CN104130262A - Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains - Google Patents
Ertapenem and ertapenem side chain, as well as preparation methods of ertapenem and ertapenem side chains Download PDFInfo
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- CN104130262A CN104130262A CN201410394494.6A CN201410394494A CN104130262A CN 104130262 A CN104130262 A CN 104130262A CN 201410394494 A CN201410394494 A CN 201410394494A CN 104130262 A CN104130262 A CN 104130262A
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- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
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- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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Abstract
The invention discloses ertapenem and ertapenem side chains, as well as preparation methods of ertapenem and ertapenem side chains. L-hydroxyproline is protected by p-nitrobenzyl ester to obtain (2S,4R)-4-hydroxyl-1-(((4-Nitrobenzformyl)-oxyl)caboyl)pyrrolidine-2-carboxylic acid; then 4-nitro(1S,4S)-3-oxo-2-thia-5-azabicyclo[2.2.1]heptan-5-carboxylic anhydride can be obtained, and reacts with m-aminobenzoic acid p-nitrobenzyl ester to obtain ertapenem side chain III; and the ertapenem can be synthesized through two-step chemical reaction of condensation and deprotection to the ertapenem side chain III and a raw material MAP. An ertapenem side chain I (10), an ertapenem side chain II (13) and the ertapenem side chain III (2) which are prevailing in the market can be synthesized through simple steps, without the need of ultralow temperature, industrialization is easy, and the product purity is high, and the operation is simple and convenient.
Description
Technical field
The present invention relates to microbiotic preparing technical field, particularly a kind of ertapenem, ertapenem side chain and preparation method thereof.
Background technology
In prior art, ertapenem preparation method is as follows:
US2011/288289, US2009/312539, WO2013/121279, US2011/288289, Journal of Organic Chemistry; Vol.70; Nb.19; (2005); P.7479 report synthetic route one:
Journal of Organic Chemistry; Vol.70; Nb.19; (2005); P.7479 report following synthetic route two:
US2009/312539, WO2013/121279 report following synthetic route three:
WO2013/121279, US2010/4463, EP2388261 report following synthetic route four:
WO2013/150550 reports following synthetic route five:
US5478820 reports following synthetic route six:
EP2388261 reports following synthetic route seven:
EP 0579826; JP 1994506704; US 5478820; US 5652233; US 5856321; WO 9315078, parent nucleus and the synthetic ertapenem synthetic route eight of side chain of allyl group protection for report:
There are a lot of enterprises to generate the parent nucleus MAP to nitrobenzyl protection due to domestic, therefore, with the synthetic ertapenem of this parent nucleus, close raw material and be easy to get; Cheap.In order to make parent nucleus and side chain deprotection base under identical conditions, so side chain and parent nucleus use identical protecting group, the side chain that ertapenem uses mainly contains following three kinds:
Ertapenem side chain I (10)
Ertapenem side chain II and hydrochloride thereof (13)
Ertapenem side chain III (2)
As shown in above-mentioned ertapenem synthetic route, the method of the domestic report of ertapenem side chain III (2) is by compound 6 warps, p-Nitrobenzyl to be protected, amidation, methylsulfonyl, thioacetyl, hydrolysis five step reactions can obtain side chain III (2); Further hydrolysis can obtain ertapenem side chain I (10); ertapenem side chain I (10) is removed protecting group can obtain ertapenem side chain II (13); because hydrolysis reaction is restive; except complete hydrolysis intermediateness is very rambunctious, the ertapenem side chain III (2) once obtaining and ertapenem side chain I (10) are all often mixtures.Thereby the quality that improves side chain itself is difficult to.Need to purify by the method for recrystallization or column chromatography repeatedly.Complex operation, yield is low, and raw materials cost cost of labor is all higher.
Summary of the invention
Technical problem to be solved by this invention is that a kind of comparatively succinct ertapenem, ertapenem side chain and preparation method thereof are provided.
The technical solution used in the present invention is: a kind of preparation method of ertapenem, L-oxyproline process is protected to obtain to (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) to p-Nitrobenzyl;
Described (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is condensed into active ester (2S with isopropyl chlorocarbonate, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), continue methylsulfonic acid esterification and obtain (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then react with sodium sulphite and obtain (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3),
Described 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain III (2) with gavaculine to p-Nitrobenzyl ring-opening reaction;
Described 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) reacts with gavaculine and obtains ertapenem side chain I (10);
Described ertapenem side chain III (2) and ertapenem side chain I (10), through sloughing protecting group, obtain ertapenem side chain II (13);
Described ertapenem side chain III (2) and raw material MAP are through condensation and the synthetic ertapenem of deprotection two step chemical reactions.
