CN104130262B - A kind of ertapenem, ertapenem side chain and preparation method thereof - Google Patents
A kind of ertapenem, ertapenem side chain and preparation method thereof Download PDFInfo
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- CN104130262B CN104130262B CN201410394494.6A CN201410394494A CN104130262B CN 104130262 B CN104130262 B CN 104130262B CN 201410394494 A CN201410394494 A CN 201410394494A CN 104130262 B CN104130262 B CN 104130262B
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- C07—ORGANIC CHEMISTRY
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- C07D477/00—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
- 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
- C07D477/20—Sulfur atoms
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—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
- 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 a kind of ertapenem, ertapenem side chain and preparation method thereof; L hydroxy-prolines are by protecting (2S, 4R) 4 hydroxyl 1 (((4 nitro benzoyl) epoxide) carbonyl) carboxylic acid of pyrrolidines 2 to p-Nitrobenzyl；Then the carboxylic acid anhydrides of 4 nitros (1S, 4S) 3 oxo, 2 thia, 5 azabicyclo [2.2.1] heptane 5 is obtained, ertapenem side chain III is obtained to p-Nitrobenzyl reaction with gavaculine；Ertapenem side chain III and raw material MAP are by condensation and the step chemical reactive synthesis ertapenem of deprotection two.The present invention can be by the ertapenem side chain I (10) of more succinct step synthesis in the market main flow, ertapenem side chain II (13) and ertapenem side chain III (2), without ultralow temperature, easily industrialization, and product purity is high, it is easy to operate.
Description
Technical field
The present invention relates to antibiotic preparing technical field, particularly a kind of ertapenem, ertapenem side chain and its preparation
Method.
Background technology
In the 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 synthetic route one is reported：
Journal of Organic Chemistry；vol.70；nb.19；(2005)；P.7479 following synthesis road is reported
Line 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 side chain synthesis ertapenem synthetic route eight that report is protected with pi-allyl：
Synthesis of MK-0826
Because there is parent nucleus MAP of many enterprise's generations to nitrobenzyl protection the country, therefore synthesize E Tapei with this parent nucleus
South, closes raw material and is easy to get；It is cheap.In order that parent nucleus and side chain the deprotection base under identical conditions, so side chain and parent nucleus
Using identical protection group, the side chain that ertapenem is used mainly has following three kinds：
Ertapenem side chain I (10)
Ertapenem side chain II and its hydrochloride (13)
Ertapenem side chain III (2)
As shown in above-mentioned ertapenem synthetic route, the method for the domestic report of ertapenem side chain III (2) is by compound 6
Protected through to p-Nitrobenzyl, amidatioon, Mesylation, thioacetyl, hydrolysis five steps reaction can obtain side chain III (2)；Enter
One one-step hydrolysis can obtain ertapenem side chain I (10), and ertapenem side chain I (10) removes protection group can obtain ertapenem
Side chain II (13), because hydrolysis is difficult to control, except complete hydrolysis intermediateness is strategic point very rambunctious, once obtaining
He trains southern side chain III (2) and ertapenem side chain I (10) is all often mixture.Side chain quality in itself is thus improved to be difficult.
The method of recrystallization or column chromatography repeatedly is needed to use to purify.Cumbersome, yield is low, cost of material cost of labor compared with
It is high.
The content of the invention
The technical problems to be solved by the invention be to provide a kind of more succinct ertapenem, ertapenem side chain and
Its preparation method.
The technical solution adopted by the present invention is：A kind of preparation method of ertapenem, L- hydroxy-prolines are passed through to nitre
Base benzyl ester protects (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)；
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5) and chlorine
Isopropyl formate is condensed into active ester (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2-
Carboxylic acid (isopropyl carbonic acid) acid anhydride (4a), continues methanesulfonic acid esterification and obtains (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) oxygen
Base) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acid anhydrides (4b), then obtained with vulcanized sodium reaction
The thio S- acid of (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2-
(4c), cyclization obtains 4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)；
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) and
Aminobenzoic acid obtains ertapenem side chain III (2) to p-Nitrobenzyl ring-opening reaction；
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) and
Aminobenzoic acid reaction obtains ertapenem side chain I (10)；
The ertapenem side chain III (2) and ertapenem side chain I (10) obtain ertapenem side by sloughing protection group
Chain II (13)；
The ertapenem side chain III (2) and raw material MAP are by condensation and the step chemical reactive synthesis E Tapei of deprotection two
South.
