CN110642805A - Synthetic method of ethyl aminothiazoly loximate - Google Patents
Synthetic method of ethyl aminothiazoly loximate Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
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Abstract
The invention discloses a synthetic method of ethyl aminothiazoly loximate, which is characterized by comprising the following steps: a. the diketene is chloridized and alcoholyzed to synthesize 4-chloroacetoacetic acid ethyl ester; b. oximation of 4-chloroacetoacetic acid ethyl ester to synthesize 4-chloro-2-hydroxyiminoacetoacetate ethyl ester; c. 4-chloro-2-hydroxyiminoacetoacetate and thiourea react to synthesize ethyl noraminothiazolime; d. and (3) carrying out alkylation on the ethyl noraminothiazolioximate to synthesize the ethyl aminothiazolioximate. The invention has the advantages that: 1. the chlorination reaction in the step a is a continuous reaction, the reaction speed is high, no large amount of dangerous materials are accumulated, and the danger is low; 2. the equipment cost is low, the equipment is conventional organic synthesis equipment, expensive and special equipment is not needed, the duplication is convenient, and the production efficiency is improved; 3. the diketene is directly used as the raw material, the cost of the raw material is low, the synthesis step is simple to operate, and the production cost of the ethyl aminothiazolyloximate is favorably reduced.
Description
Technical Field
The invention belongs to the technical field of chemical production, and relates to a synthetic method of ethyl aminothiazoly loximate.
Background
Ethyl aminothiazoloxime ate, chemical name: 2-methoxyimino-2- (2-aminothiazole) -4-ethyl acetate is an important side chain intermediate for synthesizing cefatrix, cefotaxime, cefetamet and other cefamaseparately medicinal products. There are two main routes for the production of ethyl aminothiazoloxime ate: the ethyl acetoacetate process and the ethyl 4-chloroacetoacetate process. The ethyl acetoacetate method is to obtain a product by taking ethyl acetoacetate as a raw material and carrying out oximation of sodium nitrite, alkylation of dimethyl sulfate, bromination of bromine (or chlorination of chlorine gas) and cyclization of thiourea; ethyl 4-chloroacetoacetate method: the product is obtained by taking 4-chloroacetoacetic acid ethyl ester as a raw material and carrying out oximation of sodium nitrite, alkylation of dimethyl sulfate and cyclization of thiourea.
The 4-chloroacetoacetic acid ethyl ester method is less in pollution and short in operation flow, but cannot be widely used because the raw material (4-chloroacetoacetic acid ethyl ester) used as the raw material is expensive. The production of ethyl 4-chloroacetoacetate has two problems, namely, the reaction needs to be carried out under the conditions of low temperature and low concentration due to too high activity of reactants (chlorine and diketene), which is not beneficial to the expansion of yield; secondly, the poor thermal stability and high boiling point of ethyl 4-chloroacetoacetate lead to easy decomposition during the product post-treatment (vacuum rectification).
At present, the industrial production is mostly carried out by an ethyl acetoacetate method, but in the step 3, a halogenating reagent Br is used2、Cl2Or SO2Cl2Therefore, there are problems of high raw material cost, poor selectivity and large amount of waste acid which are difficult to avoid.
