CN101805311A - Synthetic method of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid - Google Patents
Synthetic method of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid Download PDFInfo
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- CN101805311A CN101805311A CN 201010149423 CN201010149423A CN101805311A CN 101805311 A CN101805311 A CN 101805311A CN 201010149423 CN201010149423 CN 201010149423 CN 201010149423 A CN201010149423 A CN 201010149423A CN 101805311 A CN101805311 A CN 101805311A
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- Prior art keywords
- aceto acetate
- reaction
- methyl aceto
- ainothiazoly loximate
- synthetic method
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 31
- NLARCUDOUOQRPB-WTKPLQERSA-N (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CO\N=C(/C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-WTKPLQERSA-N 0.000 title abstract 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims abstract description 21
- -1 2-methoxyimino ethyl Chemical group 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 238000007069 methylation reaction Methods 0.000 claims abstract description 8
- 238000006146 oximation reaction Methods 0.000 claims abstract description 8
- 238000007670 refining Methods 0.000 claims abstract description 8
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
- 125000004494 ethyl ester group Chemical group 0.000 claims description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 14
- 239000003444 phase transfer catalyst Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 235000010288 sodium nitrite Nutrition 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 229960004249 sodium acetate Drugs 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 4
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000001035 methylating effect Effects 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 230000001988 toxicity Effects 0.000 abstract description 6
- 231100000419 toxicity Toxicity 0.000 abstract description 6
- 229930186147 Cephalosporin Natural products 0.000 abstract description 4
- 229940124587 cephalosporin Drugs 0.000 abstract description 4
- 150000001780 cephalosporins Chemical class 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract description 2
- POBMBNPEUPDXRS-WDZFZDKYSA-N ethyl (2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetate Chemical compound CCOC(=O)C(=N/OC)\C1=CSC(N)=N1 POBMBNPEUPDXRS-WDZFZDKYSA-N 0.000 abstract 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 abstract 2
- 239000012320 chlorinating reagent Substances 0.000 abstract 1
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- 238000011112 process operation Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000000605 extraction Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 7
- 238000004821 distillation Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000007034 nitrosation reaction Methods 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 description 1
- 229960001958 cefodizime Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 1
- 229960000466 cefpirome Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- WJXAHFZIHLTPFR-JLRJEBFFSA-N ceftiolene Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C\SC1=NNC(=O)C(=O)N1CC=O WJXAHFZIHLTPFR-JLRJEBFFSA-N 0.000 description 1
- 229950008880 ceftiolene Drugs 0.000 description 1
- CXHKZHZLDMQGFF-ZSDSSEDPSA-N cefuzonam Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=CN=NS1 CXHKZHZLDMQGFF-ZSDSSEDPSA-N 0.000 description 1
- 229950000807 cefuzonam Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to a synthetic method of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid, which belongs to the synthetic methods of heterocyclic compounds containing 1,3-thiazole ring. The synthetic method is characterized by comprising the following operation steps: 1) homogeneous oximation reaction: preparing 2-hydroxamic ethyl acetoacetate; 2) methylation reaction: preparing 2-methoxyimino ethyl acetoacetate; 3) triphosgene chlorination reaction: preparing 4-chloro-2-methoxyimino ethyl acetoacetate; 4) cyclization reaction: preparing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid ethyl ester; 5) hydrolysis: preparing a crude product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid; and 6) refining: preparing a product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid. The invention provides an oximating agent system which is applicable to homogeneous nitrosification reaction. The invention provides a triphosgene chlorinating agent which has the advantages of small toxicity, safe and convenient storage, transportation and use, easy control of process operation and high yield. The yield of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid ethyl ester is not less than 95.4%; the yield of the crude product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid is not less than 94.4%; and the yield of the finished product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid is not less than 90.5%. The purity of the finished product of the 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid is not less than 99.06%, and the melting point is 182.1 DEG C-183.9 DEG C. The synthetic method is used for synthesizing raw materials of the third generation of cephalosporins.
Description
Technical field
The present invention is a kind of synthetic method of ainothiazoly loximate.Belong to the heterogeneous ring compound synthetic method that contains the 1,3-thiazoles ring, particularly do not contain the preparation method that the heterogeneous ring compound of two two keys is arranged between the annular atoms of other condensed ring.
