CN112300212A - Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists - Google Patents
Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists Download PDFInfo
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- CN112300212A CN112300212A CN202011372594.0A CN202011372594A CN112300212A CN 112300212 A CN112300212 A CN 112300212A CN 202011372594 A CN202011372594 A CN 202011372594A CN 112300212 A CN112300212 A CN 112300212A
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- fosaprepitant
- borane
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- pyridine complex
- receptor antagonist
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- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title claims abstract description 43
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title claims abstract description 43
- 239000002464 receptor antagonist Substances 0.000 title claims abstract description 41
- 229940044551 receptor antagonist Drugs 0.000 title claims abstract description 41
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical class [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims description 48
- 229940044880 fosaprepitant dimeglumine Drugs 0.000 claims abstract description 63
- VRQHBYGYXDWZDL-OOZCZQCLSA-N fosaprepitant dimeglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NN(P(O)(O)=O)C(=O)N1 VRQHBYGYXDWZDL-OOZCZQCLSA-N 0.000 claims abstract description 63
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 229960002891 fosaprepitant Drugs 0.000 claims abstract description 37
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 claims abstract description 34
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 claims abstract description 32
- 229960001372 aprepitant Drugs 0.000 claims abstract description 32
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 claims abstract description 18
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008367 deionised water Substances 0.000 claims abstract description 11
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 11
- 230000003197 catalytic effect Effects 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- 238000003756 stirring Methods 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 11
- 239000010452 phosphate Substances 0.000 claims description 11
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003759 ester based solvent Substances 0.000 claims description 3
- 239000004210 ether based solvent Substances 0.000 claims description 3
- -1 fosaprepitant compound Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 7
- 239000012043 crude product Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007787 solid Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000013557 residual solvent Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical compound C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229910001385 heavy metal Inorganic materials 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 239000002895 emetic Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[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 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 2
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 229910015844 BCl3 Inorganic materials 0.000 description 1
- 102000002397 Kinins Human genes 0.000 description 1
- 108010093008 Kinins Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- YTFJQDNGSQJFNA-UHFFFAOYSA-N benzyl dihydrogen phosphate Chemical compound OP(O)(=O)OCC1=CC=CC=C1 YTFJQDNGSQJFNA-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- NKIZJHWBAYUHPE-UHFFFAOYSA-N dichloromethane;trichloroborane Chemical compound ClCCl.ClB(Cl)Cl NKIZJHWBAYUHPE-UHFFFAOYSA-N 0.000 description 1
- 229940108890 emend Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
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- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
- B01J31/14—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides of aluminium or boron
- B01J31/146—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides of aluminium or boron of boron
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention provides an application of borane-pyridine complex in preparing NK-1 receptor antagonist fosaprepitant dimeglumine, which is characterized by comprising the following steps: step 1), catalyzing aprepitant dibenzyl phosphate under the action of borane-pyridine complex to prepare fosaprepitant; and step 2), enabling fosaprepitant to react with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine. According to the invention, borane-pyridine complex is used as a catalyst, aprepitant dibenzylphosphate can directly generate fosaprepitant, and then the fosaprepitant dibenzylphosphate reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine, so that the reaction is mild, the conversion of raw materials can be rapidly completed at a temperature around room temperature only by using a small amount of catalyst, the catalytic efficiency is high, the reaction condition is mild, and the yield is high. The reaction crude product is recrystallized by using deionized water to obtain fosaprepitant with high purity and high yield, the post-treatment is extremely simple, and fosaprepitant dimeglumine is generated by reacting the reaction crude product with N-methyl-D-glucosamine, so that the fosaprepitant is high in purity and yield.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of a pharmaceutical compound, and more particularly relates to a preparation method of important NK-1 receptor antagonist fosaprepitant dimeglumine.
