物中间体不含叔丁氧羰基 (Boc)保护基 团， 制备方法简单， 用于制备多尼培南， 避免了酸解所产生的副反应， 给产品 的純化带来便利。 同时由该中间体脱乙酰基所得的 (2S,4S)-1-对硝基苄氧談基 -2-(N-对硝基苄氧羰基 -N-氨磺酰氨基)曱基 -4-巯基吡咯烷是固体粉末， 这就为 工业化生产中的计量投料带来便利。

The novel pyrrolidine derivative intermediate provided by the invention does not contain a tert-butoxycarbonyl (Boc) protecting group, and the preparation method is simple, and is used for preparing doripenem, thereby avoiding side reactions caused by acid hydrolysis, and giving products Purification brings convenience. (2S,4S)-1-p-nitrobenzyloxyl group obtained by deacetylation of the intermediate 2-(N-p-Nitrobenzyloxycarbonyl-N-sulfamoylamino)nonyl-4-mercaptopyrrolidine is a solid powder, which facilitates the metering of industrial production.

 The invention is further described in detail below by way of specific examples, but should not be construed as limiting the invention. Various modifications, changes or substitutions made in accordance with the above described aspects of the invention are within the scope of the invention. DETAILED DESCRIPTION OF THE INVENTION

 [Example 1] Preparation of pyrrolizine derivative

 Step 1 Preparation of N-p-nitrobenzyloxycarbonylsulfonamide

 A solution of 38.285 g (250 mmol) of p-nitrobenzyl alcohol tetrahydrofuran was cooled to -40 ° C, and 21.75 ml (250 mmol) of chlorosulfonyl isocyanate was added dropwise thereto, and after stirring, stirring was continued for 30 minutes, and then ammonia gas was introduced. After 30 minutes, the reaction mixture was acidified with EtOAc EtOAc (EtOAc)EtOAc. White flaky crystal 55 g (yield 80%), melting point: 160-162 °C.

HRESI-MS: 298.0096 [M+Na] ⁺ , C ₈ H ₉ N ₃ 0 ₆ S.

^NMR^OOMH^DMSO-ds) δ 5.29 (s, 2H, -0-CH ₂ - Ar), 7.54 (br, 2H, -S0 ₂ NH ₂ ), 7.64 (A ₂ B ₂ ,

2H, J=8.7 Hz, -ArN0 ₂ mbit), 8.26 (A ₂ B ₂ , 2H, J=8.7 Hz, - ArN0 ₂ ortho),

11.38(br,lH,-CO-NH-S0 ₂ -);

¹³ C NMR (600MHz, DMSO-d ₆ ) δ 65.6(-0-CH ₂ -Ar), 124.1 (-Ar-N0 ₂ ortho), 128.8 (-Ar-N0 ₂ meta), 144.3 (-Ar- N0 ₂ align), 147.6 (-Ar-N0 ₂ in situ), 152.0 (C=O, PNZ -).

 Step 2 Preparation of acetylthiopyrrolidine derivatives

 35.5 g (100 mmol) of (2S,4S)-4-acetylthio-1-p-nitrobenzyloxycarbonylpyrrolidin-2-indole, 41.25 g (150 mmol) of N-p-nitrobenzyloxycarbonylsulfonamide and 34.125 g (130 mmol) of triphenylphosphine was dissolved in 1000 ml of tetrahydrofuran, and 22 ml (130 mmol) of diisopropyl azodicarboxylate was added dropwise under ice cooling. After the addition was completed, the reaction was allowed to proceed to room temperature for 120 minutes, and the reaction solution was reduced. After concentration by pressure, it was dissolved in 500 ml of absolute ethanol, and 54 g of a pale yellow amorphous solid powder was frozen and precipitated in a yield of 88%.

