WO2023206607A1

WO2023206607A1 - Method for preparing oxacephem parent nucleus intermediate

Info

Publication number: WO2023206607A1
Application number: PCT/CN2022/092235
Authority: WO
Inventors: 程伟; 单秉泉; 来超; 罗雯倩; 张向龙; 王振; 张钰; 焦玉翠; 宋雪冉; 来新胜
Original assignee: 陕西友帮生物医药科技有限公司; 山东省科学院菏泽分院
Priority date: 2022-04-27
Filing date: 2022-05-11
Publication date: 2023-11-02
Also published as: CN114805395B; CN114805395A

Abstract

The present invention provides a method for preparing an oxacephem parent nucleus intermediate. ACB-7 is continuously prepared from ACB-3, or ACB-7 is directly prepared from ACB-5. The preparation method of the present invention is simple to operate, intermediate steps for purification are reduced through by means of continuous reaction for purification, the yield is increased, the solvent can be recycled, a highly toxic or strongly corrosive reagent is prevented from being used in the reaction process, and finally a target product is obtained with a high yield.

Description

A kind of preparation method of oxycephem core intermediate

Technical field

The invention belongs to the technical field of pharmaceutical and chemical engineering, and specifically relates to a preparation method of oxycephem core intermediate.

Background technique

Oxycephem core intermediate is an important intermediate for the preparation of fluoxycephalosporin and laoxycephalosporin. This type of antibiotic has a structure similar to cephalosporins of oxycephem antibiotics, and its antibacterial spectrum is similar to other third-generation cephalosporins. Such as laxacephalosporin and flurocephalosporin. This type of drug has a strong effect on anaerobic bacteria and is used for respiratory tract infections, urinary tract infections, gynecological infections, surgical infections and otolaryngology infections. It has broad application prospects and huge demand at home and abroad.

At present, there are few domestic studies on oxycephem core intermediates, and some products are produced step by step. The preparation cost is high and is not suitable for industrial production.

Patent JP2005179336 discloses the following synthetic route of oxycephem core intermediate:

There is a difference in the molecular structure between the oxycephem core intermediate and the oxycephem core intermediate of the present invention in terms of methyl group, and there are also different requirements for the design of reaction conditions; the reaction is a discontinuous reaction, and the reaction The steps are complicated, the cycle is long, the cost is high, and the reaction yield is only 54%, which is not conducive to industrial production. Moreover, the reaction uses boron trifluoride, a highly corrosive substance, which is already a restricted substance in the current field of chemical medicine.

Patent CN103254215B discloses the following synthetic route of oxycephem core intermediate:

This reaction involves the addition of chlorine gas, causing the double bond at the allyl position to undergo an addition reaction with chlorine gas to obtain a dichloride product, which is then subjected to elimination reaction, hydrolysis reaction, and ring-closing reaction to obtain the key intermediate of the oxyhead-based antibiotics. However, this The structure of the relevant intermediates in the route is different, avoiding the exposure of the double bond at the propylene position.

The paper "Research on the Synthesis Process of Oxycephem Antibiotic Intermediates" published by Zhejiang University of Technology in 2018 involves the following synthesis route of the oxycephem core intermediate:

There is an ortho-methyl difference in molecular structure between the oxycephem core intermediate and the oxycephem core intermediate of the present invention, and the synthesis route specifically avoids the use of NaI. However, after research and experiments, the patent applicant has It was found that chlorination of the allyl position inevitably occurs during double bond addition. The reaction has more impurities and a lower yield. If iodide is not used, the reaction activity of the chlorine position of the allyl position is poor, and the hydrolysis reaction is difficult to carry out efficiently. . Moreover, the yield published in this paper is only 57.9%, and the highly corrosive substance boron trifluoride complex is used, which is not suitable for industrial production.

