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【结 构 式】 
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【分子编号】35151 【品名】triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride 【CA登记号】73870-25-4 |
【 分 子 式 】C24H21ClNP 【 分 子 量 】389.863942 【元素组成】C 73.94% H 5.43% Cl 9.09% N 3.59% P 7.94% |
合成路线1
该中间体在本合成路线中的序号：(XI)6-Aminopenicillanic acid benzhydryl ester (I) was protected as the carbamate (II) using allyl chloroformate. Subsequent oxidation of (II) with m-chloroperbenzoic acid provided sulfoxide (III). Opening of the thiazolidine ring of (III) by means of 2-mercaptobenzothiazole (IV) produced disulfide (V), which was further cyclized in the presence of arylacetic acid (VI) and silver acetate to furnish a 4:1 mixture of penicillanic ester (VII) and the cephalosporanic analogue (VIII). Deprotection of the required isomer (VII) employing Pd(PPh3)4 and Bu3SnH afforded amine (IX). Diazotization of (IX) with isopropyl nitrite, followed by treatment with propylene oxide and Rh2(OAc)4 gave rise to oxolactam (X). Wittig reaction of (X) with the ylide resulting from phosphonium salt (XI) and NaNH2 provided the (pyridylmethylene) derivative (XII). Finally, oxidation to the corresponding sulfone and cleavage of the protecting groups provided the title compound.
| 【1】 Buynak, J.D.; et al.; New beta-lactamase inhibitors of the class A and class C enzymes. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 194. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 | |
| (I) | 35142 | benzhydryl (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H22N2O3S | 详情 | 详情 | |
| (II) | 35143 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O5S | 详情 | 详情 | |
| (III) | 35144 | benzhydryl (2S,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C25H26N2O6S | 详情 | 详情 | |
| (IV) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (V) | 35145 | benzhydryl (2R)-2-[(2R,3R)-3-[[(allyloxy)carbonyl]amino]-2-(1,3-benzothiazol-2-yldisulfanyl)-4-oxoazetidinyl]-3-methyl-3-butenoate | C32H29N3O5S3 | 详情 | 详情 | |
| (VI) | 35146 | 2-[3,4-di(tert-butoxy)phenyl]acetic acid | C16H24O4 | 详情 | 详情 | |
| (VII) | 35147 | benzhydryl (2S,3R,5R,6R)-6-[[(allyloxy)carbonyl]amino]-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (VIII) | 35148 | benzhydryl (2R,3S,7R)-7-[[(allyloxy)carbonyl]amino]-3-([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | C41H48N2O9S | 详情 | 详情 | |
| (IX) | 35149 | benzhydryl (2S,3R,5R,6R)-6-amino-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H44N2O7S | 详情 | 详情 | |
| (X) | 35150 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-6,7-dioxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C37H41NO8S | 详情 | 详情 | |
| (XI) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (XII) | 35152 | benzhydryl (2S,3R,5R)-3-[([2-[3,4-di(tert-butoxy)phenyl]acetyl]oxy)methyl]-3-methyl-7-oxo-6-[(Z)-2-pyridinylmethylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C43H46N2O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)7-Aminocephalosporanic acid (I) was esterified with diphenyldiazomethane to produce the benzhydryl ester (II). Diazotization of (II) with isopropyl nitrite in the presence of trifluoroacetic acid, followed by treatment of the resulting diazo compound with propylene oxide and a catalytic amount of rhodium (II) octanoate, gave the corresponding 7-oxocephalosporanate (III). Wittig reaction of ketone (III) with the ylide resulting from 2-picolyltriphenylphosphonium chloride (IV) and NaNH2 in cold THF yielded olefin (V). Cephem double-bond isomerization upon treatment with triethylamine produced the 2-cephem derivative (VI) as the major compound, which was separated from the unreacted 3-cephem by flash chromatography. Acid hydrolysis of acetate ester (VI) gave rise to the corresponding alcohol (VII), which was further oxidized to aldehyde (VIII) by using pyridinium dichromate. Condensation of aldehyde (VIII) with the Wittig reagent (III) produced adduct (IX).
