CN115368385A - Biapenem production process and system - Google Patents
Biapenem production process and system Download PDFInfo
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- CN115368385A CN115368385A CN202211015583.6A CN202211015583A CN115368385A CN 115368385 A CN115368385 A CN 115368385A CN 202211015583 A CN202211015583 A CN 202211015583A CN 115368385 A CN115368385 A CN 115368385A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D1/00—Evaporating
- B01D1/0011—Heating features
- B01D1/0017—Use of electrical or wave energy
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D1/00—Evaporating
- B01D1/0082—Regulation; Control
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D1/00—Evaporating
- B01D1/30—Accessories for evaporators ; Constructional details thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a biapenem production process and system, and belongs to the technical field of biapenem production. The method comprises the following steps of A: synthesizing a branched chain intermediate K with a structure shown in a formula I, and then carrying out substitution reaction with a compound J with a structure shown in a formula II to synthesize a compound K with a structure shown in a formula III; and B, step B: and (3) carrying out reduction reaction on the compound K with the formula structure and zinc powder to obtain biapenem. According to the biapenem production process and the biapenem production system, the yield of the synthetic method is higher than that of the traditional route, the requirement on the quality of an intermediate is lower, the production is easy to carry out, and the production cost is lower than that of the traditional route.
Description
Technical Field
The invention relates to a biapenem production process and a biapenem production system, and belongs to the technical field of biapenem production.
Background
Biapenem is a carbapenem synthetic antibiotic; white or off-white powder of inner salt. Soluble in water and insoluble in common organic solvents.
Biapenem (biapenem) is a novel 1 beta-methylcarbapenem antibiotic for injection developed by Lederle corporation and cyanamide corporation in 1989 in Japan, and has been marketed in Japan in 3 months 2002, and is widely clinically used for acute and chronic infections caused by gram-negative aerobic bacteria, gram-positive aerobic bacteria and anaerobic bacteria sensitive to biapenem, wherein the biapenem is mainly used for concurrent intra-abdominal infections, lower respiratory tract infections (including bacterial pneumonia) and concurrent urinary tract infections, and moreover, biapenem has a good curative effect in treating plastic surgery infections, gynecological infections and otorhinolaryngological infections.
The existing production line of biapenem is as follows: p-nitrobenzyl (1R, 5R, 6S) -6- [ (1R) -1-hydroxyethyl ] -2- [ (diphenylphosphoryl) oxy ] -1-methylcarbapen-2-ene-3-carboxylic ester is condensed with 4-mercapto-N, N-di (p-nitrobenzyloxycarbonyl) pyrazolidine, and then reacts with ethoxyazomethine hydrochloride to prepare biapenem.
The biapenem prepared by the synthesis method has low purity, high requirement on the quality of an intermediate, difficult production and high production cost.
Disclosure of Invention
According to the defects in the prior art, the technical problems to be solved by the invention are as follows: in order to solve one of the problems, a production process and a system of biapenem are provided.
The biapenem production process and system provided by the invention are characterized in that: comprises the following steps of (a) carrying out,
step A: synthesizing a branched chain intermediate K with a structure shown in a formula I, and then carrying out substitution reaction with a compound J with a structure shown in a formula II to synthesize a compound K with a structure shown in a formula III;
and B: and carrying out reduction reaction on the compound K with the formula structure and zinc powder to obtain biapenem.
Further, the specific steps of the step a are as follows:
suspending a compound J with a structure shown in a formula II and a branched chain intermediate K with a structure shown in a formula I in a mixed solution of acetonitrile, acetone and DMF, cooling to 0 ℃, dropwise adding N, N-diisopropylethylamine, keeping the temperature between 0 and 5 ℃ during dropwise adding, continuing stirring after dropwise adding, precipitating a large amount of light yellow solids in a reaction solution, and filtering after reaction to obtain a solid heat exchange jacket, namely the compound K with a structure shown in a formula III.
Further, the specific steps of the step B are as follows:
dissolving a compound K with a structure shown in a formula III in a phosphate buffer solution, adding zinc powder, stirring at room temperature, finishing the reaction, filtering the reaction solution by using a diatomite layer, collecting the filtrate, washing the diatomite filter cake by using water, combining the filtrates, adjusting the pH of the filtrates to be =5.5, then concentrating under reduced pressure, enabling the concentration temperature to be lower than 35 ℃, carrying out column chromatography on the obtained oily substance by using a resin column, and performing isopropanol: and (3) taking the mixed solvent of water as eluent, collecting the eluent containing the product, and freeze-drying the collected eluent to obtain a white solid, namely biapenem.