Zhengzhou University disclosed the following synthetic route of oxycephem core intermediate in patent CN106188097A:

The allylic position chlorination reaction of this synthesis route uses chlorosuccinimide as the chlorination reagent, and the allylic position chlorination is a free radical reaction. The reaction activity of chlorosuccinimide is not as good as that of chlorine gas, and its price is more expensive than chlorine gas. This results in higher production costs, the two methyl groups at the allyl position are more likely to undergo multiple substitution side reactions, and the reaction selectivity is poor. In the final ring-closing reaction, boron trifluoride complex, a highly corrosive substance, is used to catalyze the reaction, which is already a restricted substance in the current field of chemical medicine. At the same time, it is well known that boron trifluoride reaction needs to be carried out in an anhydrous environment, and this comparison document shows that boron trifluoride catalyzes the reaction with water, and its reaction effect is questionable. Although the reference document method claims that seven steps have been optimized into three steps, with a yield of 76%, the overall yield is still low, and the reagents used are relatively expensive and are not suitable for industrial production.

Contents of the invention

In response to the above problems, it is necessary to improve and optimize the preparation method of oxycephem core intermediate, and develop a synthetic route with higher yield, lower cost and more suitable for industrial production.

The invention provides a preparation method of ACB-7, which continuously prepares ACB-7 from ACB-3. The reaction route is as follows:

Among them, ACB-3, ACB-4, ACB-5, and ACB-7 are the codes of the corresponding compounds respectively.

ACB-3 is 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]

Hept-2-en-6-yl)-but-3-enoic acid diphenylmethyl ester

ACB-7 is 3-methylene-7-[(4-methylbenzoyl)amino]-8-oxo-5-oxa-1-azabicyclo[4.2.0]octane-2- diphenylmethylcarboxylate

The embodiments of the present invention provide a variety of specific operating steps for continuously producing ACB-7 from ACB-3.

The present invention provides a method for continuously preparing ACB-7 from ACB-3. The key to the continuous preparation is that the yield and purity of the products in each intermediate step are high enough, so each reaction parameter needs to be strictly controlled.

Specifically, through the optimized configuration of various parameters, the product yield of ACB-4 produced from ACB-3 (mass ratio of ACB-4 to ACB-3) can reach 91.5%, and the purity can reach 98.6%.

The chloride raw material is preferably chlorine, ACB-3: chlorine molar ratio = 1: (1-2.5), preferably 1: (1-2), 1: (1-1.5) or 1: (1-1.2); the reaction solvent is preferably Ethyl acetate or methylene chloride, more preferably ethyl acetate. The mass ratio between ACB-3 and solvent is 1: (10-20). The temperature is controlled at 30-45°C, and the reaction time is 1-3h.

Specifically, through the optimized configuration of various parameters, the product yield of ACB-5 produced from ACB-4 (mass ratio of ACB-5 to ACB-4) can reach 96.5%, and the purity can reach 99.0%.

The iodide is preferably NaI or KI. The reaction solution is stirred for 1-2h, preferably 1.5-2h, and the temperature is controlled to 20-45°C, preferably 30-35°C.

The reactant ratio is calculated based on ACB-4, ACB-4: iodide molar ratio = 1: (0.8-1.5), preferably 1: (1-1.5), 1: (1-1.2).

The reactant ratio is calculated based on ACB-3, ACB-3: iodide molar ratio = 1: (1-1.5).

The reaction solvent is preferably ethyl acetate or acetone, and the mass ratio between ACB-4 and the solvent ethyl acetate or acetone is 1: (3-10).

Furthermore, iodide can be recycled and reused, further saving industrial costs.

Specifically, through the optimized configuration of various parameters, the product yield of ACB-7 produced from ACB-5 (mass ratio of ACB-7 to ACB-5) can reach 96.5%, and the purity can reach 98.8%.

