WO2021081714A1 - 一种培南中间体map的连续化制备方法 - Google Patents

一种培南中间体map的连续化制备方法 Download PDF

Info

Publication number
WO2021081714A1
WO2021081714A1 PCT/CN2019/113744 CN2019113744W WO2021081714A1 WO 2021081714 A1 WO2021081714 A1 WO 2021081714A1 CN 2019113744 W CN2019113744 W CN 2019113744W WO 2021081714 A1 WO2021081714 A1 WO 2021081714A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
continuous reactor
solution
column
crystallization
Prior art date
Application number
PCT/CN2019/113744
Other languages
English (en)
French (fr)
Inventor
洪浩
詹姆斯·盖吉
陈朝勇
卢江平
蒋勇
陶建
罗勇
Original Assignee
吉林凯莱英制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 吉林凯莱英制药有限公司 filed Critical 吉林凯莱英制药有限公司
Priority to PCT/CN2019/113744 priority Critical patent/WO2021081714A1/zh
Priority to KR1020227018044A priority patent/KR20220093156A/ko
Priority to US17/626,790 priority patent/US20220315615A1/en
Priority to EP19950893.8A priority patent/EP3978505A4/en
Priority to JP2022525639A priority patent/JP7383812B2/ja
Publication of WO2021081714A1 publication Critical patent/WO2021081714A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
    • B01J31/08—Ion-exchange resins
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/165—Polymer immobilised coordination complexes, e.g. organometallic complexes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
    • B01J31/223—At least two oxygen atoms present in one at least bidentate or bridging ligand
    • B01J31/2239—Bridging ligands, e.g. OAc in Cr2(OAc)4, Pt4(OAc)8 or dicarboxylate ligands
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J8/00—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes
    • B01J8/02—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds
    • B01J8/0278—Feeding reactive fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • B01J2231/32—Addition reactions to C=C or C-C triple bonds
    • B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
    • B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0213—Complexes without C-metal linkages
    • B01J2531/0219—Bimetallic complexes, i.e. comprising one or more units of two metals, with metal-metal bonds but no all-metal (M)n rings, e.g. Cr2(OAc)4
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/822—Rhodium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the technical field of preparation of penem intermediates, in particular to a continuous preparation method of penem intermediates MAP.
  • Penem antibiotics namely carbapenem antibiotics, belong to ⁇ -lactam antibacterial drugs, which have strong antibacterial activity and broad antibacterial spectrum.
  • This product is clinically suitable for the treatment of the following moderate and severe infections caused by sensitive bacteria: complicated abdominal cavity infection, complicated skin and soft tissue infection, community-acquired pneumonia, complicated urinary tract infection, acute pelvic infection, severe enterobacteriaceae bacterial infection Etc. Therefore, the drug has broad application prospects.
  • Today's industrial scale-up production technology mainly uses batch chemical production (ie batch reaction production).
  • the solvent, raw materials and rhodium catalyst are put into the reactor in sequence, and the temperature is raised to perform the ring closure reaction.
  • the obtained intermediates are sequentially cooled after being cooled.
  • the patent application with application publication number CN108948086A discloses a process for the continuous synthesis of penem antibiotic core MAP, in which methyl tert-butyl ketone is used as a solvent to dissolve (3S, 4R)-3-[ -1-Hydroxyethyl]-4-[(1R)-1-Methyl-3-diazo-3-p-nitrobenzyloxyformyl-2-one-propyl]-2-azetidin Ketone, with rhodium octanoate dimer as a catalyst, is continuously reacted in a first-stage pipeline reactor to prepare intermediates; diphenyl chlorophosphate and N,N-diisopropylethylammonium are mixed to form mixture II, After the intermediate is cooled, it undergoes continuous reaction with the mixture II in a secondary pipeline reactor to prepare the penem antibiotic mother nucleus MAP.
  • reaction temperature in the first-stage pipeline reactor of this process can achieve a higher product yield, but the reaction temperature in the second-stage pipeline reactor is between -25 and -5°C, and the temperature difference between the two It is larger, so the intermediate needs to be cooled, resulting in higher energy consumption, especially when it is scaled up to industrial applications, resulting in higher production costs of MAP and lower economic benefits for producers.
  • the main purpose of the present invention is to provide a continuous preparation method of penem intermediate MAP, so as to solve the problem of high energy consumption in the process of continuous preparation of penem intermediate MAP in the prior art.
  • a continuous preparation method of penem intermediate MAP includes: step S1, in a column-type continuous reactor, using a supported rhodium catalyst to catalyze (R)-4 -Nitrobenzyl-2-diazo-4-[(2R,3S)-3-((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxy
  • the ring-closing reaction of the valerate ester forms the first intermediate, wherein the supported rhodium catalyst is loaded in a continuous column reactor, and the supported rhodium catalyst has the following structural formula: Wherein, R 1 represents any alkyl group from C1 to C10; P-COO- represents the residue after dehydrogenation of the polymer, and x represents any number from 0.1 to 4.0; step S2, the first intermediate, chlorophosphoric acid Diphenyl ester and diisopropylethylamine undergo an esterification
  • the above-mentioned column-type continuous reactor includes a reaction column, the reaction column includes a bottom-up configuration: a feed section with a liquid inlet, and a liquid distribution device is arranged above the liquid inlet; a reaction section, a reaction section and a feed section Isolation by the porous bottom plate, the reaction section is filled with inert fillers and supported rhodium catalysts and has a plurality of circumferentially arranged first partitions. Each first partition extends in the vertical direction to divide the inner cavity of the reaction section into a plurality of The first reaction chamber; the discharging section, the discharging section and the reaction section are separated by a porous top plate, and the discharging section has a liquid product outlet and an exhaust port.
  • the inner cavity of the reaction section is further provided with a second partition, the second partition is a cylindrical partition arranged coaxially with the reaction column, and the second partition divides the inner cavity of the reaction section into an inner reaction chamber And the outer reaction chamber, the first partition is arranged in the outer reaction chamber to divide the outer reaction chamber into a plurality of first reaction chambers.
  • R 1 represents a C1-C10 alkyl group, preferably methyl, ethyl, tert-butyl, n-hexyl or n-heptyl.
  • step S1 includes: adding (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-((R)-1-hydroxyethyl)-aza Cyclobutan-4-one-2-yl]-3oxopentanoate is dissolved in the first organic solvent to form the first raw material liquid, and the first organic solvent is selected from ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane , Any one or more of the group consisting of chloroform and methyl isobutyl ketone; send the first raw material liquid to the column-type continuous reactor, and use the supported rhodium catalyst to catalyze (R)-4-nitro Benzyl-2-diazo-4-[(2R,3S)-3-((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoic acid The ester undergoes cyclization reaction at 30-60°
  • step S2 includes: precooling the second continuous reactor to -32 ⁇ 12°C; sending the first intermediate system, the solution of diphenyl chlorophosphate and the solution of diisopropylethylamine into the precooling respectively
  • the esterification reaction is carried out in the second continuous reactor to obtain a product system containing the penem intermediate MAP, wherein the solvent in the solution of diphenyl chlorophosphate and the solvent in the solution of diisopropylethylamine are independently selected Any one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, chloroform and methyl isobutyl ketone, preferably before performing step S2, the step S1 obtained
  • the first intermediate system is collected in the receiving device and pre-cooled to -12-25°C, and the collecting device is connected to the column-type continuous reactor and the second continuous reactor.
  • the above-mentioned second continuous reactor is a one-stage coil continuous reactor or a multi-stage coil serial continuous reactor, and the retention time of the reactants in the second continuous reactor is 2-40 min, preferably 4-20 min.
  • step S3 includes: sending the product system, the quenching agent and the crystallization solution into a third continuous reactor for continuous crystallization to obtain a crystallization system
  • the quenching agent is selected from pure water, potassium dihydrogen phosphate Any one or more of the group consisting of buffer solution, potassium hydrogen phosphate buffer solution, sodium dihydrogen phosphate buffer solution, and sodium hydrogen phosphate buffer solution.
  • the crystallization solution is selected from the group consisting of hexane, heptane, octane, and methylcyclopentane Any one or more of the group consisting of alkane and petroleum ether; the crystallization system is subjected to solid-liquid separation to obtain the penem intermediate MAP.
  • the above-mentioned third continuous reactor is a one-stage coil continuous reactor or a continuous reactor with multiple coils connected in series.
  • step S3 includes: sending the product system into a quenching agent for quenching, and then sending a crystallization solution into the product system for crystallization to obtain a crystallization system, wherein the quenching agent is selected from pure water, phosphoric acid diphosphate Any one or more of the group consisting of potassium hydrogen phosphate buffer solution, potassium hydrogen phosphate buffer solution, sodium dihydrogen phosphate buffer solution, and sodium hydrogen phosphate buffer solution.
  • the crystallization solution is selected from the group consisting of hexane, heptane, octane, and methyl Any one or more of the group consisting of cyclopentane and petroleum ether; the crystallization system is subjected to solid-liquid separation to obtain the penem intermediate MAP.
  • this application uses a column-type continuous reactor as the place where the ring closure reaction occurs. Since the ring-closure reaction forms a gaseous product while forming the first intermediate, the gaseous product rises in the column-type continuous reactor During the process, it has a disturbing effect on the supported rhodium catalyst, which is beneficial to (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-((R)-1-hydroxyethyl )-Azetidin-4-keto-2-yl)-3oxopentanoate ((R)-4-nitrobenzyl2-diazo-4-((2R,3S)-3-((R)-1 -hydroxyethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate) and the high-efficiency contact with the catalyst to improve the catalytic effect, and the supported rhodium catalyst of the present application uses a polymer as
