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【结 构 式】 
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【分子编号】15793 【品名】3-(Chloromethyl)pyridine 【CA登记号】3099-31-8 |
【 分 子 式 】C6H6ClN 【 分 子 量 】127.57308 【元素组成】C 56.49% H 4.74% Cl 27.79% N 10.98% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 3-chloromethylpyridine (I) with the Grignard reagent of 4-bromobenzaldehyde diethylacetal (II) in THF gives 4-(3-pyridylmethyl)benzaldehyde diethylacetal (III), which is hydrolyzed with aqueous 1N HCl to 4-(3-pyridylmethyl)benzaldehyde (IV). The Wittig condensation of (IV) with 1-(ethoxycarbonyl)ethylidenetriphenylphosphorane (V) in CHCl3 affords 3-[4-(3-pyridylmethyl)phenyl]-2-methylacryl ic acid ethyl ester (VI), which is finally hydrolyzed with aqueous NaOH.
| 【1】 Tanouchi, T.; et al.; Pyridine derivatives. DE 2951786; FR 2445319; FR 2510108; GB 2039903; US 4271170; US 4317828 . |
| 【2】 Hillier, K.; Serradell, M.N.; Blancafort, P.; Castaner, J.; OKY-1581. Drugs Fut 1982, 7, 6, 399. |
| 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) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (II) | 23171 | bromo[4-(diethoxymethyl)phenyl]magnesium | C11H15BrMgO2 | 详情 | 详情 | |
| (III) | 37069 | 3-[4-(diethoxymethyl)benzyl]pyridine; ethoxy[4-(3-pyridinylmethyl)phenyl]methyl ethyl ether | C17H21NO2 | 详情 | 详情 | |
| (IV) | 37070 | 4-(3-pyridinylmethyl)benzaldehyde | C13H11NO | 详情 | 详情 | |
| (V) | 37071 | ethyl 2-(triphenylphosphoranylidene)propanoate | 5717-37-3 | C23H23O2P | 详情 | 详情 |
| (VI) | 37072 | ethyl (E)-2-methyl-3-[4-(3-pyridinylmethyl)phenyl]-2-propenoate | C18H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)By condensation of 3-(chloromethyl)pyridine (I) with 2-mercaptopyrimidine (II) in ethanol-water at room temperature.
| 【1】 Engler, H.; Schickaneder, H.; Szelenyi, I. (Heumann Pharma GmbH & Co.); Imidazoyl-substd. thiomethylpyridine derivs., method of administration thereof and medicaments containing them. DE 3216843; EP 0093252; US 4810715 . |
| 【2】 Castaner, J.; Prous, J.; Tasuldine. Drugs Fut 1986, 11, 5, 397. |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of 3-(chloromethyl)pyridine (I) with thiourea (II) in ethanol gives S-(3-pyridylmethyl)isothiourea (III), which is condensed with 4-chlorobutyl bromide (IV) by means of NaOH in dichloromethane to yield 3-(4-chlorobutylsulfanylmethyl)pyridine (V). The careful oxidation of (V) with MCPBA in dichloromethane affords the corresponding sulfoxide (VI), which is cyclized by means of potassium tert-butoxide in THF, providing a mixture of cis- and trans-2-(3-pyridyl)tetrahydrothiopyran S-oxide (VII + VIII). This mixture can be separated by conventional methods; however, when this mixture (VII + VIII), or either (VII) or (VIII) separately, are treated with NaNH2 and methyl isothiocyanate, only the target (1RS,2RS)-compound is obtained. Alternatively, the mixture (VII + VIII) or either (VII) or (VIII) can also be treated with potassium tert-butoxide, CS2 and methyl iodide to yield the (1RS,2RS)-dithioester (IX), which is finally converted into the target compound by reaction with methylamine.
