CN104402907A - Production process for improved cephalosporin intermediate-GCLE - Google Patents
Production process for improved cephalosporin intermediate-GCLE Download PDFInfo
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- CN104402907A CN104402907A CN201410727298.6A CN201410727298A CN104402907A CN 104402907 A CN104402907 A CN 104402907A CN 201410727298 A CN201410727298 A CN 201410727298A CN 104402907 A CN104402907 A CN 104402907A
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- Prior art keywords
- gcle
- chlorination
- product
- reaction
- cephalosporin intermediate
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- 0 *S[C@@]([C@](*c1ccccc1)C1)N1C(C(Cl)=C)=C Chemical compound *S[C@@]([C@](*c1ccccc1)C1)N1C(C(Cl)=C)=C 0.000 description 6
- GNKZMNRKLCTJAY-UHFFFAOYSA-N CC(c1ccc(C)cc1)=O Chemical compound CC(c1ccc(C)cc1)=O GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 description 1
- YLFQNYIFDGCSHY-UHFFFAOYSA-N Cc(cc1)c(C2)c2c1OC Chemical compound Cc(cc1)c(C2)c2c1OC YLFQNYIFDGCSHY-UHFFFAOYSA-N 0.000 description 1
- CHLICZRVGGXEOD-UHFFFAOYSA-N Cc(cc1)ccc1OC Chemical compound Cc(cc1)ccc1OC CHLICZRVGGXEOD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
-
- 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
- C07D501/08—Preparation by forming the ring or condensed ring systems
-
- 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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a production process for an improved cephalosporin intermediate-GCLE (7-phenylacetamido-3-chloromethyl-p-methoxybenzyl cephalosporanate). The process comprises the following steps: chlorinating 4-benzenesulfonylthio-3-phenylacetamido-1-[1-(4-methoxybenzyloxy)carbonyl-2-methyl-2-allyl]azetidin-2-one as a raw material by taking NCS (N-Chlorosuccinimide) as a chlorination reagent to obtain chlorination product reaction liquid; heating in vacuum for concentration, strictly controlling the heating temperature and time, and producing cyclization reaction by taking ammonia water as alkali to obtain GCLE. The process has the benefits that NCS is adopted as the chlorination reagent, so that the adoption of chlorine gas produced in a conventional electrolytic process as the chlorination reagent can be avoided and the production safety can be greatly improved; the vacuum heating concentration process is adopted in post-treatment of the chlorination process and the optimal treatment temperature and time are obtained by optimization, so that the product quality can be stable and the product yield can be increased; the process is simple to improve and convenient to carry out, and the process adjustment can be realized without modifying equipment based on an original process.
Description
Technical field
The present invention relates to medicine intermediate production field, especially design the production technique of a kind of cephalosporin intermediate GCLE of improvement.
Background technology
GCLE, i.e. GCLE, molecular formula is C
24h
23clN
2o
5, relative molecular mass is 486.5, is the another main intermediate that 7-amino-cephalosporanic acid (7-ACA) and 7-ADCA (7-ADCA) synthesize cephalosporin medicament afterwards.The synthetic method of GCLE is mainly divided into two large classes, halogenation two kinds after halogen process and ring expansion before ring expansion, before current ring expansion, halogenation uses more extensive, this method take potassium penicillin G as starting raw material, obtain GCLE through over-churning, oxidation, open loop, conversion, chlorination, cyclization six step successively, reaction skeleton symbol is as follows:
Wherein chlorination, cyclization two step are the keys restricting whole reaction yield, and the solvent in chlorinating step remain involutive ring reaction impact larger, therefore concentration process is the very important operation determining final quality and yield, this just needs us to carry out refinement analysis to it, finds out suitable technology controlling and process point.Directly affect quality product and the yield of GCLE.
Summary of the invention
The object of the invention is to there is quality product and yield instability for chlorination process in GCLE production technique, directly affect yield and the quality of GCLE, a kind of cephalosporin intermediate GCLE production technique of improvement is provided, thus reaches the object of stabilized product quality, raising product yield.
Technical scheme of the present invention is as follows:
A cephalosporin intermediate GCLE production technique for improvement, it is characterized in that, processing step is as follows:
(1) with 4-benzenesulfonyl sulfo--3-phenylacetyl amido-1-[1-(4-methoxyl group benzyloxy) carbonyl-2-methyl-2-propenyl] nitrogen heterocyclic din-2-ketone (1) for raw material; with N-chlorosuccinimide (NCS) for chlorination reagent; carry out chlorination, obtain chlorizate (2) reaction solution
(2) the reaction solution heated under vacuum of the chlorizate obtained (2) is concentrated;
(3) pour DMF in the concentrated solution obtained in step (2) into and stir fully dissolving, be that alkali carries out cyclization reaction with ammoniacal liquor, obtain GCLE crude product reaction solution;
(4) obtain being poured into water crystallization in reaction solution in step (3), filtration drying obtains GCLE product
Further, the concentrated condition in described step (2) is: thickening temperature 38 ~ 40 DEG C, time 80 ~ 110min.
