CN109485613B - Preparation method of aprepitant and fosaprepitant side chain fragments - Google Patents
Preparation method of aprepitant and fosaprepitant side chain fragments Download PDFInfo
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- CN109485613B CN109485613B CN201811406758.XA CN201811406758A CN109485613B CN 109485613 B CN109485613 B CN 109485613B CN 201811406758 A CN201811406758 A CN 201811406758A CN 109485613 B CN109485613 B CN 109485613B
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- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical group 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 abstract description 24
- 229960001372 aprepitant Drugs 0.000 title abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 12
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical group 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 title abstract description 9
- 239000012634 fragment Substances 0.000 title abstract description 4
- KYGYCAUNXCVLQM-UHFFFAOYSA-N 2-phenylmethoxyacetohydrazide Chemical compound NNC(=O)COCC1=CC=CC=C1 KYGYCAUNXCVLQM-UHFFFAOYSA-N 0.000 claims abstract description 8
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- UPCXBOISTZRVFS-UHFFFAOYSA-N 5-(hydroxymethyl)-1,2-dihydro-1,2,4-triazol-3-one Chemical compound OCC1=NNC(=O)N1 UPCXBOISTZRVFS-UHFFFAOYSA-N 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 229910006124 SOCl2 Inorganic materials 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 206010047700 Vomiting Diseases 0.000 description 6
- 229960002891 fosaprepitant Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- ZLRBJVJEQXBAAI-UHFFFAOYSA-N 5-(chloromethyl)-1,2-dihydro-1,2,4-triazol-3-one Chemical compound ClCC1=NC(=O)NN1 ZLRBJVJEQXBAAI-UHFFFAOYSA-N 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- MDTUWBLTRPRXBX-UHFFFAOYSA-N 1,2,4-triazol-3-one Chemical group O=C1N=CN=N1 MDTUWBLTRPRXBX-UHFFFAOYSA-N 0.000 description 2
- NPEIUNVTLXEOLT-UHFFFAOYSA-N 2-chloro-1,1,1-trimethoxyethane Chemical compound COC(CCl)(OC)OC NPEIUNVTLXEOLT-UHFFFAOYSA-N 0.000 description 2
- -1 3, 5-bis (trifluoromethyl) benzyl Chemical group 0.000 description 2
- UJTTUOLQLCQZEA-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(4-hydroxybutyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCCCCO)C3=CC=CC=C3C2=C1 UJTTUOLQLCQZEA-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 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 1
- WXQSDWRPHBGYGS-LOSJGSFVSA-N (2r,3s)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethenoxy]-3-(4-fluorophenyl)morpholine Chemical compound C1=CC(F)=CC=C1[C@@H]1N(CC=2C=CC=CC=2)CCO[C@@H]1OC(=C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WXQSDWRPHBGYGS-LOSJGSFVSA-N 0.000 description 1
- JKFYKCYQEWQPTM-ZETCQYMHSA-N (2s)-2-amino-2-(4-fluorophenyl)acetic acid Chemical compound OC(=O)[C@@H](N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-ZETCQYMHSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- GSZAAEJBPFTBKG-INIZCTEOSA-N (3s)-4-benzyl-3-(4-fluorophenyl)morpholin-2-one Chemical compound C1=CC(F)=CC=C1[C@H]1C(=O)OCCN1CC1=CC=CC=C1 GSZAAEJBPFTBKG-INIZCTEOSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- QISAUDWTBBNJIR-UHFFFAOYSA-N 2-phenylmethoxyacetyl chloride Chemical compound ClC(=O)COCC1=CC=CC=C1 QISAUDWTBBNJIR-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
- 229940113081 5 Hydroxytryptamine 3 receptor antagonist Drugs 0.000 description 1
- 102100024954 5-hydroxytryptamine receptor 3A Human genes 0.000 description 1
