CN116874499A - Synthesis method of meropenem side chain - Google Patents
Synthesis method of meropenem side chain Download PDFInfo
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- CN116874499A CN116874499A CN202310862920.3A CN202310862920A CN116874499A CN 116874499 A CN116874499 A CN 116874499A CN 202310862920 A CN202310862920 A CN 202310862920A CN 116874499 A CN116874499 A CN 116874499A
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- VGLBNJWGUYQZHD-STQMWFEESA-N (4-nitrophenyl)methyl (2s,4s)-2-(dimethylcarbamoyl)-4-sulfanylpyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 VGLBNJWGUYQZHD-STQMWFEESA-N 0.000 title claims abstract description 100
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims abstract description 33
- 239000002253 acid Substances 0.000 claims abstract description 29
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000012043 crude product Substances 0.000 claims abstract description 28
- 229960002260 meropenem Drugs 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 14
- 230000001105 regulatory effect Effects 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 13
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 30
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 abstract description 25
- 239000000543 intermediate Substances 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 238000000605 extraction Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 239000012071 phase Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000007670 refining Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical compound CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/08—Bridged systems
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a synthesis method of a meropenem side chain. Taking a meropenem side chain intermediate and a dimethylamine aqueous solution as raw materials, taking ethanol as a solvent, taking tributyl phosphorus as a catalyst for reaction, adjusting acid after the reaction is finished, and filtering to obtain a meropenem side chain crude product; adding the crude product of the meropenem side chain into water, regulating alkali, extracting with a solvent, regulating acid, crystallizing, filtering and drying to obtain the fine product of the meropenem side chain. The invention has low preparation cost and convenient operation, is suitable for industrialization, can completely remove the impurity meropenem side chain disulfide to obtain high-purity meropenem side chain fine product, has the purity of more than 99.9 percent, and is beneficial to improving the purity of meropenem synthesized subsequently.
Description
Technical Field
The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a synthesis method of a meropenem side chain.
Background
The meropenem side chain is an important intermediate for synthesizing meropenem, and has the following structural formula:
there are many routes for the synthesis of meropenem side chains, examples of which are as follows:
activating carboxyl of PNZ protected L-hydroxyproline by isopropyl chloroformate in the presence of triethylamine, then reacting with dimethylamine to obtain an intermediate, activating hydroxyl by methylsulfonyl chloride, adding potassium thioacetate for reaction, and hydrolyzing to obtain a meropenem side chain.
Heterocarpels, 1995,41 (1): 147-159.Matsumura et al first synthesized PNZ-protected thiolactone as a key intermediate for meropenem side chain synthesis, which synthesized key intermediate 3d, and thiolactone was readily ammonolyzed to give meropenem side chain.
Because the sulfhydryl group is unstable and is easy to oxidize to generate disulfide bond, the generation of impurity meropenem side chain disulfide is unavoidable in the synthetic route, and the structural formula is as followsThe impurity is meropenem side chainIs a major impurity of (2); in the subsequent synthesis of meropenem +.>In the case of this impurity, it cannot be bound to the main ring +.>The reaction, through multiple batches of inspection, finds that the impurity exists more or less in the final product meropenem, which is unfavorable for the purification of meropenem.
Chinese patent CN 115490625a discloses a method for synthesizing and refining meropenem side chain, comprising a reaction stage and a refining stage, the reaction stage comprising the steps of: (1) Under the protection of nitrogen, adding thiolactone, a reaction solvent and a catalyst into a reaction kettle, stirring and dissolving; (2) Dropwise adding dimethylamine solution or dimethylamine hydrochloride solution into a reaction kettle at the liquid temperature of 15-30 ℃ for reaction; (3) Adding extraction water once after the reaction is finished, then adjusting the pH value to 6.0-8.0 by acid, and extracting to obtain a crude organic phase; (4) Adding the crude organic phase into the secondary extraction water for secondary extraction to obtain an organic phase; (5) Concentrating and distilling the organic phase under reduced pressure to obtain concentrated solution and a reaction solvent; (6) And (3) growing crystals in the concentrated solution, centrifuging, washing and drying in vacuum to obtain a crude product of the meropenem side chain. The refining stage comprises the following steps: (a) Adding the meropenem side chain crude product into a dissolving reagent for dissolving, adding active carbon, stirring, and filtering to obtain filtrate; (b) And (3) dropwise adding a crystallization reagent into the filtrate at room temperature for crystallization, and obtaining the meropenem side chain fine product through crystal growth, centrifugation and vacuum drying. The reaction stage of the patent has the advantages of multiple extraction steps, distillation steps, complex operation, high energy consumption, and no contribution to industrial production, and the refining stage can not thoroughly remove disulfide impurities.
