CN108017658A - A kind of synthetic method of Cefprozil - Google Patents
A kind of synthetic method of Cefprozil Download PDFInfo
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- CN108017658A CN108017658A CN201711429626.4A CN201711429626A CN108017658A CN 108017658 A CN108017658 A CN 108017658A CN 201711429626 A CN201711429626 A CN 201711429626A CN 108017658 A CN108017658 A CN 108017658A
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- OZYXQMKAFMKLKV-ZCFIWIBFSA-N C[C@H]1C[F](C)CC1 Chemical compound C[C@H]1C[F](C)CC1 OZYXQMKAFMKLKV-ZCFIWIBFSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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Abstract
The present invention relates to a kind of synthetic method of Cefprozil, which includes the following steps：Using 7 ACA as starting material, after silanization is protected, iodo, Wittig reactions occurs, generates compound 2；The compound 2 is in AlMe3Catalysis is lower and D-HPG methyl esters generates compound 1, up to target product Cefprozil.High conversion rate of the present invention, technique is simple, and cis-isomer content is high, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, and in particular to a kind of synthetic method of Cefprozil.
Background technology
Cefprozil (Cefprozil), chemical name：(6R, 7R) -7- [(2R)-amino (4- hydroxyphenyls) acetamido] -8-
Thio -1- azabicyclics [4.2.0] oct-2-ene -2- carboxylic acids of oxo -3- (1- acrylic) -5-, resist for second generation cephalosporin class
Raw element, is the cephalosporins spectrum antibacterial medicine that Bristol-Myers Squibb Co. of the U.S. develops, to the antibacterial of G+, G- bacterium and anaerobic bacteria
Activity is very strong, light, the grade and moderate infection that are clinically used for sensitive bacteria caused by especially prominent to G+ bacterium activity, including upper lower respiratory tract
Infection, and skin and skin soft-tissue infection.Its structural formula such as following formula I：
What it is due to C3- connections of Cefprozil is acrylic, therefore the compound, there are two geometric isomers, one is suitable
Formula Cefprozil, one is trans Cefprozil, clinically uses mixture, document report cis-trans-isomer is in chemistry
It is identical in terms of stability and anti-Grain-positive streptococcus and activity against staphylococci, but in the anti-uncommon bar of Grain-negative large intestine angstrom
Bacterium, Klebsiella Pneumoniae etc., cis antibacterial activity are trans 6~8 times.The synthesis on Cefprozil has been reported at present
Several preparation methods in road are as follows：
Route 1：United States Patent (USP) US4694079, US2004132992, China Patent Publication No. CN1694888 etc. with
GCLE is Material synthesis 7-APCA.Synthetic route is as follows：
Using GCLE as Material synthesis 7-APCA, synthesis yield is relatively low, and molar yield is 60% or so, and there are GCLE
The shortcomings of domestic source of goods is in short supply, and cost of material is higher, synthesis step length, complicated and three waste discharge is more.
Route 2：101798312 B of patent CN disclose a kind of method for preparing cefprozil compound, and this method is to adopt
It is raw material with 7-Phenylacetamide-3-Chloromethylcephalosporanate-p-methoxybenzoate (GCLE), is made by multistep reaction and purifying
Cefprozil.It is no selective when in the route due to connecing 3 side chains, mix more E-isomer by-product in Z-type product
Thing, since its structure, property are close, it is difficult to separate, or even can remain in last Cefprozil, influence medicine effect；And need
The phenol big to environmental hazard, trifluoroacetic acid, phosphorus pentachloride etc. are used, corrosivity is strong, and severe reaction conditions, yield are low.
