CN105601647B - One kind 7 α-cephamycin intermediate 7-MAC synthesis technologies - Google Patents
One kind 7 α-cephamycin intermediate 7-MAC synthesis technologies Download PDFInfo
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- CN105601647B CN105601647B CN201510804705.3A CN201510804705A CN105601647B CN 105601647 B CN105601647 B CN 105601647B CN 201510804705 A CN201510804705 A CN 201510804705A CN 105601647 B CN105601647 B CN 105601647B
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- tmca
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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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention belongs to biochemical industry fields; specifically provide a kind of synthesis technology of 7 α cephamycins intermediate, 7 MAC; first; in the case where not needing BSA or HMDS protections; 7 TMCA occur imidization with methyl sulphur chlorine and obtain; then with the intermediate of hexichol diazomethane reaction, last intermediate, which is directly reacted with methanol in the case where there is water condition, generates 7 MCA of final product.This technological reaction mild condition, step are simple, industrialized production easy to implement.Product purity reaches 97.5% or more, and single contaminant 0.5% is hereinafter, fully meet the standard of outlet.
Description
（One）Technical field
The invention belongs to biochemical industry field, more particularly to one kind 7 α-cephamycin intermediates 7-MAC synthesizes work
Skill.
（Two）Background technology
Currently, about 7-7 α of beta-amino-methoxyl group-3-（1- methyl-1 H- tetrazolium -5- sulfidomethyls）- 3- cephem -4- carboxylics
Acid-benzhydryl ester（Hereinafter referred to as 7-MAC）Synthesis, started from earliest in the 1970s, its research is carrying out always so far, though
So have a plurality of synthesis technology to be reported, but these techniques always more or less come with some shortcomings, it is extensive to be difficult to
Industrialized production.The first, when 7-TMCA and methyl sulphur chlorimideization are reacted, amino and carboxyl on raw material, which need to undergo to protect, to be taken off
The step of protection, processing step is more, cumbersome.Such as Liu Changbao, the synthetic route of Xue Liang et al. and Niu Zhigang, kahikatea be bright,
The patent that Li Zhigang, Yu Shuling are delivered（The patent No.：CN101696213A）.The second, when introducing methoxyl group, some techniques use
Toxic catalyst（Such as mercuric acetate）, some use expensive methoxylating reagent（Such as lithium, palladium）Or even some works
Skill uses the aluminium methoxide of severe reaction conditions as methoxylating reagent.Such as the patent of Fang Ying, Cai Jianping, Zhang Lifeng（It is open
Number：CN102199164B）And the patent of Zhang Xiaoguang, Qi Zhenhai, Liu Xing, Liu Jie, Xing Yanzhao, Zhang Qingpo（Publication number：
CN101792454B）Deng the reaction of the above methoxyl group is carried out under anhydrous harsh conditions.
（Three）Invention content
A kind of in order to compensate for the shortcomings of the prior art, the present invention provides steps 7 α-methoxies cephalo simple, easy to operate
Rhzomorph intermediate 7-MAC synthesis technologies.
The present invention is achieved through the following technical solutions：
One kind 7 α-cephamycin intermediate 7-MAC synthesis technologies include following operating procedure：
（1）7-TMCA and methyl sulphur chlorine, hexichol diazomethane reaction obtain intermediate；
（2）Product 7-MAC is directly obtained by the reaction with methanol in intermediate in the presence of water.
Wherein, the step（1）Middle 7-TMCA is added to n,N-Dimethylformamide, and acid binding agent and methyl sulphur chlorine is added,
Controlling reaction temperature is -2~0 DEG C of 0.5~1h of reaction, then heats to 5~10 DEG C of addition hexichol diazomethanes, keeps reaction temperature
Degree is 13~17 DEG C of 0.5~1h of reaction, and extraction and separation after reaction obtain intermediate.
Above-mentioned acid binding agent includes propylene oxide, ethylene oxide, 1,2- epoxy butane.
The molar ratio of above-mentioned 7-TMCA and methyl sulphur chlorine is 1:3~5.