- 101710138027 5-hydroxytryptamine receptor 3A Proteins 0.000 description 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 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
- 206010066962 Procedural nausea Diseases 0.000 description 1
- 102100024304 Protachykinin-1 Human genes 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 102100037342 Substance-K receptor Human genes 0.000 description 1
- 102100037346 Substance-P receptor Human genes 0.000 description 1
- 229910010068 TiCl2 Inorganic materials 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 230000000095 emetic effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PUADMGQHCWUWEM-UHFFFAOYSA-N n-benzylcarbamoyl chloride Chemical compound ClC(=O)NCC1=CC=CC=C1 PUADMGQHCWUWEM-UHFFFAOYSA-N 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 229940078646 other antiemetics in atc Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a novel method for preparing aprepitant and fosaprepitant side chain fragments, in particular to a method for preparing 5-chloromethyl-2, 4-dihydro [1,2,4] dihydro]A method for preparing triazole-3-ketone. The method uses 2-benzyloxy acethydrazide and benzylaminoyl formyl chloride as starting materials, and firstly adopts a one-pot method to realize 5-hydroxymethyl-2, 4-dihydro [1,2, 4-dihydro]Preparation of triazol-3-one followed by 5-hydroxymethyl-2, 4-dihydro [1,2,4] -a]Triazol-3-ones in SOCl2Under the action of the catalyst, 5-chloromethyl-2, 4-dihydro [1,2,4] is completed]Preparation of triazol-3-ones.
Description
Technical Field
The invention relates to the field of chemical synthesis, and relates to a novel method for preparing aprepitant and fosaprepitant side chain fragments, in particular to a novel method for preparing 5-chloromethyl-2, 4-dihydro [1,2,4] triazole-3-ketone.
Background
Aprepitant (Aprepitant), also known as acenidazole, is an off-white to yellowish crystal-like solid chemical. Aprepitant from Merck was approved by the FDA in 2003 as the first NK-1 receptor antagonist for the first time in the United states under the trade name EmendTM。EmendTMAs a capsule formulation for administration in combination with other antiemetics, is suitable for the prevention of acute and delayed nausea and vomiting during the initial and repeated treatments of highly emetogenic anti-tumor chemotherapy. Aprepitant is an NK-I receptor blocker, blocking the action of substance P by binding to NK-I receptors, mainly present in the central nervous system and its periphery. Aprepitant can occupy NK-I receptors in the brain through the blood brain barrier, has selectivity and high affinity, and has very low affinity to NK-2 and NK-3 receptors. The medicine can be used for treating nausea and emesis (CINV) and postoperative nausea and emesis (PONV) caused by chemotherapyThe target of action of the drug (1) is low or no affinity for 5-hydroxytryptamine receptor 3(5-HT3), dopamine receptor and glucocorticoid receptor. Aprepitant can inhibit acute-phase and delayed-phase emesis caused by cisplatin, and enhance antiemetic activity of 5-HT3 receptor antagonist ondansetron and glucocorticoid dexamethasone on emesis caused by cisplatin.
Meanwhile, researches also show that Aprepitant can be used as microemulsion for injection, and the U.S. FDA approves Aprepitant (CINVANTI) injection type emulsion to be on the market in 2017, and is also used for preventing and treating nausea and vomiting when a high-emetic chemotherapeutic drug is used for treating tumor patients.