Its synthetic route is as follows：
Route 3：CN101225088B discloses a kind of Cefprozil preparation method, and this method is with 3- acetyl-o-methyls -5-
- 2 carboxylic acid (7-ACA) of sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene is starting material, by wittig reactions and acetaldehyde
With reference to, reacted afterwards with D-pHPG dane potassium salts, after hydrolysis process Cefprozil.Although this method reaction letter
It is single, easy to operate, but Wittig reaction yields are not high, reaction is slow and selective poor, mixes in Z-type product more
E-isomer accessory substance, since its structure, property are close, it is difficult to separate, or even can remain in last Cefprozil, influence
Medicine effect and security.Synthetic route is as follows：
Route 4：Patent CN101058584B is reported with 7-ACA synthesis Cefprozil key intermediate 7- amino -3- third
The method of alkenyl cephalosporanic acid, the technique instead of source of goods GCLE in short supply with 7-ACA cheap and easy to get, have the cost of raw material compared with
It is low, the advantages that process route is simple and practicable, but yield is relatively low, the weight yield of 7-APCA is (with 7-
ACA is counted) it is only 0.38~0.4.This method Wittig reaction yields are not high at the same time, react slow and selective poor, same Z-type
Mix more E-isomer accessory substance in product, trans-isomer content is excessive, influences medicine effect and security.Tool
Body synthetic route is as follows：
In conclusion at present, the Cefprozil synthetic method reported mainly uses two kinds of routes：1) using 7-ACA as rise
Beginning raw material, side chain is introduced after introducing acrylic, 7- Deprotections at 3-, finally hydrolyzes and Cefprozil is made.2) with GCLE
Or GCLH is starting material, such as US4694079, CN101024649 etc..Itself common disadvantage is that reactions steps too complex,
Conversion ratio is relatively low, and obtained product purity is not high, and trans-isomer content is excessive.Therefore need to research and develop a kind of technique
Simply, high conversion rate, cis-isomer content is high, and is suitable for the synthetic technology of large-scale industrial production.
The content of the invention
It is an object of the invention to in the prior art the defects of, there is provided a kind of technique is simple, high conversion rate, cis different
Structure body content is high, and is suitable for the new synthesis process of large-scale industrial production, applied to Cefprozil or other compounds
Synthesis.Technical scheme is as follows：
A kind of synthetic method of Cefprozil, it is characterised in that include the following steps：
1) under nitrogen protection, by -2 carboxylic acid of 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene
(7-ACA), N, the double trimethylsilyl acetamides (BSA) of O- are dissolved in acetonitrile, reaction 4h are stirred at room temperature, N, N- diethylbenzenes is added dropwise
Amine, Iodotrimethylsilane (TMSI), react 1h in 10~15 DEG C, add triphenyl phosphorus (PPh3), the reaction was continued 1h, addition pregnancy
Two silicon amine sodium (NaN (SiMe of base3)2), 45min is stirred at room temperature, post-processes to obtain compound 3；
2) compound 3 is dissolved in [C4MIm]PF6In ionic liquid, lower addition acetaldehyde, DBU (1,8- diazabicyclos are stirred
[5.4.0] 11 carbon -7- alkene), in room temperature reaction 1.5h.Extracted through ether, remove to obtain crude product under reduced pressure.By crude product add methanol,
The in the mixed solvent of water, stirs l h, filters, and washing, is dried in vacuo and obtains i.e. compound 2；
3) above-claimed cpd 2 is slowly dissolved in dichloromethane, is sufficiently stirred, after be gradually added catalyst trimethyl aluminium
(AlMe3), then D-HPG methyl esters is added portionwise, 35 DEG C of reaction 2h of temperature control, are cooled to room temperature, add water quenching to go out instead
Should, stratification, collects water phase, adds activated carbon stirring 30min, decolorization filtering, diluted hydrochloric acid aqueous solution is added into filtrate, is adjusted
PH to 5.0 or so has solid precipitation, stirs, and filters, and filter cake is washed with acetone, drained, and is dried in vacuo to obtain Cefprozil crude product；
In step 1), 7-ACA, BSA, TMSI, triphenyl phosphorus, hmds sodium material amount ratio be 1:1.0~
1.3:1~1.2:1~1.1:1.Preferably, the amount of the material of 7-ACA, BSA, TMSI, triphenyl phosphorus, hmds sodium
Than for 1:1.15:1.1:1.05:1.
