Synthesis method of key intermediate of cefoxitin sodium
阅读说明：本技术 一种头孢西丁钠关键中间体的合成方法 (Synthesis method of key intermediate of cefoxitin sodium ) 是由 王金龙 侯仲轲 张宜仲 阮剑 王亮 王超奇 史锰锰 摆皓文 王兆刚 于 2021-08-30 设计创作，主要内容包括：本申请提供一种头孢西丁钠关键中间体的合成方法,属于杂环化合物技术领域。以头孢噻吩酸溶液为处理对象,加入有机碱,加入卤代剂,经卤代甲氧化反应后,加入乙酸、盐水,调酸分层,有机层干燥、浓缩,加入环己胺成盐,过滤、烘干,得到关键中间体7-α甲氧化头孢噻吩环己胺盐。本申请实现了7-α甲氧化头孢噻吩环己胺盐的一步法合成,且从源头有效降低后续的头孢西丁钠主要杂质,提高产品质量和纯度,提升头孢西丁产品竞争力且产品稳定可靠,收率高,大大简化了合成工艺,具有产业化前景。(The application provides a synthesis method of a key intermediate of cefoxitin sodium, belonging to the technical field of heterocyclic compounds. Adding organic base and a halogenating agent into a cephalothin acid solution serving as a processing object, adding acetic acid and brine after halogenated methoxylation reaction, adjusting acid for layering, drying and concentrating an organic layer, adding cyclohexylamine for salifying, filtering and drying to obtain a key intermediate 7-alpha methoxylated cephalothin cyclohexylamine salt. The method realizes the one-step synthesis of the 7-alpha methoxylated cephalothin cyclohexylamine salt, effectively reduces the subsequent main impurities of cefoxitin sodium from the source, improves the product quality and purity, improves the competitiveness of cefoxitin products, has stable and reliable products and high yield, greatly simplifies the synthesis process, and has industrial prospect.)
1. A synthetic method of a key intermediate of cefoxitin sodium is characterized by comprising the following steps: adding organic base at-60 to-90 ℃ with a cephalothin acid solution as a treatment object, adding a halogenating agent in batches, carrying out halogenated methoxylation reaction, adding acetic acid and brine, regulating acid, layering, drying and concentrating an organic layer, adding cyclohexylamine to form a salt, filtering and drying to obtain a key intermediate 7-alpha methoxylated cephalothin cyclohexylamine salt.
2. The method for synthesizing the key intermediate of cefoxitin sodium as claimed in claim 1, wherein the solution of cefoxitin acid is a solution of wet cefoxitin acid after solvent dissolution, liquid separation and water removal, a solution of cefoxitin sodium after solvent and acid dissolution, or a solution of cefoxitin acid after reaction.
3. The synthesis method of key intermediate of cefoxitin sodium as claimed in claim 2, characterized in that: the solvent is any one or a mixture of more of dichloromethane, methanol, DMF, DMAC, tetrahydrofuran and ethyl acetate.
4. The method for synthesizing key intermediate of cefoxitin sodium as claimed in claim 1, wherein: the organic base is any one of sodium methoxide, sodium hydrogen and potassium methoxide.
5. The method for synthesizing key intermediate of cefoxitin sodium as claimed in claim 1, wherein: the halogenating agent is any one of thionyl chloride, N-chlorosuccinimide, N-bromosuccinimide, N-chloroisopropylamine, trimethylchlorosilane and tert-butyl hypochlorite.
6. A synthetic method of a key intermediate of cefoxitin sodium is characterized by comprising the following steps: adding 2-thiophene acetyl chloride into 7-ACA serving as a raw material to react to obtain a cephalothin acid solution, cooling to-60 to-90 ℃, adding an organic base, adding a halogenating agent in batches, controlling the molar ratio of the halogenating agent added firstly to the 7-ACA to be 0.1-1.5:1, adding acetic acid and saline water after halogenating methoxylation reaction, adjusting acid to layer, drying and concentrating an organic layer, adding cyclohexylamine to form a salt, filtering and drying to obtain a key intermediate 7-alpha methoxylated cephalothin cyclohexylamine salt.
7. The method for synthesizing key intermediate of cefoxitin sodium as claimed in claim 6, wherein: the solvent is any one or a mixture of more of dichloromethane, methanol, DMF, DMAC, tetrahydrofuran and ethyl acetate.
8. The method for synthesizing key intermediate of cefoxitin sodium as claimed in claim 6, wherein: the mol ratio of the halogenated agent added firstly to the 7-ACA is 0.6-0.9: 1.
