|
【结 构 式】 
|
【分子编号】18290 【品名】3,5-Bis(trifluoromethyl)benzoyl chloride 【CA登记号】785-56-8 |
【 分 子 式 】C9H3ClF6O 【 分 子 量 】276.5653392 【元素组成】C 39.09% H 1.09% Cl 12.82% F 41.22% O 5.79% |
合成路线1
该中间体在本合成路线中的序号：(X)Alkylation of methyl [1-(4-chlorobenzyl)but-3-enyl]carbamate (I) with chloromethyl ethyl ether in the presence of NaH afforded carbamate (II). Cyclization of (II) using chlorosulfonic acid in acetonitrile gave the trans-acetylamino piperidine (III). After removal of the carbamate group of (III) with HBr in HOAc, the racemic piperidine (IV) was resolved by acylation with (S)-O-acetylmandelic acid chloride (V), followed by recrystallization of the desired diastereoisomer (VI). Hydrolysis of (VI) with aqueous HCl furnished the chiral amino piperidine (VII), which was selectively protected with benzaldehyde (VIII) at the primary amino group as the corresponding benzaldimine (IX). Condensation of piperidine (IX) with 3,5-bis(trifluoromethyl)benzoyl chloride (X) followed by acid hydrolysis of the benzaldimine function produced the amino amide (XI). This was finally coupled with quinoline-4-carbonyl chloride (XII), yielding the title compound.
| 【1】 Ofner, S.; Veenstra, S.J.; Schilling, W. (Novartis AG); Aroyl-piperidine derivs.. CA 2160444; EP 0707006; JP 1996176145; US 5965562 . |
| 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) | 46477 | methyl 1-(4-chlorobenzyl)-3-butenylcarbamate | C13H16ClNO2 | 详情 | 详情 | |
| (II) | 46478 | methyl 1-(4-chlorobenzyl)-3-butenyl(ethoxymethyl)carbamate | C16H22ClNO3 | 详情 | 详情 | |
| (III) | 46479 | methyl (2R,4S)-4-(acetamido)-2-(4-chlorobenzyl)-1-piperidinecarboxylate | C16H21ClN2O3 | 详情 | 详情 | |
| (IV) | 46480 | N-[(2R,4S)-2-(4-chlorobenzyl)piperidinyl]acetamide | C14H19ClN2O | 详情 | 详情 | |
| (V) | 46481 | (1S)-2-chloro-2-oxo-1-phenylethyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (VI) | 46482 | (1S)-2-[(2R,4S)-4-(acetamido)-2-(4-chlorobenzyl)piperidinyl]-2-oxo-1-phenylethyl acetate | C24H27ClN2O4 | 详情 | 详情 | |
| (VII) | 46483 | (2R,4S)-2-(4-chlorobenzyl)piperidinylamine; (2R,4S)-2-(4-chlorobenzyl)-4-piperidinamine | C12H17ClN2 | 详情 | 详情 | |
| (VIII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IX) | 46484 | N-[(2R,4S)-2-(4-chlorobenzyl)piperidinyl]-N-[(E)-benzylidene]amine; (2R,4S)-2-(4-chlorobenzyl)-N-[(E)-benzylidene]-4-piperidinamine | C19H21ClN2 | 详情 | 详情 | |
| (X) | 18290 | 3,5-Bis(trifluoromethyl)benzoyl chloride | 785-56-8 | C9H3ClF6O | 详情 | 详情 |
| (XI) | 46485 | [(2R,4S)-4-amino-2-(4-chlorobenzyl)piperidinyl][3,5-bis(trifluoromethyl)phenyl]methanone | C21H19ClF6N2O | 详情 | 详情 | |
| (XII) | 46486 | 4-quinolinecarbonyl chloride | C10H6ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Reduction of morpholinone (I) with L-Selectride in THF at -78 C produced the intermediate lactol (II), which was condensed at low temperature with 3,5-bis(trifluoromethyl)benzoyl chloride (III) to afford acyl acetal (IV). Further reaction with dimethyl titanocene in THF-toluene at 80 C provided enol ether (V). Catalytic hydrogenation of the double bond, with concomitant N-benzyl group hydrogenolysis, yielded a 8:1 mixture of diastereomers, from which the major isomer (VI) was isolated by column chromatography. Alkylation of morpholine (VI) with N-methoxycarbonyl-2-chloroacetamidrazone (VII) (obtained by reaction of chloroacetonitrile (IX) with NaOMe and methyl carbazate in MeOH) in the presence of N-ethyl diisopropylamine (DIEA) in acetonitrile gave the intermediate (VIII), which was finally cyclized to the desired triazolone in refluxing xylene.
