CN115286654B - Synthesis method of clarithromycin intermediate - Google Patents
Synthesis method of clarithromycin intermediate Download PDFInfo
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- CN115286654B CN115286654B CN202210793253.3A CN202210793253A CN115286654B CN 115286654 B CN115286654 B CN 115286654B CN 202210793253 A CN202210793253 A CN 202210793253A CN 115286654 B CN115286654 B CN 115286654B
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- oxime
- erythromycin
- clarithromycin
- hydrochloric acid
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- 229960002626 clarithromycin Drugs 0.000 title claims abstract description 45
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 title claims abstract description 45
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 109
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 72
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 58
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 57
- FSGHEPDRMHVUCQ-UHFFFAOYSA-N 2-ethoxyprop-1-ene Chemical compound CCOC(C)=C FSGHEPDRMHVUCQ-UHFFFAOYSA-N 0.000 claims abstract description 53
- KYTWXIARANQMCA-RWJQBGPGSA-N (3r,4s,5s,6r,7r,9r,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecan-2 Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=NO)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-RWJQBGPGSA-N 0.000 claims abstract description 50
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 53
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 53
- 239000003960 organic solvent Substances 0.000 claims description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012044 organic layer Substances 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 238000001704 evaporation Methods 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000003651 drinking water Substances 0.000 claims description 10
- 235000020188 drinking water Nutrition 0.000 claims description 10
- 239000010410 layer Substances 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 64
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 abstract description 22
- 230000006378 damage Effects 0.000 abstract description 11
- 238000002360 preparation method Methods 0.000 abstract description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 25
- -1 0.0293 mol) Chemical compound 0.000 description 18
- KYTWXIARANQMCA-PGYIPVOXSA-N (3r,4s,5s,6r,7r,9r,10z,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradec Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N\O)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-PGYIPVOXSA-N 0.000 description 15
- 150000002923 oximes Chemical class 0.000 description 15
- 229960003276 erythromycin Drugs 0.000 description 14
- 230000000694 effects Effects 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 7
- 230000007613 environmental effect Effects 0.000 description 7
- 238000006266 etherification reaction Methods 0.000 description 6
- 230000007423 decrease Effects 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical group ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011268 retreatment Methods 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/20—Purification, separation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Saccharide Compounds (AREA)
Abstract
The application provides a synthesis method of clarithromycin intermediates, and belongs to the technical field of heterocyclic compounds. Adding erythromycin A-9-oxime into a methanol solution of hydrochloric acid and 2-ethoxypropene, reacting for 0.5-1h at 15-30 ℃, adding imidazole and trimethylchlorosilane, reacting for 1-3h at 20-50 ℃, adding water to terminate the reaction, and separating and purifying the reaction liquid to obtain the clarithromycin intermediate. The method is applied to the preparation of clarithromycin intermediates and clarithromycin, and hydrochloric acid methanol solution is used to completely replace pyridine hydrochloride, so that the use of pyridine hydrochloride with great harm to the environment and great harm to human bodies is avoided, and the method has the characteristics of low cost, less three wastes, safety, reliability, high reaction rate and the like, and is suitable for industrial production.
Description
Technical Field
The application relates to a synthesis method of clarithromycin intermediates, and belongs to the technical field of heterocyclic compounds.
Background
Clarithromycin (Clarithromycin), abbreviated CAM, chemical name: (-) -2R,3S,4S,5R,6R,8R,10R,11R,12S,13R-3- [ (2, 6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribopyranosyl) oxy ] -13-ethyl-11,12-dihydroxy-6-methoxy-2,4,6,8,10,12-hexamethyl { [ (3, 4,6 trideoxy-3-dimethylamino) -beta-D-xylopyranosyl ] oxy } -14-oxocyclotetradecane-1, 9-dione, (-) -2R,3S,4S,5R,6R,8R,10R,11R,12S,13R-3- [ (2, 6-Dideoxy 3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) -oxy ] -13-ethyl-11, 12-dihydro-6-methoxy-2, 4,6,8,10,12-hexamethyl { [ (3, 4, 6-trideoxy-3-dimethyl lamino) -beta-D-xy-lo-hexopyranosyl } -14-oxadecane-1, 9-dione was discovered in 1980, and was successfully developed by American Atlantic company (Abbott Laboratories) after 1991 month by FDA new class of erythromycin approval from the FDA in the United states for 10 months. The erythromycin has the advantages of overcoming the defect of unstable erythromycin to acid, reducing adverse reaction of gastrointestinal tract, high bioavailability, strong tissue penetrating power, broad antibacterial spectrum and long half-life.
Clarithromycin is a product of methylation of the hydroxy group at position 6 of erythromycin and its industrial synthetic route is now very mature, as in WO9736913A1: firstly, oximating erythromycin to obtain erythromycin A-9-oxime, then protecting 9-oxime hydroxyl by using an etherifying agent in the presence of pyridine hydrochloride, protecting 2 '-hydroxyl and 4' -hydroxyl by using a silanization reagent, and then selectively methylating 6-hydroxyl, and then deprotecting and deoximating to obtain clarithromycin. In the process, the pyridine hydrochloride is easy to corrode equipment, the pyridine is easy to explode, the pyridine hydrochloride has strong irritation and neurotoxicity, and great potential safety hazards and environmental protection hazards exist. In addition, the use of pyridine hydrochloride has the defects of high environmental protection cost pressure, difficult recycling and the like.
