CN112300193A - Synthesis method of latamoxef intermediate - Google Patents
Synthesis method of latamoxef intermediate Download PDFInfo
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- CN112300193A CN112300193A CN202011163339.5A CN202011163339A CN112300193A CN 112300193 A CN112300193 A CN 112300193A CN 202011163339 A CN202011163339 A CN 202011163339A CN 112300193 A CN112300193 A CN 112300193A
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- Prior art keywords
- latamoxef
- intermediates
- isobutanol
- synthesis process
- acetone
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- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 title claims abstract description 23
- 229960000433 latamoxef Drugs 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000000543 intermediate Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- -1 4-methyl-benzoylamino Chemical group 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims abstract description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- 239000013078 crystal Substances 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000006227 byproduct Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012452 mother liquor Substances 0.000 claims description 6
- YAYJPHUDZGLRHQ-UHFFFAOYSA-N benzhydryl 3-methyl-2-[3-(4-methylphenyl)-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]but-3-enoate Chemical compound CC(C(C(OC(C1=CC=CC=C1)C1=CC=CC=C1)=O)N(C1OC(C2=CC=C(C)C=C2)=NC11)C1=O)=C YAYJPHUDZGLRHQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- QTPJMTACJMLPLL-UHFFFAOYSA-N triethoxy(sulfanylidene)-$l^{5}-phosphane Chemical compound CCOP(=S)(OCC)OCC QTPJMTACJMLPLL-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000003115 biocidal effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000005650 intramolecular substitution reaction Methods 0.000 description 1
- 229940035429 isobutyl alcohol Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention particularly relates to a synthesis method of an latamoxef intermediate, belonging to the technical field of synthesis of antibiotic drug intermediates. The synthesis method of the latamoxef intermediate takes 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate as a raw material, and the raw material is refluxed with triethyl phosphite in isobutanol solvent to obtain the product 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-diphenylmethyl enoate. The method is simple and easy to implement, reduces the production cost, improves the product yield, recycles the solvent, and has higher economic value and environmental protection benefit.
Description
Technical Field
The invention particularly relates to a synthesis method of an latamoxef intermediate, belonging to the technical field of synthesis of antibiotic drug intermediates.
Background
Latamoxef intermediate 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-enoic acid benzhydryl ester is an intermediate of latamoxef. Latamoxef is a semi-synthetic cephalosporin antibiotic, has wide clinical application and increasingly large market demand. Latamoxef is included in the catalog of national basic medical insurance and industry injury insurance products published in 9 months 2004.
Domestic and foreign cephalosporin antibiotic production enterprises need a large amount of 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-enoic acid benzhydryl ester, wherein the market of Japan salt and wilderness companies is stable, and the annual demand for it has been around 20 tons for many years.
Currently, the preparation process of latamoxef intermediate has the following disadvantages:
(1) tributylphosphine is used as a desulfurizer, but the tributylphosphine has strong reducibility, and has the risk of causing combustion when meeting high heat, open fire or being contacted with an oxidant, so that a substitute desulfurizer needs to be selected;
(2) the solvent is a mixture of toluene and 1, 2-dichloroethane, and the toluene is extremely easy to burn and explode when meeting open fire and high heat and has high toxicity, so that a substitute solvent needs to be selected;
(3) methanol is adopted for crystallization, and the yield is low.
Therefore, a new synthesis process needs to be developed.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: overcomes the defects of the prior art, provides a synthesis method of an latamoxef intermediate, is simple and easy to implement, reduces the production cost, improves the product yield, recycles the solvent, and has higher economic value and environmental protection benefit.
The synthesis method of the latamoxef intermediate takes 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate as a raw material, and the raw material is refluxed with triethyl phosphite in isobutanol solvent to obtain the product 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-diphenylmethyl enoate.
The synthesis method of the latamoxef intermediate preferably comprises the following steps:
adding isobutanol into a three-necked bottle, detecting that the water content of a solvent is less than or equal to 0.1 wt%, and adding 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate (I);
heating to 45-50 ℃ while stirring, and adding triethyl phosphite;
thirdly, heating reflux reaction, and discharging the byproduct water under the micro negative pressure of-0.005 to-0.01 MPa;
detecting that the residual 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester is less than or equal to 1 wt% of the raw material, and after the reaction is finished, distilling isobutanol out;
fifthly, adding acetone into the reaction liquid after the isobutanol is evaporated, controlling the temperature to be 35-40 ℃ and growing the crystals for 3-4 hours;
sixthly, cooling to 0-5 ℃, performing suction filtration, and washing materials with acetone;
seventhly, drying for 6-7 hours at 35-40 ℃ in vacuum to obtain a target product (II);
eighthly, detecting the water content of the distilled isobutanol, and directly applying the water content after the water content is qualified;
ninthly, evaporating the pumping filtration mother liquor out of acetone for reuse, wherein the residual liquid is mainly triethyl thiophosphate, and detecting the content for post-treatment;
the reaction route is as follows:
preferably, the mass ratio of 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-enoic acid benzhydryl ester, isobutyl alcohol, triethyl phosphite, acetone for crystal growing and acetone for washing is 1: 7.4-7.5: 0.34-0.35: 4.0-4.1: 1.3-1.4.