The steps to prepare ACB-7 from ACB-5 require further explanation. The existing technology generally prepares ACB-6 from ACB-5 by adding cuprous oxide/dimethyl sulfoxide/acid/water system, reacting, crystallizing and purifying ACB-6, and then adding boron trifluoride to catalyze ring closure. ACB-7 (such as the technical solution disclosed in JP2005179336, the background technology of the present invention). The chemical structure of ACB-6 is as follows:

The present invention unexpectedly discovered during the research and development process of preparing ACB-6 from ACB-5 that when only cuprous oxide/dimethyl sulfoxide/benzenesulfonic acid acidic catalyst was added to the reactants without adding water, the reaction product Some of the peaks in the detection are shown to be ACB-7 (see Figure 7). The inventor speculates that ACB-7 can be prepared from ACB-5 in one step, thus avoiding the preparation of hydroxyl compounds such as hydroxyl compounds in a water environment in the prior art. After ACB-6, the hydroxyl compounds need to be extracted and then ring-closed in an anhydrous environment, and the use of strong acid such as boron trifluoride for catalytic ring-closure is avoided. Therefore, by controlling precise reaction conditions, the present invention can convert ACB-5 into ACB-7 in one step with high efficiency and high yield, with low cost and simple operation, and avoids the use of boron trifluoride.

The above-mentioned benzenesulfonic acid acidic catalyst may be any one of p-toluenesulfonic acid, benzenesulfonic acid, and p-methoxybenzenesulfonic acid. The temperature of the above reaction adopts step temperature. When the initial temperature is controlled at 10-15°C, the reaction will last for 2-3 hours, and then when the temperature is raised to 40-60°C, the reaction will take 0.5-2 hours. The temperature rise temperature is preferably 45-55°C.

The reactant ratio is calculated based on ACB-5. The mass ratio of ACB-5 to p-toluenesulfonic acid is 1: (0.02-0.45), preferably 1: (0.02-0.12). The mass ratio of ACB-5 to solvent dimethyl sulfoxide is 1: (6-10). The mass ratio of ACB-3 to cuprous oxide is 1: (0.27-0.45).

The reactant ratio is calculated based on ACB-3. The mass ratio of ACB-3 to p-toluenesulfonic acid is 1: (0.03-0.5), preferably 1: (0.03-0.15); ACB-3 and solvent dimethyl The mass ratio of base sulfoxide is 1: (5-15); the mass ratio of ACB-3 to cuprous oxide is 1: (0.2-0.5).

certainly,

After ACB-7 is prepared from ACB-5 in one step, the crystallization operation steps need to be optimized. For example, the preferred crystallization solvent is: one of methanol, ethanol, isopropyl alcohol, n-hexane, and ethyl acetate, with methanol being preferred. Optimal solvent ratio:

Calculated based on ACB-5, the mass ratio of the crystallization solvent to ACB-3 is: 1: (3-6), preferably 1: (1-4).

Calculated based on ACB-3, the mass ratio of the crystallization solvent to ACB-3 is: 1: (1-5), preferably 1: (1-4).

In addition, the present invention also provides a method for preparing ACB-7 from ACB-5. The embodiments of the present invention provide specific operating steps for preparing ACB-7 from ACB-5 in one step.

The preferred solvent for the entire process of continuously producing ACB-7 from ACB-3 provided by the present invention is ethyl acetate. After the ACB-5 is produced, the ethyl acetate solvent can also be recycled. For example, the ethyl acetate solution of ACB-5 can be partially evaporated for reuse. The specific evaporation amount is determined based on the principle of convenience for process use. For example, it is generally evaporated until about half of the solution is retained.

Beneficial effects of the present invention:

The invention provides a method for preparing an oxycephem core intermediate, which continuously prepares ACB-7 from ACB-3. The operation is simple, the intermediate links for purification are reduced through continuous reactions, and the yield is improved. Moreover, the solvent can be recycled and the reaction The process also avoids the use of highly toxic or corrosive reagents, and ultimately obtains the target product in high yield. This technology has been successfully used in industrial production and has very high economic and environmental value.

Description of the drawings

Figure 1 is the HPLC spectrum of the product ACB-7 of Example 1.1.

Figure 2 is the NMR spectrum of the product ACB-7 of Example 1.1.