Background
Fosaprepitant dimeglumine (Fosaprepitant dimeglumine, trade name: Emend), Chinese cultureNamed as deoxy-1- (methylamino) -D-sorbitol [3- [ [ (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ]]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl-2, 5-dihydro-5-oxo-1H-1, 2, 4-triazol-1-yl]Phosphate (2:1) with the molecular formula of C23H22F7N4O6P·2C7H17NO5The molecular weight is 1004.83, and the powder is white to white-like powder, odorless, hygroscopic, soluble in methanol and water, and slightly soluble in absolute ethanol, and has a specific rotation degree of +28 ° - +33 °. The drug is a novel chemotherapy-related antiemetic drug developed by Merck corporation and first marketed in the united states in 2008. The medicine is a prodrug of Aprepitant (Aprepitant), which is the first human kinin NK-1 receptor blocker and is developed by Merck company, and is quickly converted into Aprepitant after entering a body as an injection, so that the Aprepitant can be used for preventing and treating acute and delayed nausea and vomiting caused by initial or repeated chemotherapy of moderate emetic and severe emetic anticancer drugs. Different from the action mechanism of the traditional setron antiemetic, fosaprepitant dimeglumine and aprepitant belong to high-selectivity antagonists of human neurokinin-1 (NK-1) receptors, the NK-1 receptor is a binding site of human tachykinin P substances and is mainly positioned in a brain stem vomiting center and a gastrointestinal tract, and the NK-1 receptor antagonist achieves the antiemetic effect by blocking brain nausea and vomiting signals. Research reports indicate that compared with setron drugs, the pitant drugs improve the control rate of acute nausea and vomiting by 20 percent, and further improve the control rate of delayed nausea and vomiting by 30 percent, and the occurrence of the pitant drugs updates the standard of treatment of high-grade emetic chemotherapeutic drugs in the American National Comprehensive Cancer Network (NCCN) treatment guidelines. The structural formula of fosaprepitant dimeglumine is as follows:
the existing preparation method of fosaprepitant dimeglumine mainly comprises the following methods:
(1) the method takes heavy metal palladium as a catalyst, is expensive, has harsh reaction conditions, needs a pressure container for hydrogenation reaction, has poor safety performance, and is not suitable for industrial production.
(2) The preparation method comprises the steps of taking aprepitant dibenzyl phosphate as a raw material, reacting the aprepitant dibenzyl phosphate with methanol to prepare aprepitant monobenzyl phosphate, and carrying out hydrogenation reaction in the presence of N-methyl-D-glucosamine to obtain fosaprepitant dimeglumine.
(3) Taking aprepitant dibenzylphosphate as a raw material and BCl3Or BF3The isoLewis is used as a catalyst, a fosaprepitant crude product is generated by debenzylation, and then the fosaprepitant crude product and N-methyl-D-glucosamine are reacted to generate fosaprepitant dimeglumine, the reaction replaces hydrogenation by the deprotection of Lewis acid, the use of hydrogen is avoided, the reaction under a high-pressure environment is not needed, the safety problem is solved, meanwhile, heavy metal palladium is not adopted, the standard exceeding of heavy metal is avoided, but the reaction at a low temperature is needed, and the operation is not easy.
Disclosure of Invention
The invention aims to overcome a series of defects existing in fosaprepitant dimeglumine preparation in the prior art, and provides a fosaprepitant dimeglumine preparation method which is characterized by comprising the following steps: step 1), carrying out catalytic preparation on aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to obtain an intermediate fosaprepitant; step 2) fosaprepitant reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine
The structural formula of the dibenzyl aprepitant phosphate is as follows:
wherein R is independently selected from a hydrogen atom, a C1-6 alkyl group, a halogen atom, preferably a hydrogen atom.
The preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine disclosed by the invention comprises the following steps of 1): adding dibenzyl aprepitant phosphate and borane-pyridine complex into a first organic solvent, stirring for reaction, concentrating under reduced pressure, and recrystallizing to obtain the fosaprepitant compound.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the molar ratio of the dibenzyl aprepitant phosphate to the borane-pyridine complex is 1: 0.1-0.5.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the first organic solvent is selected from alcohols, ester solvents or ether solvents.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the first organic solvent is preferably an alcohol solvent.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the alcohol solvent is selected from methanol, ethanol, propanol or isopropanol.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the reaction temperature is 20-30 ℃, and the reaction time is 0.5-2 hours.