| 【1】 Aloup, J.C.; Farge, D.; James, C.; Mondot, S.; Cavero, I.; 2-(3-PYRIDYL)-TETRAHYDROTHIOPYRAN-2-CARBOTHIOAMIDE DERIVATIVES AND ANALOGUES: A NOVEL FAMILY OF POTENT POTASSIUM CHANNEL OPENERS. Drugs Fut 1990, 15, 11, 1097. |
| 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) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 44408 | 3-([[amino(imino)methyl]sulfanyl]methyl)pyridine | C7H9N3S | 详情 | 详情 | |
| (IV) | 16141 | 1-bromo-4-chlorobutane | 6940-78-9 | C4H8BrCl | 详情 | 详情 |
| (V) | 44409 | 4-chlorobutyl 3-pyridinylmethyl sulfide; 3-[[(4-chlorobutyl)sulfanyl]methyl]pyridine | C10H14ClNS | 详情 | 详情 | |
| (VI) | 44410 | 3-[[(4-chlorobutyl)sulfinyl]methyl]pyridine; 4-chlorobutyl 3-pyridinylmethyl sulfoxide | C10H14ClNOS | 详情 | 详情 | |
| (VII) | 44412 | (2R)-2-(3-pyridinyl)tetrahydro-1lambda(4)-thiopyran-1(2H)-one | C10H13NOS | 详情 | 详情 | |
| (VIII) | 44411 | (2R)-2-(3-pyridinyl)tetrahydro-1lambda(4)-thiopyran-1(2H)-one | C10H13NOS | 详情 | 详情 | |
| (IX) | 44413 | methyl (2S)-1-oxo-2-(3-pyridinyl)hexahydro-1lambda(4)-thiopyran-2-carbodithioate | C12H15NOS3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II), which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III). The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV), which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V). The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI), which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII). The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX), which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X). The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII), which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII). The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV), which is finally hydrolyzed with NaOH in methanol/water.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Setoi, H.; Sawada, A.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrrolidine derivs. AU 8943753; EP 0367130; JP 1990152960; US 5130323; US 5264453; US 5514701 . |
| 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) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (II) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (III) | 15782 | 1-(tert-butyl) 2-methyl (2S,4S)-4-(benzoyloxy)tetrahydro-1H-pyrrole-1,2-dicarboxylate | C18H23NO6 | 详情 | 详情 | |
| (IV) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (V) | 15784 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (VI) | 15785 | 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VII) | 15786 | 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IX) | 15788 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H23ClN2O6S | 详情 | 详情 | |
| (X) | 15789 | tert-butyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-2-formyltetrahydro-1H-pyrrole-1-carboxylate | C16H21ClN2O5S | 详情 | 详情 | |
| (XI) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XII) | 15791 | (Z)-6-((2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoic acid | C21H29ClN2O6S | 详情 | 详情 | |
| (XIII) | 15792 | methyl (Z)-6-((2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoate | C17H23ClN2O4S | 详情 | 详情 | |
| (XIV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XV) | 15794 | methyl (Z)-6-[(2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-2-yl]-5-hexenoate | C23H28ClN3O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.
| 【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8. |
| 【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 . |
| 【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 . |
| 【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6. |
| 【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 | |
| (I) | 16238 | (1S,2R)-2,3-dihydro-1H-indene-1,2-diol | 67528-22-7 | C9H10O2 | 详情 | 详情 |
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (III) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (V) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (VI) | 16243 | (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO3 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (X) | 16247 | (2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one | C24H27NO2 | 详情 | 详情 | |
| (XI) | 16248 | (2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone | C24H28INO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)3) The alkylation of 5(S)-(tert-butyldimethylsilyloxymethyl)tetrahydrofuran-2-one (XII) by means of benzyl bromide (XIII) and lithium diisopropylamide (LDA) gives the corresponding 3(R)-benzyl derivative (XIV), which is deprotected with aqueous HF, yielding the hydroxymethyl compound (XV). The esterification of (XV) with trifluoromethanesulfonic anhydride affords the corresponding triflate (XVI), which is condensed with the chiral piperazine (VII) by means of diisopropylethylamine in isopropanol, giving the substituted furanone (XVII). Ring opening of the furanone (XVII) with LiOH, DME and imidazole yields the substituted hydroxypentanamide (XVIII), which is protected with tert-butyldimethylsilyl chloride to afford the protected amide (XIX). The trans-amidation of (XIX) with 2-hydroxyindan-1-amine (II) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) in DMF gives the protected dihydroxy diamide (XX), which is deprotected with trimethylsilyl triflate, affording the dihydroxy diamide (VII), already obtained. This compound is then alkylated with 3-(chloromethyl)pyridine (IX) as before.
