CN100460389C - Pentazane derivative intermediate, its preparation and use - Google Patents
Pentazane derivative intermediate, its preparation and use Download PDFInfo
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- CN100460389C CN100460389C CNB2005100212701A CN200510021270A CN100460389C CN 100460389 C CN100460389 C CN 100460389C CN B2005100212701 A CNB2005100212701 A CN B2005100212701A CN 200510021270 A CN200510021270 A CN 200510021270A CN 100460389 C CN100460389 C CN 100460389C
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Abstract
A pentazane derivative intermediate, its production and use are disclosed. PNZ expresses p-nitrocarbobenzoxy, R represents Ac(acetyl) or-H. It is simple and has no side reaction. It can be used for donippenan.
Description
Technical field
The present invention relates to a kind of new pyrrolidin derivatives intermediate and preparation method thereof, belong to the field of chemical synthesis.
Background technology
Carbapenem antibiotic owing to its widely anti-microbial activity obtain paying attention to.This similar drug that has gone on the market has imipenum, Meropenem etc., is 1 a new beta-methylcarbapenem antibiotics by formula (II) expression S-4661, and 2 side chains are Pyrrolidine rings that SULFAMIDE replaces.Structure activity study shows; the increase that the acidylate of S-4661 side chain amino or sulfonylation help anti-microbial activity; inhibition activity to gram-positive microorganism is higher than Meropenem; inhibition activity to Gram-negative bacteria is higher than imipenum; also effective to the imipenum resistant organism; stable to Serine β-Nei Xiananmei and dehydropeptidase of kidney, can be used for the treatment [2003 the 12nd volumes of Chinese Journal of New Drugs the 9th phase 700-703] of the severe infections of brain, kidney and lung.
The production route of S-4661 has two kinds at present, route 1 is to adopt (1R, 5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid benzhydryl ester and (2S, 4S)-reaction of 1-tertbutyloxycarbonyl-2-(N-tertbutyloxycarbonyl-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine generates the pyrrolidine sulfsulopenem of protection, prepares S-4661 (Organic Process Research ﹠amp with Lewis acid aluminum chloride deprotection then; Development 2003,7,846-850; CN1032257) (shown in figure-3); the employed carboxylic acid benzhydryl ester of this route intermediate is domestic still not to have raw material supply; cost is very high; need to use divinylbenzene type macroporous resin column to carry out purifying after adopting Lewis acid aluminum chloride deprotection; make troubles to suitability for industrialized production; remaining aluminum ion is difficult to eliminate in the product simultaneously, and the difficulty of purifying products is very big.
Another kind of route 2, adopt (2S, 4S)-methyl-4-acetylthio tetramethyleneimine removes tertbutyloxycarbonyl with sulfuric acid and ethanoyl obtains (2S to nitro carbobenzoxy-(Cbz)-2-(N-tertbutyloxycarbonyl-N-sulfamoylamino group) for 1-, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-sulfamoylamino group) methyl-4-mercapto pyrrolidine, use then and (1R, 5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy reacts the pyrrolidine sulfsulopenem that generates protection, carries out the hydrogenolysis deprotection with palladium/carbon as catalyzer again and prepare S-4661 (Organic ProcessResearch ﹠amp; Development 2003,7,846-850; CN1032257) (shown in figure-4); this route uses sulfuric acid to remove tertbutyloxycarbonyl and ethanoyl preparation (2S; 4S)-carbonium ion that produces in the process of 1-to nitro carbobenzoxy-(Cbz)-2-(N-sulfamoylamino group) methyl-4-mercapto pyrrolidine brought more side reaction; the impurity that produces is difficult to remove; if add the carbonium ion trapping agent then improved production cost; and sulfuric acid deprotection gained intermediate normal temperature is down oily matter, feeds intake for the metering of suitability for industrialized production and brings difficulty.
Summary of the invention
Technical program of the present invention lies in providing a kind of novel pyrrolidin derivatives intermediate, another technical scheme of the present invention provides this intermediates preparation and is applied to prepare 1 beta-methylcarbapenem antibiotics-S-4661.