Figure 3 is the HPLC spectrum of the product ACB-4 of Example 3.1.

Figure 4 is the nuclear magnetic resonance spectrum of the product ACB-4 of Example 3.1.

Figure 5 is the HPLC spectrum of the product ACB-5 of Example 4.1.

Figure 6 is the nuclear magnetic resonance spectrum of the product ACB-5 of Example 4.1.

Figure 7 is a diagram of the reaction process of preparing ACB-7 from ACB-5 according to the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts fall within the scope of protection of the present invention.

Sources of raw materials in the following examples:

The present invention will be further described below in conjunction with examples.

Example 1: Preparation of ACB-7 by continuous reaction of ACB-3

Example 1.1

Add 90g ACB-3 (0.19mol) and 1300g ethyl acetate to the reactor, stir until ACB-3 is completely dissolved, pass 20g chlorine gas (0.285mol) into the reactor, control the temperature at 30°C, and stir the reaction liquid for 3 hours. . HPLC detects that the raw material ACB-3 residue is <0.5%, and adds sodium bicarbonate and sodium sulfite solutions for washing. The reaction solution was allowed to stand and separated into layers, and the organic phase, ethyl acetate phase, was separated, washed with purified water, washed with saturated brine, and dried over magnesium sulfate for later use. Centrifuge the magnesium sulfate, and protect the centrifugal liquid with nitrogen. Add 34.2g sodium iodide (0.228mol) and stir the reaction solution for 1.5 hours. The temperature is controlled at 35°C. After the reaction is complete, add the reaction solution to sodium bicarbonate and sodium sulfite alkali solution, and react. The liquid was allowed to stand for layering, and the organic phase, the ethyl acetate layer, was separated and washed with purified water, washed with saturated brine, dried over magnesium sulfate, centrifuged, and part of the ethyl acetate was evaporated from the centrifuged liquid to obtain the ethyl acetate phase of ACB-5 for later use. . The evaporated ethyl acetate was dried and used. Add 1000g dimethyl sulfoxide, 43g cuprous oxide and 6.0g p-toluenesulfonic acid to the new reactor. Control the temperature at 12°C. Stir the reaction solution for 30 minutes and then add the ethyl acetate phase of ACB-5. Control the temperature at 12°C and react for 3 hours. Start to raise the temperature to 45°C and continue stirring for 2 hours. Cool the reaction solution to 0°C. Add ice water and activated carbon to the reaction solution. After stirring for 30 minutes, centrifuge and wash with ethyl acetate. Layer the layers, separate the organic phase ethyl acetate layer, wash with 5% sodium bicarbonate solution until neutral, then wash with purified water, wash with saturated brine, concentrate the ethyl acetate, add 350g methanol to crystallize, centrifuge and dry to obtain the target product 77.6g of oxycephem core intermediate ACB-7 in white powder form has a purity of 98.8% and a total yield of 84.8%. The HPLC spectrum of ACB-7 is shown in Figure 1, and the nuclear magnetic resonance spectrum is shown in Figure 2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.32 (d, J = 7.9 Hz, 1H), 7.87–7.80 (m, 2H) ,7.55–7.44(m,4H),7.42–7.25(m,8H),6.89(s,1H),5.49(d,J＝2.0Hz,2H),5.40(s,1H),5.35(d,J ＝0.9Hz,1H),4.79(dd,J＝7.8,0.9Hz,1H),4.42(d,J＝13.3Hz,1H),4.20(d,J＝13.2Hz,1H),2.37(s,3H ).