Further, L-oxyproline, in aqueous sodium hydroxide solution, dissolve, cool to-5～5 DEG C, react washed with dichloromethane with nitrobenzyl chloroformate ester dichloromethane solution, it is 2 that water sulfuric acid regulates pH value, filter, be dried to obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5);
(2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is through isopropyl chlorocarbonate, at triethylamine, in methylene dichloride, reaction generates (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), then react at triethylamine with Methanesulfonyl chloride, in methylene dichloride, (sec.-propyl carbonic acid) (2S is produced in reaction, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), add again sodium sulphite reaction to produce (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization generates 4-nitro (1S again, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3),
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain III (2) with gavaculine to p-Nitrobenzyl ring-opening reaction;
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain I (10) with gavaculine ring-opening reaction;
Ertapenem side chain III (2) and ertapenem side chain I (10) are sloughed protecting group through catalytic hydrogenation, obtain ertapenem side chain II (13);
Described ertapenem side chain III (2) and raw material MAP are through condensation and the synthetic ertapenem of deprotection two step chemical reactions, and it specifically comprises the steps:
Raw material MAP and described ertapenem side chain III (2) condensation in acetonitrile under nitrogen protection, add a small amount of tri-n-butyl phosphine, at-5～5 DEG C of reaction 3-8 hour, HPLC detects raw material MAP and is less than 1%, then concentrated solution, crystallizes out and obtains protecting ertapenem;
Protection ertapenem is dissolved in water, tetrahydrofuran (THF) or water, tetrahydrofuran (THF), ethyl acetate; make catalyzer with 5% palladium carbon; under 1.0～2.5 MPa hydrogen pressures, react; temperature 25-40 DEG C, reaction is finished, and separates ethyl acetate; then regulate pH value with sodium hydroxide; ethyl acetate cleaning product reaction solution, water adds ethanol, acetone or Virahol at low temperatures, separates out ertapenem.
The preparation method of described ertapenem, specifically can comprise the steps:
Step 1: (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) synthetic:
L-oxyproline is starting raw material, and in aqueous sodium hydroxide solution, 0-5 DEG C drips nitrobenzyl chloroformate ester, time for adding approximately 2 hours; In this thermotonus 3 hours, detection reaction is complete, isolate methylene dichloride, with washed with dichloromethane once, it is 2 that water drips vitriol oil adjusting pH value, cools to 0-5 DEG C, filters, obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5);
Step 2: 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is synthetic:
(2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid under nitrogen protection in dichloromethane solution, add triethylamine, drip isopropyl chlorocarbonate, temperature is at-15 DEG C, form mixed acid anhydride (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), then add triethylamine, at-15 DEG C, drip Methanesulfonyl chloride, synthetic compound (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then add triethylamine and sodium sulfide solution, synthetic compound (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), compound (4c) again cyclization becomes 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3), synthetic 4-nitro (1S, the pilot process of 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is without separation,
Step 3: ertapenem side chain III (2) synthetic:
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) under nitrogen protection in dichloromethane solution, add 3-benzaminic acid to p-Nitrobenzyl stirring at room temperature reaction about 7 hours, solvent distillation obtains ertapenem side chain III (2);
Synthesizing of ertapenem side chain I (10):
4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is under nitrogen protection; add glacial acetic acid, gavaculine (normal temperature), solution colour is become slightly clearly finally and is become muddiness from muddiness, and stirring is spent the night.Next day, suction filtration, dry, obtains white solid ertapenem side chain I (10);
Synthesizing of ertapenem side chain II (13):
Ertapenem side chain I (10) or ertapenem side chain III (2) are made solvent at tetrahydrofuran (THF), and 5% palladium carbon makees catalyzer, and under 1-2 MPa hydrogen pressure, hydrogenation catalysis is sloughed protecting group and obtained ertapenem side chain II (13);
Step 4: protect the synthetic of ertapenem:
Under nitrogen protection, raw material MAP and ertapenem side chain III (2), in acetonitrile, add a small amount of DMF,
Under diisopropyl ethyl amine exists, at-18～5 DEG C of reaction 3-8 hour, HPLC detects raw material MAP and is less than 1%, and then concentrated solution, crystallizes out, and obtains protecting ertapenem (1);
Step 5: ertapenem synthetic:
Above-mentioned protection ertapenem is dissolved in water, tetrahydrofuran (THF) or water, tetrahydrofuran (THF), ethyl acetate, is added in 5% palladium carbon and makees catalyzer, under weak basic condition, the alkali adding has: 2,6-lutidine, sodium-acetate and composition thereof; React at 1.0-2.5 MPa hydrogen pressure, temperature 25-40 DEG C, reaction is finished, separate ethyl acetate, then regulate pH value 7.2～7.5 with sodium hydroxide, ethyl acetate cleaning product reaction solution, point removes ester layer, and water adds ethanol, acetone or Virahol to separate out product at low temperature-15～0 DEG C is ertapenem.
4, the preparation method of ertapenem according to claim 3, it is characterized in that, synthetic three kinds of side chains of ertapenem: ertapenem side chain I, ertapenem side chain II, ertapenem side chain III, and with ertapenem side chain III and raw material MAP, through the synthetic ertapenem of two-step reaction, then ertapenem is further purified and obtains medicinal ertapenem.
Described (2S, the synthetic method of 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is: 20L reactor adds water 12kg, sodium hydroxide 1kg, stirring and dissolving, cool to 25～30 DEG C, add L-oxyproline 1.5kg, stir molten clear, cool to 0～5 DEG C, control 0～5 DEG C of temperature and start to drip nitrobenzyl chloroformate ester 2.7kg and methylene dichloride 3kg solution; Time for adding approximately 2 hours, dropwises, and keeps 0～5 DEG C of left and right stirring reaction 3 hours; Detection reaction is complete; Divide and go methylene dichloride phase, water 3kg washed with dichloromethane, separate water, control only 15 degree of temperature, it is 2 that the vitriol oil is adjusted pH value, cools to 0 DEG C of filtration, washing, be dried to obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) 31.95kg;
Described 4-nitro (1S, the synthetic method of 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is: under nitrogen protection, (2S, 4R)-4-hydroxyl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) 31.3g is dissolved in 300mL methylene dichloride, add triethylamine 12.1g, stirring and dissolving is cooled to-15 DEG C, drip isopropyl chlorocarbonate 13.5g, stirring reaction 30 minutes at this temperature; Add triethylamine 16.2g, at this temperature, drip Methanesulfonyl chloride 16g, at this temperature, stir 30 minutes; Add triethylamine 25.3g, add 10.2g sodium sulphite water 100mL solution; 5-10 DEG C of reaction 1 hour; React complete, 1N hydrochloric acid 300mL washs once, and saturated brine 300mL washs once, and water merges 200mL dichloromethane extraction once; Merge anhydrous sodium sulfate drying, filter, filtrate condensing crystal obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) 20.2g.