A new synthesis method of meropenem side chain, xuzhou medical college pharmaceutical college, guangzhou chemical industry, 11 months 2013, discloses that a crude meropenem side chain synthesized by a one-pot method is used as a raw material, and meropenem side chain is obtained through reverse extraction. The method adds methanol during alkali adjustment, so that the meropenem side chain disulfide impurities cannot be completely extracted when dichloromethane is used for extraction, ethyl acetate is used for extraction after acid adjustment is finished, and the meropenem side chain disulfide impurities are extracted at the moment, so that the method cannot remove the meropenem side chain disulfide impurities completely. The method does not study the side chain disulfide impurities of the meropenem in detail, and the side chain crude product of the meropenem has more impurities and lower purity, and the purity is still only 98.8 percent although the purity is improved after purification, wherein the impurities influence the purity of the subsequent meropenem synthesis, which is unfavorable for the purification of the meropenem, and the post-treatment process also comprises the procedures of washing, drying, distilling and the like of saturated sodium chloride, so that the operation is complex, and the industrial production is unfavorable.
At present, there is no effective method for removing the impurity meropenem side chain disulfide.
Disclosure of Invention
The invention aims to provide a synthesis method of a meropenem side chain, which has the advantages of low preparation cost, convenient operation and suitability for industrialization, and can completely remove impurity meropenem side chain disulfide to obtain high-purity meropenem side chain fine product, wherein the purity is more than 99.9%, and the method is favorable for improving the purity of meropenem synthesized subsequently.
The synthesis method of the meropenem side chain comprises the following steps:
(1) Taking a meropenem side chain intermediate and a dimethylamine aqueous solution as raw materials, taking ethanol as a solvent, taking tributyl phosphorus as a catalyst for reaction, adjusting acid after the reaction is finished, and filtering to obtain a meropenem side chain crude product;
(2) Adding the crude product of the meropenem side chain into water, regulating alkali, extracting with a solvent, regulating acid, crystallizing, filtering and drying to obtain the fine product of the meropenem side chain.
The structural formula of the meropenem side chain intermediate in the step (1) is as follows:
the concentration of the aqueous dimethylamine solution in step (1) is 30-40%, preferably 40%.
The concentration of ethanol in step (1) is 95-99%, preferably 95%.
The mass ratio of the meropenem intermediate to the dimethylamine aqueous solution in the step (1) is 45-98:20-70, the mass ratio of the meropenem intermediate to the ethanol is 1:1-5, and the mass ratio of the meropenem intermediate to the tributyl phosphate is 1:0.006-0.035.
The reaction temperature in the step (1) is-30 to-10 ℃ and the reaction time is 1 to 3 hours.
The acid regulating step (1) is to add acid to regulate the pH to 4-6, wherein the acid is one or more of hydrochloric acid, acetic acid or phosphoric acid, preferably acetic acid.
The mass ratio of the meropenem side chain crude product to water in the step (2) is 1:2-20.
The alkali regulation in the step (2) is to add alkali to regulate the pH value to be 9-12, wherein the alkali is one or more of sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate, preferably sodium hydroxide; the molar ratio of the meropenem side chain crude product to the alkali is 1:1-3.
The alkali regulating temperature in the step (2) is 0-25 ℃.