Example 1.2

Add 90g ACB-3 (0.19mol) and 900g ethyl acetate to the reactor, stir until ACB-3 is completely dissolved, pass 20g chlorine gas (0.285mol) into the reactor, control the temperature at 30°C, and stir the reaction liquid for 3 hours. . HPLC detects that the raw material ACB-3 residue is <0.5%, and adds sodium bicarbonate and sodium sulfite solutions for washing. The reaction solution was allowed to stand and separated into layers, and the organic phase, ethyl acetate phase, was separated, washed with purified water, washed with saturated brine, and dried over magnesium sulfate for later use. Centrifuge the magnesium sulfate, and protect the centrifugal liquid with nitrogen. Add 48.5g potassium iodide (0.292mol) and stir the reaction solution for 1.5 hours. The temperature is controlled at 30°C. After the reaction is complete, the reaction solution is added to the sodium bicarbonate and sodium sulfite alkali solution. The reaction solution is allowed to stand still. Separate the layers, separate the organic phase and the ethyl acetate layer, wash with purified water, wash with saturated brine, dry over magnesium sulfate, centrifuge, and evaporate part of the ethyl acetate from the centrifugal liquid to obtain the ethyl acetate phase of ACB-5 for later use. The evaporated ethyl acetate was dried and used. Add 500g dimethyl sulfoxide, 40g cuprous oxide and 10.8g p-toluenesulfonic acid to the new reactor. Control the temperature at 15°C. Stir the reaction solution for 30 minutes and then add the ethyl acetate phase of ACB-5. Control the temperature at 15°C and react for 3 hours. Start to raise the temperature to 50°C and continue stirring the reaction for 2 hours. Cool the reaction solution to 3°C. Add ice water and activated carbon to the reaction solution. After stirring for 30 minutes, centrifuge and wash with ethyl acetate. Layer the layers, separate the organic phase ethyl acetate layer, wash with 5% sodium bicarbonate solution until neutral, then wash with purified water, wash with saturated brine, concentrate the ethyl acetate, add 300g methanol to crystallize, centrifuge and dry to obtain the target product The oxycephem core intermediate ACB-7 is 70.4g in white powder form, with a purity of 98.4% and a total yield of 76.9%.

Example 1.3

Add 90g ACB-3 (0.19mol) and 900g ethyl acetate to the reactor, stir until ACB-3 is completely dissolved, pass 20g chlorine gas (0.285mol) into the reactor, control the temperature at 35°C, and stir the reaction liquid for 3 hours. . HPLC detects that the raw material ACB-3 residue is <0.5%, and adds sodium bicarbonate and sodium sulfite solutions for washing. The reaction solution was allowed to stand and separated into layers, and the organic phase, ethyl acetate phase, was separated, washed with purified water, washed with saturated brine, and dried over magnesium sulfate for later use. Centrifuge the magnesium sulfate, and protect the centrifugal liquid with nitrogen. Add 28.5g sodium iodide (0.19mol) and stir the reaction solution for 1.5 hours. The temperature is controlled at 35°C. After the reaction is complete, add the reaction solution to sodium bicarbonate and sodium sulfite alkali solution, and react. The liquid was allowed to stand for layering, and the organic phase, the ethyl acetate layer, was separated and washed with purified water, washed with saturated brine, dried over magnesium sulfate, centrifuged, and part of the ethyl acetate was evaporated from the centrifuged liquid to obtain the ethyl acetate phase of ACB-5 for later use. . The evaporated ethyl acetate was dried and used. Add 450g dimethyl sulfoxide, 45g cuprous oxide and 9.0g p-toluenesulfonic acid to the new reactor. Control the temperature at 10°C. Stir the reaction solution for 30 minutes and then add the ethyl acetate phase of ACB-5. Control the temperature at 10°C and react for 2.5 hours. Start to raise the temperature to 45°C and continue stirring the reaction for 2 hours. Cool the reaction solution to 3°C. Add ice water and activated carbon to the reaction solution. After stirring for 30 minutes, centrifuge, wash with ethyl acetate, and centrifuge. Separate the liquid layer, separate the organic phase ethyl acetate layer, wash with 5% sodium bicarbonate solution until neutral, then wash with purified water, wash with saturated brine, concentrate the ethyl acetate, add 300g methanol to crystallize, centrifuge and dry to obtain the target The product oxycephem core intermediate ACB-7 is 76.9g in the form of white powder, with a purity of 98.6% and a total yield of 83.9%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.32 (d, J = 7.9 Hz, 1H), 7.87–7.80 (m, 2H), 7.55–7.44 (m, 4H), 7.42–7.25 (m, 8H) ),6.89(s,1H),5.49(d,J＝2.0Hz,2H),5.40(s,1H), 5.35(d,J＝0.9Hz,1H),4.79(dd,J＝7.8,0.9Hz ,1H),4.42(d,J＝13.3Hz,1H),4.20(d,J＝13.2Hz,1H),2.37(s,3H).