| 【1】 Adam, G.; Doppalapudi, V.R.; Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; New cephalosporin-derived beta-lactamase inhibitors. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F403. |
| 【2】 Nidamarthy, S.D.; Buynak, J.D.; Rao, A.S.; Doppalapudi, V.R.; Adam, G.C. (Research Corporation Technologies, Inc.); beta-Lactamase inhibiting cpds.. WO 0063213 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (II) | 39849 | benzhydryl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H22N2O5S | 详情 | 详情 | |
| (III) | 47065 | benzhydryl (6R)-3-[(acetoxy)methyl]-7,8-dioxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H19NO6S | 详情 | 详情 | |
| (IV) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (V) | 47066 | benzhydryl (6R)-3-[(acetoxy)methyl]-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C29H24N2O5S | 详情 | 详情 | |
| (VI) | 47067 | benzhydryl (2R,6R)-3-[(acetoxy)methyl]-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C29H24N2O5S | 详情 | 详情 | |
| (VII) | 47068 | benzhydryl (2R,6R)-3-(hydroxymethyl)-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C27H22N2O4S | 详情 | 详情 | |
| (VIII) | 47069 | benzhydryl (2R,6R)-3-formyl-8-oxo-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C27H20N2O4S | 详情 | 详情 | |
| (IX) | 47070 | benzhydryl (2R,6R)-8-oxo-3-[(E)-2-(2-pyridinyl)ethenyl]-7-[(Z)-2-pyridinylmethylidene]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate | C33H25N3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Iodination of 6-nitroindazole (I) utilizing iodine in the presence of NaOH provides 3-iodo-6-nitroindazole (II). Subsequent protection of indazole (II) with 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) under phase-transfer conditions, followed by Suzuki coupling of the SEM-protected compound (III) with styrylboronic acid, gives the styryl indazole (IV). The nitro group of (IV) is reduced by means of SnCl2 to produce amine (V), which is then converted to the iodoindazole analogue (VI) by diazotization followed by reaction with I2 and KI. Ozonization of the styryl moiety of (VI) and further reductive work-up leads to the aldehyde (VII), which is subjected to Wittig reaction with 2-picolyl triphenylphosphonium chloride (VIII) to produce the pyridylvinylindazole (IX). Displacement of the iodoindazole (IX) with methyl 2-mercaptobenzoate (X) in the presence of Cs2CO3 and palladium catalyst gives the thioether (XI). After alkaline hydrolysis of the methyl ester (XI), the resulting carboxylic acid (XII) is coupled with methylamine in the presence of HATU to furnish the N-methyl amide (XIII). Axitinib is then obtained by removal of the SEM protecting group of (XIII) by means of tetrabutylammonium fluoride and ethylenediamine (1). Scheme 1.
| 【1】 Kania, R.S., Wallace, M.B., Borchardt, A.J. et al. (Agouron Pharmaceuticals, Inc.). Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use. EP 1614683, JP 2003503481, JP 2006348043, WO 0102369. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 65335 | 6-Nitroindazole | 7597-18-4 | C7H5N3O2 | 详情 | 详情 |
| (II) | 65336 | 3-Iodo-6-nitroindazole; 3-Iodo-6-nitro-1H-indazole | 70315-70-7 | C7H4IN3O2 | 详情 | 详情 |
| (III) | 65337 | 3-Iodo-6-nitro-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C13H18IN3O3Si | 详情 | 详情 | |
| (IV) | 65338 | 6-Nitro-3-styryl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H25N3O3Si | 详情 | 详情 | |
| (V) | 65339 | 6-Amino-3-styryl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H27N3OSi | 详情 | 详情 | |
| (VI) | 65340 | 6-Iodo-3-styryl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H25IN2OSi | 详情 | 详情 | |
| (VII) | 65341 | 3-formyl-6-iodo-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C14H19IN2O2Si | 详情 | 详情 | |
| (VIII) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
| (IX) | 65342 | 6-Iodo-3-(pyrid-2-ylvinyl)-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H24IN3OSi | 详情 | 详情 | |
| (X) | 65343 | Methyl 2-mercaptobenzoate; Methyl thiosalicylate | 4892-02-8 | C8H8O2S | 详情 | 详情 |
| (XI) | 65344 | C29H31N3O3SSi | 详情 | 详情 | ||
| (XII) | 65345 | C28H29N3O3SSi | 详情 | 详情 | ||
| (XIII) | 65346 | C29H32N4O2SSi | 详情 | 详情 |