  • the ring closure reaction of the present application can be carried out efficiently at a lower temperature, which reduces the temperature difference between the ring closure reaction and the esterification reaction, thereby reducing
  • the cooling source required for the cooling of the first intermediate, thereby reducing energy consumption, is especially suitable for industrial applications.
  • Figure 1 shows a schematic structural diagram of a column-type continuous reactor according to an embodiment of the present invention
  • Figure 2 shows a transverse cross-sectional view of the reaction section of the reaction column of the column-type continuous reactor shown in Figure 1;
  • Figure 3 shows the HPLC spectrum of the MAP purity and content test of the product of Example 18
  • Figure 4 shows the HPLC spectrum of the ⁇ -isomer test in the product of Example 18
  • Figure 5 shows the IR spectrum of MAP in the product of Example 18.
  • Figure 6 shows the thermogravimetric analysis spectrum of the product of Example 18
  • Figure 7 shows the XRD spectrum of the product of Example 18.
  • FIG. 8 shows the GC spectrum of the solvent residue detection in the product of Example 18.
  • the prior art continuous preparation process of penem intermediate MAP requires a large amount of cold source to be consumed for cooling due to the high temperature of the first cyclization reaction, resulting in high energy consumption.
  • this application provides a continuous preparation method of penem intermediate MAP.
  • the continuous preparation method includes: step S1, in a column-type continuous reactor, using a supported rhodium catalyst to catalyze (R)-4-nitrobenzyl-2-diazo-4- [(2R,3S)-3-((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate undergoes ring reaction to form the first intermediate ,
  • the supported rhodium catalyst is loaded in a column-type continuous reactor, and the supported rhodium catalyst has the following structural formula: Wherein, R 1 represents any alkyl group from C1 to C10; P-COO- represents the residue after dehydrogenation of the polymer, and x represents any number from 0.1 to 4.0; step S2, the first intermediate, chlorophosphoric acid Diphenyl ester and diisopropylethylamine undergo an esterification reaction in the second continuous reactor to obtain a product system containing the penem intermediate MAP; and step S
  • This application uses a column-type continuous reactor as the place where the ring-closing reaction occurs. Since the ring-closing reaction forms a gaseous product while forming the first intermediate, the gaseous product forms a reaction to the supported rhodium catalyst during the ascent process in the column-type continuous reactor.
  • the ring closure reaction of the present application can be carried out efficiently at a lower temperature, which reduces the temperature difference between the ring closure reaction and the esterification reaction, thereby reducing
  • the cooling source required for the cooling of the first intermediate, thereby reducing energy consumption, is especially suitable for industrial applications.
  • the above-mentioned column-type continuous reactor includes a reaction column, and the reaction column includes a bottom-up feeding section 11, a reaction section 12, and a discharging section. 13.
  • the feed section 11 has a liquid inlet 111, and a liquid distribution device is arranged above the liquid inlet 111; the reaction section 12 and the feed section 11 are separated by a porous bottom plate 14, and the reaction section 12 is filled with inert fillers 121 and supported rhodium catalysts.
  • first partitions 122 arranged in a circumferential direction, and each first partition 122 extends in a vertical direction to partition the inner cavity of the reaction section 12 into a plurality of first reaction chambers; the discharge section 13 and the reaction section 12 pass through The porous top plate 15 is isolated, and the discharge section 13 has a liquid product outlet 131 and an exhaust port 132.
  • the reaction column of the above-mentioned column-type continuous reactor can realize continuous feeding and discharging, thereby realizing continuous reaction; a liquid distribution device is arranged above the liquid inlet 111, so that the reaction is physically fed in a uniform manner; the second set in the reaction section 12 A partition 122 divides the reaction chamber into small-volume reaction chambers.
  • a filler is arranged in the reaction chamber to disperse the supported rhodium catalyst placed in it during the reaction, and to prevent the upward flow of gas by-products from driving the supported rhodium catalyst to accumulate and cause the reaction
  • the problem of excessive pressure drop in the column when the liquid reaction material enters each reaction chamber, because the volume of the reaction chamber is small, the gaseous by-products produced by the reaction will not be excessively concentrated, causing transitional impact on the packing and the supported rhodium catalyst, forming large-area cavities
  • the presence of the filler can further prevent the supported rhodium catalyst from forming channeling and bypassing due to the above impact effect, thereby making the mass transfer between the liquid phase and the solid phase uniform during the reaction process, and the flow of the gas phase in the liquid phase and the solid phase is also uniform.
  • the feeding section 11, the reaction section 12 and the discharging section 13 of the above reaction column may be arranged in an integrated reaction column, or the sections may be connected by connecting pieces. And in order to increase productivity, the above-mentioned column-type continuous reactor can be used in multiple stages in series.
  • a second partition 123 is further provided in the inner cavity of the reaction section 12, and the second partition 123 is a cylindrical partition arranged coaxially with the reaction column, and the second partition 123
  • the inner cavity of the reaction section 12 is divided into an inner reaction chamber and an outer reaction chamber, and the first partition 122 is arranged in the outer reaction chamber to divide the outer reaction chamber into a plurality of first reaction chambers.
  • the inner cavity of the reaction section 12 is further separated, so that the mass transfer between the liquid phase and the solid phase is more uniform.
  • the above-mentioned second partition 123 is a cylindrical partition parallel to the side wall of the reaction section 12.
  • the above-mentioned cylindrical second partition 123 and the first partition 122 are combined, so that the formed first reaction chamber does not have dead corners, and the material flow in each reaction chamber is smoother and the objects are in contact with each other. More evenly.
  • the inner diameter of the inner reaction chamber is 1/4 to 1/3 of the inner diameter of the reaction zone 12. In order to make the volume of the inner reaction chamber and each first reaction chamber relatively uniform, the reactions in each reaction chamber are relatively synchronized.
  • the reaction section 12 adopts DN10-DN800 pipes, and the length-to-diameter ratio of the reaction section 12 is 0.05:1-50:1; preferably 0.2:1-20: 1.
  • R 1 represents a C1-C10 alkyl group, preferably methyl, ethyl, tert-butyl, n-hexyl or n-heptyl.
  • R 1 represents a C1-C10 alkyl group, preferably methyl, ethyl, tert-butyl, n-hexyl or n-heptyl.
  • the supported rhodium catalyst of the present application can adopt the supported rhodium catalyst in the prior art or the preparation method of the prior art to prepare the supported rhodium catalyst, for example, the supported rhodium catalyst disclosed in the patent number 201410459708.3 or the method for preparing the supported rhodium catalyst.
  • the above-mentioned step S1 includes: adding (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)- 3-((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate is dissolved in the first organic solvent to form the first raw material liquid, the first organic
  • the solvent is selected from any one or more of the group consisting of ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, chloroform and methyl isobutyl ketone.
  • the above-mentioned first raw material liquid is formed by stirring at 10-40°C.
  • the first raw material liquid is sent to a column-type continuous reactor, and the supported rhodium catalyst is used to catalyze (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-((R) -1-Hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate undergoes cyclization reaction at 30-60°C to form the first intermediate system containing the first intermediate,
  • the retention time of the first raw material liquid in the column-type continuous reactor is 2-40 min, preferably 4-20 min.
  • Add (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-((R)-1-hydroxyethyl)-azetidin-4-one-2 -Yl]-3 oxopentanoate is prepared into a solution in advance, and then sent to the column-type continuous reactor to facilitate the control of the ring closure reaction process.
  • the above-mentioned ring closure reaction can occur at 30-60°C, which is greatly reduced compared to the 80-100°C of the prior art; in addition, due to the improvement of catalytic efficiency, the retention time of the first raw material liquid in the column-type continuous reactor can also be relatively low. Shortening, such as in the range of 2-40 min, or even shortening to the range of 4-20 min, can obtain a higher yield of the first intermediate.
  • (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-((R)-1-hydroxyethyl)-azetidin in the above-mentioned first raw material liquid The content of -4-keto-2-yl]-3oxopentanoate is 0.2-0.6 mmol/mL.
  • the above step S2 includes: pre-cooling the second continuous reactor to -32 ⁇ 12°C; , The solution of diphenyl chlorophosphate and the solution of diisopropylethylamine are respectively sent to the second continuous pre-cooled reactor for esterification reaction to obtain a product system containing the penem intermediate MAP, wherein the reactant is in the first
  • the retention time of the two continuous reactor is 2-40 min, preferably 4-20 min, preferably the solvent in the solution of diphenyl chlorophosphate and the solvent in the solution of diisopropylethylamine are each independently selected from ethyl acetate, Any one or more of the group consisting of methyl acetate, tetrahydrofuran, dichloromethane, chloroform and methyl isobutyl ketone.
  • the second continuous reactor is pre-cooled to -32 ⁇ 12°C in advance
  • (R)-4-nitrobenzyl-2-diazo-4-[( The first organic solvent of 2R,3S)-3-((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate is the same.
  • the content of diphenyl chlorophosphate in the solution of diphenyl chlorophosphate is 0.6-3.0 mmol/mL; the content of diisopropylethylamine in the solution of diisopropylethylamine is 0.6-3.0 mmol/mL.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate and the solution of diisopropylethylamine is 1:0.5-2.0:0.1-1.0:0.1 ⁇ 1.0.