Disclosure of Invention
The invention aims to solve the problems, and provides a method for synthesizing ethyl aminothiazoly loximate, which reduces pollution, simplifies the operation process and reduces the production cost.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a synthetic method of ethyl aminothiazoly loximate is characterized by comprising the following steps:
a. synthesis of 4-chloroacetoacetic acid ethyl ester by chlorination and alcoholysis of diketene
a1. Mixing diketene and dichloromethane according to a volume ratio of 1:1 ~ 2 to form a mixed solution, adding the mixed solution from an inlet above a glass extraction tube at a speed of 5 ~ 15 mL/min, and adding chlorine from an inlet at the side surface of the glass extraction tube at a speed of 2 ~ 6 g/min according to a molar ratio of the diketene to the chlorine of 1:0.95 ~ 1;
a2. adding absolute ethyl alcohol from a side inlet of a straight vacuum receiving pipe at the speed of 2 ~ 7 mL/min, controlling the molar ratio of the diketene to the absolute ethyl alcohol to be 1:1.2 ~ 1.3.3, introducing condensed water (20-30 ℃) from a water inlet at the lower part of a serpentine condenser pipe, controlling the reaction temperature to be 50 ~ 70 ℃, and carrying out the reaction process for 2 ~ 5 h to obtain a crude product (brown to wine red liquid);
a3. performing reduced pressure rectification (glass spring packed column) on the crude product, controlling the pressure to be 1 ~ 3 mmHg and the overhead temperature to be 45 ~ 60 ℃, and obtaining a pure 4-chloroacetoacetic acid ethyl ester product (the content is more than or equal to 99.5 percent);
b. oximation synthesis of 4-chloro-2-hydroxyiminoacetoacetate ethyl 4-chloroacetoacetate
Mixing ethyl 4-chloroacetoacetate, acetic acid and dichloromethane, stirring and vacuumizing to 60-70 KPa, gradually reducing the temperature in a bottle to-5 ℃ by virtue of the gasification of the dichloromethane, then dropwise adding a saturated aqueous solution of sodium nitrite to carry out oximation reaction, simultaneously keeping the vacuum degree and continuously supplementing the dichloromethane, keeping the temperature at-5 ~ 0 ℃ in the dropwise adding process, continuously keeping the temperature after the dropwise adding is finished, and continuously stirring for 3 hours to obtain a crude product (red viscous liquid) of the ethyl 4-chloro-2-hydroxyiminoacetoacetate, wherein the molar ratio of the ethyl 4-chloroacetoacetate, the sodium nitrite and the acetic acid is controlled to be 1:1.25:2.5 ~ 3, and the volume ratio of the ethyl 4-chloroacetoacetate to the dichloromethane is 1:2 ~ 3;
c. 4-chloro-2-hydroxyiminoacetoacetate and thiourea react to synthesize ethyl noraminothiazoloxime ate
Mixing thiourea and water in a flask according to the mass ratio of 1:1.5, dropwise adding (a dropping funnel) the crude product 4-chloro-2-hydroxyiminoacetoacetate ethyl ester obtained in the step b into the flask, keeping the temperature to be less than or equal to 20 ℃ (cold bath) in the dropwise adding process, keeping the molar ratio of 4-chloroacetoacetate ethyl ester to thiourea at 1:1 ~ 1.2, continuously reacting for 4 hours at 20 ~ 25 ℃ after the dropwise adding is finished, then dropwise adding a saturated sodium carbonate solution to adjust the pH to 5.0 ~ 6.0.0, continuously stirring for 15 min, and performing suction filtration to obtain yellow solid ethyl noraminothiazolime;
d. alkylation of ethyl noraminothiazoloximate for synthesis of ethyl aminothiazoloximate
Mixing ethyl demethylaminothiazolime, acetone (solvent) and tetrabutylammonium bromide (surfactant) in a flask, keeping a cooling bath at 0 ℃, dropwise adding a 40% sodium hydroxide aqueous solution, continuously stirring for 1 hour, dropwise adding a mixture of dimethyl sulfate and acetone (solvent), controlling the molar ratio of ethyl demethylthiazolime, sodium hydroxide, dimethyl sulfate and tetrabutylammonium bromide to be 1:1 ~ 1.1.1: 1.25:0.05 ~ 0.1.1, controlling the total usage amount of the solvent acetone to be 1250 ~ 1500 mL/mol of ethyl methoxythiazolime to be not more than 0 ℃, continuously stirring for 1 hour after dropwise adding is finished, heating to 35 ~ 40 ℃ for reaction for 3 ~ 5 hours, pouring the reaction liquid into water, extracting with dichloromethane, and evaporating an organic phase to dryness to obtain yellow solid ethyl aminothiazolime.