Further, in described step (3), temperature of reaction is-5 ~-3 DEG C.
Further, the water in described step (4) is the frozen water of 0 DEG C, and crystallization condition is 0 DEG C, 12h, finished product dry 40 DEG C, 10h.
Beneficial effect of the present invention is: chloridization process of the present invention adopts NCS to be chlorination reagent, and the chlorine avoiding the generation of traditional electrical solution is chlorination reagent, substantially increases the security in production; The aftertreatment of chloridization process adopts heating under vacuum to concentrate, differing temps and time are investigated to the impact of chlorizate dissolvent residual, obtain best treatment temp and time, constant product quality, product yield are improved, and this process modification is simple, easy to operate, original technique can realize technique adjustment without the need to changing equipment.
Embodiment
By the following examples the present invention is specifically described.
Embodiment:
15g 4-benzenesulfonyl sulfo--3-phenylacetyl amido-1-[1-(4-methoxyl group benzyloxy) carbonyl-2-methyl-2-propenyl] nitrogen heterocyclic din-2-ketone 150mL dioxane is dissolved; add 90g salt of wormwood; 1g Benzoyl Peroxide, slowly adds the carbon tetrachloride solution of 10g N-chlorosuccinimide (NCS), reacts 1 hour; after reaction terminates, reaction is also filtered; by washed with dichloromethane, add 450mL cold water, be separated organic phase; anhydrous sodium sulfate drying, filters.
Pour in distilling flask by 400ml chlorination reaction liquid, open and stir, carry out concentration operation in heated under vacuum, timing also weighs dense fluid volume, recording process temperature.
In concentrated solution, pour 40mlDMF into stir fully dissolving 5 minutes, start cooling, when interior temperature reaches-2 DEG C, add 10g Calcium Chloride Powder Anhydrous, continue to be cooled to-5 DEG C and start to drip cp ammoniacal liquor, controlling rate of addition makes interior temperature control below-3 DEG C, judges that reaction terminates according to liquid chromatogram result.Add 3mlcp hydrochloric acid and 30ml ethyl acetate fully stirs.
In reaction solution, pour 300ml frozen water into, stirring and crystallizing, holding temperature, at about 0 DEG C, is incubated 12 hours, filters, with the drip washing of 80ml frozen water, then pours in culture dish and put into loft drier in 40 DEG C of dryings 10 hours.
1, the impact that must measure quality product of concentration time:
Change concentration time, investigating affects situation to product net result.Experimental result (table 1) shows, the volume of the dense fluid of the prolongation along with concentration time increases thereupon, liquid phase main peak and the finished product must be measured and also improve thereupon, this illustrates that residual chlorination reaction solvent can have a negative impact to follow-up cyclization reaction, thus affect final must measuring, remain so we will reduce solvent in concentrated solution as far as possible.But the increasing amount of the dense fluid of the prolongation along with concentration time goes to zero, and the long time can cause the decline of concentrated solution liquid phase main peak and finally cause amount reduction, illustrate that concentration process overlong time can cause destruction to a certain degree to the muriate in solution.As seen from Table 2, residual chlorination reaction solvent does not have a direct impact quality product, but long concentration time can produce impurity while destruction chloride structure, thus affects quality product.
The impact that table 1 concentration time must be measured GCLE product.
Table 2 inspection after construction result
| No. 1 | No. 2 | No. 3 | No. 4 | |
| Outward appearance | Off-white color | Off-white color | Off-white color | Off-white color |
| Content | 95.35％ | 95.41％ | 95.29％ | 95.06％ |
| Moisture | 0.34 | 0.37 | 0.32 | 0.31 |
| Fusing point (DEG C) | 155.5-157 | 156-158 | 156-157.5 | 156.5-158 |
| Front assorted | 0.10 | 0.12 | 0.12 | 0.16 |
| Rear assorted | 1.61 | 1.63 | 1.62 | 1.81 |
| Total assorted | 2.24 | 2.32 | 2.33 | 2.79 |
| Detected result judges | Conform with the regulations | Conform with the regulations | Conform with the regulations | Conform with the regulations |
2, the impact that in striking point, temperature must be measured quality product:
Change temperature in striking point, investigating affects situation to product net result.Along with the carrying out of concentration operation, in material, temperature also rises thereupon, and along with the minimizing of steam output, interior temperature lift velocity is accelerated, to concentrated later stage material Nei Wenyin operation control, rangeability is very little, and this just causes material can be in striking point temperature within a very long time.Experimental result (table 3) shows, along with in striking point, the volume of the dense fluid of raising of the upper limit of temperature increases thereupon, in concentrated solution, chlorination reaction solvent remains corresponding minimizing, and liquid phase main peak and the finished product must be measured and also improve thereupon, and this conforms to the conclusion in 3.1.But along with the continuation of striking point temperature is risen, the increasing amount of dense fluid goes to zero, and too high temperature can cause declining to a great extent of concentrated solution liquid phase main peak and finally cause obtaining the reduction of amount, this just the too high meeting of explanation concentration process temperature very large destruction is caused to the muriate in solution.As seen from Table 4, residual chlorination reaction solvent does not have a direct impact quality product, and this conforms to conclusion in 3.1, but too high thickening temperature is understood havoc chloride structure and produced a large amount of impurity, thus have a strong impact on quality product, there is situation off quality.