The invention relates to a preparation method of NK-1 receptor antagonist fosaprepitant dimeglumine, which is characterized in that a solvent used for recrystallization is deionized water according to the method of claims 2 to 6.
The preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine comprises the following steps in the step 2): dissolving the intermediate fosaprepitant obtained in the step 1) in a second organic solvent, adding N-methyl-D-glucosamine, stirring for 0.5-1 h, then dropwise adding a third organic solvent, and stirring for crystallization to obtain fosaprepitant dimeglumine.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the second organic solvent is selected from alcohol solvents; the third organic solvent is selected from one or more of acetone, isopropanol, acetonitrile, ethyl acetate, isopropyl ether or methyl tert-butyl ether.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the second organic solvent is preferably methanol or ethanol.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the third organic solvent is preferably acetone.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the molar feeding ratio of the N-methyl-D-glucosamine to the intermediate fosaprepitant is 2-3: 1.
Further, the present invention also provides the use of a borane-pyridine complex for the preparation of an NK-1 receptor antagonist, preferably said NK-1 receptor antagonist is selected from fosaprepitant dimeglumine.
The main contributions of the present invention with respect to the prior art are the following:
(1) according to the invention, the borane-pyridine complex is used as a catalyst creatively, at the temperature of 20-30 ℃, aprepitant dibenzylphosphate can directly generate fosaprepitant, and then the fosaprepitant dibenzylphosphate reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine, so that a palladium catalyst and hydrogen are not needed, the use of a high-pressure environment and heavy metals is avoided, and the safety is increased.
(2) The method can quickly finish the conversion of the raw materials at the temperature of about room temperature by only using a small amount of catalyst, and has the advantages of high catalytic efficiency, mild reaction conditions and high yield.
(3) The reaction crude product is recrystallized by using deionized water to obtain fosaprepitant with high purity and high yield, the post-treatment is extremely simple, and the deionized water is used as a solvent, so that the method is more economic and environment-friendly.
In a word, the preparation method can greatly improve the production efficiency of fosaprepitant and fosaprepitant dimeglumine and greatly reduce the production cost, and is very suitable for industrial production of fosaprepitant and fosaprepitant dimeglumine.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present disclosure more apparent, the technical solutions of the embodiments of the present disclosure are clearly and completely described. It is to be understood that the described embodiments are only a few embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the disclosure without any inventive step, are within the scope of protection of the disclosure.
The invention provides a preparation method of fosaprepitant dimeglumine, which is characterized by comprising the following steps of: step 1), carrying out catalytic preparation on aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to obtain an intermediate fosaprepitant; step 2) fosaprepitant reacts with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine
The structural formula of the dibenzyl aprepitant phosphate is as follows:
wherein R is independently selected from a hydrogen atom, a C1-6 alkyl group, a halogen atom, preferably a hydrogen atom.
The preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine disclosed by the invention comprises the following steps of 1): adding dibenzyl aprepitant phosphate and borane-pyridine complex into a first organic solvent, stirring for reaction, concentrating under reduced pressure, and recrystallizing to obtain the fosaprepitant compound.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the molar ratio of the dibenzyl aprepitant phosphate to the borane-pyridine complex is 1: 0.1-0.5.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the first organic solvent is selected from alcohols, ester solvents or ether solvents.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the first organic solvent is preferably an alcohol solvent.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the alcohol solvent is selected from methanol, ethanol, propanol or isopropanol.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the reaction temperature is 20-30 ℃, and the reaction time is 0.5-2 hours.
The invention relates to a preparation method of NK-1 receptor antagonist fosaprepitant dimeglumine, which is characterized in that a solvent used for recrystallization is deionized water according to the method of claims 2 to 6.
The preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine comprises the following steps in the step 2): dissolving the intermediate fosaprepitant obtained in the step 1) in a second organic solvent, adding N-methyl-D-glucosamine, stirring for 0.5-1 h, then dropwise adding a third organic solvent, and stirring for crystallization to obtain fosaprepitant dimeglumine.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the second organic solvent is selected from alcohol solvents; the third organic solvent is selected from one or more of acetone, isopropanol, acetonitrile, ethyl acetate, isopropyl ether or methyl tert-butyl ether.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the second organic solvent is preferably methanol or ethanol.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the third organic solvent is preferably acetone.
According to the preparation method of the NK-1 receptor antagonist fosaprepitant dimeglumine, the molar feeding ratio of the N-methyl-D-glucosamine to the intermediate fosaprepitant is 2-3: 1.
Example 1
Step (1)
Under the nitrogen atmosphere, 500ml of tetrahydrofuran, 0.1mol of aprepitant and 0.12mol of tetrabenzyl pyrophosphate are sequentially added into a reaction bottle, the temperature of the system is reduced to about 0 ℃, 0.2mol of sodium hexamethyldisilazane dissolved in the tetrahydrofuran is dropwise added into the system, and after the dropwise addition is finished, the heat preservation reaction is carried out for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 200ml of saturated sodium hydrogen sulfate solution, 200ml of saturated sodium bicarbonate solution, and 200ml of saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and concentrated to give dibenzyl aprepitant phosphate as a white solid in a yield of 93.6%.
Step (2)
Under the atmosphere of nitrogen, mixing 50mmol of the product obtained in the previous step with 100mL of methanol, stirring uniformly at normal temperature, slowly dropping 1mmol of borane-pyridine complex into a mixed system, keeping the reaction for 2 hours after the dropping is finished, concentrating the system under reduced pressure until a small amount of residual solvent (about one fifth of the residual solvent) is obtained, adding 200mL of deionized water, continuously stirring, slowly separating out crystals, filtering, and drying the solid in vacuum to obtain an intermediate fosaprepitant, wherein the yield is 95.5% and the purity is 99.8%.
Step (3)
Dissolving 30mmol of fosaprepitant obtained in the step (2) in 50ml of methanol, adding 65mmol of N-methyl-D-glucosamine, stirring for 1h at room temperature, dropwise adding 150ml of isopropanol into the system after the reaction is finished, stirring for crystallization for 1h, filtering, dissolving the solid in 20ml of methanol again, adding the solid into 200ml of acetone, continuously stirring for crystallization, and performing vacuum drying to obtain white solid fosaprepitant dimeglumine, wherein the yield is 96.3% and the purity is 99.8%.
Example 2
Step (1)
Under the nitrogen atmosphere, 500ml of tetrahydrofuran, 0.1mol of aprepitant and 0.12mol of tetrabenzyl pyrophosphate are sequentially added into a reaction bottle, the temperature of the system is reduced to about 5 ℃, 0.2mol of sodium hexamethyldisilazane dissolved in the tetrahydrofuran is dropwise added into the system, and after the dropwise addition is finished, the heat preservation reaction is carried out for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 200ml of saturated sodium hydrogen sulfate solution, 200ml of saturated sodium bicarbonate solution, and 200ml of saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and concentrated to give dibenzyl aprepitant phosphate as a white solid in a yield of 93.1%.
Step (2)
Under the atmosphere of nitrogen, mixing 100mmol of the product obtained in the previous step with 180mL of methanol, stirring uniformly at normal temperature, slowly dropping 20mmol of borane-pyridine complex into a mixed system, keeping the reaction for 2 hours after the dropping is finished, concentrating the system under reduced pressure until a small amount of residual solvent (about one fifth of the residual solvent) is obtained, adding 300mL of deionized water, continuously stirring, slowly separating out crystals, filtering, and drying the solid in vacuum to obtain an intermediate fosaprepitant, wherein the yield is 96.3% and the purity is 99.7%.