9. The method for synthesizing key intermediate of cefoxitin sodium as claimed in claim 6, wherein: the halogenating agent is any one of thionyl chloride, N-chlorosuccinimide, N-bromosuccinimide, N-chloroisopropylamine, trimethylchlorosilane and tert-butyl hypochlorite.
10. The method for synthesizing key intermediate of cefoxitin sodium as claimed in claim 6, wherein: the organic base is any one of sodium methoxide, sodium hydrogen and potassium methoxide.
Technical Field
The application relates to a synthesis method of a key intermediate of cefoxitin sodium, belonging to the technical field of heterocyclic compounds.
Background
Cefoxitin sodium was developed by the company mershadong, usa, and marketed in 1974 as a cephalosporin antibiotic, which is chemically similar to cephalosporin, but has a methoxylation at the 7-carbon of the cephem nucleus. The methoxylation is in a trans-form, which can prevent the beta-lactam enzyme from approaching the beta-lactam ring and reduce the affinity of the enzyme for the drug, thereby protecting the beta-lactam ring from being damaged. The cefoxitin has wider and more balanced antibacterial spectrum coverage, stronger activity to gram positive and negative bacteria, anaerobic bacteria or aerobic bacteria and high beta-lactamase resistance. It is clinically used for peritonitis and other intraperitoneal, pelvic and gynecological infections, as well as septicemia, endocarditis, urinary tract infection (including gonorrhea), respiratory tract infection, bone joint infection, skin and soft tissue infection, etc.
The molecular formula is as follows: c16H16N3O7NaS2，
Molecular weight: 449.43,
CAS accession number: 33564-30-6.
Several main impurities in cefoxitin sodium, such as non-methoxylated cefoxitin, cefoxitin bis (oxide) R (impurity E) and cefoxitin bis (oxide) S (impurity F), are all clearly required in European pharmacopoeia EP8.0 and need to be controlled for known impurities. The main impurities of cefoxitin sodium are generated from the halogenated methoxylation process of a key intermediate 7 alpha methoxylated cefoxitin cyclohexylamine salt of cefoxitin sodium, and are derived and transmitted to cefoxitin sodium. The research on the synthesis control method of the compound has important significance.
In a cefoxitin sodium route taking cephamycin C as an initial raw material, the raw material is difficult to obtain, the reaction route is long, the process is complex, the yield is low, the cost is high, and the cefoxitin sodium route is not suitable for industrial production; in the cefoxitin sodium route taking 7-MAC as the raw material, the raw material is not easy to obtain, and the production cost is higher; at present, 7-ACA or cephalothin is adopted as a starting material in most processes, the reaction selectivity of the route is high, the raw material is easy to obtain, but the positive line yield is low, and the quality is unstable.
Some of the synthetic routes that are currently common are:
in the literature with application number of CN201910037285.9 and name of 'application of cefoxitin sodium in preventing infection before transvaginal hysterectomy, abdominal hysterectomy and cesarean section', the synthesis process is as follows: synthesizing cephalothin acid by 7-ACA and 2-thiophene acetyl chloride, drying, cooling, adding sodium methoxide, adopting tert-butyl ester of hypochloride as halogenating agent, and adding quantitatively.
In the document with application number CN201210521436.6 and name of 'synthetic method of 7-alpha-methoxy-3-deacetyl cephalothin benzathine salt', the synthetic process comprises the following steps: the cephalothin acid needs to be dried, the halogenating agent adopts tert-butyl ester hypochlorite, and the adding mode is quantitative adding.
The patent application No. CN201811640066.1, entitled "a method for synthesizing cefoxitin sodium", comprises the following steps: the cephalothin acid needs to be dried, and the halogenating agent is quantitatively added by using tert-butyl ester hypochlorite.
The periodical "improvement of cefoxitin synthesis process" (Wang Yanfeng, Wu national glu, etc., chemical production and technology 2010, 17(4):25-27), synthesis process: the cephalothin acid needs to be dried, the halogenating agent adopts tert-butyl ester hypochlorite, the addition mode is quantitative, and the product purity is very low and is only about 90 percent.
In the above-mentioned various journal literatures and patent literatures, the synthesis of cefoxitin sodium key intermediate, 7 α methoxylated cephalothin cyclohexylamine salt, is a two-step process, namely: firstly, preparing cephalothin acid, and drying to obtain a dry product; and secondly, carrying out halogenated methyl oxidation on the dry cephalothin acid product, wherein the reaction is anhydrous, and a halogenating agent is added quantitatively.