 HRESI-MS : 634.0901 [ M+Na ] ^C^E NsOnS^

_3⁄4 NMR (600MHz, CDC1 ₃ ) δ 1.6 (m, lH, pyrrole ring H-3 β ), 2.33 (s, 3H, AcS -), 2.59 (dt, lH, J = 14.0, 8.7 Hz, pyrrole ring H-3 a ), 3.17 (dd, lH, J = 11.9, 6, 24 Hz, pyrrole ring H-5 β ), 3.71 (dd, lH, J =14.9 Hz, -CH ₂ N(PNZ)SO _r ), 3.92 (m, lH, pyrrole ring H-4), 4.10 (dd, lH, J = 15.3, 10.2 Hz, -CH ₂ N(PNZ)SO ₂ -), 4.20 (dd, lH, J = 11.7, 7.5 Hz, pyrrole ring H-5 a ),

4.52 (m, lH, pyrrole ring H-2 a ), 5.16 (AB _q , 2H, J = 13.4 Hz, -0-CH ₂ - Ar),

5.25(br,2H,-0-CH ₂ -Ar), 5.86(br,2H,-S0 ₂ NH ₂ ),

7.47 (A ₂ B ₂ , 2H, J = 8.46 Hz, -ArN0 ₂ meta position), 7.51 (A ₂ B ₂ , 2H, J = 8.46 Hz, -ArN0 ₂ meta position), 8.21 (A ₂ B ₂ , 2H) , J = 8.52 Hz, -ArN0 ₂ ortho), 8.23 (A ₂ B ₂ , 2H, J = 8.28 Hz, - ArN0 ₂ ortho); 1 ³ C NMR (600MHz, CDC1 ₃ ) δ 30.5 (Me -, AcS-), 34.7 (pyrrole ring C-3), 39.1 (pyrrole ring C-4),

50.6 (-CH ₂ NSO ₂ -), 52.2 (pyrrole ring C-5), 56.7 (pyrrole ring C-2), 66.1 (-OCH ₂ -Ar), 67.4 (-OCH ₂ -Ar), 123.9 (-ArN0) ₂ , ortho), 124.0 (-ArNO ₂ , ortho), 128.0 (- ArN0 ₂ , meta), 128.5 (-ArN0 _2j ), 141.7 (-ArN0 ₂ , para), 143.1 (-ArN0 ₂ , align), 147.8 (-ArN0 ₂ , in situ), 148.0 (-ArNO ₂ , in situ), 152.7 (C=0, PNZ-), 155.4 (C=0, PNZ-), 194.6 (C=0 , AcS -).

[Example 2] Synthesis of (3S,5S)-pyrrolidinothiocarbapene derivatives

 Step 1 Preparation of decylpyrrolidine derivatives

 (2S,4S)-1-p-Nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indolyl-4-acetylthiopyrrolidine 50 g (81.8 m Mol) is dissolved in 200 ml of tetrahydrofuran, and a 20-liter aqueous solution of 6 g of lithium hydroxide is added dropwise in an ice bath. After the completion of the dropwise addition, stirring is continued for 120 minutes, acidified with 6 equivalents of hydrochloric acid, and a solid viscous material is precipitated, which is used in acetic acid. After the ester was dissolved, ethanol was added thereto, and 32 g of a pale yellow amorphous solid powder was frozen and precipitated, and the yield was 68.8%.

HRESI-MS: 592.0779 [M+Na] ⁺ , C ₂₁ H ₂₃ N ₅ O ₁₀ S ₂ .

1H NMR (600MHz, CDC1 ₃ ) δ

 1.52 (m, lH, pyrrole ring H-3p), 1.83 (d, lH, J = 6.12 Hz, HS-), 2.62 (m, lH, pyrrole ring

Η-3α),

3.13 (dd, lH, J = 11.64,7.68Hz, pyrrole ring Η-5β), 3.39 (ιη , 1Η, pyrrole H-4), 3.75 (d , lH, J = 153Hz, - CH 2 N (PNZ) SO ₂ -), 4.10 (dd, lH, J = 11.64, 7, 26 Hz, pyrrole ring H-5a) ₃ 4.27 (dd, lH, J = 15.3, 10.32 Hz -CH ₂ N(PNZ)SO ₂ -), 4.48 (m, lH, pyrrole ring H-2a), 5.15 (AB _q , 2H, J = 13.74 Hz, -OCH ₂ -Ar), 5.26 (AB _q , 2H, J = 13.74 Hz ₅ -OCH ₂ -Ar) ₃ 5. 84(br, 2H, -S0 ₂ N3⁄4), 7.45 (A ₂ B ₂ , 2H, J = 8.22 Hz, - ArN0 ₂ meta position), 7.51 (A ₂ B ₂ , 2H, J = 8.4 Hz, - ArN0 ₂ Interdigit), 8.21 (m, 4H, -ArN0 ₂ ortho).