Further, the vacuum concentration operation in step B is performed in a vacuum concentrator, and the vacuum concentrator is made of one of enamel, graphite and lining PTFE.
The vacuum concentration device comprises an evaporation chamber, a heat exchange jacket, a circulating delivery pump, a gas-liquid separator, a condenser, a liquid collector, an evaporation chamber vacuum pump and a heat source supply device, wherein the top of the evaporation chamber is connected with the gas-liquid separator through a steam pipeline, the bottom of the evaporation chamber is provided with a feed inlet, a liquid backflow outlet of the gas-liquid separator is connected with a backflow liquid inlet at the top of the evaporation chamber through a backflow pipe, a gas outlet of the gas-liquid separator is connected with the condenser, a vacuumizing port is formed in the top of the condenser, non-condensable gas in gas flowing out of the gas-liquid separator is discharged, a condensate outlet of the condenser is connected with the liquid collector, the bottom of the liquid collector is a discharge port, an exhaust port of the condenser is communicated with an air suction port of the vacuum pump, the heat exchange jacket is arranged on the outer wall of the evaporation chamber (1), and the heat source supply device provides energy for the heat exchange jacket.
Furthermore, the evaporator also comprises a circulating delivery pump, wherein an inlet and an outlet of the circulating delivery pump are respectively connected to the upper part of the bottom of the evaporation chamber through a pipeline, and the material at the bottom in the evaporation chamber is circulated to the upper part in the evaporation chamber.
Further, the vacuum pump is started, the negative pressure in the evaporation chamber is adjusted, and the filtrate enters the evaporation chamber through the bottom of the evaporation chamber serving as a feed inlet; starting a heat source supply device, heating an evaporation chamber by a heat exchange jacket, separating steam in a gas-liquid separator, refluxing liquid into the evaporation chamber, and continuously cooling the steam in a condenser; the top of the condenser is provided with a vacuum pumping port, so that non-condensable gas in the gas flowing out of the gas-liquid separator is discharged; the condensate in the condenser flows back to the liquid collector for preservation.
Further, the return pipe is provided with a control valve, the control valve is a one-way valve, and the one-way valve enables liquid discharged by the gas-liquid separator to flow into the evaporation chamber in a one-way mode.
Further, the material of the inner wall of the evaporation chamber comprises one of enamel, graphite and lining PTFE.
Furthermore, the heat exchange jacket outside the evaporation chamber is a ceramic ring heating jacket and adopts electric heating.
Further, compared with the prior art, the invention has the following beneficial effects:
according to the biapenem production process and the biapenem production system, the yield of the synthetic method is higher than that of the traditional route, the requirement on the quality of an intermediate is lower, the production is easy to carry out, and the production cost is lower than that of the traditional route.
Drawings
In order to more clearly illustrate the detailed description of the invention or the technical solutions in the prior art, the drawings used in the detailed description or the prior art description will be briefly described below. Throughout the drawings, like elements or portions are generally identified by like reference numerals. In the drawings, elements or portions are not necessarily drawn to scale.
FIG. 1 is a process flow diagram of intermediate K;
fig. 2 is a process flow diagram of biapenem.
FIG. 3 is a schematic view of the vacuum concentrator.
In the figure: 1. an evaporation chamber 2, a heat exchange jacket 3, a circulating delivery pump 4, a gas-liquid separator 5, a condenser 6, a liquid collector 7, a vacuum pump 8 and a heat source supply device.
Detailed Description
The invention is further described below with reference to the accompanying drawings:
the present invention is further illustrated by the following specific examples, which are not intended to limit the scope of the invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Example one
The biapenem production process and the system are characterized in that: the method comprises the following steps of A: firstly synthesizing a branched chain intermediate K with a structure shown in a formula I, and then carrying out substitution reaction with a compound J with a structure shown in a formula II to synthesize a compound K with a structure shown in a formula III; and B: and carrying out reduction reaction on the compound K with the formula structure and zinc powder to obtain biapenem.
Preferably, the specific steps of step a are as follows: suspending a compound J with a structure shown in a formula II and a branched chain intermediate K with a structure shown in a formula I in a mixed solution of acetonitrile, acetone and DMF, cooling to 0 ℃, dropwise adding N, N-diisopropylethylamine, keeping the temperature between 0 and 5 ℃ during dropwise adding, continuously stirring after dropwise adding is finished, precipitating a large amount of light yellow solid in a reaction solution, and filtering after the reaction is finished to obtain a solid heat exchange jacket, namely the compound K with the structure shown in the formula III.