Step (3)
Dissolving 50mmol of fosaprepitant obtained in the step (2) in 80ml of methanol, adding 110mmol of N-methyl-D-glucosamine, stirring for 1h at room temperature, dropwise adding 200ml of isopropanol into the system after the reaction is finished, stirring for crystallization for 1.5h, filtering, dissolving the solid in 50ml of methanol again, adding the solid into 300ml of acetone, continuously stirring for crystallization, and performing vacuum drying to obtain white solid fosaprepitant dimeglumine, wherein the yield is 95.9% and the purity is 99.8%.
Example 3
Step (1)
Under the nitrogen atmosphere, 800ml of tetrahydrofuran, 0.2mol of aprepitant and 0.25mol of tetrabenzyl pyrophosphate are sequentially added into a reaction bottle, the temperature of the system is reduced to about 0 ℃, 0.45mol of sodium hexamethyldisilazane dissolved in the tetrahydrofuran is dropwise added into the system, and after the dropwise addition is finished, the heat preservation reaction is carried out for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 300ml of saturated sodium hydrogen sulfate solution, 300ml of saturated sodium bicarbonate solution, 300ml of saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and concentrated to give white solid aprepitant dibenzyl phosphate with a yield of 92.0%.
Step (2)
Under the atmosphere of nitrogen, mixing 100mmol of the product obtained in the previous step with 180mL of methanol, stirring uniformly at normal temperature, slowly dropping 50mmol of borane-pyridine complex into a mixed system, keeping the reaction for 1h after the dropping is finished, concentrating the system under reduced pressure until a small amount of residual solvent (about one fifth of the residual solvent) is obtained, adding 300mL of deionized water, continuously stirring, slowly separating out crystals, filtering, and drying the solid in vacuum to obtain an intermediate fosaprepitant, wherein the yield is 95.7% and the purity is 99.8%.
Step (3)
Dissolving 100mmol of fosaprepitant obtained in the step (2) in 150ml of methanol, adding 220mmol of N-methyl-D-glucosamine, stirring for 1h at room temperature, dropwise adding 400ml of isopropanol into the system after the reaction is finished, stirring for crystallization for 2h, filtering, dissolving the solid in 120ml of methanol again, adding the solid into 500ml of acetone, continuously stirring for crystallization, and performing vacuum drying to obtain white solid fosaprepitant dimeglumine, wherein the yield is 94.8% and the purity is 99.7%.
Example 4
Step (1)
Adding 5L of tetrahydrofuran, 1mol of aprepitant and 1.2mol of tetrabenzyl pyrophosphate into a reaction bottle in sequence under the nitrogen atmosphere, reducing the temperature of the system to about 0 ℃, dropwise adding 2mol of sodium hexamethyldisilazane dissolved in tetrahydrofuran into the system, and after dropwise adding, carrying out heat preservation reaction for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with 2L of saturated sodium hydrogen sulfate solution, 2L of saturated sodium bicarbonate solution, and 2L of saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and concentrated to give white solid aprepitant dibenzyl phosphate with a yield of 91.7%.
Step (2)
Under the atmosphere of nitrogen, 1mol of the product obtained by the reaction in the previous step is mixed with 1.5L of methanol, the mixture is stirred uniformly at normal temperature, 0.5mol of borane-pyridine complex is slowly dripped into the mixed system, the reaction is kept for 1.5h after the dripping is finished, the system is decompressed and concentrated until a small amount of solvent (about one fifth of the solvent) is remained, 2L of deionized water is added, the stirring is continuously carried out, crystals are slowly separated out and filtered, the solid is dried in vacuum, and an intermediate fosaprepitant is obtained, wherein the yield is 93.3% and the purity is 99.6%.
Step (3)
Dissolving 1mol of fosaprepitant obtained in the step (2) in 1.5L of methanol, adding 2.5mol of N-methyl-D-glucosamine, stirring for 1h at room temperature, dropwise adding 4L of isopropanol into the system after the reaction is finished, stirring for crystallization for 2h, filtering, dissolving the solid in 1.5L of methanol again, adding the solid into 5L of acetone, continuously stirring for crystallization, and performing vacuum drying to obtain white solid fosaprepitant dimeglumine, wherein the yield is 94.0% and the purity is 99.5%.