  • the above-mentioned second continuous reactor is a one-stage coil continuous reactor or a continuous reactor with multiple coils connected in series. Among them, a continuous reactor with multiple coils connected in series can improve production efficiency.
  • the above-mentioned esterification reaction has a wider applicable temperature range and is easier to control, and the retention time can be relatively shortened to 2-40 min, or even 4-20 min.
  • the first intermediate system obtained in step S1 can be collected in a receiving device such as a storage tank or an enamel kettle and pre-cooled to -12-25°C (preferably -10-10°C), and the collecting device is connected After the column-type continuous reactor and the second continuous reactor are collected, the reaction of step S2 is performed after a certain amount is collected, so as to further ensure the continuity and stability of the process.
  • a receiving device such as a storage tank or an enamel kettle and pre-cooled to -12-25°C (preferably -10-10°C)
  • the reaction of step S2 is performed after a certain amount is collected, so as to further ensure the continuity and stability of the process.
  • Step S3 of this application is to separate the product MAP by crystallization.
  • the crystallization method that can be used in this application can be continuous crystallization or batch crystallization.
  • the above step S3 includes: The system, quencher and crystallization solution are sent to the third continuous reactor for continuous crystallization to obtain a crystallization system, wherein the quencher is selected from pure water, potassium dihydrogen phosphate buffer solution, potassium hydrogen phosphate buffer solution, phosphoric acid Any one or more of the group consisting of sodium dihydrogen buffer solution and sodium hydrogen phosphate buffer solution, the crystallization solution is selected from any group consisting of hexane, heptane, octane, methyl cyclopentane and petroleum ether One or more; the crystallization system is subjected to solid-liquid separation to obtain the penem intermediate MAP.
  • the above-mentioned buffer solutions such as potassium dihydrogen phosphate buffer solution adopt a conventional mass concentration, such as 2-10%.
  • the continuous crystallization method can improve production efficiency.
  • the product system and quenching agent can be sent to the third continuous reactor for quenching, and then the crystallization solution can be sent in.
  • the three can be sent at the same time.
  • the feeding speed of the other is used to control the effect and rate of quenching and crystallization, such as the flow ratio of the first raw material liquid, the control product system, the quenching agent and the crystallization liquid of 1:0.7 ⁇ 4.0:0.5 ⁇ 5.0:0.5 ⁇ 5.0.
  • the above-mentioned third continuous reactor is a one-stage coil continuous reactor or a continuous reactor with multiple coils connected in series.
  • the above step S3 includes: sending the product system into a quenching agent for quenching, and then sending a crystallization solution to the product system for crystallization to obtain a crystallization system, wherein the quenching agent is selected from Any one or more of the group consisting of pure water, potassium dihydrogen phosphate buffer solution, potassium hydrogen phosphate buffer solution, sodium dihydrogen phosphate buffer solution, and sodium hydrogen phosphate buffer solution.
  • the crystallization solution is selected from the group consisting of hexane, heptane, Any one or more of the group consisting of octane, methylcyclopentane and petroleum ether; solid-liquid separation of the crystallization system is performed to obtain the penem intermediate MAP.
  • the batch crystallization method is adopted, and the above-mentioned method of first quenching and then crystallization is beneficial to improve the efficiency of crystallization and the purity of the product.
  • the solid-liquid separation method in the above two embodiments can be filtration, suction filtration or centrifugation, and the specific operating conditions can be referred to the prior art and will not be repeated here.
  • the first raw material liquid prepared in step (1) is pumped into the column-type continuous reactor shown in Figures 1 and 2 for reaction.
  • the residence time in the column-type continuous reactor is 2-40 min, and the reaction temperature is 30-60 °C, under the catalysis of the supported rhodium catalyst, the ring-closing reaction takes place to form a first intermediate system containing the first intermediate.
  • the first intermediate system flows out of the column-type continuous reactor into the receiving device.
  • the inner reaction chamber of the column-type continuous reactor The inner diameter is 1/4 to 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 0.05:1-50:1; preferably 0.2:1-20:1.
  • the first intermediate system is sent to the multi-stage coil-type continuous reactor; at the same time, the solution of diphenyl chlorophosphate and diisopropyl chlorophosphate prepared in step (1) are sent to the multi-stage coil-type continuous reactor.
  • the first intermediate system, the solution of diphenyl chlorophosphate and the solution of diisopropylethylamine enter the multi-stage coil-type continuous reactor pre-cooled to -32 ⁇ 12°C for esterification reaction.
  • the residence time of each reactant in the multi-stage coil type continuous reactor is 2-40min.
  • the crystallization system flows out of the multi-stage coil-type continuous reactor and then undergoes centrifugal separation to finally obtain the product penem intermediate MAP ((4R, 5R, 6S) -3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid(4 -nitrophenyl)methylester);
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:0.5 ⁇ 2.0: 0.1 ⁇ 1.0: 0.1 ⁇ 1.0: 0.7 ⁇ 4.0: 0.5 ⁇ 5.0: 0.5 ⁇ 5.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 20 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 40 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 4 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 30° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 60° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.25: 0.25: 1.5: 2.0: 2.5.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -32°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 minutes, and the reaction temperature is -10°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is 12°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 40 minutes, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 20 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 4 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.6 mmol/mL; the concentration of diphenyl chlorophosphate is 3.0mmol/mL; the solution concentration of diisopropylethylamine is 3.0mmol/mL, and the supported rhodium catalyst is That is, compound 62 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 40 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 40 minutes, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxovalerate solution is 0.2mmol/mL; the concentration of diphenyl chlorophosphate is 0.6mmol/mL; the solution concentration of diisopropylethylamine is 0.6mmol/mL, and the supported rhodium catalyst is That is, compound 63 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 2 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 2 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL, and the supported rhodium catalyst is That is, compound 64 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3-
  • the content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.5 mmol/mL; the concentration of diphenyl chlorophosphate is 2.5mmol/mL; the solution concentration of diisopropylethylamine is 2.5mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.3: 0.3: 1.6: 2.5: 3.0.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3- The content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxovalerate solution is 0.4mmol/mL; the concentration of diphenyl chlorophosphate is 1.0mmol/mL; the solution concentration of diisopropylethylamine is 1.0mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • the residence time of step (1) is 10 min, the reaction temperature is 20° C.
  • the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • the concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.4: 0.4: 1.8: 1.6: 2.1.
  • the penem intermediate MAP is prepared by the above process, wherein in step (1), (R)-4-nitrobenzyl-2-diazo-4-[(2R,3S)-3- The content of ((R)-1-hydroxyethyl)-azetidin-4-one-2-yl]-3oxopentanoate solution is 0.45mmol/mL; the concentration of diphenyl chlorophosphate is 1.1mmol/mL; the solution concentration of diisopropylethylamine is 1.1mmol/mL.
  • the supported rhodium catalyst is That is, compound 61 in the patent number 201410459708.3.
  • step (1) The residence time of step (1) is 10 min, the reaction temperature is 40° C., the inner diameter of the inner reaction chamber of the column-type continuous reactor is 1/3 of the inner diameter of the reaction section, and the aspect ratio of the reaction section is 10:1.
  • step (2) a coiled tube continuous reactor is used, the residence time is controlled to be 10 min, and the reaction temperature is -5°C.
  • concentration of the potassium dihydrogen phosphate buffer solution in step (3) is 5%.
  • the flow ratio of the first raw material liquid, the first intermediate system, the solution of diphenyl chlorophosphate, the solution of diisopropylethylamine, the product system, the potassium dihydrogen phosphate buffer solution, and the heptane per unit time is 1:1.0: 0.4: 0.4: 1.8: 1.8: 2.3.
  • Figure 4 corresponds to the data description in Table 2.
  • Figure 8 corresponds to the data description in Table 3.
  • Example 10 Example 10
  • Example 11 85
  • Example 3 88
  • Example 12 86
  • Example 13 89
  • Example 5 87
  • Example 14 87
  • Example 6 83
  • Example 15 85
  • Example 7 85
  • Example 16 86
  • Example 8 88
  • Example 17 81
  • Example 9 85
  • Example 18 87
  • the ring closure reaction in the first step can be carried out at a lower temperature (30-60°C). Ensure the high yield of the final product MAP.
  • This application uses a column-type continuous reactor as the place where the ring-closing reaction occurs. Since the ring-closing reaction forms a gaseous product while forming the first intermediate, the gaseous product forms a reaction to the supported rhodium catalyst during the ascent process in the column-type continuous reactor.
  • the ring closure reaction of the present application can be carried out efficiently at a lower temperature, and the temperature difference between the ring closure reaction and the esterification reaction is reduced, thereby reducing
  • the cooling source required for the cooling of the first intermediate, thereby reducing energy consumption, is especially suitable for industrial applications.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

