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【结 构 式】

【分子编号】18620

【品名】tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone

【CA登记号】79099-07-3

【 分 子 式 】C10H17NO3

【 分 子 量 】199.24992

【元素组成】C 60.28% H 8.6% N 7.03% O 24.09%
与该中间体有关的原料药合成路线共 37 条
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合成路线1

该中间体在本合成路线中的序号：(II)

Swern oxidation of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I) with oxalyl chloride in DMSO/dichloromethane gives the corresponding piperidone (II), which is submitted to a Grignard reaction with [U-14C]phenylmagnesium bromide (III) in THF to yield 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (IV). The reaction of (IV) with BF3/Et2O in dichloromethane affords labeled 4-phenyl-1,2,3,6-tetrahydropyridine (V), which is condensed with 3-phenyl-3-cyclohexene-1(R)-carboxylic acid (VI) by means of HOBT, DCC and TEA in ethyl acetate to provide the labeled 1-(3-phenyl-3-cyclohexen-1(R)-yl)-1-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methanone (VII). Finally, this compound is reduced with LiAlH4 and AlCl3 in THF to obtain the target tetrahydropyridine derivative.

参考文献 中间体
合成目标
【1】 Ekhato, I.V.; Huang, C.C.; Synthesis of (R)-(+)-1,2,3,6-tetrahydro-4-[U-14C]phenyl-1[(3-phenyl-3-cyclohexenyl-1-yl)methyl]pyridine, a potential antipsychotic agent. J Label Compd Radiopharm 1995, 36, 1, 57.
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) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 45167 　 C6H5BrMg 详情 详情
(III) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(IV) 57878 tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(IV) 64702 tert-butyl 4-hydroxy-4-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(V) 13002 4-Phenyl-1,2,3,6-tetrahydropyridine; 1,2,3,6-Tetrahydro-4-phenyl-pyridine 10338-69-9 C11H13N 详情 详情
(V) 64703 4-Phenyl-1,2,3,6-tetrahydro-pyridine 10338-69-9 C11H13N 详情 详情
(VI) 57879 (1R)-3-phenyl-3-cyclohexene-1-carboxylic acid C13H14O2 详情 详情
(VII) 54955 [(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone C24H25NO 详情 详情
(VII) 64704 [(1R)-3-phenyl-3-cyclohexen-1-yl][4-phenyl-3,6-dihydro-1(2H)-pyridinyl]methanone C24H25NO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

1) 2-Aminobenzyl alcohol (I) was condensed with N-tert-butoxycarbonyl-4-piperidone (II) in toluene with azeotropical removal of water, and the resulting imine (III) was reduced with sodium cyanoborohydride to yield the secondary amine (IV). Further treatment of (IV) with triphosgene in the presence of N,N-diisopropyl ethylamine (DIEA) produced the benzoxazinone (V), which was then deprotected with HCl in EtOAc to give piperidine (VI).

参考文献 中间体
合成目标
【1】 Development of orally active oxytocin antagonists: Studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl]piperidin-4-yl)-1, 4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines. J Med Chem 1998, 41, 12, 2146.
【2】 Bock, M.G.; Evans, B.E.; Hobbs, D.W.; Williams, P.D.; Anderson, P.S.; Freidinger, R.M.; Pettibone, D.J. (Merck & Co., Inc.); Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists. EP 0714299; JP 1997500134; US 5665719; WO 9502405 .
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) 18619 (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 5344-90-1 C7H9NO 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 19417 tert-butyl 4-[[2-(hydroxymethyl)phenyl]imino]-1-piperidinecarboxylate C17H24N2O3 详情 详情
(IV) 18621 tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate C17H26N2O3 详情 详情
(V) 18622 tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate C18H24N2O4 详情 详情
(VI) 19420 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one C13H16N2O2 详情 详情
(VII) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(VIII) 16623 methyl 2,4-dihydroxybenzoate 2150-47-2 C8H8O4 详情 详情
(IX) 19423 tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate C18H25NO6 详情 详情
(X) 18627 tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate C19H27NO6 详情 详情
(XI) 18628 4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid C18H25NO6 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