In step 2), compound 3, acetaldehyde, DBU material amount ratio be 1:1.2~1.6:0.4~0.7；KPF6
[C4MIm]PF6In molar fraction be 0.60；The volume ratio of in the mixed solvent methanol and water is 1:1.Preferably, compound 3,
Acetaldehyde, DBU material amount ratio be 1:1.4:0.55.
In step 3), compound 2, trimethyl aluminium, D-HPG methyl esters material amount ratio for 1.0~
1.2:1.0~1.5:1.0；The mass fraction of the diluted hydrochloric acid aqueous solution solute is 6%.Preferably, compound 2, front three
Base aluminium, D-HPG methyl esters material amount ratio be 1.1:1.25:1.0.
Compared with the prior art, the synthetic method of Cefprozil according to the present invention, this method have reaction condition temperature
With, product purity is high, cis-isomer content is high, process stabilizing, the features such as being easy to amplify, be suitable for industrialized production, its core
Heart advantage be using 7-ACA as starting material, after silanization is protected, occur iodo, Wittig reaction, and use ionic liquid for
Catalyst, avoids the excessive Cefprozil E isomer of generation, influences medicine effect；Trimethyl is used in ester-amide condensation at the same time
Aluminium has been raised as catalyst, reactivity.The preparation method is adapted to industrialization amplification to require, and is Cefprozil or other changes
The synthesis of compound provides another important and practical new compound.
Abbreviation implication used in specification and claims is as follows：
Embodiment
Technical solution of the present invention is further non-limitingly described below in conjunction with several preferred embodiments.
Embodiment 1
Under the protection of step 1) nitrogen, by 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
Carboxylic acid 10.89g (40mmol), acetonitrile 100mL, the double trimethylsilyl acetamides (BSA) of 46mmol N, O- are put in reaction bulb, in room
Temperature stirring reaction 4h, is added dropwise N, 4~6mL of N- diethylanilines, Iodotrimethylsilane (TMSI) 44mmol, in 10~15 DEG C of reactions
1h, adds triphenyl phosphorus 11.02g (42mmol), the reaction was continued 1h, addition hmds sodium 7.34g (40mmol), room temperature
45min is stirred, organic layer is separated and is washed with water, then washed with 20%w/w NaCl aqueous solutions, anhydrous MgSO4It is dry, obtain
22.16g compounds 3, yield 89.6%.
Step 2)
[C4MIm]PF6The preparation of ionic liquid：Will be dissolved with 6.896g KPF650mL acetone solns be placed in tri- mouthfuls of 250mL
In bottle, 10mL is then added dropwise and contains 5.47g [C4MIm] Br acetone soln, occur white precipitate immediately, after 2h is stirred at room temperature,
The solid KBr for removing and separating out is filtered, revolving removes acetone, is down to room temperature, obtains yellow liquid crude product.With 30mL CH2Cl2Processing
3-5 time, until completing to remove KBr solids, the dichloromethane solution of ionic liquid is dried overnight with anhydrous magnesium sulfate, is filtered,
Revolving removes dichloromethane, obtains thick pale yellow shape fluid product [C4MIm]PF6。
18.55g (30mmol) compound 3 is dissolved in 50mL [C4MIm]PF6In, stir lower addition acetaldehyde 1.85g
(42mmol), DBU (1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene) 2.51g, in room temperature reaction 1.5h.Extracted with ether
(3 × 40mL), merges ether layer, removes ether under reduced pressure and obtain crude product.The remnants of (3 × 40mL) after ether extracts are extracted with toluene
Liquid, by remaining POPh3Extract and, easy to the reuse of ionic liquid.Mixed solvent of the crude product through addition methanol 30mL, water 30mL
In, l h, filtering are stirred after adding, filter cake is washed with methanol 50mL, is dried in vacuo to obtain yellow product, i.e. 6.95g compounds 2, is received
Rate 96.34%, purity 99.82%, is 98.1 along inverse ratio:1.9.