Compared with the prior art, the invention has the following beneficial effects:
(1) according to the invention, isobutanol with low toxicity is used as a reflux solvent, so that the waste gas treatment pressure is reduced, and the environment-friendly benefit is good;
(2) the invention uses acetone as a crystallization solvent, the obtained product has good crystal form, and the molar yield can reach 78%;
(3) the method uses triethyl phosphite to carry out intramolecular substitution reaction, has simple process, and reduces the generation of byproduct sulfur dioxide;
(4) the isobutanol distilled by the method can be recycled, so that the production cost is reduced;
(5) the invention has the advantages that the distilled acetone mother liquor is mainly triethyl thiophosphate, the post-treatment procedure is simplified, and the cost is reduced.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
370g of isobutanol is added to a three-necked flask, the solvent moisture is detected at 0.05%, and 50g of 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid benzhydryl ester is added.
② stirring and heating to 50 ℃, and adding 17g triethyl phosphite.
Thirdly, heating up and refluxing, and separating out the byproduct water under micro negative pressure (-0.005 MPa).
Fourthly, detecting that the residue of the raw material is 0.9 percent, and distilling the isobutanol after the reaction is finished.
Fifthly, adding 200g of acetone into the reaction liquid after the isobutanol is distilled, controlling the temperature at 40 ℃, and growing the crystals for 4 hours.
Sixthly, after the crystal growth is finished, cooling to 5 ℃, filtering, and washing 65g of acetone.
Seventhly, drying for 7 hours in vacuum at 35 ℃ to obtain the product (II), wherein the molar yield is 78.12 percent, and the purity is 98.85 percent.
And evaporating the suction filtration mother liquor to remove acetone, and directly mechanically applying the acetone to the next batch.
Example 2
375g of isobutanol is added into a three-necked flask, the solvent moisture is detected at 0.06%, and 50g of 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid benzhydryl ester is added.
② stirring and heating to 47 ℃, and adding 17.5g triethyl phosphite.
Thirdly, heating up and refluxing, and separating out the byproduct water under micro negative pressure (-0.008 MPa).
Fourthly, detecting that the residue of the raw materials is 0.85 percent, and distilling the isobutanol after the reaction is finished.
Fifthly, adding 203g of acetone into the reaction liquid after the isobutanol is distilled, controlling the temperature to be 35 ℃, and growing the crystals for 3 hours.
Sixthly, after the crystal growth is finished, cooling to 2 ℃, filtering, and washing 70g of acetone.
Seventhly, vacuum drying for 6.5 hours at 38 ℃ to obtain the product (II), wherein the molar yield is 78.04%, and the purity is 98.91%.
And evaporating the suction filtration mother liquor to remove acetone, and directly mechanically applying the acetone to the next batch.
Example 3
370g of isobutanol is added to a three-necked flask, the solvent moisture is detected at 0.08%, and 50g of 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid benzhydryl ester is added.
② stirring and heating to 45 ℃, and adding 17.5g triethyl phosphite.
Thirdly, heating up and refluxing, and separating out the byproduct water under the micro negative pressure (-0.01 MPa).
Fourthly, detecting that the residue of the raw material is 0.92 percent, and distilling the isobutanol after the reaction is finished.
Fifthly, adding 205g of acetone into the reaction liquid after the isobutanol is distilled, controlling the temperature at 38 ℃ and growing the crystals for 3.5 hours.
Sixthly, after the crystal growth is finished, cooling to 0 ℃, filtering, and washing 70g of acetone.
Seventhly, drying for 6 hours in vacuum at 40 ℃ to obtain the product (II), wherein the molar yield is 78.27%, and the purity is 98.81%.
And evaporating the suction filtration mother liquor to remove acetone, and directly mechanically applying the acetone to the next batch.
Comparative example 1
370g of toluene and 35g of 1, 2-dichloroethane are added to a three-necked flask, stirred uniformly and 50g of 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid benzhydryl ester is added.
