CN118324683A - Preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester - Google Patents
Preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 239000002253 acid Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 21
- 239000011230 binding agent Substances 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012312 sodium hydride Substances 0.000 claims abstract description 13
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 13
- 238000006482 condensation reaction Methods 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 claims abstract description 10
- FRKGSNOMLIYPSH-UHFFFAOYSA-N 3-hydroxypyrrolidin-2-one Chemical compound OC1CCNC1=O FRKGSNOMLIYPSH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 8
- 238000007112 amidation reaction Methods 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000002635 aromatic organic solvent Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
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- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
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- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 229960000466 cefpirome Drugs 0.000 description 8
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 8
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- 238000002425 crystallisation Methods 0.000 description 6
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- -1 halogenoalkyl acyl chloride Chemical class 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
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- 229930186147 Cephalosporin Natural products 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
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- 238000007363 ring formation reaction Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
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- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 3
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 3
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- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- QPMSJEFZULFYTB-UHFFFAOYSA-N pyrrolidin-1-ium-3-ol;chloride Chemical compound Cl.OC1CCNC1 QPMSJEFZULFYTB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ULUNQYODBKLBOE-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)-1h-pyrrole Chemical group C1=CNC(C=2NC=CC=2)=C1 ULUNQYODBKLBOE-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention relates to a preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester, belonging to the technical field of synthesis of pharmaceutical intermediates. In order to solve the problems of complex existing route and poor product yield, the preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester is provided, and is characterized in that the method comprises the steps of carrying out amidation reaction on a compound shown in a formula VI or acid salt thereof serving as a raw material and allyl chloroformate shown in a formula V in the presence of an acid binding agent to generate a compound shown in a formula IV; in the presence of sodium hydride, carrying out condensation reaction on 3-hydroxy-2 pyrrolidone of a compound of a formula III and a compound of a formula IV to obtain a compound of a formula II; the compound of formula II and chlorinating agent are subjected to chlorination reaction to obtain the compound of formula I, namely 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester. Has the advantages of high yield of the reaction intermediate products of each step, effectively avoids the separation mode purification by column chromatography, and has high yield.
Description
Technical Field
The invention relates to a preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester, belonging to the technical field of synthesis of pharmaceutical intermediates.
Background
Cefpirome is a prodrug form of cefpirome, enters a human body and can be rapidly hydrolyzed into an active form by nonspecific esterifying enzyme, is a new generation of cephalosporin for broad-spectrum intravenous injection, and has the activities of resisting methicillin-resistant staphylococcus aureus and gram-negative bacteria (including partial pseudomonas aeruginosa). As with other cephalosporins, cefpirome does not have activity against atypical respiratory pathogens. Cefpirome exhibits potent activity in vitro against a variety of gram-positive and gram-negative bacteria leading to HAP and CAP, and is the first single drug in the european union to be used as a new cephalosporin against MRSA for the treatment of HAP (excluding VAP) and CAP. On the 10 th month and 27 th year of 2020, the warrior of the infection is introduced into ceftarabil sodium for injection from Baselia pharmaceutical company of the enterprise in Switzerland to formally obtain a drug registration certificate approved by the national drug administration (NMPA) to become the first fifth generation of domestic primary cephalosporin. Therefore, the cefpirome sodium has very good market prospect, and 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester is used as an important side chain intermediate for synthesizing the novel antibiotic cefpirome sodium, and a process route suitable for industrial production is developed, so that the novel antibiotic cefpirome sodium has very high economic benefit and social value. Wherein the chemical structure of the intermediate compound 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester is shown as follows:
referring to the related data of domestic and foreign documents about cefpirome, there is a related synthesis method for reporting side chain intermediates, but the related synthesis method involves complex operation, poor reaction effect, use of reagents which are not friendly to the environment, lower product yield and purity, high production cost, trouble of industrial scale-up production, and similar cyclization reaction with halogenoalkyl acyl chloride raw materials such as 1-chloro-3-bromobutyryl chloride and the like to form a corresponding dipyrrole ring structure is disclosed in the prior documents, and then subsequent bromine removal and other reactions are performed, wherein the cyclization reaction adopts complex conditions, the processing steps of a reaction route are complex, and the yield of a product is poor.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester, which solves the problems of complex reaction route and poor product yield in the prior art.
