CN111004190A - Preparation method of aprepitant intermediate - Google Patents
Preparation method of aprepitant intermediate Download PDFInfo
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- CN111004190A CN111004190A CN201911093818.1A CN201911093818A CN111004190A CN 111004190 A CN111004190 A CN 111004190A CN 201911093818 A CN201911093818 A CN 201911093818A CN 111004190 A CN111004190 A CN 111004190A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 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 title claims abstract description 19
- 229960001372 aprepitant Drugs 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- -1 (2R) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3-bromomorpholine Chemical compound 0.000 claims abstract description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 4
- AFBDSAJOMZYQAI-CNOZUTPLSA-N (2s,3r)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine Chemical compound C1([C@@H]2NCCO[C@@H]2O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=CC=C(F)C=C1 AFBDSAJOMZYQAI-CNOZUTPLSA-N 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 37
- 239000003054 catalyst Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 9
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 7
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 abstract description 27
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- DWCCMKXSGCKMJF-YNXGUESPSA-N (2r,3s)-2-[(1r)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholine;hydrochloride Chemical compound Cl.C1([C@@H]2NCCO[C@@H]2O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)=CC=C(F)C=C1 DWCCMKXSGCKMJF-YNXGUESPSA-N 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 239000001301 oxygen Substances 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000004321 preservation Methods 0.000 description 7
- 239000012535 impurity Substances 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 3
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 150000002780 morpholines Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QCSLIRFWJPOENV-UHFFFAOYSA-N (2-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1F QCSLIRFWJPOENV-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-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
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 108010040722 Neurokinin-2 Receptors Proteins 0.000 description 1
- 108010040716 Neurokinin-3 Receptors Proteins 0.000 description 1
- 102000002003 Neurokinin-3 Receptors Human genes 0.000 description 1
- 102100037342 Substance-K receptor Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification 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
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
Abstract
The invention provides a preparation method of an aprepitant intermediate, and belongs to the technical field of chemical synthesis. The invention obtains (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine by Suzuki coupling reaction of (2R) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3-bromomorpholine, and then the (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine hydrochloride by reacting the (2R) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine hydrochloride. According to the invention, in the preparation process, the environmental humidity and oxygen content do not need to be controlled, the hydrogenation is also not needed, the operation is safer, simpler and more convenient, the industrial amplification production is easy, the by-products in the reaction process are less, and the aprepitant prepared from the obtained key intermediate I has higher purity.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, relates to a preparation method of a drug intermediate, and particularly relates to a preparation method of an NK-1 receptor blocker aprepitant intermediate.
Background
Aprepitant, the first NK-1 receptor blocker developed by Merck Drugs & Biotechnology in germany, has selectivity and high affinity for NK-1 receptors in the brain, but has very low affinity for NK-2 and NK-3 receptors, is mainly used for treating nausea and vomiting caused by chemotherapeutic Drugs, has been approved by FDA for marketing at 3.27 of 2003, and is now marketed in several countries and regions in north america, europe, korea, hong kong, etc., with a rapid increase in sales year by year.
The aprepitant has the chemical name of 5- [ [ (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) -4-morpholinyl ] methyl ] -1, 2-dihydro-3H-1, 2, 4-triazole-3-ketone, and the chemical structure is shown as follows:
many documents and patents have been reported on the synthesis method of aprepitant, and there are two main methods: one is a method disclosed in patent CN1293077C, in which morpholine derivatives (intermediate i) containing three chiral centers are used as mother nucleus, and chloroaminohydrazone is used as side chain to perform condensation and cyclization to generate aprepitant; the other method is a method disclosed in patent CN1131864C, in which morpholine derivative (intermediate I) containing three chiral centers is used as a mother nucleus, and 3-chloromethyl-1, 2, 4-triazole-5-ketone is used as a side chain to directly condense to generate the aprepitant. In each of the above processes, a morpholine derivative (intermediate i) containing three chiral centers is used, and the chemical name of the compound is: (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine hydrochloride, and the specific chemical structural formula is as follows:
at present, the intermediate I (i.e. the compound I) is prepared mainly according to the method reported in J.AM.CHEM.S0C.2003,125, 2129-2135 and Organic Process Research & Development2006,10,109-117, p-bromofluorobenzene is used as an initial raw material to prepare a Grignard reagent, and then the Grignard reagent is reacted with the compound IV, and the product compound V is salified by hydrochloric acid after catalytic hydrogenation reaction to obtain the key intermediate I, wherein the specific reaction formula is as follows:
the above process adopts a continuous operation mode of one-pot method, and directly prepares the key intermediate I without separation and purification after generating the compound V, and the following defects exist in actual operation: (1) the Grignard reaction needs strict anhydrous and anaerobic operation, which is not beneficial to production amplification; (2) in the hydrogenation process, p-toluenesulfonic acid is used as a pH regulator, sulfonate potentially genotoxic impurities are easily generated in the reaction process, the reaction and products need to be strictly controlled, and the safety of the hydrogenation process is poor, so that the production of a pharmaceutical factory is not facilitated; (3) the intermediate compound V in the process has poor stability, and excessive impurities cannot be avoided even if a one-pot continuous operation mode is adopted, so that the purity of the product is influenced; (4) in the scale-up test, the proportion of defluorinated impurities forming intermediate I increased, and the impurities produced corresponding defluorinated impurity byproducts in the process of preparing aprepitant and were difficult to remove.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method of an aprepitant intermediate, which aims to solve the problem that the key intermediate I is not beneficial to production amplification due to strict anhydrous and anaerobic operation, and the preparation process does not need hydrogenation, is safer and simpler to operate, has few byproducts in the reaction process, and is suitable for industrial production due to higher purity of aprepitant prepared from the obtained key intermediate I.