本发明提供了一种培南中间体MAP的连续化制备方法。该连续化制备方法包括：步骤S1，在柱式连续反应器中，利用负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯发生合环反应形成第一中间体，其中，负载铑催化剂装载在柱式连续反应器中，负载铑催化剂具有如下结构式：(I) 步骤S2，将第一中间体、氯磷酸二苯酯和二异丙基乙胺在第二连续反应器中进行酯化反应，得到包含培南中间体MAP的产物体系；以及步骤S3，对产物体系进行析晶处理，得到培南中间体MAP。柱式连续反应器和负载铑催化剂使得合环反应在较低的温度下高效进行，进而降低能耗。

Description

一种培南中间体MAP的连续化制备方法 技术领域
本发明涉及培南中间体的制备技术领域，具体而言，涉及一种培南中间体MAP的连续化制备方法。
背景技术
培南类抗生素，即碳青霉烯类抗生素，属于β-内酰胺类抗菌药物，它具有强效的抗菌活性，抗菌谱广。该品临床上适用于治疗敏感菌所致的下列中、重度感染：复杂性腹腔感染、复杂性皮肤软组织感染、社区获得性肺炎、复杂性尿路感染、急性盆腔感染、严重肠杆菌科细菌感染等，因此该药具有广阔的应用前景。
现今的工业放大生产技术，主要是使用批次化学技术生产(即间歇反应生产)，将溶剂、原料和铑催化剂依次投入反应釜中，升温进行合环反应，所得到的中间体经过降温后依次加入氯磷酸二苯酯，二异丙基乙胺，在低温下进行酯化反应。该体系再经过淬灭，析晶等后处理操作得到培南中间体MAP。申请公布号为CN108948086A的专利申请公开了一种连续化合成培南类抗生素母核MAP的工艺，其中采用甲基叔丁基甲酮为溶剂溶解(3S,4R)-3-[
Figure PCTCN2019113744-appb-000001
-1-羟乙基]-4-[(1R)-1-甲基-3-重氮-3-对硝基苄氧基甲酰-2-酮-丙基]-2-氮杂环丁酮，以辛酸铑二聚体作为催化剂，在一级管道反应器中进行连续化反应制备中间体；氯磷酸二苯酯和N,N-二异丙基乙基氨混合后形成混合料II，将中间体冷却后与混合料II在二级管道反应器中进行连续化反应，制备培南类抗生素母核MAP。但是，该工艺一级管道反应器中的反应温度为80～100℃才能实现较高的产品收率，但是二级管道反应器中的反应温度在-25～-5℃之间，二者温差较大，因此需要对中间体进行冷却，导致耗能较高，尤其在放大至工业化应用中时，导致MAP的生产成本较大，生产者经济收益降低。
发明内容
本发明的主要目的在于提供一种培南中间体MAP的连续化制备方法，以解决现有技术中连续化制备培南中间体MAP的工艺能耗高的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种培南中间体MAP的连续化制备方法，包括：步骤S1，在柱式连续反应器中，利用负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯发生合环反应形成第一中间体，其中，负载铑催化剂装载在柱式连续反应器中，负载铑催化剂具有如下结构式：
Figure PCTCN2019113744-appb-000002
其中，R 1代表C1～C10的任意一个烷基；P-COO-代表聚合物经脱除氢后的残基，x代表0.1～4.0的任意数；步骤S2，将第一中间体、氯磷酸二苯酯 和二异丙基乙胺在第二连续反应器中进行酯化反应，得到包含培南中间体MAP的产物体系；以及步骤S3，对产物体系进行析晶处理，得到培南中间体MAP。
进一步地，上述柱式连续反应器包括反应柱，反应柱包括自下而上设置的：进料段，具有液体进口，且液体进口上方设置有液体分布装置；反应段，反应段与进料段通过多孔底板隔离，反应段内装填有惰性填料和负载铑催化剂且具有多个周向排布的第一隔板，各第一隔板沿竖直方向延伸将反应段的内腔分隔为多个第一反应室；出料段，出料段与反应段通过多孔顶板隔离，出料段具有液态产物出口和排气口。
进一步地，上述反应段的内腔中还设置有第二隔板，第二隔板为与反应柱同轴设置的筒状隔板，第二隔板将反应段的内腔分隔为内反应室和外反应室，第一隔板设置在外反应室中将外反应室分隔为多个第一反应室。
进一步地，上述结构式中，R 1代表C1～C10的烷基，优选甲基、乙基、叔丁基、正己基或正庚基。
进一步地，上述步骤S1包括：将(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶解于第一有机溶剂中形成第一原料液，第一有机溶剂选自乙酸乙酯、乙酸甲酯、四氢呋喃、二氯甲烷、三氯甲烷和甲基异丁基酮组成的组中的任意一种或多种；将第一原料液送入柱式连续反应器中，利用负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯在30～60℃下发生合环反应形成含有第一中间体的第一中间体系，优选第一原料液在柱式连续反应器中的保留时间为2～40min，优选为4～20min。
进一步地，上述步骤S2包括：将第二连续反应器预冷至-32～12℃；将第一中间体系、氯磷酸二苯酯的溶液和二异丙基乙胺的溶液分别送入预冷的第二连续反应器中进行酯化反应得到包含培南中间体MAP的产物体系，其中，氯磷酸二苯酯的溶液中的溶剂和二异丙基乙胺的溶液中的溶剂各自独立地选自乙酸乙酯、乙酸甲酯、四氢呋喃、二氯甲烷、三氯甲烷和甲基异丁基酮组成的组中的任意一种或多种，优选在进行步骤S2之前，将步骤S1所得到的第一中间体系收集至接收装置中并预冷至-12～25℃，收集装置连接柱式连续反应器和第二连续反应器。
进一步地，上述第二连续反应器为一级盘管连续反应器或多级盘管串联的连续反应器，反应物在第二连续反应器的保留时间为2～40min，优选为4～20min。
进一步地，上述步骤S3包括：将产物体系、淬灭剂和析晶液送入第三连续反应器中进行连续析晶，得到析晶体系，其中淬灭剂选自纯水、磷酸二氢钾缓冲溶液、磷酸氢钾缓冲溶液、磷酸二氢钠缓冲溶液、磷酸氢钠缓冲溶液组成的组中的任意一种或多种，析晶液选自己烷、庚烷、辛烷、甲基环戊烷和石油醚组成的组中的任意一种或多种；将析晶体系进行固液分离，得到培南中间体MAP。
进一步地，上述第三连续反应器为一级盘管连续反应器或多级盘管串联的连续反应器。
进一步地，上述步骤S3包括：将产物体系送入淬灭剂中淬灭后再向产物体系中送入析晶液进行析晶，得到析晶体系，其中淬灭剂选自纯水、磷酸二氢钾缓冲溶液、磷酸氢钾缓冲溶液、磷酸二氢钠缓冲溶液、磷酸氢钠缓冲溶液组成的组中的任意一种或多种，析晶液选自己烷、庚烷、辛烷、甲基环戊烷和石油醚组成的组中的任意一种或多种；将析晶体系进行固液分离，得到培南中间体MAP。
应用本发明的技术方案，本申请利用柱式连续反应器作为合环反应发生的场所，由于该合环反应在形成第一中间体的同时形成气态产物，气态产物在柱式连续反应器内上升过程中对负载铑催化剂形成扰动作用，进而有利于(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯((R)-4-nitrobenzyl2-diazo-4-((2R,3S)-3-((R)-1-hydroxyethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate)与催化剂的高效接触提高催化效果，而且本申请的负载铑催化剂以聚合物做载体因此具备较高的机械性能和催化活性，易于回收。在上述柱式连续反应器和负载铑催化剂的协同作用下，使得本申请的合环反应在较低的温度下即可高效进行，减小了合环反应和酯化反应的温差，从而减少了第一中间体降温所需冷源，进而降低了能耗，尤其适用于工业化应用。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了根据本发明的一种实施例采用的柱式连续反应器的结构示意图；
图2示出了图1所示的柱式连续反应器的反应柱的反应段横向剖面图；
图3示出了实施例18的产物MAP纯度和含量测试的HPLC谱图；
图4示出了实施例18的产物中α-异构体测试的HPLC谱图；
图5示出了实施例18的产物中MAP的IR谱图；
图6示出了实施例18的产物的热重分析谱图；
图7示出了实施例18的产物的XRD谱图；以及
图8示出了实施例18的产物中溶剂残留检测的GC谱图。
其中，上述附图包括以下附图标记：
11、进料段；111、液体进口；12、反应段；121、惰性填料；122、第一隔板；123、第二隔板；13、出料段；131、液态产物出口；132、排气口；14、多孔底板；15、多孔顶板。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
如本申请背景技术所述，现有技术的连续化制备培南中间体MAP的工艺，由于第一步合环反应的温度较高导致需要消耗大量冷源进行降温，导致能耗较高。为了解决该问题，本申请提供了一种培南中间体MAP的连续化制备方法。在一种典型的实施方式中，该连续化制备方法包括：步骤S1，在柱式连续反应器中，利用负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯发生合环反应形成第一中间体，其中，负载铑催化剂装载在柱式连续反应器中，负载铑催化剂具有如下结构式：
Figure PCTCN2019113744-appb-000003
其中，R 1代表C1～C10的任意一个烷基；P-COO-代表聚合物经脱除氢后的残基，x代表0.1～4.0的任意数；步骤S2，将第一中间体、氯磷酸二苯酯和二异丙基乙胺在第二连续反应器中进行酯化反应，得到包含培南中间体MAP的产物体系；以及步骤S3，对产物体系进行析晶处理，得到培南中间体MAP。
上述制备方法的合环反应和酯化反应的主要反应式如下：
Figure PCTCN2019113744-appb-000004
本申请利用柱式连续反应器作为合环反应发生的场所，由于该合环反应在形成第一中间体的同时形成气态产物，气态产物在柱式连续反应器内上升过程中对负载铑催化剂形成扰动作用，进而有利于(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯((R)-4-nitrobenzyl 2-diazo-4-((2R,3S)-3-((R)-1-hydroxyethyl)-4-oxoazetidin-2-yl)-3-oxopentanoate)与催化剂的高效接触提高催化效果，而且本申请的负载铑催化剂以聚合物做载体因此具备较高的机械性能和催化活性，易于回收。在上述柱式连续反应器和负载铑催化剂的协同作用下，使得本申请的合环反应在较低的温度下即可高效进行，减小了合环反应和酯化反应的温差，从而减少了第一中间体降温所需冷源，进而降低了能耗，尤其适用于工业化应用。
