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【结 构 式】

【分子编号】10045

【品名】Diethyl cyanomethylphosphonate

【CA登记号】2537-48-6

【 分 子 式 】C6H12NO3P

【 分 子 量 】177.139982

【元素组成】C 40.68% H 6.83% N 7.91% O 27.1% P 17.49%
与该中间体有关的原料药合成路线共 15 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(II)

A new synthesis for LY-134046 has been described: The reaction of 6,7-dichloro-3-hydroxyphthalide (I) with diethyl cyanomethylphosphonate (II) by means of NaH in dimethoxyethane gives 2-carboxy-3,4-dichlorocinnamonitrile (III), which is reduced with NaBH4 in refluxing isopropanol to yield 3-(2-carboxy-3,4-dichlorophenyl)propionitrile (IV). The esterification of (IV) with methyl iodide and K2CO3 affords the cyano ester (V), which is reduced with BH3 in THF giving 6-(3-aminopropyl)-2,3-dichlorobenzoic acid methyl ester (VI). The cyclization of (VI) by means of sodium methoxide in methanol yields 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (VII), which is finally reduced with BH3 in refluxing THF.

参考文献 中间体
合成目标
【1】 Paradkar, V.M.; Grunewald, G.L.; A regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046), a potent phenylethanolamine N-methyltransferase inhibitor. Bioorg Med Chem Lett 1991, 1, 1, 59-60.
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) 10044 6,7-Dichloro-3-hydroxy-2-benzofuran-1(3H)-one C8H4Cl2O3 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 10046 2,3-Dichloro-6-[(E)-2-cyanoethenyl]benzoic acid C10H5Cl2NO2 详情 详情
(IV) 10047 2,3-Dichloro-6-(2-cyanoethyl)benzoic acid C10H7Cl2NO2 详情 详情
(V) 10048 methyl 2,3-dichloro-6-(2-cyanoethyl)benzoate C11H9Cl2NO2 详情 详情
(VI) 10049 methyl 6-(3-aminopropyl)-2,3-dichlorobenzoate C11H13Cl2NO2 详情 详情
(VII) 10050 8,9-Dichloro-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one C10H9Cl2NO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

This compound can be obtained by two related ways: 1) The Wittig condensation of 2-benzoylpyridine (I) with diethyl cyanomethylphosphonate (II) by means of sodium ethoxide in hot ethanol gives 3-phenyl-3-(2-pyridyl)acrylonitrite (III), which is reduced with NaBH4 in refluxing ethanol to yield 3-phenyl-3-(2-pyridyl)propionitrite (IV). Finally, this compound is cyclized with ethylenediamine (V) at reflux temperature. 2) The cyctization of 3-phenyl-3-(2-pyridyl)acrylonitrite (III) with ethylenediamine (V) at reflux temperature gives 2-[2-phenyl-2-(2-pyridyl)viny]-2-imidazoline (VI), which is then reduced with H2 over Pd/C in ethanol.

参考文献 中间体
合成目标
【1】 Ishikawa, F.; Cyclic guanidines. X. Synthesis of 2-(2,2-disubstituted ethenyl- and ethyl)-2-imidazolines as potent hypoglycemics. Chem Pharm Bull 1980, 28, 5, 1394-1402.
【2】 Castaner, J.; Hillier, K.; Blancafort, P.; Serradell, M.N.; DG-5128. Drugs Fut 1982, 7, 8, 550.
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) 32233 2-Benzoylpyridine; Phenyl(2-pyridinyl)methanone 91-02-1 C12H9NO 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 37098 (E)-3-phenyl-3-(2-pyridinyl)-2-propenenitrile C14H10N2 详情 详情
(IV) 37100 3-phenyl-3-(2-pyridinyl)propanenitrile C14H12N2 详情 详情
(V) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(VI) 37099 2-[(E)-2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethenyl]pyridine C16H15N3 详情 详情

合成路线3

该中间体在本合成路线中的序号：

A systematic chiral synthesis of NK-104 and its enantiomer (X) has been reported: The oxidation of the already known 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-methanol (I) with DMSO, P2O5 and triethylamine gives the corresponding aldehyde (II), which is condensed with diethyl cyanomethylphosphonate by means of NaOH in toluene yielding the propenenitrile (III). The reduction of (III) with DIBAL affords the unsaturated aldehyde (IV), which is condensed with ethyl acetoacetate by means of NaH and n-BuLi to provide the 3-oxo-5-hydroxy-6-heptenoic acid ethyl ester derivative (V). The highly syn stereoselective reduction of (V) by means of diethylmethoxyborane and NaBH4 yields the desired syn racemic mixture of erythro-beta,delta-dihydroxyesters (VII), which is submitted to optical resolution with chiral (+)-alpha-methylbenzylamine [(+)-MBA] to obtain NK-104 free acid (VIII), which is finally treated with NaOH and CaCl2. The enantiomer of NK-104 has been obtained by optical resolution of the racemic mixture (VII) with (-)-alpha-methylbenzylamine to obtain the enantiomeric free acid (IX), which is treated with NaOH and CaCl2 as before.

