CN102093266B - Method for preparing O-tosyl-2-carbamoyl-2-methoxyl-imido-acetamido-oxime - Google Patents
Method for preparing O-tosyl-2-carbamoyl-2-methoxyl-imido-acetamido-oxime Download PDFInfo
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Abstract
The invention relates to a method for preparing O-tosyl-2-carbamoyl-2-methoxyl-imido-acetamido-oxime, which comprises the following steps: (1) reacting cyanoacetamide, which is used as an initial raw material, with sodium nitrite in a nitrosation mode to obtain a reaction intermediate, and reacting the reaction intermediate with dimethyl sulfate in an esterification mode to obtain 2-cyano-2-methoxyl-imido-acetamide; and (2) under the action of hydroxylamine hydrochloride, hydrolyzing cyano groups in the 2-cyano-2-methoxyl-imido-acetamide obtained in the step (1) into amino groups, and reacting with p-methylbenzene sulfonyl chloride in an esterification mode to generate the O-tosyl-2-carbamoyl-2-methoxyl-imido-acetamido-oxime. The preparation method provided by the invention has the advantages of accessible raw materials, short technical process and high yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to the organic synthesis field, relate to a kind of synthetic method that can be used for the important intermediate O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime of synthetic Cefozopran side-chain acid.
Background technology
In recent years, along with the raising of people's living standard, people increase day by day to healthy concern.The mean lifetime of global human progressively increases.In China, reached 72 years old to people's in 2008 mean lifetime.The trend that people's life-span increases still can continue, and why this good result is arranged, and depends on the raising of China's medical level after all.And the very big part of the raising of medical level comes from the development of antibiotic medicine.To 2008, development of antibiotics obtained significant progress, the 4th generation the microbiotic cefclidin and Cefozopran also put on market, for very big pushing effect is played in the development of social medical and health care system.
O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime is the important intermediate of 7 side chains of Cefozopran, and its synthetic method is studied and optimized, and is an important problem in the synthetic field of medicine.Because have only the synthetic of intermediate to be optimized, just can improve yield, reduce the production cost of cephalosporins medicine, for human health is made bigger contribution.
EP0203271 discloses a kind of Cefozopran 3 and has been the preparation method of level Four ammonium methyl structural.CN101265267A discloses the preparation method of cefozopran hydrochloride and the preparation method of powder injection.CN200510064421.1 discloses the method that " one kettle way " prepares Cefozopran and intermediate.But seldom there is patent to relate to the preparation method of Cefozopran side-chain acid.
" (z)-2-(5-amino-1; 2; 4-thiadiazoles-3-yl)-2-methoxyimino acetate graphical Synthetic Routes ". (Liu Mingliang, Liu Bingquan, Cao Jue, Guo Huiyuan etc., Chinese Journal of Pharmaceuticals, 2006,37 (11): 789-791) set forth the synthetic route of cefozopran hydrochloride side-chain acid, wherein side-chain acid synthetic is divided into two kinds of methods: the one, on the side-chain acid structure, introduce methoxyimino earlier, and the 2nd, methoxyimino is introduced in the back on the side-chain acid structure.Intermediate described in the present invention is for preparing the important intermediate of Cefozopran side-chain acid according to the method for introducing methoxyimino earlier.Because it is tediously long to prepare Cefozopran side-chain acid route according to the back preparation method who introduces methoxyimino, severe reaction conditions, yield is lower, and production cost is very high, unsuitable suitability for industrialized production.And the reaction conditions temperature, the method for introducing methoxyimino earlier that production cost is low then is the important route of research Cefozopran side-chain acid, and studies the intermediate of this route is synthetic, then is replenishment of process, the effective ways that reduce production costs.Bibliographical information does not all have provides the synthetic method of carrying out Cefozopran side-chain acid intermediate in detail, yet the technical study of Cefozopran side-chain acid intermediate can obviously reduce industrial production cost, improves the market competitiveness.The present invention just is being based on this kind consideration, and the intermediate of Cefozopran side-chain acid synthetic studied and to process optimization, obtain a practicable suitability for industrialized production route.