The solvent in the step (2) is one or more of dichloromethane, chloroform, ethyl acetate or diethyl ether, preferably ethyl acetate, and the mass ratio of the meropenem side chain crude product to the solvent is 1:1-5.
The acid regulation in the step (2) is to add acid to regulate the pH value to 4-6, wherein the acid is one or more of hydrochloric acid, phosphoric acid or acetic acid, preferably acetic acid, and the molar ratio of the meropenem side chain crude product to the acid is 1:1-3.
The acid regulating temperature in the step (2) is 0-25 ℃.
The crystallization temperature in the step (2) is 0-25 ℃, and the crystallization time is 1-2 hours.
The synthesis method of the meropenem side chain comprises the following specific steps:
(1) Under the protection of nitrogen, adding the meropenem side chain intermediate and tributyl phosphorus into ethanol, and dropwise adding dimethylamine aqueous solution for reaction, wherein the dropwise adding temperature is-30 to-10 ℃;
(2) After the reaction is finished, adjusting the pH to 4-6 by acid; filtering after the acid adjustment is finished, and leaching with 95% ethanol to obtain a meropenem side chain crude product;
(3) Under the protection of nitrogen, adding the crude meropenem side chain product into water, dropwise adding an alkali solution, and stirring for 1-2 hours after the dropwise adding is finished, wherein the pH value is 9-12, so that the solid is completely dissolved;
(4) Extracting with solvent for 2 times, separating, and collecting water phase;
(5) Adding an acid solution into the water phase to regulate the pH value of the acid to 4-6, stirring for crystallization, filtering and drying to obtain a high-purity meropenem side chain fine product.
The reaction equation of the present invention is as follows:
when meropenem side chain is synthesized, meropenem side chain disulfide impurities are more or less always present, and the impurities are always present in the final product meropenem, so that the purity of meropenem is affected, and the purification of meropenem is not facilitated. In the prior art, one or more solvents such as ethyl acetate, ethanol, petroleum ether, acetonitrile and the like are used for recrystallization, activated carbon, silica gel, diatomite and the like are used for adsorption, and solvent beating and other methods are used for refining, so that the side chain disulfide impurities of meropenem cannot be completely removed.
The synthesis of the meropenem side chain is carried out under the low temperature condition, the content of the disulfide of the meropenem side chain can be controlled to be the minimum, and then the meropenem side chain disulfide can be completely removed, and the purity of the meropenem side chain can be improved to be more than 99.9%, so that the subsequent synthesis of the meropenem is facilitated to be improved.
According to the invention, the meropenem side chain crude product is added into water and then is subjected to alkali adjustment, so that the meropenem side chain can be salified, but disulfide impurities cannot be salified, the disulfide impurities are removed by extraction with an organic solvent, and then the meropenem side chain finished product is separated out by acid adjustment, so that the disulfide impurities can be completely removed by the method.
The beneficial effects of the invention are as follows:
(1) The preparation cost is low, the operation is convenient, and the method is suitable for industrialization;
(2) The purity of the obtained product is high, and the purity of the meropenem side chain refined product can reach more than 99.9 percent;
(3) The impurity meropenem side chain disulfide can be completely removed, so that the purity of the meropenem side chain is improved, and the purity of the meropenem synthesized subsequently is improved.
Drawings
FIG. 1 is an infrared spectrum of the product obtained in example 1.
FIG. 2 is an HPLC chart of the product obtained in example 1.
FIG. 3 is an HPLC chart of the product obtained in example 2.
FIG. 4 is an HPLC chart of the product obtained in example 3.
FIG. 5 is an HPLC chart of the product obtained in comparative example 1.
FIG. 6 is an HPLC chart of the product obtained in comparative example 2.
FIG. 7 is an HPLC chart of the product of comparative example 3.
FIG. 8 is an HPLC chart of the product of comparative example 4.
FIG. 9 is an HPLC chart of the product of comparative example 5.
Detailed Description
The invention is further described below with reference to examples.