参考文献 中间体
合成目标
【1】 Yanagihara, K.; Iwasaki, H.; Yanagawa, Y.; Yazaki, Y.; Suzuki, M.; Kanda, H.; Matsumoto, H.; Ohara, Y.; Sakoda, R.; First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104. Bioorg Med Chem Lett 1999, 9, 20, 2977.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(IX),(X) 39670 (3S,5R,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid C25H24FNO4 详情 详情
(I) 17472 [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol C19H16FNO 详情 详情
(II) 17425 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde 121660-37-5 C19H14FNO 详情 详情
(III) 39665 (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenenitrile C21H15FN2 详情 详情
(IV) 39666 (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal C21H16FNO 详情 详情
(V) 39667 ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-3-oxo-6-heptenoate C27H26FNO4 详情 详情
(VI) 39668 ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate C27H28FNO4 详情 详情
(VII) 39669 (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid C25H24FNO4 详情 详情
(VIII) 39671 (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoic acid C25H24FNO4 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XII)

A synthesis of pitavastatin has been reported: Cyclization of 2-amino-4'-fluorobenzophenone (I) with 3-cyclopropyl-3-oxopropionic acid methyl ester (II) by means of H2SO4 in refluxing acetic acid or methanesulfonic acid in refluxing benzene gives 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid methyl ester (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). Oxidation of compound (IV) with PCC and AcONa in dichloromethane affords carbaldehyde (V), which is condensed with tributylstannane (VI) by means of BuLi in THF to provide the enol ether (VII). Hydrolysis of (VII) by means of TsOH in THF/water gives the unsaturated carbaldehyde (VIII), which is condensed with acetoacetic ester (IX) by means of NaH and BuLi in THF to yield the 5-hydroxy-3-oxoheptenoic ester derivative (X). Stereoselective reduction of the oxo group of (X) by means of diethylmethoxyborane and NaBH4 in THF/methanol gives the racemic syn-dihydroxy compound (XI) in a syn/anti ratio of 98:2. Finally, compound (XI) is hydrolyzed with NaOH in aqueous ethanol to yield racemic pitavastatin sodium. Alternatively, the unsaturated carbaldehyde (VIII) can also be obtained by reaction of carbaldehyde (V) with phosphonate (XII) by means of NaOH in toluene/water to give the unsaturated nitrile (XIII), which is finally reduced with DIBAL in toluene to afford the target carbaldehyde (VIII).

参考文献 中间体
合成目标
【1】 Fujikawa, Y.; Suzuki, M.; Iwasaki, H.; Kitahara, M.; Sakashita, M.; Sakoda, R.; Synthesis and biological evaluations of quinolone-based HMG-CoA reductase inhibitors. Bioorg Med Chem 2001, 9, 10, 2727.
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) 17467 (2-aminophenyl)(4-fluorophenyl)methanone C13H10FNO 详情 详情
(II) 51482 Methyl 3-cyclopropyl-3-oxopropanoate 32249-35-7 C7H10O3 详情 详情
(III) 51483 methyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate C20H16FNO2 详情 详情
(IV) 17472 [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol C19H16FNO 详情 详情
(V) 17425 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde 121660-37-5 C19H14FNO 详情 详情
(VI) 51484 ethyl (E)-2-(tributylstannyl)ethenyl ether; tributyl[(E)-2-ethoxyethenyl]stannane C16H34OSn 详情 详情
(VII) 51485 (E)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-ethoxy-2-propen-1-ol C23H22FNO2 详情 详情
(VIII) 39666 (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenal C21H16FNO 详情 详情
(IX) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(X) 39667 ethyl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-3-oxo-6-heptenoate C27H26FNO4 详情 详情
(XI) 51486 ethyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate C27H28FNO4 详情 详情
(XII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIII) 39665 (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-propenenitrile C21H15FN2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.