When the halomethylation process is analyzed, on one hand, due to the strong activity, the halogenating agent is easy to deteriorate or be damaged in the reaction, so that the addition mode is a fixed amount, the reaction of the halomethylation is uncontrollable, the dosage of the halogenating agent cannot be adjusted along with the reaction process, and the reaction yield and the quality are low. On the other hand, the existing literature has few researches on the halogenated methoxylation process of the key intermediate, but the yield of the step is unstable and the quality is uncontrollable, and the problems that the quality and the yield of the final product cefoxitin sodium are unstable and the corresponding cefoxitin sodium product is stable are reflected.
Disclosure of Invention
In view of the above, the application provides a synthesis method of a key intermediate of cefoxitin sodium, namely 7-alpha methoxylated cefoxitin cyclohexylamine salt, which realizes the preparation of the 7-alpha methoxylated cefoxitin cyclohexylamine salt by a one-step method, realizes the fine control of the halogenated methoxylation process in the halogenated methoxylation process, effectively controls and greatly reduces side reactions, improves the product yield, has a simple process, effectively controls and reduces the main transmission impurities in cefoxitin sodium from the source, obviously improves the product stability, and obviously improves the market competitiveness.
Specifically, the method is realized through the following scheme:
a synthesis method of a key intermediate of cefoxitin sodium comprises the steps of taking a cefoxitin acid solution as a raw material, adding an organic base at-60 ℃ to-90 ℃, adding a halogenating agent in batches, carrying out halogenated methoxylation reaction, adding acetic acid and saline water, adjusting acid for layering, drying and concentrating an organic layer, adding cyclohexylamine for salification, filtering and drying to obtain a key intermediate 7-alpha methoxylated cefoxitin cyclohexylamine salt.
According to the scheme, a cefoxitin sodium key intermediate 7-alpha methoxylated cefoxitin cyclohexylamine salt is directly synthesized by a one-step method by using a cefoxitin acid solution; adding organic base and halogenating agent into the cephalothin acid solution to carry out methoxylation reaction, adding acetic acid and saline water, adjusting acid to layer, and salifying the organic layer to obtain a key intermediate. The core reaction is a halogenated methoxylation reaction of a cephalothin acid solution, an organic base and a halogenating agent, the halogenated methoxylation reaction is uniform, the product has a good crystal form and is easy to filter and dry, the process conditions of ultralow temperature methoxylation can realize a regioselective methoxylation process, the halogenating agent is added in batches for many times in a matching manner, and the halogenating agent addition amount is calculated according to the detection of raw material residues in the methoxylation process, so that the reaction end point is accurately controlled, the side reaction is reduced, the subsequent main impurities of cefoxitin sodium are effectively reduced from the source, the product quality and purity are improved, and the product quality and yield are remarkably improved; then adding acetic acid and brine to regulate acid and layer, carrying out salt forming reaction on an organic layer to obtain a key intermediate, and synthesizing the key intermediate by using cyclohexylamine as a salt forming agent, so that the steps of crystallization and purification are reduced, the competitiveness of the cefoxitin product is improved, the product is stable and reliable, the material loss is avoided, and the total yield is high.
Further, as preferable:
the cephalothin acid solution includes but is not limited to a solution obtained by dissolving a wet cephalothin acid product with a certain solvent, separating the solution by liquid and removing water, or a solution obtained by dissolving cephalothin sodium with an organic solvent and an acid. At this time, the solvent includes, but is not limited to, dichloromethane, methanol, DMF, DMAC, tetrahydrofuran, ethyl acetate, and a mixed solvent of one or more thereof, preferably a dichloromethane and methanol mixed solvent.
The organic base is selected from any one of solid or solution such as sodium methoxide, sodium hydrogen carbonate, potassium methoxide, etc., and sodium methoxide solution is the most preferable.
The halogenating agent is any one of thionyl chloride, N-chlorosuccinimide, N-bromosuccinimide, N-chloroisopropylamine, trimethylchlorosilane and tert-butyl hypochlorite, and tert-butyl hypochlorite is taken as the best.
As another implementation manner, the above scheme may also be implemented according to the following procedures:
a synthesis method of a key intermediate of cefoxitin sodium comprises the steps of taking 7-ACA as a raw material, adding 2-thiopheneacetyl chloride for reaction, dissolving the raw material by using a solvent to obtain a solution, cooling the solution to a temperature of between 60 ℃ below zero and 95 ℃ below zero, adding an organic base, adding a halogenating agent in batches, controlling the molar ratio of the halogenating agent added firstly to the 7-ACA to be 0.1 to 1.5:1, carrying out halogenating and methoxylation reaction, adding acetic acid and saline water, adjusting acid for layering, drying and concentrating an organic layer, adding cyclohexylamine for salifying, filtering and drying to obtain a key intermediate of 7-alpha methoxylated cefoxitin cyclohexylamine salt.