Example 1.4

Add 90g ACB-3 (0.19mol) and 1300g ethyl acetate to the reactor, stir until ACB-3 is completely dissolved, pass 21g chlorine gas (0.285mol) into the reactor, control the temperature at 45°C, and stir the reaction liquid for 3 hours. . HPLC detects that the raw material ACB-3 residue is <0.5%, and adds sodium bicarbonate and sodium sulfite solutions for washing. The reaction solution was allowed to stand and separated into layers, and the organic phase, ethyl acetate phase, was separated, washed with purified water, washed with saturated brine, and dried over magnesium sulfate for later use. Centrifuge the magnesium sulfate, and protect the centrifugal liquid with nitrogen. Add 34.2g sodium iodide (0.228mol) and stir the reaction solution for 1.5 hours. The temperature is controlled at 35°C. After the reaction is complete, add the reaction solution to sodium bicarbonate and sodium sulfite alkali solution, and react. The liquid was allowed to stand for layering, and the organic phase, the ethyl acetate layer, was separated and washed with purified water, washed with saturated brine, dried over magnesium sulfate, centrifuged, and part of the ethyl acetate was evaporated from the centrifuged liquid to obtain the ethyl acetate phase of ACB-5 for later use. . The evaporated ethyl acetate was dried and used. Add 1080g dimethyl sulfoxide, 45g cuprous oxide and 16g p-methoxybenzenesulfonic acid to the new reactor. Control the temperature at 15°C. Stir the reaction solution for 30 minutes and then add the ethyl acetate phase of ACB-5. Control the temperature at 15°C and react for 2 hours. Start to raise the temperature to 55°C and continue stirring for 2 hours. Cool the reaction solution to 0°C. Add ice water and activated carbon to the reaction solution. After stirring for 30 minutes, centrifuge and wash with ethyl acetate. Layer the layers, separate the organic phase ethyl acetate layer, wash with 5% sodium bicarbonate solution until neutral, then wash with purified water, wash with saturated brine, concentrate the ethyl acetate, add 350g methanol to crystallize, centrifuge and dry to obtain the target product 65.4g of oxycephem core intermediate ACB-7 white powder has a purity of 97.6% and a total yield of 71.3%.

Example 1.5

Add 90g ACB-3 (0.19mol) and 1300g ethyl acetate to the reactor, stir until ACB-3 is completely dissolved, pass 20g chlorine gas (0.285mol) into the reactor, control the temperature at 35°C, and stir the reaction liquid for 3 hours. . HPLC detects that the raw material ACB-3 residue is <0.5%, and adds sodium bicarbonate and sodium sulfite solutions for washing. The reaction solution was allowed to stand and separated into layers, and the organic phase, ethyl acetate phase, was separated, washed with purified water, washed with saturated brine, and dried over magnesium sulfate for later use. Centrifuge the magnesium sulfate, and protect the centrifugal liquid with nitrogen. Add 34.3g sodium iodide (0.228mol) and stir the reaction solution for 1.5 hours. The temperature is controlled at 35°C. After the reaction is complete, add the reaction solution to sodium bicarbonate and sodium sulfite alkali solution, and react. The liquid was allowed to stand for layering, and the organic phase, the ethyl acetate layer, was separated and washed with purified water, washed with saturated brine, dried over magnesium sulfate, centrifuged, and part of the ethyl acetate was evaporated from the centrifuged liquid to obtain the ethyl acetate phase of ACB-5 for later use. . The evaporated ethyl acetate was dried and used. Add 1080g dimethyl sulfoxide, 45g cuprous oxide and 6.5g p-methoxybenzenesulfonic acid to the new reactor. Control the temperature at 15°C. Stir the reaction solution for 30 minutes and then add the ethyl acetate phase of ACB-5. Control the temperature at 15°C and react for 2 hours. Start to raise the temperature to 50°C and continue stirring for 2 hours. Cool the reaction solution to 0°C. Add ice water and activated carbon to the reaction solution. After stirring for 30 minutes, centrifuge and wash with ethyl acetate. Layer the layers, separate the organic phase ethyl acetate layer, wash with 5% sodium bicarbonate solution until neutral, then wash with purified water, wash with saturated brine, concentrate the ethyl acetate, add 400g of ethanol to crystallize, centrifuge and dry to obtain the target product 77.1g of oxycephem core intermediate ACB-7 white powder, purity 98.5%, total yield 84.2%.