Pyrrolidin derivatives intermediate provided by the invention has the structure of formula (I):
Wherein, PNZ represents the nitro carbobenzoxy-(Cbz), R is-Ac (ethanoyl) or-H.
The structure pyrrolidin derivatives intermediate preparation method of formula provided by the invention (I), it by (2S, 4S)-4-acetylthio-1-generates nitro carbobenzoxy-(Cbz) sulfuryl amine reaction nitro benzyloxy carbonyl pyrrolidine alkane-2-methyl alcohol and N-.
Specifically it comprises (as Fig. 1):
A, N-are to the preparation of nitro carbobenzoxy-(Cbz) sulphonamide
To generate N-to nitro benzyloxycarbonyl amino SULPHURYL CHLORIDE with chloro sulfonyl isocyanate through addition reaction earlier to nitrobenzyl alcohol, feed ammonia again through the N-acylation reaction, obtain N-to nitro carbobenzoxy-(Cbz) sulphonamide, use acidifying again, solvent extraction and recrystallization obtain N-to nitro carbobenzoxy-(Cbz) sulphonamide plate crystal;
The preparation of b, acetylthio pyrrolidin derivatives
With (2S, 4S)-4-acetylthio-1-to nitro benzyloxy carbonyl pyrrolidine alkane-2-methyl alcohol, N-to nitro carbobenzoxy-(Cbz) sulphonamide and triphenylphosphine dissolved, the ice bath cooling drips diisopropyl azodiformate (forming active intermediate as condensing agent with triphenylphosphine) down, rise to room temperature after dropwising and continue reaction 30-240 minutes, to add anhydrous alcohol solution behind the reaction solution concentrating under reduced pressure, freezing separate out precipitation promptly get (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine.
(2S, 4S)-1-obtains mercaptopyrrolidine derivatives to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine deacetylation.
The preparation method of S-4661 provided by the invention is to be feedstock production by above-mentioned pyrrolidin derivatives intermediate, comprising: (as Fig. 2)
A, acetylthio pyrrolidin derivatives deacetylation prepare mercaptopyrrolidine derivatives;
B, mercaptopyrrolidine derivatives are through nucleophilic substitution reaction preparation (1R, 5R, 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy;
C, (1R; 5R; 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy deprotection is promptly.
Wherein, the method of the described deacetylation of a step is: (2S; 4S)-1-is dissolved in organic solvents such as tetrahydrofuran (THF) to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine; ice bath adds mineral alkali (sodium hydroxide down; potassium hydroxide or lithium hydroxide etc.) aqueous hydrolysis remove ethanoyl and get (2S; 4S)-1-is to the salt of nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine; use acidifying; separate out the solid dope; it is dissolved with a small amount of solvent; add another kind of solvent and make it precipitation; filter; be drying to obtain (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine.
The described nucleophilic substitution reaction reaction of b step is: be (the 1R of 1:1-1.5 with mol ratio, 5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid is to nitrobenzyl ester and (2S, 4S)-1-is dissolved in DMF (N to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine, dinethylformamide), the ice bath cooling adds tertiary amine (diisopropylethylamine or triethylamine etc.) reaction 1～4 hour down, reaction mixture dilutes with ethyl acetate, use hydrochloric acid successively, saturated sodium bicarbonate and saturated brine washing are with the flush away tertiary amine, DMF, and the phosphoric acid hexichol fat that generates, be concentrated into small volume behind the anhydrous sodium sulfate drying, add solvent and separate out precipitation, filter, be drying to obtain.
The method of the described deprotection of c step is:
With (1R, 5R, 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy dissolving, hydrogenolysis reducing get (1R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-[(3S, 5S)-5-sulfamoylamino group methylpyrrolidin-3-yl] sulfenyl-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid.