Disclosure of Invention
In view of the above, the present application provides a method for synthesizing clarithromycin intermediates, which can replace pyridine hydrochloride, and realizes stable reaction, high yield, low environmental protection cost and environmental protection.
Specifically, the application is realized through the following scheme:
a synthetic method of clarithromycin intermediate, erythromycin A-9-oxime (formula II) is dissolved in organic solvent, hydrochloric acid methanol solution is added, part of the organic solvent is distilled out under reduced pressure and low temperature and cooled to room temperature, 2-ethoxypropene is added, the internal temperature is controlled to be 15-30 ℃ for reaction for 0.5-1h, imidazole and trimethylchlorosilane are added for reaction for 1-3h at 20-50 ℃, water is added for stopping reaction, and the clarithromycin intermediate (formula I) is prepared by separating and purifying reaction liquid; the ratio of the amount of the substances of the hydrogen chloride and the 2-ethoxypropene in the erythromycin A-9-oxime and the hydrochloric acid methanol solution is 1.0:1.1-1.5: 1.5 to 4.0, preferably 1.0:1.1 to 1.5:2.0 to 4.0, the mass ratio of erythromycin A-9-oxime, imidazole, trimethylchlorosilane is 1.0:3.0 to 6.0:2.0 to 5.0;
the reaction formula of the synthesis method is as follows:
further, as preferable:
the preparation method of the hydrochloric acid methanol solution comprises the following steps: introducing hydrogen chloride gas into a methanol solution, wherein the mass ratio of the hydrogen chloride gas to the methanol in the solution is 1.0:4.0-9.0; preferably, the mass ratio of the concentrated hydrochloric acid to the methanol is 1.0:4.0.
The organic solvent is selected from one of the following: dichloromethane, chloroform, toluene, dihydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran; preferably dichloromethane, dihydrofuran, N-dimethylformamide; most preferred is methylene chloride.
The reduced pressure distillation conditions are as follows: the internal temperature in the recovery process is not more than 30 ℃, and the vacuum degree is between-0.08 and 0.1MPa.
The amount of the organic solvent distilled out under reduced pressure is 10-20 g/g based on the amount of the hydrochloric acid methanol solution; preferably 15-20 g/g, and the total amount of the organic solvent is 1-20 g/g based on the mass of the erythromycin A-9-oxime; preferably 5 to 20g/g.
The separation and purification method is one of the following modes:
mode one: standing the reaction solution for layering, taking an organic layer, washing the organic layer with saturated sodium chloride solution, washing the organic layer with drinking water, separating the liquid to remove a water layer, and evaporating the organic solvent to obtain a clarithromycin intermediate of the formula II;
mode two: adding an organic solvent B for extraction without layering, sequentially washing an organic layer with a saturated sodium chloride solution, washing with drinking water, separating to obtain an organic layer, and evaporating the organic solvent to obtain a clarithromycin intermediate, wherein the organic solvent B is ethyl acetate or n-hexane; ethyl acetate is preferred;
the synthesis method of the intermediate can also be carried out by the following steps: respectively weighing erythromycin A-9-oxime, hydrogen chloride and 2-ethoxypropylene in a methanol solution of hydrochloric acid according to the mass ratio of substances of 1.0:1.1-1.5:2.0-4.0, adding the erythromycin A-9-oxime and an organic solvent into a reaction bottle, then adding the methanol solution of hydrochloric acid, decompressing and distilling out 15-20 g/g of the organic solvent based on the mass of the methanol solution of hydrochloric acid, cooling to room temperature, adding an etherifying agent, reacting for 1h at 15-30 ℃, adding imidazole and trimethylchlorosilane, controlling the internal temperature to react for 1h at 20-50 ℃, adding water to terminate the reaction, standing and layering the reaction solution, taking an organic layer, washing with a saturated sodium chloride solution, washing with drinking water, separating liquid to remove a water layer, and steaming to obtain a clarithromycin intermediate after the organic solvent is removed; adding an organic solvent B for extraction without layering, sequentially washing an organic layer with a saturated sodium chloride solution, washing with drinking water, separating to obtain the organic layer, and evaporating the organic solvent to obtain the clarithromycin intermediate, wherein the organic solvent B is ethyl acetate or n-hexane.
The preparation method of the hydrochloric acid methanol solution comprises the following steps: according to the hydrogen chloride: methanol=1.0:4.0, hydrogen chloride is introduced into methanol.
The organic solvent is selected from one of the following: dichloromethane, chloroform, toluene, dihydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran.
The amount of the organic solvent distilled out under reduced pressure is 10-20 g/g based on the amount of the hydrochloric acid methanol solution; the total amount of the organic solvent is 1-20 g/g based on the mass of erythromycin A-9-oxime shown in the formula II.
Compared with the prior art, the advantage of this application mainly stands in: the hydrochloric acid methanol solution is used for completely replacing pyridine hydrochloride, so that pyridine with great environmental harm and great damage to human body is avoided; methanol can be removed by evaporating the organic solvent, and the methanol can be separated by washing the organic solvent in the follow-up process, so that the methanol can be reused; the catalyst of organic hydrochloride is avoided, and three wastes are reduced; the reaction is safe and reliable, the efficiency is high, the purity of the product is high, and the method can be applied to industrial production.