| 【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211. |
| 【2】 Cowden, C.J.; et al.; A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist. Tetrahedron Lett 2000, 41, 44, 8661. |
| 【4】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 . |
| 【5】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 . |
| 【6】 MacCoss, M.; Hale, J.J.; Mills, S.G.; et al.; Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J Med Chem 2000, 43, 6, 1234. |
| 【7】 Dolling, U.H.; Wilson, R.D.; Hands, D.; Cottrell, I.F. (Merck Sharp & Dohme Ltd.); Chemical synthesis of morpholine derivs.. WO 9965900 . |
| 【8】 Cowden, C.J. (Merck Sharp & Dohme Ltd.); Process for the preparation of 1,2,4-triazolin-5-one derivs.. WO 0196315 . |
| 【3】 Hale, J.J.; Mills, S.G.; MacCoss, M.; Finke, P.E.; Cascieri, M.A.; Sadowski, S.; Ber, E.; Chicchi, G.G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N.N.; Tattersall, F.D.; Rupniak, N.M.; Williams, A.R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D.E.; Structural optimization affording 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J Med Chem 1998, 41, 23, 4607. |
| 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) | 18288 | (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone | C17H16FNO2 | 详情 | 详情 | |
| (II) | 18289 | (2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol | C17H18FNO2 | 详情 | 详情 | |
| (III) | 18290 | 3,5-Bis(trifluoromethyl)benzoyl chloride | 785-56-8 | C9H3ClF6O | 详情 | 详情 |
| (IV) | 18291 | (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate | C26H20F7NO3 | 详情 | 详情 | |
| (V) | 18292 | (2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether | C27H22F7NO2 | 详情 | 详情 | |
| (VI) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (VII) | 18294 | methyl (Z)-2-chloro-1-hydrazinoethylidenecarbamate | C4H8ClN3O2 | 详情 | 详情 | |
| (VIII) | 18295 | methyl (Z)-2-[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholinyl]-1-hydrazinoethylidenecarbamate | C24H25F7N4O4 | 详情 | 详情 | |
| (IX) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)(3,4-Dichlorophenyl)alanine methyl ester (I) was converted to the N-Boc amino ester (II), which was subsequently alkylated with iodomethane in the presence of Ag2O, yielding the N-methyl derivative (III). Partial reduction of the ester group of (III) to the aldehyde (IV) was carried out using DIBAL in toluene at -78 C. Horner-Emmons reaction of aldehyde (IV) with triethyl phosphonoacetate (V) furnished the arylpentenoate ester (VI), which was further hydrolyzed to acid (VII) with LiOH. Coupling of acid (VII) with D-3-amino-epsilon-caprolactam (VIII) gave rise to amide (IX). The N-Boc group of (IX) was removed by treatment with trifluoroacetic acid, and the resulting amine (X) was finally acylated with 3,5-bis(trifluoromethyl)benzoyl chloride to produce the target amide.
| 【1】 Gerspacher, M.; Von Sprecher, A.; Mah, R.; Roggo, S.; Stutz, S. (Novartis AG); Acylaminoalkenylene-amide derivs. as NK1 and NK2 antagonists. EP 0923550; JP 2001503387; US 6319917; WO 9807694 . |
| 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) | 51615 | methyl (2R)-2-amino-3-(3,4-dichlorophenyl)propanoate | C10H11Cl2NO2 | 详情 | 详情 | |
| (II) | 51616 | methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dichlorophenyl)propanoate | C15H19Cl2NO4 | 详情 | 详情 | |
| (III) | 51617 | methyl (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(3,4-dichlorophenyl)propanoate | C16H21Cl2NO4 | 详情 | 详情 | |
| (IV) | 51618 | tert-butyl (1R)-1-(3,4-dichlorobenzyl)-2-oxoethyl(methyl)carbamate | C15H19Cl2NO3 | 详情 | 详情 | |
| (V) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VI) | 51619 | ethyl (E,4R)-4-[(tert-butoxycarbonyl)(methyl)amino]-5-(3,4-dichlorophenyl)-2-pentenoate | C19H25Cl2NO4 | 详情 | 详情 | |
| (VII) | 51620 | (E,4R)-4-[(tert-butoxycarbonyl)(methyl)amino]-5-(3,4-dichlorophenyl)-2-pentenoic acid | C17H21Cl2NO4 | 详情 | 详情 | |