Condensation of 2-(hydroxymethyl)aniline (I) with N-Boc-4-piperidone (II), followed by reduction with NaBH3CN provided anilinopiperidine (III). Cyclization of aminoalcohol (III) with triphosgene gave benzoxazinone (IV), which was deprotected by acidic treatment to yield piperidinylbenzoxazinone (V). Methyl 2,4-dihydroxybenzoate (VI) was selectively alkylated on the 4-position by coupling with N-Boc-4-piperidinol (VII) under Mitsunobu conditions to give ether (VIII). Then, the remaining 2-OH group was methylated with MeI and NaH to give (IX), which was saponified to provide the benzoic acid derivative (X). Coupling of amine (V) and acid (X) using EDC and HOBt produced amide (XI). Then, removal of the tert-butoxycarbonyl group by acid treatment, followed by acetylation of the resulting piperidine (XII) with Ac2O, furnished the target compound.

参考文献 中间体
合成目标
【1】 Williams, P.D.; et al.; 1-[1-[4-[(N-Acetyl-4-piperidinyl)oxy]-2-methoxybenzoyl]piperidin-4-yl]-4H-3,1-benzoxazin-2(1H)-one (L-371, 257): A new, orally bioavailable, non-peptide oxytocin antagonist. J Med Chem 1995, 38, 23, 4634.
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) 18619 (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 5344-90-1 C7H9NO 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 18621 tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate C17H26N2O3 详情 详情
(IV) 18622 tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate C18H24N2O4 详情 详情
(V) 18623 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride C13H17ClN2O2 详情 详情
(VI) 16623 methyl 2,4-dihydroxybenzoate 2150-47-2 C8H8O4 详情 详情
(VII) 18625 tert-butyl 4-hydroxy-1-piperidinecarboxylate C10H19NO3 详情 详情
(VIII) 19423 tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate C18H25NO6 详情 详情
(IX) 18627 tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate C19H27NO6 详情 详情
(X) 18628 4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid C18H25NO6 详情 详情
(XI) 18629 tert-butyl 4-[3-methoxy-4-([4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinyl]carbonyl)phenoxy]-1-piperidinecarboxylate C31H39N3O7 详情 详情
(XII) 18630 1-[1-[2-methoxy-4-(4-piperidinyloxy)benzoyl]-4-piperidinyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride C26H32ClN3O5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(III)

Friedel-Crafts acetylation of acetaminophen (I) using acetyl chloride and AlCl3 gave acetophenone (II). Subsequent condensation of (II) with N-(tert-butoxycarbonyl)-4-piperidone (III) in the presence of pyrrolidine provided the spirochroman-2,4'-piperidine (IV), from which the diamine (V) was obtained by acid hydrolysis. The piperidine amino group of (VI) was then alkylated with 1-(2-bromoethyl)naphthalene (VI) to afford (VII). Finally, condensation of the remaining amino group of (VII) with the sulfonyl chloride (VIII) furnished the title sulfonamide.

参考文献 中间体
合成目标
【1】 Nerenberg, J.B.; et al.; 4-Oxospiro[benzopyran-2,4'-piperidines] as selective alpha1a-adrenergic receptor antagonists. Bioorg Med Chem Lett 1999, 9, 2, 291.
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) 21611 4'-Hydroxyacetanilide;4-Acetamidophenol;N-Acetyl-4-aminophenol;Paracetamol;Acetaminophen;p-Hydroxyacetanilide; Paracetamol; N-(4-hydroxyphenyl)acetamide 103-90-2 C8H9NO2 详情 详情
(II) 21612 N-(3-acetyl-4-hydroxyphenyl)acetamide C10H11NO3 详情 详情
(III) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IV) 21614 6-Aceatmido-4-oxo-3,4-dihydro-2H-spiro[1-benzopyran-2,4'-piperidin]-1'-ylcarboxylic acid tert-butyl ester C20H26N2O5 详情 详情
(V) 21615 6-Amino-3,4-dihydro-2H-spiro[1-benzopyran-2,4'-piperidin]-4-one C13H16N2O2 详情 详情
(VI) 21616 1-(2-bromoethyl)naphthalene 13686-49-2 C12H11Br 详情 详情
(VII) 21617 6-Amino-1'-[2-(1-naphthyl)ethyl]-3,4-dihydro-2H-spiro[1-benzopyran-2,4'-piperidin]-4-one C25H26N2O2 详情 详情
(VIII) 21618 3,5-dimethyl-4-isoxazolesulfonyl chloride 80466-79-1 C5H6ClNO3S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VII)