The trimethyl aluminium hexane solution of step 3) compound concentration 2M at 5 DEG C, it is spare；By 5.28g (22mmol) compound 2
Be slowly dissolved in 50mL dichloromethane, be sufficiently stirred, after be gradually added concentration be 2M trimethyl aluminium hexane solution 12.5mL
(25mmol), is stirred at room temperature 2h, then D-HPG methyl esters 3.62g (20mmol), temperature control 35 is added portionwise
DEG C reaction 2h, TLC monitoring reaction is completed, and is cooled to room temperature, is added 50mL water quenchings to go out reaction, stratification, collects water phase, adds work
Property carbon stirring 30min, decolorization filtering adds 6% dilute hydrochloric acid into filtrate, adjusts pH to 5.0 or so to have solid precipitation, stir, take out
Filter, filter cake are washed with acetone, drained, and are dried in vacuo to obtain Cefprozil crude product 7.56g, yield 96.83%, purity 99.63%.
Embodiment 2
Under the protection of step 1) nitrogen, by 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
Carboxylic acid 10.89g (40mmol), acetonitrile 100mL, the double trimethylsilyl acetamides (BSA) of 40mmol N, O- are put in reaction bulb, in room
Temperature stirring reaction 4h, is added dropwise N, 4~6mL of N- diethylanilines, Iodotrimethylsilane (TMSI) 40mmol, in 10~15 DEG C of reactions
1h, adds triphenyl phosphorus 10.49g (40mmol), the reaction was continued 1h, addition hmds sodium 7.34g (40mmol), room temperature
45min is stirred, organic layer is separated and is washed with water, then washed with 20%w/w NaCl aqueous solutions, anhydrous MgSO4It is dry, obtain
20.11g compounds 3, yield 81.3%.
Step 2)
[C4MIm]PF6The preparation of ionic liquid：Will be dissolved with 6.896g KPF650mL acetone solns be placed in tri- mouthfuls of 250mL
In bottle, 10mL is then added dropwise and contains 5.47g [C4MIm] Br acetone soln, occur white precipitate immediately, after 2h is stirred at room temperature,
The solid KBr for removing and separating out is filtered, revolving removes acetone, is down to room temperature, obtains yellow liquid crude product.Use 30mLCH2Cl2Processing
3-5 time, until completing to remove KBr solids, the dichloromethane solution of ionic liquid is dried overnight with anhydrous magnesium sulfate, is filtered,
Revolving removes dichloromethane, obtains thick pale yellow shape fluid product [C4MIm]PF6。
18.55g (30.0mmol) compound 3 is dissolved in 50mL [C4MIm]PF6In, stir lower addition acetaldehyde 1.59g
(36.0mmol), DBU (1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene) 1.83g, in room temperature reaction 1.5h.Extracted with ether
Take (3 × 40mL), merge ether layer, remove ether under reduced pressure and obtain crude product.The remnants of (3 × 40mL) after ether extracts are extracted with toluene
Liquid, by remaining POPh3Extract and, easy to the reuse of ionic liquid.Mixed solvent of the crude product through addition methanol 30mL, water 30mL
In, l h, filtering are stirred after adding, filter cake is washed with methanol 50mL, is dried in vacuo to obtain yellow product, i.e. 6.62g compounds 2, is received
Rate 90.82%, purity 98.85%, is 92.2 along inverse ratio:7.8.
The trimethyl aluminium hexane solution of step 3) compound concentration 2M at 5 DEG C, it is spare；By 4.80g (20mmol) compound 2
Be slowly dissolved in 50mL dichloromethane, be sufficiently stirred, after be gradually added concentration be 2M trimethyl aluminium hexane solution 10mL
(20mmol), is stirred at room temperature 2h, then D-HPG methyl esters 3.62g (20mmol), temperature control 35 is added portionwise
DEG C reaction 2h, TLC monitoring reaction is completed, and is cooled to room temperature, is added 50mL water quenchings to go out reaction, stratification, collects water phase, adds work
Property carbon stirring 30min, decolorization filtering adds 6% dilute hydrochloric acid into filtrate, adjusts pH to 5.0 or so to have solid precipitation, stir, take out
Filter, filter cake are washed with acetone, drained, and are dried in vacuo to obtain Cefprozil crude product 6.92g, yield 87.27%, purity 98.21%.