在本申请一种优选的实施例中，如图1和2所示，上述柱式连续反应器包括反应柱，反应柱包括自下而上设置的进料段11、反应段12和出料段13，进料段11具有液体进口111，且液体进口111上方设置有液体分布装置；反应段12与进料段11通过多孔底板14隔离，反应段12内装填有惰性填料121和负载铑催化剂且具有多个周向排布的第一隔板122，各第一隔板122沿竖直方向延伸将反应段12的内腔分隔为多个第一反应室；出料段13与反应段12通过多孔顶板15隔离，出料段13具有液态产物出口131和排气口132。
上述柱式连续反应器的反应柱可以实现连续进料、连续出料，进而实现连续反应；在液体进口111上方设置液体分布装置，使得反应物理以均匀方式进料；在反应段12设置的第一 隔板122将反应腔分割为小容积的各反应室，反应室内设置有填料将反应时设置在其中的负载铑催化剂分散，并避免气体副产物的向上流动时带动负载铑催化剂向上堆积导致反应柱内压降过大的问题；当液体反应物料进入各反应室时，由于反应室的容积小因此反应产生的气态副产物不会过度集中对填料和负载铑催化剂造成过渡冲击形成大面积空穴，且填料的存在可以进一步防止负载铑催化剂由于上述冲击作用形成沟流和旁路，进而使得反应过程中液相和固相间传质均匀，气相在液相和固相中的流动也均匀，从而提高负载铑催化剂的催化效率，使得(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯在较低的温度下即可高效进行合环反应。
上述反应柱的进料段11、反应段12和出料段13可以在一体设置的反应柱中设置，也可以通过连接件将各段连接起来。且为了提高产能上述柱式连续反应器可以多级串联使用。
进一步地，优选如图2所示，上述反应段12的内腔中还设置有第二隔板123，第二隔板123为与反应柱同轴设置的筒状隔板，第二隔板123将反应段12的内腔分隔为内反应室和外反应室，第一隔板122设置在外反应室中将外反应室分隔为多个第一反应室。通过上述第二隔板123和第一隔板122进行组合，将反应段12的内腔进一步分隔，使得液相和固相间传质更均匀。优选地，上述第二隔板123为与反应段12的侧壁平行的筒状隔板。比如如图1所示，利用上述筒状的第二隔板123与第一隔板122进行组合，使所形成的第一反应室不具有死角，各反应室内的物料流动更顺畅，物相接触更均匀。
此外，优选上述内反应室的内径为反应段12内径的1/4～1/3。以使得内反应室和各第一反应室的容积相对均匀，各反应室内的反应相对较为同步。
为了使反应柱10各反应室内的压降维持稳定，优选上述反应段12采用DN10～DN800的管道，反应段12的长径比为0.05：1～50：1；优选为0.2:1～20:1。
优选地，上述结构式中，R 1代表C1～C10的烷基，优选甲基、乙基、叔丁基、正己基或正庚基。以降低催化剂载体的合成难度。
本申请的负载铑催化剂可以采用现有技术中的负载铑催化剂或者采用现有技术的制备方法制备负载铑催化剂，比如采用专利号为201410459708.3中披露的负载铑催化剂或者采用其方法制备负载铑催化剂。
利用上述柱式连续反应器实现上述合环反应的方式有多种，优选上述步骤S1包括：将(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶解于第一有机溶剂中形成第一原料液，第一有机溶剂选自乙酸乙酯、乙酸甲酯、四氢呋喃、二氯甲烷、三氯甲烷和甲基异丁基酮组成的组中的任意一种或多种。采用在10～40℃下搅拌的方式形成上述第一原料液。将第一原料液送入柱式连续反应器中，利用负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯在30～60℃下发生合环反应形成含有第一中间体的第一中间体系，优选第一原料液在柱式连续反应器中的保留时间为2～40min，优选为4～20min。将(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯事先配制成溶液，然后送入柱式连续反应器中，便于合环反 应过程的控制。上述合环反应可以在30～60℃下发生，相对于现有技术的80～100℃大大降低；另外由于催化效率的改善，第一原料液在柱式连续反应器中的保留时间也可以相对缩短，比如在2～40min范围内，甚至缩短至4～20min范围内，都可得到较高的第一中间体收率。
优选上述第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯的含量为0.2～0.6mmol/mL。
在本申请另一种实施例中，由于酯化反应的温度较低，为了提高制备效率，优选上述步骤S2包括：将第二连续反应器预冷至-32～12℃；将第一中间体系、氯磷酸二苯酯的溶液和二异丙基乙胺的溶液分别送入预冷的第二连续反应器中进行酯化反应得到包含培南中间体MAP的产物体系，其中，反应物在第二连续反应器的保留时间为2～40min，优选为4～20min，优选氯磷酸二苯酯的溶液中的溶剂和二异丙基乙胺的溶液中的溶剂各自独立地选自乙酸乙酯、乙酸甲酯、四氢呋喃、二氯甲烷、三氯甲烷和甲基异丁基酮组成的组中的任意一种或多种。事先将第二连续反应器预冷至-32～12℃，从而使得物料进入第二连续反应器(PFR)内即可快速进入反应状态，进而提高了制备效率。
为了简化操作，优选上述氯磷酸二苯酯的溶液中的溶剂和二异丙基乙胺的溶液中的溶剂和溶解(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯的第一有机溶剂相同。优选上述氯磷酸二苯酯的溶液中氯磷酸二苯酯的含量为0.6～3.0mmol/mL；二异丙基乙胺的溶液中二异丙基乙胺的含量为0.6～3.0mmol/mL。为了提高各物质的利用率，优选第一原料液、第一中间体系、氯磷酸二苯酯的溶液和二异丙基乙胺的溶液的流量比为1：0.5～2.0：0.1～1.0：0.1～1.0。
上述第二连续反应器为一级盘管连续反应器或多级盘管串联的连续反应器。其中多级盘管串联的连续反应器可以提高生产效率。盘管连续反应器的使用时的上述酯化反应可适用温度范围更广、更容易控制，且保留时间也可以相对缩短至2～40min，甚至4～20min。
在进行步骤S2之前，可以将步骤S1所得到的第一中间体系收集到接收装置比如储罐或搪瓷釜中并预冷至-12～25℃(优选-10～10℃)，该收集装置连接柱式连续反应器和第二连续反应器，然后在收集到一定量之后再进行步骤S2的反应，以进一步保证工艺的连续性和稳定性。
本申请的步骤S3是为了将产物MAP析晶而分离，可用于本申请的析晶方式可以为连续析晶也可以为批次析晶，在一种实施例中，上述步骤S3包括：将产物体系、淬灭剂和析晶液送入第三连续反应器中进行连续析晶，得到析晶体系，其中淬灭剂选自纯水、磷酸二氢钾缓冲溶液、磷酸氢钾缓冲溶液、磷酸二氢钠缓冲溶液、磷酸氢钠缓冲溶液组成的组中的任意一种或多种，析晶液选自己烷、庚烷、辛烷、甲基环戊烷和石油醚组成的组中的任意一种或多种；将析晶体系进行固液分离，得到培南中间体MAP。上述磷酸二氢钾缓冲溶液等缓冲液采用常规质量浓度比如2～10％。
采用连续析晶方式，可以提高生产效率。在步骤S3开始之初可以先将产物体系和淬灭剂送入第三连续反应器中进行淬灭然后再将析晶液送入，在正常运行时，三者同时送入，可以通过控制三者的送入速度来控制淬灭和析晶的效果和速率，比如第一原料液、控制产物体系、 淬灭剂和析晶液的流量比为1：0.7～4.0：0.5～5.0：0.5～5.0。上述的第三连续反应器为一级盘管连续反应器或多级盘管串联的连续反应器。
在另一种实施例中，上述步骤S3包括：将产物体系送入淬灭剂中淬灭后再向产物体系中送入析晶液进行析晶，得到析晶体系，其中淬灭剂选自纯水、磷酸二氢钾缓冲溶液、磷酸氢钾缓冲溶液、磷酸二氢钠缓冲溶液、磷酸氢钠缓冲溶液组成的组中的任意一种或多种，析晶液选自己烷、庚烷、辛烷、甲基环戊烷和石油醚组成的组中的任意一种或多种；将析晶体系进行固液分离，得到培南中间体MAP。采用批次析晶方式，按照上述先淬灭后析晶的方式有利于提高析晶的效率和产物纯度。
上述两种实施例中的固液分离方式可以为过滤、抽滤或离心，具体的操作条件可以参考现有技术在此不再赘述。
以下将结合实施例和对比例，进一步说明本申请的有益效果。
(1)将(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯、氯磷酸二苯酯、二异丙基乙胺各自溶解于乙酸乙酯中，分别得到第一原料液、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液；第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.2～0.6mmol/mL；氯磷酸二苯酯的溶液浓度为0.6～3.0mmol/mL；二异丙基乙胺的溶液浓度为0.6～3.0mmol/mL。
(2)将步骤(1)配制的第一原料液泵入图1和2所示的柱式连续反应器中反应，在柱式连续反应器的停留时间为2～40min，反应温度30～60℃，在负载型铑催化剂的催化下发生合环反应生成包含第一中间体的第一中间体系，第一中间体系流出柱式连续反应器进入接收装置，柱式连续反应器的内反应室的内径为反应段内径的1/4～1/3，反应段的长径比为0.05：1～50：1；优选为0.2:1～20:1。
(3)第一中间体系送入多级盘管式连续反应器中；同时，向多级盘管式连续反应器中送入步骤(1)配制的氯磷酸二苯酯的溶液和二异丙基乙胺的溶液，使第一中间体系、氯磷酸二苯酯溶液、二异丙基乙胺的溶液进入预冷至-32～12℃的多级盘管式连续反应器中发生酯化反应，各反应物在多级盘管式连续反应器中的停留时间为2～40min。
(4)连续析晶：流出多级盘管式连续反应器的产物体系被送入另一个多级管式连续反应器中，并向其中送入2～10％磷酸二氢钾缓冲溶液进行混合淬灭，然后送入庚烷进行连续析晶得到析晶体系，析晶体系流出该多级盘管式连续反应器之后经过离心分离最终得到产物培南中间体MAP((4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid(4-nitrophenyl)methyl ester)；
