CN115286654A - Method for synthesizing clarithromycin intermediate - Google Patents
Method for synthesizing clarithromycin intermediate Download PDFInfo
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- CN115286654A CN115286654A CN202210793253.3A CN202210793253A CN115286654A CN 115286654 A CN115286654 A CN 115286654A CN 202210793253 A CN202210793253 A CN 202210793253A CN 115286654 A CN115286654 A CN 115286654A
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- oxime
- erythromycin
- solution
- clarithromycin
- reaction
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- 229960002626 clarithromycin Drugs 0.000 title claims abstract description 36
- 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 36
- 238000000034 method Methods 0.000 title claims abstract description 33
- 230000002194 synthesizing effect Effects 0.000 title claims description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims abstract description 57
- 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 51
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 51
- FSGHEPDRMHVUCQ-UHFFFAOYSA-N 2-ethoxyprop-1-ene Chemical group CCOC(C)=C FSGHEPDRMHVUCQ-UHFFFAOYSA-N 0.000 claims abstract description 48
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 92
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 82
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 60
- 239000003960 organic solvent Substances 0.000 claims description 48
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 47
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012044 organic layer Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 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
- 238000001704 evaporation Methods 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- 239000010410 layer Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 4
- SFTHBPKNOPSKEE-CATVDQELSA-N (3r,4s,5s,6r,7r,9r,10e,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-6-methyl-3-trimethylsilyloxyoxan-2-yl]oxy-10-(2-ethoxypropan-2-yloxyimino)-14-ethyl-12,13-dihydroxy-7-methoxy-4-[(2r,4r,5s,6s)-4-methoxy-4,6-dimethyl-5-trimethylsilyloxyoxan-2-yl]o Chemical compound O([C@H]1[C@](C)(OC)C[C@@H](C)\C([C@@H]([C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[Si](C)(C)C)[C@](C)(OC)C2)[C@@H]1C)C)=N/OC(C)(C)OCC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O[Si](C)(C)C SFTHBPKNOPSKEE-CATVDQELSA-N 0.000 claims 3
- 238000002955 isolation Methods 0.000 claims 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 abstract description 20
- 230000006378 damage Effects 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 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
- 239000000543 intermediate Substances 0.000 description 57
- 239000012535 impurity Substances 0.000 description 22
- 150000002923 oximes Chemical class 0.000 description 17
- 229960003276 erythromycin Drugs 0.000 description 14
- -1 0.0293 mol) Chemical compound 0.000 description 12
- 230000035484 reaction time Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 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 9
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin 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)(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 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000007613 environmental effect Effects 0.000 description 6
- 238000006266 etherification reaction Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000047 product Substances 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
- 150000001875 compounds Chemical class 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 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 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000006146 oximation reaction Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000003786 synthesis reaction 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
- 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
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000001035 methylating effect Effects 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
- 238000004537 pulping Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011268 retreatment Methods 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 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 a clarithromycin intermediate, belonging to the technical field of heterocyclic compounds. Adding a hydrochloric acid methanol solution and 2-ethoxypropylene into erythromycin A-9-oxime, reacting at 15 to 30 ℃ for 0.5 to 1h, adding imidazole and trimethylchlorosilane, reacting at 20 to 50 ℃ for 1 to 3h, adding water to stop the reaction, and separating and purifying the reaction liquid to obtain a clarithromycin intermediate. The method is applied to the preparation of clarithromycin intermediate and clarithromycin, and the hydrochloric acid methanol solution is used for completely replacing pyridine hydrochloride, so that the pyridine hydrochloride which has great harm to the environment and the human body is avoided, the characteristics of reduced cost, less three wastes, safety, reliability, high reaction rate and the like are achieved, and the method is suitable for industrial production.
Description
Technical Field
The application relates to a method for synthesizing a clarithromycin intermediate, belonging 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-oxycyclotetradecane-1, 9-dione, (-) -2R,3S,4S,5R,6R,8R,10R,11R,12S,13R-3- [ (2, 6-Dideoxy3-C-methyl-3-O-methyl- α -L-ribo-hexopyranosyl) -oxy ] -13-ethyl-11,12-dihydroxy-6-methoxy-2,4,6,8,10, 12-hexamethoxy { [ (3, 4, 6-trioxy-3-dimethy lamino) - β -D-xy-lo-hexopyranosyl ] oxy } -14-oxostuck tetracaine-1, 9-dione, a novel drug developed by Abeliott corporation, abelitoyomyces, abelit, USA after 0, was successfully developed by Abelitoyor corporation, abelitoyomycins, abeliophytin 19810. The erythromycin A-D-arginine derivative overcomes the defect that erythromycin is unstable to acid, reduces adverse reaction of gastrointestinal tract, and has the advantages of high bioavailability, strong tissue penetrating power, wide antibacterial spectrum and long half-life period.