Further, L- hydroxy-prolines, dissolve in sodium hydrate aqueous solution, -5~5 DEG C are cooled to, with chloro-carbonic acid pair
P-Nitrobenzyl dichloromethane solution reacts, and dichloromethane washing, phase sulfur acid for adjusting pH value is 2, filtering, and dry (2S, 4R)-
4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)；
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5) is by chloromethane
Isopropyl propionate, reacts generation (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) in triethylamine, dichloromethane
Carbonyl) pyrrolidines -2- carboxylic acids (isopropyl carbonic acid) acid anhydride (4a), then with methylsufonyl chloride reaction in triethylamine, dichloromethane
Reaction production (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl)
Pyrrolidines -2- carboxylic acid anhydrides (4b), adds vulcanized sodium reaction production (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitre
Base benzoyl) epoxide) carbonyl) thio S- acid (4c) of pyrrolidines -2-, then cyclization generation 4- nitro (1S, 4S) -3- oxos -2-
Thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)；
4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) and an amino
Benzyl acetate ring-opening reaction obtains ertapenem side chain III (2)；
4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) and an amino
Benzoic acid ring-opening reaction obtains ertapenem side chain I (10)；
Ertapenem side chain III (2) and ertapenem side chain I (10) slough protection group by catalytic hydrogenation, obtain E Tapei
Southern side chain II (13)；
The ertapenem side chain III (2) and raw material MAP are by condensation and the step chemical reactive synthesis E Tapei of deprotection two
South, it specifically includes following steps：
The lower raw material MAP of nitrogen protection and the ertapenem side chain III (2) are condensed in acetonitrile, add a small amount of three normal-butyl
Phosphine, reacts 3-8 hours at -5~5 DEG C, and HPLC detection raw materials MAP is less than 1%, and then concentrate solution, crystallizes out and protected
Ertapenem；
Protection ertapenem is dissolved in water, tetrahydrofuran or water, tetrahydrofuran, ethyl acetate, is urged with 5% palladium carbon
Agent, is reacted, 25-40 DEG C of temperature under 1.0~2.5 MPas of Hydrogen Vapor Pressures, and reaction is finished, and separates ethyl acetate, then uses hydrogen-oxygen
Change sodium regulation pH value, ethyl acetate cleaning product reaction solution, water mutually adds ethanol, acetone or isopropanol, separates out at low temperature
Ertapenem.
The preparation method of the ertapenem, specifically may include following steps：
Step one：(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
Synthesis：
L- hydroxy-prolines are initiation material, in sodium hydrate aqueous solution, 0-5 DEG C of dropwise addition nitrobenzyl chloroformate ester,
Time for adding about 2 hours；In this thermotonus 3 hours, detection reaction was finished, and isolates dichloromethane, is washed with dichloromethane
Once, it is 2 that water is mutually added dropwise concentrated sulfuric acid regulation pH value, cools to 0-5 DEG C, and filtering obtains (2S, 4R) -4- hydroxyls -1- (((4- nitre
Base benzoyl) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)；
Step 2：4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)
Synthesis：
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids are protected in nitrogen
Under in dichloromethane solution, add triethylamine, be added dropwise isopropyl chlorocarbonate, temperature at -15 DEG C, formed mixed acid anhydride (2S,
4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (isopropyl carbonic acid) acid anhydride (4a), then
Triethylamine is added, at -15 DEG C, methylsufonyl chloride is added dropwise, synthesize compound (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl)
Epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acid anhydrides (4b), it is subsequently adding triethylamine and vulcanization
Sodium water solution, synthesis compound (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl)
Thio S- acid (4c) of pyrrolidines -2-, cyclization is double into 4- nitros (1S, 4S) -3- oxo -2- thia -5- azepines again for compound (4c)
Ring [2.2.1] heptane -5- carboxylic acid anhydrides (3), synthesizes 4- nitro (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptan
The pilot process of alkane -5- carboxylic acid anhydrides (3) is without separating；
Step 3：The synthesis of ertapenem side chain III (2)：
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) is protected in nitrogen
Under shield in dichloromethane solution, add 3- aminobenzoic acids that reaction 7 hours or so, solvent distillation are stirred at room temperature to p-Nitrobenzyl
Obtain ertapenem side chain III (2)；
The synthesis of ertapenem side chain I (10)：
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) is protected in nitrogen
Under shield, glacial acetic acid, gavaculine (normal temperature) are added, solution colour is changed into slightly eventually becoming muddiness clearly from muddiness, stirred
Night.Next day suction filtration, dries, and obtains white solid ertapenem side chain I (10)；
The synthesis of ertapenem side chain II (13)：
Ertapenem side chain I (10) or ertapenem side chain III (2) make solvent in tetrahydrofuran, and 5% palladium carbon is catalyzed
Agent, hydrogenating catalytic sloughs protection group and obtains ertapenem side chain II (13) under 1-2 MPas of Hydrogen Vapor Pressure；
Step 4：Protect the synthesis of ertapenem：
The lower raw material MAP of nitrogen protection and ertapenem side chain III (2) add a small amount of DMF in acetonitrile,
In the presence of diisopropyl ethyl amine, reacted 3-8 hours at -18~5 DEG C, HPLC detection raw materials MAP is less than 1%, so
Concentrate solution, crystallizes out afterwards, obtains protection ertapenem (1)；
Step 5：The synthesis of ertapenem：
Above-mentioned protection ertapenem is dissolved in water, tetrahydrofuran or water, tetrahydrofuran, ethyl acetate, is added in
5% palladium carbon makees catalyst, and under weak basic condition, the alkali of addition has：2,6- lutidines, sodium acetate and its mixture；
1.0-2.5 MPas of Hydrogen Vapor Pressure reaction, 25-40 DEG C of temperature, reaction is finished, and separates ethyl acetate, then adjusts pH with NaOH
Value 7.2~7.5, ethyl acetate cleaning product reaction solution divides and goes ester layer, and water adds ethanol, acetone at low temperature -15~0 DEG C
Or it is ertapenem that isopropanol separates out product.