Detailed Description
In this section, the hydrochloric acid methanol solution was prepared as follows:
a methanol solution of hydrochloric acid was prepared in a mass ratio of hydrogen chloride to methanol of 1.0:4.0, in which hydrogen chloride (10 g,0.274 mol) was introduced into methanol (40 g) and stored at a temperature below 0 ℃.
The hydrochloric acid methanol solution prepared above was used in the following examples.
Example 1
The synthetic method of the clarithromycin intermediate comprises the following steps:
(1) And (3) batching: according to erythromycin A-9-oxime: hydrogen chloride in methanol hydrochloric acid solution: 2-ethoxypropene=1.0:1.1:4.0 (molar ratio), erythromycin a-9-oxime: imidazole: trimethylchlorosilane=1.0:1.9:3.0 (molar ratio), wherein erythromycin oxime 20g (0.0267 mol, purity 95.0%), hydrochloric acid methanol solution 5.35g (HCl, 0.0293 mol), 2-ethoxypropene 9.20g (0.107 mol), imidazole 3.5g (0.0514 mol), trimethylchlorosilane 8.70g (0.0801 mol), organic solvent dichloromethane (relative density 1.3266), 180ml (mass about 238 g) were charged.
(2) And (3) synthesis: adding erythromycin oxime and methylene dichloride into a reaction bottle, starting stirring, adding a hydrochloric acid methanol solution into the reaction bottle, evaporating 70ml of methylene dichloride (the evaporation mass is about 93 g) at low temperature and under reduced pressure, cooling to room temperature, adding 2-ethoxypropylene, reacting for 30min at 20-25 ℃, adding imidazole and trimethylchlorosilane, controlling the temperature to be 25-35 ℃ for reacting for 1h, and adding 60ml of water to terminate the reaction.
(3) And (3) separating and purifying: the system is stood for layering, 50ml of saturated sodium chloride solution is used for washing a dichloromethane layer after separating, 50ml of drinking water is used for washing the dichloromethane layer for layering, the solvent is distilled off, white solid is obtained, and the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime is obtained after drying, wherein the mass of the clarithromycin intermediate is 19.2g, the molar yield is 96%, and the purity is 94% through HPLC detection.
Example 2
This example is identical to the process of example 1, except that: in the step (1), the ratio of the amounts of the substances of erythromycin A-9-oxime, hydrogen chloride and 2-ethoxypropene in the hydrochloric acid methanol solution was 1.0:1.3:3.0, wherein, erythromycin oxime was 20g (0.0267 mol, purity was 95.0%), hydrochloric acid methanol solution was 6.33g (HCl, 0.0347 mol), and 2-ethoxypropene was 6.90g (0.0801 mol).
The mass of the obtained clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime was 19.4g, the molar yield was 95%, and the purity was 95% as determined by HPLC.
Example 3
This example is identical to the process of example 1, except that: in the step (1), the ratio of the amount of the hydrogen chloride to the amount of the 2-ethoxypropene in the erythromycin A-9-oxime, the hydrochloric acid methanol solution is 1.0:1.1:2.5, wherein the erythromycin oxime is 20g (0.0267 mol, the purity is 95.0%), the hydrochloric acid methanol solution is 5.35g (HCl, 0.0293 mol), and the 2-ethoxypropene is 5.75 (0.0668 mol).
The mass of the obtained clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime was 19.6g, the molar yield was 95%, and the purity was 96% as determined by HPLC.
Example 4
This example is identical to the process of example 1, except that: in the step (1), the ratio of the amounts of the substances of hydrogen chloride and 2-ethoxypropene in erythromycin A-9-oxime and hydrochloric acid methanol solution was 1.0:1.5:2.0, wherein erythromycin oxime was 20g (0.0267 mol, purity was 95.0%), hydrochloric acid methanol solution was 7.31g (HCl, 0.0401 mol), and 2-ethoxypropene was 4.60g (0.0534 mol).
The mass of the obtained clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime was 19.6g, the molar yield was 94%, and the purity was 96% as determined by HPLC.
As can be seen from the above examples 1-4, when the ratio of the amount of hydrogen chloride to the amount of 2-ethoxypropene in the erythromycin A-9-oxime and the methanol hydrochloride solution is controlled to be 1.0:1.1-1.5:2.0-4, the molar yield can be ensured to be 94-96%, the purity can reach 93-96%, and the industrial application of the clarithromycin intermediate can be completely satisfied.
Example 4-1
Based on example 4, the applicant made a first set of parallel cases, differing in that: the effect on unetherified impurities, intermediate yields and intermediate purity was observed by varying the amount of 2-ethoxypropene added relative to erythromycin A-9-oxime, as shown in Table 1 (HCl refers to hydrogen chloride in methanol hydrochloride solution, C) 5 H 10 O refers to 2-ethoxypropene).