Embodiment 3
Under the protection of step 1) nitrogen, by 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
Carboxylic acid 10.89g (40mmol), acetonitrile 100mL, the double trimethylsilyl acetamides (BSA) of 52mmol N, O- are put in reaction bulb, in room
Temperature stirring reaction 4h, is added dropwise N, 4~6mL of N- diethylanilines, Iodotrimethylsilane (TMSI) 40mmol, in 10~15 DEG C of reactions
1h, adds triphenyl phosphorus 11.54g (44mmol), the reaction was continued 1h, addition hmds sodium 7.34g (40mmol), room temperature
45min is stirred, organic layer is separated and is washed with water, then washed with 20%w/w NaCl aqueous solutions, anhydrous MgSO4It is dry, obtain
21.05g compounds 3, yield 85.1%.
Step 2)
[C4MIm]PF6The preparation of ionic liquid：Will be dissolved with 6.896g KPF650mL acetone solns be placed in tri- mouthfuls of 250mL
In bottle, 10mL is then added dropwise and contains 5.47g [C4MIm] Br acetone soln, occur white precipitate immediately, after 2h is stirred at room temperature,
The solid KBr for removing and separating out is filtered, revolving removes acetone, is down to room temperature, obtains yellow liquid crude product.Use 30mLCH2Cl2Processing
3-5 time, until completing to remove KBr solids, the dichloromethane solution of ionic liquid is dried overnight with anhydrous magnesium sulfate, is filtered,
Revolving removes dichloromethane, obtains thick pale yellow shape fluid product [C4MIm]PF6。
18.55g (30mmol) compound 3 is dissolved in 50mL [C4MIm]PF6In, stir lower addition acetaldehyde 1.98g
(45mmol), DBU (1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene) 2.74g, in room temperature reaction 1.5h.Extracted with ether
(3 × 40mL), merges ether layer, removes ether under reduced pressure and obtain crude product.The remnants of (3 × 40mL) after ether extracts are extracted with toluene
Liquid, by remaining POPh3Extract and, easy to the reuse of ionic liquid.Mixed solvent of the crude product through addition methanol 30mL, water 30mL
In, l h, filtering are stirred after adding, filter cake is washed with methanol 50mL, is dried in vacuo to obtain yellow product, i.e. 6.75g compounds 2, is received
Rate 93.21%, purity 99.36%, is 96.4 along inverse ratio:3.6.
The trimethyl aluminium hexane solution of step 3) compound concentration 2M at 5 DEG C, it is spare；By 5.28g (22mmol) compound 2
Be slowly dissolved in 50mL dichloromethane, be sufficiently stirred, after be gradually added concentration be 2M trimethyl aluminium hexane solution 15mL
(30mmol), is stirred at room temperature 2h, then D-HPG methyl esters 3.62g (20mmol), temperature control 35 is added portionwise
DEG C reaction 2h, TLC monitoring reaction is completed, and is cooled to room temperature, is added 50mL water quenchings to go out reaction, stratification, collects water phase, adds work
Property carbon stirring 30min, decolorization filtering adds 6% dilute hydrochloric acid into filtrate, adjusts pH to 5.0 or so to have solid precipitation, stir, take out
Filter, filter cake are washed with acetone, drained, and are dried in vacuo to obtain Cefprozil crude product 7.17g, yield 91.28%, purity 99.03%.
Embodiment 4
Under the protection of step 1) nitrogen, by 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene -2
Carboxylic acid 10.89g (40mmol), acetonitrile 100mL, the double trimethylsilyl acetamides (BSA) of 52mmol N, O- are put in reaction bulb, in room
Temperature stirring reaction 4h, is added dropwise N, 4~6mL of N- diethylanilines, Iodotrimethylsilane (TMSI) 48mmol, in 10~15 DEG C of reactions
1h, adds triphenyl phosphorus 11.54g (44mmol), the reaction was continued 1h, addition hmds sodium 7.34g (40mmol), room temperature
45min is stirred, organic layer is separated and is washed with water, then washed with 20%w/w NaCl aqueous solutions, anhydrous MgSO4It is dry, obtain
21.64g compounds 3, yield 87.5%.