参考文献 中间体
合成目标
【1】 Graul, A.; Prous, J.; Castañer, J.; Sabcomeline Hydrochloride. Drugs Fut 1998, 23, 1, 41.
【2】 Clark, M.S.G.; Bromidge, S.M.; Oriek,B.S.; Cassidy, F.; Eggleston, D.S.; Synthesis and properties of [R-(Z)]-(+)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)-alpha-(methoxyimino) acetonitrile, a novel functionally selective muscarinic partial agonist. J Chem Soc Chem Commun 1994, 18, 18, 2189-90.
【3】 Cassidy, F.; Bromidge, S.M.; Clark, M.S.G.; Brown, F.; Riley, G.J.; Dabbs, S.; Loudon, J.M.; Hawkins, J.; Orlek, B.S.; A novel and selective class of azabicyclic muscarinic agonists incorporating an N-methoxy imidoyl halide or nitrile functionality. Bioorg Med Chem Lett 1992, 2, 8, 791-6.
【4】 Orlek, B.S.; Bromidge, S.M.; Dabbs, S. (SmithKline Beecham plc); Novel cpds. AU 9053159; EP 0392803; JP 1991007285; JP 1997188678; JP 1997188679; US 5278170 .
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) 16921 N-methoxy-3-quinuclidinecarboxamide C9H16N2O2 详情 详情
(II) 16922 N-methoxy-3-quinuclidinecarboximidoyl chloride C9H15ClN2O 详情 详情
(III) 16923 N-methoxy-3-quinuclidinecarboximidoyl cyanide C10H15N3O 详情 详情
(IV) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(V) 16925 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one 1193-65-3 C7H11NO 详情 详情
(VI) 16926 2-(1-azabicyclo[2.2.2]oct-3-ylidene)acetonitrile C9H12N2 详情 详情
(VII) 16927 2-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile C9H14N2 详情 详情
(VIII) 16928 N-hydroxy-3-quinuclidinecarboximidoyl cyanide C9H13N3O 详情 详情
(IX) 12591 Cyanoacetic Acid; 2-Cyanoacetic acid 372-09-8 C3H3NO2 详情 详情
(X) 16930 2-(1-azabicyclo[2.2.2]oct-3-ylidene)-2-cyanoacetic acid C10H12N2O2 详情 详情
(XI) 16931 2-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyanoacetic acid C10H14N2O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(III)

Addition of methyllithium to 3,5-di-tert-butylbenzoic acid (I) at -78 C gave acetophenone (II). The Horner-Emmons condensation of acetophenone (II) with diethyl (cyanomethyl)phosphonate (III) resulted in a mixture of isomeric alpha,beta-unsaturated nitriles (IV). After isolation of the major E-isomer by preparative TLC, cyano group reduction employing DIBAL in CH2Cl2 at -78 C provided aldehyde (V). This was subjected to a new Horner-Emmons condensation with phosphonate (VI) to provide the octatrienoate ester (VII). The target carboxylic acid was then prepared by saponification of ester (VII) with methanolic KOH.

参考文献 中间体
合成目标
【1】 Zhang, L.; et al.; Discovery of novel retinoic acid receptor agonists having potent antiproliferative activity in cervical cancer cells. J Med Chem 1996, 39, 14, 2659.
【2】 Boehm, M.F.; Zhang, L.; Bennani, Y.L.; Nadzan, A.M. (Ligand Pharmaceuticals, Inc.); Novel trienoic retinoid cpds. and methods. JP 1998511948; US 5721103; US 6083977; WO 9620913 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IVa) 56192 (E)-3-[3,5-di(tert-butyl)phenyl]-2-butenenitrile C18H25N 详情 详情
(IVb) 56193 (Z)-3-[3,5-di(tert-butyl)phenyl]-2-butenenitrile C18H25N 详情 详情
(I) 56190 3,5-Di-tert-butylbenzoic acid 16225-26-6 C15H22O2 详情 详情
(II) 56191 1-[3,5-di(tert-butyl)phenyl]-1-ethanone C16H24O 详情 详情
(III) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(V) 56194 (E)-3-[3,5-di(tert-butyl)phenyl]-2-butenal C18H26O 详情 详情
(VI) 44704 ethyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate 41891-54-7 C11H21O5P 详情 详情
(VII) 56195 ethyl (2E,4E,6E)-7-[3,5-di(tert-butyl)phenyl]-3-methyl-2,4,6-octatrienoate C25H36O2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

This compound has been obtained by two related ways: 1) The condensation of 3,3'-difluorobenzophenone (I) with diethyl cyanomethylphosphonate (II) by means of NaH in dimethoxyethane gives 3,3-bis(3-fluorophenyl)-2-propenenitrile (III), which is reduced with H2 over Pd(OH)2 in ethanol yielding 3,3-bis(3-fluorophenyl)propionitrile (IV). Finally, this compound is reduced with B2H6 in THF. 2) The condensation of 3,3'-difluorobenzophenone (I) with acetonitrile (V) by means of BuLi in THF gives 3,3-bis(3-fluorophenyl)-3-hydroxypropionitrile (VI), which is reduced with H2 over Ni/Al in ethanol yielding 3,3-bis(3-fluorophenyl)-3-hydroxypropylamine (VII). The dehydration of (VII) by means of HCl in refluxing ethanol affords 3,3-bis(3-fluorophenyl)-2-propenamine (VIII), which is finally reduced with H2 over Pd/C in ethanol.

参考文献 中间体
合成目标
【1】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 .
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) 35077 bis(3-fluorophenyl)methanone 345-70-0 C13H8F2O 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 35078 3,3-bis(3-fluorophenyl)acrylonitrile C15H9F2N 详情 详情
(IV) 35079 3,3-bis(3-fluorophenyl)propanenitrile C15H11F2N 详情 详情
(V) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(VI) 37211 3,3-bis(3-fluorophenyl)-3-hydroxypropanenitrile C15H11F2NO 详情 详情
(VII) 37212 3-amino-1,1-bis(3-fluorophenyl)-1-propanol C15H15F2NO 详情 详情
(VIII) 37213 3,3-bis(3-fluorophenyl)-2-propen-1-amine; 3,3-bis(3-fluorophenyl)-2-propenylamine C15H13F2N 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XIII)

The reaction of 2,3-dihydrobenzofuran (I) with dichloromethyl methyl ether (II) by means of TiCl4 in dichloromethane gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of NaH in THF to yield the propenoic ester (V). The reduction of (V) with H2 over Pd/C in ethanol affords the saturated propionic ester (VI), which is brominated with Br2 in HOAc providing the 7-bromo derivative (VII). Further bromination of (VII) with Br2 and Fe in HOAc gives the 6,7-dibromo derivative (VIII), which is hydrolyzed with NaOH in THF/water to yield the propionic acid derivative (IX). The reaction of (IX) with hot SOCl2 affords the corresponding acyl chloride (X), which is cyclized by means of AlCl3 in dichloroethane to provide 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The debromination of (XI) by means of H2 over Pd/C in Ac-OH gives 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XII), which is condensed with the phosphorane (XIII) by means of NaH in THF to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV). The selective reduction of the cyano group of (XIV) by means of H2 over Raney cobalt in ethanol/NH3 affords 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XV), which is condensed with propionyl chloride (XVI) by means of TEA in THF to provide the propionamide (XVII). Finally this compound is enantioselectively reduced with H2 over a chiral Ru catalyst (Ru(OAc)2-(S)-BINAP) in methanol to give rise to the target (S)-enantiomer. Alternatively, the reduction of 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV) with H2 over RaNi in ethanol/NH3 gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethylamine (XVIII), which is acylated with propionyl chloride (XVI) and TEA in DMF to yield the racemic propionamide (XIX). Finally this compound is submitted to optical resolution by means of chiral HPLC to afford the target (S)-enantiomer.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Ohkawa, S.; Uchikawa, O.; Fukatsu, K.; Miyamoto, M. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0885210; JP 1998287665; JP 1999152281; WO 9732871 .
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) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 40668 dichloro(methoxy)methane; dichloromethyl methyl ether 4885-02-3 C2H4Cl2O 详情 详情
(III) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 57393 ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate C13H14O3 详情 详情
(VI) 57394 ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate C13H16O3 详情 详情
(VII) 57395 ethyl 3-(7-bromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H15BrO3 详情 详情
(VIII) 57396 ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H14Br2O3 详情 详情
(IX) 57397 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid C11H10Br2O3 详情 详情
(X) 57398 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride C11H9Br2ClO2 详情 详情
(XI) 57399 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H8Br2O2 详情 详情
(XII) 57400 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H10O2 详情 详情
(XIII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIV) 57401 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile C13H11NO 详情 详情
(XV) 57402 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine C13H15NO 详情 详情
(XVI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XVII) 57403 N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethyl]propanamide C16H19NO2 详情 详情
(XVIII) 57404 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-1-ethanamine; 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine C13H17NO 详情 详情
(XIX) 57405 N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propanamide C16H21NO2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XII)