1 ³ C NMR (600MHz, CDC1 ₃ ) δ

34.5 (pyrrole ring C-3), 39.4 (pyrrole ring C-4), 50.9 (-CH ₂ N(PNZ)SO ₂ - ), 55.3 (pyrrole ring C-5), 57.2 (pyrrole ring C-2), 66.1 (-OCH ₂ -Ar), 67.3 (-OCH ₂ -Ar), 123.9 and 124.0 (-ArNO ₂ , ortho), 128.0 and 128.5 (-ArN0 ₂ , meta), 141.9 and 143.2 (-ArN0 ₂ , Parant), 147.8 and 148.0 (-ArNO ₂ , in situ), - 152.8 and 155.3 (C=0, PNZ -).

 Step 2 Preparation of protected pyrrolidinyl carbapenem

(lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1-indenyl-1-carbo-2-penemene-3 - p-nitrobenzyl carboxylate (17.8 ² g, ³⁰ mmol) and ( ² S, ⁴ S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N -Aminosulfonylamino)methyl-4-mercaptopyrrolidine (22 g, 38.66 mmol) dissolved in 250 mL of DMF, EtOAc (EtOAc: EtOAc (EtOAc) After that, the reaction mixture was washed with ethyl acetate #, and then washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated to a small volume, toluene was added to precipitate solids, filtered and dried. 27 g of yellow amorphous solid powder (yield 98.5%).

HRESI-MS: 936.1787 [M+Na] ⁺ , C ₃₈ H ₃₉ N ₇ 0 ₁₆ S ₂ .

1H NMR (600MHz, CDC1 ₃ ) δ

1.26 (d, 3H, J = 7.14 Hz, C ₄ fluorenyl), 1.37 (d, 3H, J = 6.18 Hz, CH ₃ CHOH-), 1.64 (m, lH, pyrrole ring Η-3β), 2.62 ( Ign, 1 Η, pyrrole ring H-3a), 3.27 (m, 1 Η, Η-4α), 3.27 (m, 1 Η, Η-6),

3.27 (m, lH, pyrrole ring-5β), 3.73 (πι, 1Η, - C3⁄4N(PNZ)S0 ₂ -), 3.73 (m, lH, pyrrole ring H-4), 4.10 (m, lH, pyrrole ring H-5a), 4.25 (m , lH, H-5), 4.25 (m, lH, -CH (OH) CH 3), 4.25 (m, lH, ~ CH 2 N (PNZ) S0 2 -), 4.54 (m, 1H, pyrrole ring H-2a), 5.125.48 (m, 6H ₅ -OCH ₂ -Ar), 5.85 (br, 2H, -S0 ₂ NH ₂ ), 7.47 (m, 4H, -ArN0 ₂ Bit), 7.63 (A ₂ B ₂ , 2H, J = 8.7 Hz, - ArN0 ₂ meta), 8.16 (A ₂ B ₂ , 2H, J = 8.28 Hz, -ArN0 ₂ ortho), 8.20 (m, 4H) , -ArNO ₂ ortho).

¹³ C NMR (600MHz, CDC1 ₃ ) δ

16.9 (C ₄ methyl group), ² 2.0 (C3⁄4CHOH-upper methyl ^4.7 (pyrrole ring C_ ³ ), ⁴ 0.5 (pyrrole ring C-4), 44.0 (C-4), 50.7 (-CH ₂ N (PNZ)SO ₂ -), 54.0 (pyrrole ring C-5), 56.2 (C-5), 56.8 (pyrrole ring) C-2), 59.8 (C-6), 65.5 (-CH-, CH ₃ CHOH-), 66.2, 67.4, 68.4 (- OCH ₂ -Ar), 123.8, 123.9, 124.0 (-ArNO ₂ , ortho) , 125.8 (C-2), 128.3, 128.4 (-ArN0 ₂ , meta), 141.8, 142.6, 143.0 (-ArNO ₂ , para), 147.7, 147.8, 148.0 (-ArNO ₂ , in situ), 148.2 ( C-3), 152.7, 155.0 (C=O, PNZ-), 160.0 (C=O, PNB-), 172.4 (C=0, C-7).