Background technology
The ainothiazoly loximate chemical name is 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate or thiazolamine-4-methyl isoxime acid, English 2-(2-Amino-4-thiazolyl) by name-2-methoxyiminoacetic acid, and structural formula is:
Ainothiazoly loximate is the raw material that is used for synthetic third generation cephalosporin, the ainothiazoly loximate cephalosporins is for by the infection due to some resistant organisms and the difficult control pathogenic bacteria good curative effect being arranged all, and toxicity is low, broad-spectrum long-acting, and its curative effect is than high tens of times of penicillin.Utilize the ainothiazoly loximate compounds to mainly contain: Cefixime Micronized, Cefpodoxime, cefotaxime, cefepime, the special human relations of cephalo, cefuzonam, cefodizime, cefpirome and ceftiolene etc. as antibiotic side chain synthetic cephalosporins medicine.Therefore, ainothiazoly loximate is a kind of important medicine intermediate.
The synthetic method of traditional ainothiazoly loximate mainly contains three kinds: methyl acetoacetate method, methyl aceto acetate method and 4-chloroacetyl acetacetic ester method.Wherein methyl acetoacetate method and methyl aceto acetate method are to be raw material with methyl acetoacetate or methyl aceto acetate, through nitrosification, methylate, chlorination, cyclization, hydrolysis, the refining ainothiazoly loximate that obtains.And 4-chloroacetyl acetacetic ester method is to be raw material with the 4-chloroacetyl acetacetic ester, through nitrosification, methylate, cyclization, hydrolysis, the refining ainothiazoly loximate that obtains.
In the above-mentioned prior art, the synthetic method of ainothiazoly loximate remains in following technical problem:
1. the nitrosation reaction technological process is an inhomogeneous reaction, and it is long that not only speed of response causes the cycle slowly, and yield is lower.
2. be chlorizating agent with chlorine in the chloridization process process, chlorine is the very big gas of a kind of toxicity, all can bring disadvantageous effect in case take place to reveal to operator's health and environmental safety, and react wayward.
Summary of the invention
The objective of the invention is to avoid above-mentioned weak point of the prior art, and a kind of oximate agent system that is suitable for the homogeneous phase nitrosation reaction is provided,, shorten the production cycle to improve speed of reaction.
The present invention also aims to provide a kind of toxicity less, accumulating, safe and convenient to use, technological operation are easy to control and the higher chlorizating agent of productive rate.
Purpose of the present invention can reach by following measure:
The synthetic method of ainothiazoly loximate of the present invention is characterized in that comprising following operation steps:
1.. homogeneous phase oximation reaction: preparation 2-hydroxyl oxime methyl aceto acetate
The oximate agent adopts Sodium Nitrite to add Glacial acetic acid, its parts by weight ratio is a Sodium Nitrite: Glacial acetic acid=1: 1～5, the consumption of oximate agent is 1～3 times of methyl aceto acetate consumption, under 0 ℃～5 ℃ temperature, methyl aceto acetate and oximate agent homogeneous phase oximation reaction in solvent made 2-hydroxyl oxime methyl aceto acetate in 1～4 hour;
2.. methylation reaction: preparation 2-methoxy imino methyl aceto acetate
The 2-hydroxyl oxime methyl aceto acetate that 1. step is prepared is dissolved in the certain amount of solvent, under the effect of phase-transfer catalyst, add the methylating reagent methyl-sulfate and carry out methylation reaction, the temperature of control reaction system is 5 ℃～15 ℃, the pH value is 8～10, reaction times is 2～4 hours, and the consumption of methyl-sulfate is 1～1.5 times of methyl aceto acetate, makes 2-methoxy imino methyl aceto acetate;
3.. triphosgene chlorination reaction: preparation 4-chloro-2-methoxy imino methyl aceto acetate
The 2-methoxy imino methyl aceto acetate that 2. step is prepared is dissolved in the certain amount of solvent, add a certain amount of organic bases, add triphosgene solution again, wherein, the parts by weight of triphosgene are 0.4～1.0 times of methyl aceto acetate, and the weight percentage of organic bases is 1%～5% of a triphosgene, and the control temperature of reaction system is 10 ℃～20 ℃, reaction times is 1～3 hour, makes 4-chloro-2-methoxy imino methyl aceto acetate;
4.. ring-closure reaction: preparation ainothiazoly loximate ethyl ester