Preferably, the specific steps of step B are as follows: dissolving a compound K with a structure shown in a formula III in a phosphate buffer solution, adding zinc powder, stirring at room temperature, finishing the reaction, filtering the reaction solution by using a diatomite layer, collecting the filtrate, washing the diatomite filter cake by using water, combining the filtrates, adjusting the pH of the filtrates to be =5.5, then concentrating under reduced pressure, enabling the concentration temperature to be lower than 35 ℃, carrying out column chromatography on the obtained oily substance by using a resin column, and performing isopropanol: and (3) taking the mixed solvent of water as eluent, collecting the eluent containing the product, and freeze-drying the collected eluent to obtain a white solid, namely biapenem.
Example two
Referring to fig. 3, the vacuum concentration operation in step B is performed in a vacuum concentrator, and the vacuum concentrator is made of one of enamel, graphite and lining PTFE; the reduced-pressure concentrator comprises an evaporation chamber 1, a heat exchange jacket 2, a circulating delivery pump 3, a gas-liquid separator 4, a condenser 5, a liquid collector 6, a vacuum pump 7 of the evaporation chamber 1 and a heat source supply device 8, wherein the top of the evaporation chamber 1 is connected with the gas-liquid separator 4 through a steam pipeline, the bottom of the evaporation chamber 1 is provided with a feed inlet, a liquid backflow outlet of the gas-liquid separator 4 is connected with a backflow liquid inlet at the top of the evaporation chamber 1 through a backflow pipe, a gas outlet of the gas-liquid separator 4 is connected with the condenser 5, the top of the condenser 5 is provided with a vacuum pumping port, non-condensable gas in gas flowing out from the gas-liquid separator 4 is discharged, a condensate outlet of the condenser 5 is connected with the liquid collector 6, the bottom of the liquid collector 6 is a discharge port, an exhaust port of the condenser 5 is communicated with an air suction port of the vacuum pump 7, the heat exchange jacket 2 is arranged on the outer wall of the evaporation chamber 1, and the heat source supply device 8 provides energy for the heat exchange jacket 2; the material circulation device further comprises a circulating delivery pump 3, wherein an inlet and an outlet of the circulating delivery pump 3 are respectively connected to the upper part of the bottom of the evaporation chamber 1 through a pipeline, and the material at the bottom in the evaporation chamber 1 is circulated to the upper part in the evaporation chamber 1; the vacuum pump 7 is started, the negative pressure in the evaporation chamber 1 is adjusted, and the filtrate enters the evaporation chamber 1 through the bottom of the evaporation chamber 1 as a feed inlet; starting a heat source supply device 8, heating the evaporation chamber 1 by the heat exchange jacket 2, separating steam in the gas-liquid separator 4, refluxing liquid in the evaporation chamber 1, and continuously cooling the steam in the condenser 5; the top of the condenser 5 is provided with a vacuum pumping port to discharge non-condensable gas in the gas flowing out of the gas-liquid separator 4; the condensate in the condenser 5 flows back to the liquid collector 6 for storage; the return pipe is provided with a control valve which is a one-way valve, and the one-way valve enables the liquid discharged by the gas-liquid separator 4 to flow into the evaporation chamber 1 in one way; the material of the inner wall of the evaporation chamber 1 comprises one of enamel, graphite and lining PTFE; the heat exchange jacket 2 outside the evaporation chamber 1 is a ceramic ring heating jacket and adopts electric heating, and the heat source supply device 8 is an external power supply.
EXAMPLE III
1. Preparation of intermediate A
After 56.6g of 85% hydrazine hydrate and 130ml of glacial acetic acid are respectively placed in a 250ml three-necked flask for mixing and stirring, the mixture is cooled to 0-5 ℃ by using an ice salt bath, then 60ml of ethyl formate is dropwise added, the temperature is kept at minus 5-0 ℃, the mixture is dripped off for about 1.5hr, the mixture is continuously stirred for 45min at minus 4 ℃, then the mixture is gradually increased to the room temperature and stirred overnight, acetone is dropwise added into the mixture for 160ml, the mixture is dripped off for 30min, then the mixture is stirred for 1hr at the room temperature, and the content is detected by TLC (a developing agent: petroleum ether: ethyl acetate =7, GF 254 Silica gel plate) and the raw materials are basically completely reacted. Concentration under reduced pressure gave a pale yellow solid which, after crystallization from glacial acetic acid, gave 82.7g of white crystals in 86.4% yield and a melting point of 68 ℃.