Clarithromycin is a product obtained by methylating the 6-hydroxyl group of erythromycin, and its industrial synthetic route is now well established, for example, in WO9736913A1: oximation of erythromycin is carried out to obtain erythromycin A-9-oxime, then oximation of erythromycin A-9-oxime is carried out to protect oxime hydroxyl at 9 position by etherifying agent under existence of pyridine hydrochloride, 2 'hydroxyl and 4' hydroxyl are protected by silanizing agent, and then selective methylation of 6 hydroxyl is carried out to obtain clarithromycin through deprotection and oxime removal. In the process, the pyridine hydrochloride is easy to corrode equipment, the pyridine is explosive, has strong irritation and neurotoxicity, and has great potential safety hazard and environmental protection hazard. In addition, the use of pyridine hydrochloride has the defects of high environmental protection cost and pressure, difficult recovery and reuse and the like.
Disclosure of Invention
In view of this, the application provides a method for synthesizing a clarithromycin intermediate, which can replace pyridine hydrochloride, and has the advantages of stable reaction, high yield, environmental protection, low cost and environmental friendliness.
Specifically, the method is realized through the following scheme:
a method for synthesizing a clarithromycin intermediate comprises the steps of dissolving erythromycin A-9-oxime (shown as a formula II) in an organic solvent, adding a methanol solution of hydrochloric acid, distilling out a part of the organic solvent at a low temperature under reduced pressure, cooling to room temperature, adding 2-ethoxypropylene, controlling the internal temperature to be 15-30 ℃ for reaction for 0.5-1h, adding imidazole and trimethylchlorosilane for reaction for 1-3h at 20-50 ℃, adding water to stop the reaction, and separating and purifying the reaction solution to obtain the clarithromycin intermediate (shown as a formula I); the mass ratio of the erythromycin A-9-oxime to the hydrogen chloride in the hydrochloric acid methanol solution to the 2-ethoxypropene is 1.0: 1.5-4.0, preferably 1.0-1.5, and the mass ratio of erythromycin A-9-oxime, imidazole and trimethylchlorosilane is 1.0: 3.0-6.0;
the reaction formula of the synthesis method is as follows:
further, it is preferable that:
the preparation method of the hydrochloric acid methanol solution comprises the following steps: 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); preferably, the mass ratio of concentrated hydrochloric acid to methanol is 1.0.
The organic solvent is selected from one of the following: dichloromethane, trichloromethane, toluene, dihydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran; preferably dichloromethane, dihydrofuran, N-dimethylformamide; most preferred is dichloromethane.
The reduced pressure distillation conditions are as follows: the temperature in the recovery process is not more than 30 ℃, and the vacuum degree is-0.08-0.1 MPa.
The amount of the organic solvent evaporated by decompression is 10 to 20g/g based on the amount of the hydrochloric acid methanol solution; preferably 15 to 20g/g, and the total dosage of the organic solvent is 1 to 20g/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:
the first method is as follows: standing and layering the reaction solution, washing an organic layer with a saturated sodium chloride solution, then washing with drinking water, separating the liquid to remove a water layer, and evaporating to remove an organic solvent to obtain a clarithromycin intermediate of a formula II;
the second method comprises the following steps: adding an organic solvent B into the reaction solution without layering, extracting, sequentially washing the organic layer with a saturated sodium chloride solution, then washing with drinking water, separating liquid to obtain an organic layer, and evaporating to remove the organic solvent to obtain a clarithromycin intermediate, wherein the organic solvent B is selected from ethyl acetate or n-hexane; preferably ethyl acetate;
the synthesis method of the intermediate can also be carried out by the following steps: weighing erythromycin A-9-oxime, hydrogen chloride in a methanol hydrochloride solution and 2.0-4.0 according to the mass ratio of 1.0-1.5, respectively, adding the erythromycin A-9-oxime and an organic solvent into a reaction bottle, then adding the methanol hydrochloride solution, decompressing and steaming out the organic solvent of 15-20 g/g based on the mass of the methanol hydrochloride, 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 stop the reaction, standing and layering the reaction solution, taking an organic layer, washing with a saturated sodium chloride solution, then washing with drinking water, removing a water layer by liquid separation, and steaming out the organic solvent to obtain a clarithromycin intermediate; and (3) adding an organic solvent B for extraction without layering, sequentially washing the organic layer with a saturated sodium chloride solution, washing with drinking water, separating to obtain an organic layer, and evaporating to remove the organic solvent to obtain a clarithromycin intermediate, wherein the organic solvent B is selected from ethyl acetate or n-hexane.