| 【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【2】 Vacca, J.P.; Holloway, M.K.; Dorsey, B.D.; Hungate, R.W.; Guare, J.P. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0541168; JP 1993279337; WO 9309096 . |
| 【3】 Vacca, J.P.; Guare, J.P.; Dorsey, B.D.; Holloway, M.K.; Hungate, R.W. (Merck & Co., Inc.); HIV protease inhibitors in pharmaceutical combinations for the treatment of AIDS. EP 0617968; JP 1996508496; WO 9422480 . |
| 【4】 Vacca, J.P.; Dorsey, B.D.; Guare, J.P.; Holloway, M.K.; Hungate, R.W.; Levin, R.B. (Merck & Co., Inc.); HIV protease inhibitors useful for the treatment of AIDS. EP 0696277; JP 1996509980; US 5413999; WO 9426717 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XII) | 16249 | (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C11H22O3Si | 详情 | 详情 | |
| (XIII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XIV) | 16251 | (3R,5S)-3-benzyl-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)dihydro-2(3H)-furanone | C18H28O3Si | 详情 | 详情 | |
| (XV) | 16252 | (3R,5S)-3-benzyl-5-(hydroxymethyl)dihydro-2(3H)-furanone | C12H14O3 | 详情 | 详情 | |
| (XVI) | 16253 | [(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl trifluoromethanesulfonate | C13H13F3O5S | 详情 | 详情 | |
| (XVII) | 16254 | tert-butyl (3S)-4-[[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]methyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | C26H39N3O5 | 详情 | 详情 | |
| (XVIII) | 16255 | tert-butyl (3S)-4-[(2S,4R)-5-amino-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | C26H42N4O5 | 详情 | 详情 | |
| (XIX) | 16256 | tert-butyl (3S)-4-((2S,4R)-5-amino-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C32H56N4O5Si | 详情 | 详情 | |
| (XX) | 16257 | tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C41H64N4O6Si | 详情 | 详情 | |
| (XXI) | 16258 | tert-butyl (3S)-4-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C35H50N4O6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)4) The condensation of the chiral piperazine (VII) with (S)-(+)-glycicyl 3-nitrobenzenesulfonate (XXII) by means of diisopropylethylamine in DMF [or with (S)-glycidol (XXIII), tosyl chloride and NaH] gives the epoxide (XXIV), which is condensed with the propionamide (IV) by means of butyllithium in THF, yielding the protected hydroxyamide (XXV). The deprotection of (XXV) with aqueous HCl affords the dihydroxy-diamide (VIII), already obtained, which is finally alkylated with 3-(chloromethyl)pyridine (IX) as before.
| 【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【2】 Askin, D.; Reider, P.; Rossen, K.; Varsolona, R.J.; Wells, K.M. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502583 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XXII) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (XXIII) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (XXIV) | 16261 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]-4-[(2R)oxiranylmethyl]tetrahydro-1(2H)-pyrazinecarboxylate | C17H31N3O4 | 详情 | 详情 | |
| (XXV) | 16262 | tert-butyl (3S)-4-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C38H54N4O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Alkylation of benzodiazepinone (I) with 3-(chloromethyl)- pyridine (II) in the presence of NaH gave the 1-substituted benzodiazepinone (III). Reduction of the amide group of (III) with borane in THF afforded benzodiazepine (IV). Subsequent condensation with 4-nitrobenzoyl chloride (V) gave nitrobenzamide (VI), which was reduced to amine (VII) by hydrogenation in the presence of Pd/C. This compound was coupled with acid chloride (IX) (prepared by treatment of 2-phenylbenzoic acid (VIII) with oxalyl chloride) to yield the title compound.