2. Preparation of intermediate B
Respectively putting the intermediate A28.6g and 200ml of ethyl acetate into a 500ml three-necked flask, stirring, then adding 37ml of allyl bromide and 100g of potassium carbonate, heating to 80-85 ℃ under stirring, keeping the temperature for 8hr, detecting the reaction condition by TCL (developing agent: petroleum ether: ethyl acetate = 7). Cooled to room temperature, filtered, and the filtrate was concentrated to give a light brown oil, which was distilled under reduced pressure (60 ℃/4mmHg as in the literature) to give 27.3g of a colorless transparent liquid in a yield of 68.1%.
3. Preparation of intermediate C
66.2g of intermediate B and 130ml of formic acid are respectively placed in a 250ml three-neck flask, stirred and heated to 78-83 ℃, and kept warm overnight, TCL detects the reaction condition (a developing agent: petroleum ether: ethyl acetate = 1), and the raw materials are basically completely reacted. Excess formic acid was evaporated under reduced pressure to give a pale yellow oil which was not purified and dosed directly down (52.7 g).
4. Preparation of intermediate D
The unpurified oil from the previous step was dissolved in 400ml of dichloromethane, 66.5g of lithium bromide monohydrate in formic acid (120 ml) was added, the mixture was cooled to 0 ℃ in an ice-salt bath, and 106.6g of bromine in dichloromethane (130 ml) was added dropwise while maintaining the temperature0 to 5 ℃, stirred for 30min at 0 ℃ after the dripping, the reaction condition is detected by TCL (a developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate) and the raw materials are basically completely reacted. Then, a suspension prepared from 220g of ammonium carbonate and 150ml of water was added to the reaction mixture, and 150ml of a saturated sodium sulfite solution was added thereto, followed by liquid separation to separate dichloromethane, and then the aqueous layer was extracted with 3X 300ml of ethyl acetate, and the dichloromethane and ethyl acetate extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a light brown oil which was directly fed downward (110 g) without being purified.
5. Preparation of intermediate E
110g of the obtained unpurified intermediate D was dissolved in 580ml of ethyl acetate, and 84g of anhydrous potassium carbonate powder was added, followed by heating to 40 ℃, stirring for 6 to 7 hours, and the reaction condition was checked by TLC (developing agent: petroleum ether: ethyl acetate =3, gf 254 Silica gel plate) and the raw materials are basically completely reacted. Filtering, distilling under reduced pressure to remove solvent to obtain brown oily substance, dissolving in ethyl acetate 50ml, adding petroleum ether 80ml dropwise under stirring, dripping within 15min, stirring at room temperature for 1hr, and separating out light yellowish white crystal. Filtration and drying gave 46.7g, with a yield of 50.2% in three successive steps.
6. Preparation of intermediate F
Taking 24g of the intermediate E in the previous step, dissolving the intermediate E in 100ml of ethyl acetate, adding 19g of potassium thioacetate, stirring at 40-45 ℃ for 6-8hr, detecting the reaction condition by TLC (a developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate) and the raw materials are basically completely reacted. Filtering, washing filter cakes by using a small amount of ethyl acetate, combining filtrates, evaporating the solvent under reduced pressure to obtain 22.9g of light brown oily substance which is not purified and directly used for the next reaction.
7. Preparation of intermediate G
The oil obtained in the above step was dissolved in 350ml of methanol, cooled to 0 ℃ with ice bath, added with a solution of 4.5g of potassium hydroxide in methanol (66 ml), stirred for 20min, and then subjected to TLC detection for reaction (developer: petroleum ether: ethyl acetate =3, gf 254 Silica gel plate), the raw materials are basically completely reacted. Adding 10ml formic acid for neutralization, concentrating to dryness, extracting the residue with 300ml dichloromethane, filtering, and filteringThe mixture was concentrated under reduced pressure to give 15.7g of a light brown oil which was not purified and directly subjected to the next reaction.
8. Preparation of intermediate H
The oily substance obtained in the above step was dissolved in 150ml of methanol, cooled to 0 ℃, added with a methanol (20 ml) solution of ferric chloride (186 mg), then blown with air, and after 2 hours, the reaction was checked by TLC (developer: petroleum ether: ethyl acetate = 3), the reaction was completed, filtered, the filtrate was concentrated to dryness under reduced pressure, added with 400ml of dichloromethane for extraction, and the dichloromethane extract was concentrated to obtain 16.1g of oily substance, which was not purified and directly put into the next step of reaction.
