CN112480172A - Use of borane-pyridine complexes for the preparation of pharmaceutical compounds - Google Patents
Use of borane-pyridine complexes for the preparation of pharmaceutical compounds Download PDFInfo
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- CN112480172A CN112480172A CN202011391808.9A CN202011391808A CN112480172A CN 112480172 A CN112480172 A CN 112480172A CN 202011391808 A CN202011391808 A CN 202011391808A CN 112480172 A CN112480172 A CN 112480172A
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- Prior art keywords
- fosaprepitant
- borane
- pyridine complex
- preparation
- aprepitant
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 30
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical class [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 34
- 229960002891 fosaprepitant Drugs 0.000 claims abstract description 58
- 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 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 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 27
- 229960001372 aprepitant Drugs 0.000 claims abstract description 27
- 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 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000008367 deionised water Substances 0.000 claims abstract description 12
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 238000003756 stirring Methods 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 150000001298 alcohols Chemical class 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
- 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
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 21
- 239000003814 drug Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 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
- 239000013557 residual solvent Substances 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 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 description 4
- 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
- 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
- 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
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 2
- 239000002895 emetic Substances 0.000 description 2
- -1 fosaprepitant compound Chemical class 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
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002246 antineoplastic agent 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
- 238000002512 chemotherapy Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect 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
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- 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
- B01J31/16—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an application of a borane-pyridine complex in preparing a pharmaceutical compound fosaprepitant, which is characterized by comprising the following steps: the aprepitant dibenzyl phosphate is catalyzed by borane-pyridine complex to prepare fosaprepitant. According to the invention, the borane-pyridine complex is used as a catalyst, the aprepitant dibenzylphosphate can directly generate fosaprepitant, the reaction is mild, the conversion of raw materials can be rapidly completed at about 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 the deionized water is used as a solvent, so that the method is more economic and environment-friendly.
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 an important pharmaceutical compound fosaprepitant.
Background
Fosaprepitant, also known as fosaprepitant, is a novel substance P (NK-1) receptor antagonist developed by merck and approved for marketing in FD-a 2008, used for intravenous administration for the prevention and treatment of acute and delayed nausea and vomiting caused by initial and repeated chemotherapy administration of moderately emetic and high dose emetic anti-cancer drugs (e.g., high dose cisplatin) and its chemical name [3- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) basic ] ethoxy ] -3- (4-fluorophenyl) -4, 5-dihydro-5-oxo-1H-1, 2, 4-triazol-1-yl ] phosphonic acid having the following structural formula:
the existing preparation method of fosaprepitant mainly comprises the following steps:
(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 then carrying out hydrogenation reaction to obtain fosaprepitant.
(3) Taking aprepitant dibenzylphosphate as a raw material and BCl3Or BF3When Lewis is used as a catalyst, fosaprepitant is generated through debenzylation, hydrogenation is replaced by Lewis acid deprotection in the reaction, hydrogen is avoided, the reaction is not needed in a high-pressure environment, the safety problem is solved, heavy metal palladium is not adopted, the heavy metal standard exceeding is avoided, only a crude fosaprepitant product is obtained, and pure fosaprepitant is not obtained.
Disclosure of Invention
The invention aims to overcome a series of defects existing in fosaprepitant preparation in the prior art, and provides a fosaprepitant preparation method which is characterized by comprising the following steps: the method comprises the following steps of (1) catalyzing and preparing aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to obtain fosaprepitant, wherein the structural formula of the aprepitant dibenzyl 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.
According to the preparation method of the drug compound fosaprepitant, the dibenzyl aprepitant phosphate and the borane-pyridine complex are added into an organic solvent, stirred for reaction, decompressed, concentrated and recrystallized to obtain the fosaprepitant compound.
According to the preparation method of the drug compound fosaprepitant, the molar ratio of the aprepitant dibenzylphosphate to the borane-pyridine complex is 1: 0.1-0.5.
According to the preparation method of the drug compound fosaprepitant, the organic solvent is selected from alcohols, ester solvents or ether solvents,
according to the preparation method of the drug compound fosaprepitant, the organic solvent is preferably an alcohol solvent.
According to the preparation method of the drug compound fosaprepitant, the alcohol solvent is selected from methanol, ethanol, propanol or isopropanol.
According to the preparation method of the drug compound fosaprepitant, the reaction temperature is 20-30 ℃, and the reaction time is 0.5-2 h.
According to the preparation method of the drug compound fosaprepitant, the reaction temperature is preferably room temperature.
According to the preparation method of the drug compound fosaprepitant, the solvent adopted by recrystallization is deionized water.