| 【1】 Matsuhisa, A.; Koshio, H.; Sakamoto, K.; Taniguchi, N.; Yatsu, T.; Tanaka, A.; Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors: Synthesis and pharmacological properties of 2-phenyl-4'-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carbonyl)benzanilide derivatives. Chem Pharm Bull 1998, 46, 10, 1566. |
| 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) | 18498 | 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C9H10N2O | 详情 | 详情 | |
| (II) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (III) | 18500 | 1-(3-pyridinylmethyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C15H15N3O | 详情 | 详情 | |
| (IV) | 18501 | 1-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine | C15H17N3 | 详情 | 详情 | |
| (V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (VI) | 18503 | (4-nitrophenyl)[5-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]methanone | C22H20N4O3 | 详情 | 详情 | |
| (VII) | 18504 | (4-aminophenyl)[5-(3-pyridinylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]methanone | C22H22N4O | 详情 | 详情 | |
| (VIII) | 18505 | [1,1'-biphenyl]-2-carboxylic acid | 947-84-2 | C13H10O2 | 详情 | 详情 |
| (IX) | 18506 | [1,1'-biphenyl]-2-carbonyl chloride | C13H9ClO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Sulfonylation of methyl 3-methylanthranilate (I) with 4-methoxybenzenesulfonyl chloride (II) provided the sulfonamide (III). This was then N-alkylated with 3-picolyl chloride hydrochloride (IV) in the presence of K2CO3 to afford (V). Ester (V) hydrolysis with LiOH or NaOH provided carboxylic acid (VI), which was further activated as the corresponding acid chloride (VII) using oxalyl chloride in the presence of DMF. Coupling of acid chloride (VII) with hydroxylamine hydrochloride furnished the target hydroxamic acid, which was finally treated with HCl to produce the title hydrochloride salt.
| 【1】 Levin, J.I.; DiJoseph, J.F.; Du, M.T.; et al.; The discovery of anthranilic acid-based MMP inhibitors. Part 1. SAR of the 3-position. Bioorg Med Chem Lett 2001, 11, 2, 235. |
| 【2】 Gu, Y.; Nelson, F.C.; Zask, A.; Du, M.T.; Levin, J.I.; Venkatesan, M. (American Cyanamid Co.); Preparation and use of orthosulfonamido aryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors. US 5929097 . |
| 【3】 Nelson, F.C.; Venkatesan, A.M.; Levin, J.I.; Du, M.T.; Gu, Y.; Zask, A. (American Cyanamid Co.); The preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors. WO 9816503 . |
| 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) | 48424 | methyl 2-amino-3-methylbenzoate | C9H11NO2 | 详情 | 详情 | |
| (II) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (III) | 48425 | methyl 2-[[(4-methoxyphenyl)sulfonyl]amino]-3-methylbenzoate | C16H17NO5S | 详情 | 详情 | |
| (IV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (V) | 48426 | methyl 2-[[(4-methoxyphenyl)sulfonyl](3-pyridinylmethyl)amino]-3-methylbenzoate | C22H22N2O5S | 详情 | 详情 | |
| (VI) | 48427 | 2-[[(4-methoxyphenyl)sulfonyl](3-pyridinylmethyl)amino]-3-methylbenzoic acid | C21H20N2O5S | 详情 | 详情 | |
| (VII) | 48428 | 2-[[(4-methoxyphenyl)sulfonyl](3-pyridinylmethyl)amino]-3-methylbenzoyl chloride | C21H19ClN2O4S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IX)Cleavage of the methyl ether function of (VII) by means of BBr3 in cold CH2Cl2 leads to phenol (VIII). This is finally alkylated by 3-picolyl chloride (IX) in the presence of K2CO3/NaI to furnish the title compound.
| 【1】 Muraoka, M.; Ioriya, K.; Ohashi, N.; Yagi, H. (Sumitomo Pharmaceuticals Co., Ltd.); Novel naphthyridine derivs.. EP 0947515; JP 1998212288; WO 9823615 . |
| 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) | 63690 | N-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,2-dihydro[1,8]naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea | C32H38N4O3 | 详情 | 详情 | |
| (VIII) | 63691 | N-[1-butyl-4-(3-hydroxyphenyl)-2-oxo-1,2-dihydro[1,8]naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea | C31H36N4O3 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |