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【结 构 式】

【分子编号】17410

【品名】Ethyl isonipecotate; ethyl 4-piperidinecarboxylate

【CA登记号】1126-09-6

【 分 子 式 】C8H15NO2

【 分 子 量 】157.21264

【元素组成】C 61.12% H 9.62% N 8.91% O 20.35%
与该中间体有关的原料药合成路线共 18 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16合成路线17合成路线18

合成路线1

该中间体在本合成路线中的序号：(I)

AHR-53338 is synthesized in an overall yield of 62% from ethyl isonipecotate (I): Ethyl isonipecotate (I) is protected with benzyl bromide (II) to give (III), which is then treated with 2.5 moles of 4-fluorophenylmagnesium bromide to give the tertiary alcohol (IV). The benzyl group is removed by catalytic hydrogenolysis to give the secondary piperidine (V). The reaction of 1-bromo-3-chloropropane (VI) with acetovanillone (VII) gives 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (VIII) in excellent yield. A mixture of (V) and (VIII) in 1-butanol and triethylamine heated at reflux yields AHR-53338 isolated as the mandelic acid salt.

参考文献 中间体
合成目标
【1】 Yanni, J.M.; Walsh, D.A.; Franzyshen, S.K.; The synthesis and antiallergy activity of 1-[4-[3-. 193rd ACS Natl Meet 1987, Abst MEDI 85.
【2】 Yanni, J.M.; Walsh, D.A.; AHR-5333B. Drugs Fut 1988, 13, 7, 605.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
(B) 28161 2-hydroxy-2-phenylacetic acid 611-72-3 C8H8O3 详情 详情
(I) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 22600 ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine 24228-40-8 C15H21NO2 详情 详情
(IV) 22601 (1-benzyl-4-piperidinyl)[bis(4-fluorophenyl)]methanol C25H25F2NO 详情 详情
(V) 22602 bis(4-fluorophenyl)(4-piperidinyl)methanol 60284-98-2 C18H19F2NO 详情 详情
(VI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VII) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(VIII) 22605 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone 58113-30-7 C12H15ClO3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

3) Racemic MDL-100907 (VII) can also be obtained as follows: The reaction of piperidine-4-carboxylic acid ethyl ester (XVIII) with the previously mentioned bromide (II) by means of K2CO3 as before gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxylic acid ethyl ester (XIX), which is treated with N,O-dimethylhydroxylamine (XIII) to afford carboxamide (XX). The condensation of (XX) with veratrole (VI) by means of BuLi as before yields the ketonic precursor (XVII), which is finally reduced as before. 4) [11C]-Radiolabeled MDL-100907 can be obtained as follows: Racemic MDL-100907 (VII) is treated with L-Selectride in THF, yielding racemic 1-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]-1-(3-hydroxy-2-methoxy-phenyl)methanol (rac-XXI), which is submitted to semi-preparative HPLC separation over Chiracel OD, affording pure (R-XXI). Finally, this compound is methylated with [11C]-methyl iodide and KOH in HMPA. If this methylation is performed with nonlabeled methyl iodide, MDL-100907 is obtained. 5) The radiolabeling of phenol (R-XXI) can also be performed with better yields using [11C]-methyl trifluoromethanesulfonate (XXII) as methylating agent. Triflate (XXII) is obtained by reaction of silver triflate with [11C]-methyl iodide.