Ortho lithiation of sulfonamide (I) with n-butyllithium, followed by carbonation with CO2 afforded benzoic acid (II). Subsequent cyclization with PPA with concomitant elimination of the N-tert-butyl group provided the saccharin analogue (III). Alkylation of the sodium salt of (III) with 1,4-dibromobutane (IV) in DMF yielded bromide (V). The reductive alkylation of 2-aminophenol (VI) with 1-tert-butoxycarbonyl-4-piperidone (VII) in the presence of sodium tri(acetoxy)borohydride provided the aminopiperidine (VIII), which was cyclized with triphosgene to afford benzoxazolone (IX). Then, removal of the N-Boc protecting group provided piperidine (X), which was finally alkylated with bromide (V) in the presence of Et3N in DMF at 80 C to furnish the title compound.

参考文献 中间体
合成目标
【1】 Nerenberg, J.B.; Erb, J.M.; Thompson, W.J.; Lee, H.Y.; Guare, J.P.; Munson, P.M.; Bergman, J.M.; Huff, J.R.; Broten, T.P.; Chang, R.S.; Chen, T.B..; O'Malley, S.; Schorn, T.W.; Scott, A.L.; Design and synthesis of N-alkylated saccharins as selective alpha1-a adrenergic receptor antagonists. Bioorg Med Chem Lett 1998, 8, 18, 2467.
【2】 Lombardino, J.G.; Preparation of substituted 1,2-benzoisothiazolin-3-one 3 1,1-dioxides (o-benzoic sulfimides). J Org Chem 1971, 36, 13, 1843.
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) 18658 N-(tert-butyl)-4-chlorobenzenesulfonamide C10H14ClNO2S 详情 详情
(II) 18659 2-[(tert-butylamino)sulfonyl]-5-chlorobenzoic acid C11H14ClNO4S 详情 详情
(III) 18660 5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione C7H4ClNO3S 详情 详情
(IV) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(V) 18400 2-(4-bromobutyl)-5-chloro-1H-1,2-benzisothiazole-1,1,3(2H)-trione C11H11BrClNO3S 详情 详情
(VI) 18663 o-aminophenol; 2-aminophenol 95-55-6 C6H7NO 详情 详情
(VII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VIII) 18665 tert-butyl 4-(2-hydroxyanilino)-1-piperidinecarboxylate C16H24N2O3 详情 详情
(IX) 18666 tert-butyl 4-[2-oxo-1,3-benzoxazol-3(2H)-yl]-1-piperidinecarboxylate C17H22N2O4 详情 详情
(X) 18667 3-(4-piperidinyl)-1,3-benzoxazol-2(3H)-one C12H14N2O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VIII)

The asymmetric 1,3-dipolar cycloaddition of the nitrile oxide resulting from 4-bromo-N-hydroxybenzenecarboximidoyl chloride (I) to allyl alcohol (II) in the presence of (R,R)-diisopropyl tartrate and diethylzinc afforded the (R)-5-(hydroxymethyl)isoxazoline (III). After conversion of (III) to the mesylate (IV), treatment with ammonium hydroxide in a sealed vessel provided primary amine (V), which was then acetylated with Ac2O and pyridine to give amide (VI). Further treatment of (VI) with hexamethylditin and dichlorobis(triphenylphosphine) palladium yielded the trimethylstannyl derivative (VII). Reaction of N-Boc-4-piperidone (VIII) with lithium diisopropylamide and N-phenyl-trifluoromethanesulfonimide at low temperature furnished the corresponding vinyl triflate (IX). Subsequent coupling of (IX) with stannyl derivative (VII) in the presence of tris(dibenzylideneacetone)dipalladium and triphenylarsine gave rise to the N-Boc-tetrahydropyridylphenylisoxazole (X). The Boc group of (X) was then deprotected using trifluoroacetic acid, and the deprotected tetrahydropyridine (XI) was condensed with acetoxyacetyl chloride (XII), yielding the acetoxyacetamide (XIII). The acetate ester of (XIII) was finally hydrolyzed by means of K2CO3 in MeOH.