Table 1: influence of the amount of 2-ethoxypropene added on the reaction
| Sequence number | Erythromycin A-9-oxime: HCl: c (C) 5 H 10 O | Unetherified impurity content% | Intermediate yield, percent | Intermediate purity, percent |
| 1-1 | 1:1.5:1.8 | 0.89 | 93.8 | 93.7 |
| 1-2 | 1:1.5:1.6 | 0.90 | 93.5 | 92.8 |
| 1-3 | 1:1.5:1.5 | 0.91 | 92.1 | 92.4 |
| 1-4 | 1:1.5:1.3 | 0.96 | 91.7 | 91.1 |
| 1-5 | 1:1.5:1.1 | 0.99 | 91.5 | 91.7 |
| 1-6 | 1:1.5:1.0 | 1.09 | 91.1 | 86.8 |
| 1-7 | 1:1.5:0.8 | 1.24 | 89.6 | 84.4 |
| 1-8 | 1:1.5:0.5 | 1.56 | 88.7 | 82.7 |
| 1-9 | 1:1.5:4.5 | 0.94 | 92.6 | 91.1 |
| 1-10 | 1:1.5:4.8 | 0.95 | 91.8 | 90.9 |
| 1-11 | 1:1.5:5 | 0.97 | 89.7 | 89.4 |
| 1-12 | 1:1.5:6 | 1.07 | 89.9 | 85.7 |
| 1-13 | 1:1.1:1.8 | 0.67 | 94.7 | 93.7 |
| 1-14 | 1:1.1:1.5 | 0.69 | 93.6 | 93.5 |
| 1-15 | 1:1.1:1.0 | 0.90 | 90.2 | 90.7 |
| 1-16 | 1:1.1:0.8 | 1.11 | 91.1 | 89.6 |
| 1-17 | 1:1.1:4.5 | 0.77 | 94.7 | 92.4 |
| 1-18 | 1:1.1:5.0 | 0.92 | 94.6 | 90.1 |
| 1-19 | 1:1.3:1.8 | 0.71 | 93.4 | 95.5 |
| 1-20 | 1:1.3:1.5 | 0.96 | 92.8 | 94.7 |
| 1-21 | 1:1.3:1.0 | 1.07 | 91.7 | 91.3 |
| 1-22 | 1:1.3:0.8 | 1.23 | 91.6 | 88.8 |
| 1-23 | 1:1.3:4.5 | 0.91 | 92.4 | 91.4 |
| 1-24 | 1:1.3:5.0 | 0.96 | 92.2 | 90.5 |
Comparative examples 1, 2, 3,4 can be seen from table 1: when the ratio of the amount of 2-ethoxypropene to the substance of erythromycin a-9-oxime is in the range of 1:1.5-2.0 (erythromycin a-9-oxime: hydrogen chloride in methanol hydrochloride solution: 2-ethoxypropene=1.0:1.5:1.5-2.0, and 2.0 is not taken), the reaction can be carried out normally, but the yield and purity are relatively weak (see numbers 1-1 to 1-5 in table 1); and when the mass ratio of 2-ethoxypropene to erythromycin A-9-oxime is less than 1:1.1 (see sequence numbers 1-6 to 1-8 in Table 1), the content of unetherified impurities increases, and the yield and purity of intermediates decrease; however, when the ratio of the amount of 2-ethoxypropene to the erythromycin A-9-oxime is more than 1:4 (see the numbers 1-9 to 1-12 in Table 1), the content of unetherified impurities increases and the intermediate purity and intermediate yield decrease.
This case also has the same tendency at other ratios (see numbers 1-13 to 1-24 in table 1), namely: the 2-ethoxypropylene plays a main role in the reaction: the method has the advantages that the method is subjected to etherification reaction with oxime hydroxyl to form an oxime ether structure, the oxime hydroxyl is protected, and the influence on the reaction is shown as incomplete reaction caused by lower feeding amount of 2-ethoxypropylene, and the purity and yield of the intermediate are reduced; when the feeding amount of the 2-ethoxypropene is excessive, side reactions occur, other impurities are excessive, incomplete reactions can be caused, and the purity and yield of the intermediate are reduced; however, when the ratio of the intermediate to erythromycin A-9-oxime is lower than 1:2.0, particularly lower than 1.1, the content of the non-etherified impurities is increased, the yield and purity of the intermediate are reduced, and when the ratio of the intermediate to erythromycin A-9-oxime is higher than 1:4, the content of the non-etherified impurities is increased, and the yield and purity of the intermediate are reduced.
Thus, considering the cost and effect together, it is appropriate to control the molar ratio of 2-ethoxypropene to erythromycin A-9-oxime to 1:1.1-4.0 (erythromycin A-9-oxime: 2-ethoxypropene), and preferably 1:2.0-4.0.
Example 4-2
Based on example 4, the applicant has made a second set of parallel cases, differing in that: changing the relative addition amount of hydrogen chloride in hydrochloric acid methanol, observing whether the added hydrochloric acid methanol solution forms salt (the system is clarified after oxime salification), acid damage impurities, unetherified impurity content, intermediate yield and intermediate purity, specifically as shown in Table 2 (HCl refers to hydrogen chloride in hydrochloric acid methanol solution, C) 5 H 10 O refers to 2-ethoxypropene).
Table 2: influence of the addition of Hydrogen chloride in methanol hydrochloride on the reaction
Comparative examples 1, 2, 3,4 and table 2 can be seen: when the mass ratio of hydrogen chloride to erythromycin A-9-oxime in the hydrochloric acid methanol solution is lower than 1:1.1 (see the sequence numbers 2-1 to 2-4 in Table 2), the erythromycin oxime is not salified, the content of the final non-etherified impurities is increased, and the yield and purity of the intermediate are reduced; however, when the ratio of the amount of hydrogen chloride to the erythromycin A-9-oxime in the hydrochloric acid methanol solution is more than 1:1.5 (see the numbers 2-5 to 2-9 in Table 2), the acid damage becomes large, the content of non-etherified impurities increases, and the purity and yield of the intermediate decrease.