参考文献 中间体
合成目标
【1】 Mathis, C.A.; Mahmood, K.; Price, J.C.; Huang, Y.; Gerdes, J.M.; Simpson, N.R.; Synthesis and preliminary in vivo evaluation of [11C]MDL 100907: A potent and selective radioligand for the 5-HT2A receptor system. Med Chem Res 1996, 6, 1, 1-10.
【2】 Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; MDL-100907. Drugs Fut 1998, 23, 9, 955.
【3】 Hiyama, T.; Minami, T.; Hanamoto, T.; Reddy, G.B. (Sagami Chemical Research Center); Optically active esters of 7-substd. 3,5-difunctionalized 6-heptenoic acids. EP 0475627 .
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) 17394 1-(2-bromoethyl)-4-fluorobenzene C8H8BrF 详情 详情
(VI) 17398 2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene 91-16-7 C8H10O2 详情 详情
(VII) 17399 (2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol C22H28FNO3 详情 详情
(XIII) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XVII) 17409 (2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone C22H26FNO3 详情 详情
(XVIII) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(XIX) 17411 ethyl 1-(4-fluorophenethyl)-4-piperidinecarboxylate C16H22FNO2 详情 详情
(XX) 17412 1-(4-fluorophenethyl)-N-methoxy-N-methyl-4-piperidinecarboxamide C16H23FN2O2 详情 详情
(XXI) 17413 3-[(R)-[1-(4-fluorophenethyl)-4-piperidinyl](hydroxy)methyl]-2-methoxyphenol C21H26FNO3 详情 详情
(XXII) 17414 methyl trifluoromethane sulfonate; methyl trifluoromethanesulfonate 333-27-7 C2H3F3O3S 详情 详情
(XXII) 45233 methyl trifluoromethanesulfonate C2H3F3O3S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The synthesis of MDL-100907 [11C]-labeled at the 2'-methoxy group has been reported: Condensation of 2-(4-fluorophenyl)ethyl bromide (I) with piperidine-4-carboxylic acid ethyl ester (II) by means of K2CO3 in DMF gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxylic acid ethyl ester (III), which is treated with N,O-dimethylhydroxylamine and ethylmagnesium bromide in THF to yield compound (IV). Condensation of (IV) with veratrole (V) by means of BuLi in THF affords the 4-benzoylpiperidine derivative (VI), which is reduced with NaBH4 in methanol to give the racemic carbinol (VII). Optical resolution of (VII) by esterification with (S)-2-methoxy-2-phenylacetic acid (VIII) by means of DCC and DMAP in chloroform followed by column chromatography yields the diastereomer (IX), which is hydrolyzed with K2CO3 in methanol to afford MDL-100907 (X). Selective demethylation of (X) with L-selectride in THF gives the 2'-hydroxy derivative (XI), which is finally remethylated with [11C]-methyl iodide and K2CO3 in methanol.

参考文献 中间体
合成目标
【1】 Mathis, C.A.; Huang, Y.Y.; Mahmood, K.; An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions. J Label Compd Radiopharm 1999, 42, 10, 949.
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) 17394 1-(2-bromoethyl)-4-fluorobenzene C8H8BrF 详情 详情
(II) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(III) 17411 ethyl 1-(4-fluorophenethyl)-4-piperidinecarboxylate C16H22FNO2 详情 详情
(IV) 17412 1-(4-fluorophenethyl)-N-methoxy-N-methyl-4-piperidinecarboxamide C16H23FN2O2 详情 详情
(V) 40496 tert-butyl(2-methoxyphenoxy)diphenylsilane; tert-butyl(diphenyl)silyl 2-methoxyphenyl ether C23H26O2Si 详情 详情
(VI) 17409 (2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone C22H26FNO3 详情 详情
(VII) 17399 (2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol C22H28FNO3 详情 详情
(VIII) 17400 (2S)-2-methoxy-2-phenylethanoic acid C9H10O3 详情 详情
(IX) 17401 (R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate C31H36FNO5 详情 详情
(X) 40494 (R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol C22H28FNO3 详情 详情
(XI) 40495 2-[(R)-[1-(4-fluorophenethyl)-4-piperidinyl](hydroxy)methyl]-6-methoxyphenol C21H26FNO3 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 synthesis of MDL-100907 [11C]-labeled at the 3'-methoxy group has been described: Condensation of 2-(4-fluorophenyl)ethyl bromide (I) with piperidine-4-carboxylic acid ethyl ester (II) by means of K2CO3 in DMF gives 1-[2-(4-fluorophenyl)ethyl]piperidine-4-carboxylic acid ethyl ester (III), which is treated with N,O-dimethylhydroxylamine and ethylmagnesium bromide in THF yielding the carbohydroxamic ester (IV). The condensation of (IV) with the silylated guaiacole (V) by means of n-BuLi in THF affords the 4-benzoylpiperidine (VI), which is reduced with NaBH4 in methanol giving the racemic carbinol (VII). Optical resolution of (VII) by esterification with (S)-2-methoxy-2-phenylacetic acid (VIII) by means of DCC and DMAP in chloroform followed by column chromatography yields the diastereomer (IX), which is simultaneously hydrolyzed and desilylated with K2CO3 in methanol affording the chiral carbinol (X). Finally, (X) is methylated with [11C]-methyl iodide and K2CO3 in methanol.