Example 1
Under the protection of nitrogen, 46g of meropenem side chain intermediate, 138g of 95% ethanol and 0.3g of tributyl phosphorus are added into a four-mouth bottle, the temperature is reduced to-15 ℃, 20.3g of 40% dimethylamine aqueous solution is dropwise added, after the dropwise addition is finished, the temperature is controlled to-15 to-10 ℃, the temperature is kept for 1h, the pH value is regulated to be 4 by hydrochloric acid, the filtration and the leaching of 95% ethanol are carried out, and 50g of meropenem side chain crude product is obtained.
Under the protection of nitrogen, 50g of meropenem side chain crude product is added into a four-mouth bottle, 150g of purified water is added, the temperature is reduced to 2 ℃, 18.9g of 30% sodium hydroxide solution is dripped, the temperature is controlled to be 0-5 ℃, the dripping is completed, the pH=11 is achieved, the mixture is stirred for 1 hour, the solid is completely dissolved, 200g of ethyl acetate is added, the mixture is extracted for 2 times, the liquid is analyzed, 8.5g of acetic acid is dripped into the water phase, the temperature is controlled to be 10-20 ℃, the pH value is 5, the mixture is stirred and crystallized for 1 hour at 10-20 ℃, the mixture is filtered, and the mixture is dried in vacuum at 40 ℃ to obtain 48.4g of meropenem side chain refined product, the yield is 96.8%, the purity is 99.93%, the infrared spectrogram of the product is shown in a figure 1, and the HPLC spectrogram of the product is shown in a figure 2. As can be seen from fig. 2, there is no meropenem side chain disulfide impurity in the product.
Example 2
Under the protection of nitrogen, 95g of meropenem side chain intermediate, 475g of 95% ethanol and 3g of tributyl phosphorus are added into a four-mouth bottle, the temperature is reduced to minus 30 ℃, 69.3g of 40% dimethylamine aqueous solution is dripped, after the dripping is finished, the temperature is controlled to minus 30 ℃ to minus 25 ℃, the temperature is kept for 3 hours, acetic acid is used for regulating the pH to be=5, filtering and leaching with 95% ethanol are carried out, and 100g of meropenem side chain crude product is obtained.
Under the protection of nitrogen, adding 100g of meropenem side chain crude product into a four-mouth bottle, adding 500g of purified water, cooling to 10 ℃, dropwise adding 317g of 10% potassium hydroxide solution, controlling the temperature to 10-15 ℃, after the dropwise adding, the pH=12, stirring for 2 hours, completely dissolving the solid, adding 100g of dichloromethane, extracting for 2 times, separating liquid, collecting water phase, dropwise adding 83.2g of phosphoric acid into the water phase, controlling the temperature to 15-25 ℃, controlling the pH value to 6, stirring and crystallizing at 15-25 ℃ for 1.5 hours, filtering, and drying at 40 ℃ in vacuum to obtain 96.4g of meropenem side chain refined product, wherein the yield is 96.4%, the purity is 99.93%, and the HPLC spectrogram of the product is shown in figure 3. As can be seen from fig. 3, there is no meropenem side chain disulfide impurity in the product.
Example 3
Under the protection of nitrogen, 48g of meropenem side chain intermediate, 96g of 95% ethanol and 0.3g of tributyl phosphorus are added into a four-mouth bottle, the temperature is reduced to-20 ℃, 26.3g of 40% dimethylamine aqueous solution is dropwise added, after the dropwise addition is finished, the temperature is controlled to-20 to-10 ℃, the temperature is kept for 2 hours, the pH value is regulated to be 6 by phosphoric acid, the filtration and the leaching of 95% ethanol are carried out, and 50g of meropenem side chain crude product is obtained.