参考文献 中间体
合成目标
【1】 Ukaji, Y.; et al.; Enantioselective synthesis of 2-isoxazolines via asymmetric 1,3-dipolar cycloaddition of nitrile oxides to achiral allyl alcohols. Chem Lett 1993, 11, 1847.
【2】 Barbachyn, M.R.; Thomas, R.C.; Cleek, G.J. (Pharmacia & Upjohn AB); Isoxazoline derivs. useful as antimicrobials. EP 0920421; US 5990136; WO 9807708 .
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) 32966 4-bromo-N-hydroxybenzenecarboximidoyl chloride C7H5BrClNO 详情 详情
(II) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(III) 32967 [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanol C10H10BrNO2 详情 详情
(IV) 32968 [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methyl methanesulfonate C11H12BrNO4S 详情 详情
(V) 32969 [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methylamine; [(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methanamine C10H11BrN2O 详情 详情
(VI) 32970 N-[[(5R)-3-(4-bromophenyl)-4,5-dihydro-5-isoxazolyl]methyl]acetamide C12H13BrN2O2 详情 详情
(VII) 32971 N-([(5R)-3-[4-(trimethylstannyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl)acetamide C15H22N2O2Sn 详情 详情
(VIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IX) 32972 tert-butyl 4-[[(trifluoromethyl)sulfonyl]oxy]-3,6-dihydro-1(2H)-pyridinecarboxylate C11H16F3NO5S 详情 详情
(X) 32973 tert-butyl 4-(4-[(5R)-5-[(acetamido)methyl]-4,5-dihydro-3-isoxazolyl]phenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate C22H29N3O4 详情 详情
(XI) 32974 N-([(5R)-3-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-4,5-dihydro-5-isoxazolyl]methyl)acetamide C17H21N3O2 详情 详情
(XII) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(XIII) 32975 2-[4-(4-[(5R)-5-[(acetamido)methyl]-4,5-dihydro-3-isoxazolyl]phenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-oxoethyl acetate C21H25N3O5 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

The Grignard reaction of 1-(tert-butoxycarbonyl)piperidin-4-one (I) with 3-fluorophenylmagnesium bromide (II) in THF gives the tertiary alcohol (III), which is dehydrated with TFA or HCl in dioxane yielding the tetrahydropyridine (IV). The condensation of (IV) with 2,4-dichloro-6-methylpyrimidine (V) by means of DIEA in ethanol affords 2-chloro-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine (VI), which is further condensed with 4-isopropyl-2-(methylsulfanyl)aniline (VII) by means of DIEA in refluxing ethylene glycol to give the secondary amine (VIII). Finally, this compound is alkylated with ethyl iodide and NaH in DMF.