9. Preparation of intermediate I
Dissolving the oily substance in 250ml methanol, adding concentrated hydrochloric acid 25ml, stirring at room temperature for 6hr to precipitate crystal, filtering, concentrating the filtrate to dryness, adding small amount of methanol to precipitate crystal under stirring, and mixing the two parts to obtain 10.3g. The melting point was found to be 194 ℃ and the yield in three consecutive steps was 61.8%.
10. Preparation of intermediate J
21g of the intermediate I is dissolved in 550ml of water, then 15g of potassium bicarbonate is added, the mixture is cooled to 0 ℃, 82g of ethoxymethanimine hydrochloride is added, after stirring for 15-30 min at 0 ℃, the reaction condition is detected by TLC (developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate), after the reaction, PH =2 was adjusted with 6N hydrochloric acid, and then evaporated to dryness under reduced pressure to obtain a solid, which was extracted with 300ml of methanol, filtered, and the methanol extract was concentrated to obtain an oily substance, and the resultant was separated with a domestic 732 strong acid type cation exchange resin, and after adsorption, first with methanol-water (1: 1) Was eluted with a mixed solvent of 6N hydrochloric acid-methanol (1: 1) The product was washed out with the mixed solvent of (1) and concentrated under reduced pressure to give an oil, which was crystallized by adding a small amount of methanol to give 16.4g of pale yellowish white crystals with a yield of 61.9%. The melting point of the recrystallized methanol is 182-183 ℃.
11. Preparation of intermediate K
Dissolving 25g of intermediate (10) in 125ml of water, adding 125ml of tetrahydrofuran, cooling to 0 deg.C, adding tributyl phosphorus 28.7g, stirring at 0 deg.C for 1hr, and detecting by TLC (developing agent: petroleum ether: ethyl acetate)Acid ethyl ester =3:7,GF 254 Silica gel plate), after the reaction is finished, the tetrahydrofuran is evaporated under reduced pressure, the ethyl acetate is extracted by 3X 100ml, the water layer is concentrated to be dry, an oil is obtained, the oil is purified by SP207 resin and eluted by water, the eluent is collected and concentrated to be dry, 17.5g of light yellow white solid is obtained, and the yield is 70.1%. The melting point of the recrystallized n-propanol is 127-129 ℃.
Example four
1. Preparation of Compound (A)
30g of salicylamide, 23.6g of cyclohexanone, 4.5g of p-toluenesulfonic acid and 450ml of toluene are added into a reaction bottle, the temperature is raised to reflux, a water separator is used for separating water, after 8 hours, the water is completely removed, and the reaction condition is detected by TLC (developing agent: petroleum ether: ethyl acetate =5, GF 254 Silica gel plate), after the reaction is finished. Cooling to room temperature to gradually precipitate crystals, filtering to obtain colorless crystals, concentrating the mother liquor, adding a small amount of toluene to precipitate crystals, filtering, combining to obtain 44.8g, obtaining the yield of 93.7 percent, and measuring the melting point to be 189-191 ℃.
2. Preparation of Compound (B)
20g of the compound (a) and 200ml of toluene were put into a reaction flask, and then 11.6g of propionyl chloride was added, the mixture was heated to 70 to 75 ℃, and a toluene (40 ml) solution of triethylamine (13 g) was added dropwise, and after completion of the dropwise addition, stirring was continued, and the reaction condition was checked by TLC (developing agent: petroleum ether: ethyl acetate =3, gf 254 Silica gel plate) raw materials are completely reacted, and then cooled, washed by water, washed by 500ml of 5% ammonium carbonate, dried by toluene layer magnesium sulfate, filtered and concentrated to obtain brown oily matter, and added with methanol in a small amount, cooled, and precipitated with 20.6g of crystal with melting point of 59-60 ℃.
3. Preparation of Compound (C)
15g of the compound (B) was dissolved in dichloromethane (150 ml), cooled to 0 to 5 ℃ and a solution of titanium tetrachloride (10.4 g) in dichloromethane (15 ml) was added, followed by incubation at 5 ℃ for 30min, a solution of diisopropylethylamine (7.8 g) in dichloromethane (15 ml) was added, a solution of 4-AA (7.9 g) in dichloromethane (30 ml) was added and incubation at 5 ℃ was continued for 1 to 2 hours, and the reaction was checked by TLC (developer: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate), heating to room temperature, stirring for 3hr, and reactingThe solution was added to 500ml of ice water, and the temperature was kept at 5 ℃ or lower when the addition was completed, and then stirred for 45min, the methylene chloride layer was separated, and the residue obtained by concentration was subjected to silica gel column chromatography to separate the product, whereby 9.8g of white crystals were obtained, and the melting point was 154 to 155 ℃.