The invention aims at realizing the following technical scheme, and discloses a preparation method of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester, which is characterized by comprising the following steps:
A. in the presence of an acid binding agent, carrying out amidation reaction on a compound of a formula VI or acid salt thereof serving as a raw material and allyl chloroformate of a compound of a formula V to generate a compound of a formula IV;
B. in the presence of sodium hydride, carrying out condensation reaction on 3-hydroxy-2 pyrrolidone of a compound of a formula III and a compound of a formula IV to obtain a compound of a formula II;
C. carrying out chlorination reaction on a compound of a formula II and a chlorinating agent to obtain a compound of a formula I;
the raw materials adopted in the synthetic route are easy to obtain, the compound of the formula VI or the acid salt thereof and allyl chloroformate are subjected to condensation reaction, the reaction conditions are mild, micromolecular acid generated in the reaction process can be better removed in the presence of an acid binding agent, the reaction is easy to carry out, an intermediate product with higher yield is obtained, the compound of the formula IV can be directly subjected to condensation reaction with the raw material 3-hydroxy-2-pyrrolidone under the action of sodium hydride to obtain the compound of the formula II, the high activity and the strong alkaline characteristic of sodium hydride are mainly utilized, the condensation reaction of the reaction can be effectively carried out, the micromolecular acid formed in the reaction process can be removed to a certain extent by utilizing the strong alkaline, the reaction is promoted, the operability of the reaction is better improved in the step without adopting a ring closure mode in the existing reaction process, and the intermediate product obtained by the reaction also has high yield; then, the compound of the formula II and a chlorinating agent are subjected to chlorination reaction to obtain a product 3-chloro-2-oxo- [1,3'] dipyrrolidinyl-1' -carboxylic acid allyl ester, so that the reaction can be effectively realized, and the method has the advantages of high product yield and less byproducts of the reaction, thereby effectively avoiding the separation mode of purification by column chromatography, simplifying the operation, improving the purity and yield of the product, enabling the yield of each single-step product to reach high level, enabling the yield to reach more than 85%, and enabling the purity quality of each intermediate to be high. In a more preferred form, the acid which further enables the acid salt of the compound of formula VI described above may be an inorganic acid, such as HX, X being a halogen atom.
In the above process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, the temperature of the condensation reaction in step B is preferably controlled to 60℃to 80 ℃. The reaction directly carries out direct reaction through two raw materials with pyrrole ring structures, does not need to adopt a cyclization reaction mode, so that the reaction can be better controlled to be carried out in the temperature range, the stability is good, the generation of unnecessary impurities is better avoided, and the obtained intermediate product has the advantages of high purity and high yield.
In the above-mentioned process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, it is preferable that the condensation reaction in step B is carried out in a water-insoluble aromatic organic solvent. Is favorable for stable reaction, is easy to post-treat after the reaction is finished, and has the advantage of convenient operation. As a further preferred aspect, the water-insoluble aromatic organic solvent is selected from one or more of toluene, xylene and benzene. Furthermore, the amount of the water-insoluble aromatic organic solvent may be added according to the actual situation, and may be any amount as is generally used in chemical reaction synthesis in the art.
In the above process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, preferably, the compound of formula IV as described in step B: the compound 3-hydroxy-2-pyrrolidone of formula III: the molar ratio of sodium hydride is 1.0:1.0 to 3.0:1.0 to 3.0. The effective proceeding of the reaction can be better ensured. The reaction is carried out in the presence of sodium hydride, so that the sodium hydride has the characteristic of strong alkali and has better catalytic activity on the reaction, the reaction can be effectively carried out, and the intermediate product obtained by the reaction has the effects of high yield and high purity.
In the above process for preparing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, preferably, the acid-binding agent in step a is selected from an organic base or an inorganic base, and the inorganic base is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate; the organic base is selected from one or more of triethylamine, diethylamine, dicyclohexylamine, diisopropylamine, pyridine and piperidine. The reaction is carried out in the presence of the acid binding agent, so that small molecular acid generated in the reaction process can be effectively removed, the reaction is more facilitated, and the conversion rate of reaction raw materials, the yield and purity quality of the product are improved.
In the above-mentioned process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, preferably, the amidation reaction in step A is carried out in a mixed solvent of a water-insoluble organic solvent selected from one or more of ethyl acetate, methylene chloride and chloroform and water.