参考文献 中间体
合成目标
【1】 Chaki, S.; Nakazato, A.; Okubo, T.; Kumagai, T.; Tomisawa, K.; Okuyama, S.; CRF1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives. Symp Med Chem 1998, Abst 1-P-26.
【2】 Okubo, T.; Tanaka, H.; Chaki, S.; Okuyama, S.; Tomisawa, K.; Kumagai, T.; Nakazato, A.; Design, synthesis and structure-affinity relationships of 4-methylidenepiperidine and 4-aryl-1,2,3,6-tetrahydropyridine derivatives as corticotropin-releasing factor1 receptor antagonists. Bioorg Med Chem 2000, 8, 5, 1183.
【3】 Okubo, T.; Okuyama, S.; Nakazato, A.; Tomisawa, K.; Aibe, I.; Chaki, S.; Kumagai, T.; Tanaka, H. (Taisho Pharmaceutical Co., Ltd.); 4-Tetrahydropyridylpyrimidine derivs.. EP 0976745; JP 1999228568; WO 9842699 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 35384 bromo(3-fluorophenyl)magnesium C6H4BrFMg 详情 详情
(III) 35385 tert-butyl 4-(3-fluorophenyl)-4-hydroxy-1-piperidinecarboxylate C16H22FNO3 详情 详情
(IV) 35386 4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine C11H12FN 详情 详情
(V) 35387 2,4-dichloro-6-methylpyrimidine 5424-21-5 C5H4Cl2N2 详情 详情
(VI) 35388 2-chloro-4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methylpyrimidine C16H15ClFN3 详情 详情
(VII) 35389 4-isopropyl-2-(methylsulfanyl)phenylamine; 4-isopropyl-2-(methylsulfanyl)aniline C10H15NS 详情 详情
(VIII) 35390 N-[4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-6-methyl-2-pyrimidinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]amine; 4-[4-(3-fluorophenyl)-3,6-dihydro-1(2H)-pyridinyl]-N-[4-isopropyl-2-(methylsulfanyl)phenyl]-6-methyl-2-pyrimidinamine C26H29FN4S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(I)

The Grignard reaction of 1-(tert-butoxycarbonyl)piperidin-3-one (I) with 2-methylphenylmagnesium bromide (II) in THF gives the tertiary alcohol (III), which is dehydrated with TFA or HCl in dioxane yielding the tetrahydropyridine (IV). The condensation of (IV) with 2,4-dichloro-6-methylpyrimidine (V) by means of DIEA in ethanol affords 2-chloro-6-methyl-4-[3-(2-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]pyrimidine (VI), which is further condensed with 4-isopropyl-2-(methylsulfanyl)aniline (VII) by means of DIEA in refluxing ethylene glycol to give the secondary amine (VIII). Finally, this compound is alkylated with ethyl iodide and NaH in DMF.

参考文献 中间体
合成目标
【1】 Chaki, S.; Nakazato, A.; Okubo, T.; Kumagai, T.; Tomisawa, K.; Okuyama, S.; CRF1 receptor antagonists: Aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives. Symp Med Chem 1998, Abst 1-P-26.
【2】 Okubo, T.; Okuyama, S.; Nakazato, A.; Tomisawa, K.; Aibe, I.; Chaki, S.; Kumagai, T.; Tanaka, H. (Taisho Pharmaceutical Co., Ltd.); 4-Tetrahydropyridylpyrimidine derivs.. EP 0976745; JP 1999228568; WO 9842699 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(I) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 35391 bromo(2-methylphenyl)magnesium C7H7BrMg 详情 详情
(III) 35392 tert-butyl 3-hydroxy-3-(2-methylphenyl)-1-piperidinecarboxylate C17H25NO3 详情 详情
(IV) 35393 5-(2-methylphenyl)-1,2,3,6-tetrahydropyridine C12H15N 详情 详情
(V) 35387 2,4-dichloro-6-methylpyrimidine 5424-21-5 C5H4Cl2N2 详情 详情
(VI) 35394 2-chloro-4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]pyrimidine C17H18ClN3 详情 详情
(VII) 35389 4-isopropyl-2-(methylsulfanyl)phenylamine; 4-isopropyl-2-(methylsulfanyl)aniline C10H15NS 详情 详情
(VIII) 35395 N-[4-isopropyl-2-(methylsulfanyl)phenyl]-4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-pyrimidinamine; N-[4-isopropyl-2-(methylsulfanyl)phenyl]-N-[4-methyl-6-[5-(2-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]-2-pyrimidinyl]amine C27H32N4S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

Lithiation of 2-bromobenzyl thiol (I) followed by addition to N-Boc-4-piperidone (II) gave mercapto alcohol (III), which was cyclized to the spiro derivative by refluxing in 4N sulfuric acid. Protection as the tert-butyl carbamate (IV), followed by oxidation with m-chloroperbenzoic acid produced sulfoxide (V). After acid cleavage of the Boc protecting group of (V), resolution with (S)-(+)-mandelic acid furnished the required (S)-enantiomer (VII). Alternatively, asymmetric oxidation of sulfide (IV) with (3'S,2R)-(-)-N-(phenylsulfonyl)(3,3-dichlorocamphoryl)oxaziridine produced the (S)-sulfoxide (VI), which was further deprotected to (VII) with HCl in dioxan.