Further, in the step b, the sodium nitrite can also be a mixture of nitric oxide and nitrogen dioxide, nitrosyl chloride, organic nitrite, nitrosyl bromide, nitroso sulfuric acid and other substances containing nitroso.
Further, the steps a1-a3 in the step a adopt the following devices: the three-mouth flask comprises a three-mouth flask, a snake-shaped condensation pipe, a straight vacuum receiving pipe and a glass exhaust pipe, wherein the snake-shaped condensation pipe, the straight vacuum receiving pipe and the glass exhaust pipe are sequentially and vertically connected above a middle inlet of the three-mouth flask, one of two side mouths of the three-mouth flask is connected with an exhaust device, the other side mouth of the three-mouth flask is connected with a thermometer, and the length of a discharge pipe of the glass exhaust pipe is 100-300 mm.
The diketene is an unstable and easily polymerizable compound, and tends to have lower yield under severe reaction conditions, and the reduction of the reaction temperature and the reduction of the reaction time are beneficial to the reduction of side reactions. In the invention, a glass exhaust tube (a common glass instrument for generating vacuum by using a Venturi effect, wherein liquid and gas are violently collided and mixed) is adopted to realize the reaction of diketene and chlorine, dichloromethane is used as a solvent, and meanwhile, part of heat can be taken away by using the gasification of dichloromethane, so that local overheating is avoided. Pumping by using a water jet pump (preferably a circulating water vacuum pump) to ensure that the flask is at a negative pressure, wherein the negative pressure can reduce the boiling point of dichloromethane, so that the reaction process is maintained at a lower temperature; the water jet pump is used because the gas to be pumped out contains volatile hydrogen chloride gas and methylene dichloride steam, the water jet pump can take the hydrogen chloride and the methylene dichloride away by water, the methylene dichloride is recovered by separating, and hydrochloric acid can be produced as a byproduct after the hydrogen chloride is dissolved into the water, and other types of vacuum pumps, such as a piston pump, an oil ring pump and the like, are not suitable for working under the conditions of strong acid and organic matters.
In the invention, the product of the oximation reaction (crude product of 4-chloro-2-oximino ethyl acetoacetate) directly performs cyclization reaction with thiourea without post-treatment to generate thiazole ring.
The alkylation is carried out using the highly efficient methylating agent dimethyl sulfate, and when the hydrocarbyl group required is not a methyl group but another group, such as ceftazidime side chain acid ethyl ester, then an additional hydrocarbylating agent is required. In the invention, alkylation reaction is carried out on ethyl demethylaminothiazolyloximate and dimethyl sulfate to obtain ethyl aminothiazolyloximate; the solvent is acetone, the ethyl demethylaminothiazolyloximate is firstly alkalized by sodium hydroxide, then dimethyl sulfate is dripped, and tetrabutylammonium bromide is used as a surfactant for reaction.
In the production process of 4-chloroacetoacetic acid ethyl ester, various impurities are difficult to avoid: including ethyl acetoacetate, ethyl 2, 4-dichloroacetoacetate, ethyl 4-chloro-3-ethoxycrotonate, etc., must be reduced to a sufficiently low level during the post-treatment process to be acceptable for sale. In the reaction process of the invention, both ethyl acetoacetate and 4-chloro-3-ethoxy ethyl crotonate cannot react with thiourea in the cyclization step, and ethyl 2, 4-dichloroacetoacetate cannot generate substances containing hydroxyimino in the oximation process; the by-products caused by the 3 impurities are easy to remove in the post-treatment process of each step of reaction, and the harm to the subsequent reaction is small, so the raw material 4-chloroacetoacetic acid ethyl ester used in the invention has high tolerance to the impurities, the requirement on the post-treatment process in the step a is reduced, and the cost can be saved.
The invention has the advantages that: 1. the chlorination reaction in the step a is a continuous reaction, the reaction speed is high, a large amount of dangerous materials (chlorine and diketene) cannot be accumulated, and the danger is low; 2. the equipment cost is low, the equipment is conventional organic synthesis equipment, expensive and special equipment is not needed, the duplication is convenient, and the production efficiency is improved; 3. the diketene is directly used as the raw material, the cost of the raw material is low, the synthesis step is simple to operate, and the production cost of the ethyl aminothiazolyloximate is favorably reduced.