② stirring and heating to 50 ℃, and adding 21g of tributyl phosphine.
And thirdly, heating reflux reaction.
Fourthly, after the reaction is finished, the solvent is distilled off.
Fifthly, adding 200g of methanol into the reaction solution after solvent evaporation, controlling the temperature at 40 ℃ and growing crystals for 4 hours.
Sixthly, after the crystal growth is finished, cooling to 5 ℃, filtering, and washing 60g of methanol.
Seventhly, drying for 7 hours in vacuum at 40 ℃ to obtain the product (II), wherein the molar yield is 48 percent, and the purity is 97.23 percent.
Of course, the foregoing is only a preferred embodiment of the invention and should not be taken as limiting the scope of the embodiments of the invention. The present invention is not limited to the above examples, and equivalent changes and modifications made by those skilled in the art within the spirit and scope of the present invention should be construed as being included in the scope of the present invention.
Claims (10)
1. A synthesis method of latamoxef intermediate is characterized in that: 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid diphenylmethyl ester is taken as a raw material, and is refluxed and reacted with triethyl phosphite in solvent isobutanol to obtain a product, namely 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-enoic acid diphenylmethyl ester.
2. The synthesis process of latamoxef intermediates as claimed in claim 1, characterized in that: the method specifically comprises the following steps:
adding isobutanol into a three-mouth bottle, detecting the moisture of a solvent, and adding 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate (I);
② stirring and heating, and adding triethyl phosphite;
thirdly, heating up and carrying out reflux reaction, and separating out by-product water under micro negative pressure;
fourthly, detecting the residue of the raw materials, and after the reaction is finished, distilling the isobutanol out;
fifthly, adding acetone into the reaction liquid after the isobutanol is steamed, and controlling the temperature to grow crystals;
cooling, suction filtering and washing with acetone;
drying in vacuum to obtain a target product (II);
eighthly, detecting the water content of the distilled isobutanol, and directly applying the water content after the water content is qualified;
ninthly, evaporating the pumping filtration mother liquor out of acetone for reuse, wherein the residual liquid is mainly triethyl thiophosphate, and detecting the content for post-treatment;
the reaction route is as follows:
3. a synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -but-3-enoic acid benzhydryl ester, isobutanol, triethyl phosphite, acetone used for crystal growing and acetone used for washing are in a mass ratio of 1: 7.4-7.5: 0.34-0.35: 4.0-4.1: 1.3-1.4.
4. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: in the step I, the water content of the solvent is detected to be less than or equal to 0.1 wt%.
5. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: and step two, stirring and heating to 45-50 ℃.
6. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: in the third step, the micro negative pressure is-0.005 to-0.01 MPa.
7. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: in the step (iv), the residue of the raw material is detected to be 3, 3-dimethyl-6- (4-methyl-benzoylamino) -4, 7-dioxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid benzhydryl ester which is less than or equal to 1 wt%.
8. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: in the fifth step, the temperature is controlled to be 35-40 ℃ after the acetone is added, and the crystal growing time is 3-4 hours.
9. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: and sixthly, cooling to 0-5 ℃.
10. A synthesis process of latamoxef intermediates as claimed in claim 2, characterized in that: and step (c), drying for 6-7 hours at the vacuum drying temperature of 35-40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011163339.5A CN112300193A (en) | 2020-10-27 | 2020-10-27 | Synthesis method of latamoxef intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011163339.5A CN112300193A (en) | 2020-10-27 | 2020-10-27 | Synthesis method of latamoxef intermediate |
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| CN112300193A true CN112300193A (en) | 2021-02-02 |
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| CN202011163339.5A Pending CN112300193A (en) | 2020-10-27 | 2020-10-27 | Synthesis method of latamoxef intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875571A (en) * | 2012-10-30 | 2013-01-16 | 陕西思尔生物科技有限公司 | Latamoxef Sodium midbody synthetic method |
| CN108840877A (en) * | 2018-06-12 | 2018-11-20 | 赤峰迪生药业有限责任公司 | A kind of preparation method of oxygen cephalosporin intermediate |
-
2020
- 2020-10-27 CN CN202011163339.5A patent/CN112300193A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875571A (en) * | 2012-10-30 | 2013-01-16 | 陕西思尔生物科技有限公司 | Latamoxef Sodium midbody synthetic method |
| CN108840877A (en) * | 2018-06-12 | 2018-11-20 | 赤峰迪生药业有限责任公司 | A kind of preparation method of oxygen cephalosporin intermediate |
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