In order to achieve the purpose, the invention adopts the technical scheme that: the preparation method of the aprepitant intermediate comprises the following steps:
(1) carrying out Suzuki coupling reaction on a compound (2R) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3-bromomorpholine shown as a structural formula (II) to obtain a compound (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine shown as a structural formula (III):
(2) reacting the compound shown in the structural formula (III) with hydrochloric acid to obtain a compound (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine hydrochloride shown in the structural formula (I):
wherein the compound shown in the structural formula (I) is the aprepitant intermediate.
As a preferable embodiment of the preparation method of the present invention, the mass concentration of the hydrochloric acid is 20% to 38%.
As a preferred embodiment of the preparation method of the present invention, in the step (1), the compound represented by the structural formula (ii), 4-fluorobenzeneboronic acid, alkali liquor and organic solvent a are uniformly mixed, then a catalyst is added to carry out stirring and heating reaction, after the reaction is finished, a layered liquid is obtained by cooling, solid-liquid separation and standing in sequence, and the upper organic phase of the layered liquid is taken, washed with saturated saline solution and then concentrated to obtain the compound represented by the structural formula (iii).
As a preferred embodiment of the preparation method of the present invention, the molar ratio of the compound represented by the structural formula (II) to the 4-fluorobenzeneboronic acid is 1:1 to 1.5.
As a further preferable embodiment of the production method of the present invention, the molar ratio of the compound represented by the structural formula (II) to the 4-fluorobenzeneboronic acid is 1:1.1 to 1.2.
As a preferred embodiment of the preparation method of the present invention, the alkali solution is a saturated aqueous sodium carbonate solution.
As a preferable embodiment of the preparation method of the invention, the ratio of the volume of the alkali liquor to the mass of the compound represented by the structural formula (II) is 10-20mL:1 g.
As a further preferable embodiment of the preparation method of the present invention, the mass ratio of the alkali solution to the compound represented by the structural formula (II) is 13-15mL:1 g.
As a preferred embodiment of the preparation method of the present invention, the organic solvent a is toluene.
As a preferred embodiment of the preparation method of the invention, the volume ratio of the organic solvent A to the alkali liquor is 1.5-3: 1.
As a further preferred embodiment of the preparation method of the present invention, the volume ratio of the organic solvent A to the alkali liquor is 1.8-2: 1.
As a preferred embodiment of the preparation method of the present invention, the catalyst is at least one of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, dichlorodiammine palladium, bis (triphenylphosphine) palladium dichloride, and tetrakis (triphenylphosphine) palladium.
As a preferable embodiment of the preparation method of the present invention, the mass ratio of the catalyst to the compound represented by the structural formula (II) is 1:80 to 120.
As a further preferable embodiment of the preparation method of the present invention, the mass ratio of the catalyst to the compound represented by the structural formula (II) is 1: 100-110.
As a preferable embodiment of the production method of the present invention, the volume ratio of the organic solvent A to the saturated saline solution is 1.5 to 3: 1.
In a further preferred embodiment of the production method of the present invention, the volume ratio of the organic solvent a to the saturated saline solution is 1.8 to 2: 1.
