CN118388562A - Improved method of clindamycin hydrochloride alcoholate synthesis process - Google Patents
Improved method of clindamycin hydrochloride alcoholate synthesis process Download PDFInfo
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- CN118388562A CN118388562A CN202410758261.3A CN202410758261A CN118388562A CN 118388562 A CN118388562 A CN 118388562A CN 202410758261 A CN202410758261 A CN 202410758261A CN 118388562 A CN118388562 A CN 118388562A
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- clindamycin
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- clindamycin hydrochloride
- alcoholate
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- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 61
- 229960001200 clindamycin hydrochloride Drugs 0.000 title claims abstract description 51
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 30
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- 239000002904 solvent Substances 0.000 claims abstract description 53
- 238000010438 heat treatment Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000001816 cooling Methods 0.000 claims abstract description 32
- 239000000047 product Substances 0.000 claims abstract description 27
- 239000007787 solid Substances 0.000 claims abstract description 27
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000002425 crystallisation Methods 0.000 claims abstract description 25
- 230000008025 crystallization Effects 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 22
- 229960002227 clindamycin Drugs 0.000 claims abstract description 18
- 239000003513 alkali Substances 0.000 claims abstract description 17
- 230000001105 regulatory effect Effects 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 claims abstract description 13
- 229960001595 lincomycin hydrochloride Drugs 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 10
- 238000004821 distillation Methods 0.000 claims abstract description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 8
- 238000010791 quenching Methods 0.000 claims abstract description 8
- 230000000171 quenching effect Effects 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000000630 rising effect Effects 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 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
- 230000007363 regulatory process Effects 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims 1
- 230000035484 reaction time Effects 0.000 abstract description 4
- 239000012320 chlorinating reagent Substances 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 25
- 239000012065 filter cake Substances 0.000 description 14
- 238000010025 steaming Methods 0.000 description 12
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 9
- 229960005287 lincomycin Drugs 0.000 description 9
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical group CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000005660 chlorination reaction Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000002386 leaching Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- KDLRVYVGXIQJDK-KIDUDLJLSA-N (2s,4r)-n-[(1s,2r)-2-chloro-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-KIDUDLJLSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- RMQIGGGBJDZABU-VNCRYVLQSA-N n-[2-chloro-1-[(3r,4r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propyl-2,5-dihydropyrrole-2-carboxamide Chemical compound CN1CC(CCC)=CC1C(=O)NC(C(C)Cl)C1[C@H](O)[C@@H](O)C(O)[C@@H](SC)O1 RMQIGGGBJDZABU-VNCRYVLQSA-N 0.000 description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004714 clindamycin palmitate Drugs 0.000 description 1
- OYSKUZDIHNKWLV-PRUAPSLNSA-N clindamycin palmitate Chemical compound O1[C@H](SC)[C@H](OC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@@H](O)[C@H]1[C@@H]([C@H](C)Cl)NC(=O)[C@H]1N(C)C[C@H](CCC)C1 OYSKUZDIHNKWLV-PRUAPSLNSA-N 0.000 description 1
- 229960002291 clindamycin phosphate Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an improved method of a clindamycin hydrochloride alcoholate synthesis process, which belongs to the technical field of organic chemical synthesis, and comprises the following synthesis processes: sequentially adding lincomycin hydrochloride, a catalyst and a solvent into a reaction kettle, then dripping a solid phosgene solvent into the reaction kettle, and heating the reaction kettle for reaction in two stages; cooling the reaction kettle to room temperature after the reaction is finished, and then quenching the reaction liquid with alkali water and extracting a crude clindamycin product; and (3) carrying out high-temperature distillation on the obtained clindamycin crude product, concentrating to remove the organic solvent, then dissolving the clindamycin crude product by using a crystallization solvent, and regulating acid after dissolving to obtain the clindamycin hydrochloride alcoholized product. The invention takes lincomycin hydrochloride as raw material, adopts solid phosgene solvent as chlorinating agent, synthesizes clindamycin hydrochloride alcoholate by one-pot method, has the purity of the finished product of more than 96 percent, and has the advantages of short reaction time, high safety coefficient, high selectivity, easy large-scale preparation and the like.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to an improved method of a clindamycin hydrochloride alcoholate synthesis process.