Under the protection of nitrogen, 50g of meropenem side chain crude product is added into a four-mouth bottle, 500g of purified water is added, 600g of 5% sodium carbonate solution is dropwise added, the temperature is controlled to be 20-25 ℃, the mixture is completely stirred for 1.5 hours at the pH value of 9 after being dropwise added, 250g of diethyl ether is added for extraction for 2 times, the analysis liquid is collected, 36.9g of 35% hydrochloric acid is dropwise added into the water phase, the temperature is controlled to be 0-10 ℃, the pH value is 4, the mixture is stirred and crystallized for 2 hours at the temperature of 0-10 ℃, the mixture is filtered, and the mixture is dried in vacuum at the temperature of 40 ℃ to obtain 48.3g of meropenem side chain refined product, the yield is 96.6%, the purity is 99.92%, and the HPLC spectrogram of the product is shown in figure 4. As can be seen from fig. 4, there is no meropenem side chain disulfide impurity in the product.
Comparative example 1
Under the protection of nitrogen, 48g of meropenem side chain intermediate, 96g of 95% ethanol and 0.3g of tributyl phosphorus are added into a four-mouth bottle, the temperature is reduced to 10 ℃, 26.3g of 40% dimethylamine aqueous solution is added dropwise, the temperature is controlled to 10-20 ℃ after the dropwise addition, the temperature is kept for 2 hours, the pH value is regulated to be=6 by phosphoric acid, and the mixture is filtered and leached by 95% ethanol, thus obtaining 50g of meropenem side chain crude product.
Under the protection of nitrogen, 50g of meropenem side chain crude product is added into a four-mouth bottle, 500g of purified water is added, 600g of 5% sodium carbonate solution is dropwise added, the temperature is controlled to be 20-25 ℃, the mixture is completely stirred for 1.5 hours at the pH value of 9 after being dropwise added, 250g of diethyl ether is added for extraction for 2 times, the analysis liquid is collected, 36.9g of 35% hydrochloric acid is dropwise added into the water phase, the temperature is controlled to be 0-10 ℃, the pH value is 4, the mixture is stirred and crystallized for 2 hours at the temperature of 0-10 ℃, the mixture is filtered, and the mixture is dried in vacuum at the temperature of 40 ℃ to obtain 48.1g of meropenem side chain refined product, the yield is 96.2%, the purity is 99.32%, and the HPLC spectrogram of the product is shown in figure 5. As can be seen from FIG. 5, the product still contains meropenem side chain disulfide impurity at 0.41%.
Comparative example 2
The procedure for the preparation of crude meropenem side chain was as in example 1.
Under the protection of nitrogen, 20g of meropenem side chain crude product and 320g of ethyl acetate are added into a four-mouth bottle, the temperature is raised to be dissolved, the temperature is lowered to the room temperature, petroleum ether is dropwise added into filtrate, crystals are grown for 1 hour after turbidity, petroleum ether is continuously dropwise added, 300g of petroleum ether is dropwise added together, crystals are grown for 1 hour after dropwise addition, centrifugation and vacuum drying at 30 ℃ are carried out, 18.3g of meropenem side chain refined product is obtained, the yield is 91.5%, the purity is 98.68%, and the HPLC spectrum of the product is shown in figure 6. As can be seen from FIG. 6, the product still contains meropenem side chain disulfide impurity at 0.85%.
Comparative example 3
The procedure for the preparation of crude meropenem side chain was as in example 1.
Under the protection of nitrogen, 20g of meropenem side chain crude product and 320g of dichloromethane are added into a four-mouth bottle, stirring is carried out until the crude product and the dichloromethane are dissolved, 1g of active carbon and 2g of silica gel are added, stirring is carried out for 1 hour, filtering is carried out, filtrate is concentrated, 18.4g of meropenem side chain refined product is obtained, the yield is 92.0%, the purity is 98.80%, and an HPLC (high performance liquid chromatography) spectrum of a product is shown in figure 7. As can be seen from FIG. 7, the product still contains meropenem side chain disulfide impurity at 0.85%.
Comparative example 4
The synthesis was carried out according to the process described in the background art of Heteromyces, 1995,41 (1): 147-159.Matsumura, the yield of the synthesized meropenem side chain was 58.3%, the purity was 98.73%, and the HPLC profile of the product was shown in FIG. 8. As can be seen from FIG. 8, the product still contains meropenem side chain disulfide impurity at 0.83%.