Novel pyrrolidin derivatives intermediate provided by the invention does not contain tertbutyloxycarbonyl (Boc) blocking group, and the preparation method is simple, is used to prepare S-4661, has avoided the side reaction that acidolysis produced, and offers convenience for the purifying of product.Simultaneously by this intermediate deacetylation gained (2S, 4S)-1-is a pressed powder to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine, this just is that metering in the suitability for industrialized production feeds intake and offers convenience.
Description of drawings
Fig. 1 is the preparation route of pyrrolidin derivatives intermediate of the present invention;
Fig. 2 is the route that the present invention adopts pyrrolidin derivatives intermediate preparation S-4661;
Fig. 3 is that S-4661 prepares route 1;
Fig. 4 is that S-4661 prepares route 2.
Below mode by specific embodiment the present invention is further described, be limitation of the invention but should not be construed as.The modification of all various ways of making based on such scheme of the present invention, conversion or replace and all belong to the present invention.
Embodiment
The preparation of embodiment 1 pyrrolidin derivatives
Step 1 N-is to the preparation of nitro carbobenzoxy-(Cbz) sulphonamide
38.285g (250mmol) is cooled to-40 ℃ to the nitrobenzyl alcohol tetrahydrofuran solution; to wherein dripping 21.75ml (250mmol) chloro sulfonyl isocyanate; dropwising the back continues to stir 30 minutes; feed ammonia then; 30 minutes afterreaction mixtures are with 1 equivalent hcl acidifying; with the precipitation acetic acid ethyl dissolution that generates; water and salt water washing, anhydrous sodium sulfate drying according to this; behind the concentrating under reduced pressure in ethyl acetate-hexane recrystallization; get white plates crystallization 55g (yield 80%), fusing point: 160-162 ℃.
ESI-MS：298[M+Na]
+，314[M+K]
+
1HNMR (600MHz, DMSO-d
6) δ 5.29 (s, 2H ,-O-CH
2-Ar), 7.54 (br, 2H ,-SO
2NH
2), 7.64 (A
2B
22H, J=8.7Hz ,-ArNO
2Between the position), 8.26 (A
2B
2, 2H, J=8.7Hz ,-ArNO
2The ortho position), 11.38 (br, 1H ,-CO-NH-SO
2-);
13CNMR (600MHz, DMSO-d
6) δ 65.6 (O-CH
2-Ar), 124.1 (Ar-NO
2The ortho position), 128.8 (Ar-NO
2Between the position), 144.3 (Ar-NO
2Contraposition), 147.6 (Ar-NO
2Original position), 152.0 (C=O, PNZ-).
The preparation of step 2 acetylthio pyrrolidin derivatives
With (2S, 4S)-4-acetylthio-1-restrains (130mmol) to nitro benzyloxy carbonyl pyrrolidine alkane-2-methyl alcohol 35.5 grams (100mmol), N-to nitro carbobenzoxy-(Cbz) sulphonamide 41.25 grams (150mmol) and triphenylphosphine 34.125 and is dissolved in 1000 milliliters of tetrahydrofuran (THF)s, the ice bath cooling drips 22ml (130mmol) diisopropyl azodiformate down, rise to room temperature after dropwising and continue reaction 120 minutes, 500 milliliters of anhydrous alcohol solutions will be added behind the reaction solution concentrating under reduced pressure, freezing, be settled out faint yellow amorphous solid powder 54 grams, yield 88%.