A kind of ertapenem, described ertapenem obtains ertapenem side chain III by L-oxyproline through serial reaction; Again by synthetic through condensation and deprotection two step chemical reactions to ertapenem side chain III and raw material MAP; Its molecular structural formula is:
A preparation method for ertapenem side chain, described ertapenem side chain is ertapenem side chain I, ertapenem side chain II or ertapenem side chain III;
The preparation method of the preparation method of described ertapenem side chain III, the preparation method of ertapenem side chain I, ertapenem side chain II is respectively:
The preparation method of ertapenem side chain III is as follows:
L-oxyproline process is protected to obtain to (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) to p-Nitrobenzyl;
Described (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is condensed into active ester (2S with isopropyl chlorocarbonate, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), continue methylsulfonic acid esterification and obtain (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then react with sodium sulphite and obtain (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3),
Described 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain III (2) with gavaculine to p-Nitrobenzyl ring-opening reaction;
The preparation method of ertapenem side chain I is as follows:
Above-mentioned 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is reacted with para-amino benzoic acid and obtains ertapenem side chain I;
The preparation method of ertapenem side chain II is as follows:
Above-mentioned ertapenem side chain I or ertapenem side chain III are removed to blocking group, obtain ertapenem side chain II.
Further, 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride, under nitrogen protection, adds glacial acetic acid, gavaculine, and solution colour is become slightly clearly finally and become muddiness from muddiness, and stirring is spent the night; Next day, suction filtration, dry, obtains white solid ertapenem side chain I;
By ertapenem side chain I or ertapenem side chain III, make solvent with tetrahydrofuran (THF), 5% palladium carbon makees catalyzer, and hydrogenation catalysis is sloughed protecting group and is obtained ertapenem side chain II.
The synthetic method of described ertapenem side chain I is: under nitrogen protection, 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride adds 700mL glacial acetic acid, 50g gavaculine, solution colour is become slightly clearly finally and is become muddiness from muddiness, and stirring is spent the night; Next day, suction filtration, dry, obtains white solid (10) 80g;
The synthetic method of described ertapenem side chain III is: under nitrogen protection; 4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride 20g; be dissolved in methylene dichloride 140mL; add 3-benzaminic acid to p-Nitrobenzyl 19.5g; stirring at room temperature reaction 7 hours, distills dry solvent and obtains ertapenem side chain III.
The synthetic method of described ertapenem side chain II be in following two kinds any:
The first: ertapenem side chain I 10g adds tetrahydrofuran (THF) 200mL to dissolve, and 5% palladium carbon 2g, at 30～40 DEG C, 1.0MPa is hydrogenated to without inhaling hydrogen, cross filtration catalizer, add ethanol solution of hydrogen chloride, concentrated ertapenem side chain II (13) 6.0g that obtains;
The second: ertapenem side chain III 10g adds tetrahydrofuran (THF) 200mL to dissolve, and 5% palladium carbon 2g, at 30～40 DEG C, 1.0MPa is hydrogenated to without inhaling hydrogen, cross filtration catalizer, ethanol solution of hydrogen chloride stirs, concentrated ertapenem side chain II (13) 5.4g that obtains.
A kind of ertapenem side chain, described ertapenem side chain is ertapenem side chain I, ertapenem side chain II or ertapenem side chain III;
The molecular structural formula of described ertapenem side chain I is:
The molecular structural formula of described ertapenem side chain II is:
The molecular structural formula of described ertapenem side chain III is:
The invention has the advantages that, can be through the ertapenem side chain I (10) of main flow on the synthetic market of comparatively succinct step, ertapenem side chain II (13) and ertapenem side chain III (2), design a kind of method of new synthetic ertapenem side chain III (2) simultaneously, pass through nitro benzyloxy carbonyl-protection with L-oxyproline, four one pot of step go out to synthesize thiolactone 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3), obtaining ertapenem side chain III (2) with the amino methyl p-nitrobenzoate open loop of 3-.
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) can obtain ertapenem side chain I (10) with the direct open loop of the amino p-nitrobenzoic acid of 3-.
Ertapenem side chain III (2) or ertapenem side chain I (10) all can obtain side chain ertapenem side chain II (13) by deprotection.For above three kinds of ertapenem side chains all provide good solution.
Ertapenem side chain III (2) is protected in ertapenem process synthetic, without very low temperature, and easily industrialization, and also product purity is high.Easy and simple to handle.
(the 2S that the present invention is designed; the synthetic route of 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2) (that is: ertapenem side chain III, same in full) unlike the prior art.