The scheme realizes a one-pot process from 7-ACA to 7-alpha methoxylated cephalothin cyclohexylamine salt, after 7-ACA and 2-thiophene acetyl chloride react in an organic solvent, the organic reaction liquid directly carries out halogenated methoxylation reaction, cephalothin acid obtained in the reaction process does not need to be taken out and baked, and baking steps and equipment are reduced; in the process of synthesizing the 7-alpha methoxylated cephalothin cyclohexylamine salt, the regiostereoselective methyl oxidation process of the ultralow temperature methyl oxidation process adopts multiple additions, namely, part of the halogenating agent is added firstly, and the addition amount of the halogenating agent is calculated according to the detection raw material residue, so that the reaction endpoint is accurately controlled, the subsequent main impurities of cefoxitin sodium are effectively reduced from the source, the side reaction is reduced, and the product quality and the yield are obviously improved.
Further, as preferable:
the solvent includes but is not limited to dichloromethane, methanol, DMF, DMAC, tetrahydrofuran, ethyl acetate and a mixed solvent of one or more of the above, preferably dichloromethane and methanol mixed solvent.
The organic base is selected from any one of solid or solution such as sodium methoxide, sodium hydrogen carbonate, potassium methoxide, etc., and sodium methoxide solution is the most preferable.
The halogenating agent is any one of thionyl chloride, N-chlorosuccinimide, N-bromosuccinimide, N-chloroisopropylamine, trimethylchlorosilane and tert-butyl hypochlorite, and tert-butyl hypochlorite is taken as the best.
When the halogenated agents are added in batches, the molar ratio of the halogenated agents to the 7-ACA is 0.6-0.9: 1.
In the preparation process, during the process of adding the halogenating agent in batches, the reaction conditions such as raw material residue and various side reactions are detected by detection methods including but not limited to point plate, liquid phase, gas phase, mass spectrum, infrared and the like, and preferably high performance liquid phase. The subsequent addition amount of the halogenated agent can be determined by methods including, but not limited to, derivation formula, calculation formula, empirical derivation, calibration method, etc. Side reactions include, but are not limited to, side chain halogenation and hydrolysis reactions, bis-methide side reactions, cephalothin acid starting material residues.
In the two modes, the main side reaction and the transferred impurities are obviously reduced, the weight yield of the step can be improved by more than 15 percent, the purity can reach more than 97 percent, no water is needed in the reaction process, the anhydrous requirements on related equipment and solvents are greatly reduced, and the reaction control difficulty is reduced; the cefoxitin sodium prepared subsequently has the advantages of obviously improved product stability, obviously reduced main transfer impurities, obvious improvement over the market level, solving the problems of unstable process and low yield of cefoxitin sodium at home and abroad, and greatly improving the competitiveness of the international market.
Detailed Description
Example 1
Adding 7-ACA10.0g (36.76mmol) into a 250ml three-necked bottle, adding a mixed solvent of 100ml of water and 10ml of EA (ethyl acetate) while stirring, heating to 20 ℃, adding 8.0g of sodium bicarbonate (95.24mmol), stirring until the mixture is dissolved and clarified, cooling to 0 ℃, dropwise adding 8.0g of 2-thiopheneacetyl chloride (49.84mmol), reacting for 2 hours until the raw material residue is less than or equal to 1.0%, heating to 25 ℃, adding hydrochloric acid to adjust the pH to 1.5-2.5, and filtering to obtain a wet cephalothin acid product. Adding 100ml of dichloromethane for dissolving, layering and removing water, cooling a lower organic layer to-60 ℃, adding 25.0g (138.89mmol) of 30% sodium methoxide methanol solution, adding 2.8g of tert-butyl hypochlorite (25.79mmol, tert-butyl hypochlorite: 7-ACA ≈ 0.7:1), detecting the residue of raw materials, supplementing tert-butyl hypochlorite according to a certain method, adding acetic acid after the raw materials are qualified, adding sodium chloride solution, adding dilute hydrochloric acid to control the pH to be 1.8-2.2, standing for layering, concentrating the lower layer to dryness, adding 5.0g (50.42mmol) of cyclohexylamine, crystallizing, filtering, rinsing with acetone, and drying to obtain 15.4g (29.30mmol) of 7-alpha methoxycefalotin cyclohexylamine salt, wherein the molar yield is 79.78% based on 7-ACA, and impurities in the 7-alpha methoxycefalotin cyclohexylamine salt mainly comprise 3-hydroxymethyl, cephalothin acid, cephalothin acid, alpha-methoxycefalotin salt, sodium chloride and sodium chloride, The proportion of the double-oxidation R-type impurity and the double-oxidation S-type impurity is respectively about 0.8 percent, 1.0 percent and 1.1 percent, the stability of the 7-alpha methoxylated cephalothin cyclohexylamine salt is good, the purity is 94.5 percent, and the white powder is obtained.