参考文献 中间体
合成目标
【1】 Mathis, C.A.; Huang, Y.Y.; Mahmood, K.; An efficient synthesis of the precursors of [11C]MDL 100907 labeled in two specific positions. J Label Compd Radiopharm 1999, 42, 10, 949.
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) 17394 1-(2-bromoethyl)-4-fluorobenzene C8H8BrF 详情 详情
(II) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(III) 17411 ethyl 1-(4-fluorophenethyl)-4-piperidinecarboxylate C16H22FNO2 详情 详情
(IV) 17412 1-(4-fluorophenethyl)-N-methoxy-N-methyl-4-piperidinecarboxamide C16H23FN2O2 详情 详情
(V) 40496 tert-butyl(2-methoxyphenoxy)diphenylsilane; tert-butyl(diphenyl)silyl 2-methoxyphenyl ether C23H26O2Si 详情 详情
(VI) 40497 (3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanone C37H42FNO3Si 详情 详情
(VII) 40498 (3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methanol C37H44FNO3Si 详情 详情
(VIII) 17401 (R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate C31H36FNO5 详情 详情
(IX) 40499 (R)-(3-[[tert-butyl(diphenyl)silyl]oxy]-2-methoxyphenyl)[1-(4-fluorophenethyl)-4-piperidinyl]methyl (2S)-2-methoxy-2-phenylethanoate C46H52FNO5Si 详情 详情
(X) 17413 3-[(R)-[1-(4-fluorophenethyl)-4-piperidinyl](hydroxy)methyl]-2-methoxyphenol C21H26FNO3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VI)

The chlorination of 8-acetamido-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (I) with chlorine in acetic acid gives the 7-chloro derivative (II), which is treated with aqueous NaOH to yield 8-amino-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (III). The reaction of (III) with carbonyldiimidazole (CDI) affords the activated intermediate (IV), which is finally condensed with 1-(1-butylpiperidin-4-yl)methanol (V) by means of MeLi in THF. The intermediate 1-(1-butylpiperidin-4-yl)methanol (V) has been obtained by condensation of piperidine-4-carboxylic acid ethyl ester (VI) with 1-bromobutane (VII) by means of K2CO3 in methanol, followed by reduction of the ester group with LiAlH4 in THF.

参考文献 中间体
合成目标
【1】 Bulteau, G.; Acher, J.; Thominet, M.; Collignon, C. (Ile de France); Substituted 2,3-alkylenedioxybenzamides. DE 2734270; FR 2360305; GB 1571278; GB 1571447; JP 53018570; US 4186135; US 4248885; US 4255580 .
【2】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 12, 1109.
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) 41270 8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid C11H11NO5 详情 详情
(II) 41271 8-(acetamido)-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid C11H10ClNO5 详情 详情
(III) 41272 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid C9H8ClNO4 详情 详情
(IV) 41273 (8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)(1H-imidazol-1-yl)methanone C12H10ClN3O3 详情 详情
(V) 41274 (1-butyl-4-piperidinyl)methanol C10H21NO 详情 详情
(VI) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(VII) 28721 1-bromobutane 109-65-9 C4H9Br 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

Condensation of ethyl 4-piperidinecarboxylate (I) with benzoyl chloride in pyridine afforded the corresponding benzamide (II). After reduction of the ester group of (II) with NaBH4, the resulting alcohol (III) was converted to chloride (IV) by means of SOCl2. Elimination of the chlorine atom of (IV) with potassium tert-butoxide produced N-benzoyl-4-methylenepiperidine (V), which was hydrolyzed with KOH to yield 4-methylenepiperidine (VI). Finally, condensation of (VI) with the known epoxide (VII) in refluxing EtOH furnished the title compound.