The same trend is also adopted in other proportions (see the sequence numbers 2-10 to 2-21 in the table 2), and the hydrogen chloride in the hydrochloric acid methanol solution plays a main role in the reaction: 1. and erythromycin oxime reaction to form salt, 2, providing proton catalytic etherification reaction, wherein the influence on the reaction is shown that when the feeding amount of hydrogen chloride is too small, the reaction is insufficient to catalyze the reaction, the reaction is incomplete, and when the feeding molar amount of the hydrogen chloride is more than that of erythromycin oxime, the normal catalytic reaction can be performed, and the yield and the purity are gradually improved along with the increment of the adding ratio of 2-ethoxypropylene (see the sequence numbers 2-22 to 2-25 in the table 2); however, when the ratio of the total amount of the non-etherified impurities to the erythromycin A-9-oxime is lower than 1:1.1, the reaction rate is reduced, the non-etherified impurities are increased, the yield and purity of the intermediate are obviously reduced, and when the ratio of the total amount of the non-etherified impurities to the erythromycin A-9-oxime is higher than 1:1.5, the acid damage impurities are increased, the non-etherified impurities are increased, and the yield and purity of the intermediate are reduced.
Therefore, considering the cost and effect together, it is suitable to control the molar ratio of hydrogen chloride of the hydrochloric acid methanol solution to erythromycin A-9-oxime to 1:1.1-1.5 (erythromycin A-9-oxime: hydrogen chloride of the hydrochloric acid methanol solution), and preferably 1:1.3-1.5.
Examples 4 to 3
Based on example 4, the applicant has made a third set of parallel cases, differing in that: the type and the amount of distilled organic solvent were changed, and the reaction conditions of the final non-etherified impurity content, the intermediate yield and the intermediate purity were observed, as shown in Table 3.
Table 3: influence of organic solvent on the reaction
The added hydrochloric acid methanol solution contains a certain amount of methanol, which can affect the etherification reaction, so that the methanol is carried away in the earlier-stage carrying process to ensure the normal operation of the reaction.
Thus, the organic solvent chosen should take into account both 1, the solvent itself not reacting with the reactants; 2. the solvent has a certain azeotropic proportion with methanol, and can be used for distilling the methanol through azeotropy.
The influence of organic solvents is largely divided into two aspects:
(1) Type of solvent: when different solvents shown in Table 3 are selected, it can be seen that methanol can be removed azeotropically and the reaction is not affected when methylene dichloride, chloroform, toluene, dihydrofuran, N-dimethylformamide and 2-methyltetrahydrofuran are adopted (see the sequence numbers 3-1 to 3-5 in Table 3), especially the performance of methylene dichloride, dihydrofuran and N, N-dimethylformamide is more prominent (see the sequence numbers 3-3 to 3-4 in Table 3), and compared with the examples 1, 2, 3 and 4, the effect is optimal when methylene dichloride is also seen; when the serial numbers 3-6 and 3-7 are adopted, the solvent can react with the materials to influence the reaction, so that the unetherified impurities are larger, the yield and purity of the intermediate are reduced, and the solvent is not selected. .
The above rule also applies in the case of other organic solvent steaming ratios (see numbers 3-8 to 3-13 in Table 1).
The methylene dichloride is taken as an organic solvent, the content of the non-etherified impurities gradually decreases along with the increment of the steaming amount, the yield and the purity of the intermediate gradually increase, and when the steaming amount of the methylene dichloride is lower than 50g, the reaction is still worse, which indicates that a small amount of methanol still remains, and the reaction is poor; when the steaming amount of the dichloromethane is 53.5-107g, the reaction is good, which indicates that the system does not contain methanol, and the methanol is completely entrained; however, when the amount of the distilled methylene chloride is 110g or more, the reaction is deteriorated again, and the reason is that the amount of the distilled methylene chloride is too large, which may result in a high system hydrogen chloride concentration and an increased acid destruction, which may deteriorate the reaction.
Based on the above experiment, we also carried out experiments on the total addition amount of the organic solvent, and the results show that: this trend can also be achieved when the organic solvent is selected to be added in an amount ranging from 1 to 20g/g relative to the total addition amount of erythromycin A-9-oxime.
Therefore, the cost and the effect are comprehensively considered, and the selected organic solvent is any one of dichloromethane, chloroform, toluene, dihydrofuran, N-dimethylformamide and 2-methyltetrahydrofuran; the total addition amount of the organic solvent relative to the erythromycin A-9-oxime is 1-20 g/g, namely, the mass of the organic solvent added per 20g of erythromycin A-9-oxime is about 20-400g, the mass of the organic solvent distilled off under reduced pressure relative to the hydrochloric acid methanol solution is 10-20 g/g, namely, the mass of the organic solvent distilled off per 5.35g of the hydrochloric acid methanol solution is about 53.5-107g, and the effect is optimal when the distillation amount relative to the hydrochloric acid methanol is in the range of 80.25-107g (namely, the distillation amount of the organic solvent is 15-20 g/g relative to the hydrochloric acid methanol solution).