Background
Clindamycin hydrochloride alcoholate is called as clindamycin hydrochloride, the molecular formula is C 20H40Cl2N2O6 S, the molecular weight is 506.2, and the chemical structure is shown as follows. The product is white crystalline powder, odorless, very soluble in water, very soluble in methanol or pyridine, slightly soluble in ethanol, and almost insoluble in acetone. White or almost white crystalline solid at normal temperature.
The clindamycin hydrochloride alcoholate is an important medical intermediate for preparing clindamycin hydrochloride, clindamycin phosphate and clindamycin palmitate, and is generated by substituting the hydroxyl on the 7-position of lincomycin with chlorine atom. In recent years, research on a synthesis method of clindamycin hydrochloride alcoholate is also attracting more and more attention. The synthesis method of clindamycin hydrochloride alcoholate mainly comprises the following steps:
in the 4 th period of the 2002 Anhui chemical industry, authors firstly mix POCl 3 with DMF under the protection of N 2, then throw lincomycin hydrochloride into the mixture in batches, react for 10 hours in a solvent of 1, 2-dichloroethane, and then obtain clindamycin hydrochloride after treatments of hydrolysis, concentration, crystallization and the like. The HPLC content of the product obtained by the method is only 86.12 percent, and the operation is not suitable for large-scale industrial production.
In Guangdong pharmaceutical 1998, the authors first prepared the chloroalkenamine reagent using SOCl 2 and DMF, and evaporated the solvent and residual sulfoxide to give a solid-borne chloridizing reagent, which was then heated by the addition of lincomycin in portions for 10h. The use of thionyl chloride to generate a large amount of SO 2 is not friendly to the environment, and the extraction mode of firstly adjusting alkali, then adjusting acid and then adjusting alkali is adopted, SO that the process is complicated, the production cost is increased, and the method is not suitable for large-scale production.
In addition, the authors of patent application number 202010561572.2 mention a method for increasing the purity of clindamycin. The authors introduce that the Raney nickel catalyst can reduce dehydroclindamycin, the filtrate after reduction is poured into an aqueous solution of inorganic alkali for crystallization, and the high-purity clindamycin hydrochloride is obtained by salifying the filtrate with hydrochloric acid in acetone after filtration. The authors report that the literature method can lead the removal rate of dehydroclindamycin to be more than 99%, the removal rate of clindamycin B and epiclindamycin to be more than 95%, and the recovery rate to be more than 98%. In this regard, the present inventors conducted repeated experiments according to the technical scheme disclosed therein, and the measured experimental results were greatly different from the disclosed results.
In summary, the above disclosed method has the following drawbacks: long reaction time, difficult post-treatment, serious environmental pollution, unfavorable mass production and the like. Therefore, the method has important significance for improving the synthesis process of the clindamycin hydrochloride alcoholate.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide an improved method for the synthesis process of clindamycin hydrochloride alcoholate, which has the characteristics of short reaction time, high product purity, high production safety coefficient and suitability for large-scale production.
In order to achieve the above object, the present invention provides the following solutions:
An improved method for synthesizing clindamycin hydrochloride alcoholate comprises the following steps: mixing lincomycin hydrochloride with a catalyst, a solvent and a solid phosgene solvent, and obtaining clindamycin hydrochloride alcoholate through alkali water quenching, extraction concentration, dissolution of a crystallization solvent and acid regulation after reaction; the specific reaction process is as follows:
。
Preferably, the synthesis process of the clindamycin hydrochloride alcoholate specifically comprises the following steps: sequentially adding lincomycin hydrochloride, a catalyst and a solvent into a reaction kettle, then dripping a solid phosgene solvent into the reaction kettle, and heating the reaction kettle for reaction in two stages; cooling the reaction kettle to room temperature after the reaction is finished, and then quenching the reaction liquid with alkali water and extracting a crude clindamycin product; and (3) carrying out high-temperature distillation on the obtained clindamycin crude product, concentrating to remove the organic solvent, then dissolving the clindamycin crude product by using a crystallization solvent, and regulating acid after dissolving to obtain the clindamycin hydrochloride alcoholized product.