As a preferred embodiment of the preparation method of the present invention, in the step (1), the reaction time is 5 to 15 hours and the reaction temperature is 80 to 100 ℃.
As a further preferable embodiment of the production method of the present invention, in the step (1), the reaction time is 8 to 12 hours and the reaction temperature is 95 to 100 ℃.
As a preferred embodiment of the preparation method of the present invention, in the step (2), the compound represented by the structural formula (i) is obtained by dissolving the compound represented by the structural formula (iii) in an organic solvent B, adding hydrochloric acid to adjust the pH value to 1-2, concentrating, and cooling.
As a preferable embodiment of the preparation method of the present invention, the organic solvent B is at least one of methanol, ethanol, ethyl acetate, and methyl isobutyl ketone.
As a further preferable embodiment of the production method of the present invention, the organic solvent B is methyl isobutyl ketone.
As a preferable embodiment of the production method of the present invention, the ratio of the volume of the organic solvent B to the amount of the compound represented by the structural formula (III) is 10 to 20mL:1 g.
As a further preferable embodiment of the production method of the present invention, the ratio of the volume of the organic solvent B to the amount of the compound represented by the structural formula (III) is 13 to 15mL:1 g.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the Suzuki coupling reaction is adopted, the humidity and the oxygen content of the production environment do not need to be controlled, and the method is more favorable for industrial scale-up production than the Grignard reaction adopted by the original grinding process;
(2) the invention avoids the potential safety hazard caused by adopting a hydrogenation process, and is more beneficial to the production of pharmaceutical factories;
(3) the method has high process stability, generates few impurities in an amplification test, can remove a small amount of by-products through a hydrochloric acid salifying crystallization process, and can be used for preparing high-purity aprepitant.
Drawings
FIG. 1 is a schematic diagram of a representative synthesis method of an aprepitant intermediate (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine hydrochloride according to the present invention;
FIG. 2 is a high performance liquid chromatogram of Compound III;
FIG. 3 is a high performance liquid chromatogram of intermediate I;
FIG. 4 is a nuclear magnetic hydrogen spectrum of intermediate I.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1: preparation of Compound III
(1) Influence of the type of catalyst on the preparation of Compound III
Setting experiment groups 1-4, respectively mixing and uniformly stirring 42.2g of a compound II, 16g of 4-fluorobenzeneboronic acid, 630mL of a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding 0.422g of a catalyst, heating to 100 ℃ while stirring, preserving heat for reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering and recovering the catalyst, standing and layering a filtrate, washing an upper layer of an organic phase with 630mL of saturated saline solution, separating the organic phase, concentrating and recovering the toluene to obtain a white massive solid, namely a free alkali of an intermediate I, namely a compound III, and performing a high performance liquid chromatogram of the compound III as shown in FIG 2. The differences between the experimental groups 1 to 4 and the experimental results are shown in Table 1.
TABLE 1 influence of the catalyst type on the preparation of Compound III
(2) Effect of the amount of catalyst on the preparation of Compound III
Setting an experimental group 5-9, respectively mixing and uniformly stirring 42.2g of a compound II, 16g of 4-fluorobenzeneboronic acid, 630mL of a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating to 100 ℃ while stirring, then carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering and recovering the catalyst, standing and layering the filtrate, washing the upper layer of organic phase with 630mL of saturated saline solution, separating the solution to obtain an organic solution, concentrating and recovering the toluene to obtain a white blocky solid, namely the free alkali of the intermediate I, namely the compound III. The differences between the experimental groups 5 to 9 and the experimental results are shown in Table 2.
TABLE 2 influence of the amount of catalyst on the preparation of Compound III
(3) Effect of the amount of 4-Fluorophenylboronic acid on the preparation of Compound III
Setting experimental groups 10-13, respectively mixing and uniformly stirring 42.2g of a compound II, 4-fluorophenylboronic acid, 630mL of a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding 0.422g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating to 100 ℃ while stirring, then carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering and recovering the catalyst, standing and layering the filtrate, washing the upper layer of organic phase with 630mL of saturated saline solution, then carrying out liquid separation, obtaining organic liquid, concentrating and recovering the toluene to obtain a white blocky solid, namely the free alkali of the intermediate I, namely a compound III. The differences between the experimental groups 10 to 13 and the experimental results are shown in Table 3.