The 3-((2S that the present invention is designed, 4S)-4-sulfydryl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (10) (that is: ertapenem side chain I, in full with) synthetic route unlike the prior art.
The 3-((2S that the present invention is designed; 4S)-4-sulfydryl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (13) (that is: ertapenem side chain II, in full with) synthetic route unlike the prior art.
The condition that the synthetic protection of the present invention ertapenem uses is unlike the prior art, easy and simple to handle, reaction conditions gentleness, and product purity is high.
Deprotection of the present invention synthesizes ertapenem crude product, and condition is different from prior art, can obtain crude product by direct crystallization.
Embodiment
The present invention has developed a kind of novel process of new synthetic ertapenem side chain III, ertapenem side chain II and ertapenem side chain I.And by the synthetic protection of ertapenem side chain III ertapenem; Then the synthetic ertapenem of deprotection.Also attempted the synthetic protection of ertapenem side chain I and ertapenem side chain II ertapenem, but the contained active group of these two kinds of side chains is more, needs at lower temperature, the longer time just can obtain reasonable condensation effect.And the purity of product and yield do not have the ertapenem side chain III of all protections high.The present invention synthesizes ertapenem with ertapenem side chain III (2) and MAP through condensation and deprotection two step chemical reactions.
L-oxyproline (6) is through protecting to obtain (2S to p-Nitrobenzyl, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5), then be condensed into active ester (2S with isopropyl chlorocarbonate, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), without processing out product, continue methylsulfonic acid esterification and obtain (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), without processing out product, then react with sodium sulphite and obtain (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3), with gavaculine, p-Nitrobenzyl is reacted and obtains ertapenem side chain III (2), 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) reacts with para-amino benzoic acid and obtains ertapenem side chain I (10), and ertapenem side chain III (2) or ertapenem side chain I (10) are removed blocking group can obtain ertapenem side chain II (13).
Synthesizing of protection ertapenem:
Under nitrogen protection, MAP and ertapenem side chain III (2) condensation in acetonitrile, add a small amount of tri-n-butyl phosphine, and at-5～5 DEG C of reaction 3-8 hour, HPLC detects raw material MAP and is less than 1%, and then concentrated solution, crystallizes out.Product purity is 99～99.7%.
Advantage: because side chain has protection, reaction is carried out very fast temperature and is controlled at 0～5 DEG C, can high yield obtain product.Reaction times shortens a lot.Without-30 DEG C of low-temp reactions.Reaction yield is high, and product purity is high.Operation is easy.
Synthesizing of ertapenem:
Protection ertapenem is dissolved in water, tetrahydrofuran (THF) or water, tetrahydrofuran (THF), ethyl acetate, make catalyzer at 5% palladium carbon, in 1.0～2.5 MPa hydrogen pressure reactions, temperature 25-40 DEG C, reaction is finished, and separates ethyl acetate, then regulates pH value with sodium hydroxide, ethyl acetate cleaning product reaction solution, water adds ethanol at low temperatures; Acetone or Virahol are separated out product, yield 81%.Be further purified and can obtain pharmaceutical grade ertapenem.
The synthetic route of ertapenem is as follows:
The present invention can synthesize ertapenem side chain I (10), ertapenem side chain II (13), ertapenem side chain III (2); And with ertapenem side chain III (2) and MAP process condensation and the synthetic ertapenem of deprotection two step chemical reactions.
Synthesizing of (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5):
L-oxyproline (6) is starting raw material, and in aqueous sodium hydroxide solution, 0-5 DEG C drips nitrobenzyl chloroformate ester, time for adding approximately 2 hours.In this thermotonus 3 hours; detection reaction is complete; isolate methylene dichloride; with washed with dichloromethane once; it is 2 that water drips vitriol oil adjusting pH value, cools to 0-5 DEG C, filters; obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5).Advantage: condition is comparatively gentle, and washed with dichloromethane can be removed the impurity in reaction system, improves the purity of product.
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is synthetic:
(2S, under 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) nitrogen protection in dichloromethane solution, add triethylamine, drip isopropyl chlorocarbonate, temperature is at-15 DEG C, form mixed acid anhydride (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), then add triethylamine, at-15 DEG C, drip Methanesulfonyl chloride, synthetic (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then add triethylamine and sodium sulfide solution, synthetic (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c) again cyclization becomes 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3), the pilot process of synthetic (3) is without separation.Advantage: because active intermediate in reaction is not processed direct utilization and saved the treatment time, reduced conversion unit, reduced sepn process in the middle of material.Thereby improve efficiency.
Synthesizing of (2S, 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2):
4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) under nitrogen protection in dichloromethane solution; add 3-benzaminic acid to p-Nitrobenzyl stirring at room temperature reaction about 7 hours; solvent distillation obtains (2S, 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2).Advantage: mild condition, the side reaction of having gone up blocking group is less.
Synthesizing of 3-((2S, 4S)-4-sulfydryl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (10):
4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is under nitrogen protection; add glacial acetic acid, gavaculine (normal temperature), solution colour is become slightly clearly finally and is become muddiness from muddiness, and stirring is spent the night.Next day, suction filtration, dry, obtains white solid 3-((2S, 4S)-4-sulfydryl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (10).
Synthesizing of 3-((2S, 4S)-4-sulfydryl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (13):
3-((2S, 4S)-4-sulfydryl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (10) or (2S, 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2) can be made solvent at tetrahydrofuran (THF), 5% palladium carbon makees catalyzer, hydrogenation catalysis is sloughed protecting group and is obtained 3-((2S, 4S)-4-sulfydryl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (13).