Example 2: Preparing ACB-7 from ACB-5 in one step

Add ACB-5 and ethyl acetate to the reactor, then add the dimethyl sulfoxide/cuprous oxide/benzenesulfonic acid series to control the initial reaction temperature and reaction time; after HPLC detects that the ACB-5 reaction is complete, start the temperature-raising reaction , cool the reaction solution to 3°C, add ice water and activated carbon to the reaction solution, stir for 30 minutes, centrifuge, wash with ethyl acetate, separate the centrifugal solution, separate the organic phase ethyl acetate layer, and use 5% sodium bicarbonate The solution was washed until neutral, then washed with purified water, washed with saturated brine, concentrated with ethyl acetate, crystallized by adding methanol, centrifuged and dried to obtain the target product oxycephem core intermediate ACB-7 as white powder.

The following table shows the yield and purity results of ACB-7 obtained by adjusting various process parameters. The yield is the mass ratio of ACB-7 to ACB-5.

In order to realize the continuous production of ACB-7 from ACB-3 and ensure that the yield and purity of ACB-7 are high enough, the present invention needs to optimize the preparation process of each intermediate product. Examples 3 and 4 give some experiments. example:

Example 3. Example of preparation of ACB-4 from ACB-3

Add ACB-3 and ethyl acetate to the reactor, stir until ACB-3 is completely dissolved, pass chlorine gas into the reactor, control the reaction temperature and time to obtain an ACB-4 solution, and obtain ACB-4 solid after crystallization and drying. The following table shows the yield and purity results of ACB-4 obtained by adjusting various process parameters. The yield is the mass ratio of ACB-4 to ACB-3.

The HPLC spectrum of ACB-4 of Example 3.1 is shown in Figure 3, and the nuclear magnetic resonance spectrum is shown in Figure 4. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.75–7.68 (m, 2H), 7.36–7.20 (m, 12H) ),6.85(s,1H),6.16(d,J＝3.2Hz,1H),5.40(d,J＝3.2Hz,1H),5.15–5.05(m,2H),2.36(s,3H),1.76 (s,3H).

Example 4. Process optimization example for preparing ACB-5 from ACB-4

Add ACB-4, iodide, and reaction solvent to the reactor, and control a certain reaction temperature and reaction time. After the reaction is complete, add the reaction solution to sodium bicarbonate and sodium sulfite alkali solution, and let the reaction solution stand for stratification and separate. The organic phase layer was washed with purified water, washed with saturated brine, dried over magnesium sulfate, and centrifuged. The centrifuged liquid was crystallized and dried to obtain ACB-5 solid. The following table shows the yield and purity results of ACB-5 obtained by adjusting various process parameters. The yield is the mass ratio of ACB-5 to ACB-4.

The HPLC spectrum of ACB-5 in Example 4.1 is shown in Figure 5, and the nuclear magnetic resonance spectrum is shown in Figure 6. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.76–7.69 (m, 2H), 7.37–7.20 (m, 13H) ),6.86(s,1H),6.14(d,J＝3.2Hz,1H),5.71(s,1H),5.40(d,J＝3.3Hz,1H),5.27(d,J＝13.1Hz,2H ),4.39(s,2H),2.35(s,3H).