Preferably, the solvent is one or more of 1, 2-dichloroethane, chloroform, dichloromethane, toluene, acetonitrile, acetone, ethyl acetate, N-dimethylformamide, N-methylpyrrolidone.
Preferably, the molar ratio of the catalyst to the solid phosgene solvent is in the range of 1:1.0-5.0.
Preferably, the catalyst is N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
Preferably, the dropping temperature range of the solid phosgene solvent is 0-60 ℃; the temperature rising range of the first stage is 40-62 ℃, the heating time is 1-10 h, the temperature rising range of the second stage is 50-65 ℃, and the heating time is 5-20 h.
Preferably, the raw material component of the alkaline water is one of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide or potassium ethoxide;
the crystallization solvent is one of absolute ethanol, 95% ethanol, 90% ethanol, 85% ethanol, 80% ethanol, ethyl acetate, acetone, 1, 2-dichloroethane, chloroform or dichloromethane.
Preferably, the temperature range of the high-temperature distillation is 80-120 ℃, and the distillation time is 0.5-5 h.
Preferably, the acid regulating process is as follows: and (3) regulating the acid of the reaction liquid after the crystallization solvent is dissolved by using concentrated hydrochloric acid, a hydrogen chloride ethanol solution or hydrogen chloride gas.
Preferably, the molar ratio of the lincomycin hydrochloride to the solid phosgene solvent is 1:0.3-3.0 based on the weight ratio of the materials.
According to the specific embodiment provided by the invention, the invention discloses the following technical effects:
The invention provides an improved method of a clindamycin hydrochloride alcoholate synthesis process, which comprises the following steps: sequentially adding lincomycin hydrochloride, a catalyst and a solvent into a reaction kettle, then dripping a solid phosgene solvent into the reaction kettle, and heating the reaction kettle for reaction in two stages; cooling the reaction kettle to room temperature after the reaction is finished, and then quenching the reaction liquid with alkali water and extracting a crude clindamycin product; and (3) carrying out high-temperature distillation on the obtained clindamycin crude product, concentrating to remove the organic solvent, then dissolving the clindamycin crude product by using a crystallization solvent, and regulating acid after dissolving to obtain the clindamycin hydrochloride alcoholized product. The method is characterized in that lincomycin hydrochloride is used as a raw material, a solid phosgene solvent is used as a chlorinating reagent, the clindamycin hydrochloride alcoholate is synthesized by a one-pot method, the purity of a finished product is over 96 percent, and the method has the advantages of short reaction time, high safety coefficient, high selectivity, easiness in large-scale preparation and the like.
Detailed Description
The following description of the embodiments of the present invention will clearly and fully describe the technical solutions of the embodiments of the present invention in conjunction with the detailed description provided below, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides an improved method of a clindamycin hydrochloride alcoholate synthesis process, which comprises the following steps: mixing lincomycin hydrochloride with a catalyst, a solvent and a solid phosgene solvent, and performing alkali water quenching, extraction concentration, dissolution of a crystallization solvent and acid adjustment to obtain clindamycin hydrochloride alcoholate; the specific reaction process is as follows:
。
the synthesis process of the clindamycin hydrochloride alcoholate specifically comprises the following steps: sequentially adding lincomycin hydrochloride, a catalyst and a solvent into a reaction kettle, then dripping a solid phosgene solvent into the reaction kettle, and heating the reaction kettle for reaction in two stages; cooling the reaction kettle to room temperature after the reaction is finished, and then quenching the reaction liquid with alkali water and extracting a crude clindamycin product; and (3) carrying out high-temperature distillation on the obtained clindamycin crude product, concentrating to remove the organic solvent, then dissolving the clindamycin crude product by using a crystallization solvent, and regulating acid after dissolving to obtain the clindamycin hydrochloride alcoholized product.
Specifically, in the synthesis process, the solvent is one or more of 1, 2-dichloroethane, chloroform, dichloromethane, toluene, acetonitrile, acetone, ethyl acetate, N-dimethylformamide and N-methylpyrrolidone; the catalyst is N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; the alkaline water comprises one of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide or potassium ethoxide; the crystallization solvent is one of absolute ethanol, 95% ethanol, 90% ethanol, 85% ethanol, 80% ethanol, ethyl acetate, acetone, 1, 2-dichloroethane, chloroform or dichloromethane.