TABLE 34 Effect of the amount of fluorobenzeneboronic acid used on the preparation of Compound III
(4) Effect of the amount of saturated aqueous sodium carbonate solution on the preparation of Compound III
Setting experimental groups 14-17, respectively mixing and uniformly stirring 42.2g of a compound II, 16g of 4-fluorophenylboronic acid, a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding 0.422g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating to 100 ℃ while stirring, then carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering and recovering the catalyst, standing and layering the filtrate, washing the upper organic phase with 630mL of saturated saline solution, then carrying out liquid separation, obtaining an organic liquid, concentrating and recovering the toluene to obtain a white blocky solid, namely a free alkali of an intermediate I, namely a compound III. The differences between the experimental groups 14 to 17 and the experimental results are shown in Table 4.
TABLE 4 influence of the amount of saturated aqueous sodium carbonate solution on the preparation of Compound III
(5) Influence of the amount of toluene on the preparation of Compound III
Setting experimental groups 18-21, respectively mixing and stirring 42.2g of a compound II, 16g of 4-fluorophenylboronic acid, 630mL of a saturated sodium carbonate aqueous solution and toluene uniformly, adding 0.422g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating to 100 ℃ while stirring, then carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering and recovering the catalyst, standing and layering the filtrate, washing the upper organic phase with 630mL of saturated saline solution, then carrying out liquid separation, obtaining organic liquid, concentrating and recovering toluene to obtain white blocky solid, namely the free alkali of the intermediate I, namely the compound III. The differences between the experimental groups 18 to 21 and the experimental results are shown in Table 5.
TABLE 5 influence of the amount of toluene used on the preparation of Compound III
(6) Effect of the amount of saturated salt solution on the preparation of Compound III
Setting an experimental group 22-25, respectively mixing and uniformly stirring 42.2g of a compound II, 16g of 4-fluorophenylboronic acid, 630mL of a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding 0.422g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating to 100 ℃ while stirring, carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering to recover the catalyst, standing and layering the filtrate, washing the upper organic phase with saturated saline solution, separating the solution to obtain an organic solution, concentrating and recovering the toluene to obtain a white blocky solid, namely a free alkali of an intermediate I, namely a compound III. The differences between the experimental groups 22 to 25 and the experimental results are shown in Table 6.
TABLE 6 Effect of saturated brine dosage on Compound III preparation
(7) Influence of the reaction temperature on the preparation of Compound III
Setting experimental groups 26-29, respectively mixing and uniformly stirring 42.2g of a compound II, 16g of 4-fluorophenylboronic acid, 630mL of a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding 0.422g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating while stirring, then carrying out heat preservation reaction for 10 hours, cooling to room temperature after the reaction is finished, filtering to recover the catalyst, standing and layering the filtrate, washing the upper layer of an organic phase with 630mL of saturated saline solution, separating the solution to obtain an organic solution, concentrating and recovering the toluene to obtain a white blocky solid, namely a free base of an intermediate I, namely a compound III. The differences between the experimental groups 26 to 29 and the experimental results are shown in Table 7.
TABLE 7 influence of the reaction temperature on the preparation of Compound III
(8) Effect of reaction time on the preparation of Compound III
Setting experimental groups 30-34, respectively mixing and uniformly stirring 42.2g of a compound II, 16g of 4-fluorophenylboronic acid, 630mL of a saturated sodium carbonate aqueous solution and 1260mL of toluene, adding 0.422g of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride as a catalyst, heating to 100 ℃ while stirring, carrying out heat preservation reaction, cooling to room temperature after the reaction is finished, filtering and recovering the catalyst, standing and layering the filtrate, washing the upper organic phase with 630mL of saturated saline solution, then carrying out liquid separation, obtaining organic liquid, concentrating and recovering the toluene to obtain a white blocky solid, namely the free alkali of the intermediate I, namely the compound III. The differences between the experimental groups 30 to 34 and the experimental results are shown in Table 8.
TABLE 8 Effect of reaction time on the preparation of Compound III
Example 2: preparation of intermediate I
(1) Effect of organic solvent type on intermediate I preparation
Setting experiment groups 35-38 to respectively dissolve 44g of the compound III obtained in the experiment group 1 in 660mL of organic solvent, adding hydrochloric acid with the mass concentration of 20% -38% to adjust the pH value to 1-2, then carrying out reduced pressure distillation until the volume is 30% of the original volume, then cooling to 0 ℃ to precipitate white solid, filtering and drying to obtain white solid powder, namely an intermediate I, wherein the high performance liquid chromatogram of the white solid powder is shown in FIG. 3, and the nuclear magnetic hydrogen spectrum is shown in FIG. 4. The differences between the experimental groups 36 to 39 and the experimental results are shown in Table 9.