ESI-MS：610.2[M-H]
-；
1H NMR (600MHz, CDCl
3) δ 1.6 (m, 1H, pyrrole ring H-3 β), 2.33 (s, 3H, AcS-),
(2.59 dt, 1H, J=14.0,8.7Hz, pyrrole ring H-3 α), 3.17 (dd, 1H, J=11.9,6.24Hz, pyrrole ring H-5 β), 3.71 (dd, 1H, J=14.9Hz ,-CH
2N (PNZ) SO
2-), 3.92 (m, 1H, pyrrole ring H-4), 4.10 (dd, 1H, J=15.3,10.2Hz ,-CH
2N (PNZ) SO
2-), 4.20 (dd, 1H, J=11.7,7.5Hz, pyrrole ring H-5 α),
(4.52 m, 1H, pyrrole ring H-2 α), 5.16 (AB
q, 2H, J=13.4Hz ,-O-CH
2-Ar),
5.25(br，2H，-O-CH
2-Ar)，5.86(br，2H，-SO
2NH
2)，
7.47 (A
2B
2, 2H, J=8.46Hz ,-ArNO
2Between the position), 7.51 (A
2B
2, 2H, J=8.46Hz ,-ArNO
2Between the position),
8.21 (A
2B
2, 2H, J=8.52Hz ,-ArNO
2The ortho position), 8.23 (A
2B
2, 2H, J=8.28Hz ,-ArNO
2The ortho position);
13C NMR (600MHz, CDCl
3) δ 30.5 (Me-, AcS-), 34.7 (pyrrole ring C-3), 39.1 (pyrrole ring C-4),
50.6 (CH
2NSO
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 (ArNO
2, the ortho position), 124.0 (ArNO
2, the ortho position), 128.0 (ArNO
2, a position), 128.5 (ArNO
2, a position), 141.7 (ArNO
2, contraposition), 143.1 (ArNO
2, contraposition), 147.8 (ArNO
2, original position), 148.0 (ArNO
2, original position), 152.7 (C=O, PNZ-), 155.4 (C=0, PNZ-), 194.6 (C=0, AcS-).
Embodiment 2 (3S, 5S)-pyrrolidine sulfsulopenem derivative synthetic
The preparation of step 1 mercaptopyrrolidine derivatives
With (2S, 4S)-1-is dissolved in 200 milliliters of tetrahydrofuran (THF)s to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine 50 grams (81.8 mmole), ice bath drips 20 ml water solution of 6 gram lithium hydroxides down, dropwising the back continues to stir 120 minutes, with 6 equivalent hcl acidifyings, separate out the solid dope, it is added ethanol after with acetic acid ethyl dissolution again, freezing, be settled out faint yellow amorphous solid powder 32 grams, yield 68.8%.
ESI-MS：592.1[M+Na]，608.1[M+K]
+
13C NMR (600MHz, CD
3COCD
3) δ 34.3 (pyrrole ring C-3), 39.0 (pyrrole ring C-4),
50.2 (CH
2NSO
2-), 55.3 (pyrrole ring C-5), 57.1 (pyrrole ring C-2), 65.4 (OCH
2-Ar), 66.8 (OCH
2-Ar), 123.5 (ArNO
2, the ortho position), 128.2 (ArNO
2, a position), 128.4 (ArNO
2, a position), 143.5 (ArNO
2, contraposition), 144.6 (ArNO
2, contraposition), 147.6 (ArNO
2, original position), 147.7 (ArNO
2, original position), 152.9 (C=0, PNZ-), 154.9 (C=0, PNZ-).
The preparation of the pyrrolidine sulfsulopenem of step 2 protection
With (1R, 5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-(17.82 restrain 2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid to the nitrobenzyl ester, 30 mmoles) and (2S, 4S)-(22 restrain 1-to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine, 38.66 mmole) be dissolved in 250 milliliters of DMF, the ice bath cooling adds (7.23 milliliters of diisopropylethylamine down, 42.5 mmole), after 120 minutes, reaction mixture dilutes with ethyl acetate, use 1 equivalent hydrochloric acid according to this, saturated sodium bicarbonate and saturated common salt water washing, be concentrated into small volume behind the anhydrous sodium sulfate drying, add toluene and be settled out solid, filter, dry that faint yellow amorphous solid powder 27 restrains (yield 98.5%).