Specifically, in the synthesis process, the molar ratio of the lincomycin hydrochloride to the solid phosgene solvent is 1:0.3-3.0 in terms of the weight ratio of materials; the mol ratio of the catalyst to the solid phosgene solvent is 1:1.0-5.0,
Specifically, in the synthesis process, the dropping temperature range of the solid phosgene solvent is 0-60 ℃; the temperature rising range of the first stage is 40-62 ℃, the heating time is 1-10 h, the temperature rising range of the second stage is 50-65 ℃, and the heating time is 5-20 h.
Specifically, in the synthesis process, the temperature range of high-temperature distillation is 80-120 ℃, and the distillation time is 0.5-5 h. The purpose of the high temperature process in the reaction is to eliminate the 7-chlorine atom of clindamycin under alkaline conditions, and the reaction equation is as follows:
；
Specifically, the acid regulating process comprises the following steps: and (3) regulating the acid of the reaction liquid after the crystallization solvent is dissolved by using concentrated hydrochloric acid, a hydrogen chloride ethanol solution or hydrogen chloride gas. Hydrochloric acid is added in the crystallization process to separate out the product, if the temperature is too high or the crystallization time is too long, amide hydrolysis byproducts are easy to appear, and the reaction equation is as follows:
；
the present invention will be described in further detail with reference to the following embodiments.
Examples
The synthesis process is as follows: to the chlorination tank, 20kg of lincomycin, 83kg of dichloromethane and 21kgDMF kg of dichloromethane were charged, and after cooling to 15.+ -. 5 ℃ a solution of 24kg of solid phosgene solvent and 83kg of dichloromethane was added dropwise. Reflux reaction is carried out for 24 hours after the completion of the dripping.
After cooling, the reaction solution was transferred to a mixture of 48kg of 30% aqueous alkali and 84kg of water, and hydrolyzed for 2 hours at ph=10.5. Separating chloroform, extracting the water phase with chloroform for 2 times, washing with water once, steaming at 35+ -5deg.C until no fraction is present, introducing steam, heating to 100deg.C, and heating for 1 hr. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using a concentrated hydrochloric acid solution for crystallization. Cooling to 15 ℃ and stirring for 14h. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
Examples
The synthesis process is as follows: to the chlorination tank, 300kg of lincomycin, 1245kg of chloroform and 315kgDMF kg of chloroform were charged, and after cooling to 15.+ -. 5 ℃ a solution of 360kg of solid phosgene solvent and 1245kg of chloroform was added dropwise. After the dripping is finished, the temperature is raised to 60 ℃ for heating reaction for 2 hours, and the temperature is raised to 65 ℃ for reaction for 6 hours.
After cooling, the reaction solution is transferred to 700kg of a mixed solution of 30% liquid alkali and 1260kg of water, and the pH=10.5 is controlled for hydrolysis for 2 hours. Separating chloroform, extracting with water phase chloroform for 2 times, washing with water once, steaming at 55+ -5deg.C until no fraction is present, steaming, heating to 100deg.C, and heating for 1 hr. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using a concentrated hydrochloric acid solution for crystallization. Cooling to 15 ℃ and stirring for 13h. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
Examples
The synthesis process is as follows: 20kg of lincomycin, 83kg of 1, 2-dichloroethane and 21kgDMF were charged into a chlorination tank, cooled to 15.+ -. 5 ℃ and then a solution of 24kg of solid phosgene solvent and 83kg of 1, 2-dichloroethane was added dropwise. After the dripping is finished, the temperature is raised to 75 ℃ and the reaction is heated for 5 hours.