Aprepitant is chemically named as 5- [2(R) - [1(R) - [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3(S) - (4-fluorophenyl) morpholin-4-ylmethyl ] -3, 4-dihydro-2H-1, 2, 4-triazol-3-one, and the compound contains three chiral centers and a dihydro [1,2,4] triazol-3-one structure, and has the following chemical structural formula:
and fosaprepitant is used as a Prodrug (Prodrug) of aprepitant, has the same clinical curative effect as aprepitant, and the American FDA and European EMA approve the application of fosaprepitant on the market in 1 month in 2008, and are used as auxiliary drugs of chemotherapy to prevent nausea, vomiting and the like caused by the chemotherapy. The fosaprepitant is synthesized by aprepitant through 2-step reaction, and the structure and the synthetic route of fosaprepitant are as follows:
the earliest synthesis route for aprepitant is disclosed in patent WO9516679/EP0577394/WO9702824, wherein starting materials are L-4-fluorophenylglycine and benzaldehyde, which are condensed and then reduced to give the product, which is reacted with 1, 2-dibromoethane to give (S) -3- (4-fluorophenyl) -4-benzyl-2-morpholinone, which is then reacted with 3, 5-bis (trifluoromethyl) benzyl under the action of L-SelectrideAcyl chloride reacts to obtain (2R,3S) -4-benzyl-3- (4-fluorophenyl) morpholine-2-yl-3, 5-bis (trifluoromethyl) benzoate. The ester carbonyl group in the resulting compound is in Cp2TiCl2The reaction is carried out under the action of MeLi to generate (2R,3S) -4-benzyl-2- ((1- (3, 5-bis (trifluoromethyl) phenyl) ethenyl) oxy) -3- (4-fluorophenyl) morpholine, the double bond is reduced and benzyl protection is removed through Pd/C hydrogenation, and secondary amine on the morpholine ring of the obtained intermediate is K2CO3Under the action of the reaction, the aprepitant reacts with 2- (2-chloro-1-ethylidene) hydrazide methyl formate, and the aprepitant is prepared through high-temperature cyclization at 140 ℃.
The process reported in patent WO9516679/EP0577394/WO9702824 for the formation of a 1,2, 4-triazole-3-one ring involves a two-step reaction using methyl 2- (2-chloro-1-ethylene) hydrazide formate as nitrogen source for triazole. Because the ring closing process involves 140 ℃ of high temperature, the industrial production has certain limitations, and the specific reaction is as follows:
the Merck company subsequently reports a new process for preparing aprepitant (WO 01/94324; JACS,2003,2129-2135 etc.), which is simpler, involves mild reaction conditions and has high yield. The new route is that 5-chloromethyl-2, 4-dihydro [1,2,4] triazole-3-ketone is directly reacted with morpholine intermediate, and the preparation of aprepitant can be completed without high temperature, and the synthetic route is as follows:
compared with the method using 5-chloromethyl-2, 4-dihydro [1,2,4] triazole-3-ketone, which avoids high-temperature cyclization and has industrial advantages, the patent WO99/65900 and WO2001096315 patente two preparation methods of the compound, one relates to the reaction of semicarbazide hydrochloride and benzyloxy acetyl chloride under the improved Schotten-Baumann condition to generate addition products, then 5-benzyloxymethyl-2, 4-dihydro [1,2,4] triazole-3-ketone is generated under the action of alkali, the latter generates 5-hydroxymethyl-2, 4-dihydro [1,2,4] triazole-3-ketone after removing benzyl protection, finally converts hydroxymethyl into chloromethyl to complete 5-chloromethyl-2, 4-dihydro [1, preparing 2,4] triazole-3-ketone; in the other route, semicarbazide hydrochloride and 2-chloro-1, 1, 1-trimethoxy ethane directly react to obtain 5-chloromethyl-2, 4-dihydro [1,2,4] triazole-3-ketone. One of the two routes involves multi-step reaction, and the total yield is low; the 2-chloro-1, 1, 1-trimethoxyethane used in the other route is expensive and not easy to be purchased commercially, and the reaction time is as long as 3 days. Therefore, the development of a novel method for preparing 5-chloromethyl-2, 4-dihydro [1,2,4] triazol-3-one is very important for the industrial production of aprepitant and fosaprepitant. The two synthetic routes reported in patent WO2001096315 for the preparation of 5-chloromethyl-2, 4-dihydro [1,2,4] triazol-3-one are as follows:
disclosure of Invention
The technical problem to be solved by the invention is to provide a novel synthetic method for preparing 5-chloromethyl-2, 4-dihydro [1,2,4] triazole-3-ketone.