The starting materials may be used in the course of the reaction according to the amounts of starting materials generally used in the art, and it is further preferred that the compound of formula VI is preferred for better utilization of the starting materials and for more stable reaction: water-insoluble organic solvent: the mass ratio of water is 1: 5-15: 2 to 5. The water-soluble substance salt or the corresponding hydrochloride form can be removed more effectively by carrying out the reaction under the mixed solvent system of water and the organic solvent, so that the materials can be better dissolved in the organic solvent, the subsequent acylation reaction is facilitated, and the conversion rate and the efficiency of the reaction are improved
Further, it is preferred to use the compound of formula VI: acid binding agent: the molar ratio of allyl chloroformate of the compound of formula v is 1.0:1.0 to 5.0:1.0 to 5.0. The conversion rate of the reaction is improved. When the acid salt (HX) of the compound shown in the formula VI is shown as the hydrochloride of the compound shown in the formula VI, a certain amount of alkali can be added according to the feeding amount of the acid salt raw material of the compound shown in the formula VI to neutralize and remove acid, and then the acid is reacted with the allyl chloroformate shown in the formula V. As a still further preference, the compound of formula vi: acid binding agent: the molar ratio of allyl chloroformate of the compound of formula v is 1.0:1.1 to 2.5:1.1 to 2.5. The above-mentioned base may be an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate for neutralizing the acid.
In the above process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, the amidation reaction in step A is preferably carried out at a temperature of-5℃to 15 ℃.
In the above process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, it is preferable that the chlorinating agent in the step C is selected from thionyl chloride, and the temperature of the first chlorination reaction is 45℃to 65 ℃. Preferably, the compound of formula II: the mole ratio of the chlorinating agent is 1.0:1.0 to 5.0, as a further preference, the compounds of the formula II: the mole ratio of the chlorinating agent is 1.0:1.1 to 3.0.
Further, it is preferable that the post-treatment is performed after the completion of the chlorination reaction, specifically:
After the chlorination reaction is finished, adding water into the reaction liquid for mixing, adding an alkaline reagent to adjust the pH value to be neutral, standing for layering, collecting an organic layer, and concentrating to remove a solvent to obtain a concentrate. Can better remove some water-soluble impurities and further improve the purity and quality of the product. Optionally adding mixed solvent of petroleum ether and ethyl acetate for recrystallization.
In the above process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, preferably, the compound of formula VI or an acid salt thereof in step A is obtained by the following process:
The compound of formula VII or the hydrochloride thereof is taken as a raw material, and is subjected to chlorination reaction with thionyl chloride to obtain a corresponding compound of formula VI or the hydrochloride thereof;
the compound of the formula VII is further used as a starting material, so that the compound of the formula VI is cheap and easy to obtain, and the intermediate is obtained through chlorination reaction, so that the compound of the formula VI has better operability, and the advantage of high intermediate product yield can be realized.
In the above-mentioned process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, it is preferable to conduct the chlorination reaction in an organic solvent, the reaction is carried out more gently, and it is further preferable to conduct the reaction in an aromatic organic solvent such as toluene, xylene or benzene. Preferably, the chlorination reaction is carried out in a toluene solvent, and the temperature of the chlorination reaction is 50 to 60 ℃.
In the above-mentioned process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, the amount of the solvent may be any one according to the usual amount, and the compound of the formula VII is preferably used: the mass ratio of the organic solvent is 1: 10-20 parts; further, it is preferable to use the VII compound: molar ratio of thionyl chloride: 1.0:1.0 to 5.0. The raw materials are more fully utilized, the waste is reduced, and the utilization rate of the raw materials is improved. The first and second chlorination reactions mentioned herein are only for better distinguishing descriptions, and are meant to be illustrative, not limiting.
The chemical reaction equation of the preparation method of the 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester is as follows (the compound hydrochloride of the formula VII is taken as a starting material):
in summary, compared with the prior art, the invention has the following advantages:
1. The method has the advantages that the adopted raw materials are easy to obtain, the reaction condition is mild by adopting the condensation reaction of the compound shown in the formula VI and allyl chloroformate, the intermediate product with higher yield can be obtained, the condensation reaction is effectively carried out by mainly utilizing the high activity and strong alkalinity of sodium hydride under the action of sodium hydride, the reaction can be promoted, the adoption of a cyclization synthesis mode in the existing reaction process is not needed, the operability of the reaction is improved, and the intermediate product of the reaction has the effect of high yield; the method has the advantages of high yield of the reaction intermediate products in each step, and can also realize the advantages of high yield of the products and less byproducts, thereby effectively avoiding the separation mode purification by column chromatography, simplifying the operation and improving the purity and yield of the products.