The impact that when table 3 concentrates, temperature of charge must be measured GCLE product.
Table 4 inspection after construction result
| No. 1 | No. 2 | No. 3 | No. 4 | |
| Outward appearance | Off-white color | Off-white color | Off-white color | Off-white color |
| Content | 95.27％ | 95.31％ | 95.25％ | 94.66％ |
| Moisture | 0.36％ | 0.39％ | 0.41％ | 0.33％ |
| Fusing point (DEG C) | 156.5-157.5 | 156-157.5 | 155.5-157 | 155.5-157.5 |
| Front assorted | 0.12 | 0.10 | 0.13 | 0.17 |
| Rear assorted | 1.54 | 1.62 | 1.58 | 1.96 |
| Total assorted | 2.34 | 2.41 | 2.37 | 3.06 |
| Detected result judges | Conform with the regulations | Conform with the regulations | Conform with the regulations | Against regulation |
3, conclusion:
Novel process from open sulphur thing to the concentration process the reaction of GCLE for concentration time and concentration process in temperature of charge have certain strict restriction, concentration process has quality product yield to be affected significantly, control temperature in striking point from the experimental results and be no more than 42 DEG C, dense fluid per-cent is about 88% process can be made to reach higher level.
Above one embodiment of the present of invention have been described in detail, but described content being only preferred embodiment of the present invention, can not being considered to for limiting practical range of the present invention.All equalizations done according to the present patent application scope change and improve, and all should still belong within patent covering scope of the present invention.
Claims (4)
1. the cephalosporin intermediate GCLE production technique improved, it is characterized in that, processing step is as follows:
(1) with 4-benzenesulfonyl sulfo--3-phenylacetyl amido-1-[1-(4-methoxyl group benzyloxy) carbonyl-2-methyl-2-propenyl] nitrogen heterocyclic din-2-ketone (1) for raw material; with N-chlorosuccinimide (NCS) for chlorination reagent; carry out chlorination, obtain chlorizate (2) reaction solution
(2) the reaction solution heated under vacuum of the chlorizate obtained (2) is concentrated;
(3) pour DMF in the concentrated solution obtained in step (2) into and stir fully dissolving, be that alkali carries out cyclization reaction with ammoniacal liquor, obtain GCLE crude product reaction solution;
(4) obtain being poured into water crystallization in reaction solution in step (3), filtration drying obtains GCLE product
2. the cephalosporin intermediate GCLE production technique of a kind of improvement according to claim 1, is characterized in that: the concentrated condition in described step (2) is: thickening temperature 38 ~ 40 DEG C, time 80 ~ 110min.
3. the cephalosporin intermediate GCLE production technique of a kind of improvement according to claim 1, is characterized in that: in described step (3), temperature of reaction is-5 ~-3 DEG C.
4. the cephalosporin intermediate GCLE production technique of a kind of improvement according to claim 1, is characterized in that: the water in described step (4) is the frozen water of 0 DEG C, and crystallization condition is 0 DEG C, 12h, finished product dry 40 DEG C, 10h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410727298.6A CN104402907A (en) | 2014-12-03 | 2014-12-03 | Production process for improved cephalosporin intermediate-GCLE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410727298.6A CN104402907A (en) | 2014-12-03 | 2014-12-03 | Production process for improved cephalosporin intermediate-GCLE |
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| Publication Number | Publication Date |
|---|---|
| CN104402907A true CN104402907A (en) | 2015-03-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410727298.6A Pending CN104402907A (en) | 2014-12-03 | 2014-12-03 | Production process for improved cephalosporin intermediate-GCLE |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926705A (en) * | 2015-05-05 | 2015-09-23 | 宁波人健医药化工有限公司 | Method for preparing cephalosporin parent nucleus intermediate |
| CN107033162A (en) * | 2016-02-03 | 2017-08-11 | 湖北凌晟药业有限公司 | The preparation of GCLE |
-
2014
- 2014-12-03 CN CN201410727298.6A patent/CN104402907A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926705A (en) * | 2015-05-05 | 2015-09-23 | 宁波人健医药化工有限公司 | Method for preparing cephalosporin parent nucleus intermediate |
| CN107033162A (en) * | 2016-02-03 | 2017-08-11 | 湖北凌晟药业有限公司 | The preparation of GCLE |
| CN107033162B (en) * | 2016-02-03 | 2020-05-01 | 湖北凌晟药业有限公司 | Preparation of 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester |
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Application publication date: 20150311 |