The reaction of 2,3-dihydrobenzofuran (I) with DMF (II) and POCl3 gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of t-BuONa in toluene to yield the acrylate (V). The reduction of (V) with H2 over Pd/C in AcOH affords the corresponding propionate (VI), which is brominated with Br2 in AcOH to provide the dibromo derivative (VII). The hydrolysis of the ester group of (VII) in acidic medium gives the expected propionic acid derivative (VIII), which is treated with SOCl2 in dichloromethane to yield the propionyl chloride (IX). The cyclization of (IX) by means of AlCl3 in dichloromethane affords the 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (X), which is submitted to an hydrogenolytic debromination with H2 over Pd/C in methanol to provide the 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The Wittig condensation of (XI) with phosphonate (XII) by means of NaOMe in toluene gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIII), which is reduced with H2 and Raney-Co in toluene/MeOH to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XIV). The asymmetric reduction of (XIV) with H2 and a chiral Ru catalyst in toluene/MeOH affords the 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8(S)-yl)ethylamine (XV), which is finally acylated with propionyl chloride (XVI) and NaOH in aq. THF to provide the target chiral propionamide.

参考文献 中间体
合成目标
【1】 Ohkawa, S.; Discovery of the novel melatonin agonist TAK-375. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst IL 11.
【2】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
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) 14499 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran 496-16-2 C8H8O 详情 详情
(II) 45439 dimethylformamide C3H7NO 详情 详情
(III) 52198 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde C9H8O2 详情 详情
(IV) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(V) 57393 ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate C13H14O3 详情 详情
(VI) 57394 ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate C13H16O3 详情 详情
(VII) 57396 ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate C13H14Br2O3 详情 详情
(VIII) 57397 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid C11H10Br2O3 详情 详情
(IX) 57398 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride C11H9Br2ClO2 详情 详情
(X) 57399 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H8Br2O2 详情 详情
(XI) 57400 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one C11H10O2 详情 详情
(XII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XIII) 57401 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile C13H11NO 详情 详情
(XIV) 57402 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine C13H15NO 详情 详情
(XV) 62217 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]-1-ethanamine; 2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethylamine C13H17NO 详情 详情
(XVI) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(II)

The condensation of 6-methoxyindan-1-one (I) with phosphonate (II) by means of NaH in THF gives 2-(6-methoxyindan-1-ylidene)acetonitrile (III), which is hydrogenated with h2 over Raney Co in ethanol/NH3 to yield 2-(6-methoxyindan-1-ylidene)ethylamine (IV). The acylation of (IV) with propionyl chloride (V) and TEA in THF affords the corresponding amide (VI), which is submitted to an asymmetric reduction with H2 and a chiral Ru catalyst to provide N-[2-(6-methoxyindan-1(S)-yl)ethyl]propionamide (VII). The bromination of (VII) with Br2 and NaOAc in methanol gives the 5-bromo derivative (VIII), which is demethylated by means of BBr3 in dichloromethane to yield the hydroxy compound (IX). The reaction of (IX) with allyl bromide (X) by means of NaH in DMF affords the allyl ether (XI), which is submitted to a Claisen rearrangement in N,N-diethylaniline at 200 C to provide the 7-allyl derivative (XII).The reaction of (XII) with ozone in methanol gives the acetaldehyde derivative (XIII), which is reduced with NaBH4 in methanol to yield the ethanol derivative (XIV). The hydrogenolysis of the Br substituent of (XIV) by means of H2 over Pd/C in methanol/TEA affords the dihydroxy compound (XV), which is treated with MsCl and pyridine to provide the mesylate (XVI). Finally, this compound is cyclized by means of TEA in refluxing ethyl acetate to furnish the target indeno[5,4-b]furan derivative.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; et al.; Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem 2002, 45, 19, 4222.
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) 34515 6-methoxy-1-phenyl-1-indanol C16H16O2 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 62218 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile C12H11NO 详情 详情
(IV) 62219 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethylamine; 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)-1-ethanamine C12H15NO 详情 详情
(V) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(VI) 62220 N-[2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]propanamide C15H19NO2 详情 详情
(VII) 62221 N-{2-[(1S)-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C15H21NO2 详情 详情
(VIII) 62222 N-{2-[(1S)-5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C15H20BrNO2 详情 详情
(IX) 62223 N-{2-[(1S)-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C14H18BrNO2 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 62224 N-{2-[(1S)-6-(allyloxy)-5-bromo-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C17H22BrNO2 详情 详情
(XII) 62225 N-{2-[(1S)-7-allyl-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C17H22BrNO2 详情 详情
(XIII) 62226 N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H20BrNO3 详情 详情
(XIV) 62227 N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H22BrNO3 详情 详情
(XV) 62228 N-{2-[(1S)-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H23NO3 详情 详情
(XVI) 62229 2-{(3S)-5-hydroxy-3-[2-(propionylamino)ethyl]-2,3-dihydro-1H-inden-4-yl}ethyl methanesulfonate C17H25NO5S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