4th, the preparation method of ertapenem according to claim 3, it is characterized in that, three kinds of sides of synthesis ertapenem
Chain：Ertapenem side chain I, ertapenem side chain II, ertapenem side chain III, and with ertapenem side chain III and raw material MAP, pass through
Two-step reaction synthesis ertapenem is crossed, then ertapenem is further purified and is obtained medicinal ertapenem.
The conjunction of (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
It is into method：20L reactors add water 12kg, and NaOH 1kg, stirring and dissolving cools to 25~30 DEG C, adds L- hydroxyl dried meat ammonia
Sour 15kg, stirs molten clear, cools to 0~5 DEG C, and 0~5 DEG C of temperature of control starts that nitrobenzyl chloroformate ester 2.7kg and two is added dropwise
Chloromethanes 3kg solution；Time for adding about 2 hours, completion of dropping, 0~5 DEG C or so of holding stirring reaction 3 hours；Detection has been reacted
Entirely；Divide and go dichloromethane phase, the washing of water phase 3kg dichloromethane separates water phase, controls only 15 degree of temperature, and the concentrated sulfuric acid adjusts pH value
It is 2, cools to 0 DEG C of filtering, washes, dry (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrole
Cough up alkane -2- carboxylic acid (5) 31.95kg；
The conjunction of 4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)
It is into method：Under nitrogen protection, (2S, 4R) -4- hydroxyls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
31.3g is dissolved in 300mL dichloromethane, adds triethylamine 12.1g, and stirring and dissolving is cooled to -15 DEG C, and isopropyl chlorocarbonate is added dropwise
13.5g, at this temperature stirring reaction 30 minutes；Triethylamine 16.2g is added, methylsufonyl chloride 16g is added dropwise at this temperature,
Stirred 30 minutes at a temperature of this；Triethylamine 25.3g is added, 10.2g vulcanized sodium water 100mL solution is added；It is small in 5-10 DEG C of reaction 1
When；Reaction is finished, and 1N hydrochloric acid 300mL washed once, and saturated brine 300mL washed once, and water mutually merges 200mL dichloromethane extraction
Take once；Merge anhydrous sodium sulfate drying, filtering, filtrate condensing crystallizing obtains 4- nitros (1S, 4S) -3- oxo -2- thias -5-
Azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) 20.2g.
A kind of ertapenem, the ertapenem obtains ertapenem side chain by L- hydroxy-prolines by serial reaction
Ⅲ；Again by ertapenem side chain III and raw material MAP by condensation and the step chemical reactive synthesis of deprotection two；Its molecular structural formula
For：
A kind of preparation method of ertapenem side chain, the ertapenem side chain is ertapenem side chain I, ertapenem side
Chain II or ertapenem side chain III；
The preparation method of the ertapenem side chain III, the preparation method of ertapenem side chain I, ertapenem side chain II
Preparation method is respectively：
The preparation method of ertapenem side chain III is as follows：
By L- hydroxy-prolines by protecting (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) to p-Nitrobenzyl
Epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)；
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5) and chlorine
Isopropyl formate is condensed into active ester (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2-
Carboxylic acid (isopropyl carbonic acid) acid anhydride (4a), continues methanesulfonic acid esterification and obtains (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) oxygen
Base) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acid anhydrides (4b), then obtained with vulcanized sodium reaction
The thio S- acid of (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2-
(4c), cyclization obtains 4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)；
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) and
Aminobenzoic acid obtains ertapenem side chain III (2) to p-Nitrobenzyl ring-opening reaction；
The preparation method of ertapenem side chain I is as follows：
By above-mentioned 4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) with
P-aminobenzoic acid reaction 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 into blocking group, ertapenem side chain II is obtained.
Further, 4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides exists
Under nitrogen protection, glacial acetic acid, gavaculine are added, solution colour is changed into slightly eventually becoming muddiness clearly from muddiness, stirred
Night；Next day suction filtration, dries, and obtains white solid ertapenem side chain I；
By ertapenem side chain I or ertapenem side chain III, solvent is made with tetrahydrofuran, 5% palladium carbon does catalyst, hydrogen
Change catalysis is sloughed protection group and obtains ertapenem side chain II.
The synthetic method of the ertapenem side chain I is：Under nitrogen protection, 4- nitros (1S, 4S) -3- oxo -2- thias -
5- azabicyclos [2.2.1] heptane -5- carboxylic acid anhydrides adds 700mL glacial acetic acids, 50g gavaculines, and solution colour is by muddiness
It is changed into slightly eventually becoming muddiness clearly, is stirred overnight；Next day suction filtration, dries, and obtains white solid (10) 80g；
The synthetic method of the ertapenem side chain III is:Under nitrogen protection, 4- nitros (1S, 4S) -3- oxo -2- sulphur
Miscellaneous -5- azabicyclos [2.2.1] heptane -5- carboxylic acid anhydrides 20g, are dissolved in dichloromethane 140mL, add 3- aminobenzoic acids to nitro
Benzyl ester 19.5g, is stirred at room temperature reaction 7 hours, distills dry solvent and obtains ertapenem side chain III.