Examples 4 to 4
Based on example 4, the applicant has made a fourth set of parallel cases, differing in that: in this embodiment, the separation and purification process is performed by the following two steps:
the reaction solution is not layered, ethyl acetate is added for extraction, an organic layer is firstly washed by 50ml of saturated sodium chloride solution, then is washed by 50ml of drinking water, the organic layer is obtained after liquid separation, after the organic solvent is distilled off, the organic layer is pulped by 50ml of acetone for 1h, then is decompressed and recycled, and is dried to obtain clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime, the mass is 19.2g, the molar yield is 96.0%, and the HPLC detection purity is 95.4%.
The scheme adopts the reaction liquid to directly separate and purify in an extraction reagent extraction mode without layering, and can be seen from the standing layering retreatment of comparative example 4,
the advantages of standing and layering are that new solvents are avoided being introduced, the cost is reduced, the environmental pressure is low, the defects are that the target product intermediate and other byproducts are all in an organic layer, no further separation is performed, the final intermediate yield is slightly higher, but the purity is somewhat lower; the extraction mode has the advantages that the purity of the intermediate is improved by further separating the intermediate and related impurities in the extraction mode, and the defects that 1, new solvent is added and needs to be removed in consideration later, so that certain cost is brought; 2. the equipment cost and the environmental protection cost are increased; 3. there is some loss of extraction itself, resulting in reduced yields of intermediates.
Further experiments are continued, and the reaction liquid is treated by non-layering extraction, and n-hexane and methyl tertiary butyl ether are respectively added for extraction, so that the results show that: the methyl tertiary butyl ether has no separation effect on the reaction product, and only n-hexane and ethyl acetate have obvious influence on the purity and yield of the intermediate, while the methyl tertiary butyl ether has no obvious influence on the purity and yield of the intermediate.
Example 5
(1) And (3) batching: according to erythromycin A-9-oxime: hydrogen chloride in methanol hydrochloric acid solution: 2-ethoxypropene=1.0:1.5:2.0 (mol), erythromycin a-9-oxime: imidazole: trimethylchlorosilane=1.0:1.9:3.0 (molar ratio), wherein erythromycin oxime 20g (0.0267 mol, purity 95.0%), hydrochloric acid methanol solution 7.31g (HCl, 0.0401 mol), 2-ethoxypropene 4.60g (0.0534 mol), organic solvent 180ml, imidazole 3.5 (0.0514 mol), trimethylchlorosilane 8.70g (0.0801 mol) were dosed.
(2) And (3) synthesis: adding erythromycin oxime and 180ml of dichloromethane into a reaction bottle, starting stirring, dissolving hydrochloric acid methanol into the reaction bottle, evaporating 60ml of dichloromethane under reduced pressure at low temperature (evaporating the mass to be about 80g, cooling to room temperature, adding 2-ethoxypropylene, reacting for 1h at 20-25 ℃, adding imidazole and trimethylchlorosilane, controlling the temperature to be 25-35 ℃ and reacting for 1h, and adding 60ml of water to terminate the reaction;
(3) And (3) separating and purifying: the system was allowed to stand for delamination, after which the methylene chloride layer was washed with 50ml of saturated sodium chloride solution, and the layers were separated, and then the methylene chloride layer was washed with 50ml of drinking water, and after the solvent was distilled off, a white solid was obtained, and the mass of the clarithromycin intermediate (2', 4 "-O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime obtained by drying was 18.2g, the molar yield was 91%, and the purity was 85% by HPLC detection.
Example 6
This example is identical to the process of example 5, except that: in step (1), erythromycin A-9-oxime: hydrogen chloride in methanol hydrochloric acid solution: 2-ethoxypropene=1.0:1.3:3.0 (molar ratio), wherein erythromycin oxime 20g (0.0267 mol, purity 95.0%), hydrochloric acid methanol solution 6.33g (HCl, 0.0347 mol), 2-ethoxypropene 6.90g (0.0801 mol), organic solvent 180ml, imidazole 3.5g (0.0514 mol), trimethylchlorosilane 8.70g (0.0801 mol).
The mass of the obtained clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime was 18.9g, the molar yield was 94.5%, and the purity was 90% as determined by HPLC.
Example 7
This example is identical to the process of example 5, except that: in step (1), erythromycin A-9-oxime: hydrogen chloride in methanol hydrochloric acid solution: 2-ethoxypropene was 1.0:1.1:4.0 (molar ratio), of which erythromycin oxime 20g (0.0267 mol, purity 95.0%), hydrochloric acid methanol solution 5.35g (HCl, 0.0293 mol), 2-ethoxypropene 9.22g (0.107 mol), organic solvent 180ml, imidazole 3.5g (0.0514 mol), trimethylchlorosilane 8.70g (0.0801 mol).
The mass of the obtained clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime was 19.1g, the molar yield was 95.5%, and the purity was 94% as determined by HPLC.
Example 8
This example is identical to the process of example 5, except that: in step (1), erythromycin A-9-oxime: hydrogen chloride in methanol hydrochloric acid solution: 2-ethoxypropene was 1.0:1.1:2.5 (molar ratio), of which erythromycin oxime 20g (0.0267 mol, purity 95.0%), hydrochloric acid methanol solution 5.35g (HCl, 0.0293 mol), 2-ethoxypropene 5.75 (0.0668 mol), organic solvent 180ml, imidazole 3.5g (0.0514 mol), trimethylchlorosilane 8.70g (0.0801 mol).