The preparation method of the hydrochloric acid methanol solution comprises the following steps: according to the following formula: methanol =1.0 and 4.0, and hydrogen chloride is introduced into methanol.
The organic solvent is selected from one of the following: dichloromethane, trichloromethane, toluene, dihydrofuran, N-dimethylformamide, 2-methyltetrahydrofuran.
The amount of the organic solvent evaporated by decompression in the method is 10 to 20g/g based on the amount of the methanol hydrochloride solution; the total dosage of the organic solvent is 1-20 g/g based on the mass of the erythromycin A-9-oxime shown in the formula II.
Compared with the prior art, the application has the advantages that: pyridine hydrochloride is completely replaced by hydrochloric acid methanol solution, so that pyridine which is harmful to the environment and human body is avoided; the methanol can be removed by evaporating the organic solvent, and the subsequent organic solvent can be separated by water washing to realize the application; the use of organic hydrochloride catalysts is avoided, and three wastes are reduced; the reaction is safe and reliable, the efficiency is high, the product purity is high, and the method can be applied to industrial production.
Detailed Description
In this section, the methanolic hydrochloric acid solution was prepared in the following manner:
a methanol solution of hydrochloric acid was prepared in a mass ratio of hydrogen chloride to methanol of 1.0, in which hydrogen chloride (10g, 0.274mol) was introduced into methanol (40 g), and stored at 0 ℃ or below.
The methanol hydrochloride solution prepared above was used in the following examples.
Example 1
The method for synthesizing the clarithromycin intermediate comprises the following steps:
(1) Preparing materials: according to erythromycin A-9-oxime: hydrogen chloride in hydrochloric acid methanol solution: 2-ethoxypropene =1.0, 4.0 (mole ratio), erythromycin a-9-oxime: imidazole: trimethylchlorosilane =1.0, 1.9 (molar ratio) and a molar ratio of erythromycin oxime 20g (0.0267 mol, purity 95.0%), methanol hydrochloride 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), and dichloromethane (relative density 1.3266) as an organic solvent 180ml (mass about 238 g) were fed thereto.
(2) Synthesizing: putting erythromycin oxime and dichloromethane into a reaction bottle, starting stirring, adding a hydrochloric acid methanol solution into the reaction bottle, distilling 70ml of dichloromethane (the distilled mass is about 93 g) at low temperature under reduced pressure, cooling to room temperature, adding 2-ethoxypropylene, reacting for 30min at 20-25 ℃, adding imidazole and trimethylchlorosilane, reacting for 1h at 25-35 ℃, and adding 60ml of water to terminate the reaction.
(3) Separation and purification: the system is kept stand for layering, after the layering, a dichloromethane layer is washed by 50ml of saturated sodium chloride solution, the layering is carried out, then a dichloromethane layer is washed by 50ml of drinking water, the layering is carried out, after the solvent is evaporated, a white solid is obtained, and the Clarithromycin intermediate (2 ', 4' -O-bis (trimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime with the mass of 19.2g and the molar yield of 96 percent is obtained after drying, and the purity of 94 percent is detected by HPLC.
Example 2
This example is the same as example 1, except that: in the step (1), the ratio of the amounts of erythromycin A-9-oxime, hydrogen chloride and 2-ethoxypropene in the methanol solution of hydrochloric acid to the amounts of 2-ethoxypropene is 1.0.
The mass of the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime thus obtained was 19.4g, the molar yield was 95%, and the purity was 95% by HPLC.
Example 3
This example is the same as example 1, except that: in the step (1), the ratio of the amounts of erythromycin A-9-oxime, hydrogen chloride and 2-ethoxypropene in the methanol solution of hydrochloric acid is 1.0.
The mass of the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime thus obtained was 19.6g, the molar yield was 95%, and the purity was 96% by HPLC.
Example 4
This example is the same as example 1, except that: in the step (1), the mass ratio of erythromycin A-9-oxime to hydrogen chloride to 2-ethoxypropene in the methanol hydrochloric acid solution is 1.0.
The mass of the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime thus obtained was 19.6g, the molar yield was 94%, and the purity by HPLC was 96%.