ESI-MS：911.9[M-H]
-，
13C?NMR(600MHz，CD
3COCD
3)δ?16.6，22.3，34.1，40.2，43.6，50.1，54.3，56.1，56.8，60.2，64.8，65.2，65.3，66.8，67.7，123.4，123.5，125.0，128.2，128.3，128.4，143.4，143.9，144.5，147.6，147.7，149.6，152.9，154.9，160.1，173.4。
Step 3 deprotection
With (1R, 5R, 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy (10 grams, 10.95 mmole) be dissolved in 180 milliliters of tetrahydrofuran (THF)s, add 120 ml waters and 10 gram 10% palladium/carbon (water content 54%), after stirring 4 hours under the 0.5MPa hydrogen-pressure, reaction mixture removes by filter catalyzer, add 1.4 gram magnesium chloride hexahydrates, add 300 milliliters of tetrahydrofuran (THF) phase-splittings again, add the long-pending Virahol of triploid after telling water, freezing, precipitate dried under reduced pressure is got (1R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-[(3S, 5S)-5-sulfamoylamino group methylpyrrolidin-3-yl] the white powder 2.269g (yield 49%) of sulfenyl-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid.
ESI-MS：421.1[M+H]
+；
1H?NMR(600MHz，D
2O)δ：1.11(d，J＝7.26Hz，3H)，1.18(d，J＝6.48Hz，3H)，1.62-1.67(m，1H)，2.60-2.65(m，1H)，3.25-3.35(m，3H)，3.36(dd，J＝2.58，6Hz，1H)，3.43(dd，J＝4.77，10.11Hz，1H)，3.60(dd，J＝6.96，12.48Hz，1H)，3.8-3.84(m，1H)，3.92-3.96(m，1H)，4.12-4.16(m，2H)。
In a word, the present invention prepares many Buddhist nuns and joins south and used novel pyrrolidin derivatives intermediate, this intermediate does not contain tertbutyloxycarbonyl (Boc) blocking group, be used to prepare S-4661, the preparation method is simple, avoided use sulfuric acid remove the preparation of tertbutyloxycarbonyl and ethanoyl (2S, 4S)-carbonium ion that produces in the process of 1-to nitro carbobenzoxy-(Cbz)-2-(N-sulfamoylamino group) methyl-4-mercapto pyrrolidine brought the defective of more side reaction; Simultaneously, avoid the very high carboxylic acid benzhydryl ester intermediate of use cost, and avoid adopting Lewis acid aluminum chloride deprotection, overcome the defective that remaining aluminum ion is difficult to eliminate.While is by (the 2S of intermediate deacetylation gained provided by the invention; 4S)-and 1-is a pressed powder to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine, this just offers convenience for the metering in the suitability for industrialized production feeds intake.
Claims (10)
1. the pyrrolidin derivatives intermediate that has (I) structure:
Wherein, PNZ represents the nitro carbobenzoxy-(Cbz), R is-Ac or-H.
2. pyrrolidin derivatives intermediate according to claim 1 is characterized in that: described R is-Ac.
3. pyrrolidin derivatives intermediate according to claim 1 is characterized in that: described R is-H.
4. the method for preparing the described pyrrolidin derivatives intermediate of claim 2, it is characterized in that it by (2S, 4S)-4
-acetylthio-1-generates the condensation reaction of nitro carbobenzoxy-(Cbz) sulphonamide nitro benzyloxy carbonyl pyrrolidine alkane-2-methyl alcohol and N-.
5. preparation method according to claim 4 is characterized in that it comprises:
A, N-are to the preparation of nitro carbobenzoxy-(Cbz) sulphonamide
To generate N-to nitro benzyloxycarbonyl amino SULPHURYL CHLORIDE with chloro sulfonyl isocyanate through addition reaction earlier to nitrobenzyl alcohol, feed ammonia again through the N-acylation reaction, obtain N-to nitro carbobenzoxy-(Cbz) sulphonamide, use acidifying again, solvent extraction, recrystallization obtain N-to nitro carbobenzoxy-(Cbz) sulphonamide plate crystal;
B, (2S, 4S)-1-is to the preparation of nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine
With (2S, 4S)-4-acetylthio-1-to nitro benzyloxy carbonyl pyrrolidine alkane-2-methyl alcohol, N-to nitro carbobenzoxy-(Cbz) sulphonamide and triphenylphosphine dissolved, the ice bath cooling, drip diisopropyl azodiformate or diethyl azodiformate, be warming up to room temperature and continue reaction 30-240 minutes, to add anhydrous alcohol solution behind the reaction solution concentrating under reduced pressure, freezing separate out precipitation promptly get (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine.