The method uses 2-benzyloxy acetyl hydrazine (formula I) and benzylamino formyl chloride (formula II) as starting materials, and has the following specific reaction formula:
the first step uses 2-benzyloxyacethydrazide (formula I) and benzylaminoyl chloride (formula II) as starting materials in a base/solvent and Pd/C/H2The 5-hydroxymethyl-2, 4-dihydro [1,2,4] is realized by one-pot reaction under the condition]Preparation of triazol-3-ones (formula III).
The alkali used in the first step reaction comprises NaOH, KOH and LiOH;
the solvent used in the first reaction step is THF/H2O/MeOH or THF/H2O/EtOH；
The reaction temperature of the first step is 50-100 ℃, and the reaction time is 5-24 hours;
the second reaction step involves 5-hydroxymethyl-2, 4-dihydro [1,2,4]]Triazol-3-ones in SOCl2Reacting under the action of the catalyst to complete the reaction of 5-chloromethyl-2, 4-dihydro [1,2,4]]Preparing triazole-3-ketone;
the solvent for the second reaction step comprises CH3CN, Dioxane, THF,2-MeTHF, etc.
The route adopts a one-pot method to realize the preparation of the 5-hydroxymethyl-2, 4-dihydro [1,2,4] triazole-3-ketone, avoids the defects of high production cost, low yield and the like caused by multi-step reaction, is easy to realize industrial production, and has certain advantages compared with the existing route.
Detailed Description
The present invention will be more specifically understood from the following examples, which are given by way of illustration and are not intended to limit the scope of the present invention.
Examples
1. Preparation of 5-hydroxymethyl-2, 4-dihydro [1,2,4] triazol-3-one
Sequentially adding H into a 10L high-pressure reaction kettle2O (2L) and THF (1L), the system was cooled to 5 ℃ and then 2-benzyloxyacethydrazide (500g,2.77mol) and benzylaminoyl chloride (495g,2.92mmol) were added to the system in this order, and after the addition, the system was naturally warmed to 25 ℃ and stirred for 2 hours, followed by addition of NaOH (222g,5.55mol) in powder form, methanol (2L) and Pd/C (10%, 60g) in this order to the reaction system under nitrogen protection. Then after nitrogen replacement of the system, in H2(5atm) and 50 ℃ for 12 hours, cooling the system to room temperature naturally, and filtering to remove insoluble substances. The solvent is removed under reduced pressure and H is added to the residue2O (2L) and CH2Cl2(1L), stirring for 0.5 h, standing, separating out organic phase, and using CH as aqueous phase2Cl2(2X 300 mL). Combining organic phases, removing the solvent in the organic phase under reduced pressure, and recrystallizing the residue with acetonitrile to obtain 5-hydroxymethyl-2, 4-dihydro [1,2,4]Triazol-3-one (solid, 239.1g, 75% yield based on 2-benzyloxyacethydrazide)。
2. Preparation of 5-hydroxymethyl-2, 4-dihydro [1,2,4] triazol-3-one
H was sequentially added to a 1L small autoclave2O (150mL) and THF (100mL), cooling the system to 0-5 ℃, then adding 2-benzyloxy acethydrazide (50g,0.28mol) and benzylaminoyl chloride (50g,0.29mmol) to the system in sequence, after the addition, naturally raising the temperature of the system to 25 ℃ and stirring for 2 hours, and adding powdered KOH (31.5g,0.56mol), ethanol (200mL) and Pd/C (10%, 6g) to the reaction system in sequence under the protection of nitrogen. Then after nitrogen replacement of the system, in H2(2atm) and 80 ℃ for 24 hours, naturally cooling the system to room temperature, and filtering to remove insoluble substances. The solvent is removed under reduced pressure and H is added to the residue2O (200mL) and CH2Cl2(150mL), stirred for 0.5 hour, left to stand, the organic phase was separated, and the aqueous phase used CH2Cl2(2X 50 mL). The organic phases are combined, the solvent is removed from the organic phase under reduced pressure, and the residue is freed from CH2Cl2Performing MeOH column chromatography to obtain 5-hydroxymethyl-2, 4-dihydro [1,2,4]]Triazol-3-one (solid, 27.6g, 85.6% yield based on 2-benzyloxyacethydrazide).
