|
【结 构 式】 
|
【分子编号】37210 【品名】acetonitrile 【CA登记号】75-05-8 |
【 分 子 式 】C2H3N 【 分 子 量 】41.05256 【元素组成】C 58.52% H 7.37% N 34.12% |
合成路线1
该中间体在本合成路线中的序号：(V)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.
| 【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2
该中间体在本合成路线中的序号：(III)The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).
| 【1】 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145. |
| 【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 . |
| 【3】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38542 | tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate | C37H44N2O3 | 详情 | 详情 | |
| (IX) | 38543 | tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 | |
| (X) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 | |
| (XI) | 38545 | tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate | C33H42N2O5 | 详情 | 详情 | |
| (XII) | 38546 | N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide | C28H34N2O3 | 详情 | 详情 | |
| (XIII) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (XIV) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (XV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XVI) | 38544 | ethyl 2-(2,6-dimethylphenoxy)acetate | C12H16O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot EtOH/H2O gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII) (slightly impurified (~10%) with other diastereomers that are not eliminated at this stage). The condensation of (VII) with acid chloride (VIII) (obtained by reaction of acid (IX) with SOCl2) in the presence of imidazole yields the amide (X), which is debenzylated with ammonium formate over Pd/C in methanol affording the amine (XI). At this stage the purification (elimination of the diastereomers) has been performed by crystallization of its salt with L-pyroglutamic acid (XII) in EtOH/DMF, pure salt (XIII) being obtained. Finally, this compound is condensed with the acid chloride (XIV) (obtained by reaction of acid (XV) with SOCl2) by means of NaHCO3 in ethyl acetate/water. The intermediates, the acids (IX) and (XV), have been obtained as indicated in schemes 24659001a and 24659001b (intermediates (XIII) and (X) of these schemes, respectively).
| 【1】 Stoner, E.J.; et al.; Synthesis of HIV protease inhibitor ABT-378 (lopinavir). Org Process Res Dev 2000, 4, 4, 264. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38265 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl chloride | C9H15ClN2O2 | 详情 | 详情 | |
| (IX) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (X) | 38266 | (2S)-N-[(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide | C41H50N4O3 | 详情 | 详情 | |
| (XI) | 38267 | (2S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide | C27H38N4O3 | 详情 | 详情 | |
| (XII) | 32406 | (2S)-5-oxo-2-pyrrolidinecarboxylic acid | 98-79-3 | C5H7NO3 | 详情 | 详情 |
| (XIII) | 38268 | (2S,3S,5S)-3-hydroxy-5-([(2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl]amino)-1,6-diphenyl-2-hexanaminium (2S)-5-oxo-2-pyrrolidinecarboxylate | C32H45N5O6 | 详情 | 详情 | |
| (XIV) | 38269 | 2-(2,6-dimethylphenoxy)acetyl chloride | C10H11ClO2 | 详情 | 详情 | |
| (XV) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The cyclization of 3-methyl-2-buten-1-ol (I) with acetonitrile (II) gives 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine (III), which is hydrolyzed with NaOH to yield 3-amino-3-methyl-1-butanol (IV). The protection of the amino group of (IV) with (Boc)2O in isopropanol affords the carbamate (V), which is oxidized at the primary OH group with SO3/pyridine and TEA to provide the aldehyde (VI). The condensation of (VI) with triethyl phosphonoacetate (VII) by means of potassium tert-butoxide in hot toluene gives the desired hexenoic ester (intermediate 27230), which is hydrolyzed with NaOH in refluxing ethanol to yield the corresponding acid intermediate (intermediate 22191).
| 【1】 Jessen, C.U.; et al.; Synthesis of N-protected 14C-labelled (2E)-5-amino-5-methylhex-2-enoic acid analogues. J Label Compd Radiopharm 2001, 44, 4, 265. |
| 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) | 37754 | 3-methyl-2-buten-1-ol | 556-82-1 | C5H10O | 详情 | 详情 |
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (III) | 46630 | 2,4,4-trimethyl-5,6-dihydro-4H-1,3-oxazine | C7H13NO | 详情 | 详情 | |
| (IV) | 46631 | 3-amino-3-methyl-1-butanol | C5H13NO | 详情 | 详情 | |
| (V) | 22194 | tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (VI) | 22195 | tert-butyl 1,1-dimethyl-3-oxopropylcarbamate | C10H19NO3 | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 27230 | ethyl (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoate | C14H25NO4 | 详情 | 详情 | |
| (IX) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Alkylation of 4-hydroxy-5-methoxy benzoic acid methyl ester (I) with 3-chloropropyl p-toluene sulfonate (III) by means of K2CO3 and methyl-tricapryl ammonium chloride (Aliquat 128) in refluxing acetone affords compound (III), which is then nitrated by means of HNO3 in HOAc to furnish 2-nitro derivative (IV). Reduction of the nitro moiety of (IV) by means of Fe in H2O/MeOH in the presence of ammonium chloride yields 2-amino compound (V), which is subjected to reaction with refluxing dimethylformamide dimethylacetal (VI) to provide amidine (VII). Condensation of (VII) with acetonitrile by means of n-BuLi in hexane/THF/HOAc gives substituted quinoline-carbonitrile (IX), whose hydroxyl group is replaced by a chlorine by treatment of (IX) with refluxing POCl3 to afford compound (X). Coupling of (X) with 2,4-dichloro-5-methoxyaniline (XI) in 2-ethoxyethanol in the presence of pyridine hydrochloride yields compound (XII), which is finally converted into the desired compound by condensation with 1-methylpiperazine (XII) by means of NaI in refluxing ethylene glycol dimethyl ether.