4. Preparation of Compound (D)
Compound (C) 20g was dissolved in 50ml of methanol: to a mixture of water (2 254 Silica gel plate) until the raw material disappears, then adding 150ml of ice water, separating out white solid, filtering, washing with a small amount of water, filtering with 37500, washing the filtrate with 50ml of dichloromethane, adding 35% hydrochloric acid into the water layer to adjust the pH to =3, separating out white crystals, filtering, and drying to obtain 12g. The melting point is measured to be 140-143 ℃.
5. Preparation of Compound (F)
Under the protection of nitrogen, suspending 30g of the compound (D) in 300ml of anhydrous acetonitrile, adding 18g of carbonyldiimidazole, stirring at room temperature for 45 min-1 hr, then adding 55g of magnesium mono-p-nitrobenzyl malonate and 35ml of triethylamine, heating to 50-55 ℃, keeping the temperature for 6hr, and detecting the reaction condition by TLC (developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate), after the reaction was completed, most of the solvent was distilled off under reduced pressure to leave about 50ml, and 500ml of ethyl acetate was added, followed by 500ml of 1N hydrochloric acid, 500ml of water, and 500ml of 5% sodium hydrogencarbonate were successively washed, finally washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a light brown oil which was directly fed to the next reaction.
6. Preparation of Compound (G)
The oily substance obtained in the previous step is dissolved in 75ml dichloromethane, 21.5g of p-toluenesulfonic acid azide and 2.5ml triethylamine are added under the protection of nitrogen, the mixture is stirred for 1-1.5 hr at room temperature, and the reaction condition is detected by TLC (developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate), after the reaction is finished, the reaction solution is decompressed and concentrated to obtain light brown oily substance, and the material is directly fed to the next step.
7. Preparation of Compound (H)
The oily substance obtained in the previous reaction was dissolved in 400ml of methanol, 22ml of concentrated hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours, followed by TLC detection of the reaction (developer: petroleum ether: ethyl acetate =5, GF 254 Silica gel plate), after completion of the reaction, the pH was adjusted to neutral with a solid potassium hydrogencarbonate, and then 500ml of dichloromethane and 500ml of saturated saline were added to separate a dichloromethane layer, followed by concentration to obtain a brown oil.
8. Preparation of Compound (I)
Dissolving the oily matter obtained in the last step in 200ml ethyl acetate, adding 0.3g rhodium octanoate, heating to 80-85 deg.c (generating a great amount of bubbles in the reaction liquid), and reacting for 30-45 min. The reaction was checked by TLC (developing agent: petroleum ether: ethyl acetate =5,gf 254 Silica gel plate), after the reaction was completed, the reaction solution was cooled to room temperature.
9. Preparation of Compound (J)
Cooling the reaction solution in the previous step to-5 ℃ by using a ice salt bath, adding 30g of diphenyl chlorophosphate, 250mg of 4-N, N-dimethylaminopyridine, then dropwise adding 23.4ml of N, N-diisopropylethylamine, keeping the temperature below 0 ℃ during dropwise adding, completing dropwise adding within about 3 hours, continuing stirring for 1hr after completing dropwise adding, and detecting the reaction condition by TLC (developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate), after the reaction is finished, the solvent is evaporated under reduced pressure to obtain a residue, the product is separated by silica gel column chromatography, and the eluent is dichloromethane: acetone =10:1, collecting the eluent, concentrating under reduced pressure to obtain 33g of white solid, and measuring the melting point to be 135-136 ℃ (ethyl acetate recrystallization).
10. Preparation of Compound (K)
Suspending 25g of the compound (J) and 9.7g of the intermediate (11) in a mixed solution of 75ml of acetonitrile, 75ml of acetone and 75ml of DMF, cooling to 0 ℃, dropwise adding 8.8g of N, N-diisopropylethylamine, keeping the temperature between 0 and 5 ℃ during dropwise adding, continuing stirring for 2 hours after dropwise adding, precipitating a large amount of light yellow solid in the reaction solution, and detecting the reaction condition by TLC (a developing agent: petroleum ether: ethyl acetate =3, GF 254 Silica gel plate), after the reaction was completed, filtration was performed to obtain a solid, and after vacuum drying, 18.5g of the solid was weighed, yield was 84.7%, and decomposed at 163 to 166 ℃.