2. The compound of the formula VII is used as a starting material, is low in cost and easy to obtain, and the intermediate compound of the formula VI is obtained through chlorination reaction, so that the method has better operability and can realize the advantage of high product yield of the intermediate.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Under the protection of nitrogen, 5.0g (0.040mol, 1.0 eq) of hydrochloride (3-hydroxypyrrolidine hydrochloride) of a compound of formula VII is added into a clean reaction bottle, 60ml of solvent toluene is added, stirring is carried out, the temperature is controlled at 20-30 ℃, 9.5g (0.080 mol,2.0 eq) of thionyl chloride is slowly added dropwise, after the dropwise addition, the temperature is controlled at 50-60 ℃ for carrying out chlorination reaction for 4 hours, after the reaction is finished, the reaction liquid is cooled to 20-25 ℃ for fully crystallizing for 2 hours, filtering is carried out, 10ml of toluene is used for leaching a filter cake, thus obtaining a wet product of the compound of the intermediate formula VI, then the wet product is placed into a vacuum drying box, the temperature is controlled at 55-65 ℃ for drying, and finally, the light yellow solid of the dry product is obtained, namely 5.2g of hydrochloride of the compound of the intermediate formula VI, the water content is less than 0.5%, the molar yield is 91.3%, and the HPLC detection purity is 99.2%.
Example 2
5G (0.035 mol,1.0 eq) of the hydrochloride of the intermediate compound VI, 65ml of dichloromethane and 20ml of water are added into a clean reaction bottle at normal temperature, 2.1g (0.053 mol,1.5 eq) of sodium hydroxide is added in portions under stirring, stirring is carried out for 20 minutes, standing and layering are carried out, an organic layer is collected, the obtained organic layer feed liquid is cooled to 0-10 ℃, 6.4g (0.063 mol,1.8 eq) of an acid-binding agent triethylamine is added, then 7.2g (0.060 mol,1.7 eq) of the allyl chloroformate of the compound V is slowly added, after the addition, the temperature of the system is controlled to 0-10 ℃ and the reaction is carried out for 5 hours under stirring, 50ml of water is added after the reaction, the pH is regulated to be neutral by a proper amount of hydrochloric acid, the stirring is carried out for 10 minutes, the standing and layering is carried out, the organic layer is collected, and the organic layer feed liquid is decompressed and concentrated to obtain a light yellow solid, namely the intermediate compound IV 6.0g, the molar yield is 89.8%, and the purity of HPLC is detected to be 7%.
Example 3
Under the protection of nitrogen, adding 3.2g (0.032 mol,1.2 eq) of 3-hydroxy-2-pyrrolidone of a compound of formula III and 75ml of toluene into a clean reaction bottle, stirring and dissolving, controlling the temperature to be 10-20 ℃, adding 0.9g (0.039 mol,1.4 eq) of sodium hydride, stirring and reacting for 1 hour, adding 5g (0.026 mol,1.0 eq) of an intermediate formula IV compound, controlling the temperature to be 60-65 ℃ for reacting for 4 hours, cooling the reaction liquid to 20-30 ℃ after the reaction is finished, adding 50ml of water, stirring for 10 minutes, standing and layering, and collecting an organic layer; the resulting organic layer was concentrated under reduced pressure to remove the solvent to give a pale yellow gum, 5.7g of the intermediate compound of formula II, 86.3% in molar yield and 98.9% in purity by HPLC.