或者(4)批次析晶：流出多级盘管式连续反应器的产物体系进入提前配制好的2～10％磷酸二氢钾缓冲溶液中淬灭，再向其中加入庚烷进行析晶，得到析晶体系，该析晶体系经过离心分离，最终得到产物培南中间体MAP((4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid(4-nitrophenyl)methyl ester)；
上述第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：0.5～2.0：0.1～1.0：0.1～1.0：0.7～4.0：0.5～5.0：0.5～5.0。
实施例1
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000005
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例2
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000006
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为20min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例3
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000007
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为40min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留 时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例4
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000008
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为4min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例5
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000009
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为30℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例6
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000010
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为60℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留 时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.25：0.25：1.5：2.0：2.5。
实施例7
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000011
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-32℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例8
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000012
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-10℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例9
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000013
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，1反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留 时间为10min，反应温度为12℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例10
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000014
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为40min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例11
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000015
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为20min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例12
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000016
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留 时间为4min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例13
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.6mmol/mL；氯磷酸二苯酯的溶液浓度为3.0mmol/mL；二异丙基乙胺的溶液浓度为3.0mmol/mL，负载铑催化剂为
Figure PCTCN2019113744-appb-000017
即专利号为201410459708.3中的化合物62。步骤(1)的停留时间为40min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为40min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例14
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.2mmol/mL；氯磷酸二苯酯的溶液浓度为0.6mmol/mL；二异丙基乙胺的溶液浓度为0.6mmol/mL，负载铑催化剂为
Figure PCTCN2019113744-appb-000018
即专利号为201410459708.3中的化合物63。步骤(1)的停留时间为2min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为2min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例15
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL，负载铑催化剂为
Figure PCTCN2019113744-appb-000019
即专利号为201410459708.3中的化合物64。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留 时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例16
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.5mmol/mL；氯磷酸二苯酯的溶液浓度为2.5mmol/mL；二异丙基乙胺的溶液浓度为2.5mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000020
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.3：0.3：1.6：2.5：3.0。
实施例17
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.4mmol/mL；氯磷酸二苯酯的溶液浓度为1.0mmol/mL；二异丙基乙胺的溶液浓度为1.0mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000021
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为20℃柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.4：0.4：1.8：1.6：2.1。
实施例18
采用上述流程制备培南中间体MAP，其中，步骤(1)中，第一原料液中(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶液的含量为0.45mmol/mL；氯磷酸二苯酯的溶液浓度为1.1mmol/mL；二异丙基乙胺的溶液浓度为1.1mmol/mL。负载铑催化剂为
Figure PCTCN2019113744-appb-000022
即专利号为201410459708.3中的化合物61。步骤(1)的停留时间为10min，反应温度为40℃，柱式连续反应器的内反应室的内径为反应段内径的1/3，反应段的长径比为10：1。步骤(2)采用盘管连续反应器，控制停留 时间为10min，反应温度为-5℃。步骤(3)中磷酸二氢钾缓冲溶液的浓度为5％。第一原料液、第一中间体系、氯磷酸二苯酯的溶液、二异丙基乙胺的溶液、产物体系、磷酸二氢钾缓冲溶液、庚烷单位时间内的流量比为1：1.0：0.4：0.4：1.8：1.8：2.3。