The synthetic method of the ertapenem side chain II is any one in following two kinds:
The first：The 10g of ertapenem side chain I adds tetrahydrofuran 200mL to dissolve, 5% palladium carbon 2g, at 30~40 DEG C,
1.0MPa is hydrogenated to without hydrogen is inhaled, and is crossed and is filtered catalyst, adds ethanol solution of hydrogen chloride, is concentrated to give ertapenem side chain II (13)
6.0g；
Second：The 10g of ertapenem side chain III adds tetrahydrofuran 200mL to dissolve, 5% palladium carbon 2g, at 30~40 DEG C,
1.0MPa is hydrogenated to without hydrogen is inhaled, and is crossed and is filtered catalyst, ethanol solution of hydrogen chloride stirring, is concentrated to give ertapenem side chain II (13)
5.4g。
A kind of ertapenem side chain, the ertapenem side chain is ertapenem side chain I, ertapenem side chain II or strategic point
He trains southern side chain III；
The molecular structural formula of the ertapenem side chain I is:
The molecular structural formula of the ertapenem side chain II is：
The molecular structural formula of the ertapenem side chain III is：
It is an advantage of the current invention that the ertapenem side chain I of in the market main flow can be synthesized by more succinct step
(10), ertapenem side chain II (13) and ertapenem side chain III (2), while designing a kind of new synthesis ertapenem side chain
III (2) method, is passed through with L- hydroxy-prolines and nitrobenzyloxycarbonyl is protected, and four one pot of steps go out to synthesize thiolactone 4- nitros
(1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3), with 3- amino p-nitrophenyl first
Sour methyl esters open loop obtains ertapenem side chain III (2).
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) uses 3- amino
The direct open loop of paranitrobenzoic acid can obtain ertapenem side chain I (10).
Ertapenem side chain III (2) or ertapenem side chain I (10) can obtain side chain ertapenem side chain with deprotection
Ⅱ(13).For three of the above ertapenem side chain is each provided with preferable solution.
Ertapenem side chain III (2), without ultralow temperature, is easily industrialized during synthesis protection ertapenem, and
Product purity is high.It is easy to operate.
(2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyls designed by the present invention
Base) phenyl) carbamoyl) pyrrolidines -1- formic acid esters (2) is (i.e.：Synthetic route ertapenem side chain III, in full together) with it is existing
There is technology different.
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- first designed by the present invention
Acylamino-) benzoic acid (10) is (i.e.：Synthetic route ertapenem side chain I, in full together) is unlike the prior art.
Designed by the present invention 3- ((2S, 4S) -4- sulfydryls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -
2- formamido groups) benzoic acid (13) is (i.e.：Synthetic route ertapenem side chain II, in full together) is unlike the prior art.
Unlike the prior art, easy to operate, reaction condition is gentle for the condition that present invention synthesis protection ertapenem is used,
Product purity is high.
Deprotection of the present invention synthesizes ertapenem crude product, and condition is different from prior art, can obtain crude product with direct crystallization.
Specific embodiment
The present invention develops a kind of new synthesis ertapenem side chain III, ertapenem side chain II and ertapenem side chain I
New technology.And protection ertapenem is synthesized by ertapenem side chain III；Then deprotection synthesizes ertapenem.Also strategic point has been attempted
He trains southern side chain I and the synthesis protection ertapenem of ertapenem side chain II, but active group contained by both side chains is more,
Need at relatively low temperature, longer time can just obtain relatively good condensation effect.And the purity and yield of product do not have
There is the ertapenem side chain III of all protections high.The present invention ertapenem side chain III (2) and MAP are by condensation and deprotection two
Step chemical reactive synthesis ertapenem.
L- hydroxy-prolines (6) are by protecting (2S, 4R) -4- hydroxyls -1- (((4- nitrobenzene formyls to p-Nitrobenzyl
Base) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5), active ester (2S, 4R) -4- hydroxyls -1- is then condensed into isopropyl chlorocarbonate
(((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (isopropyl carbonic acid) acid anhydride (4a), without processing out product, after
Continuous methanesulfonic acid esterification obtains (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) oxygen
Base) carbonyl) pyrrolidines -2- carboxylic acid anhydrides (4b), without processing out product, then obtain (2S, 4R) -4- ((first with vulcanized sodium reaction
Sulfonyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- thio S- acid (4c), cyclization obtains 4- nitre
Base (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3), with gavaculine to nitre
The reaction of base benzyl ester obtains ertapenem side chain III (2)；4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclos [2.2.1]
The reaction of heptane -5- carboxylic acid anhydrides (3) and p-aminobenzoic acid obtains ertapenem side chain I (10), ertapenem side chain III (2) or
Ertapenem side chain I (10) removes blocking group can obtain ertapenem side chain II (13).
Protect the synthesis of ertapenem：
The lower MAP of nitrogen protection and ertapenem side chain III (2) are condensed in acetonitrile, a small amount of tri-n-butyl phosphine are added, -5
~5 DEG C are reacted 3-8 hours, and HPLC detection raw materials MAP is less than 1%, and then concentrate solution, crystallizes out.Product purity 99~
99.7%.
Advantage：Because side chain has protection, reaction carries out very fast temperature control at 0~5 DEG C, you can produced with high yield
Product.Reaction time shortens a lot.Without -30 DEG C of low-temp reactions.Reaction yield is high, and product purity is high.Operation is easy.