The examples described above represent only several embodiments of the invention, which are described with specificity and detail. The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range. For those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be determined by the appended claims. shall prevail.

Claims

A method for preparing an oxycephem core intermediate, which is characterized in that ACB-7 is continuously prepared from ACB-3, and the reaction route is as follows:
The preparation method of an oxycephem core intermediate according to claim 1, characterized in that: in the step of preparing ACB-4 from ACB-3, the molar ratio of ACB-3: chlorine = 1: (1- 2.5), preferably 1: (1-2), 1: (1-1.5) or 1: (1-1.2).
The method for preparing an oxycephem core intermediate according to claim 1, characterized in that in the step of preparing ACB-4 from ACB-3, the temperature is controlled at 30-45°C.
The preparation method of an oxycephem core intermediate according to claim 1, characterized in that: in the step of preparing ACB-5 from ACB-4, the iodide is NaI or KI, and ACB-3: iodide Molar ratio = 1: (1-1.5).
The preparation method of an oxycephem core intermediate according to claim 1, characterized in that: in the step of preparing ACB-5 from ACB-4, the temperature is controlled to 20-45°C, preferably 30-35°C. .
The preparation method of an oxycephem core intermediate according to claim 1, characterized in that: in the step of preparing ACB-7 from ACB-5, cuprous oxide/dimethyl sulfoxide/benzenesulfonic acid is selected. Acid-like catalyst system.
The preparation method of an oxycephem core intermediate according to claim 6, characterized in that: the reaction temperature adopts a step temperature, and the initial temperature is controlled at 10-15°C and after 2-3 hours of reaction, the temperature is raised to 40-55°C. The reaction takes 0.5-2h at ℃.
The preparation method of an oxycephem core intermediate according to claim 6, characterized in that: the mass ratio of ACB-3 to p-toluenesulfonic acid is 1: (0.03-0.5), preferably 1: (0.03 -0.15).
The preparation method of an oxycephem core intermediate according to claim 6, characterized in that: the mass ratio of ACB-3 to solvent dimethyl sulfoxide is 1: (5-15).
The preparation method of an oxycephem core intermediate according to claim 6, characterized in that: the mass ratio of ACB-3 to cuprous oxide is 1: (0.2-0.5).
The preparation method of an oxycephem core intermediate according to claim 1, characterized in that: after ACB-7 is prepared from ACB-5, the crystallization solvent is methanol, ethanol, isopropyl alcohol, n-hexane, acetic acid One of the ethyl esters, the mass ratio of solvent to ACB-3: 1: (1-5).
The preparation method of an oxycephem core intermediate according to claim 1, characterized in that: the selected solvent for the entire reaction process is ethyl acetate, and after the ACB-5 is prepared, the ethyl acetate solvent can also be used Apply in a loop.
A method for preparing an oxycephem core intermediate, which is characterized in that ACB-5 is directly prepared from ACB-5, and the reaction formula of the cuprous oxide/dimethyl sulfoxide/benzenesulfonic acid acidic catalyst system is selected:
The method for preparing ACB-7 from ACB-5 according to claim 13, characterized in that: the reaction temperature adopts step temperature, and the initial temperature is controlled at 10-15°C and after 2-3 hours of reaction, the temperature is raised to 40-60°C. The reaction time is 0.5-2h.
The method for preparing ACB-7 from ACB-5 according to claim 14, characterized in that: the reactant ratio is calculated based on ACB-5, and the mass ratio of ACB-5 to p-toluenesulfonic acid is 1 (0.02-0.45), preferably 1: (0.02-0.12), the mass ratio of ACB-5 to solvent dimethyl sulfoxide is 1: (6-10), the mass ratio of ACB-3 to cuprous oxide is 1 :(0.27-0.45).