参考文献 中间体
合成目标
【1】 Ogura, H.; et al.; Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives as topical antifungal agents. Chem Pharm Bull 1999, 47, 10, 1417.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(I) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 31733 ethyl 1-benzoyl-4-piperidinecarboxylate C15H19NO3 详情 详情
(III) 31734 [4-(hydroxymethyl)-1-piperidinyl](phenyl)methanone C13H17NO2 详情 详情
(IV) 31735 [4-(chloromethyl)-1-piperidinyl](phenyl)methanone C13H16ClNO 详情 详情
(V) 31736 (4-methylene-1-piperidinyl)(phenyl)methanone C13H15NO 详情 详情
(VI) 31737 4-methylenepiperidine C6H11N 详情 详情
(VII) 31738 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

Ethyl isonipecotate (I) was protected as the N-trityl derivative (II) using triphenylmethyl chloride and triethylamine. Addition of Grignard reagent (IV) (prepared from 1-bromo-4-fluorobenzene (III) and magnesium in Et2O) to (II) produced the diaryl carbinol (V). Alcohol dehydration with simultaneous trityl group cleavage under acidic conditions yielded 4-[bis(4-fluorophenyl)methylene]piperidine (VI). 4-Chlorobutyrylpyrrolidine (IX), prepared by coupling of 4-chlorobutyryl chloride (VII) and pyrrolidine (VIII), was then condensed with piperidine (VI) to yield the target compound.

参考文献 中间体
合成目标
【1】 Rae, D.R.; Jaap, D.R. (Akzo Nobel N.V.); Diphenylmethylene piperidine derivs.. EP 0842170; JP 1999508907; US 5935974; WO 9703065 .
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 33780 ethyl 1-trityl-4-piperidinecarboxylate C27H29NO2 详情 详情
(III) 29012 1-bromo-4-fluorobenzene 460-00-4 C6H4BrF 详情 详情
(IV) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
(V) 33781 bis(4-fluorophenyl)(1-trityl-4-piperidinyl)methanol C37H33F2NO 详情 详情
(VI) 24706 4-[bis(4-fluorophenyl)methylene]piperidine C18H17F2N 详情 详情
(VII) 11265 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride 4635-59-0 C4H6Cl2O 详情 详情
(VIII) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IX) 33782 4-chloro-1-(1-pyrrolidinyl)-1-butanone C8H14ClNO 详情 详情

合成路线8

该中间体在本合成路线中的序号：(I)

Reduction of ethyl 4-piperidinecarboxylate (I) with LiAlH4 in THF provided 4-piperidinemethanol (II), which was coupled with 3-ethoxybenzoyl chloride (III) in the presence of Et3N, yielding amide (IV). Subsequent treatment of (IV) with p-toluenesulfonyl chloride in pyridine afforded the corresponding tosylate (V. This was finally condensed with 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (VI) to furnish the title compound.

参考文献 中间体
合成目标
【1】 George, P.; Sevrin, M.; Maloizel, C.; Tixidre, A.; Froissant, J. (Sanofi-Synthelabo ); Derivs. of 2-[(4-piperidinyl)methyl]-1,2,3, 4-tetrahydroisoquinoline, their use in therapy. AU 8929617; EP 0351255; JP 1990025481; US 4925850 .
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 32954 4-piperidinylmethanol C6H13NO 详情 详情
(III) 32955 3-ethoxybenzoyl chloride 61956-65-8 C9H9ClO2 详情 详情
(IV) 32956 (3-ethoxyphenyl)[4-(hydroxymethyl)-1-piperidinyl]methanone C15H21NO3 详情 详情
(V) 32957 [1-(3-ethoxybenzoyl)-4-piperidinyl]methyl 4-methylbenzenesulfonate C22H27NO5S 详情 详情
(VI) 32958 5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 5-methoxy-1,2,3,4-tetrahydro-8-isoquinolinyl methyl ether C11H15NO2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

Protection of 3-methyl-3-sulfanylbutanoic acid (I) by treatment with 2,4,6-trimethoxybenzyl alcohol (II) and trifluoroacetic acid produced the trimethoxybenzyl thioether (III). Subsequent coupling of (III) with ethyl isonipecotate (IV) using EDC and DMAP gave amide (V). The ethyl ester group of (V) was then hydrolyzed to carboxylic acid (VI) by means of ethanolic NaOH. This was then condensed with 4-[2-(dimethylamino)ethoxy]-2-methyl-5-isopropylphenol (VIII), prepared by basic hydrolysis of moxisylyte (VII), and the resulting ester (IX) was deprotected with trifluoroacetic acid to give thiol (X). Finally, S-nitrosation of (X) with tert-butyl nitrite, followed by treatment with succinic acid furnished the title compound.