After cooling, the reaction solution was transferred to 45kg of a mixture of 30% caustic soda liquid and 84kg of water, and hydrolyzed for 2 hours at ph=10.5. Separating chloroform, extracting the water phase with chloroform for 2 times, washing with water once, steaming at 75+ -5deg.C until no fraction is present, introducing steam, heating to 100deg.C, and heating for 1 hr. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using a concentrated hydrochloric acid solution for crystallization. Cooling to 15 ℃ and stirring for 14h. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
Examples
The synthesis process is as follows: to the chlorination tank, 300kg of lincomycin, 1245kg of chloroform and 315kgDMF kg of chloroform were charged, and after cooling to 15.+ -. 5 ℃ a solution of 360kg of solid phosgene solvent and 1245kg of chloroform was added dropwise. After the dripping is finished, the temperature is raised to 60 ℃ for heating reaction for 2 hours, and the temperature is raised to 65 ℃ for reflux for 6 hours.
After cooling, the reaction solution is transferred to 700kg of a mixed solution of 30% liquid alkali and 1260kg of water, and the pH=10.5 is controlled for hydrolysis for 2 hours. Separating chloroform, extracting with water phase chloroform for 2 times, washing with water once, steaming at 55+ -5deg.C until no fraction is present, steaming, heating to 90deg.C, and heating at 2h. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using a concentrated hydrochloric acid solution for crystallization. Cooling to 15 deg.c and stirring for 4-18 hr. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
Examples
The synthesis process is as follows: to the chlorination tank, 300kg of lincomycin, 1245kg of chloroform and 315kgDMF kg of chloroform were charged, and after cooling to 15.+ -. 5 ℃ a solution of 360kg of solid phosgene solvent and 1245kg of chloroform was added dropwise. After the dripping is finished, the temperature is raised to 60 ℃ for heating reaction for 2 hours, and the temperature is raised to 65 ℃ for reflux for 6 hours.
After cooling, the reaction solution is transferred to 700kg of a mixed solution of 30% liquid alkali and 1260kg of water, and the pH=10.5 is controlled for hydrolysis for 2 hours. Separating chloroform, extracting with water phase chloroform for 2 times, washing with water once, steaming at 55+ -5deg.C until no fraction is present, steaming, heating to 110deg.C, and heating for 20min. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using a concentrated hydrochloric acid solution for crystallization. Cooling to 15 deg.c and stirring for 4-18 hr. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
Examples
The synthesis process is as follows: to the chlorination tank, 300kg of lincomycin, 1245kg of chloroform and 315kgDMF kg of chloroform were charged, and after cooling to 15.+ -. 5 ℃ a solution of 360kg of solid phosgene solvent and 1245kg of chloroform was added dropwise. After the dripping is finished, the temperature is raised to 60 ℃ for heating reaction for 2 hours, and the temperature is raised to 65 ℃ for reflux for 6 hours.
After cooling, the reaction solution is transferred to 700kg of a mixed solution of 30% liquid alkali and 1260kg of water, and the pH=10.5 is controlled for hydrolysis for 2 hours. Separating chloroform, extracting with water phase chloroform for 2 times, washing with water once, steaming at 55+ -5deg.C until no fraction is present, steaming, heating to 120deg.C, and heating for 10min. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using a concentrated hydrochloric acid solution for crystallization. Cooling to 15 deg.c and stirring for 4-18 hr. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
Examples
The synthesis process is as follows: to the chlorination tank, 300kg of lincomycin, 1245kg of chloroform and 315kgDMF kg of chloroform were charged, and after cooling to 15.+ -. 5 ℃ a solution of 360kg of solid phosgene solvent and 1245kg of chloroform was added dropwise. After the dripping is finished, the temperature is raised to 60 ℃ for heating reaction for 2 hours, and the temperature is raised to 65 ℃ for reaction for 6 hours.
After cooling, the reaction solution is transferred to 700kg of a mixed solution of 30% liquid alkali and 1260kg of water, and the pH=10.5 is controlled for hydrolysis for 2 hours. Separating chloroform, extracting with water phase chloroform for 2 times, washing with water once, steaming at 55+ -5deg.C until no fraction is present, steaming, heating to 100deg.C, and heating for 1 hr. Cooling to 40-50deg.C, and adding ethanol. And (5) heating to 65+/-5 ℃ and regulating acid by using an ethanol solution of hydrogen chloride for crystallization. Cooling to 15 ℃ and stirring for 13h. And (3) leaching the filter cake by using ethanol after the filter cake is subjected to the throwing filtration to obtain the clindamycin hydrochloride alcoholized product.