Summary of the invention
The present invention aims to provide a kind of method of improved synthetic Cefozopran important intermediate, and this method starting raw material is easy to get, and yield height, purity height, cost are low, are more suitable for suitability for industrialized production.
The method for preparing O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime provided by the invention comprises the steps:
1) with the Malonamide nitrile be starting raw material, earlier carry out nitrosation reaction and obtain reaction intermediate, and then carry out esterification with methyl-sulfate and obtain 2-cyano group-2-methoxyimino ethanamide with Sodium Nitrite:
2) the 2-cyano group that step 1 is obtained-2-methoxyimino ethanamide becomes amino with the cyan-hydrolysis in 2-cyano group-2-methoxyimino ethanamide under the effect of oxammonium hydrochloride, and then generates 0-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime with p-methyl benzene sulfonic chloride generation esterification:
Wherein, in the step 1), be starting raw material with the Malonamide nitrile, earlier carry out nitrosation reaction with Sodium Nitrite and sulfuric acid, after the reaction, with in the alkali and remaining sulfuric acid to weakly alkaline, reaction product is not handled, directly add methyl-sulfate and carry out esterification.
Step 2) in; 2-cyano group-2-methoxyimino ethanamide that step 1 is obtained becomes amino with the cyan-hydrolysis in 2-cyano group-2-methoxyimino ethanamide under the effect of oxammonium hydrochloride; the not treated direct input Tosyl chloride of product after hydrolysis finishes carries out esterification, obtains 0-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime through aftertreatment.
In the step 1), the mol ratio of the amount of Malonamide nitrile, Sodium Nitrite, sulfuric acid and methyl-sulfate is n
1: n
2: n
3: n
4=1.0: 1.0～1.2: 0.4～0.6: 1.0～1.5, preferred n
1: n
2: n
3: n
4=1: 1: 0.45: 1.
In the step 1), the nitrosation reaction condition is 40～50 ℃ of temperature, reaction times 2～5h.
In the step 1), the remaining sulfuric acid of nitrosification post neutralization descends the esterification in step then, and neutralisation of sulphuric acid is selected sodium hydroxide or yellow soda ash for use, preferred yellow soda ash.
Step 2) in, compound (IV) with the reaction mol ratio of oxammonium hydrochloride is: 1: 1.0～1.5, and preferred 1: 1.1.
Step 2) in, hydrolysis temperature is 15～30 ℃, preferred 25 ℃.
Step 2) in, compound (IV) with the reaction mol ratio of p-methyl benzene sulfonic chloride is: 1: 1.0～1.5, and preferred 1: 1.1.
Step 2) in, temperature of reaction is 0～10 ℃, preferred 5 ℃.
Beneficial effect of the present invention is as follows:
1) determines with Malonamide nitrile (Compound I I) to be the synthesis route of starting raw material.The side-chain acid of production Cefozopran in the market has two kinds of operational paths basically, and their starting raw material separately is respectively the 3-An isoxazole and third dicyan.Wherein 3-An isoxazole is hard to buy, and third dicyan is comparatively expensive, is not suitable for suitability for industrialized production, causes the production cost of Cefozopran higher, and China's market competitiveness of antibiotic in the world descends.With the excellent honest and clean Malonamide nitrile of price is raw material, then can solve the difficult and high problem of cost of raw material sources.
2) preparation of product is utilized the method for twice " cooking different foods in one pot ", carry out nitrated, esterification and hydrolysis, esterification.Only need carry out twice " cooking different foods in one pot " for four reactions that take place and get final product, shorten technical process, reduce production cost, yield height, purity height, the demand of suitable suitability for industrialized production.
3) Malonamide nitrile carries out nitration reaction, catalyzer is the vitriol oil, controlled temperature is between 38-48 ℃, directly add yellow soda ash then and be neutralized to meta-alkalescence, need not reaction product is handled, utilize the method input the next step raw material sulphuric acid dimethyl ester of " cooking different foods in one pot " to carry out esterification, obtain intermediate 2-cyano group-2-methoxyimino ethanamide (compound III).