Parallel case 1: influence of solvent constitution
This example was set up identically to example 1, except that the halomethoxylation solvent was set up differently, as shown in Table 1.
TABLE 1 Effect of different solvents on the reaction
As can be seen by combining Table 1 and example 1, different solvents are adopted, the influence on the treatment effect is mainly reflected in the low-temperature solubility of the cephalothin acid, and the treatment layering treatment after the reaction, compared with the pure solvents (numbers 1-1 to 1-5 in Table 1), the dichloromethane and other dissolved mixed solvents (numbers 1-7 to 1-12 in Table 1) have good solubility, good dispersibility, stable property and easier control of the reaction at low temperature for the cephalothin acid, the halogenating agent and the organic base. Among them, a mixed solvent of dichloromethane, methanol and the like is more effective.
Parallel case 2: effect of the mode of addition of the halogenating agent
This parallel case was set up identically to example 1, except that the mode of addition of the halogenating agent was different, as shown in Table 2.
TABLE 2 Effect of different halogenating agent additions on the reaction
Serial number
Firstly adding the halogenating agent 7-ACA
Molar yield
Impurity content in intermediate
Remarks for note
2-1
0.4:1
62.1％
6.9％
2-2
0.5:1
63.6％
5.8％
2-3
0.6:1
72.3％
3.5％
2-4
0.8:1
75.5％
2.6％
2-5
0.9:1
79.3％
2.5％
2-6
1:1 (i.e. one-time addition)
64.2％
6.5％
Side reaction is greater
As can be seen by combining Table 2 with example 1, the influence of the formation of the first addition of the halogenating agent tert-butyl hypochlorite relative to 7-ACA on the treatment effect is mainly reflected in the control accuracy of the reaction endpoint, and when the addition ratio is lower than 0.6:1 (tert-butyl hypochlorite: 7-ACA), the raw material residue is large, so that the detection is not easy to be accurate, the calculated addition amount is easy to deviate, and the reaction control is not good; with the increase of the first addition ratio, the influence is embodied in that the raw material residue is reduced, the addition amount obtained according to calculation is more accurate, and the reaction control is good; compared with one-time addition, the difference is mainly embodied in that the reaction end point is controllable, and the addition amount of the halogenating agent can be adjusted according to the reaction condition, so that the reaction process is accurately controlled, the side reaction is effectively reduced, and the yield and the quality of the product are improved.
Parallel case 3: effect of different halogenating agents
This parallel case was set up identically to example 1, except for the different type of halogenating agent, as shown in Table 3.
TABLE 3 Effect of different halogenating agents on the reaction
Serial number
Halogenated agents
Molar yield
Impurity content in intermediate
Remarks for note
3-1
Thionyl chloride
42.3％
31.5％
Large residue of raw material
3-2
N-chlorosuccinimide
67.2％
1.8％
3-3
N-bromosuccinimide
68.6％
1.9％
3-4
N-chloro-isopropylamine
23.1％
36.5％
Large residue of raw material
3-5
Trimethylchlorosilane
26.5％
45.2％
Large residue of raw material
It can be seen from table 3 and example 1 that the influence of the halogenating agent on the reaction is mainly reflected in the aspects of the speed and selectivity of the halogenation reaction, and thionyl chloride is not easy to store and is easy to hydrolyze and deteriorate; the N-chlorosuccinimide has the advantages of solid form and easy storage, but has the defects of easy hydrolysis, slow reaction and high price; the N-bromosuccinimide has the advantages that the N-bromosuccinimide is solid and easy to store, but has the defects of easy hydrolysis, slow reaction and high price; the N-chloro-isopropylamine has the advantages of mainly liquid, but has the defects of difficult storage and big smell; the advantages of the trimethylchlorosilane are mainly that the properties are stable, the solution is beneficial to closed feeding, but the defects are that the selectivity is poor and the solution is acidic; compared with the halogenating agent, the tert-butyl hypochlorite has the advantages of convenient preparation, lower price, favorable closed feeding in a solution state, strong reaction activity, quick reaction and the like, thereby having the best use effect.
Parallel case 4: influence of different organic base compositions
This parallel case was set up identically to example 1, except that the organic base composition was different, as shown in table 4.