Horner-Emmons reaction of 1-benzyl-4-piperidone (I) with diethyl cyanomethylphosphonate (II) in the presence of K2CO3 provided the piperidinilydeneacetonitrile (III). Reduction of the double bond of (III) with magnesium in MeOH yielded the saturated nitrile (IV), which was further reduced to amine (V) using LiAlH4. Treatment of 6-phenyl-3-pyridazinone (VI) with POCl3 gave the chloropyridazine (VII). This was coupled with diamine (V) in the presence of ammonium chloride in refluxing butanol to furnish the title pyridazinamine, which was finally converted to the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Rival, Y.M.; Bourguignon, J.-J.; Contreras, J.-M.; Chayer, S.; Wermuth, C.G.; Aminopyridazines as acetylcholinesterase inhibitors. J Med Chem 1999, 42, 4, 730.
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) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 31448 2-(1-benzyl-4-piperidinylidene)acetonitrile C14H16N2 详情 详情
(IV) 31449 2-(1-benzyl-4-piperidinyl)acetonitrile C14H18N2 详情 详情
(V) 17606 2-(1-benzyl-4-piperidinyl)-1-ethanamine; 2-(1-benzyl-4-piperidinyl)ethylamine C14H22N2 详情 详情
(VI) 31450 6-phenyl-3(2H)-pyridazinone C10H8N2O 详情 详情
(VII) 31451 3-chloro-6-phenylpyridazine C10H7ClN2 详情 详情

合成路线12

该中间体在本合成路线中的序号：

Horner-Emmons condensation of 3,3'-difluorobenzophenone (I) with diethyl (cyanomethyl)phosphonate provided 3,3-bis(3-fluorophenyl)acrylonitrile (II). The olefinic double bond of (II) was then reduced using catalytic hydrogenation to give (III). After deprotonation of (III) with either lithium diisopropylamide or lithium hexamethyldisilazide at -78 C, alkylation with iodomethane afforded the racemic alpha-methyl nitrile (IV). Isolation of the required (R)-enantiomer (V) was accomplished by means of chiral HPLC. Finally, reduction of the nitrile group of (V) with borane-dimethyl sulfide complex provided the title amine, which was isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Moe, S.T.; Shimizu, S.M.; Smith, D.L.; et al.; Synthesis, biological activity, and absolute stereochemical assignment NPS 1392: A potent and stereoselective NMDA receptor antagonist. Bioorg Med Chem Lett 1999, 9, 14, 1915.
【2】 Moe, S.T.; Mueller, A.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9856752 .
【3】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(I) 35077 bis(3-fluorophenyl)methanone 345-70-0 C13H8F2O 详情 详情
(II) 35078 3,3-bis(3-fluorophenyl)acrylonitrile C15H9F2N 详情 详情
(III) 35079 3,3-bis(3-fluorophenyl)propanenitrile C15H11F2N 详情 详情
(IV) 35080 3,3-bis(3-fluorophenyl)-2-methylpropanenitrile C16H13F2N 详情 详情
(V) 35081 (2R)-3,3-bis(3-fluorophenyl)-2-methylpropanenitrile C16H13F2N 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VII)

Alternatively, the desired compound can be obtained as follows: Treatment of diethyl cyanomethyl phosphonate (VII) with NaH in dimethoxyethane (DME) followed by reaction with 3,3'-difluorobenzophenone (VIII) gives alkene derivative (IX), which is then hydrogenated over Pd(OH)2 to provide compound (X). Reduction of the cyano moiety of (X) by means of B2H6-THF followed by treatment with refluxing HCl yields substituted propylamine (XI), which is then converted into formamide (XIII) by treatment with refluxing ethyl formate (XII). Compound (XIII) is then reduced by means of borane-methyl sulfide in refluxing THF and finally treated with HCl. Propylamine (XI) can also be obtained following these steps: Treatment of benzophenone derivative (VIII) with n-BuLi and acetonitrile in THF affords cyano derivative (XIV), which is then hydrogenated over Ni/Al and NaOH in EtOH to furnish amine (XV). Elimination of the tertiary alcohol (XV) by refluxing with HCl in EtOH gives substituted diphenylpropenamine hydrochloride (XVI), which is hydrogenated over Pd/C in EtOH and finally subjected to hydrochloride salt neutralization.