Step 2)
[C4MIm]PF6The preparation of ionic liquid：Will be dissolved with 6.896g KPF650mL acetone solns be placed in tri- mouthfuls of 250mL
In bottle, 10mL is then added dropwise and contains 5.47g [C4MIm] Br acetone soln, occur white precipitate immediately, after 2h is stirred at room temperature,
The solid KBr for removing and separating out is filtered, revolving removes acetone, is down to room temperature, obtains yellow liquid crude product.Use 30mLCH2Cl2Processing
3-5 time, until completing to remove KBr solids, the dichloromethane solution of ionic liquid is dried overnight with anhydrous magnesium sulfate, is filtered,
Revolving removes dichloromethane, obtains thick pale yellow shape fluid product [C4MIm]PF6。
18.55g (30mmol) compound 3 is dissolved in 50mL [C4MIm]PF6In, stir lower addition acetaldehyde 2.11g
(48mmol), DBU (1,8- diazabicyclo [5.4.0], 11 carbon -7- alkene) 3.19g, in room temperature reaction 1.5h.Extracted with ether
(3 × 40mL), merges ether layer, removes ether under reduced pressure and obtain crude product.The remnants of (3 × 40mL) after ether extracts are extracted with toluene
Liquid, by remaining POPh3Extract and, easy to the reuse of ionic liquid.Mixed solvent of the crude product through addition methanol 30mL, water 30mL
In, l h, filtering are stirred after adding, filter cake is washed with methanol 50mL, is dried in vacuo to obtain yellow product, i.e. 6.67g compounds 2, is received
Rate 91.71%, purity 99.07%, is 94.2 along inverse ratio:5.8.
The trimethyl aluminium hexane solution of step 3) compound concentration 2M at 5 DEG C, it is spare；By 5.76g (24mmol) compound 2
Be slowly dissolved in 50mL dichloromethane, be sufficiently stirred, after be gradually added concentration be 2M trimethyl aluminium hexane solution 15mL
(30mmol), is stirred at room temperature 2h, then D-HPG methyl esters 3.62g (20mmol), temperature control 35 is added portionwise
DEG C reaction 2h, TLC monitoring reaction is completed, and is cooled to room temperature, is added 50mL water quenchings to go out reaction, stratification, collects water phase, adds work
Property carbon stirring 30min, decolorization filtering adds 6% dilute hydrochloric acid into filtrate, adjusts pH to 5.0 or so to have solid precipitation, stir, take out
Filter, filter cake are washed with acetone, drained, and are dried in vacuo to obtain Cefprozil crude product 7.34g, yield 93.59%, purity 99.27%.
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, ripe its object is to allow
Present disclosure can be understood and implement according to this by knowing the personage of technique, and the protection model of the present invention can not be limited with this
Enclose.Any equivalent change or modification in accordance with the spirit of the invention, should be covered by the protection scope of the present invention.
Claims (9)
1. a kind of synthetic method of Cefprozil, it is characterised in that including following operating procedure：
1) under nitrogen protection, by -2 carboxylic acid (7- of 3- acetyl-o-methyl -5- sulphur -7- amino -8- oxygen -1- azabicyclics oct-2-ene
ACA the double trimethylsilyl acetamides (BSA) of), N, O- are dissolved in acetonitrile, are stirred at room temperature and are reacted 4h, dropwise addition N, N- diethylanilines,
Iodotrimethylsilane (TMSI), reacts 1h in 10~15 DEG C, adds triphenyl phosphorus (PPh3), the reaction was continued 1h, addition hexamethyl
Two silicon amine sodium (NaN (SiMe3)2), 45min is stirred at room temperature, post-processes to obtain compound 3；
2) compound 3 is dissolved in [C4MIm]PF6In ionic liquid, lower addition acetaldehyde, DBU (1,8- diazabicyclos are stirred
[5.4.0] 11 carbon -7- alkene), in room temperature reaction 1.5h.Extracted through ether, remove to obtain crude product under reduced pressure.By crude product add methanol,
The in the mixed solvent of water, stirs 1h, filters, and washing, is dried in vacuo and obtains i.e. compound 2；
3) above-claimed cpd 2 is slowly dissolved in dichloromethane, is sufficiently stirred, after be gradually added catalyst trimethyl aluminium
(AlMe3), then D-HPG methyl esters is added portionwise, 35 DEG C of reaction 2h of temperature control, are cooled to room temperature, add water quenching to go out instead
Should, stratification, collects water phase, adds activated carbon stirring 30min, decolorization filtering, diluted hydrochloric acid aqueous solution is added into filtrate, is adjusted
PH to 5.0 or so has solid precipitation, stirs, and filters, and filter cake is washed with acetone, drained, and is dried in vacuo to obtain Cefprozil crude product；
A kind of 2. synthetic method of Cefprozil according to claim 1, it is characterised in that in step 1), 7-ACA,
BSA, TMSI, triphenyl phosphorus, hmds sodium material amount ratio be 1:1.0~1.3:1~1.2:1~1.1:1.