Synthesizing of protection ertapenem (1):
Under nitrogen protection, MAP and ertapenem side chain III (2), in acetonitrile, add a small amount of DMF, and under diisopropyl ethyl amine exists, at-18～5 DEG C of reaction 3-8 hour, HPLC detects raw material MAP and is less than 1%, and then concentrated solution, crystallizes out.Product purity is at 99～99.7%.
Advantage: because side chain has protection, reaction is carried out very fast temperature and is controlled at-18～5 DEG C, can high yield obtain product.Reaction times shortens a lot.Without-30 DEG C of low-temp reactions.Reaction yield is high, and product purity is high.Operation is easy.
Synthesizing of ertapenem (12):
Protection ertapenem is dissolved in water, tetrahydrofuran (THF) or water, tetrahydrofuran (THF), ethyl acetate, is added in 5% palladium carbon and makees catalyzer, and under weak basic condition, the alkali that can add has: 2,6-lutidine, sodium-acetate and composition thereof.In 1.0-2.5 MPa hydrogen pressure reaction, temperature 25-40 DEG C, reaction is finished, and separates ethyl acetate, then regulates pH value 7.2～7.5 with sodium hydroxide, and ethyl acetate cleaning product reaction solution point removes ester layer, and water adds ethanol at low temperature-15～0 DEG C; Acetone or Virahol are separated out product, yield 81%.Be further purified and can obtain pharmaceutical grade ertapenem.Advantage: ethyl acetate can change solvent property and increase material solubleness, and washing can be removed the impurity such as other by products.
Embodiment 1:
Synthesizing of (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5):
20L reactor adds water 12kg, sodium hydroxide 1kg, stirring and dissolving, cool to 25～30 DEG C, add L-oxyproline 1.5kg, stir molten clear, cool to 0～5 DEG C, control 0～5 DEG C of temperature and start to drip nitrobenzyl chloroformate ester 2.7kg and methylene dichloride 3kg solution.Time for adding approximately 2 hours, dropwises, and keeps 0～5 DEG C of left and right stirring reaction 3 hours.Detection reaction is complete.Divide and go methylene dichloride phase; water 3kg washed with dichloromethane; separate water; control only 15 degree of temperature; it is 2 that the vitriol oil is adjusted pH value, cools to 0 DEG C of filtration, washing; be dried to obtain product (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) 31.95kg.mp:132～134℃。
Embodiment 2:
Synthesizing of 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3):
Under nitrogen protection; (2S; 4R)-4-hydroxyl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) 31.3g is dissolved in 300mL methylene dichloride; add triethylamine 12.1g; stirring and dissolving is cooled to-15 DEG C; drip isopropyl chlorocarbonate 13.5g, stirring reaction 30 minutes at this temperature.Add triethylamine 16.2g, at this temperature, drip Methanesulfonyl chloride 16g, at this temperature, stir 30 minutes.Add triethylamine 25.3g, add 10.2g sodium sulphite water 100mL solution.5-10 DEG C of reaction 1 hour.React complete, 1N hydrochloric acid 300mL washs once, and saturated brine 300mL washs once, and water merges 200mL dichloromethane extraction once.Merge anhydrous sodium sulfate drying, filter, filtrate condensing crystal obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) 20.2g.mp.103-106℃。
Embodiment 3:
Synthesizing of (2S, 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2) (that is: ertapenem side chain III):
Under nitrogen protection; 4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) 20g; be dissolved in methylene dichloride 140mL; add 3-benzaminic acid to p-Nitrobenzyl 19.5g; stirring at room temperature reaction 7 hours; distill dry solvent and obtain (2S, 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2).mp.148-150℃。
Embodiment 4:
Synthesizing of 3-((2S, 4S)-4-sulfydryl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (10) (that is: ertapenem side chain I)
Under nitrogen protection; 4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) adds 700mL glacial acetic acid, 50g gavaculine (normal temperature); solution colour is become slightly clearly finally and is become muddiness from muddiness, and stirring is spent the night.Next day, suction filtration, dry, obtains white solid (10) 80g.
Embodiment 5:
Synthesizing of 3-((2S, 4S)-4-sulfydryl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (13) (that is: ertapenem side chain II):
3-((2S; 4S)-4-sulfydryl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (10) 10g add tetrahydrofuran (THF) 200mL dissolve; 5% palladium carbon 2g; at 30～40 DEG C; 1.0MPa is hydrogenated to without inhaling hydrogen; cross filtration catalizer; add ethanol solution of hydrogen chloride; concentrated 3-((2S, 4S)-4-sulfydryl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (13) 6.0g that obtains.
(2S; 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2) 10g adds tetrahydrofuran (THF) 200mL to dissolve; 5% palladium carbon 2g; at 30～40 DEG C; 1.0MPa is hydrogenated to without inhaling hydrogen; cross filtration catalizer; ethanol solution of hydrogen chloride stirs; concentrated 3-((2S, 4S)-4-sulfydryl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-formamido group) phenylformic acid (13) 5.4g that obtains.