Drawings
FIG. 1 is a diagram showing a synthesis procedure of ethyl aminothiazoloxime ate;
FIG. 2 is a schematic view of an apparatus for synthesizing ethyl 4-chloroacetoacetate.
Detailed Description
With reference to fig. 2, a synthesis apparatus for ethyl 4-chloroacetoacetate: three-neck flask (inside has the magneton) including 5000 mL, snakelike condenser pipe (the snake pipe part is 250 mm), straight type vacuum receiver tube, glass exhaust tube (discharge tube length is 200 mm), connect gradually the snakelike condenser pipe perpendicularly in the middle entry top of three-neck flask, straight type vacuum receiver tube, the glass exhaust tube, lean on rubber buffer sealing connection between straight type vacuum receiver tube and the glass exhaust tube, diketene, chlorine, absolute ethyl alcohol all uses the tetrafluoro pipe of external diameter eighth inch to carry, tetrafluoro pipe and glass exhaust tube junction use multilayer raw material area winding sealed.
Example 1
With reference to fig. 1, a method for synthesizing ethyl aminothiazoly loximate comprises the following specific implementation steps:
1. synthesis of 4-chloroacetoacetic acid ethyl ester by chlorination and alcoholysis of diketene
(1) 1100 g of diketene is diluted to 2500 mL by dichloromethane, the mixed solution is pumped into a connector above a glass exhaust tube by a constant flow pump, and chlorine is pumped into a connector at the side of the glass exhaust tube from a liquid chlorine steel cylinder; both diketene and chlorine are conveyed by a tetrafluoride pipe with the outer diameter of one eighth inch, and the joint of the tetrafluoride pipe and the glass exhaust pipe is wound and sealed by a plurality of layers of raw material belts;
(2) pumping by using a circulating water vacuum pump to ensure that the internal pressure of the flask is 0.03 MPa lower than the atmospheric pressure, adjusting a constant flow pump to feed a mixture of diketene and dichloromethane at the speed of 15 mL/min, adjusting the speed of chlorine to be 5.56 g/min by using a tetrafluoro needle valve (the molar ratio of the diketene to the chlorine is 1: 1), and introducing absolute ethyl alcohol from the side inlet of the straight vacuum receiving pipe at the speed of 5.7 mL/min by using the constant flow pump;
(3) closing all feeding materials after the feeding is finished, maintaining the vacuum degree unchanged and increasing the temperature, gradually increasing the temperature to 70 ℃ after 1 hour, starting to gradually increase the vacuum degree, and reducing the internal pressure of the bottle to 0.095 MPa lower than the atmospheric pressure after 3 hours to obtain a crude product which is brown to wine red liquid;
(4) rectifying the crude product with a glass spring packed column with height of 50 cm, wherein the bottom temperature is 90 deg.C, the internal pressure is 2 mmHg, and collecting when the top temperature is 50 ~ 55 deg.C to obtain 4-chloroacetoacetic acid ethyl ester (content is 97.5%, yield is 93%).