Further, the present invention also provides the use of a borane-pyridine complex for the preparation of a pharmaceutical compound, preferably, said pharmaceutical compound is selected from fosaprepitant.
The main contributions of the present invention with respect to the prior art are the following:
(1) the invention creatively takes borane-pyridine complex as a catalyst, at the temperature of 20-30 ℃, aprepitant dibenzylphosphate can directly generate fosaprepitant without using a palladium catalyst and hydrogen, the use of high-pressure environment and heavy metal is avoided, and the safety is improved.
(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 greatly reduce the production cost, and is very suitable for industrial production of fosaprepitant.
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, which is characterized by comprising the following steps of: the method comprises the following steps of (1) catalyzing and preparing aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to obtain fosaprepitant, wherein the structural formula of the aprepitant dibenzyl 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.
According to the preparation method of the drug compound fosaprepitant, the dibenzyl aprepitant phosphate and the borane-pyridine complex are added into an organic solvent, stirred for reaction, decompressed, concentrated and recrystallized to obtain the fosaprepitant compound.
According to the preparation method of the drug compound fosaprepitant, the molar ratio of the aprepitant dibenzylphosphate to the borane-pyridine complex is 1: 0.1-0.5.
According to the preparation method of the drug compound fosaprepitant, the organic solvent is selected from alcohols, ester solvents or ether solvents,
according to the preparation method of the drug compound fosaprepitant, the organic solvent is preferably an alcohol solvent.
According to the preparation method of the drug compound fosaprepitant, the alcohol solvent is selected from methanol, ethanol, propanol or isopropanol.
According to the preparation method of the drug compound fosaprepitant, the reaction temperature is 20-30 ℃, and the reaction time is 0.5-2 h.
According to the preparation method of the drug compound fosaprepitant, the reaction temperature is preferably room temperature.
According to the preparation method of the drug compound fosaprepitant, the solvent adopted by recrystallization is deionized water.
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 the fosaprepitant product, 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 a white solid, 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 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 a white solid, 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 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 a white solid, 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 fosaprepitant product is obtained, the yield is 93.3 percent, and the purity is 99.6 percent.
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 a white solid, wherein the yield is 94.0% and the purity is 99.5%.
Comparative example 1
Under the atmosphere of nitrogen, 100mmol of the 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 the mixed system, the dropwise addition is finished, the reaction is kept for 2 hours, after the reaction is finished, the system is decompressed and concentrated to the residual small amount of solvent (about one fifth of the residual), 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, the fosaprepitant product 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 (7)
1. Use of a borane-pyridine complex for the preparation of the pharmaceutical compound fosaprepitant, characterized in that: the method comprises the following steps of (1) catalyzing and preparing aprepitant dibenzyl phosphate under the action of a borane-pyridine complex to obtain fosaprepitant, wherein the structural formula of the aprepitant dibenzyl 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. The use of borane-pyridine complex in the preparation of fosaprepitant as claimed in claim 1, wherein the compound fosaprepitant is prepared by adding dibenzyl aprepitant phosphate and borane-pyridine complex into an organic solvent, stirring for reaction, concentrating under reduced pressure, and recrystallizing.
3. Use of borane-pyridine complex according to claim 2 for the preparation of the pharmaceutical compound fosaprepitant, the molar ratio of the dibenzyl aprepitant phosphate to the borane-pyridine complex being 1: 0.1-0.5.
4. Use of a borane-pyridine complex according to any one of claims 2 to 3 for the preparation of the pharmaceutical compound fosaprepitant, said organic solvent being selected from the group consisting of alcohols, ester solvents or ether solvents, preferably alcohol solvents.
5. Use of a borane-pyridine complex according to any one of claims 2 to 4 for the preparation of the pharmaceutical compound fosaprepitant, the alcoholic solvent being selected from methanol, ethanol, propanol or isopropanol.
6. Use of a borane-pyridine complex according to any one of claims 2 to 5 for the preparation of the pharmaceutical compound fosaprepitant at a temperature of 20 to 30 ℃ for a reaction time of 0.5 to 2 h.
7. Use of a borane-pyridine complex according to any one of claims 2 to 6 for the preparation of the pharmaceutical compound fosaprepitant, the solvent employed for the recrystallization being deionized water.
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| CN104650142A (en) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | Preparation method of fosaprepitant dimeglumine |
| CN112300212A (en) * | 2020-11-30 | 2021-02-02 | 商河探荣新技术开发中心 | Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists |
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| CN104650142A (en) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | Preparation method of fosaprepitant dimeglumine |
| CN112300212A (en) * | 2020-11-30 | 2021-02-02 | 商河探荣新技术开发中心 | Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists |
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