The mass of the obtained clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime was 19.3g, the molar yield was 96.5%, and the purity was 95% as determined by HPLC.
The main difference between this example and example 3 is the difference in the amount of the organic solvent distilled off at low temperature under reduced pressure and the reaction time with 2-ethoxypropene. The former effect is mainly manifested in that the residual methanol affects the etherification reaction, resulting in reduced yields and purities of intermediates, which have been demonstrated in examples 4-3 above, whereas comparative examples 1-4 and examples 5-8 show that the effect on the reaction time with 2-ethoxypropene is manifested in that: too short a reaction time with 2-ethoxypropene can result in incomplete reaction and larger unetherified impurities; the reaction time with 2-ethoxypropene is too long, which can lead to the etherified oxime to react with 2-ethoxypropene again to generate double etherified impurities, in addition, the 2-ethoxypropene can be decomposed under the acidic condition for too long to generate impurities such as acetone, ethanol and the like, and further the reaction is influenced, so that the reaction time is suitably controlled to be 0.5-1h, the occurrence of side reaction caused by the too long reaction time is avoided, and finally, the purity and the yield of the intermediate are reduced.
Meanwhile, the reaction time between the imidazole and the trimethylchlorosilane is tested, and the result shows that: the reaction time is properly controlled within 1-3h, the problem of insufficient reaction exists when the reaction time is too short, and the intermediate is decomposed due to the destruction of the intermediate under the acidic condition when the reaction time is too long, so that the yield and purity of the final intermediate are reduced.
Example 9
The synthesis method of clarithromycin intermediate in this example mainly verifies the effect of the composition of methanol hydrochloride, and includes the following steps:
(1) Preparation of methanol hydrochloride solution: according to Table 4 (A9 oxime means erythromycin A-9-oxime, HCl means hydrogen chloride in methanol hydrochloride solution, CH) 3 OH represents methanol, C 5 H 10 O represents 2-ethoxypropene), hydrogen chloride is introduced into methanol, and the mixture is stored at a temperature of 0 ℃ or lower.
(2) And (3) batching: according to erythromycin A-9-oxime: the ratio of the amounts of the substances of 2-ethoxypropene is 1.0:2.0, erythromycin A-9-oxime: imidazole: trimethylchlorosilane=1.0:1.9:3.0 (molar ratio), wherein erythromycin oxime 20g (0.0267 mol, purity 95.0%), 2-ethoxypropene 9.20g (0.107 mol), imidazole 3.5g (0.0514 mol), trimethylchlorosilane 8.70g (0.0801 mol), organic solvent dichloromethane (relative density 1.3266), 180ml (mass about 238 g) were charged.
(3) And (3) synthesis: adding erythromycin oxime and methylene dichloride into a reaction bottle, starting stirring, adding a hydrochloric acid methanol solution into the reaction bottle, evaporating 70ml of methylene dichloride (the evaporation mass is about 93 g) at low temperature and under reduced pressure, cooling to room temperature, adding 2-ethoxypropylene, reacting for 30min at 20-25 ℃, adding imidazole and trimethylchlorosilane, controlling the temperature to be 25-35 ℃ for reacting for 1h, and adding 60ml of water to terminate the reaction.
(4) And (3) separating and purifying: the system is stood for layering, 50ml of saturated sodium chloride solution is used for washing a dichloromethane layer after separating, 50ml of drinking water is used for washing the dichloromethane layer for layering, the solvent is distilled off after layering, white solid is obtained, and clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime is obtained after drying.
Table 4: influence of different hydrochloric acid methanol solutions on the reaction
The hydrochloric acid methanol solution is used for replacing conventional pyridine hydrochloride to carry out catalytic etherification. As can be seen from Table 4, when the same addition ratio (erythromycin A-9-oxime: hydrogen chloride: 2-ethoxypropene in hydrochloric acid methanol solution is 1.0:1.5:2.0, molar ratio) is adopted, as the addition amount of methanol decreases, namely the concentration of hydrogen chloride in the hydrochloric acid methanol solution increases gradually (see the sequence numbers 4-1 to 4-14 in Table 4), even if the feeding amount of acid is in a proper range, the oxime is damaged to some extent due to the fact that the hydrochloric acid methanol solution with too high concentration reacts with oxime, so that acid damage impurities are obviously increased, and the yield and purity of the intermediate start to be reduced; when the content of hydrogen chloride in the hydrochloric acid methanol solution is too low, a large amount of methanol is additionally added when acid is added, and the methanol cannot be removed by reduced pressure distillation, so that methanol residues influence etherification reaction, the concentration of hydrogen chloride in the solution is not easy to be too high or too low, and as can be seen from the above examples 4-6 to 4-11, when the mass ratio of the hydrogen chloride to the methanol falls within the range of 1.0:4.0-9.0, the acid damage impurity, the intermediate yield and the purity meet the requirements of us under the proper feeding ratio, and the reaction is good.