The synthesis of ertapenem：
Protection ertapenem is dissolved in water, tetrahydrofuran or water, tetrahydrofuran, ethyl acetate, is urged in 5% palladium carbon
Agent, in 1.0~2.5 MPas of Hydrogen Vapor Pressure reactions, 25-40 DEG C of temperature, reaction is finished, and separates ethyl acetate, then uses hydroxide
Sodium adjusts pH value, and ethyl acetate cleaning product reaction solution, water mutually adds ethanol at low temperature；Acetone or isopropanol are separated out and produced
Product, yield 81%.Being further purified 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 by condensation and the step chemical reactive synthesis ertapenem of deprotection two.
The synthesis of (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)：
L- hydroxy-prolines (6) are initiation material, and in sodium hydrate aqueous solution, 0-5 DEG C is added dropwise chloro-carbonic acid to nitrobenzyl
Ester, time for adding about 2 hours.In this thermotonus 3 hours, detection reaction was finished, and isolates dichloromethane, is washed with dichloromethane
Wash once, it is 2 that water is mutually added dropwise concentrated sulfuric acid regulation pH value, cool to 0-5 DEG C, filtering obtains (2S, 4R) -4- hydroxyl -1- (((4-
Nitro benzoyl) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5).Advantage：Condition is more gentle, and dichloromethane washing can be removed
Impurity in dereaction system, improves the purity of product.
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) synthesizes：
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acid (5) nitrogen is protected
Under in dichloromethane solution, add triethylamine, be added dropwise isopropyl chlorocarbonate, temperature at -15 DEG C, formed mixed acid anhydride (2S,
4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (isopropyl carbonic acid) acid anhydride (4a), then
Triethylamine is added, at -15 DEG C, dropwise addition methylsufonyl chloride, synthesis (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) epoxide) -
1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acid anhydrides (4b), is subsequently adding triethylamine and vulcanized sodium is water-soluble
Liquid, (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- is thio for synthesis
S- acid (4c), (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- sulphur
For S- acid (4c) again cyclization into 4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides
(3), the pilot process of synthesis (3) is without separating.Advantage：Because reactive intermediate is not processed directly using saving in reaction
Process time, reduces consersion unit, reduces separation process in the middle of material.So as to improve efficiency.
(2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) phenyl) carbamyls
Base) pyrrolidines -1- formic acid esters (2) synthesis：
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) is protected in nitrogen
Under shield in dichloromethane solution, add 3- aminobenzoic acids that reaction 7 hours or so, solvent distillation are stirred at room temperature to p-Nitrobenzyl
Obtain (2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) phenyl) carbamoyl)
Pyrrolidines -1- formic acid esters (2).Advantage：Mild condition, the side reaction for having gone up blocking group is less.
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzoic acid
(10) synthesis：
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) is protected in nitrogen
Under shield, glacial acetic acid, gavaculine (normal temperature) are added, solution colour is changed into slightly eventually becoming muddiness clearly from muddiness, stirred
Night.Next day suction filtration, dries, and obtains white solid 3- ((2S, 4S) -4- sulfydryls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrroles
Alkane -2- formamido groups) benzoic acid (10).
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzene
The synthesis of formic acid (13)：
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzoic acid
Or (2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) phenyl) carbamyls (10)
Base) pyrrolidines -1- formic acid esters (2) can make solvent in tetrahydrofuran, and 5% palladium carbon makees catalyst, and hydrogenating catalytic sloughs protection group
Obtain 3- ((2S, 4S) -4- sulfydryls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzoic acid
(13)。
The synthesis of protection ertapenem (1)：
The lower MAP of nitrogen protection and ertapenem side chain III (2) add a small amount of DMF, diisopropyl ethyl amine to deposit in acetonitrile
Under, reacted 3-8 hours at -18~5 DEG C, HPLC detection raw materials MAP is less than 1%, and then concentrate solution, crystallizes out.Product
Purity is in 99~99.7%.
Advantage：Because side chain has protection, reaction carries out very fast temperature control at -18~5 DEG C, you can obtained with high yield
Product.Reaction time shortens a lot.Without -30 DEG C of low-temp reactions.Reaction yield is high, and product purity is high.Operation is easy.
The synthesis of ertapenem (12)：
Protection ertapenem is dissolved in water, tetrahydrofuran or water, tetrahydrofuran, ethyl acetate, is added in 5% palladium carbon
Catalyst is made, under weak basic condition, the alkali that can be added has：2,6- lutidines, sodium acetate and its mixture.In 1.0-
2.5 MPas of Hydrogen Vapor Pressure reactions, 25-40 DEG C of temperature, reaction is finished, and separates ethyl acetate, then adjusts pH value 7.2 with NaOH
~7.5, ethyl acetate cleaning product reaction solution divides and goes ester layer, and water adds ethanol at low temperature -15~0 DEG C；Acetone is different
Propyl alcohol separates out product, yield 81%.Being further purified can obtain pharmaceutical grade ertapenem.Advantage：Ethyl acetate can change
Becoming solvent property increases material dissolution degree, and washing can remove the impurity such as other accessory substances.