 Step 3 Deprotection

 (lR,5R,6S)-2-[(3S,5S) small p-nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)decylpyrrolidine Thio-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbo-2-penems-3-carboxylic acid p-nitrobenzyl ester (10 g, 10.95 m Mole) was dissolved in 180 ml of tetrahydrofuran, 120 ml of water and 10 g of 10% palladium/carbon (54% water content) were added, and stirred under a hydrogen pressure of 0.5 MPa for 4 hours, the reaction mixture was filtered to remove the catalyst, and 1.4 g of hexahydrate was added. Magnesium chloride, adding 300 ml of tetrahydrofuran phase separation, separating the aqueous phase, adding three volumes of isopropanol, freezing, and drying the precipitate under reduced pressure to obtain (lR, 5S, 6S)-6-[(1R)-1-hydroxyl Ethyl]-2-[(3S,5S)-5-sulfamoylaminodecylpyrrolidin-3-yl]thio-1-indolyl-1-carbo-2-penicillin-3-carboxylate The acid white powder was 2.269 g (yield 49%). The melting point is 175 ± 2. C.

HRESI-MS: 443.1029 [M+Na] ⁺ , C ₁₅ H ₂₄ N ₄ 0 ₆ S ₂ .

3⁄4 NMR (600MHz, D ₂ O) δ: l.ll (d, J = 7.26 Hz, 3H), 1.18 (d, J = 6.48 Hz, 3H),

1.62-1.67 (m, lH), 2.60-2.65 (m, lH), 3.25-3.35 (m, 3H), 3.36 (dd, J = 2.58, 6 Hz, lH), 3.43 (dd, J = 4.77, ΙΟ. ΙΙΗζ,ΙΗ), 3.60 (dd, J=6.96, 12.48 Hz, lH), 3.8- 3.84 (m, lH), 3.92-3.96 (m _? lH), 4.12-4.16 (m, 2H). Industrial application, weisheng

 The preparation of the doxorphane of the invention uses a novel pyrrole oxime derivative intermediate, which is not a k-butoxycarbonyl (Boc) protecting group, is used for preparing doripenem, has a simple preparation method and avoids the use of sulfuric acid. Removal of tert-butoxycarbonyl and acetyl groups to prepare (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-sulfamoylamino)nonyl-4-mercaptopyrrolidine Ions bring a lot of side reaction defects; at the same time, avoid the use of very expensive benzoyl benzoate intermediates, and avoid the use of Lewis acid aluminum trichloride deprotection, to overcome the residual aluminum ions difficult to remove defect. Therefore, it is convenient to obtain more pure doripenem, which reduces the production cost of doripenem. (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indenyl group obtained by deacetylation of the intermediate provided by the present invention - Mercaptopyrrolidine is a solid powder, which facilitates the metering of materials in industrial production.

Claims

Claim  1. Pyrrolidine derivative intermediate having the structure of (I):