| 【1】 Boschelli, D.H.; Ye, F.; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F.; Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 2001, 44, 23, 3965. |
| 【2】 Boschelli, D.H.; Dutia, M.; Ye, F.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles Part 2: Optimization of the side chain at C-7. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 145. |
| 【3】 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822. |
| 【4】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 . |
| 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) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 50008 | methyl 4-(3-chloropropoxy)-3-methoxybenzoate | C12H15ClO4 | 详情 | 详情 | |
| (IV) | 50009 | methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate | C12H14ClNO6 | 详情 | 详情 | |
| (V) | 50010 | methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate | C12H16ClNO4 | 详情 | 详情 | |
| (VI) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (VII) | 50011 | methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate | C15H21ClN2O4 | 详情 | 详情 | |
| (VIII) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 50012 | 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile | C14H13ClN2O3 | 详情 | 详情 | |
| (X) | 48519 | 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile | C14H12Cl2N2O2 | 详情 | 详情 | |
| (XI) | 50013 | 2,4-dichloro-5-methoxyphenylamine; 2,4-dichloro-5-methoxyaniline | C7H7Cl2NO | 详情 | 详情 | |
| (XII) | 50014 | 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile | C21H18Cl3N3O3 | 详情 | 详情 | |
| (XIII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Reaction of 3-(tetrahydropyranyloxy)benzaldehyde (I) with acetonitrile (II) in the presence of t-BuOK in THF gives the b-hydroxypropionitrile (III), which by reduction with LiAlH4 in THF/Et2O yields the primary amine (IV). N-Protection of amine (IV) with ethyl trifluoroacetate (V) in THF affords the carbamate (VI), whose secondary hydroxyl group is oxidized with MnO2 in CH2Cl2 to yield the ketone (VII). Enantioselective reduction of ketone (VII) with (–)-DIP-Cl and DIEA in THF provides the (R)-alcohol (VIII), which is O-alkylated at its phenolic hydroxyl group with cyclohexylmethyl bromide (IX) and K2CO3 in DMF to give ether (X). Finally, compound (X) is N-deprotected by means of K2CO3 in MeOH/H2O and treated with HCl in i-PrOH .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 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) | 67832 | 3-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde | C12H14O3 | 详情 | 详情 | |
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (III) | 67833 | 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propanenitrile | C14H17NO3 | 详情 | 详情 | |
| (IV) | 67834 | 3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propan-1-ol | C14H21NO3 | 详情 | 详情 | |
| (V) | 14588 | Ethyl 2,2,2-trifluoroacetate; Trifluoroethyl acetate | 383-63-1 | C4H5F3O2 | 详情 | 详情 |
| (VI) | 67835 | 2,2,2-trifluoro-N-(3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H20F3NO4 | 详情 | 详情 | |
| (VII) | 67836 | 2,2,2-trifluoro-N-(3-oxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)propyl)acetamide | C16H18F3NO4 | 详情 | 详情 | |
| (VIII) | 67837 | (R)-2,2,2-trifluoro-N-(3-hydroxy-3-(3-hydroxyphenyl)propyl)acetamide | C11H12F3NO3 | 详情 | 详情 | |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (X) | 67838 | (R)-N-(3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide | C18H24F3NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Mitsunobu reaction of 3-hydroxybenzaldehyde (XI) with cyclohexylmethanol (XII) using PPh3 and DEAD in THF or condensation of 3-hydroxybenzaldehyde (XI) with cyclohexylmethyl bromide (IX) using K2CO3 and NMP in DMF at 75 °C give ether (XIII), which by reaction with acetonitrile (II) by means of LDA in THF at –78 °C or t-BuOK in THF yields the b-hydroxynitrile (XIV). Reduction of nitrile (XIV) with LiAlH4 or BH3·Me2S in THF affords the primary amine (XV), which by N-protection with Fmoc-Cl and DIEA in CH2Cl2 provides carbamate (XVI). Oxidation of secondary alcohol (XVI) with MnO2 in CH2Cl2 leads to the ketone (XVII), which is finally submitted to enantioselective reduction using (–)-DIP-Cl (prepared in situ by treating (–)-a-pinene with chloroborane-methyl sulfide complex in hexane) and DIEA in THF, followed by deprotection of the obtained N-Fmoc protected compound with DBU in THF. Alternatively, resolution of racemic emixustat (XV) can be performed using D-mandelic acid .