4-chloro-2-methoxy imino methyl aceto acetate and thiocarbamide, sodium-acetate that 3. step is prepared are dissolved in the certain amount of solvent, wherein, the consumption of thiocarbamide and sodium-acetate is respectively 0.3～0.7 times and 0.5～1.2 times of methyl aceto acetate consumption, under the phase-transfer catalyst effect, control reaction temperature was reacted 3～5 hours between 20 ℃～40 ℃, regulated the pH value, the cooling crystallization gets the ainothiazoly loximate ethyl ester;
5.. hydrolysis: preparation ainothiazoly loximate crude product
The ainothiazoly loximate ethyl ester that 4. step is prepared is dissolved in a certain amount of sodium hydroxide solution, the concentration of sodium hydroxide solution is: sodium hydroxide: water=1: 3～8, the consumption of sodium hydroxide solution is 2～8 times of ainothiazoly loximate ethyl ester, controlled temperature is between 20 ℃～50 ℃, and stirring reaction 2～5 hours is after reacting completely, use activated carbon decolorizing, regulate the pH value, the cooling crystallization gets the ainothiazoly loximate crude product;
6.. refining: preparation ainothiazoly loximate product
Ainothiazoly loximate refluxed in appropriate solvent 1～8 hour, and the cooling crystallization obtains purified ainothiazoly loximate product.
The present inventor adopts Sodium Nitrite to add Glacial acetic acid and replaces as the oximate agent, substitute the Sodium Nitrite of always continuing to use in the traditional technology and added the agent of sulfuric acid oximate, make reaction be converted into homogeneous reaction, shortened the reaction times, improved the yield of oximate product by inhomogeneous reaction.Adopt solid-state triphosgene as chlorizating agent, replaced the chlorinated with chlorine agent of traditional technology, solved chlorine toxicity big, react uppity problem, eliminated with chlorine as chlorizating agent, all can bring disadvantageous effect in case take place to reveal to operator's health and environmental safety.Thereby finished task of the present invention.
Purpose of the present invention can also reach by following measure:
The synthetic method of ainothiazoly loximate of the present invention is characterized in that the aqueous solution that the 1. described solvent of step is ethanol or ethylene glycol, and the volume ratio of the aqueous solution is ethanol or ethylene glycol: water=1: 1～3, amount of aqueous solution used are 2～5 times of methyl aceto acetate weight.
The synthetic method of ainothiazoly loximate of the present invention is characterized in that the 2. described solvent of step is methylene dichloride or chloroform, and consumption is 1～2 times of methyl aceto acetate volume.
The synthetic method of ainothiazoly loximate of the present invention, it is characterized in that the 2. described phase-transfer catalyst of step is a kind of in tetramethyl ammonium chloride, Tetrabutyl amonium bromide, benzyltrimethylammonium bromide, benzyl trimethyl ammonium chloride or the polyoxyethylene glycol, the consumption of phase-transfer catalyst is 0.5%～10% of a methyl aceto acetate volume.
The synthetic method of ainothiazoly loximate of the present invention is characterized in that the used alkali of the 2. described adjusting of step pH value is a kind of in salt of wormwood, yellow soda ash, potassium hydroxide, the sodium hydroxide.
The synthetic method of ainothiazoly loximate of the present invention is characterized in that the solvent described in step 3. is a kind of in chloroform, ethylene dichloride or the cyclohexane, and the consumption of solvent is 1～4 times of methyl aceto acetate volume.
The synthetic method of ainothiazoly loximate of the present invention is characterized in that the organic bases described in step 3. is a kind of in DMF, pyridine or the triethylamine.
The synthetic method of ainothiazoly loximate of the present invention, it is characterized in that the solvent described in step 4. is methyl alcohol, ethanol, or the mixture of methyl alcohol, ethanol and water, wherein, the volume ratio of mixture is methyl alcohol (ethanol): water=1: 1～2, the volumetric usage of solvent are 2～5 times of methyl aceto acetate volume; Described phase-transfer catalyst is a kind of in tetramethyl ammonium chloride, Tetrabutyl amonium bromide, benzyltrimethylammonium bromide, benzyl trimethyl ammonium chloride or the polyoxyethylene glycol, and the consumption of phase-transfer catalyst is 0.5%～10% of a methyl aceto acetate weight.The scope of described pH value is 6～8.