 (I)  Wherein PNZ represents p-nitrobenzyloxycarbonyl and R is -H or a thiol protecting group.  The pyrrolidine derivative intermediate according to claim 1, wherein the R is a thiol protecting group.  The pyrrolidine derivative intermediate according to claim 1, wherein: R is -H.  A process for producing the pyrrole oxime derivative intermediate according to claim 2, which comprises (2S,4S)-4-acetylthio-1-y-nitrobenzyloxycarbonylpyrrolidine-2-methanol and N-p-nitrobenzyloxycarbonylsulfonamide condensation reaction.  5. The preparation method according to claim 4, characterized in that it comprises:  Preparation of a, N-p-nitrobenzyloxycarbonylsulfonamide  The p-nitrobenzyl alcohol is firstly reacted with chlorosulfonyl isocyanate to form N-p-nitrobenzyloxycarbonylaminosulfonyl chloride, and then subjected to N-acylation reaction to obtain N-p-nitrobenzyloxycarbonyl group. Sulfonamide, acidified with acid, solvent extraction, recrystallization to obtain N-p-nitrobenzyloxycarbonylsulfonamide plate crystal; b, preparation of acetylthiopyrrolidine derivative  Dissolving (2S,4S)-4-acetylthio-1-y-nitrobenzyloxycarbonylpyrrolidine-2-nonanol, N-p-nitrobenzyloxycarbonylsulfonamide and triphenylphosphine, cooling in water bath, dropping Add diisopropyl azodicarboxylate or diethyl azodicarboxylate, heat to room temperature and continue to react for 30-240 minutes. Concentrate the reaction solution under reduced pressure, add anhydrous ethanol to dissolve, and freeze the precipitate to obtain (2S , 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)nonyl-4-acetylthiopyrrolidine. 6. The method of claim 3 for preparing intermediates pyrrolidine derivative as claimed in claim, characterized in that: it is composed of (2S, 4S) -1- p-nitrobenzyl oxycarbonyl - ² - (N- nitro-benzyloxycarbonyl carbonyl-N-sulfamoylamino)methyl-4- Acetylthiopyrrolidine is obtained by hydrolysis and deacetylation.  A method for preparing doripenem, which comprises the pyrrolidine derivative intermediate according to claim 2 as a raw material, and the preparation method comprises the following steps:  a. Deacetylation of an acetylthiopyrrolidine derivative to prepare a mercaptopyrrolidine derivative;  b. The mercaptopyrrolidine derivative is subjected to (lR,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1-indenyl-1-carbon Preparation of (lR,5R,6S)-2-[(3S,5S)-1-p-nitrobenzyloxycarbonyl- by nucleophilic substitution of p-nitropenten-3-carboxylic acid p-nitrobenzyl ester 5-(N-p-Nitrobenzyloxycarbonyl-N-sulfamoylsulfonylpyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-indolyl- 1- Carbon-5-penems-3-carboxylic acid p-nitrobenzyl ester;  c, (lR,5R,6S)-2-[(3S,5S)-1-p-nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)methylpyrrole Alkyl-3-yl]thio-6-[(1R)-1-hydroxyethyl] benzhydrin-1-carbo-2-penemene-3-carboxylic acid p-nitrobenzyl ester by hydrogenation reduction Deprotection is more than Niperan.  8. The preparation method according to claim 7, wherein: the step of deacetylating in step a is: (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-(N-p-nitro group) Benzyloxycarbonyl-N-sulfamoylamino)methyl-4-acetylthiopyrrolidine is dissolved in an organic solvent, hydrolyzed by adding an aqueous solution of an inorganic base, and the acetyl group is removed to obtain (2S, 4S)-1-p-nitro group. a salt of benzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)indolyl-4-mercaptopyrrolidine, acidified with an acid to precipitate a solid viscous material, dissolved and refined in an organic solvent Filtration and drying gave (2S, 4S) small p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-sulfamoylamino)methyl-4-mercaptopyrrole.  9. The preparation method according to claim 7, wherein: the nucleophilic substitution reaction in step b is: (lR, 5R, 6S)-6- [(1R) having a molar ratio of 1:1 to 1.5. 1-hydroxyethyl]-2-diphenoxyphosphoryloxy-1-mercapto-1-carbo-2-penem-2-carboxylic acid p-nitrobenzyl ester and (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2-(N-p-nitrobenzyloxycarbonyl-N-amidoamido)indolyl-4-mercaptopyrrolidine is dissolved in DMF, and a tertiary amine is added under cooling in a water bath. After 4 hours, the reaction mixture was diluted with ethyl acetate and washed with aq. EtOAc EtOAc EtOAc EtOAc. Filter and dry.  10. The preparation method according to claim 7, wherein: the step of deprotecting in step c is: (lR,5R,6S)-2-[(3S,5S)-1-p-Nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxycarbonyl-N-Ammonia Sulfonylamino)methylpyrrolidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-indenyl-1-carbo-2-penem-3-carboxylic acid The p-nitrobenzyl ester is dissolved and hydrogenolyzed to obtain (lR,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-5-aminoamidomethylmethyl Pyrrolidin-3-yl]thiol small methyl-1-carbo-2-penem-3-carboxylic acid.