Embodiment 6:
Synthesizing of protection ertapenem
MAP5.95g; (2S; 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2) 5.88g; be added to 100mL reaction flask; add 60mL acetonitrile; DMF5mL stirs, and nitrogen protection, cools to-18～-15 DEG C of left and right.Add diisopropyl ethyl amine 1.2 equivalents.Stir 3 hours at-18～-15 DEG C.HPLC raw material, below 1%, continues to stir and within 8 hours, separates out gradually solid.Finally stir and filter for two hours at 0～5 DEG C.Acetonitrile washing 25mL × 2.Drain.55 DEG C of oven dry.Yield 75%.HPLC purity 99.0%.
MAP5.95g; (2S; 4S)-4-nitrobenzyl-4-sulfydryl-2-((3-(((4-nitrobenzyl) oxygen base) carbonyl) phenyl) formamyl) tetramethyleneimine-1-manthanoate (2) 5.88g; be added to 100mL reaction flask; add 60mL acetonitrile; DMF5mL stirs, and nitrogen protection, cools to 0～5 DEG C of left and right.Add diisopropyl ethyl amine 1.2 equivalents.Stir 3 hours at 0～5 DEG C.HPLC raw material, below 1%, continues to stir and within 8 hours, separates out gradually solid.Finally stir and filter for two hours at 0～5 DEG C.Acetonitrile washing 25mL × 2.Drain.55 DEG C of oven dry.Yield 75%.HPLC purity 99.6%.Can evaporate to dryness in acetonitrile mother liquor, obtain portioned product with ethyl acetate crystallization.
Embodiment 7:
Synthesizing of ertapenem (1)
10g protection ertapenem adds stirring and dissolving in tetrahydrofuran (THF) 200mL, water 200mL.Add lutidine3mL.Add 10% palladium carbon 4g, stir evenly.Be added in the hydriding reactor of 1L.Vacuumize logical nitrogen 3 times.Finally vacuumize in-0.08Mpa left and right.Pass into hydrogen at 1.0Mpa, vacuumize, logical hydrogen, 3 times, finally in 2Mpa left and right.Start to heat up simultaneously.At 38～42 DEG C, 2Mpa left and right hydrogenation 1 hour.Releasing hydrogen gas, vacuumizes, and passes into nitrogen in 1Mpa left and right.Emptying nitrogen.Discharging, filters.Filtrate 5% sodium hydroxide is adjusted pH value 7.4.Water layer 200mL ethyl acetate is washed once.Divide except ethyl acetate layer.Water layer add Virahol and acetone each 10 times with respect to water, separate out yellow solid 4.2g.90％(A％)。Yield 80%.
10g protection ertapenem adds stirring and dissolving in tetrahydrofuran (THF) 200mL, water 200mL.Add lutidine1.5mL sodium-acetate 1g.Add 10% palladium carbon 4.38g, stir evenly.Be added in the hydriding reactor of 1L.Vacuumize logical nitrogen 3 times.Finally vacuumize in-0.08Mpa left and right.Pass into hydrogen at 1.0Mpa, vacuumize, logical hydrogen, 3 times, finally in 2Mpa left and right.Start to heat up simultaneously.At 38～42 DEG C, 2Mpa left and right hydrogenation 1 hour.Releasing hydrogen gas, vacuumizes, and passes into nitrogen in 1Mpa left and right.Emptying nitrogen.Discharging, filters.Filtrate 5% sodium hydroxide is adjusted pH value 7.3.Water layer 200mL ethyl acetate is washed once.Divide except ethyl acetate layer.Water layer add Virahol and acetone each 10 times with respect to water, separate out yellow solid 4g.91.4％(A％)。Yield 81%.
Embodiment 8:
Ertapenem is refining
In reaction flask, add ertapenem (1) 3g, water 120ml, stirring at room temperature adds gac 0.3g after dissolving, within 15 minutes, filter, filtrate proceeds in reaction flask and stirs, and adds ethanol 600ml, is cooled to 0 DEG C of growing the grain and filters for 1 hour, ethanol 12ml washing leaching cake, drains final vacuum and within dry 2 hours, obtains white crystal 2.84g.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment of doing, be equal to replacement, improvement etc., within being all included in protection scope of the present invention.
Claims (10)
1. a preparation method for ertapenem,
L-oxyproline process is protected to obtain to (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) to p-Nitrobenzyl;
Described (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is condensed into active ester (2S with isopropyl chlorocarbonate, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), continue methylsulfonic acid esterification and obtain (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then react with sodium sulphite and obtain (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3),
Described 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain III (2) with gavaculine to p-Nitrobenzyl ring-opening reaction;
Described ertapenem side chain III (2) and raw material MAP are through condensation and the synthetic ertapenem of deprotection two step chemical reactions.