As can be seen from the above examples 1-4, when the mass ratio of the erythromycin A-9-oxime to the hydrogen chloride in the hydrochloric acid methanol solution to the 2-ethoxypropene is controlled to be 1.0-1.5, the molar yield can be ensured to be 94-96%, and the purity can reach 93-96%, which can completely satisfy the industrial application of the clarithromycin intermediate.
Example 4-1
Based on example 4, the applicant made a first set of parallel cases, with the difference that: the effect on the non-etherified impurities, intermediate yield 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 hydrochloric acid methanol solution, C) 5 H 10 O denotes 2-ethoxypropene).
Table 2: effect of 2-ethoxypropene addition on the reaction
| Serial number | Erythromycin a-9-oxime: HCl: c 5 H 10 O | Content of non-etherified impurities,% | Yield of intermediate% | Purity of intermediate% |
| 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 |
。
Comparing examples 1, 2, 3,4 with table 1 it can be seen that: when the mass ratio of 2-ethoxypropene to erythromycin a-9-oxime is between 1.5 and 2.0 (erythromycin a-9-oxime: hydrogen chloride in methanol hydrochloride: 2-ethoxypropene =1.0 and 2.0 is not taken), the reaction can also proceed normally, but the yield and purity are relatively weak (see numbers 1-1 to 1-5 in table 1); when the mass ratio of the 2-ethoxypropene to the erythromycin A-9-oxime is lower than 1.1 (see serial numbers 1-6 to 1-8 in Table 1), the content of the non-etherified impurities is increased, and the yield and the purity of the intermediate are reduced; however, when the mass ratio of 2-ethoxypropene to erythromycin A-9-oxime is more than 1 (see numbers 1-9 to 1-12 in Table 1), the content of non-etherified impurities is also increased, and the purity of intermediates and the yield of intermediates are also decreased.
This case also has the same trend in other ratios (see numbers 1-13 to 1-24 in Table 1), namely: the 2-ethoxypropene plays a main role in the reaction: the oxime ether structure is formed by etherification reaction with oxime hydroxyl, the oxime hydroxyl is protected, and the influence on the reaction is shown in that the reaction is incomplete, and the purity and yield of an intermediate are reduced when the feed amount of 2-ethoxypropene is low; when the feeding amount of the 2-ethoxypropylene is too much, side reactions occur, and other impurities are too much, so that incomplete reaction can be caused, and the purity and yield of an intermediate are reduced; however, when the ratio of the compound to erythromycin A-9-oxime is less than 1.0, particularly less than 1.1, the content of non-etherified impurities is increased, and the yield and purity of the intermediate are reduced, and when the ratio of the compound to erythromycin A-9-oxime is more than 1.
Therefore, in view of cost and efficiency, it is desirable to control the molar ratio of 2-ethoxypropene to erythromycin A-9-oxime within a range of 1.1 to 4.0 (erythromycin A-9-oxime: 2-ethoxypropene), and preferably within a range of 1.
Example 4-2
Based on example 4, the applicant made a second set of parallel cases, with the difference that: changing the relative amount of hydrogen chloride in the hydrochloric acid methanol, observing whether the hydrochloric acid methanol solution is salified (system is clarified after oxime salified), acid-damaged impurities, the content of non-etherified impurities, the yield of the intermediate and the purity of the intermediate, as shown in Table 2 (HCl refers to hydrogen chloride in the hydrochloric acid methanol solution, C) 5 H 10 O denotes 2-ethoxypropene).
Table 2: influence of hydrogen chloride addition amount in hydrochloric acid methanol on reaction
Comparing examples 1, 2, 3,4 with table 2, it can be seen that: when the mass ratio of hydrogen chloride to erythromycin A-9-oxime in the hydrochloric acid methanol solution is lower than 1.1 (see serial numbers 2-1 to 2-4 in Table 2), no salt formation of erythromycin oxime occurs, the content of non-etherified impurities is increased, and the yield and purity of the intermediate are reduced; however, when the mass ratio of hydrogen chloride to erythromycin A-9-oxime in the hydrochloric acid methanol solution is more than 1.5 (see numbers 2-5 to 2-9 in Table 2), the acid destruction becomes large, the content of non-etherified impurities increases, and the purity and yield of the intermediate decrease.