Meanwhile, the above-mentioned numbers 4-15 to 4-32 in Table 4 also illustrate: the methanol hydrochloride solution with the same structure, with increasing addition amount, methanol remains when the addition amount exceeds the amount which can be carried by reduced pressure distillation, the subsequent reaction is affected, and the 2-ethoxypropene with different addition amounts also shows the same trend (see the serial numbers 4-15 to 4-20, 4-21 to 4-26 and 4-27 to 4-32 in the table 4).
Comparative example
CN102633851a is the previous research result of the applicant, and uses lactam salt to replace pyridine hydrochloride to overcome the pollution and safety problems existing in the participation of pyridine hydrochloride in the reaction. This comparative example mainly demonstrates the specificity of the reaction, i.e. the originality and novelty relative to earlier results.
The synthetic route, reaction stability, reaction conditions, and product yield of the two were analyzed and compared with CN102633851a as a comparative example, and the results are shown in table 5.
Table 5: table of comparison between different schemes
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Claims (9)
1. A method for synthesizing clarithromycin intermediate is characterized in that: adding erythromycin A-9-oxime into a methanol solution of hydrochloric acid and 2-ethoxypropene, reacting for 0.5-1h at 15-30 ℃, adding imidazole and trimethylchlorosilane, reacting for 1-3h at 20-50 ℃, adding water to terminate the reaction, and separating and purifying the reaction liquid to obtain a clarithromycin intermediate; the ratio of the amounts of substances of hydrogen chloride and 2-ethoxypropene in the erythromycin A-9-oxime and hydrochloric acid methanol solution is 1.0:1.1-1.5:1.5-4.0, the ratio of the amounts of substances of erythromycin A-9-oxime, imidazole and trimethylchlorosilane is 1.0:3.0-6.0:2.0-5.0, and the structural formula of the clarithromycin intermediate is as follows:
。
2. the method for synthesizing clarithromycin intermediate according to claim 1, wherein said method for preparing a methanol hydrochloride solution comprises the steps of: and (3) introducing hydrogen chloride gas into the methanol solution, wherein the mass ratio of the hydrogen chloride gas to the methanol in the solution is 1.0:4.0-9.0.
3. The method for synthesizing clarithromycin intermediate as claimed in claim 1, wherein: the ratio of the erythromycin A-9-oxime to the hydrogen chloride to the 2-ethoxypropene in the hydrochloric acid methanol solution is 1.0:1.1-1.5:2.0-4.0.
4. The method for synthesizing clarithromycin intermediate as claimed in claim 1, wherein: the erythromycin A-9-oxime is dissolved in an organic solvent, hydrochloric acid methanol solution is added first, part of the organic solvent is distilled off under reduced pressure, and after cooling to room temperature, 2-ethoxypropylene is added.
5. The method for synthesizing clarithromycin intermediate according to claim 4, wherein: the organic solvent is any one of dichloromethane, chloroform, toluene, dihydrofuran, N-dimethylformamide and 2-methyltetrahydrofuran.
6. The method for synthesizing clarithromycin intermediate according to claim 4, wherein: the total addition amount of the organic solvent relative to erythromycin A-9-oxime is 1-20 g/g, and the amount of the organic solvent distilled off under reduced pressure relative to the methanol solution of hydrochloric acid is 10-20 g/g.
7. The method for synthesizing clarithromycin intermediate according to claim 4, wherein: the total addition amount of the organic solvent relative to erythromycin A-9-oxime is 5-20 g/g, and the amount of the organic solvent distilled off under reduced pressure relative to the methanol solution of hydrochloric acid is 15-20 g/g.
8. The method for synthesizing clarithromycin intermediate according to claim 4, wherein said conditions for distillation under reduced pressure are as follows: the internal temperature in the recovery process is not more than 30 ℃, and the vacuum degree is-0.08-0.1 MPa.
9. The method for synthesizing clarithromycin intermediate according to claim 1, wherein said separation and purification method is one of the following modes:
mode one: standing the reaction solution for layering, taking an organic layer, washing the organic layer with saturated sodium chloride solution, washing the organic layer with drinking water, separating the liquid to remove a water layer, and evaporating the organic solvent to obtain a clarithromycin intermediate;
mode two: ethyl acetate or normal hexane is used as a solvent, the reaction liquid is directly added into the solvent for extraction, then the organic layer is sequentially washed by saturated sodium chloride solution and drinking water, the organic layer is obtained after liquid separation, and the clarithromycin intermediate is obtained after the solvent is distilled off from the organic layer.
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|---|---|---|---|---|
| US4990602A (en) * | 1986-12-17 | 1991-02-05 | Taisho Pharmaceutical Co., Ltd. | Erythromycin A derivatives |
| CN101623655A (en) * | 2009-08-13 | 2010-01-13 | 浙江国邦药业有限公司 | Silanization reaction catalyst |
| CN102633851A (en) * | 2012-03-15 | 2012-08-15 | 浙江工业大学 | Method for synthetizing clarithromycin intermediate |
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2022
- 2022-07-07 CN CN202210793253.3A patent/CN115286654B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4990602A (en) * | 1986-12-17 | 1991-02-05 | Taisho Pharmaceutical Co., Ltd. | Erythromycin A derivatives |
| CN101623655A (en) * | 2009-08-13 | 2010-01-13 | 浙江国邦药业有限公司 | Silanization reaction catalyst |
| CN102633851A (en) * | 2012-03-15 | 2012-08-15 | 浙江工业大学 | Method for synthetizing clarithromycin intermediate |
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