参考文献 中间体
合成目标
【1】 Earl, R.A.; et al.; Nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of erectile dysfunction. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 239.
【2】 Gaston, R.D.; Saenz de Tejada, I.; Schroeder, J.D.; Shelekhin, T.E.; Garvey, D.S.; Wang, T. (NitroMed Inc.); Nitrosated and nitrosylated alpha-adrenergic receptor antagonists, compsns. and methods of use. WO 0012075 .
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) 32947 3-methyl-3-sulfanylbutyric acid C5H10O2S 详情 详情
(II) 38877 (2,4,6-trimethoxyphenyl)methanol C10H14O4 详情 详情
(III) 38878 3-methyl-3-[(2,4,6-trimethoxybenzyl)sulfanyl]butyric acid C15H22O5S 详情 详情
(IV) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(V) 38879 ethyl 1-[3-methyl-3-[(2,4,6-trimethoxybenzyl)sulfanyl]butanoyl]-4-piperidinecarboxylate C23H35NO6S 详情 详情
(VI) 38880 1-[3-methyl-3-[(2,4,6-trimethoxybenzyl)sulfanyl]butanoyl]-4-piperidinecarboxylic acid C21H31NO6S 详情 详情
(VII) 38875 4-[2-(dimethylamino)ethoxy]-5-isopropyl-2-methylphenyl acetate C16H25NO3 详情 详情
(VIII) 38876 4-[2-(dimethylamino)ethoxy]-5-isopropyl-2-methylphenol C14H23NO2 详情 详情
(IX) 38881 4-[2-(dimethylamino)ethoxy]-5-isopropyl-2-methylphenyl 1-[3-methyl-3-[(2,4,6-trimethoxybenzyl)sulfanyl]butanoyl]-4-piperidinecarboxylate C35H52N2O7S 详情 详情
(X) 38882 4-[2-(dimethylamino)ethoxy]-5-isopropyl-2-methylphenyl 1-(3-methyl-3-sulfanylbutanoyl)-4-piperidinecarboxylate C25H40N2O4S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IX)

An alternative preparation for the title compound consisted in the reductive alkylation of ethyl isonipecotate (IX) with acetone to afford the N-isopropyl isonipecotate (X). After basic hydrolysis of the ethyl ester group of (X), the resulting carboxylic acid (XI) was activated as the mixed anhydride (XII) with isobutyl chloroformate. Anhydride (XII) was finally coupled to aniline (IV) to generate the required amide.

参考文献 中间体
合成目标
【1】 Aromatic amides. WO 0039118 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(X) 44139 ethyl 1-isopropyl-4-piperidinecarboxylate C11H21NO2 详情 详情
(XI) 44140 1-isopropyl-4-piperidinecarboxylic acid C9H17NO2 详情 详情
(XII) 44141 　 C14H25NO4 详情 详情
(XIII) 44135 2-amino-5-chloro-N-(5-chloro-2-pyridinyl)benzamide C12H9Cl2N3O 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) employing di-tert-butyl dicarbonate. Sulfenylation of the lithium enolate of ester (II) with the disulfide (IV), generated from the oxidation of 4-fluorothiophenol (III), furnished the phenylsulfanyl derivative (V). Thioether (V) was then oxidized to the corresponding sulfone (VI) by means of meta-chloroperbenzoic acid. After acidic Boc group cleavage in (VI), the resultant piperidine (VII) was alkylated with propargyl bromide (VIII) to produce the N-propargyl piperidine (IX).