The same trend is also observed in other proportions (see the numbers 2-10 to 2-21 in Table 2), and the hydrogen chloride in the hydrochloric acid methanol solution plays a main role in the reaction: 1. reacting with erythromycin oxime to form salt, and 2, providing proton to catalyze etherification reaction, wherein the influence on the reaction is shown in that when the dosage of hydrogen chloride is too small and is not enough to catalyze the reaction, the reaction is incomplete, when the dosage of the hydrogen chloride is more than that of the erythromycin oxime, the normal catalysis reaction can be carried out, and the yield and the purity are gradually improved along with the increment of the addition ratio of the 2-ethoxypropene (see serial numbers 2-22 to 2-25 in the table 2); however, when the ratio of the compound to erythromycin A-9-oxime is lower than 1.1, oxime does not form a salt completely, the reaction rate is reduced, the non-etherified impurities are increased, and the yield and purity of the intermediate are obviously reduced, while when the ratio of the compound to erythromycin A-9-oxime is higher than 1.5, the acid-destroyed impurities are increased, the non-etherified impurities are increased, and the yield and purity of the intermediate are reduced.
Therefore, in view of cost and efficiency in combination, it is desirable to control the molar ratio of hydrogen chloride of the methanol hydrochloric acid solution to erythromycin A-9-oxime to be 1.1 to 1.5 (erythromycin A-9-oxime: hydrogen chloride of the methanol hydrochloric acid solution), and preferably 1.
Examples 4 to 3
Based on example 4, the applicant made a third set of parallel cases, with the following differences: the type and the distillation amount of the organic solvent were varied, and the final non-etherified impurity content, the intermediate yield and the intermediate purity of the reaction were observed for the reaction conditions, as shown in Table 3.
Table 3: effect of organic solvents 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 removed in the early-stage entrainment process, and the normal reaction is ensured.
Therefore, the organic solvent should be selected in consideration of two aspects, 1, the solvent itself does not react with the reactants; 2. the solvent has a certain azeotropic ratio with methanol, and methanol can be distilled off by azeotropy.
The influence of organic solvents is mainly divided into two effects:
(1) Solvent type: when different solvents shown in Table 3 are selected, it can be seen that azeotropic removal of methanol can be achieved without affecting the reaction when methylene chloride, chloroform, toluene, dihydrofuran, N-dimethylformamide and 2-methyltetrahydrofuran are used (see the numbers 3-1 to 3-5 in Table 3), especially the performances of methylene chloride, dihydrofuran and N, N-dimethylformamide are more prominent (see the numbers 3-3 to 3-4 in Table 3), and the best effect is obtained when methylene chloride is used in comparison with examples 1, 2, 3 and 4; and when the serial numbers 3-6 and 3-7 are adopted, the solvent can react with materials to influence the reaction, so that the unetherified impurities are larger, and the yield and the purity of the intermediate are reduced, so that the solvent is not selected. .
The above rule applies also in the case of other organic solvent evaporation ratios (see numbers 3-8 to 3-13 in Table 1).
In the method, methylene dichloride is taken as an organic solvent, the content of non-etherified impurities is gradually reduced along with the increasing of the distilled amount, the yield and the purity of an intermediate are gradually increased, and the table shows that when the distilled amount of the methylene dichloride is less than 50g, the reaction is still poor, which indicates that a small amount of methanol remains to cause the reaction to be poor; when the evaporation 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 carried away; however, when the amount of methylene chloride distilled off is 110g or more, the reaction is deteriorated again, and the reason for this is that the amount of methylene chloride distilled off is too large, the hydrogen chloride concentration in the system becomes high, and the acid destruction becomes large, which may deteriorate the reaction.
On the basis of the above experiment, the total addition amount of the organic solvent is also tested, and the result shows that: the achievement of the above tendency can also be achieved when the organic solvent is selected to be added in an amount in the range of 1 to 20g/g relative to the total amount of erythromycin A-9-oxime added.
Therefore, considering the cost and the effect comprehensively, the organic solvent is any one of dichloromethane, trichloromethane, toluene, dihydrofuran, N-dimethylformamide and 2-methyltetrahydrofuran; the total adding 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 the erythromycin A-9-oxime is about 20-400g, the amount of the organic solvent distilled off under reduced pressure relative to the hydrochloric acid methanol solution is 10-20 g/g, namely the amount of the organic solvent to be distilled off per 5.35g of the hydrochloric acid methanol solution is about 53.5-107g, and the effect is best when the distilling-off amount relative to the hydrochloric acid methanol solution is 80.25-107g (namely the amount of the organic solvent to be distilled off relative to the hydrochloric acid methanol solution is 15-20 g/g).