The quality of the clindamycin hydrochloride alcoholates synthesized in the above examples one to seven was detected, and the content of HPLC and the content of epiclindamycin HPLC in the finished product were detected, and the obtained results are shown in Table 1.
TABLE 1 results of finished product test
Referring to the results shown in Table 1, the content of the clindamycin hydrochloride alcoholized product synthesized by the method is higher than 96%, and the content of the clindamycin hydrochloride is 0.17% -0.48%, which shows that the method effectively controls and obviously reduces the content of impurities through process optimization, and obtains a high-quality product.
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer to each other.
The principles and embodiments of the present invention have been described herein with reference to specific examples, the description of which is intended only to assist in understanding the methods of the present invention and the core ideas thereof; also, it is within the scope of the present invention to be modified by those of ordinary skill in the art in light of the present teachings. In view of the foregoing, this description should not be construed as limiting the invention.
Claims (10)
1. An improved method for synthesizing clindamycin hydrochloride alcoholate is characterized by comprising the following steps: mixing lincomycin hydrochloride with a catalyst, a solvent and a solid phosgene solvent, and obtaining clindamycin hydrochloride alcoholate through alkali water quenching, extraction concentration, dissolution of a crystallization solvent and acid regulation after reaction; the specific reaction process is as follows:
。
2. the improved method of the clindamycin hydrochloride alcoholate synthesis process according to claim 1, wherein the synthesis process of the clindamycin hydrochloride alcoholate is specifically as follows: sequentially adding lincomycin hydrochloride, a catalyst and a solvent into a reaction kettle, then dripping a solid phosgene solvent into the reaction kettle, and heating the reaction kettle for reaction in two stages; cooling the reaction kettle to room temperature after the reaction is finished, and then quenching the reaction liquid with alkali water and extracting a crude clindamycin product; and (3) carrying out high-temperature distillation on the obtained clindamycin crude product, concentrating to remove the organic solvent, then dissolving the clindamycin crude product by using a crystallization solvent, and regulating acid after dissolving to obtain the clindamycin hydrochloride alcoholized product.
3. The improvement in a process for synthesizing clindamycin hydrochloride alcoholate according to claim 2, characterized in that said solvent is one or more of 1, 2-dichloroethane, chloroform, dichloromethane, toluene, acetonitrile, acetone, ethyl acetate, N-dimethylformamide, N-methylpyrrolidone.
4. The improved method of the clindamycin hydrochloride alcoholate synthesis process according to claim 2, wherein the molar ratio of the catalyst to the solid phosgene solvent is in the range of 1:1.0-5.0.
5. The improved process for the synthesis of clindamycin hydrochloride alcoholate as recited in claim 4, wherein the catalyst is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
6. The improved method for synthesizing clindamycin hydrochloride alcoholate according to claim 2, wherein the dropping temperature of the solid phosgene solvent is in the range of 0-60 ℃; the temperature rising range of the first stage is 40-62 ℃, the heating time is 1-10 h, the temperature rising range of the second stage is 50-65 ℃, and the heating time is 5-20 h.
7. The improved method of the clindamycin hydrochloride alcoholate synthesis process according to claim 2, wherein the raw material component of the alkaline water is one of sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methylate or potassium ethylate;
the crystallization solvent is one of absolute ethanol, 95% ethanol, 90% ethanol, 85% ethanol, 80% ethanol, ethyl acetate, acetone, 1, 2-dichloroethane, chloroform or dichloromethane.
8. The improved method for synthesizing clindamycin hydrochloride alcoholate according to claim 2, wherein the high-temperature distillation is carried out at a temperature ranging from 80 ℃ to 120 ℃ for 0.5 to 5 hours.
9. The improved method of the clindamycin hydrochloride alcoholate synthesis process according to claim 2, wherein the acid regulating process is as follows: and (3) regulating the acid of the reaction liquid after the crystallization solvent is dissolved by using concentrated hydrochloric acid, a hydrogen chloride ethanol solution or hydrogen chloride gas.
10. The improved method for synthesizing clindamycin hydrochloride alcoholate according to claim 1, wherein the molar ratio of the clindamycin hydrochloride to the solid phosgene solvent is 1:0.3-3.0 based on the weight ratio of the materials.
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