参考文献 中间体
合成目标
【1】 Moe, S.T.; Mueller, A.L.; Vanwagenen, B.C.; Barmore, R.M.; Delmar, E.G.; Artman, L.D.; Balandrin, M.F.; Smith, D.L. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. WO 9746511 .
【2】 Barmore, R.M.; DelMar, E.G.; Balandrin, M.F.; VanWagenen, B.C.; Artman, L.D.; Mueller, A.L.; Moe, S.T. (NPS Pharmaceuticals, Inc.); Cpds. active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases. US 6071970 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(VIII) 35077 bis(3-fluorophenyl)methanone 345-70-0 C13H8F2O 详情 详情
(IX) 35078 3,3-bis(3-fluorophenyl)acrylonitrile C15H9F2N 详情 详情
(X) 35079 3,3-bis(3-fluorophenyl)propanenitrile C15H11F2N 详情 详情
(XI) 48851 3,3-bis(3-fluorophenyl)-1-propanamine; 3,3-bis(3-fluorophenyl)propylamine C15H15F2N 详情 详情
(XII) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(XIII) 48852 3,3-bis(3-fluorophenyl)propylformamide C16H15F2NO 详情 详情
(XIV) 37211 3,3-bis(3-fluorophenyl)-3-hydroxypropanenitrile C15H11F2NO 详情 详情
(XV) 37212 3-amino-1,1-bis(3-fluorophenyl)-1-propanol C15H15F2NO 详情 详情
(XVI) 37213 3,3-bis(3-fluorophenyl)-2-propen-1-amine; 3,3-bis(3-fluorophenyl)-2-propenylamine C15H13F2N 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XVI)

Cyclization of 2-(chloromethyl)oxirane (XI) with benzhydrylamine (XII) in MeOH, followed by reaction of the resulting compound with Na2CO3 in CH2Cl2 yields 1-benzhydrylazetidin-3-ol (XIII). Catalytic hydrogenolysis of azetidine derivative (XIII) over Pd/C, followed by re-protection with Boc2O in THF, yields carbamate (XIV), which is oxidized to N-Boc-3-oxoazetidine (XV) by means of TEMPO in the presence of KBr in EtOAc . Wittig reaction of ketone (XV) with diethyl cyanomethylphosphonate (XVI) by means of t-BuOK or NaH in THF gives N-Boc-3-(cyanomethylene)azetidine (XVII) , which is deprotected with HCl in acetonitrile to produce azetidin-3-ylideneacetonitrile hydrochloride (XVIII). Finally, azetidine derivative (XVIII) is condensed with ethanesulfonyl chloride (XIX) using DIEA in acetonitrile .

参考文献 中间体
合成目标
【1】 Rodgers, J.D., Shepard, S., Li, Y.-L., Zhou, J., Liu, P., Meloni, D., Xia, M.(Incyte Corp.). Azetidine and cyclobutane derivatives as JAK inhibitors. CN 102026999, EP 2288610, JP 2011514909, KR 2010121657, KR 2012108042, US 2009233903, US 2012077798, US 8158616, US 8420629, US 2013225556, WO 2009114512.
【2】 Friedman, P.A., Fridman, J.S., Luchi, M.E., Williams, W.V. (Incyte Corp.). Janus kinase inhibitors for treatment of dry eye and other eye related dis-eases. EP 2349260, JP 2012504639, US 201011416, US 2012301464, WO 2010039939.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 68070 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile 　 C7H10N2O2S 详情 详情
(XI) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(XII) 15149 alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine 91-00-9 C13H13N 详情 详情
(XIII) 12592 1-Benzhydryl-3-azetidinol; 1-Benzhydryl-3-hydroxyazetidine；1-benzhydrylazetidin-3-ol 18621-17-5 C16H17NO 详情 详情
(XIV) 68075 tert-butyl 3-hydroxyazetidine-1-carboxylate 141699-55-0 C8H15NO3 详情 详情
(XV) 68076 tert-butyl 3-oxoazetidine-1-carboxylate 398489-26-4 C8H13NO3 详情 详情
(XVI) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(XVII) 68077 N-Boc-3-(cyanomethylene)azetidine 　 C10H14N2O2 详情 详情
(XVIII) 68078 　 　 C5H6N2.HCl 详情 详情
(XIX) 54065 Ethanesulfonyl chloride; Ethylsulfonyl chloride 594-44-5 C2H5ClO2S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VIII)