The synthetic method of ainothiazoly loximate of the present invention, the scope that it is characterized in that the pH value described in step 5. is 2～3.
The synthetic method of ainothiazoly loximate of the present invention is characterized in that the solvent described in step 6. is a kind of in methyl alcohol, ethanol, methylene dichloride or the chloroform.
The synthetic method of ainothiazoly loximate of the present invention has produced following positively effect compared to existing technology:
1. a kind of oximate agent system that is suitable for the homogeneous phase nitrosation reaction is provided,, has shortened the production cycle to improve speed of reaction.
2. provide a kind of toxicity less, accumulating, safe and convenient to use, technological operation are easy to control and the higher triphosgene chlorizating agent of productive rate.
3. the yield of ainothiazoly loximate ethyl ester 〉=95.4%; The yield of ainothiazoly loximate crude product 〉=94.4%; The yield of ainothiazoly loximate finished product 〉=90.5%.
4. the purity of ainothiazoly loximate finished product 〉=99.06%, fusing point: 182.1 ℃～183.9 ℃.
Embodiment
The present invention will now be further detailed embodiment:
Embodiment 1
1.. homogeneous phase oximation reaction: preparation 2-hydroxyl oxime methyl aceto acetate
In there-necked flask, add aqueous ethanolic solution (volume ratio 1: 2) 60mL, methyl aceto acetate 20mL, Sodium Nitrite 10g, stir, under 0～5 ℃ of the temperature, drip the 30g Glacial acetic acid, 1h adds, and adds the back and continues stirring reaction 2h, with chloroform 25mL extraction, separatory, organic phase is directly used in next step reaction.
2.. methylation reaction: preparation 2-methoxy imino methyl aceto acetate
The 2-hydroxyl oxime methyl aceto acetate organic phase that 1. step prepares is transferred in the flask, added 20% sodium carbonate solution 110mL and 0.4g polyoxyethylene glycol.Then, begin to drip methyl-sulfate 19mL, control reaction temperature is 10 ℃～14 ℃, and the pH value is 8～10, and 1h dropwises, and adds back insulation 3h.Add chloroform 20mL, the extraction separatory.The organic phase anhydrous sodium sulfate drying filters, and underpressure distillation is removed chloroform and got yellow oil.
3.. triphosgene chlorination reaction: preparation 4-chloro-2-methoxy imino methyl aceto acetate
Earlier the 10g triphosgene is dissolved in the 20mL chloroform, and adds 0.5mLDMF, be made into triphosgene solution, be added drop-wise in the 2-methoxy imino methyl aceto acetate that 2. step prepare, control reaction temperature is 15 ℃～17 ℃ again, and the reaction times is 2.5h, react the after washing that finishes, layering.Use the 40mL chloroform extraction, the organic phase underpressure distillation is removed chloroform and is got yellow oil.
4.. ring-closure reaction: preparation ainothiazoly loximate ethyl ester
The adding volume ratio is 1: 1 methanol aqueous solution 60mL in flask, add 8g thiocarbamide, 16g sodium-acetate and polyoxyethylene glycol 0.4g, under 30～35 ℃ of temperature, drip the 4-chloro-2-methoxy imino methyl aceto acetate that 3. step prepares, the dropping time is 1.5h, dropwise, insulation reaction 2h regulates pH value to 7.0～7.5 with sodium carbonate solution again, is cooled to below 0 ℃ and separates out crystal, centrifugal, dry that yellow crystal is the ainothiazoly loximate ethyl ester, yield is 96.0%.
5.. hydrolysis: preparation ainothiazoly loximate crude product
The ainothiazoly loximate ethyl ester that 4. step is prepared is dissolved in the sodium hydroxide solution of 95mL20%, 25 ℃～30 ℃ of temperature controls, stirring reaction 3h.After reacting completely, use activated carbon decolorizing, use salt acid for adjusting pH value to 2.5～3.0 then, be cooled to below 0 ℃ and separate out crystal, centrifugal, the dry ainothiazoly loximate crude product that gets, yield is 94.6%.