对上述各实施例的产物进行了鉴定，确定得到了目标产物MAP，并且其收率记录在表4中。对各实施例所得产物进行HPLC检测以测定纯度和异构体，对产物进行红外测试以鉴定其结构，进行热重分析以进一步对产物纯度进行分析，进行X射线衍射分析以对其晶体结构进行确认，进行GC测试以对产物中残留溶剂进行分析，其中实施例18的纯度和异构体HPLC测试结果见图3和图4、红外测试测试结果见图5、热重分析结果TG和DTG曲线见图6、XRD谱图见图7、GC谱图见图8，其中，图3对应的数据说明见表1。
表1
Figure PCTCN2019113744-appb-000023
图4对应的数据说明见表2。
表2
Figure PCTCN2019113744-appb-000024
图8对应的数据说明见表3。
表3
出峰序号 保留时间/min 峰款 峰高 峰面积 名称 分离度 信噪比
1 2.345 0.09 1747 4102 1 0.0 12
2 2.438 0.12 18982 38148 14 1.6 130
3 3.323 0.15 2752 7961 ACN 14.9 19
4 3.921 0.08 4312 10408 MeOAC 8.9 29
5 4.019 0.13 78817 206309 DCM 1.4 538
6 5.590 0.07 863 1721 n-Hex 25.0 6
7 6.493 0.09 1120 2667 5 15.1 8
8 7.366 0.08 1519 3050 6 14.9 10
9 7.587 0.09 3581 7421 8 4.0 24
10 8.142 0.14 457705 860757 n-Hep 10.4 3124
11 9.622 0.07 717 1272 Tol 0.0 5
12 9.858 0.14 3733 11674 13 0.0 25
13 10.407 0.08 5442 9634 15 8.5 37
根据图6的测试结果可以看出，加热至150℃时，失重0.011mg，失重率为0.059％。
表4
  收率(％)   收率(％)
实施例1 87 实施例10 87
实施例2 85 实施例11 85
实施例3 88 实施例12 86
实施例4 86 实施例13 89
实施例5 87 实施例14 87
实施例6 83 实施例15 85
实施例7 85 实施例16 86
实施例8 88 实施例17 81
实施例9 85 实施例18 87
根据上述各实施例的结果可以看出，由于采用了本申请的柱式反应器以及负载铑催化剂，使得第一步的合环反应在较低的温度下(30～60℃)下进行也可以保证最终产物MAP的高收率。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请利用柱式连续反应器作为合环反应发生的场所，由于该合环反应在形成第一中间体的同时形成气态产物，气态产物在柱式连续反应器内上升过程中对负载铑催化剂形成扰动作用，进而有利于(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯与催化剂的高效接触提高催化效果，而且本申请的负载铑催化剂以聚合物做载体因此具备较高的机械性能和催化活性，易于回收。在上述柱式连续反应器和负载铑催化剂的协 同作用下，使得本申请的合环反应在较低的温度下即可高效进行，减小了合环反应和酯化反应的温差，从而减少了第一中间体降温所需冷源，进而降低了能耗，尤其适用于工业化应用。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种培南中间体MAP的连续化制备方法，其特征在于，包括：
    步骤S1，在柱式连续反应器中，利用负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯发生合环反应形成第一中间体，其中，所述负载铑催化剂装载在所述柱式连续反应器中，所述负载铑催化剂具有如下结构式：
    Figure PCTCN2019113744-appb-100001
    其中，R 1代表C1～C10的任意一个烷基；P-COO-代表聚合物经脱除氢后的残基，x代表0.1～4.0的任意数；
    步骤S2，将所述第一中间体、氯磷酸二苯酯和二异丙基乙胺在第二连续反应器中进行酯化反应，得到包含培南中间体MAP的产物体系；以及
    步骤S3，对所述产物体系进行析晶处理，得到所述培南中间体MAP。
  2. 根据权利要求1所述的连续化制备方法，其特征在于，所述柱式连续反应器包括反应柱，所述反应柱包括自下而上设置的：
    进料段(11)，具有液体进口(111)，且所述液体进口(111)上方设置有液体分布装置；
    反应段(12)，所述反应段(12)与所述进料段(11)通过多孔底板(14)隔离，所述反应段(12)内装填有惰性填料(121)和所述负载铑催化剂且具有多个周向排布的第一隔板(122)，各所述第一隔板(122)沿竖直方向延伸将所述反应段(12)的内腔分隔为多个第一反应室；
    出料段(13)，所述出料段(13)与所述反应段(12)通过多孔顶板(15)隔离，所述出料段(13)具有液态产物出口(131)和排气口(132)。
  3. 根据权利要求2所述的连续化制备方法，其特征在于，所述反应段(12)的内腔中还设置有第二隔板(123)，所述第二隔板(123)为与所述反应柱同轴设置的筒状隔板，所述第二隔板(123)将所述反应段(12)的内腔分隔为内反应室和外反应室，所述第一隔板(122)设置在所述外反应室中将所述外反应室分隔为多个所述第一反应室。
  4. 根据权利要求1所述的连续化制备方法，其特征在于，所述结构式中，R 1代表C1～C10的烷基，优选甲基、乙基、叔丁基、正己基或正庚基。
  5. 根据权利要求2所述的连续化制备方法，其特征在于，所述步骤S1包括：
    将所述(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯溶解于第一有机溶剂中形成第一原料液，所述第一有机溶剂选自乙酸乙酯、乙酸甲酯、四氢呋喃、二氯甲烷、三氯甲烷和甲基异丁基酮组成的组中的任意一种或多种；
    将所述第一原料液送入所述柱式连续反应器中，利用所述负载铑催化剂催化(R)-4-硝基苄基-2-重氮-4-[(2R,3S)-3-((R)-1-羟乙基)-氮杂环丁-4-酮-2-基]-3氧代戊酸酯在30～60℃下发生合环反应形成含有第一中间体的第一中间体系，优选所述第一原料液在所述柱式连续反应器中的保留时间为2～40min，优选为4～20min。
  6. 根据权利要求1所述的连续化制备方法，其特征在于，所述步骤S2包括：
    将所述第二连续反应器预冷至-32～12℃；
    将所述第一中间体系、所述氯磷酸二苯酯的溶液和所述二异丙基乙胺的溶液分别送入预冷的所述第二连续反应器中进行酯化反应得到包含培南中间体MAP的产物体系，其中，所述氯磷酸二苯酯的溶液中的溶剂和所述二异丙基乙胺的溶液中的溶剂各自独立地选自乙酸乙酯、乙酸甲酯、四氢呋喃、二氯甲烷、三氯甲烷和甲基异丁基酮组成的组中的任意一种或多种，优选在进行步骤S2之前，将步骤S1所得到的第一中间体系收集至接收装置中并预冷至-12～25℃，所述收集装置连接所述柱式连续反应器和所述第二连续反应器。
  7. 根据权利要求1所述的连续化制备方法，其特征在于，所述第二连续反应器为一级盘管连续反应器或多级盘管串联的连续反应器，反应物在第二连续反应器的保留时间为2～40min，优选为4～20min。
  8. 根据权利要求1所述的连续化制备方法，其特征在于，所述步骤S3包括：
    将所述产物体系、淬灭剂和析晶液送入第三连续反应器中进行连续析晶，得到析晶体系，其中所述淬灭剂选自纯水、磷酸二氢钾缓冲溶液、磷酸氢钾缓冲溶液、磷酸二氢钠缓冲溶液、磷酸氢钠缓冲溶液组成的组中的任意一种或多种，所述析晶液选自己烷、庚烷、辛烷、甲基环戊烷和石油醚组成的组中的任意一种或多种；
    将所述析晶体系进行固液分离，得到所述培南中间体MAP。
  9. 根据权利要求8所述的连续化制备方法，其特征在于，所述第三连续反应器为一级盘管连续反应器或多级盘管串联的连续反应器。
  10. 根据权利要求1所述的连续化制备方法，其特征在于，所述步骤S3包括：
    将所述产物体系送入淬灭剂中淬灭后再向所述产物体系中送入析晶液进行析晶，得到析晶体系，其中所述淬灭剂选自纯水、磷酸二氢钾缓冲溶液、磷酸氢钾缓冲溶液、磷酸二氢钠缓冲溶液、磷酸氢钠缓冲溶液组成的组中的任意一种或多种，所述析晶液选自己烷、庚烷、辛烷、甲基环戊烷和石油醚组成的组中的任意一种或多种；
    将所述析晶体系进行固液分离，得到所述培南中间体MAP。
PCT/CN2019/113744 2019-10-28 2019-10-28 一种培南中间体map的连续化制备方法 WO2021081714A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/CN2019/113744 WO2021081714A1 (zh) 2019-10-28 2019-10-28 一种培南中间体map的连续化制备方法
KR1020227018044A KR20220093156A (ko) 2019-10-28 2019-10-28 페넴 중간체 map의 연속 제조 방법
US17/626,790 US20220315615A1 (en) 2019-10-28 2019-10-28 Continuous preparation method for penem intermediate map
EP19950893.8A EP3978505A4 (en) 2019-10-28 2019-10-28 METHOD FOR THE CONTINUOUS PREPARATION OF A MAP-PENEM INTERMEDIATE
JP2022525639A JP7383812B2 (ja) 2019-10-28 2019-10-28 ペネム中間体ｍａｐの連続製造方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/113744 WO2021081714A1 (zh) 2019-10-28 2019-10-28 一种培南中间体map的连续化制备方法