Example 4
Under the protection of nitrogen, adding 5.0g (0.020mol, 1.0 eq) of an intermediate compound II and 70ml of solvent toluene into a clean reaction bottle, stirring and dissolving, controlling the temperature to be 20-30 ℃, slowly dropwise adding 5.9g (0.050 mol,2.5 eq) of thionyl chloride, controlling the temperature of a reaction system to be 50-60 ℃ after the dropwise adding is finished, carrying out chlorination reaction for 5 hours, cooling a reaction mixed solution to 25-30 ℃ after the reaction is finished, then adding 50ml of water, adding a proper amount of sodium carbonate to adjust the pH of the system to be neutral, stirring for 10 minutes, standing and layering, and collecting an organic layer; concentrating the obtained organic layer under reduced pressure to remove the solvent until the organic layer is thicker, controlling the temperature to be 20-30 ℃, adding 20ml of ethyl acetate into the residue for dissolution, slowly adding 60ml of petroleum ether, stirring for crystallization for 3 hours, cooling to 0-10 ℃, stirring for full crystallization for 2 hours, ending crystallization, filtering, and leaching the filter cake by using 10ml of petroleum ether. Collecting wet product, placing into a vacuum drying oven, drying at 40-50deg.C to obtain light yellow solid, namely 4.9g of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester of the compound shown in formula I, water content less than 0.5%, molar yield 89.9%, and HPLC detection purity 99.1%.
Wherein, the structure of the obtained compound of the formula I is confirmed and detected as follows:
1H-NMR(400MHz,DMSO-d6)δ(ppm)：5.78(m,1H,-COCH),4.95(m,2H,-OCH2),4.39(m,1H,N-CH),3.65-3.16(m,6H,-CH2*3),2.97(s,2H,-CH2),2.58-2.34(d,3H,CH＝CH2),1.88(s,2H,-CH2).
13C-NMR(400MHz,DMSO-d6)δ(ppm)：25.6,29.2,34.3,44.2,49.8,52.9,67.8,70.3,117.6,139.3,161.2,166.5.
ESI-MS：m/z 273.11[M+H]+。
Example 5
5G (0.035 mol,1.0 eq) of the hydrochloride of the intermediate compound VI obtained by the synthetic route of the example is added into a reaction bottle at normal temperature, 80ml of ethyl acetate and 20ml of water are added, 3.0g (0.053 mol,1.5 eq) of potassium hydroxide is added in portions under stirring, stirring is carried out for 20 minutes, standing and layering are carried out, the organic layer is collected, the obtained organic layer feed liquid is cooled to 0-10 ℃, 7.1g (0.07 mol,2.0 eq) of an acid-binding agent triethylamine is added, then 8.4g (0.07 mol,2.0 eq) of the allyl chloroformate of the compound V is slowly added into the system, after the addition, the temperature of the system is controlled to 0-5 ℃ and the reaction is carried out for 5 hours under stirring, 50ml of water is added after the reaction is finished, the pH is regulated to be neutral by a proper amount of hydrochloric acid, the stirring is carried out for 10 minutes, layering and decompression is carried out, the organic layer is collected, the organic layer feed liquid is concentrated to obtain light yellow solid, namely the intermediate compound IV is 6.07 mol, the yield is detected to be 9.98% by HPLC (high performance liquid by mole).
Example 6
Under the protection of nitrogen, 5.2g (0.052 mol,1.2 eq) of 3-hydroxy-2-pyrrolidone of the formula III obtained by adopting the synthesis mode of the example 5 and 75ml of toluene are added into a clean reaction bottle, stirred and dissolved, the temperature is controlled to be 10-20 ℃, 1.3g (0.052 mol,2.0 eq) of sodium hydride is added, stirred and reacted for 1 hour, then 5g (0.026 mol,1.0 eq) of intermediate formula IV is added, the reaction is carried out for 4.5 hours at the temperature of 65-70 ℃, after the reaction is finished, the reaction liquid is cooled to 25-30 ℃, 50ml of water is added, stirred for 10 minutes, standing and layering are carried out, and an organic layer is collected; the resulting organic layer was concentrated under reduced pressure to remove the solvent to give a pale yellow gum, 5.75g of the intermediate compound of formula II, a molar yield of 87.1% and a purity of 98.8% as measured by HPLC.