6.. refining: preparation ainothiazoly loximate product
With ainothiazoly loximate crude product reflux 6h in methyl alcohol, be cooled to below 0 ℃ and separate out crystal, centrifugal, be drying to obtain the ainothiazoly loximate purified product, purity 99.17%, yield 90.5%, 182.1～183.9 ℃ of fusing points.
Embodiment 2
1.. homogeneous phase oximation reaction: preparation 2-hydroxyl oxime methyl aceto acetate
In there-necked flask, add aqueous ethanolic solution (volume ratio 1: 2) 60mL, methyl aceto acetate 20mL, Sodium Nitrite 10g, stir, under 0～5 ℃ of the temperature, drip the 40g Glacial acetic acid, 1h adds, and adds the back and continues stirring reaction 2h, with chloroform 25mL extraction, separatory, organic phase is directly used in next step reaction.
2.. methylation reaction: preparation 2-methoxy imino methyl aceto acetate
The 2-hydroxyl oxime methyl aceto acetate organic phase that 1. step prepares is transferred in the flask, added 20% sodium carbonate solution 110mL and 0.4g Tetrabutyl amonium bromide.Then, begin to drip methyl-sulfate 19mL, control reaction temperature is 10 ℃～14 ℃, and the pH value is 8～10, and 1h dropwises, and adds back insulation 3h.Add chloroform 20mL, the extraction separatory.The organic phase anhydrous sodium sulfate drying filters, and underpressure distillation is removed chloroform and got yellow oil.
3.. triphosgene chlorination reaction: preparation 4-chloro-2-methoxy imino methyl aceto acetate
Earlier the 10g triphosgene is dissolved in the 20mL chloroform, and adds the 0.5mL pyridine, be made into triphosgene solution, be added drop-wise in the 2-methoxy imino methyl aceto acetate that 2. step prepare, control reaction temperature is 15 ℃～17 ℃ again, and the reaction times is 2.5h, react the after washing that finishes, layering.Use the 40mL chloroform extraction, the organic phase underpressure distillation is removed chloroform and is got yellow oil.
4.. ring-closure reaction: preparation ainothiazoly loximate ethyl ester
The adding volume ratio is 1: 1 methanol aqueous solution 60mL in flask, add 8g thiocarbamide, 16g sodium-acetate and Tetrabutyl amonium bromide 0.4g, under 30～35 ℃ of temperature, drip the 4-chloro-2-methoxy imino methyl aceto acetate that 3. step prepares, the dropping time is 1.5h, dropwise, insulation reaction 2h regulates pH value to 7.0～7.5 with sodium carbonate solution again, is cooled to below 0 ℃ and separates out crystal, centrifugal, dry that yellow crystal is the ainothiazoly loximate ethyl ester, yield is 95.4%.
5.. hydrolysis: preparation ainothiazoly loximate crude product
The ainothiazoly loximate ethyl ester that 4. step is prepared is dissolved in the sodium hydroxide solution of 95mL20%, 25 ℃～30 ℃ of temperature controls, stirring reaction 3h.After reacting completely, use activated carbon decolorizing, use salt acid for adjusting pH value to 2.5～3.0 then, be cooled to below 0 ℃ and separate out crystal, centrifugal, the dry ainothiazoly loximate crude product that gets, yield is 94.4%.
6.. refining: preparation ainothiazoly loximate product
With ainothiazoly loximate crude product reflux 6h in methyl alcohol, be cooled to below 0 ℃ and separate out crystal, centrifugal, be drying to obtain the ainothiazoly loximate purified product, purity 99.35%, yield 91.2%, 182.5～183.6 ℃ of fusing points.
Embodiment 3
1.. homogeneous phase oximation reaction: preparation 2-hydroxyl oxime methyl aceto acetate
In there-necked flask, add aqueous ethanolic solution (volume ratio 1: 2) 60mL, methyl aceto acetate 20mL, Sodium Nitrite 10g, stir, under 0～5 ℃ of the temperature, Dropwise 5 0g Glacial acetic acid, 1h adds, and adds the back and continues stirring reaction 2h, with chloroform 25mL extraction, separatory, organic phase is directly used in next step reaction.