Embodiment 1：
The synthesis of (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)：
20L reactors add water 12kg, and NaOH 1kg, stirring and dissolving cools to 25~30 DEG C, adds L- hydroxyl dried meat ammonia
Sour 15kg, stirs molten clear, cools to 0~5 DEG C, and 0~5 DEG C of temperature of control starts that nitrobenzyl chloroformate ester 2.7kg and two is added dropwise
Chloromethanes 3kg solution.Time for adding about 2 hours, completion of dropping, 0~5 DEG C or so of holding stirring reaction 3 hours.Detection has been reacted
Entirely.Divide and go dichloromethane phase, the washing of water phase 3kg dichloromethane separates water phase, controls only 15 degree of temperature, and the concentrated sulfuric acid adjusts pH value
It is 2, cools to 0 DEG C of filtering, washes, dry product (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyls
Base) pyrrolidines -2- carboxylic acid (5) 31.95kg.mp:132~134 DEG C.
Embodiment 2：
The synthesis of 4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)：
Under nitrogen protection, (2S, 4R) -4- hydroxyls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
31.3g is dissolved in 300mL dichloromethane, adds triethylamine 12.1g, and stirring and dissolving is cooled to -15 DEG C, and isopropyl chlorocarbonate is added dropwise
13.5g, at this temperature stirring reaction 30 minutes.Triethylamine 16.2g is added, methylsufonyl chloride 16g is added dropwise at this temperature,
Stirred 30 minutes at a temperature of this.Triethylamine 25.3g is added, 10.2g vulcanized sodium water 100mL solution is added.It is small in 5-10 DEG C of reaction 1
When.Reaction is finished, and 1N hydrochloric acid 300mL washed once, and saturated brine 300mL washed once, and water mutually merges 200mL dichloromethane extraction
Take once.Merge anhydrous sodium sulfate drying, filtering, filtrate condensing crystallizing obtains 4- nitros (1S, 4S) -3- oxo -2- thias -5-
Azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) 20.2g.mp.103-106℃.
Embodiment 3：
(2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) phenyl) carbamyls
Base) pyrrolidines -1- formic acid esters (2) is (i.e.：Ertapenem side chain III) synthesis:
Under nitrogen protection, 4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides
(3) 20g, is dissolved in dichloromethane 140mL, adds 3- aminobenzoic acids to p-Nitrobenzyl 19.5g, and reaction 7 hours is stirred at room temperature, and steams
Evaporate dry solvent and obtain (2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) phenyl) amino
Formoxyl) pyrrolidines -1- formic acid esters (2).mp.148-150℃.
Embodiment 4：
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzoic acid
(10) (i.e.：Ertapenem side chain I) synthesis
Under nitrogen protection, 4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides
(3) 700mL glacial acetic acids, 50g gavaculines (normal temperature), solution colour is added to be changed into slightly eventually becoming muddiness clearly from muddiness,
It is stirred overnight.Next day suction filtration, dries, and obtains white solid (10) 80g.
Embodiment 5：
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzene
Formic acid (13) is (i.e.:Ertapenem side chain II) synthesis:
3- ((2S, 4S) -4- sulfydryls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzoic acid
(10) 10g adds tetrahydrofuran 200mL to dissolve, 5% palladium carbon 2g, and at 30~40 DEG C, 1.0MPa is hydrogenated to without hydrogen is inhaled, and is crossed to filter and is urged
Agent, adds ethanol solution of hydrogen chloride, is concentrated to give 3- ((2S, 4S) -4- sulfydryls -1- (((4- nitro benzoyls) epoxide) carbonyls
Base) pyrrolidines -2- formamido groups) benzoic acid (13) 6.0g.
(2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) phenyl) carbamyls
Base) pyrrolidines -1- formic acid esters (2) 10g addition tetrahydrofuran 200mL dissolvings, 5% palladium carbon 2g, in 30~40 DEG C, 1.0MPa hydrogenations
To without hydrogen is inhaled, cross and filter catalyst, ethanol solution of hydrogen chloride stirring is concentrated to give 3- ((2S, 4S) -4- sulfydryls -1- (((4- nitre
Base benzoyl) epoxide) carbonyl) pyrrolidines -2- formamido groups) benzoic acid (13) 5.4g.
Embodiment 6：
Protect the synthesis of ertapenem
MAP 5.95g, (2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) benzene
Base) carbamoyl) pyrrolidines -1- formic acid esters (2) 5.88g, 100mL reaction bulbs are added to, add 60mL acetonitriles, DMF5mL to stir
Mix, nitrogen protection cools to -18~-15 DEG C or so.Add the equivalent of diisopropyl ethyl amine 1.2.3 are stirred at -18~-15 DEG C
Hour.HPLC raw materials continue stirring and gradually separate out solid in 8 hours below 1%.It is last to be filtered within two hours in 0~5 DEG C of stirring.
Acetonitrile washs 25mL × 2.Drain.55 DEG C of drying.Yield 75%.HPLC purity 99.0%.
MAP 5.95g, (2S, 4S) -4- nitrobenzyl -4- sulfydryls -2- ((3- (((4- nitrobenzyls) epoxide) carbonyl) benzene
Base) carbamoyl) pyrrolidines -1- formic acid esters (2) 5.88g, 100mL reaction bulbs are added to, add 60mL acetonitriles, DMF5mL to stir
Mix, nitrogen protection cools to 0~5 DEG C or so.Add the equivalent of diisopropyl ethyl amine 1.2.Stirred 3 hours at 0~5 DEG C.HPLC
Raw material continues stirring and gradually separates out solid in 8 hours below 1%.It is last to be filtered within two hours in 0~5 DEG C of stirring.Acetonitrile is washed
25mL×2.Drain.55 DEG C of drying.Yield 75%.HPLC purity 99.6%.Can be evaporated in acetonitrile mother liquor, use ethyl acetate knot
Crystalline substance obtains portioned product.