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 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) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (XI) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (XII) | 28360 | cyclohexylmethanol | 100-49-2 | C7H14O | 详情 | 详情 |
| (XIII) | 67839 | 3-(cyclohexylmethoxy)benzaldehyde | C14H18O2 | 详情 | 详情 | |
| (XIV) | 67840 | 3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile | C16H21NO2 | 详情 | 详情 | |
| (XV) | 67841 | 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol | C16H25NO2 | 详情 | 详情 | |
| (XVI) | 67842 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)carbamate | C31H35NO4 | 详情 | 详情 | |
| (XVII) | 67843 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-oxopropyl)carbamate | C31H33NO4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXXV)ortho-Metalation of N-Boc-m-anisidine (XXXII) with BuLi in cold THF, followed by bromination with perfluorooctyl bromide, gives N-Boc-2-bromo-3-methoxyaniline (XXXIII), which by Boc group cleavage with HCl in diglyme at 100 °C provides 2-bromo-3-methoxyaniline hydrochloride (XXXIV). Friedel–Crafts acylation of bromoanisidine (XXXIV) with acetonitrile (XXXV) in the presence of BCl3 and AlCl3 in chlorobenzene at 100 °C affords 2’-amino-3’-bromo-4’-methoxyacetophenone (XXXVI) , which is then coupled with the acid chloride (XXXVII) [prepared by chlorination of 2-isobutyrylaminothiazole-4-carboxylic acid (XXXVIII) with either (COCl)2 in DMF/THF or SOCl2 in NMP by means of Et3N and DMAP in THF to provide the corresponding carboxamide (XXXIX) . Intramolecular cyclocondensation of the ketoamide (XXXIX) in the presence of either t-BuOK in DME at 80-85 °C or KOH in t-BuOH yields the quinolinol (XL), which is then chlorinated with POCl3 in dioxane at 75 °C to obtain the 4-chloroquinoline derivative (VII) .
| 【1】 Berkenbusch, T., Busacca, C.A., Jaeger, B., Varsolona, R.J. (Boehringer Ingelheim Pharma GmbH & Co. KG). Crystalline forms of a 2-thiazolyl-4-quinolinyl-oxy derivative, a potent HCV inhibitor. CN 102159571, EP 2331538, JP 2012502910, KR 2011059841, US 2010093792, WO 2010033444. |
| 【2】 Bhardwaj, P., Forgione, P., Goudreau, N. et al. (Boehringer Ingelheim International GmbH). Hepatitis C inhibitor compounds. EP 1654261, JP 2006528937, JP 2010043129, US 2005020503, US 2011177030, US 8067438, WO 2004103996. |
| 【3】 Patel, N., Senanayake, C.H., Wei, X., Yee, N.K. (Boehringer Ingelheim Pharma GmbH & Co. KG). Process for preparing sulfonyl quinolines. EP 2408768, WO 2010107965. |
| 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) | 68430 | N-(4-(8-bromo-4-chloro-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide | C17H15BrClN3O2S | 详情 | 详情 | |
| (XXXII) | 68452 | tert-butyl (3-methoxyphenyl)carbamate | C12H17NO3 | 详情 | 详情 | |
| (XXXIII) | 68453 | tert-butyl (2-bromo-3-methoxyphenyl)carbamate | C12H16BrNO3 | 详情 | 详情 | |
| (XXXIV) | 68454 | 2-bromo-3-methoxyaniline hydrochloride | C7H8BrNO.HCl | 详情 | 详情 | |
| (XXXV) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (XXXVI) | 68455 | 1-(2-amino-3-bromo-4-methoxyphenyl)ethanone;2’-amino-3’-bromo-4’-methoxyacetophenone | 923289-30-9 | C9H10BrNO2 | 详情 | 详情 |
| (XXXVII) | 68456 | 2-isobutyramidothiazole-4-carbonyl chloride | C8H9ClN2O2S | 详情 | 详情 | |
| (XXXVIII) | 68457 | 2-isobutyramidothiazole-4-carboxylic acid | C8H10N2O3S | 详情 | 详情 | |
| (XXXIX) | 68458 | N-(6-acetyl-2-bromo-3-methoxyphenyl)-2-isobutyramidothiazole-4-carboxamide | C17H18BrN3O4S | 详情 | 详情 | |
| (XL) | 68459 | N-(4-(8-bromo-4-hydroxy-7-methoxyquinolin-2-yl)thiazol-2-yl)isobutyramide | C17H16BrN3O3S | 详情 | 详情 |