2.. methylation reaction: preparation 2-methoxy imino methyl aceto acetate
The 2-hydroxyl oxime methyl aceto acetate organic phase that 1. step prepares is transferred in the flask, added 20% sodium carbonate solution 110mL and 0.5g benzyl trimethyl ammonium chloride.Then, begin to drip methyl-sulfate 19mL, control reaction temperature is 10 ℃～14 ℃, and the pH value is 8～10, and 1h dropwises, and adds back insulation 3h.Add chloroform 20mL, the extraction separatory.The organic phase anhydrous sodium sulfate drying filters, and underpressure distillation is removed chloroform and got yellow oil.
3.. triphosgene chlorination reaction: preparation 4-chloro-2-methoxy imino methyl aceto acetate
Earlier the 10g triphosgene is dissolved in the 20mL chloroform, and adds the 0.5mL triethylamine, be made into triphosgene solution, be added drop-wise in the 2-methoxy imino methyl aceto acetate that 2. step prepare, control reaction temperature is 15 ℃～17 ℃ again, and the reaction times is 2.5h, react the after washing that finishes, layering.Use the 40mL chloroform extraction, the organic phase underpressure distillation is removed chloroform and is got yellow oil.
4.. ring-closure reaction: preparation ainothiazoly loximate ethyl ester
The adding volume ratio is 1: 1 methanol aqueous solution 60mL in flask, add 8g thiocarbamide, 16g sodium-acetate and benzyl trimethyl ammonium chloride 0.5g, under 30～35 ℃ of temperature, drip the 4-chloro-2-methoxy imino methyl aceto acetate that 3. step prepares, the dropping time is 1.5h, dropwise, insulation reaction 2h regulates pH value to 7.0～7.5 with sodium carbonate solution again, is cooled to below 0 ℃ and separates out crystal, centrifugal, dry that yellow crystal is the ainothiazoly loximate ethyl ester, yield is 96.5%.
5.. hydrolysis: preparation ainothiazoly loximate crude product
The ainothiazoly loximate ethyl ester that 4. step is prepared is dissolved in the sodium hydroxide solution of 95mL20%, 25 ℃～30 ℃ of temperature controls, stirring reaction 3h.After reacting completely, use activated carbon decolorizing, use salt acid for adjusting pH value to 2.5～3.0 then, be cooled to below 0 ℃ and separate out crystal, centrifugal, the dry ainothiazoly loximate crude product that gets, yield is 95.3%.
6.. refining: preparation ainothiazoly loximate product
With ainothiazoly loximate crude product reflux 6h in methyl alcohol, be cooled to below 0 ℃ and separate out crystal, centrifugal, be drying to obtain the ainothiazoly loximate purified product, purity 99.06%, yield 90.8%, 182.1～183.5 ℃ of fusing points.