Publications (1)

Publication Number Publication Date
WO2021081714A1 true WO2021081714A1 (zh) 2021-05-06

Family

ID=75715656

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/113744 WO2021081714A1 (zh) 2019-10-28 2019-10-28 一种培南中间体map的连续化制备方法

Country Status (5)

Country Link
US (1) US20220315615A1 (zh)
EP (1) EP3978505A4 (zh)
JP (1) JP7383812B2 (zh)
KR (1) KR20220093156A (zh)
WO (1) WO2021081714A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114534665B (zh) * 2022-02-23 2023-05-23 苏州大学张家港工业技术研究院 一种可拓展的流动管式光催化反应装置及方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262523A (zh) * 2013-11-29 2015-01-07 凯莱英医药集团（天津）股份有限公司 含有羧基的聚合物、其制备方法和用途、负载型催化剂以及培南类抗生素中间体的制备方法
CN108948086A (zh) 2018-08-22 2018-12-07 浙江海翔川南药业有限公司 培南类抗生素母核map的合成工艺及工艺系统
CN109876747A (zh) * 2019-04-02 2019-06-14 吉林凯莱英医药化学有限公司 柱式连续反应器和柱式连续反应系统
CN110790790A (zh) * 2019-10-28 2020-02-14 吉林凯莱英制药有限公司 一种培南中间体map的连续化制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101049267B1 (ko) * 2008-10-22 2011-07-13 제이더블유중외제약 주식회사 베타-메틸 비닐 포스페이트 카바페넴의 입체 선택적 제조방법
CN102153554A (zh) * 2010-09-21 2011-08-17 重庆天地药业有限责任公司 一种制备美罗培南的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262523A (zh) * 2013-11-29 2015-01-07 凯莱英医药集团（天津）股份有限公司 含有羧基的聚合物、其制备方法和用途、负载型催化剂以及培南类抗生素中间体的制备方法
CN108948086A (zh) 2018-08-22 2018-12-07 浙江海翔川南药业有限公司 培南类抗生素母核map的合成工艺及工艺系统
CN109876747A (zh) * 2019-04-02 2019-06-14 吉林凯莱英医药化学有限公司 柱式连续反应器和柱式连续反应系统
CN110790790A (zh) * 2019-10-28 2020-02-14 吉林凯莱英制药有限公司 一种培南中间体map的连续化制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3978505A4

Also Published As

Publication number Publication date
JP2023500317A (ja) 2023-01-05
US20220315615A1 (en) 2022-10-06
KR20220093156A (ko) 2022-07-05
EP3978505A1 (en) 2022-04-06
EP3978505A4 (en) 2023-03-08
JP7383812B2 (ja) 2023-11-20

Similar Documents

Publication Publication Date Title
US20040235817A1 (en) Crystalline forms of ertapenem sodium
CA2740508C (en) Improved process for the preparation of carbapenem using carbapenem intermediates and recovery of carbapenem
CN108948086B (zh) 培南类抗生素母核map的合成工艺及工艺系统
WO2021081714A1 (zh) 一种培南中间体map的连续化制备方法
CN108440330B (zh) 一种盐酸多西环素的制备方法
CN110790790A (zh) 一种培南中间体map的连续化制备方法
CN113214239B (zh) 特地唑胺的精制工艺及磷酸特地唑胺的制备方法
CN112812107B (zh) 一种sglt-2抑制剂及中间体的制备方法
CN101914098B (zh) 美罗培南三水合物结晶的制备方法
CN101891742B (zh) 美罗培南三水合物结晶的制备方法
CN109776529B (zh) 一种1,2-二酮类咪唑杂环化合物的合成方法及应用
CN101417982B (zh) 4-乙基-(2，3-二氧代)-1-哌嗪甲酰氯的合成及其结晶的制备
CN103664949A (zh) 替比培南匹伏酯结晶及其制备方法
CN111559968B (zh) 一种拉考沙胺晶型ii的制备方法
CN110668922B (zh) 一种麝香草脑的精制方法
CN114933611A (zh) 一种连续制备培南类抗生素中间体4-乙酰氧基氮杂环丁酮的方法
CN114181115A (zh) 一种原乙酸三甲酯的成盐系统、成盐工艺以及制备工艺
CN113354647A (zh) 一种更昔洛韦钠的合成工艺
CN108586277B (zh) 一种盐酸土霉素细粒盐的制备方法
JP2015533142A (ja) エルタペネム中間体の製造
CN109663546B (zh) 一种乙酰苯胺合成专用反应器
CN115286629B (zh) 一种催化制备医药中间体3-苯氨基咪唑[1，2-a]吡啶衍生物的方法
CN111377980B (zh) 一种中间体双乙酰基二茂铁的合成方法
CN109293642B (zh) 一种伊曲康唑的精制纯化方法
CN114671805A (zh) 一种微通道反应装置及其在盐酸非那吡啶连续生产上的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19950893

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019950893

Country of ref document: EP

Effective date: 20211231

ENP Entry into the national phase

Ref document number: 2022525639

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20227018044

Country of ref document: KR

Kind code of ref document: A