TABLE 9 influence of the type of organic solvent on the preparation of intermediate I
(2) Effect of the amount of methyl isobutyl ketone on the preparation of intermediate I
Setting experimental groups 39-42, respectively dissolving 44g of the compound III obtained in the experimental group 1 in methyl isobutyl ketone, adding hydrochloric acid with the mass concentration of 20% -38% to adjust the pH value to 1-2, then carrying out reduced pressure distillation until the volume is 30% of the original volume, then cooling to 0 ℃ to precipitate a white solid, filtering and drying to obtain white solid powder, namely the intermediate I. The differences among the experimental groups 39 to 42 and the experimental results are shown in Table 10.
TABLE 10 Effect of methyl isobutyl ketone dosage on intermediate I preparation
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A preparation method of an aprepitant intermediate is characterized by comprising the following steps: the preparation method comprises the following steps:
(1) carrying out Suzuki coupling reaction on a compound (2R) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3-bromomorpholine shown as a structural formula (II) to obtain a compound (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine shown as a structural formula (III):
(2) reacting the compound shown in the structural formula (III) with hydrochloric acid to obtain a compound (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3- (4-fluorophenyl) morpholine hydrochloride shown in the structural formula (I):
wherein the compound shown in the structural formula (I) is the aprepitant intermediate.
2. The method of claim 1, wherein: in the step (1), the compound shown in the structural formula (II), 4-fluorobenzeneboronic acid, alkali liquor and an organic solvent A are uniformly mixed, then a catalyst is added for stirring and heating reaction, after the reaction is finished, a layered liquid is obtained through cooling, solid-liquid separation and standing in sequence, an upper layer organic phase of the layered liquid is taken, washed with saturated saline solution and then concentrated, and the compound shown in the structural formula (III) is obtained.
3. The method of claim 2, wherein: the alkali liquor is a saturated sodium carbonate aqueous solution; the organic solvent A is toluene; the catalyst is at least one of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, dichlorodiammine palladium, bis (triphenylphosphine) palladium dichloride and tetrakis (triphenylphosphine) palladium.
4. The method of claim 2, wherein: the mol ratio of the compound shown in the structural formula (II) to the 4-fluorobenzeneboronic acid is 1: 1-1.5; the ratio of the volume of the alkali liquor to the mass of the compound shown in the structural formula (II) is 10-20mL:1 g; the volume ratio of the organic solvent A to the alkali liquor is 1.5-3: 1; the mass ratio of the catalyst to the compound shown in the structural formula (II) is 1: 80-120.
5. The method of claim 4, wherein: the mol ratio of the compound shown in the structural formula (II) to the 4-fluorobenzeneboronic acid is 1: 1.1-1.2; the ratio of the volume of the alkali liquor to the mass of the compound shown in the structural formula (II) is 13-15mL:1 g; the volume ratio of the organic solvent A to the alkali liquor is 1.8-2: 1; the mass ratio of the catalyst to the compound shown in the structural formula (II) is 1: 100-110.
6. The method of claim 2, wherein: the volume ratio of the organic solvent A to the saturated saline solution is 1.5-3: 1; preferably, the volume ratio of the organic solvent A to the saturated saline solution is 1.8-2: 1.
7. The method of claim 2, wherein: in the step (1), the reaction time is 5-15h, and the reaction temperature is 80-100 ℃; preferably, the reaction time is 8-12h and the reaction temperature is 95-100 ℃.
8. The method of claim 1, wherein: in the step (2), the compound shown in the structural formula (III) is dissolved in an organic solvent B, hydrochloric acid is added to adjust the pH value to 1-2, and then the compound shown in the structural formula (I) is obtained through concentration and cooling.
9. The method of claim 8, wherein: the organic solvent B is at least one of methanol, ethanol, ethyl acetate and methyl isobutyl ketone, and the mass concentration of the hydrochloric acid is 20-38%; preferably, the organic solvent B is methyl isobutyl ketone.
10. The method of claim 8, wherein: the ratio of the volume of the organic solvent B to the mass of the compound shown in the structural formula (III) is 10-20mL:1 g; preferably, the ratio of the volume of the organic solvent B to the mass of the compound represented by the structural formula (III) is 13-15mL:1 g.
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