2. the preparation method of ertapenem according to claim 1, is characterized in that,
L-oxyproline, in aqueous sodium hydroxide solution, dissolve, cool to-5～5 DEG C, react with nitrobenzyl chloroformate ester dichloromethane solution, washed with dichloromethane, it is 2 that water sulfuric acid regulates pH value, filters, be dried to obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5);
(2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is through isopropyl chlorocarbonate, at triethylamine, in methylene dichloride, reaction generates (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), then react at triethylamine with Methanesulfonyl chloride, in methylene dichloride, (sec.-propyl carbonic acid) (2S is produced in reaction, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), add again sodium sulphite reaction to produce (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization generates 4-nitro (1S again, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3),
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain III (2) with gavaculine to p-Nitrobenzyl ring-opening reaction;
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain I (10) with gavaculine ring-opening reaction;
Ertapenem side chain III (2) and ertapenem side chain I (10) are sloughed protecting group through catalytic hydrogenation, obtain ertapenem side chain II (13);
Described ertapenem side chain III (2) and raw material MAP are through condensation and the synthetic ertapenem of deprotection two step chemical reactions, and it specifically comprises the steps:
Raw material MAP and described ertapenem side chain III (2) condensation in acetonitrile under nitrogen protection, add a small amount of tri-n-butyl phosphine, at-5～5 DEG C of reaction 3-8 hour, HPLC detects raw material MAP and is less than 1%, then concentrated solution, crystallizes out and obtains protecting ertapenem;
Protection ertapenem is dissolved in water, tetrahydrofuran (THF) or water, tetrahydrofuran (THF), ethyl acetate; make catalyzer with 5% palladium carbon; under 1.0～2.5 MPa hydrogen pressures, react; temperature 25-40 DEG C, reaction is finished, and separates ethyl acetate; then regulate pH value with sodium hydroxide; ethyl acetate cleaning product reaction solution, water adds ethanol, acetone or Virahol at low temperatures, separates out ertapenem.
3. the preparation method of ertapenem according to claim 1, comprises the steps:
Step 1: (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) synthetic:
L-oxyproline is starting raw material, and in aqueous sodium hydroxide solution, 0-5 DEG C drips nitrobenzyl chloroformate ester, time for adding approximately 2 hours; In this thermotonus 3 hours, detection reaction is complete, isolate methylene dichloride, with washed with dichloromethane once, it is 2 that water drips vitriol oil adjusting pH value, cools to 0-5 DEG C, filters, obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5);
Step 2: 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is synthetic:
(2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid under nitrogen protection in dichloromethane solution, add triethylamine, drip isopropyl chlorocarbonate, temperature is at-15 DEG C, form mixed acid anhydride (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), then add triethylamine, at-15 DEG C, drip Methanesulfonyl chloride, synthetic compound (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then add triethylamine and sodium sulfide solution, synthetic compound (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), compound (4c) again cyclization becomes 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3), synthetic 4-nitro (1S, the pilot process of 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is without separation,
Step 3: ertapenem side chain III (2) synthetic:
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) under nitrogen protection in dichloromethane solution, add 3-benzaminic acid to p-Nitrobenzyl stirring at room temperature reaction about 7 hours, solvent distillation obtains ertapenem side chain III (2);
Synthesizing of ertapenem side chain I (10):
4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is under nitrogen protection; add glacial acetic acid, gavaculine (normal temperature), solution colour is become slightly clearly finally and is become muddiness from muddiness, and stirring is spent the night.Next day, suction filtration, dry, obtains white solid ertapenem side chain I (10);
Synthesizing of ertapenem side chain II (13):
Ertapenem side chain I (10) or ertapenem side chain III (2) are made solvent at tetrahydrofuran (THF), and 5% palladium carbon makees catalyzer, and under 1-2 MPa hydrogen pressure, hydrogenation catalysis is sloughed protecting group and obtained ertapenem side chain II (13);
Step 4: protect the synthetic of ertapenem:
Under nitrogen protection, raw material MAP and ertapenem side chain III (2), in acetonitrile, add a small amount of DMF,
Under diisopropyl ethyl amine exists, at-18～5 DEG C of reaction 3-8 hour, HPLC detects raw material MAP and is less than 1%, and then concentrated solution, crystallizes out, and obtains protecting ertapenem (1);
Step 5: ertapenem synthetic:
Above-mentioned protection ertapenem is dissolved in water, tetrahydrofuran (THF) or water, tetrahydrofuran (THF), ethyl acetate, is added in 5% palladium carbon and makees catalyzer, under weak basic condition, the alkali adding has: 2,6-lutidine, sodium-acetate and composition thereof; React at 1.0-2.5 MPa hydrogen pressure, temperature 25-40 DEG C, reaction is finished, separate ethyl acetate, then regulate pH value 7.2～7.5 with sodium hydroxide, ethyl acetate cleaning product reaction solution, point removes ester layer, and water adds ethanol, acetone or Virahol to separate out product at low temperature-15～0 DEG C is ertapenem.
4. the preparation method of ertapenem according to claim 3, it is characterized in that, synthetic three kinds of side chains of ertapenem: ertapenem side chain I, ertapenem side chain II, ertapenem side chain III, and with ertapenem side chain III and raw material MAP, through the synthetic ertapenem of two-step reaction, then ertapenem is further purified and obtains medicinal ertapenem.
5. the preparation method of ertapenem according to claim 1, is characterized in that,
Described (2S, the synthetic method of 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is: 20L reactor adds water 12kg, sodium hydroxide 1kg, stirring and dissolving, cool to 25～30 DEG C, add L-oxyproline 1.5kg, stir molten clear, cool to 0～5 DEG C, control 0～5 DEG C of temperature and start to drip nitrobenzyl chloroformate ester 2.7kg and methylene dichloride 3kg solution; Time for adding approximately 2 hours, dropwises, and keeps 0～5 DEG C of left and right stirring reaction 3 hours; Detection reaction is complete; Divide and go methylene dichloride phase, water 3kg washed with dichloromethane, separate water, control only 15 degree of temperature, it is 2 that the vitriol oil is adjusted pH value, cools to 0 DEG C of filtration, washing, be dried to obtain (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) 31.95kg;
Described 4-nitro (1S, the synthetic method of 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is: under nitrogen protection, (2S, 4R)-4-hydroxyl-1-(((4-nitrobenzyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) 31.3g is dissolved in 300mL methylene dichloride, add triethylamine 12.1g, stirring and dissolving is cooled to-15 DEG C, drip isopropyl chlorocarbonate 13.5g, stirring reaction 30 minutes at this temperature; Add triethylamine 16.2g, at this temperature, drip Methanesulfonyl chloride 16g, at this temperature, stir 30 minutes; Add triethylamine 25.3g, add 10.2g sodium sulphite water 100mL solution; 5-10 DEG C of reaction 1 hour; React complete, 1N hydrochloric acid 300mL washs once, and saturated brine 300mL washs once, and water merges 200mL dichloromethane extraction once; Merge anhydrous sodium sulfate drying, filter, filtrate condensing crystal obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) 20.2g.