Example 7
Under the protection of nitrogen, adding 5.0g (0.020mol, 1.0 eq) of an intermediate compound II and 80ml of solvent dimethylbenzene into a clean reaction bottle, stirring and dissolving, controlling the temperature to be 25-30 ℃, slowly dropwise adding 5.9g (0.050 mol,2.5 eq) of thionyl chloride, controlling the temperature of a reaction system to be 55-60 ℃ after the dropwise adding is finished, carrying out chlorination reaction for 4.5 hours, cooling a reaction mixed solution to 25-30 ℃ after the reaction is finished, then adding 50ml of water, adding a proper amount of sodium carbonate to adjust the pH of the system to be neutral, stirring for 15 minutes, standing and layering, and collecting an organic layer; concentrating the obtained organic layer under reduced pressure to remove the solvent until the organic layer is thicker, controlling the temperature to be between 25 and 30 ℃, adding 25ml of ethyl acetate into the residue for dissolution, slowly adding 70ml of petroleum ether, stirring for crystallization for 3 hours, cooling to between 0 and 5 ℃, stirring for full crystallization for 2 hours, ending crystallization, filtering, and leaching a filter cake by using 10ml of petroleum ether. Collecting wet product, placing into a vacuum drying oven, drying at 40-50deg.C to obtain light yellow solid, namely 4.8g of 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylic acid allyl ester of the compound shown in formula I, water content less than 0.5%, molar yield 88.1% and HPLC detection purity 99.2%.
The structure of the obtained compound of the formula I is confirmed, and detection data of the compound of the formula I are consistent with the analysis results of corresponding spectrogram data in the example 4, so that the compound of the formula I can be synthesized.
Example 8
5G (0.035 mol,1.0 eq) of intermediate compound hydrochloride of formula VI, 70ml of chloroform and 25ml of water are added into a clean reaction bottle at normal temperature, 7.4g (0.07 mol,2.0 eq) of sodium carbonate is added in portions under stirring, stirring is carried out for 20 minutes, standing and layering are carried out, an organic layer is collected, the obtained organic layer feed liquid is cooled to-5 ℃ to 5 ℃, 7.07g (0.07 mol,2.0 eq) of acid-binding agent diisopropylamine is added, then 10.8g (0.09 mol,2.5 eq) of compound allyl chloroformate of formula V is slowly added, after the addition, the temperature of the system is controlled to-5 ℃ to 5 ℃ and the reaction is carried out under stirring for 4.5 hours, the reaction is finished, 50ml of water is added, the pH of the system is regulated to be neutral by a proper amount of hydrochloric acid, stirring is carried out for 15 minutes, the organic layer is collected, the organic layer feed liquid is decompressed and concentrated to obtain light yellow solid, namely 5.9g of intermediate compound of formula IV, the molar percentage and the purity of HPLC detection is 3.98%.
Example 9
Under the protection of nitrogen, 7.8g (0.078 mol,3.0 eq) of 3-hydroxy-2-pyrrolidone and 75ml of toluene as a compound of formula III are added into a clean reaction bottle, stirred and dissolved, the temperature is controlled at 15-20 ℃, 0.69g (0.029 mol,1.1 eq) of sodium hydride is added, stirred and reacted for 1 hour, 5g (0.026 mol,1.0 eq) of an intermediate formula IV compound is added, the temperature is controlled at 75-80 ℃ and reacted for 3 hours, after the reaction is finished, the reaction liquid is cooled to 20-30 ℃,50 ml of water is added, stirred for 10 minutes, standing and layering are carried out, and an organic layer is collected; the resulting organic layer was concentrated under reduced pressure to remove the solvent to give a pale yellow gum, 5.9g of the intermediate compound of formula II, a molar yield of 89.3% and a purity of 99.2% as determined by HPLC.
Example 10
5G (0.035 mol,1.0 eq) of intermediate compound hydrochloride of formula VI, 70ml of ethyl acetate and 30ml of water are added into a clean reaction bottle at normal temperature, 5.4g (0.053 mol,1.5 eq) of triethylamine is added in portions under stirring, stirring is carried out for 20 minutes, standing and layering are carried out, an organic layer is collected, the obtained organic layer feed liquid is cooled to 0-10 ℃, 8.8g (0.088 mol,2.5 eq) of acid-binding agent triethylamine is added, then 8.4g (0.07 mol,2.0 eq) of compound allyl chloroformate of formula V is slowly added, after the addition, the temperature of the system is controlled to be 0-5 ℃ and the reaction is carried out for 5.5 hours under stirring, 50ml of water is added, the pH is regulated to be neutral by a proper amount of hydrochloric acid, the mixture is stirred for 20 minutes, the mixture is kept standing and layered, an organic layer is collected, and the organic layer is decompressed and concentrated to obtain a light yellow solid, namely 5.8g of intermediate compound of formula IV, the molar percentage is 86%, and the purity of HPLC detection is 98.5%.