TABLE 4 Effect of different organic bases on the reaction
Serial number
Organic base
Molar yield
Impurity content in intermediate
Remarks for note
4-1
Sodium methoxide (s, 7.50g)
56.2％
7.2％
4-2
Sodium hydrogen (s, 3.33g)
41.5％
6.2％
Poor dissolution in reaction
4-3
Potassium methoxide (s, 9.74g)
55.8％
7.7％
4-4
30% aqueous sodium methoxide solution
32.6％
73.2％
Large damage of reaction alkali
4-5
30% potassium methoxide methanol solution
79.5％
3.1％
4-6
30% aqueous potassium methoxide solution
33.5％
75.6％
Large damage of reaction alkali
As can be seen from table 4 and example 1, the effect of the organic base on the reaction is mainly reflected in the aspects of fast and slow halogenation reaction, providing methoxy group, and the like, and the use of sodium methoxide is mainly advantageous in that the organic base is not dissolved in a solvent and is directly added, but has the defects that the solid is difficult to dissolve and disperse at a low temperature, the local alkalinity is too strong, and the alkali damage is large; the sodium hydrogen has the advantages that the sodium hydrogen is directly added without solvent dissolution, but has the defects that the solid is difficult to dissolve and disperse at low temperature, the local alkalinity is too strong, and the alkali damage is large; the potassium methoxide has the advantages that the potassium methoxide is directly added without being dissolved by a solvent, but has the defects that the solid is difficult to dissolve and disperse at low temperature, the local alkalinity is too strong, and the alkali damage is large, and the specific expression is as follows: the difference between the solid and the solution is that the solid is not easy to disperse at low temperature, the local alkalinity is too strong, the side reaction is larger, and other solutions, such as an alcohol solution, can dissolve the solid, the reaction is more sufficient, the local alkali damage is small (compare table 4), and the difference between the aqueous solution and the organic (methanol is taken as an example) (compare example 1 and serial number 4-4, 4-5 and 4-6) is that the aqueous solution can cause the reaction of water and sodium methoxide or potassium methoxide, a large amount of heat is released, the alkali proportion can be insufficient, the reaction is incomplete, and the product is easy to be subjected to alkaline hydrolysis; the organic solution is well dissolved, which is beneficial to dispersion and has small alkali damage.
Parallel case 5: influence of different temperatures of methoxylation
In the application, the ultralow temperature of the methyl oxidation can be adopted because the side reaction is reduced, and the sodium methoxide is used, so that the alkalinity is strong, ester bonds and lactams of the product are easy to open, and the temperature is high, so that the side reactions such as double substitution and the like are easy to occur, therefore, the technical scheme of the application (particularly, the reaction route of using 7-ACA as a raw material, adding 2-thiopheneacetyl chloride to react and then adopting a solvent to dissolve and obtain a cephalothin acid solution) has the lowest allowable reaction temperature of-95 ℃.
This parallel case was set up identically to example 1, with the difference that the methoxylation temperatures were different, as shown in Table 5.
TABLE 5 Effect of different methoxylation temperatures on the reaction Effect
As can be seen from Table 5 in combination with example 1, the advantage of using a lower temperature for the methoxylation mainly lies in the reduction of side reactions, the reduction of alkali damage, the reduction of side reactions, and the significant reduction of impurities, especially when the methoxylation temperature is controlled at-90 ℃ to-60 ℃.
Parallel case 6
In this example, the reaction scheme is:
taking a cephalothin acid solution as a raw material, adding an organic base sodium methoxide methanol solution at-60 ℃, adding a halogenating agent for the first time (in the embodiment, tert-butyl hypochlorite is used as the halogenating agent, and the ratio of the tert-butyl hypochlorite to the cephalothin acid solution is 0.9), after a halogenating methoxylation reaction, adding acetic acid and brine, adjusting the acid for layering, drying and concentrating an organic layer, adding cyclohexylamine for salifying, filtering and drying to obtain a key intermediate 7-alpha methoxylated cephalothin cyclohexylamine salt.
Wherein, the cephalothin acid solution can adopt the following two forms:
(1) the solution of wet cephalothin acid after solvent dissolution, liquid separation and water removal is prepared by the following specific preparation process and parameter settings: adding a large amount of dichloromethane and a small amount of methanol into a wet cephalothin acid product, dissolving, and removing water by layering to obtain an organic solvent layer of the cephalothin acid, wherein the organic solvent layer contains a large amount of dichloromethane and a small amount of methanol, and the solution contains a small amount of water after layering, and is clear.
(2) The detailed preparation process and parameter settings of the solution after the reaction of the cephalothin acid are as follows: the feed liquid after the reaction of 7-ACA and 2-thiopheneacetyl chloride in organic solvents such as dichloromethane and the like is directly obtained.
Compared with the embodiment 1, the process has the advantages that the halogenated methoxylation reaction is carried out by adopting the cephalothin acid solution, the one-step process from 7-ACA to 7-alpha methoxylated cephalothin cyclohexylamine salt is realized, the operation is simple and convenient, the halogenated methoxylation reaction is more accurate and the side reaction is lower because the halogenating agent is added firstly.