Comparative example 1
Under the atmosphere of nitrogen, 100mmol of a product obtained in the step (1) of the embodiment 1 is mixed with 180mL of methanol, the mixture is stirred uniformly at normal temperature, 20mL of 1M boron trichloride dichloromethane solution is slowly dripped into a mixed system, after the dripping is finished, the reaction is kept for 2 hours, after the reaction is finished, the system is decompressed and concentrated to a small amount of residual solvent (about one fifth of the residual solvent), 200mL of deionized water is added, the stirring is continuously carried out, crystals are slowly separated out, the crystals are filtered, the solid is dried in vacuum, an intermediate fosaprepitant is obtained, and the yield is only 52.3 percent by calculation.
Finally, it should be noted that: it should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the scope of the invention.
Claims (10)
1. Use of a borane-pyridine complex for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, characterized in that: step 1), carrying out catalytic preparation on aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to obtain an intermediate fosaprepitant; step 2), enabling fosaprepitant to react with N-methyl-D-glucosamine to generate fosaprepitant dimeglumine; the structural formula of the dibenzyl aprepitant phosphate is as follows:
wherein R is independently selected from a hydrogen atom, a C1-6 alkyl group, a halogen atom, preferably a hydrogen atom.
2. Use of borane-pyridine complex according to claim 1 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, said step 1) comprising: adding dibenzyl aprepitant phosphate and borane-pyridine complex into a first organic solvent, stirring for reaction, concentrating under reduced pressure, and recrystallizing to obtain the fosaprepitant compound.
3. Use of borane-pyridine complex according to claim 2 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine in a molar ratio of 1: 0.1-0.5 aprepitant dibenzylphosphate to borane-pyridine complex.
4. Use of borane-pyridine complex according to any one of claims 2 to 3 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, the first organic solvent being selected from alcohols, ester solvents or ether solvents, preferably alcohols.
5. Use of borane-pyridine complex according to any one of claims 2 to 4 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, the alcoholic solvent being selected from methanol, ethanol, propanol or isopropanol.
6. Use of borane-pyridine complex according to any one of claims 2 to 5 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine at a temperature of 20 to 30 ℃ for a reaction time of 0.5 to 2 h.
7. Use of borane-pyridine complex according to any one of claims 2 to 6 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, the solvent used for the recrystallization being deionized water.
8. Use of borane-pyridine complex according to any one of claims 2 to 7 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, said step 2) comprising: dissolving the intermediate fosaprepitant obtained in the step 1) in a second organic solvent, adding N-methyl-D-glucosamine, stirring for 0.5-1 h, then dropwise adding a third organic solvent, and stirring for crystallization to obtain fosaprepitant dimeglumine.
9. Use of borane-pyridine complex according to claim 8 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine, the second organic solvent being selected from alcoholic solvents, preferably methanol or ethanol; the third organic solvent is selected from one or more of acetone, isopropanol, acetonitrile, ethyl acetate, isopropyl ether or methyl tert-butyl ether.
10. Use of a borane-pyridine complex according to any one of claims 8 to 9 for the preparation of the NK-1 receptor antagonist fosaprepitant dimeglumine at a molar charge ratio of N-methyl-D-glucamine to the intermediate fosaprepitant of 2 to 3: 1.
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| CN112480172A (en) * | 2020-12-02 | 2021-03-12 | 商河探荣新技术开发中心 | Use of borane-pyridine complexes for the preparation of pharmaceutical compounds |
| CN112521421A (en) * | 2020-12-07 | 2021-03-19 | 商河探荣新技术开发中心 | Preparation method of pharmaceutical compound |
| CN113045605A (en) * | 2021-03-30 | 2021-06-29 | 浙江亚瑟医药有限公司 | Preparation method and purification method of fosaprepitant dimeglumine |
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