2. Oximation synthesis of 4-chloro-2-hydroxyiminoacetoacetate ethyl 4-chloroacetoacetate
Adding 164.6 g of the product 4-chloroacetoacetic acid ethyl ester prepared in the step 1, 180 g of glacial acetic acid and 300mL of dichloromethane into a 1000 mL three-necked bottle, stirring and vacuumizing to 50 mmHg, gradually reducing the temperature in the bottle to-5 ℃ by utilizing the gasification of the dichloromethane, beginning to dropwise add a saturated aqueous solution of sodium nitrite (containing 86.5g of sodium nitrite) while continuously supplementing the dichloromethane, keeping the temperature at-5 ~ 0 ℃ in the dropwise adding process, keeping stirring at the temperature for 3 hours after the dropwise adding is finished, and obtaining red viscous liquid, namely the crude product of the 4-chloro-2-hydroxyiminoacetoacetate, wherein the volume of the crude product is about 300 mL;
3. 4-chloro-2-hydroxyiminoacetoacetate and thiourea react to synthesize ethyl noraminothiazoloxime ate
Adding 100 g of thiourea and 600 mL of water into a 2000 mL three-neck flask, completely adding the crude product into a dropping funnel, dropwise adding the crude product into the flask from the dropping funnel, maintaining the temperature at 15-20 ℃ by using a cooling bath in the dropwise adding process, preserving the temperature for 4 hours at 20 ℃ after the dropwise adding is finished, then dropwise adding a saturated sodium carbonate solution to adjust the pH to 5.0, continuously stirring for 15 minutes, and performing suction filtration to obtain 170 g of ethyl demethylaminothiazolime solid, wherein the yield is 79% (calculated by 4-chloroacetoacetate);
4. alkylation of ethyl noraminothiazoloximate for synthesis of ethyl aminothiazoloximate
43 g of ethyl demethylaminothiazolime, 250 mL of acetone and 3 g of tetrabutylammonium bromide are added into a 500 mL three-necked flask, the temperature is maintained at 0 ℃, 13 mL of 40% sodium hydroxide aqueous solution is dropwise added (the temperature does not exceed 0 ℃ when dropwise adding), stirring is continued for 1 hour, dimethyl sulfate solution (a mixture of 31.6 g of dimethyl sulfate and 30 mL of acetone) is dropwise added, the temperature does not exceed 0 ℃ when dropwise adding is finished, stirring is continued for 1 hour after dropwise adding is finished, the temperature is increased to 40 ℃ for reaction for 3 hours, the reaction solution is poured into 800 mL of water, extraction is carried out by using 300mL of dichloromethane for three times (3X 100 mL), organic phases are combined, and the solvent is removed under reduced pressure (less than or equal to-0.09 MPa), so that 40.8g of yellow solid ethyl aminothiazolime.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner; those skilled in the art can make numerous possible variations and modifications to the present teachings, or modify equivalent embodiments to equivalent variations, without departing from the scope of the present teachings, using the methods and techniques disclosed above. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention are still within the scope of the protection of the technical solution of the present invention.
Claims (3)
1. A synthetic method of ethyl aminothiazoly loximate is characterized by comprising the following steps:
a. synthesis of 4-chloroacetoacetic acid ethyl ester by chlorination and alcoholysis of diketene
a1. By adopting the device, the mixture liquid is formed by diketene and dichloromethane according to the volume ratio of 1:1 ~ 2, the mixture liquid is added from the inlet above the glass exhaust tube, the speed is controlled to be 5 ~ 15 mL/min, chlorine is added from the inlet at the side surface of the glass exhaust tube according to the molar ratio of the diketene to the chlorine of 1:0.95 ~ 1, and the speed of the chlorine is 2 ~ 6 g/min;
a2. adding absolute ethyl alcohol from a side inlet of a straight vacuum receiving pipe at the speed of 2 ~ 7 mL/min, controlling the molar ratio of diketene to the absolute ethyl alcohol to be 1:1.2 ~ 1.3.3, cooling by using a serpentine condenser pipe, controlling the reaction temperature to be 50 ~ 70 ℃, and obtaining a crude product after the reaction process is carried out for 2 ~ 5 h;