参考文献 中间体
合成目标
【1】 Becker, D.P.; Hockerman, S.L.; Barta, T.E.; et al.; Design and synthesis of beta-sulfone and alpha-sulfone hydroxamates as potent and orally active MMP inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 259.
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(III) 22971 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 371-42-6 C6H5FS 详情 详情
(IV) 52287 bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene C12H8F2S2 详情 详情
(V) 52288 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate C19H26FNO4S 详情 详情
(VI) 52289 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate C19H26FNO6S 详情 详情
(VII) 52290 ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C14H18FNO4S 详情 详情
(VIII) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(IX) 56377 ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxylate C17H20FNO4S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF. The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV), prepared by oxidation of 4-fluorothiophenol (III), yielding thioether (V). This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid. Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII), which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN. Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI). After saponification of the ester group of (XI), the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII). Finally, removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.

参考文献 中间体
合成目标
【1】 Villamil, C.I.; et al.; Design and synthesis of 4,4-disubstituted piperidine alpha-sulphone hydroxamates as potent and selective MMP inhibitors: The discovery of SC-77964. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 258.
【2】 Aromatic sulfone hydroxamic acid metalloprotease inhibitor. WO 0050396 .
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(III) 22971 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 371-42-6 C6H5FS 详情 详情
(IV) 52287 bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene C12H8F2S2 详情 详情
(V) 52288 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate C19H26FNO4S 详情 详情
(VI) 52289 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate C19H26FNO6S 详情 详情
(VII) 52290 ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C14H18FNO4S 详情 详情
(VIII) 52291 Cyclopropanone ethyl trimethylsilyl acetal; (1-Ethoxycyclopropoxy)trimethylsilane C8H18O2Si 详情 详情
(IX) 52292 ethyl 1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C17H22FNO4S 详情 详情
(X) 18780 4-(trifluoromethoxy)phenol 828-27-3 C7H5F3O2 详情 详情
(XI) 52293 ethyl 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylate C24H26F3NO6S 详情 详情
(XII) 52294 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylic acid C22H22F3NO6S 详情 详情
(XIII) 52295 1-cyclopropyl-N-(tetrahydro-2H-pyran-2-yloxy)-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxamide C27H31F3N2O7S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) and then reduced to alcohol (III) using LiAlH4. Treatment of alcohol (III) with p-toluenesulfonyl chloride in the presence of DBU afforded the intermediate tosylate (IV).

参考文献 中间体
合成目标
【1】 Hennequin, L.F.A.; Stokes, E.S.E.; Thomas, A.P. (AstraZeneca AB; AstraZeneca plc); Quinazoline derivs. as VEGF inhibitors. WO 0132651 .
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(III) 40399 tert-butyl 4-(hydroxymethyl)-1-piperidinecarboxylate C11H21NO3 详情 详情
(IV) 49848 tert-butyl 4-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-piperidinecarboxylate C18H27NO5S 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IX)

The intermediate silyl sulfide (II) was prepared by palladium-catalyzed displacement of 5-bromo-1-methylindole (I) with potassium (triisopropylsilyl)sulfide. Alternatively, 5-iodoindole (III) was N-methylated with iodomethane and NaH, yielding 5-iodo-1-methylindole (IV), which was then reacted with potassium (triisopropylsilyl)sulfide to give (II). Condensation of silyl sulfide (II) with the aryl triflate (V) in the presence of CsF as the desilylating reagent furnished the diaryl sulfide (VI). Knoevenagel condensation of aldehyde (VI) with malonic acid (VII) gave rise to the cinnamic acid derivative (VIII). This was then coupled with ethyl isonipecotate (IX), producing amide (X). The ethyl ester of (X) was finally hydrolyzed with NaOH to yield the title sodium carboxylate salt.

参考文献 中间体
合成目标
【1】 Reilly, E.B.; Liu, G.; Winn, M.; et al.; Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationships of substituents on the benzene ring of the cinnamide. J Med Chem 2001, 44, 25, 4393.
【2】 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 .
【3】 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 .
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) 29521 5-bromo-1-methyl-1H-indole C9H8BrN 详情 详情
(II) 53020 1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide n/a C18H29NSSi 详情 详情
(III) 40983 5-iodo-1H-indole C8H6IN 详情 详情
(IV) 53021 5-iodo-1-methyl-1H-indole n/a C9H8IN 详情 详情
(V) 52029 2,3-dichloro-4-formylphenyl trifluoromethanesulfonate C8H3Cl2F3O4S 详情 详情
(VI) 53022 2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]benzaldehyde n/a C16H11Cl2NOS 详情 详情
(VII) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(VIII) 53023 (E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid n/a C18H13Cl2NO2S 详情 详情
(IX) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(X) 53024 ethyl 1-((E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoyl)-4-piperidinecarboxylate n/a C26H26Cl2N2O3S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The condensation between 2-fluorobenzonitrile (I) and ethyl isonipecotate (II) produced the piperidino benzonitrile (III). Reduction of nitrile and ester functions of (III) to afford the intermediate amino alcohol (IV) was accomplished using either LiAlH4 or, in a more practical, scalable procedure, using NaBH4/ZnCl2.