Example 11
The specific experimental operation method of the intermediate compound in this embodiment is basically the same as that in embodiment 10, except that the acid binding agents are respectively implemented by sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate or potassium bicarbonate in sequence, the molar equivalent of the corresponding acid binding agents is unchanged and is 0.088mol (2.5 eq), the molar yield of the intermediate compound in the intermediate compound is up to 85% or more, and the product purity is up to 98% or more.
Example 12
The specific experimental operation method of the intermediate compound in the embodiment is basically the same as that in embodiment 2, and the difference is that the acid binding agents are respectively and sequentially implemented by using diethylamine, dicyclohexylamine, pyridine or piperidine, the molar equivalent of the corresponding acid binding agents is unchanged by using 0.063mol (1.8 eq), the molar yield of the intermediate compound in the intermediate is up to 88% or more, and the purity of the product is up to 98.5%.
Example 13
Under the protection of nitrogen, 5.0g (0.040mol, 1.0 eq) of hydrochloride (3-hydroxypyrrolidine hydrochloride) of a compound of formula VII is added into a clean reaction bottle, 80ml of solvent toluene is added, stirring is carried out for dissolution, then the temperature is controlled at 20-30 ℃, 14.3g (0.12 mol,3.0 eq) of thionyl chloride is slowly added dropwise, after the dropwise addition, the temperature is controlled at 55-60 ℃ for carrying out chlorination reaction for 3.5 hours, after the reaction is finished, the reaction liquid is cooled to 20-25 ℃ for fully crystallizing for 2 hours, filtering is carried out, 10ml of toluene is used for leaching filter cake, thus obtaining a wet product of the intermediate compound VI, then the wet product is placed into a vacuum drying box, the temperature is controlled at 55-65 ℃ for drying, and finally a light yellow solid of a dry product is obtained, namely 5.1g of hydrochloride of the intermediate compound of formula VI, the water content is less than 0.5%, the molar yield is 89.6%, and the purity detected by HPLC is 99.3%.
The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (10)
1. A process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate, characterized in that it comprises the steps of:
A. in the presence of an acid binding agent, carrying out amidation reaction on a compound of a formula VI or acid salt thereof serving as a raw material and allyl chloroformate of a compound of a formula V to generate a compound of a formula IV;
B. in the presence of sodium hydride, carrying out condensation reaction on 3-hydroxy-2 pyrrolidone of a compound of a formula III and a compound of a formula IV to obtain a compound of a formula II;
C. carrying out chlorination reaction on a compound of a formula II and a chlorinating agent to obtain a compound of a formula I;
2. The process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to claim 1, wherein the temperature of the condensation reaction in step B is controlled at 60℃to 80 ℃.
3. The process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to claim 2, wherein said condensation reaction in step B is carried out in a water-insoluble aromatic organic solvent.
4. The method for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to claim 3, wherein the water-insoluble aromatic organic solvent is one or more selected from toluene, xylene and benzene.
5. The process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to any one of claims 1 to 4, wherein the acid-binding agent in step a is selected from an organic base or an inorganic base selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate and potassium bicarbonate; the organic base is selected from one or more of triethylamine, diethylamine, dicyclohexylamine, diisopropylamine, pyridine and piperidine.
6. The process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to claim 5, wherein the amidation reaction in step A is carried out in a mixed solvent of a water-insoluble organic solvent selected from one or more of ethyl acetate, methylene chloride and chloroform and water.
7. The process for preparing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to claim 6, wherein the amidation reaction in step A is carried out at a temperature of from-5℃to 15 ℃.
8. The process for preparing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to any one of claims 1-4, wherein in step C, the chlorinating agent is selected from thionyl chloride, and the temperature of the first chlorination reaction is 45 ℃ to 65 ℃.
9. Process for the preparation of allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to any one of claims 1-4, wherein the compound of formula vi, or an acid salt thereof, in step a is obtained by:
The compound of formula VII or the hydrochloride thereof is taken as a raw material, and is subjected to chlorination reaction with thionyl chloride to obtain a corresponding compound of formula VI or the hydrochloride thereof;
10. The process for producing allyl 3-chloro-2-oxo- [1,3'] bipyrrolidinyl-1' -carboxylate according to claim 9, wherein said chlorination reaction is carried out in a toluene solvent at a temperature of 50℃to 60 ℃.
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