Further, the molar ratio of 7-TMCA and methyl sulphur chlorine is 1:4.
The molar ratio of above-mentioned 7-TMCA and hexichol diazomethane is 1:1.1~1.2.
Above-mentioned steps（2）Methanol, water and catalyst triphenyl phosphorus are added in the intermediate, it is 0~5 to keep reaction temperature
1~3h is reacted at DEG C obtains final product 7-MAC.
Wherein, the molar ratio of intermediate and methanol is 1:12~13.
Further, the molar ratio of intermediate and methanol is 1:12.7.
Above-mentioned steps（1）In, methyl sulphur chlorine is made by dimethyl double thioether with chlorine reaction, and the dimethyl double thioether is molten
In dichloromethane, methyl sulphur chlorine, the dimethyl are obtained with 1.5~2h of chlorine reaction at a temperature of -13.5~-11.5 DEG C
The molar ratio of double thioether and chlorine is 1:1.02~1.04.
Hexichol diazomethane, which is reacted by Benzophenonehydrazones with chloramine-T, to be made, and the Benzophenonehydrazones are dissolved in two with chloramine-T
In chloromethanes, initiator I2 is added, with K2CO3 offer alkaline environments, the molar ratio of Benzophenonehydrazones and chloramine-T is 1:1.20
~1.23, holding reaction temperature reacts 0.5~1h at a temperature of being 23~25 DEG C and hexichol diazomethane is made.
The beneficial effects of the invention are as follows：（One）7-TMCA is directly protected with methyl sulphur chlorine in the present invention, does not have to silane
Change reagent first to be protected, eliminates two steps of protection and deprotection in this way；（Two）, selective methoxylation reaction visit
Aluminium methoxide of the rope needed for environmentally friendly water and methanol alternative reaction, is saved with methanol and AlCl3It is tight to generate aluminium methoxide
The anhydrous operation of lattice.
（Four）Specific implementation mode
Embodiment 1：
Intermediate synthesis technology
7-TMCA 20.2g, n,N-Dimethylformamide 93g are added in a kettle, cool down -5 DEG C of addition propylene oxide
20.8g is cooled to -10 DEG C and starts that methyl sulphur chlorine 20.5g is added dropwise, keeps temperature<0 DEG C, -1 ± 1 DEG C of reaction 0.5h after dripping off
（HPLC is detected：7-TMCA<1%）, the reaction was complete is added water 100g, and 2.5 ± 2.5 DEG C are stirred 15min, and layering retains dichloromethane
The extraction of 66g dichloromethane is added in layer, water layer, stirs 10min, static layering, and combined dichloromethane phase is cooled to 7.5 ± 2.5 DEG C
Left and right starts that diphenyl diazomethane 14.5g is added dropwise, and 15 ± 2 DEG C of reaction 0.5h, it is remaining that reaction solution is concentrated under reduced pressure into feed liquid
Methanol 150g is added in 180g, and cool down 0 ± 2 DEG C of stirring 1h.Filtering, methanol washing are drained, and product 27.6g is dried to obtain.
After above-mentioned reaction following detection data is obtained through detection：
Mp:196 1 198 DEG C (decomposes)；
IR(KBr):2920,1770,1720,1660,1620,1460,1370,1240,1170,1080,770,750,
715cm-1；
HNMR(300MHz,CDCl3)：2.89(3H,s）；3.67(1H,d,J=19.2Hz)；3.75(1H,d,J=
18.9Hz)；3.84(1H,s)；4.23(1H,d,J=13.8Hz)；4.42(1H,d,J=12.9)；5.30(1H,s)；6.96(1H,
s)；7.34(10H,m).
Embodiment 2：
Embodiment is same as Example 1, only changes the dosage of the methyl sulphur chlorine of addition, dosage 29.69g, finally
Obtain intermediate be 31.6g.
Embodiment 3：
Embodiment is same as Example 1, only changes the dosage of the methyl sulphur chlorine of addition, dosage 23.76g, finally
Obtain intermediate be 23.6g.