参考文献 中间体
合成目标
【1】 Fujino, K.; et al.; Development of a practical synthetic route of a PDE V inhibitor KF31327. Org Process Res Dev 2001, 5, 4, 426.
【2】 Fujino, K.; et al.; Process development of a PDE V inhibitor KF31327. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst ORGN 612.
【3】 Onoda, Y.; Nomoto, Y.; Ohno, T.; Yamada, K.; Ichimura, M. (Kyowa Hakko Kogyo Co., Ltd.); Imidazoquinazoline derivs.. EP 0863144; WO 9808848 .
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) 41199 2-fluorobenzonitrile 394-47-8 C7H4FN 详情 详情
(II) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(III) 54824 ethyl 1-(2-cyanophenyl)-4-piperidinecarboxylate C15H18N2O2 详情 详情
(IV) 54825 {1-[2-(aminomethyl)phenyl]-4-piperidinyl}methanol C13H20N2O 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VI)

4-Hydroxydiphenylmethane (I) is condensed with tert-butyl bromoacetate (II) in the presence of NaH and Bu-4NI to form the aryloxyacetate adduct (III). Ester group reduction in (III) employing LiAlH4 provides alcohol (IV), which is further treated with p-toluenesulfonyl chloride in pyridine, yielding tosylate (V) (1,2). Finally, condensation of tosylate (V) with ethyl isonipecotate (VI) furnishes the title compound (1-3).

参考文献 中间体
合成目标
【1】 Pyrrolidine and piperidine analogues of SC-57461A as potent, orally active inhibitors of leukotriene A(4) hydrolase. Bioorg Med Chem Lett 2002, 12, 23, 3383.
【2】 Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.F.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitor pharmaceutical compsns. and methods of use. JP 1998512542; WO 9610999 .
【3】 Chandrakumar, N.S.; Chen, B.B.; Clare, M.; Desai, B.N.; Djuric, S.W.; Docter, S.H.; Gasiecki, A.; Haack, R.A.; Liang, C.-D.; Miyashiro, J.M.; Penning, T.D.; Russell, M.A.; Yu, S.S. (Pfizer Inc.); LTA4 hydrolase inhibitors. EP 0804427; EP 1221441; JP 1998512848; WO 9611192 .
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) 50817 4-Hydroxydiphenylmethane; 4-Benzylphenol; alpha-Phenyl-p-cresol; p-Benzylphenol 101-53-1 C13H12O 详情 详情
(II) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(III) 64434 tert-butyl 2-(4-benzylphenoxy)acetate C19H22O3 详情 详情
(IV) 64435 2-(4-benzylphenoxy)-1-ethanol C15H16O2 详情 详情
(V) 64436 2-(4-benzylphenoxy)ethyl 4-methylbenzenesulfonate C22H22O4S 详情 详情
(VI) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(I)

Alkylation of ethyl isonipecotate (I) with 1-bromo-2-chloroethane (II) in the presence of K2CO3 in acetone yields ethyl 1-(2-chloro-ethyl)piperidine-4-carboxylate (III), which by treatment with LDA in THF cyclizes to the quinuclidine derivative (IV) . Alternatively, quinuclidine (IV) can be prepared by alkylation of Boc-protected ethyl nipecotate (V) with 1-bromo-2-chloroethane (II) using LiHMDS in toluene to yield the 4-(2-chloroethyl)piperidine derivative (VI), which is then N-deprotected with HCl in water/dioxane, followed by cyclization of the resulting chloro amine (VII) by means of K2CO3 in refluxing toluene . Addition of phenyl lithium (VIII) to ester (IV) in THF affords 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IX), which finally undergoes quaternization with benzyl 2-bromoethyl ether (X) in acetonitrile/chloroform .