参考文献 中间体
合成目标
【1】 Kurata, H.; Ito, K.; Nakajima, K.; Yamaguchi, T.; Ishibashi, K.; Fukuzawa, T.; Nishi, T. (Sankyo Co., Ltd.); Azaheterocyclic cpds. having tachykinin receptor antagonist activity; NK1 and NK2. EP 0776893; JP 1998152478; JP 1998182649; JP 1998182650 .
【2】 Nishi, T.; Yamaguchi, T. (Sankyo Co., Ltd.); Salts of optically active sulfoxide deriv.. EP 0987269; JP 1999043490; WO 9854191 .
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) 38421 (2-bromophenyl)methanethiol; 2-bromobenzylhydrosulfide C7H7BrS 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 38422 tert-butyl 4-hydroxy-4-[2-(sulfanylmethyl)phenyl]-1-piperidinecarboxylate C17H25NO3S 详情 详情
(IV) 38423 Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-1'-carboxylic acid, 1,1-dimethylethyl ester 173944-03-1 C17H23NO2S 详情 详情
(V) 38424 (2S)-Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-1'-carboxylic acid, 1,1-dimethylethyl ester, 2-oxide 191673-21-9 C17H23NO3S 详情 详情
(VI) 38425 Spiro[benzo[C]thiophene-1(3H),4'-piperidine]-1'-carboxylic acid, 1,1-dimethylethyl ester, 2-oxide 173944-04-2 C17H23NO3S 详情 详情
(VII) 38426 (2S)-Spiro[benzo[C]thiophene-1(3H),4'-piperidine] 2-oxide 191673-15-1 C12H15NOS 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The benzonaphthyridine system (III) was prepared by condensation of 1-Boc-4-piperidone (I) with 2-aminobenzonitrile (II) in the presence of ZnCl2. After acetylation of the 10-amino group of (III) with Ac2O in pyridine to afford (IV), the N-Boc protecting group was removed by treatment with HCl in dioxan-methanol, yielding 10-acetylamino-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine (V). The tricyclic amine (V) was then alkylated with the chiral sulfonate (VI), and the target compound was finally converted to the corresponding fumarate salt.

参考文献 中间体
合成目标
【1】 Honda, M.; Sato, Y.; Oka, H.; Iida, M. (Nippon Kayaku Co., Ltd.); Novel naphthyridine derivs. or salts thereof. EP 0997462; JP 2000038386; US 6294547; WO 9900388 .
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 19493 2-aminobenzonitrile 1885-29-6 C7H6N2 详情 详情
(III) 49140 tert-butyl 10-amino-3,4-dihydrobenzo[b][1,6]naphthyridine-2(1H)-carboxylate C17H21N3O2 详情 详情
(IV) 49141 tert-butyl 10-(acetamido)-3,4-dihydrobenzo[b][1,6]naphthyridine-2(1H)-carboxylate C19H23N3O3 详情 详情
(V) 49142 N-(1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridin-10-yl)acetamide C14H15N3O 详情 详情
(VI) 49143 (3S)-4-[benzoyl(methyl)amino]-3-(3,4-dichlorophenyl)butyl benzenesulfonate C24H23Cl2NO4S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(II)

The reductocondensation of 4-benzyloxyaniline (I) with 1-(tert-butoxycarbonyl)piperidin-4-one (II) by means of NaBH(OAc)2 in dichloromethane gives N-(4-benzyloxyphenyl)-N-[1-(tert-butoxycarbonyl)piperidin-4-yl]amine (III), which is alkylated with 3-methyl-2-butenyl bromide (IV) by means of DIEA in THF yielding the tertiary amine (V). The deprotection of (V) with TFA in dichloromethane affords the piperidine (VI), which is condensed with N-(tert-butoxycarbonyl)-L-leucine (VII) by means of HBTU and DIEA in DMF to provide the intermediate (VIII). Finally, (VIII) is deprotected with TFA in dichloromethane.