11. Preparation of biapenem
Compound (K) 5g was dissolved in 150ml of 0.35n phosphate buffer (pH 5.6), zinc powder 41.5g was added, followed by stirring at room temperature for 1hr, and the reaction was checked by tlc (developing agent: petroleum ether: ethyl acetate =3, gf 254 Silica gel plate), the reaction is finished, the reaction solution is filtered by a diatomite layer, the filtrate is collected, 500ml of water is used for washing diatomite filter cakes, the filtrates are combined, the pH of the filtrate is =5.5, then the filtrate is decompressed and concentrated, the concentration temperature is lower than 35 ℃, the oily substance obtained by concentration is subjected to column chromatography by using an SP207 macroporous resin column, and the isopropanol: a mixed solvent of water (5. The collected eluent is frozen and dried to obtain 2.6g of white solid, the yield is 77.3%, the melting point is 210-217 ℃, and the method comprises the following steps: 210-218 ℃.
Treatment of three wastes
1. In the synthesis process, acid, alkali and wastewater are firstly combined and then neutralized to be neutral, and the wastewater is discharged after reaching the standard.
2. The organic solvent used in the synthesis process is recycled after being recovered.
Sources of raw materials and specifications thereof
| Raw materials | Specification of | Source |
| Hydrazine hydrate | 85% | Tianjin Fuchen chemical reagent plant |
| Potassium carbonate | AR | Economic technology for LaiyangDevelopment area refinement plant |
| 3-bromopropene | 99% | Sanli chemical Co Ltd of Qidong City |
| Formic acid | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Bromine compound | AR | Tianjin chemical reagent factory |
| Potassium thioacetate | AR | Shanghai chemical Agents Ltd |
| Methanol | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Isopropyl alcohol | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Acetone (II) | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Acetonitrile (ACN) | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Tetrahydrofuran (THF) | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Ethyl acetate | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Toluene | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| N, N diisopropylethylamine | AR | Tianjin chemical reagent Co |
| Methylene dichloride | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Methanol | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Potassium hydroxide | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Anhydrous ferric trichloride | AR | Tianjin City mao chemical instrument supply station |
| Concentrated hydrochloric acid | AR | Laiyang economic and Technological Development Zone Fine Chemical Plant |
| Ethoxy azomethine hydrochloride | 98% | Jinan Chenghuishuangda Chemical Industry Co.,Ltd. |
| Tributyl phosphorus | AR | Tianjin chemical reagent Co |
| 4-AA | 98% | Jinan Chenghuishuangda Chemical Industry Co.,Ltd. |
| Zinc powder | AR | Shanghai chemical reagent three-plant |
| SP207 type resin | Nankai University Chemical Plant | |
| Activated carbon | Pharmaceutical use | Shanghai chemical reagent three-plant |
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
The details of the present invention are not described in detail, but are known to those skilled in the art.
Claims (10)
1. A biapenem production process and a system are characterized in that: comprises the following steps of (a) carrying out,
step A: synthesizing a branched chain intermediate K with a structure shown in a formula I, and then carrying out substitution reaction with a compound J with a structure shown in a formula II to synthesize a compound K with a structure shown in a formula III;
and B: and (3) carrying out reduction reaction on the compound K with the formula structure and zinc powder to obtain biapenem.
2. The biapenem production process and system of claim 1, wherein: the specific steps of the step A are as follows:
suspending a compound J with a structure shown in a formula II and a branched chain intermediate K with a structure shown in a formula I in a mixed solution of acetonitrile, acetone and DMF, cooling to 0 ℃, dropwise adding N, N-diisopropylethylamine, keeping the temperature between 0 and 5 ℃ during dropwise adding, continuing stirring after dropwise adding, precipitating a large amount of light yellow solids in a reaction solution, and filtering after reaction to obtain a solid heat exchange jacket, namely the compound K with a structure shown in a formula III.
3. The biapenem production process and system of claim 1, wherein: the specific steps of the step B are as follows:
dissolving a compound K with a structure shown in a formula III in a phosphate buffer solution, adding zinc powder, stirring at room temperature, finishing the reaction, filtering the reaction solution by using a diatomite layer, collecting the filtrate, washing the diatomite filter cake by using water, combining the filtrates, adjusting the pH of the filtrates to be =5.5, then concentrating under reduced pressure, enabling the concentration temperature to be lower than 35 ℃, carrying out column chromatography on the obtained oily substance by using a resin column, and performing isopropanol: and (3) taking the mixed solvent of water as eluent, collecting the eluent containing the product, and freeze-drying the collected eluent to obtain a white solid, namely biapenem.