Examples 4 to 4
Based on example 4, the applicant made a fourth group of parallel cases, with the following differences: in this example, the following two processes are adopted for separation and purification:
and (2) adding ethyl acetate to extract without layering, taking an organic layer, washing the organic layer by using 50ml of saturated sodium chloride solution, washing the organic layer by using 50ml of drinking water, separating the solution to obtain an organic layer, steaming to remove the organic solvent, pulping for 1 hour by using 50ml of acetone, performing reduced pressure recovery, and drying to obtain the clarithromycin intermediate (2 ', 4' -O-bis (trimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime with the mass of 19.2g, the molar yield of 96.0% and the purity of 95.4% by HPLC (high performance liquid chromatography).
In the scheme, reaction liquid is directly separated and purified in an extraction reagent extraction mode without layering, and the standing layering retreatment of comparative example 4 can be seen,
the standing and layering have the advantages that new solvents are avoided being introduced, the cost is reduced, the environmental pressure is low, the defects that the target product intermediate and other byproducts are all in an organic layer, further separation is not performed, the yield of the final intermediate is slightly high, but the purity is slightly low to a certain extent; the extraction method has the advantages that the intermediate and related impurities are further separated by the extraction method, the purity of the intermediate is improved, and the defects that 1, a new solvent is added, and the subsequent removal needs to be considered, so that certain cost is brought; 2. equipment cost and environmental protection cost are increased; 3. the extraction itself has a certain amount of losses, resulting in a reduced yield of intermediates.
Further experiments are carried out, and similarly, the reaction solution is not separated and is extracted first, and n-hexane and methyl tert-butyl ether are respectively added for extraction, and the results show that: because the methyl tert-butyl ether has no separation effect on reaction products, only n-hexane and ethyl acetate have obvious influence on the purity and yield of the intermediate, and the methyl tert-butyl ether has no obvious influence on the purity and yield of the intermediate.
Example 5
(1) Preparing materials: according to erythromycin A-9-oxime: hydrogen chloride in hydrochloric acid methanol solution: 2-ethoxypropene =1.0 (mol), erythromycin a-9-oxime: imidazole: trimethylchlorosilane =1.0, 1.9 (mole ratio).
(2) Synthesizing: putting erythromycin oxime and 180ml of dichloromethane into a reaction bottle, starting stirring, dissolving hydrochloric acid methanol, adding into the reaction bottle, evaporating 60ml of dichloromethane (the evaporation mass is about 80g, cooling to room temperature, adding 2-ethoxypropylene, reacting for 1h at 20-25 ℃, adding imidazole and trimethylchlorosilane, reacting for 1h at 25-35 ℃, and adding 60ml of water to terminate the reaction;
(3) Separation and purification: the system is kept stand for layering, a dichloromethane layer is washed by 50ml of saturated sodium chloride solution after liquid separation, the layering is carried out, the dichloromethane layer is washed by 50ml of drinking water, the layering is carried out, a white solid is obtained after the solvent is evaporated, the weight of the clarithromycin intermediate (2 ', 4' -O-bis-trimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime obtained by drying is 18.2g, the molar yield is 91%, and the purity is 85% by HPLC detection.
Example 6
This example is the same as example 5, except that: in step (1), erythromycin A-9-oxime: hydrogen chloride in hydrochloric acid methanol solution: 2-ethoxypropene =1.0, 1.3 (molar ratio), wherein 20g (0.0267 mol, purity 95.0%), 6.33g (HCl, 0.0347 mol) of erythromycin oxime, 6.90g (0.0801 mol) of 2-ethoxypropene, 180ml of an organic solvent, 3.5g (0.0514 mol) of imidazole, 8.70g (0.0801 mol) of trimethylchlorosilane are added.
The mass of the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime thus obtained was 18.9g, the molar yield was 94.5%, and the purity was 90% by HPLC.
Example 7
This example is the same as example 5, except that: in step (1), erythromycin A-9-oxime: hydrogen chloride in hydrochloric acid methanol solution: 1.0 of 2-ethoxypropene, wherein the molar ratio of erythromycin oxime to 2-ethoxypropene is 20g (0.0267 mol, purity 95.0%), 5.35g (HCl, 0.0293 mol) of methanol hydrochloride solution, 9.22g (0.107 mol) of 2-ethoxypropene, 180ml of organic solvent, 3.5g (0.0514 mol) of imidazole, and 8.70g (0.0801 mol) of trimethylchlorosilane.
The mass of the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime obtained was 19.1g, the molar yield was 95.5%, and the purity by HPLC was 94%.