a3. carrying out reduced pressure rectification on the crude product, and controlling the pressure to be 1 ~ 3 mmHg and the overhead temperature to be 45 ~ 60 ℃, thus obtaining a 4-chloroacetoacetic acid ethyl ester pure product with the content of more than or equal to 99.5%;
b. oximation synthesis of 4-chloro-2-hydroxyiminoacetoacetate ethyl 4-chloroacetoacetate
Mixing ethyl 4-chloroacetoacetate, acetic acid and dichloromethane, stirring and vacuumizing to 60-70 KPa, gradually reducing the temperature in a bottle to-5 ℃ by virtue of the gasification of the dichloromethane, then dropwise adding a saturated aqueous solution of sodium nitrite to carry out oximation reaction, simultaneously keeping the vacuum degree and continuously supplementing the dichloromethane, keeping the temperature at-5 ~ 0 ℃ in the dropwise adding process, continuously keeping the temperature after the dropwise adding is finished, and continuously stirring for 3 hours to obtain a crude product of the ethyl 4-chloro-2-hydroxyiminoacetoacetate, wherein the molar ratio of the ethyl 4-chloroacetoacetate, the sodium nitrite and the acetic acid is controlled to be 1:1.25:2.5 ~ 3, and the volume ratio of the ethyl 4-chloroacetoacetate to the dichloromethane is 1:2 ~ 3;
c. 4-chloro-2-hydroxyiminoacetoacetate and thiourea react to synthesize ethyl noraminothiazoloxime ate
Mixing thiourea and water in a flask according to the mass ratio of 1:1.5, dropwise adding the crude product 4-chloro-2-hydroxyiminoacetoacetate obtained in the step b into the flask, maintaining the temperature to be less than or equal to 20 ℃ in the dropwise adding process, keeping the molar ratio of 4-chloroacetoacetate to thiourea to be 1:1 ~ 1.2.2, continuing to react for 4 hours at the temperature of 20 ~ 25 ℃ after the dropwise adding is finished, then dropwise adding a saturated sodium carbonate solution to adjust the pH to be 5.0 ~ 6.0.0, continuing to stir for 15 minutes, and performing suction filtration to obtain yellow solid ethyl noraminothiazolate;
d. alkylation of ethyl noraminothiazoloximate for synthesis of ethyl aminothiazoloximate
Mixing ethyl noraminothiazolime, acetone and tetrabutylammonium bromide in a flask, keeping a cooling bath at 0 ℃, dropwise adding 40% of sodium hydroxide aqueous solution, continuously stirring for 1 hour, dropwise adding a mixture of dimethyl sulfate and acetone, controlling the molar ratio of the ethyl noraminothiazolime to the dimethyl sulfate to the tetrabutylammonium bromide to be 1:1 ~ 1.1.1: 1.25:0.05 ~ 0.1.1, controlling the total using amount of the acetone to be 1250 ~ 1500 mL/mol of the ethyl aminothiazolime, keeping the temperature not more than 0 ℃ when dropwise adding is finished, continuously stirring for 1 hour after the dropwise adding is finished, heating to 35 ~ 40 ℃ for reaction for 3 ~ 5 hours, pouring a reaction solution into water, extracting with dichloromethane, and evaporating an organic phase to dryness to obtain yellow solid ethyl aminothiazolime.
2. The method for synthesizing ethyl aminothiazolime carboxylate according to claim 1, characterized in that: the sodium nitrite in the step b can also be a mixture of nitric oxide and nitrogen dioxide, nitrosyl chloride, organic nitrite, nitrosyl bromide, nitroso sulfuric acid and other substances containing nitroso.
3. The method for synthesizing ethyl aminothiazolime carboxylate according to claim 1, characterized in that: the steps a1-a3 in the step a adopt the following devices: the three-mouth vacuum heating device comprises a three-mouth flask, a snake-shaped condensation pipe, a straight vacuum receiving pipe and a glass exhaust pipe, wherein the snake-shaped condensation pipe, the straight vacuum receiving pipe and the glass exhaust pipe are sequentially and vertically connected above a middle inlet of the three-mouth flask, one of two side mouths of the three-mouth flask is connected with an air exhaust device, the other side mouth of the three-mouth flask is connected with a thermometer, and the length of a discharge pipe of the glass exhaust pipe is 100-300 mm.
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| CN111100088A (en) * | 2019-12-25 | 2020-05-05 | 山东普洛得邦医药有限公司 | Method for continuously synthesizing ethyl dithiaoximate |
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Application publication date: 20200103 |