A kind of 3. synthetic method of Cefprozil according to claim 1, it is characterised in that in step 2), compound 3,
Acetaldehyde, DBU material amount ratio be 1:1.2~1.6:0.4~0.7；KPF6In [C4MIm]PF6In molar fraction be 0.60.
4. the synthetic method of a kind of Cefprozil according to claim 1, it is characterised in that in step 2), described is mixed
The volume ratio of methanol and water is 1 in bonding solvent:1.
A kind of 5. synthetic method of Cefprozil according to claim 1, it is characterised in that in step 3), compound 2,
Trimethyl aluminium, D-HPG methyl esters material amount ratio be 1.0~1.2:1.0~1.5:1.0.
6. the synthetic method of a kind of Cefprozil according to claim 1, it is characterised in that in step 3), described is dilute
The mass fraction of aqueous hydrochloric acid solution solute is 6%.
A kind of 7. synthetic method of Cefprozil according to claim 2, it is characterised in that in step 1), 7-ACA,
BSA, TMSI, triphenyl phosphorus, hmds sodium material amount ratio be 1:1.15:1.1:1.05:1.
A kind of 8. synthetic method of Cefprozil according to claim 3, it is characterised in that in step 2), compound 3,
Acetaldehyde, DBU material amount ratio be 1:1.4:0.55.
A kind of 9. synthetic method of Cefprozil according to claim 5, it is characterised in that in step 3), compound 2,
Trimethyl aluminium, D-HPG methyl esters material amount ratio be 1.1:1.25:1.0.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115819439A (en) * | 2022-11-17 | 2023-03-21 | 新天地医药技术研究院(郑州)有限公司 | Preparation method of 7-amino-3-propylene-1-cephem-4-carboxylic acid |
| CN116003437A (en) * | 2023-01-06 | 2023-04-25 | 河南立诺制药有限公司 | Synthesis process of cefprozil bulk drug |
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| CN86105568A (en) * | 1985-07-29 | 1987-04-01 | 布里斯托尔-米尔斯公司 | 3-propenyl cynnematin solvate |
| CN101058584A (en) * | 2007-05-23 | 2007-10-24 | 上海骏捷生化科技有限公司 | Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid |
| CN101225088A (en) * | 2008-01-17 | 2008-07-23 | 南通康鑫药业有限公司 | Method for preparing cephalosporin propylene |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN86105568A (en) * | 1985-07-29 | 1987-04-01 | 布里斯托尔-米尔斯公司 | 3-propenyl cynnematin solvate |
| CN101058584A (en) * | 2007-05-23 | 2007-10-24 | 上海骏捷生化科技有限公司 | Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid |
| CN101225088A (en) * | 2008-01-17 | 2008-07-23 | 南通康鑫药业有限公司 | Method for preparing cephalosporin propylene |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115819439A (en) * | 2022-11-17 | 2023-03-21 | 新天地医药技术研究院(郑州)有限公司 | Preparation method of 7-amino-3-propylene-1-cephem-4-carboxylic acid |
| CN116003437A (en) * | 2023-01-06 | 2023-04-25 | 河南立诺制药有限公司 | Synthesis process of cefprozil bulk drug |
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