Embodiment 7：
The synthesis of ertapenem (1)
10g protection ertapenems add stirring and dissolving in tetrahydrofuran 200mL, water 200mL.Add lutidine3mL.Plus
Enter 10% palladium carbon 4g, stir evenly.It is added in the hydriding reactor of 1L.Vacuumize, lead to nitrogen 3 times.Finally vacuumize left in -0.08Mpa
It is right.Hydrogen is passed through in 1.0Mpa, is vacuumized, logical hydrogen, 3 times, finally in 2Mpa or so.Start simultaneously at intensification.At 38~42 DEG C,
2Mpa or so is hydrogenated 1 hour.Hydrogen is released, is vacuumized, be passed through nitrogen in 1Mpa or so.Emptying nitrogen.Discharging, filters.Filtrate
5% NaOH adjusts pH value 7.4.Water layer 200mL ethyl acetate washed once.Divide and remove ethyl acetate layer.Water layer adds isopropanol
10 times each with acetone, relative to water, separate out yellow solid 4.2g.90% (A%).Yield 80%.
10g protection ertapenems add stirring and dissolving in tetrahydrofuran 200mL, water 200mL.Add lutidine1.5mL
Sodium acetate 1g.10% palladium carbon 4.38g is added, is stirred evenly.It is added in the hydriding reactor of 1L.Vacuumize, lead to nitrogen 3 times.Finally vacuumize
In -0.08Mpa or so.Hydrogen is passed through in 1.0Mpa, is vacuumized, logical hydrogen, 3 times, finally in 2Mpa or so.Start simultaneously at liter
Temperature.At 38~42 DEG C, 2Mpa or so is hydrogenated 1 hour.Hydrogen is released, is vacuumized, be passed through nitrogen in 1Mpa or so.Emptying nitrogen.
Discharging, filters.The NaOH of filtrate 5% adjusts pH value 7.3.Water layer 200mL ethyl acetate washed once.Divide and remove ethyl acetate layer.
Water layer adds isopropanol and each 10 times of acetone relative to water, separates out yellow solid 4g.91.4% (A%).Yield 81%.
Embodiment 8：
Ertapenem is refined
Ertapenem (1) 3g, water 120ml is added in reaction bulb, addition activated carbon 0.3g, 15 points after dissolving is stirred at room temperature
Clock is filtered, and filtrate is transferred to stirring in reaction bulb, adds ethanol 600ml, is cooled to 0 DEG C of growing the grain and is filtered for 1 hour, ethanol 12ml washings
Filter cake, is vacuum dried 2 hours to obtain white crystal 2.84g after draining.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for those skilled in the art
For member, the present invention can have various modifications and variations.All any modifications within the spirit and principles in the present invention, made,
Equivalent, improvement etc., are all contained within protection scope of the present invention.
Claims (4)
1. a kind of preparation method of ertapenem side chain II, it is characterized in that,
L- hydroxy-prolines, dissolve in sodium hydrate aqueous solution, -5~5 DEG C are cooled to, with nitrobenzyl chloroformate ester dichloro
Dichloromethane reacts, and dichloromethane washing, phase sulfur acid for adjusting pH value is 2, filtering, dry (2S, 4R) -4- hydroxyls -1-
(((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)；
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5) is different by chloro-carbonic acid
Propyl ester, reacts generation (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) in triethylamine, dichloromethane
Pyrrolidines -2- carboxylic acids (isopropyl carbonic acid) acid anhydride (4a), then reacts life with methylsufonyl chloride reaction in triethylamine, dichloromethane
Produce (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrroles
Alkane -2- carboxylic acid anhydrides (4b), adds vulcanized sodium reaction production (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitrobenzene
Formoxyl) epoxide) carbonyl) thio S- acid (4c) of pyrrolidines -2-, then cyclization generation 4- nitro (1S, 4S) -3- oxo -2- thias -
5- azabicyclos [2.2.1] heptane -5- carboxylic acid anhydrides (3)；
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) and m-aminophenyl first
Acid obtains ertapenem side chain III (2) to p-Nitrobenzyl ring-opening reaction；
Ertapenem side chain III (2) sloughs protection group by catalytic hydrogenation, obtains ertapenem side chain II (13).