Example 8
This example is the same as example 5, except that: in step (1), erythromycin A-9-oxime: hydrogen chloride in hydrochloric acid methanol solution: 2-ethoxypropene is 1.0 (mole ratio).
The mass of the clarithromycin intermediate (2 ', 4' -O-bistrimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime thus obtained was 19.3g, the molar yield was 96.5%, and the purity was 95% by HPLC.
The main differences between this example and example 3 are the amount of organic solvent distilled off at low temperature under reduced pressure and the reaction time with 2-ethoxypropene. The former effect is mainly manifested by the influence of methanol residues on the etherification reaction, resulting in a decrease in the yield and purity of intermediates, as demonstrated in examples 4-3 above, while the effect of reaction time with 2-ethoxypropene, as seen in comparative examples 1-4 and examples 5-8, is manifested by: too short 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 cause etherified oxime to react with 2-ethoxypropene again to generate double-etherified impurities, and in addition, the reaction time is too long, 2-ethoxypropene can be decomposed under an acidic condition to generate impurities such as acetone, ethanol and the like, which further influences the reaction, so that the reaction time is properly controlled to be 0.5-1h, side reactions caused by the too long reaction time are avoided, and the purity and the yield of an intermediate are finally reduced.
Meanwhile, the reaction time with imidazole and trimethylchlorosilane is tested, and the result shows that: the reaction time of the reaction period is properly controlled within 1-3h, the reaction is insufficient when the reaction time is too short, and the intermediate is damaged under the acidic condition when the reaction time is too long, so that the intermediate is decomposed, and the yield and the purity of the final intermediate are reduced.
Example 9
The method for synthesizing the clarithromycin intermediate mainly verifies the influence of the methanol hydrochloride composition, and comprises the following steps:
(1) Preparing a hydrochloric acid methanol solution: according to Table 4 (A9 oxime means erythromycin A-9-oxime, HCl means hydrogen chloride in methanol hydrochloride solution, CH) 3 OH denotes methanol, C 5 H 10 O is 2-ethoxypropene), introducing hydrogen chloride into methanol, and storing at below 0 ℃.
(2) Preparing materials: according to erythromycin A-9-oxime: the mass ratio of 2-ethoxypropene to erythromycin A-9-oxime was 1.0: imidazole: trimethylchlorosilane =1.0, 1.9 (molar ratio) was fed, wherein 20g (0.0267 mol, purity 95.0%), 9.20g (0.107 mol) of 2-ethoxypropene, 3.5g (0.0514 mol) of imidazole, 8.70g (0.0801 mol) of trimethylchlorosilane were used, and the organic solvent was dichloromethane (relative density 1.3266) and 180ml (mass about 238 g).
(3) Synthesis: putting erythromycin oxime and dichloromethane into a reaction bottle, starting stirring, adding a hydrochloric acid methanol solution into the reaction bottle, distilling 70ml of dichloromethane (the distilled mass is about 93 g) at low temperature 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 reaction for 1h, and adding 60ml of water to terminate the reaction.
(4) Separation and purification: and standing the system for layering, washing a dichloromethane layer by using 50ml of saturated sodium chloride solution after liquid separation, layering, washing the dichloromethane layer by using 50ml of drinking water, layering, evaporating to remove the solvent to obtain a white solid, and drying to obtain the clarithromycin intermediate (2 ', 4' -O-bis (trimethylsilyl) -erythromycin A-9- [ O- (1-ethoxy-1-methylethyl) ] oxime.
Table 4: the influence of different methanol hydrochloride solution compositions on the reaction
The hydrochloric acid methanol solution is used for replacing the conventional pyridine hydrochloride for catalytic etherification. As can be seen from Table 4, when the addition ratio (erythromycin A-9-oxime: hydrogen chloride in methanol hydrochloride solution: 2-ethoxypropene: 1.0, molar ratio) is the same, the hydrogen chloride concentration in methanol hydrochloride solution increases with decreasing methanol addition amount (see the numbers 4-1 to 4-14 in Table 4), even if the acid charge amount is in a proper range, the oxime is destroyed because of the reaction of the methanol hydrochloride solution with too high concentration with the oxime, so that the acid destruction impurities are increased remarkably, and the yield and purity of the intermediate begin to decrease; when the content of hydrogen chloride in the hydrochloric acid methanol solution is too low, a large amount of methanol is additionally added during the acid addition, and the reduced pressure distillation cannot remove all methanol, so that the methanol residue affects the etherification reaction, so that the concentration of hydrogen chloride in the solution is not too high or too low easily, and as can be seen from the above examples 4-6 to 4-11, when the mass ratio of hydrogen chloride to methanol falls within the range of 4.0-9.0, the acid-damaged impurities, the yield and the purity of the intermediate all meet the requirements of us at a proper feeding ratio, and the reaction is good.