参考文献 中间体
合成目标
【1】 Lainé, D.I., McCleland, B., Thomas, S. et al. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009, 52(8): 2493-505.
【2】 Lainé, D.I., Palovich, M.R., McCleland, B.W., Neipp, C.E., Thomas, S.M.(GlaxoSmithKline plc). Muscarinic acetylcholine receptor antagonists. CA 2564742, CN 102040602, EP 1740177, JP 2007534769, KR 2011010841, US 200785155, US 7498440, US 8183257, US 2012157491, US 8309572, US 2013030015, WO 2005104745.
【3】 Carangio, A., Cheung, I., D’Souza, E.C.F., Leahy, J.H., Strachan, J.B. (GlaxoSmithKline plc). Methods of preparation of muscarinic acetylcholine receptor antagonists. WO 2011029896.
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 24271 1-bromo-2-chloroethane 107-04-0 C2H4BrCl 详情 详情
(III) 67994 ethyl 1-(2-chloroethyl)piperidine-4-carboxylate 　 C10H18ClNO2 详情 详情
(IV) 67995 ethyl quinuclidine-4-carboxylate 　 C10H17NO2 详情 详情
(V) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(VI) 67996 1-tert-butyl 4-ethyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate 　 C15H26ClNO4 详情 详情
(VII) 67997 ethyl 4-(2-chloroethyl)piperidine-4-carboxylate hydrochloride 　 C10H18ClNO2.HCl 详情 详情
(VIII) 24014 Phenyllithium 591-51-5 C6H5Li 详情 详情
(IX) 67998 diphenyl(quinuclidin-4-yl)methanol;1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol 　 C20H23NO 详情 详情
(X) 35528 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether 1462-37-9 C9H11BrO 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IX)

Bromination of 1-(4-chloro-2-thienyl)ethanone (I) with Br2 in Et2O gives 2-bromo-1-(4-chloro-2-thienyl)ethanone (II), which by cyclocondensation with thiourea (III) in EtOH at 80 °C provides 2-amino-4-(4-chloro-2-thienyl)thiazole (IV). Treatment of thiazole (IV) with NBS in DMF and subsequent condensation with 1-cyclohexylpiperazine (V) by means of Et3N at 70 °C affords the 5-piperazinyl-thiazole derivative (VI). Coupling of the 2-aminothiazole (VI) with 5,6-dichloronicotinic acid (VII) in the presence of POCl3 in pyridine yields amide (VIII), which is then condensed with ethyl isonipecotate (IX) in THF at 50 °C to obtain the ethyl 1-(pyridyl)piperidine-4-carboxylate derivative (X). Finally, ethyl ester (X) is hydrolyzed by means of NaOH in MeOH .

参考文献 中间体
合成目标
【1】 Watanuki, S., Nagata, H., Wakayama, R. et al. 2-Acylaminothiazole derivative or salt thereof. EP 1466912, EP 2314586, JP 2009111001, US 2005153977, US 7638536, US 2010222329, US 2010222361, WO 2003062233.
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) 68277 1-(4-chloro-2-thienyl)ethanone;4-Chloro-2-acetylthiophene 34730-20-6 C6H5ClOS 详情 详情
(II) 68278 2-bromo-1-(4-chloro-2-thienyl)ethanone 　 C6H4BrClOS 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 68279 2-amino-4-(4-chloro-2-thienyl)thiazole 　 C7H5ClN2S2 详情 详情
(V) 23174 1-cyclohexylpiperazine 17766-28-8 C10H20N2 详情 详情
(VI) 68280 4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine 　 C17H23ClN4S2 详情 详情
(VII) 68282 5,6-dichloronicotinic acid 41667-95-2 C6H3Cl2NO2 详情 详情
(VIII) 68281 5,6-dichloro-N-(4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)nicotinamide 　 C23H24Cl3N5OS2 详情 详情
(IX) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(X) 68283 ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate 　 C31H38Cl2N6O3S2 详情 详情
Extended Information