4. The biapenem production process and system of claim 3, wherein: and the decompression concentration operation in the step B is carried out in a decompression concentrator, and the material of the decompression concentrator comprises one of enamel, graphite and lining PTFE.
5. The biapenem production process and system of claim 4 are characterized in that: the reduced-pressure concentrator comprises an evaporation chamber (1), a heat exchange jacket (2), a circulating delivery pump (3), a gas-liquid separator (4), a condenser (5), a liquid collector (6), an evaporation chamber (1), a vacuum pump (7) and a heat source supply device (8), wherein the top of the evaporation chamber (1) is connected with the gas-liquid separator (4) through a steam pipeline, the bottom of the evaporation chamber (1) is provided with a feed inlet,
a liquid reflux outlet of the gas-liquid separator (4) is connected with a reflux inlet at the top of the evaporation chamber (1) through a reflux pipe,
the gas outlet of the gas-liquid separator (4) is connected with the condenser (5), the top of the condenser (5) is provided with a vacuum pumping port to discharge non-condensable gas in the gas flowing out of the gas-liquid separator (4),
a condensate outlet of the condenser (5) is connected with the liquid collector (6), a discharge hole is arranged at the bottom of the liquid collector (6),
the exhaust port of the condenser (5) is communicated with the air suction port of the vacuum pump (7),
the outer wall of the evaporation chamber (1) is provided with a heat exchange jacket (2), and a heat source supply device (8) provides energy for the heat exchange jacket (2).
6. The biapenem production process and system of claim 5, wherein: the material circulation device is characterized by further comprising a circulating delivery pump (3), wherein an inlet and an outlet of the circulating delivery pump (3) are respectively connected to the upper part of the bottom of the evaporation chamber (1) through a pipeline, and materials at the bottom in the evaporation chamber (1) are circulated to the upper part in the evaporation chamber (1).
7. The biapenem production process and system of claim 6, wherein: the vacuum pump (7) is started, the negative pressure inside the evaporation chamber (1) is adjusted, and the filtrate enters the evaporation chamber (1) through the bottom of the evaporation chamber (1) as a feed inlet; starting a heat source supply device (8), heating an evaporation chamber (1) by a heat exchange jacket (2), separating steam in a gas-liquid separator (4), refluxing liquid into the evaporation chamber (1), and continuously cooling the steam in a condenser (5); a vacuumizing port is arranged at the top of the condenser (5) to discharge non-condensable gas in the gas flowing out of the gas-liquid separator (4); the condensate in the condenser (5) flows back to the liquid collector (6) for preservation.
8. The biapenem production process and system of claim 7 are characterized in that: the return pipe is provided with a control valve which is a one-way valve, and the one-way valve enables the liquid discharged by the gas-liquid separator (4) to flow into the evaporation chamber (1) in one way.
9. The biapenem production process and system of claim 8, wherein: the material of the inner wall of the evaporation chamber (1) comprises one of enamel, graphite and lining PTFE.
10. The biapenem production process and system of claim 9, wherein: the heat exchange jacket (2) outside the evaporation chamber (1) is a ceramic ring heating jacket and adopts electric heating.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121716A (en) * | 2007-09-28 | 2008-02-13 | 严洁 | Synthesis method for biapenem |
| CN102617611A (en) * | 2011-01-28 | 2012-08-01 | 江苏正大天晴药业股份有限公司 | Preparation method of biapenem aseptic powder |
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
| CN104829633A (en) * | 2014-02-12 | 2015-08-12 | 天士力控股集团有限公司 | Preparation method of high-purity biapenem |
| CN111803977A (en) * | 2020-08-06 | 2020-10-23 | 中国科学院过程工程研究所 | Wall-sticking-preventing efficient pressure-reducing concentration device and application thereof |
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- 2022-08-24 CN CN202211015583.6A patent/CN115368385A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121716A (en) * | 2007-09-28 | 2008-02-13 | 严洁 | Synthesis method for biapenem |
| CN102617611A (en) * | 2011-01-28 | 2012-08-01 | 江苏正大天晴药业股份有限公司 | Preparation method of biapenem aseptic powder |
| CN103570750A (en) * | 2013-11-15 | 2014-02-12 | 安徽悦康凯悦制药有限公司 | Preparation process of biapenem |
| CN104829633A (en) * | 2014-02-12 | 2015-08-12 | 天士力控股集团有限公司 | Preparation method of high-purity biapenem |
| CN111803977A (en) * | 2020-08-06 | 2020-10-23 | 中国科学院过程工程研究所 | Wall-sticking-preventing efficient pressure-reducing concentration device and application thereof |
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