6. the method for preparing the described pyrrolidin derivatives intermediate of claim 3; it is characterized in that: it be by (2S, 4S)-1-obtains through the hydrolysis deacetylation nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine.
7. the preparation method of a S-4661, it is characterized in that: it is a raw material by the described pyrrolidin derivatives intermediate of claim 2, and the preparation method comprises:
A, (2S, 4S)-1-to the preparation of nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine deacetylation (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine;
B, mercaptopyrrolidine derivatives process and (1R, 5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid carries out nucleophilic substitution reaction preparation (1R to the nitrobenzyl ester, 5R, 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy;
C, (1R; 5R; 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy promptly gets S-4661 through the hydrogenating reduction deprotection.
8. preparation method according to claim 7; it is characterized in that: the method for the described deacetylation of a step is: (2S; 4S)-1-is dissolved in organic solvent to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-acetylthio tetramethyleneimine; the aqueous hydrolysis that adds mineral alkali; remove ethanoyl react (2S; 4S)-1-is to the salt of nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine; use acidifying; separate out the solid dope; organic solvent dissolution; refining; filter; be drying to obtain (2S, 4S)-1-is to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine.
9. preparation method according to claim 7, it is characterized in that: the described nucleophilic substitution reaction of b step is: with mol ratio is 1:1～1.5 (1R, 5R, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-hexichol oxygen phosphinylidyne Oxy-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid is to nitrobenzyl ester and (2S, 4S)-1-is dissolved in DMF to nitro carbobenzoxy-(Cbz)-2-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methyl-4-mercapto pyrrolidine, the ice bath cooling added reactive tertiary amine 1～4 hour down, reaction mixture dilutes with ethyl acetate, use hydrochloric acid successively, saturated sodium bicarbonate and saturated brine washing are with the flush away tertiary amine, DMF, and the phosphoric acid hexichol fat that generates, with concentrating behind the anhydrous sodium sulfate drying, refining, filter, be drying to obtain.
10. preparation method according to claim 7 is characterized in that: the method for the described deprotection of c step is:
With (1R, 5R, 6S)-2-[(3S, 5S)-1-is to nitro carbobenzoxy-(Cbz)-5-(N-is to nitro carbobenzoxy-(Cbz)-N-sulfamoylamino group) methylpyrrolidin-3-yl] sulfenyl-6-[(1R)-the 1-hydroxyethyl]-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxy acid mutual-nitro carbobenzoxy dissolving, hydrogenolysis reducing gets (1R, 5S, 6S)-6-[(1R)-the 1-hydroxyethyl]-2-[(3S, 5S)-5-sulfamoylamino group methylpyrrolidin-3-yl] sulfenyl-1-methyl isophthalic acid-carbon generation-2-penem-3-carboxylic acid.
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| CN102093278B (en) * | 2011-03-09 | 2012-10-03 | 北京莱瑞森医药科技有限公司 | Preparation process for intermediate of doripenem |
| CN102174047A (en) * | 2011-03-19 | 2011-09-07 | 湖南欧亚生物有限公司 | Novel process for preparing doripenem |
| CN102731505B (en) * | 2011-04-13 | 2015-09-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of preparation method of S-4661 |
| CN102249970A (en) * | 2011-05-09 | 2011-11-23 | 黄山市歙县宏辉化工有限公司 | Process for synthesizing doripenem lateral chain |
| CN102372714B (en) * | 2011-12-07 | 2014-04-16 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing doripenem |
| KR101910048B1 (en) * | 2014-04-28 | 2018-10-22 | 제이더블유중외제약 주식회사 | Novel crystal of doripenem, and preparation method therefor |
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| CN1113233A (en) * | 1991-08-20 | 1995-12-13 | 盐野义制药株式会社 | A method for producing a pyrrolidire derivative |
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