4) will go up step products obtained therefrom 2-cyano group-2-methoxyimino ethanamide and separate, and still utilize the method for " cooking different foods in one pot " directly to descend the hydrolysis reaction and the esterification in step.Hydrolysis cyano group carries out in methyl alcohol, and raw material is selected oxammonium hydrochloride for use.The not treated direct input the next step material Tosyl chloride of product (compound IV) after hydrolysis finishes, triethylamine is a catalyzer, temperature control is below 5 ℃, the reaction process heat release, the adding speed of raw material needs slowly.Esterification is carried out aftertreatment after finishing, and isolates product O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime (Compound I).
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
The first step: the preparation of intermediate 2-cyano group-2-methoxyimino ethanamide (compound III)
In the 500mL there-necked flask, drop into Malonamide nitrile 45g (0.53mol), 90mL water, drop into 36.6g (0.53mol) Sodium Nitrite then, controlled temperature is between 38-48 ℃, drip massfraction then and be 62.5% sulfuric acid 38g (0.23mol), drip the back and under same temperature, stir 2-3h, (developping agent is an ethyl acetate to TLC method monitoring reaction: sherwood oil=5: 3) to finishing, the adding massfraction is sodium carbonate solution accent reaction solution PH=8.5～9.0 of 40%, temperature control drips methyl-sulfate 67g (0.53mol) between 38-48 ℃, drip the back and continue to stir 3h,, solid crystal is filtered with the frozen water cooling, use cold water washing, drying gets 50g 2-cyano group-2-methoxyimino ethanamide, mp:165-170 ℃.Liquid phase normalization method content 98.99%, yield 73.2%.
Embodiment 2
The first step: the preparation of intermediate 2-cyano group-2-methoxyimino ethanamide (compound III)
In the 500mL there-necked flask, drop into Malonamide nitrile 45g (0.53mol), 90mL water, drop into 36.6g (0.53mol) Sodium Nitrite then, controlled temperature is between 38-48 ℃, drip massfraction then and be 62.5% sulfuric acid 50.0g (0.32mol), drip the back and under same temperature, stir 2-3h, (developping agent is an ethyl acetate to TLC method monitoring reaction: sherwood oil=5: 3) to finishing, the adding massfraction is 10% sodium hydroxide solution, control pH=7.5-8.5, temperature control drips methyl-sulfate 100.0g (0.79mol) between 38-48 ℃, drip the back and continue to stir 3h, cool off with frozen water, solid crystal is filtered, use cold water washing, drying, get 45g2-cyano group-2-methoxyimino ethanamide, mp:165-170 ℃.Liquid phase normalization method content 98.5%, yield 65.85%.
Embodiment 3
Second step: the preparation of O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime (Compound I)
In the 500mL there-necked flask, add 20g (0.16mol) 2-cyano group-2-methoxyimino ethanamide, 12g (0.17mol) oxammonium hydrochloride, 160mL methyl alcohol, at room temperature stir, and to wherein slowly dripping 24mL (0.17mol) triethylamine, added the back stir about 5 hours, expansion plate is observed and is shown no raw material point (developping agent: methyl alcohol: sherwood oil=5: 3), with the reaction solution cooling, add about 60mL methyl alcohol, and add 33.2g (0.17mol) p-methyl benzene sulfonic chloride, temperature is below 5 ℃ in the control, p-methyl benzene sulfonic chloride will little by little add, and drips 30mL (0.21mol) triethylamine simultaneously, drips the back and continues to stir 1 hour down synthermal, expansion plate is observed and is shown that (developping agent is a methyl alcohol to no raw material point: sherwood oil=5: 3), then with in the reaction solution impouring 1000mL beaker, and to wherein injecting about 830mL water, crystallization is separated out, cooling, filter, wash with water, product is the particulate state light yellow crystal.Mp:124-126 ℃, weigh 32.8g, HPLC normalization method content 95.97%, yield 66.3%.