3. Preparation of 5-chloromethyl-2, 4-dihydro [1,2,4] triazol-3-one
5-hydroxymethyl-2, 4-dihydro [1,2,4] is added into a 5L four-mouth bottle]Triazole-3-one (100g,869mmol) and anhydrous acetonitrile (1L), cooling the system to 5 ℃, and slowly adding SOCl into the system while stirring2(150g,1261 mmol). After the addition is finished, the system slowly and naturally rises to room temperature for reaction, a TLC point plate tracks until the reaction is complete, and then the system removes the solvent (including the unreacted SOCl) under the condition of high vacuum and reduced pressure2). To the residue was added EtOAc (1L) and H2O (500mL), the system was stirred for 0.5 h and then allowed to stand, the organic phase was separated and the aqueous phase was extracted with EtOAc (2X 30 mL). Mixing organic phases, washing the organic phase with saturated brine (2X 500mL), removing solvent from the organic phase under reduced pressure, adding n-heptane (1L) into the residue, stirring vigorously for 2 hr, filtering, and air drying the solid at 50 deg.C to obtain 5-chloromethyl-2, 4-dihydro [1,2,4] -methyl]Triazol-3-one (solid, 105.2g, yield 90.7%).
Claims (1)
1. A synthetic method for preparing 5-hydroxymethyl-2, 4-dihydro [1,2,4] triazol-3-one comprises the following synthetic route:
h was sequentially added to a 1L small autoclave2Cooling the system to 0-5 ℃ by O150 mL and THF 100mL, then sequentially adding 50g of 2-benzyloxy acethydrazide and 50g of benzylaminoyl formyl chloride into the system, naturally heating the system to 25 ℃ after the addition, stirring for 2 hours, sequentially adding 31.5g of powdered KOH, 200mL of ethanol and 6g of 10% Pd/C into the reaction system under the protection of nitrogen, then replacing the system by nitrogen, and then carrying out H reaction2Hydrogenating at 2atm and 80 deg.C for 24 hr, cooling the system to room temperature, filtering to remove insoluble substances, removing solvent under reduced pressure, and adding H into the residue2O200 mL and CH2Cl2150mL, stirring for 0.5 hour, standing, separating out the organic phase, and using CH as the aqueous phase2Cl22X 50mL extraction, combining the organic phases, removing the solvent from the organic phases under reduced pressure, and using CH as the residue2Cl2Performing MeOH column chromatography to obtain 5-hydroxymethyl-2, 4-dihydro [1,2,4]]Triazol-3-ones.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131864C (en) * | 1998-06-16 | 2003-12-24 | 默克·夏普-道姆公司 | Chemical synthesis of morpholine derivatives |
| WO2017106062A1 (en) * | 2015-12-15 | 2017-06-22 | Merck Sharp & Dohme Corp. | Novel compounds as indoleamine 2,3-dioxygenase inhibitors |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1131864C (en) * | 1998-06-16 | 2003-12-24 | 默克·夏普-道姆公司 | Chemical synthesis of morpholine derivatives |
| WO2017106062A1 (en) * | 2015-12-15 | 2017-06-22 | Merck Sharp & Dohme Corp. | Novel compounds as indoleamine 2,3-dioxygenase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| "A new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an NK1 antagonist";Cameron J Cowden et al.;《Tetrahedron Letters》;20001231;第41卷;第8661-8664页 * |
| "Nonsymmetrical Azocarbonamide Carboxylates as Effective Mitsunobu Reagents";Daniel P. Furkert et al.;《European Journal of Organic Chemistry》;20141029;第2014卷;第7806-7809页及Supporting Information第1-23页 * |
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