Meanwhile, the numbers 4-15 to 4-32 in the above Table 4 also indicate: the same constitution of the hydrochloric acid methanol solution shows the same trend when the addition amount of methanol is increased and the methanol is remained when the addition amount exceeds the amount that can be carried by the reduced pressure distillation, which affects the subsequent reaction (see numbers 4-15 to 4-20, 4-21 to 4-26, 4-27 to 4-32 in Table 4).
Comparative example
CN102633851A is a result of earlier research of the applicant, and overcomes the pollution and safety problems existing in the reaction of pyridine hydrochloride by replacing pyridine hydrochloride with lactam salt. This comparative example mainly demonstrates the specificity of the reaction, i.e. uniqueness and novelty over previous work.
CN102633851A is taken as a comparative example, and the results of the analysis and comparison of the synthesis route, the reaction stability, the reaction conditions and the product yield of the CN102633851A and the product yield are shown in Table 5.
Table 5: comparison table between different schemes
Claims (9)
1. A method for synthesizing a clarithromycin intermediate is characterized by comprising the following steps: adding a hydrochloric acid methanol solution and 2-ethoxypropylene into erythromycin A-9-oxime, reacting at 15 to 30 ℃ for 0.5 to 1h, adding imidazole and trimethylchlorosilane, reacting at 20 to 50 ℃ for 1 to 3h, adding water to stop the reaction, and separating and purifying the reaction liquid to obtain a clarithromycin intermediate; the mass ratio of the erythromycin A-9-oxime to the hydrogen chloride in the hydrochloric acid methanol solution to the 2-ethoxypropene is 1.0 to 1.5 to 4.0, the mass ratio of the erythromycin A-9-oxime to the imidazole to the trimethylchlorosilane is 1.0 to 3.0 to 6.0:
2. the method for synthesizing a clarithromycin intermediate as claimed in claim 1, wherein the preparation method of the methanol hydrochloride solution is: and (2) 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).
3. The method of claim 1, wherein the method comprises the steps of: the mass ratio of erythromycin A-9-oxime to hydrogen chloride to 2-ethoxypropene in the hydrochloric acid methanol solution is 1.0 to 1.5.
4. The method of claim 1, wherein the method comprises the steps of: dissolving the erythromycin A-9-oxime in an organic solvent, adding a hydrochloric acid methanol solution, decompressing and distilling part of the organic solvent, cooling to room temperature, and then adding 2-ethoxypropylene.
5. The method of claim 4, wherein the intermediate of clarithromycin comprises: the organic solvent is any one of dichloromethane, trichloromethane, toluene, dihydrofuran, N-dimethylformamide and 2-methyltetrahydrofuran.
6. The method of claim 4, wherein the intermediate of clarithromycin comprises: the total addition amount of the organic solvent relative to the erythromycin A-9-oxime is 1-20 g/g, and the amount of the organic solvent evaporated under reduced pressure relative to the hydrochloric acid methanol solution is 10-20 g/g.
7. The method of claim 4, wherein the intermediate of clarithromycin comprises: the total addition amount of the organic solvent relative to the erythromycin A-9-oxime is 5-20 g/g, and the amount of the organic solvent evaporated under reduced pressure relative to the hydrochloric acid methanol solution is 15-20 g/g.
8. The method as claimed in claim 4, wherein the reduced pressure distillation conditions are: the temperature in the recovery process is not more than 30 ℃, and the vacuum degree is-0.08 to 0.1MPa.
9. The method as claimed in claim 1, wherein the isolation and purification is performed by one of the following methods:
the method I comprises the following steps: standing and layering the reaction solution, washing an organic layer with a saturated sodium chloride solution, then washing with drinking water, separating the liquid to remove a water layer, and evaporating to remove an organic solvent to obtain a clarithromycin intermediate;
the second method comprises the following steps: and (3) taking ethyl acetate or n-hexane as a solvent, directly adding the solvent into the reaction solution for extraction, washing an organic layer with a saturated sodium chloride solution and drinking water in sequence, separating the solution to obtain an organic layer, and evaporating the solvent from the organic layer to obtain a clarithromycin intermediate.
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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 |
-
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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116239644A (en) * | 2023-01-09 | 2023-06-09 | 浙江国邦药业有限公司 | Recycling method of protective reaction auxiliary materials on clarithromycin |
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