2. the preparation method of ertapenem side chain II according to claim 1, it is characterized in that, comprise the following steps：
Step one：The conjunction of (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
Into：
L- hydroxy-prolines are initiation material, and in sodium hydrate aqueous solution, 0-5 DEG C of dropwise addition nitrobenzyl chloroformate ester is added dropwise
About 2 hours time；In this thermotonus 3 hours, detection reaction was finished, and isolates dichloromethane, be washed once with dichloromethane,
It is 2 that water is mutually added dropwise concentrated sulfuric acid regulation pH value, cools to 0-5 DEG C, and filtering obtains (2S, 4R) -4- hydroxyls -1- (((4- nitrobenzoyls
Acyl group) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)；
Step 2：4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) synthesizes：
(2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids exist under nitrogen protection
In dichloromethane solution, triethylamine is added, isopropyl chlorocarbonate is added dropwise, temperature forms mixed acid anhydride (2S, 4R) -4- at -15 DEG C
Hydroxyl -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (isopropyl carbonic acid) acid anhydride (4a), is subsequently adding three
Ethamine, at -15 DEG C, dropwise addition methylsufonyl chloride, synthesis compound (isopropyl carbonic acid) (2S, 4R) -4- ((mesyl) epoxide) -
1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acid anhydrides (4b), is subsequently adding triethylamine and vulcanized sodium is water-soluble
Liquid, synthesis compound (2S, 4R) -4- ((mesyl) epoxide) -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -
2- thio S- acid (4c), compound (4c) again cyclization into 4- nitros (1S, 4S) -3- oxo -2- thia -5- azabicyclos
[2.2.1] heptane -5- carboxylic acid anhydrides (3), synthesizes 4- nitro (1S, 4S) -3- oxo -2- thia -5- azabicyclo [2.2.1] heptan
The pilot process of alkane -5- carboxylic acid anhydrides (3) is without separating；
Step 3：The synthesis of ertapenem side chain III (2)：
4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) is under nitrogen protection
In dichloromethane solution, add 3- aminobenzoic acids that reaction 7 hours or so is stirred at room temperature to p-Nitrobenzyl, solvent distillation is obtained
Ertapenem side chain III (2)；
The synthesis of ertapenem side chain II (13)：
Ertapenem side chain III (2) makees solvent in tetrahydrofuran, and 5% palladium carbon makees catalyst, is hydrogenated under 1-2 MPas of Hydrogen Vapor Pressure
Catalysis is sloughed protection group and obtains ertapenem side chain II (13).
3. the preparation method of ertapenem side chain II according to claim 1, it is characterized in that,
The synthesis side of (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
Method is：20L reactors add water 12kg, and NaOH 1kg, stirring and dissolving cools to 25~30 DEG C, adds L- hydroxyprolines
15kg, stirs molten clear, cools to 0~5 DEG C, and 0~5 DEG C of temperature of control starts that nitrobenzyl chloroformate ester 2.7kg and dichloro is added dropwise
Methane 3kg solution；Time for adding about 2 hours, completion of dropping, 0~5 DEG C or so of holding stirring reaction 3 hours；Detection has been reacted
Entirely；Divide and go dichloromethane phase, the washing of water phase 3kg dichloromethane separates water phase, controls only 15 degree of temperature, and the concentrated sulfuric acid adjusts pH value
It is 2, cools to 0 DEG C of filtering, washes, dry (2S, 4R) -4- hydroxyls -1- (((4- nitro benzoyls) epoxide) carbonyl) pyrrole
Cough up alkane -2- carboxylic acid (5) 31.95kg；
The synthesis side of 4- nitros (1S, 4S) -3- oxos -2- thia -5- azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3)
Method is：Under nitrogen protection, (2S, 4R) -4- hydroxyls -1- (((4- nitrobenzyls) epoxide) carbonyl) pyrrolidines -2- carboxylic acids (5)
31.3g is dissolved in 300mL dichloromethane, adds triethylamine 12.1g, and stirring and dissolving is cooled to -15 DEG C, and isopropyl chlorocarbonate is added dropwise
13.5g, at this temperature stirring reaction 30 minutes；Triethylamine 16.2g is added, methylsufonyl chloride 16g is added dropwise at this temperature,
Stirred 30 minutes at a temperature of this；Triethylamine 25.3g is added, 10.2g vulcanized sodium water 100mL solution is added；It is small in 5-10 DEG C of reaction 1
When；Reaction is finished, and 1N hydrochloric acid 300mL washed once, and saturated brine 300mL washed once, and water mutually merges 200mL dichloromethane extraction
Take once；Merge anhydrous sodium sulfate drying, filtering, filtrate condensing crystallizing obtains 4- nitros (1S, 4S) -3- oxo -2- thias -5-
Azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides (3) 20.2g.
4. the preparation method of ertapenem side chain II according to claim 1, it is characterized in that,
The synthetic method of the ertapenem side chain III is:Under nitrogen protection, 4- nitros (1S, 4S) -3- oxo -2- thias -5-
Azabicyclo [2.2.1] heptane -5- carboxylic acid anhydrides 20g, are dissolved in dichloromethane 140mL, add 3- aminobenzoic acids to p-Nitrobenzyl
19.5g, is stirred at room temperature reaction 7 hours, distills dry solvent and obtains ertapenem side chain III；
The synthetic method of the ertapenem side chain II is:
The 10g of ertapenem side chain III adds tetrahydrofuran 200mL to dissolve, 5% palladium carbon 2g, and at 30~40 DEG C, 1.0MPa is hydrogenated to
Without hydrogen is inhaled, cross and filter catalyst, ethanol solution of hydrogen chloride stirring is concentrated to give the 5.4g of ertapenem side chain II.
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| US5322952A (en) * | 1992-01-10 | 1994-06-21 | Sumitomo Pharmaceuticals Company, Limited | Pyrrolidine derivatives and process for preparing the same |
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| US5322952A (en) * | 1992-01-10 | 1994-06-21 | Sumitomo Pharmaceuticals Company, Limited | Pyrrolidine derivatives and process for preparing the same |
| CN102690267A (en) * | 2011-11-02 | 2012-09-26 | 深圳市海滨制药有限公司 | Method for preparing ertapenem intermediate |
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