Embodiment 4
Second step: the preparation of O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime (Compound I)
In the 500mL there-necked flask, add 20g (0.16mol) 2-cyano group-2-methoxyimino ethanamide, 12g (0.17mol) oxammonium hydrochloride, 160mL methyl alcohol, at room temperature stir, and to wherein slowly dripping 24mL (0.17mol) triethylamine, added the back stir about 4 hours, expansion plate is observed and is shown no raw material point (developping agent: methyl alcohol: sherwood oil=5: 3), with the reaction solution cooling, add about 60mL methyl alcohol, and add 49.8g (0.255mol) p-methyl benzene sulfonic chloride, temperature is below 5 ℃ in the control, p-methyl benzene sulfonic chloride will little by little add, and drips 30mL (0.21mol) triethylamine simultaneously, drips the back and continues to stir 2 hours down synthermal, expansion plate is observed and is shown that (developping agent is a methyl alcohol to no raw material point: sherwood oil=5: 3), then with in the reaction solution impouring 1000mL beaker, and to wherein injecting about 830mL water, crystallization is separated out, cooling, filter, wash with water, product is the particulate state light yellow crystal.Mp:124-126 ℃, weigh 34.8g, HPLC normalization method content 96.0%, yield 70.5%.
Embodiment 5
Second step: the preparation of O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime (Compound I)
In the 500mL there-necked flask, add 20g (0.16mol) 2-cyano group-2-methoxyimino ethanamide, 17g (0.24mol) oxammonium hydrochloride, 160mL methyl alcohol, at room temperature stir, and to wherein slowly dripping 24mL (0.17mol) triethylamine, added the back stir about 4 hours, expansion plate is observed and is shown no raw material point (developping agent: methyl alcohol: sherwood oil=5: 3), with the reaction solution cooling, add about 60mL methyl alcohol, and add 49.8g (0.255mol) p-methyl benzene sulfonic chloride, temperature is below 5 ℃ in the control, p-methyl benzene sulfonic chloride will little by little add, and drips 30mL (0.21mol) triethylamine simultaneously, drips the back and continues to stir 2 hours down synthermal, expansion plate is observed and is shown that (developping agent is a methyl alcohol to no raw material point: sherwood oil=5: 3), then with in the reaction solution impouring 1000mL beaker, and to wherein injecting about 830mL water, crystallization is separated out, cooling, filter, wash with water, product is the particulate state light yellow crystal.Mp:124-126 ℃, weigh 35.2g, HPLC normalization method content 96.0%, yield 71.3%.
Embodiment 6
Second step: the preparation of O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime (Compound I)
In the 500mL there-necked flask, add 20g (0.16mol) 2-cyano group-2-methoxyimino ethanamide, 12g (0.17mol) oxammonium hydrochloride, 160mL methyl alcohol, at room temperature stir, and to wherein slowly dripping 24mL (0.17mol) triethylamine, added the back stir about 5 hours, expansion plate is observed and is shown no raw material point (developping agent: methyl alcohol: sherwood oil=5: 3), with the reaction solution cooling, add about 60mL methyl alcohol, and add 33.2g (0.17mol) p-methyl benzene sulfonic chloride, temperature is below 10 ℃ in the control, p-methyl benzene sulfonic chloride will little by little add, and drips 30mL (0.21mol) triethylamine simultaneously, drips the back and continues to stir 1 hour down synthermal, expansion plate is observed and is shown that (developping agent is a methyl alcohol to no raw material point: sherwood oil=5: 3), then with in the reaction solution impouring 1000mL beaker, and to wherein injecting about 830mL water, crystallization is separated out, cooling, filter, wash with water, product is the particulate state light yellow crystal.Mp:124-126 ℃, weigh 31.5g, HPLC normalization method content 95.97%, yield 63.7%.