N-Protection of 4-chloropyrrolo[2,3-d]pyrimidine (I) with either 2-(trimethylsilyl) ethoxymethyl chloride (SEM-Cl) in DMA or pivaloyloxymethyl chloride (POM-Cl) in THF in the presence of NaH yields the protected deazapurines (IIa) and (IIb) , respectively, which by Suzuki coupling with pinacol 1-(1-ethoxyethyl)-4-pyrazolylboronate (III) by means of Pd(PPh3)4 and K2CO3, followed by acidic hydrolysis of the ethoxyethyl group, affords the respective pyrazolyl deazapurines (Va) and (Vb) . Alternatively, intermediate (Va) can be obtained by Suzuki coupling of deazapurine (IIa) with unprotected pyrazolylboronate (IV) by means of Pd(PPh3)4 and K2CO3 in DMF/H2O at 125 °C . Michael addition of pyrazole derivative (Va) to 3-cyclopentylacrylonitrile (VI) (obtained by Wittig condensation of cyclopentylcarboxaldehyde [VII] with diethyl cyanomethylphosphonate [VIII] by means of t-BuOK in THF) in the presence of DBU in acetonitrile, followed by resolution using chiral preparative HPLC, provides the desired (R)-adduct (IXa) . Alternatively, in an enantioselective procedure, asymmetric aza-Michael reaction of (Va) or (Vb) with (E)-3-cyclopentylacrylaldehyde (X) in the presence of p-nitrobenzoic acid (p-NBA) and a chiral diarylprolinol silyl ether in CHCl3 gives aldehydes (XIa) and (XIb), which by subsequent condensation with NH4OH, followed by oxidation of the intermediate imines with I2 in aqueous solution, leads to the corresponding nitriles (IXa) and (IXb) . Finally, ruxolitinib is obtained by deprotection of compound (IXa) by sequential treatment with LiBF4 in refluxing acetonitrile/H2O followed by aqueous NH4OH , or with TFA in CH2Cl2 and subsequent basification of obtained TFA salt with ethylenediamine (EDA) in MeOH , or by deprotection of compound (IXb) by treatment with NaOH in MeOH/H2O .
In an alternative strategy, ruxolitinib can be directly obtained by Suzuki coupling of unprotected 4-chloropyrrolo[2,3-d]pyrimidine (I) with the pyrazolylboronate (XII) in the presence of Pd(PPh3)4 and K2CO3 in 1,4-dioxane/H2O at 100 °C .

参考文献 中间体
合成目标
【1】 Lin, Q., Meloni, D., Pan, Y. et al. Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org Lett 2009, 11(9): 1999-2002.
【2】 Rodgers, J.D., Shepard, S., Maduskuie, T.P. Jr. et al. (Incyte Corp.). Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors. US 20090181959.
【3】 Rodgers, J.D., Shepard, S., Maduskuie, T.P. Jr. et al. (Incyte Corp.). Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors. CA 2632466, EP 1966202, JP 2009519340, US 2007135461, US 7598257, WO 2007070514.
【4】 Friedman, P.A., Fridman, J.S., Luchi, M.E., Williams, W.V. (Incyte Corp.). Janus kinase inhibitors for treatment of dry eye and other eye related diseases. WO 2010039939.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIa) 68079 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 　 C12H18ClN3OSi 详情 详情
(IIb) 69168 　 　 C6H3ClN3.POM 详情 详情
(Va) 68072 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 　 C15H21N5OSi 详情 详情
(Vb) 69169 　 　 C9H6N5.POM 详情 详情
(IXa) 69172 (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile 　 C23H32N6OSi 详情 详情
(IXb) 69175 　 　 C17H17N6.POM 详情 详情
(XIa) 69173 (R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanal 　 C23H33N5O2Si 详情 详情
(XIb) 69174 　 　 C17H18N5O.POM 详情 详情
(I) 60046 4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine 3680-69-1 C6H4ClN3 详情 详情
(III) 68071 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 　 C13H23BN2O3 详情 详情
(IV) 68081 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 　 C9H15BN2O2 详情 详情
(VI) 69170 cyclopentylcarboxaldehyde;3-cyclopentyl-2-Propenenitrile 591769-05-0 C8H11N 详情 详情
(VII) 69171 cyclopentylcarboxaldehyde；Cyclopentanecarbaldehyde;Cyclopentanealdehyde;Cyclopentyl aldehyde;Cyclopentylformaldehyde;Formylcyclopentane 872-53-7 C6H10O 详情 详情
(VIII) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(X) 69176 (E)-3-cyclopentylacrylaldehyde 　 C8H12O 详情 详情
(XII) 69177 (S)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile 　 C17H26BN3O2 详情 详情
Extended Information