In the following examples 2-6, differences in reaction speed and solubility, cephalothin acid raw material residue, cephalothin acid dissolution degree, crystallization and salt formation, and the like are successively verified, and specific correspondence is shown in table 6, aiming at the aspects of amidation reaction base type and ratio, acyl chloride ratio, halogenated methoxylation reaction solvent type and ratio, organic base ratio, and organic base ratio.
TABLE 6 Effect of different classes of factors on the Effect of the reaction
Categories
Influence of
The kind and proportion of amidation reaction alkali
Reaction speed, solubility
Acyl chloride ratio
Residue of cephalothin acid raw material
The type and the proportion of the halogenated methoxylation reaction solvent
The dissolution degree of the cephalothin acid is full
Organic base ratio
Halogenated methoxylation speed, supply of methoxy
Proportioning of cyclohexylamine
Crystallization and salt formation
The following description will be made for specific examples.
Example 2
Adding 7-ACA10.0g (36.76mmol) into a 250ml three-necked bottle, adding 120ml water under stirring, heating to 25 ℃, adding 7.0g sodium bicarbonate (83.33mmol), stirring until the mixture is dissolved and clarified, cooling to 15 ℃, dropwise adding 6.0g 2-thiophene acetyl chloride (37.33mmol), reacting for 1h until the raw material residue is less than or equal to 1.0%, heating to 30 ℃, adding hydrochloric acid to adjust the pH to 1.5-2.0, filtering to obtain a cephalothin acid wet product, adding 200ml dichloromethane to dissolve, removing water by layering, cooling the lower organic layer to-90 ℃, adding 30% sodium methoxide methanol solution 40.0g (222.22mmol), adding 3.5g hypochlorous acid tert-butyl ester (32.24mmol), detecting the raw material residue, adding hypochlorous acid by a certain method, adding acetic acid, adding sodium chloride solution, adding hydrochloric acid to control the pH to 1.8-2.2, standing for layering, concentrating the lower layer to dryness, adding 52.44mmol of cyclohexylamine, crystallizing, filtering, rinsing with acetone, and drying to obtain 17.5g (33.30mmol) of 7-alpha methoxycefalotin cyclohexylamine salt, wherein the molar yield is 90.66% in terms of 7-ACA, impurities in the 7-alpha methoxycefalotin cyclohexylamine salt mainly comprise 3-hydroxymethyl impurities, cephalothin acid raw materials, bismethide R type impurities and bismethide S type impurities, the content ratios of the impurities are respectively about 0.1%, 0.6%, 0.5% and 0.5%, the purity is 97.5%, and white powder is obtained.
Example 3
Adding 7-ACA10.0g (36.76mmol) into a 250ml three-neck flask, adding 100ml dichloromethane under stirring, cooling to 0 ℃, adding 9.0g triethylamine (88.93mmol), stirring until the mixture is dissolved and clarified, dropwise adding 7.0g 2-thiophene acetyl chloride (43.61mmol), reacting for 1.5h until the raw material residue is less than or equal to 0.5%, cooling to-80 ℃, adding 30.0g (166.67mmol) of 30% sodium methoxide methanol solution, adding 4.0g tert-butyl hypochlorite (36.85mmol), detecting the raw material residue, supplementing tert-butyl hypochlorite according to a certain method, adding acetic acid, adding sodium chloride solution, adding diluted hydrochloric acid to control the pH to be 1.8-2.2, standing for layering, adding sodium bicarbonate into the lower layer to adjust the pH to be 7.5, layering, adding 100ml EA into the aqueous layer, adjusting the pH to be 1.8 by hydrochloric acid, layering, drying the EA layer by using anhydrous calcium chloride, adding 5.2g (52.44mmol) of cyclohexylamine, crystallizing, filtering, rinsing by acetone, drying to obtain 16.0g (30.44mmol) of 7-alpha methoxycefalotin cyclohexylamine salt, wherein the molar yield is 82.89% in terms of 7-ACA, impurities in the 7-alpha methoxycefalotin cyclohexylamine salt mainly comprise 3-hydroxymethyl impurities, cephalothin acid raw materials, double oxidation R type impurities and double oxidation S type impurities, the proportion of the impurities is about 0.1%, 1.0% and 1.1%, the purity is 96.1%, and the product is white powder.