Comparative example 5
The procedure for the preparation of crude meropenem side chain was as in example 1.
Under the protection of nitrogen, 50g of meropenem side chain crude product is added into a four-mouth bottle, a small amount of methanol is added, the temperature is reduced to 2 ℃, 18.9g of 30% sodium hydroxide solution is dropwise added, the temperature is controlled to be 0-5 ℃, the mixture is stirred for 0.5 hours after the completion of the dropwise addition, a small amount of water is added, 200g of dichloromethane is added, the extraction is carried out for 2 times, liquid separation is carried out, water phase is collected, hydrochloric acid is dropwise added into the water phase, the pH value is regulated to be acidic, 300g of ethyl acetate is then added, the extraction is carried out for 2 times, the organic phase is combined, saturated sodium chloride is washed once, anhydrous magnesium sulfate is dried, filtered and distilled, 45.4g of meropenem side chain refined product is obtained, the yield is 90.8%, the purity is 98.57%, and the HPLC spectrogram of the product is shown in figure 9. As can be seen from FIG. 9, the product still contains meropenem side chain disulfide impurity at 0.99%.
Claims (10)
1. The synthesis method of the meropenem side chain is characterized by comprising the following steps of:
(1) Taking a meropenem side chain intermediate and a dimethylamine aqueous solution as raw materials, taking ethanol as a solvent, taking tributyl phosphorus as a catalyst for reaction, adjusting acid after the reaction is finished, and filtering to obtain a meropenem side chain crude product;
(2) Adding the crude product of the meropenem side chain into water, regulating alkali, extracting with a solvent, regulating acid, crystallizing, filtering and drying to obtain the fine product of the meropenem side chain.
2. The method for synthesizing a meropenem side chain according to claim 1, wherein the meropenem side chain intermediate in the step (1) has the following structural formula:
3. the method for synthesizing meropenem side chains according to claim 1, wherein the concentration of the aqueous dimethylamine solution in the step (1) is 30-40%, the concentration of ethanol is 95-99%, the mass ratio of the meropenem intermediate to the aqueous dimethylamine solution is 45-98:20-70, the mass ratio of the meropenem intermediate to the ethanol is 1:1-5, and the mass ratio of the meropenem intermediate to tributyl phosphorus is 1:0.006-0.035.
4. The method for synthesizing meropenem side chains according to claim 1, wherein the reaction temperature in the step (1) is-30 to-10 ℃ and the reaction time is 1 to 3 hours.
5. The method for synthesizing meropenem side chain according to claim 1, wherein the acid adjustment in step (1) is performed by adding an acid to adjust the pH to 4-6, and the acid is one or more of hydrochloric acid, acetic acid or phosphoric acid.
6. The method for synthesizing meropenem side chains according to claim 1, wherein the mass ratio of the crude meropenem side chain in the step (2) to water is 1:2-20.
7. The method for synthesizing meropenem side chains according to claim 1, wherein in the step (2), alkali is added to adjust the ph=9-12, the alkali is one or more of sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate, the molar ratio of crude meropenem side chains to alkali is 1:1-3, and the alkali adjusting temperature is 0-25 ℃.
8. The method for synthesizing meropenem side chains according to claim 1, wherein the solvent in the step (2) is one or more of dichloromethane, chloroform, ethyl acetate or diethyl ether, and the mass ratio of the meropenem side chain crude product to the solvent is 1:1-5.
9. The method for synthesizing meropenem side chains according to claim 1, wherein the acid adjustment in the step (2) is performed by adding an acid to adjust the pH to 4-6, wherein the acid is one or more of hydrochloric acid, phosphoric acid and acetic acid, the molar ratio of crude meropenem side chains to the acid is 1:1-3, and the acid adjustment temperature is 0-25 ℃.
10. The method for synthesizing meropenem side chains according to claim 1, wherein the crystallization temperature in the step (2) is 0-25 ℃ and the crystallization time is 1-2 hours.
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