Embodiment 4：
7-MAC synthesis technologies
Intermediate 18g, triphenyl phosphorus 10.5g, dichloromethane 140ml are added in reaction bulb, is cooled to 0-5 DEG C, is added
Methanol 17ml, water 35ml, temperature control react 2h（Sample detection：Intermediate≤1%）.Reaction solution is concentrated in vacuo to 58g, and methanol is added
80ml, 0-5 DEG C of stirring 1h, filtering, methanol washing are drained, dry 7-MAC 16.1g.
After above-mentioned reaction following detection data is obtained through detection：
Mp:126 1 128 DEG C.
IR(KBr)：3360,3300,2950,1765,1720,1620,1500,1460,1350,1360,1240,1170,
1100,770,745,715cm-1。
HNMR (300MHz, CDC13) ：2.29 (2H, s)；3.50 (3H, s)；3.63(2H,d,J=5.1Hz)；3.82 (3H,
s)；4.27 (IH, d, J=13.2Hz)；
4.47(1H,d,J=13.2Hz)；4.84(1H,s)；6.92(1H,s)；7.28(10H,m).
NMR（13C）：29.03,33.44,34.82,52.4,64.32,79.72,98.11,126.19,127.07,
127.24,128.09,128.13,128.44,128.55,134.68,139.21,139.36,154.05,160.86,164.29.
Claims (7)
1. one kind 7 α-cephamycin intermediate 7-MAC synthesis technologies, it is characterised in that：Including following operating procedure：
（1）7-TMCA and methyl sulphur chlorine, hexichol diazomethane reaction obtain intermediate；
（2）Product 7-MAC is directly obtained by the reaction with methanol in intermediate in the presence of water；
Step（2）Methanol, water and catalyst triphenyl phosphorus are added in the intermediate, it is to be reacted at 0~5 DEG C to keep reaction temperature
1~3h obtains final product 7-MAC；
The step（1）Middle 7-TMCA is added in n,N-Dimethylformamide, and acid binding agent and methyl sulphur chlorine, control reaction is added
Temperature be -2~0 DEG C reaction 0.5~1h, then heat to 5~10 DEG C addition hexichol diazomethanes, keep reaction temperature be 13~
17 DEG C of 0.5~1h of reaction, after reaction extraction and separation obtain intermediate.
2. 7 α-cephamycins intermediate 7-MAC synthesis technologies according to claim 1, it is characterised in that：It is described to tie up
Sour agent is propylene oxide, ethylene oxide, one kind in 1,2- epoxy butane.
3. 7 α-cephamycins intermediate 7-MAC synthesis technologies according to claim 1, it is characterised in that：The 7-
The molar ratio of TMCA and methyl sulphur chlorine is 1:3~5.
4. 7 α-cephamycins intermediate 7-MAC synthesis technologies according to claim 3, it is characterised in that：The 7-
The molar ratio of TMCA and methyl sulphur chlorine is 1:4.
5. 7 α-cephamycins intermediate 7-MAC synthesis technologies according to claim 1, it is characterised in that：The 7-
The molar ratio of TMCA and hexichol diazomethane is 1:1.1~1.2.
6. 7 α-cephamycins intermediate 7-MAC synthesis technologies according to claim 1, it is characterised in that：In described
The molar ratio of mesosome and methanol is 1:12~13.
7. 7 α-cephamycins intermediate 7-MAC synthesis technologies according to claim 6, it is characterised in that：In described
The molar ratio of mesosome and methanol is 1:12.7.
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4109084A (en) * | 1976-12-08 | 1978-08-22 | E. R. Squibb & Sons, Inc. | Thiooxime cephalosporin derivatives |
| CN101117337A (en) * | 2006-08-03 | 2008-02-06 | 四平市精细化学品有限公司 | Method for preparing 7-alpha methoxy-7-amino-3-methyl amitrole sulfur methyl cepham alkanoates dimethyl |
| CN101696213B (en) * | 2009-10-28 | 2012-01-11 | 沧州那瑞化学科技有限公司 | Synthetic method of 7-MAC intermediate |
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