Example 4
Adding 7-ACA10.0g (36.76mmol) into a 250ml three-neck flask, adding 100ml dichloromethane under stirring, cooling to 0 ℃, adding 7.0g triethylamine (69.17mmol), stirring until the mixture is dissolved and clarified, dropwise adding 10.0g 2-thiopheneacetyl chloride (62.31mmol), reacting for 0.5h until the raw material residue is less than or equal to 0.5%, cooling to-75 ℃, adding 30% sodium methoxide methanol solution 60.0g (333.33mmol), adding 4.5g tert-butyl hypochlorite (41.45mmol), detecting the raw material residue, supplementing tert-butyl hypochlorite according to a certain method, adding acetic acid, adding sodium chloride solution, adding diluted hydrochloric acid to control pH to be 1.8-2.2, standing for layering, concentrating the lower layer, adding 8.0g (80.67mmol) of cyclohexylamine, crystallizing, filtering, rinsing with EA, drying to obtain 16.5g (31.39mmol) of 7-alpha methoxylated cephalothin cyclohexylamine salt, wherein the molar yield is 85.48% based on 7-ACA, the impurities in the 7-alpha methoxylated cephalothin cyclohexylamine salt mainly comprise 3-hydroxymethyl impurities, cephalothin acid raw materials, double oxidation R type impurities and double oxidation S type impurities, the proportion of the impurities is about 0.2 percent, 0.8 percent, 0.7 percent and 0.8 percent, the purity is 96.3 percent, and the impurities are white powder.
Example 5
Adding 7-ACA10.0g (36.76mmol) into a 250ml three-necked bottle, adding 120ml water under stirring, heating to 25 ℃, adding 6.5g sodium bicarbonate (77.38mmol), stirring until the mixture is dissolved and clarified, cooling to 10 ℃, dropwise adding 6.8g 2-thiophene acetyl chloride (42.37mmol), reacting for 2h until the raw material residue is less than or equal to 1.0%, heating to 10 ℃, adding hydrochloric acid to adjust the pH to 1.5-2.0, filtering to obtain a cephalothin acid wet product, adding 50ml dichloromethane and 10ml methanol to dissolve, removing water in a layered manner, cooling a lower organic layer to-60 ℃, adding 3.0g (111.11mmol) of sodium methoxide solid, adding 4.0g of tert-butyl hypochlorite (36.85mmol), detecting the raw material residue, supplementing tert-butyl hypochlorite according to a certain method, adding acetic acid, adding sodium chloride solution, adding dilute hydrochloric acid to control the pH to 1.8-2.2, standing for layering, concentrating the lower layer to dryness, adding 4.2g (42.35mmol) of cyclohexylamine, crystallizing, filtering, rinsing with acetone, and drying to obtain 14.8g (28.16mmol) of 7-alpha methoxycefalotin cyclohexylamine salt, wherein the molar yield is 72.67% in terms of 7-ACA, impurities in the 7-alpha methoxycefalotin cyclohexylamine salt mainly comprise 3-hydroxymethyl impurities, cephalothin acid raw materials, bismethide R type impurities and bismethide S type impurities, the content ratios of the impurities are respectively about 0.7%, 1.4%, 1.5% and 1.8%, the purity is 93.5%, and the product is white powder.
Example 6
Adding 7-ACA 10.0g (36.76mmol) into a 250ml three-necked bottle, adding 120ml water while stirring, heating to 25 ℃, adding 6.0g sodium bicarbonate (71.43mmol), stirring until the mixture is dissolved and clarified, cooling to 10 ℃, dropwise adding 7.3g 2-thiophene acetyl chloride (45.48mmol), reacting for 1h until the raw material residue is less than or equal to 0.5%, heating to 10 ℃, adding hydrochloric acid to adjust the pH to 1.5-2.0, filtering to obtain a cephalothin acid wet product, adding 200ml dichloromethane and 3ml methanol to dissolve, removing water in layers, cooling to-85 ℃, adding 30% sodium methoxide methanol solution 10.0g (111.11mmol), adding 5.0g N-chlorosuccinimide (37.45mmol), detecting the raw material residue, adding N-chlorosuccinimide according to a certain method, adding acetic acid, adding sodium chloride solution, adding dilute hydrochloric acid to control the pH to 1.8-2.2, standing for layering, concentrating and drying a lower layer, adding 4.2g (42.35mmol) of cyclohexylamine, crystallizing, filtering, rinsing with acetone, and drying to obtain 16.3g (31.01mmol) of 7-alpha-methoxycefalotin cyclohexylamine salt, wherein the molar yield is 84.44% in terms of 7-ACA, and impurities in the 7-alpha-methoxycefalotin cyclohexylamine salt mainly comprise 3-hydroxymethyl impurities, cephalothin acid raw materials, double-methoxy R-type impurities and double-methoxy S-type impurities, the proportions of the impurities are respectively about 0.2%, 1.0%, 1.1% and 1.0%, the purity is 96.2%, and white powder is obtained.
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.