6. an ertapenem, is characterized in that, described ertapenem obtains ertapenem side chain III by L-oxyproline through serial reaction; Again by synthetic through condensation and deprotection two step chemical reactions to ertapenem side chain III and raw material MAP; Its molecular structural formula is:
。
7. a preparation method for ertapenem side chain, described ertapenem side chain is ertapenem side chain I, ertapenem side chain II or ertapenem side chain III;
The preparation method of the preparation method of described ertapenem side chain III, the preparation method of ertapenem side chain I, ertapenem side chain II is respectively:
The preparation method of ertapenem side chain III is as follows:
L-oxyproline process is protected to obtain to (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) to p-Nitrobenzyl;
Described (2S, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (5) is condensed into active ester (2S with isopropyl chlorocarbonate, 4R)-4-hydroxyl-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid (sec.-propyl carbonic acid) acid anhydride (4a), continue methylsulfonic acid esterification and obtain (sec.-propyl carbonic acid) (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-carboxylic acid anhydride (4b), then react with sodium sulphite and obtain (2S, 4R)-4-((methylsulfonyl) oxygen base)-1-(((4-nitro benzoyl) oxygen base) carbonyl) tetramethyleneimine-2-sulfo-S-acid (4c), cyclization obtains 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3),
Described 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) obtains ertapenem side chain III (2) with gavaculine to p-Nitrobenzyl ring-opening reaction;
The preparation method of ertapenem side chain I is as follows:
Above-mentioned 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride (3) is reacted with para-amino benzoic acid and obtains ertapenem side chain I;
The preparation method of ertapenem side chain II is as follows:
Above-mentioned ertapenem side chain I or ertapenem side chain III are removed to blocking group, obtain ertapenem side chain II.
8. the preparation method of ertapenem side chain according to claim 7, is characterized in that,
4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride, under nitrogen protection, adds glacial acetic acid, gavaculine, and solution colour is become slightly clearly finally and become muddiness from muddiness, and stirring is spent the night; Next day, suction filtration, dry, obtains white solid ertapenem side chain I;
By ertapenem side chain I or ertapenem side chain III, make solvent with tetrahydrofuran (THF), 5% palladium carbon makees catalyzer, and hydrogenation catalysis is sloughed protecting group and is obtained ertapenem side chain II.
9. the preparation method of ertapenem side chain according to claim 7, is characterized in that,
The synthetic method of described ertapenem side chain I is: under nitrogen protection, 4-nitro (1S, 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride adds 700mL glacial acetic acid, 50g gavaculine, solution colour is become slightly clearly finally and is become muddiness from muddiness, and stirring is spent the night; Next day, suction filtration, dry, obtains white solid (10) 80g;
The synthetic method of described ertapenem side chain III is: under nitrogen protection; 4-nitro (1S; 4S)-3-oxo-2-thia-5-azabicyclo [2.2.1] heptane-5-carboxylic acid anhydride 20g; be dissolved in methylene dichloride 140mL; add 3-benzaminic acid to p-Nitrobenzyl 19.5g; stirring at room temperature reaction 7 hours, distills dry solvent and obtains ertapenem side chain III.
The synthetic method of described ertapenem side chain II be in following two kinds any:
The first: ertapenem side chain I 10g adds tetrahydrofuran (THF) 200mL to dissolve, and 5% palladium carbon 2g, at 30～40 DEG C, 1.0MPa is hydrogenated to without inhaling hydrogen, cross filtration catalizer, add ethanol solution of hydrogen chloride, concentrated ertapenem side chain II (13) 6.0g that obtains;
The second: ertapenem side chain III 10g adds tetrahydrofuran (THF) 200mL to dissolve, 5% palladium carbon 2g, at 30～40 DEG C, 1.0MPa is hydrogenated to without inhaling hydrogen, crosses filtration catalizer, and ethanol solution of hydrogen chloride stirs, the concentrated ertapenem side chain II 5.4g that obtains.
10. an ertapenem side chain, described ertapenem side chain is ertapenem side chain I, ertapenem side chain II or ertapenem side chain III;
The molecular structural formula of described ertapenem side chain I is:
The molecular structural formula of described ertapenem side chain II is:
The molecular structural formula of described ertapenem side chain III is:
。
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| CN110698480A (en) * | 2018-07-09 | 2020-01-17 | 武汉启瑞药业有限公司 | Synthesis and purification method of ertapenem intermediate |
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| CN109574899A (en) * | 2018-11-27 | 2019-04-05 | 江西如益科技发展有限公司 | A kind of refining methd of ertapenem side chain |
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