Claims (10)
1. the synthetic method of an ainothiazoly loximate is characterized in that comprising following operation steps:
1.. homogeneous phase oximation reaction: preparation 2-hydroxyl oxime methyl aceto acetate
The oximate agent adopts Sodium Nitrite to add Glacial acetic acid, its parts by weight ratio is a Sodium Nitrite: Glacial acetic acid=1: 1～5, the consumption of oximate agent is 1～3 times of methyl aceto acetate consumption, under 0 ℃～5 ℃ temperature, methyl aceto acetate and oximate agent homogeneous phase oximation reaction in solvent made 2-hydroxyl oxime methyl aceto acetate in 1～4 hour;
2.. methylation reaction: preparation 2-methoxy imino methyl aceto acetate
The 2-hydroxyl oxime methyl aceto acetate that 1. step is prepared is dissolved in the certain amount of solvent, under the effect of phase-transfer catalyst, add the methylating reagent methyl-sulfate and carry out methylation reaction, the temperature of control reaction system is 5 ℃～15 ℃, the pH value is 8～10, reaction times is 2～4 hours, and the consumption of methyl-sulfate is 1～1.5 times of methyl aceto acetate consumption, makes 2-methoxy imino methyl aceto acetate;
3.. triphosgene chlorination reaction: preparation 4-chloro-2-methoxy imino methyl aceto acetate
The 2-methoxy imino methyl aceto acetate that 2. step is prepared is dissolved in the certain amount of solvent, add a certain amount of organic bases, add triphosgene solution again, wherein, the parts by weight of triphosgene are 0.4～1.0 times of methyl aceto acetate, and the weight percentage of organic bases is 1%～5% of a triphosgene, and the control temperature of reaction system is 10 ℃～20 ℃, reaction times is 1～3 hour, makes 4-chloro-2-methoxy imino methyl aceto acetate;
4.. ring-closure reaction: preparation ainothiazoly loximate ethyl ester
4-chloro-2-methoxy imino methyl aceto acetate and thiocarbamide, sodium-acetate that 3. step is prepared are dissolved in the certain amount of solvent, wherein, the consumption of thiocarbamide and sodium-acetate is respectively 0.3～0.7 times and 0.5～1.2 times of methyl aceto acetate consumption, under the phase-transfer catalyst effect, control reaction temperature was reacted 3～5 hours between 20 ℃～40 ℃, regulated the pH value, the cooling crystallization gets the ainothiazoly loximate ethyl ester;
5.. hydrolysis: preparation ainothiazoly loximate crude product
The ainothiazoly loximate ethyl ester that 4. step is prepared is dissolved in a certain amount of sodium hydroxide solution, the concentration of sodium hydroxide solution is: sodium hydroxide: water=1: 3～8, the consumption of sodium hydroxide solution is 2～8 times of ainothiazoly loximate ethyl ester, controlled temperature is between 20 ℃～50 ℃, and stirring reaction 2～5 hours is after reacting completely, use activated carbon decolorizing, regulate the pH value, the cooling crystallization gets the ainothiazoly loximate crude product;
6.. refining: preparation ainothiazoly loximate product
Ainothiazoly loximate refluxed in appropriate solvent 1～8 hour, and the cooling crystallization obtains purified ainothiazoly loximate product.
2. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the aqueous solution that the 1. described solvent of step is ethanol or ethylene glycol, the volume ratio of the aqueous solution is ethanol or ethylene glycol: water=1: 1～3, amount of aqueous solution used are 2～5 times of methyl aceto acetate weight.
3. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the 2. described solvent of step is methylene dichloride or chloroform, consumption is 1～2 times of methyl aceto acetate volume.
4. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the 2. described phase-transfer catalyst of step is a kind of in tetramethyl ammonium chloride, Tetrabutyl amonium bromide, benzyltrimethylammonium bromide, benzyl trimethyl ammonium chloride or the polyoxyethylene glycol, the consumption of phase-transfer catalyst is 0.5%～10% of a methyl aceto acetate volume.
5. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the used alkali of step 2. described adjusting pH value is a kind of in salt of wormwood, yellow soda ash, potassium hydroxide, the sodium hydroxide.
6. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the solvent described in step is 3. is a kind of in chloroform, ethylene dichloride or the hexanaphthene, the consumption of solvent is 1～4 times of methyl aceto acetate volume.
7. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the organic bases described in step 3. is a kind of in DMF, pyridine or the triethylamine.
8. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the solvent described in step 4. is methyl alcohol, ethanol, or the mixture of methyl alcohol, ethanol and water, wherein, the volume ratio of mixture is methyl alcohol (ethanol): water=1: 1～2, the volumetric usage of solvent are 2～5 times of methyl aceto acetate volume; Described phase-transfer catalyst is a kind of in tetramethyl ammonium chloride, Tetrabutyl amonium bromide, benzyltrimethylammonium bromide, benzyl trimethyl ammonium chloride or the polyoxyethylene glycol, and the consumption of phase-transfer catalyst is 0.5%～10% of a methyl aceto acetate weight.The scope of described pH value is 6～8.
9. according to the synthetic method of the ainothiazoly loximate of claim 1, the scope that it is characterized in that the pH value described in step 5. is 2～3.
10. according to the synthetic method of the ainothiazoly loximate of claim 1, it is characterized in that the solvent described in step 6. is a kind of in methyl alcohol, ethanol, methylene dichloride or the chloroform.
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