| (VIII) | 51621 | (3R)-3-amino-2-azepanone | C6H12N2O | 详情 | 详情 | |
| (IX) | 51622 | tert-butyl (1R,2E)-1-(3,4-dichlorobenzyl)-4-oxo-4-[[(3R)-2-oxoazepanyl]amino]-2-butenyl(methyl)carbamate | C23H31Cl2N3O4 | 详情 | 详情 | |
| (X) | 51623 | (E,4R)-5-(3,4-dichlorophenyl)-4-(methylamino)-N-[(3R)-2-oxoazepanyl]-2-pentenamide | C18H23Cl2N3O2 | 详情 | 详情 | |
| (XI) | 18290 | 3,5-Bis(trifluoromethyl)benzoyl chloride | 785-56-8 | C9H3ClF6O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)Reductive alkylation of (S)-(4-fluorophenyl)glycine (VI) with benzaldehyde and NaBH4 generated the N-benzyl amino acid (XI). This was cyclized with 1,2-dibromoethane (XII) to yield the morpholinone (XIII). Reduction of the lactone function of (XIII) with L-Selectride at -70 C, followed by acylation of the intermediate lactol (XIV) with 3,5-bis(trifluoromethyl)benzoyl chloride (XV), furnished the aroyloxy morpholine (XVI) as the main isomer. Ester (XVI) was converted to the enol ether (XVII) upon treatment with dimethyltitanocene, generated from titanocene dichloride and methyllithium. Catalytic hydrogenation of the enol ether double bond of (XVII) with simultaneous benzyl group hydrogenolysis generated the desired morpholine (XVIII) along with its diastereoisomer (XIX); these were separated by flash chromatography.
| 【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 . |
| 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) | 43098 | (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid | 7292-73-1 | C8H8FNO2 | 详情 | 详情 |
| (XI) | 44190 | (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid | C15H14FNO2 | 详情 | 详情 | |
| (XII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XIII) | 18288 | (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone | C17H16FNO2 | 详情 | 详情 | |
| (XIV) | 18289 | (2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol | C17H18FNO2 | 详情 | 详情 | |
| (XV) | 18290 | 3,5-Bis(trifluoromethyl)benzoyl chloride | 785-56-8 | C9H3ClF6O | 详情 | 详情 |
| (XVI) | 18291 | (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate | C26H20F7NO3 | 详情 | 详情 | |
| (XVII) | 18292 | (2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether | C27H22F7NO2 | 详情 | 详情 | |
| (XVIII) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XIX) | 53292 | (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine | n/a | C20H18F7NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Acylation of 5-chloroanisidine (I) with 3,5-bis(trifluoromethyl)benzoyl chloride (II) affords benzamide (III). Treatment of amide (III) with PCl5, followed by reaction of the intermediate iminoyl chloride with hydrazine in THF generates the amidrazone (IV). Cyclization of (IV) with carbonyl diimidazole leads to triazolone (V). Finally, methyl ether cleavage in (V) employing pyridine hydrochloride at 225 C provides the target phenol compound.
| 【1】 Romine, J.L.; et al.; 4,5-Diphenyltriazol-3-ones: Openers of large-conductance Ca2+-activated potassium (maxi-K) channels. J Med Chem 2002, 45, 14, 2942. |
| 【2】 Meanwell, N.A.; Starrett, J.E. Jr.; Hewawasam, P.; Romine, J.L.; Martin, S.W.; Gribkoff, V.K. (Bristol-Myers Squibb Co.); Diphenyl oxadiazolones as potassium channel modulators. JP 2000516925; US 5869509; WO 9804135 . |
| 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) | 37092 | 5-chloro-2-methoxyphenylamine; 5-chloro-2-methoxyaniline | 95-03-4 | C7H8ClNO | 详情 | 详情 |
| (II) | 18290 | 3,5-Bis(trifluoromethyl)benzoyl chloride | 785-56-8 | C9H3ClF6O | 详情 | 详情 |
| (III) | 58514 | N-(5-chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)benzamide | C16H10ClF6NO2 | 详情 | 详情 | |
| (IV) | 58515 | N-(5-chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)benzenecarbohydrazonamide | C16H12ClF6N3O | 详情 | 详情 | |
| (V) | 58516 | 5-[3,5-bis(trifluoromethyl)phenyl]-4-(5-chloro-2-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C17H10ClF6N3O2 | 详情 | 详情 |