By above embodiment 1-6 as can be seen, do not have harsh reaction conditions in the method for Cefozopran side-chain acid intermediate formula of the present invention (I) compound, reaction process is short, and the yield height has been saved reaction times and energy consumption, has reduced cost, is fit to suitability for industrialized production.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (12)
1. a method for preparing O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime comprises the steps:
1) with the Malonamide nitrile be starting raw material, earlier carry out nitrosation reaction with Sodium Nitrite and sulfuric acid, after the reaction, with in the alkali and remaining sulfuric acid to weakly alkaline, reaction product is not handled, directly add methyl-sulfate and carry out esterification:
2) the 2-cyano group that step 1) is obtained-2-methoxyimino ethanamide becomes amino with the cyan-hydrolysis in 2-cyano group-2-methoxyimino ethanamide under the effect of oxammonium hydrochloride, and then generates O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime with p-methyl benzene sulfonic chloride generation esterification:
In the step 1), the mol ratio of the amount of Malonamide nitrile, Sodium Nitrite, sulfuric acid and methyl-sulfate is n
1: n
2: n
3: n
4=1.0:1.0～1.2:0.4～0.6:1.0～1.5; In the step 1), the nitrosation reaction condition is 40～50 ℃ of temperature, reaction times 2～5h; Step 2) in, hydrolysis temperature is 15～30 ℃.
2. preparation method according to claim 1; it is characterized in that; step 2) in; 2-cyano group-2-methoxyimino ethanamide that step 1 is obtained becomes amino with the cyan-hydrolysis in 2-cyano group-2-methoxyimino ethanamide under the effect of oxammonium hydrochloride; the not treated direct input Tosyl chloride of product after hydrolysis finishes carries out esterification, obtains O-tosyl group-2-carbamyl-2-methoxyimino acetyl amidoxime through aftertreatment.
3. preparation method according to claim 1 is characterized in that, in the step 1), the mol ratio of the amount of Malonamide nitrile, Sodium Nitrite, sulfuric acid and methyl-sulfate is n
1: n
2: n
3: n
4=1:1:0.45:1.
4. preparation method according to claim 1 is characterized in that, in the step 1), the remaining sulfuric acid of nitrosification post neutralization descends the esterification in step then, and neutralisation of sulphuric acid is selected sodium hydroxide or yellow soda ash for use.
5. preparation method according to claim 4 is characterized in that in the step 1), neutralisation of sulphuric acid is selected yellow soda ash for use.
6. preparation method according to claim 1 and 2 is characterized in that step 2) in, compound (III) with the reaction mol ratio of oxammonium hydrochloride is: 1:1.0～1.5.
7. preparation method according to claim 6 is characterized in that step 2) in, compound (III) with the reaction mol ratio of oxammonium hydrochloride is: 1:1.1.
8. preparation method according to claim 1 is characterized in that step 2) in, hydrolysis temperature is 25 ℃.
9. preparation method according to claim 1 and 2 is characterized in that step 2) in, compound (IV) with the reaction mol ratio of p-methyl benzene sulfonic chloride is: 1:1.0～1.5.
10. preparation method according to claim 9 is characterized in that step 2) in, compound (IV) is 1:1.1 with the reaction mol ratio of p-methyl benzene sulfonic chloride.
11. preparation method according to claim 1 and 2 is characterized in that step 2) in, temperature of reaction is 0～10 ℃.
12. preparation method according to claim 11 is characterized in that step 2) in, temperature of reaction is 5 ℃.
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| US4656287A (en) * | 1984-05-25 | 1987-04-07 | Toyoma Chemical Co., Ltd. | Aminothiazole intermediate for a cephalosporin |
| CN101265267A (en) * | 2008-02-04 | 2008-09-17 | 山东罗欣药业股份有限公司 | Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2094794B (en) * | 1981-03-06 | 1985-02-20 | Fujisawa Pharmaceutical Co | Processes for preparing 2-substituted hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid or its salt and intermediates thereof |
| JPH10195064A (en) * | 1997-01-13 | 1998-07-28 | Katayama Seiyakushiyo:Kk | Production of 5-amino-1,2,4-thiadiazoleacetic acid derivative (syn-isomer) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4656287A (en) * | 1984-05-25 | 1987-04-07 | Toyoma Chemical Co., Ltd. | Aminothiazole intermediate for a cephalosporin |
| CN101265267A (en) * | 2008-02-04 | 2008-09-17 | 山东罗欣药业股份有限公司 | Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof |
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| Title |
|---|
| (Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸合成路线图解;刘明亮等;《中国药物化学杂志》;20061231;第37卷(第11期);第789-791页 * |
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| 刘明亮等.(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸合成路线图解.《中国药物化学杂志》.2006,第37卷(第11期),第789-791页. |
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