参考文献 中间体
合成目标
【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. J Med Chem 1999, 42, 20, 4239.
【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 .
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) 22460 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine C13H13NO 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 38230 tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate C23H30N2O3 详情 详情
(IV) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(V) 38231 tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate C28H38N2O3 详情 详情
(VI) 38232 N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine C23H30N2O 详情 详情
(VII) 23663 (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine C11H21NO4 详情 详情
(VIII) 38233 tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]carbonyl)-3-methylbutylcarbamate C34H49N3O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VI)

The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).

参考文献 中间体
合成目标
【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259.
【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 .
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) 23663 (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine C11H21NO4 详情 详情
(II) 40395 tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate C13H26N2O4 详情 详情
(III) 27058 tert-butyl (1S)-1-formyl-3-methylbutylcarbamate C11H21NO3 详情 详情
(IV) 38232 N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine C23H30N2O 详情 详情
(V) 40394 tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate C34H51N3O3 详情 详情
(VI) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VII) 22460 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine C13H13NO 详情 详情
(VIII) 38230 tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate C23H30N2O3 详情 详情
(IX) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(X) 38231 tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate C28H38N2O3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

4-Piperidinone hydrochloride (I) was protected as the tert-butyl carbamate (II) using Boc2O and diisopropyl ethylamine. Condensation of (II) with 2-aminobenzyl alcohol (III) in boiling toluene, followed by reduction with sodium cyanoborohydride gave secondary amine (IV). Subsequent cyclization of (IV) in the presence of triphosgene and diisopropyl ethylamine produced the benzoxazinone (V), from which the Boc group was removed with HCl in EtOAc to yield intermediate (VI).

参考文献 中间体
合成目标
【1】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 .
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) 27115 4-piperidinone 40064-34-4 C5H9NO 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 18619 (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 5344-90-1 C7H9NO 详情 详情
(IV) 18621 tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate C17H26N2O3 详情 详情
(V) 18622 tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate C18H24N2O4 详情 详情
(VI) 19420 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one C13H16N2O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XX)

3-(Carbomethoxy)propionyl chloride (XV) is condensed with the chiral oxazolidine (XVI) to provide (XVII). Titanium-catalyzed Michael addition of acrylonitrile to the N-acyl oxazolidine (XVII) affords nitrile (XVIII), which is reduced to the primary amine (XIX) by catalytic hydrogenation in the presence of PtO2. Reductive alkylation of amine (XIX) with N-Boc-4-piperidone (XX) gives rise to the aminopiperidine (XXI). This is then cyclized to the piperidinyl piperidone (XXII) upon heating in acetonitrile. After alkaline hydrolysis of the methyl ester group of (XXII), coupling of the resultant acid (XXIII) with methylamine gives rise to the corresponding amide (XXIV). The N-Boc protecting group of (XXIV) is then removed by treatment with trifluoroacetic acid to furnish piperidine (XXV)

参考文献 中间体
合成目标
【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 .
【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 .
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) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(XV) 18060 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate 1490-25-1 C5H7ClO3 详情 详情
(XVI) 25351 (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone 102029-44-7 C10H11NO2 详情 详情
(XVII) 61347 methyl 4-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate C15H17NO5 详情 详情
(XVIII) 61348 methyl (3R)-3-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-5-cyanopentanoate C18H20N2O5 详情 详情
(XIX) 61349 methyl (3R)-6-amino-3-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}hexanoate C18H24N2O5 详情 详情
(XX) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XXI) 61350 tert-butyl 4-[((4R)-4-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-methoxy-6-oxohexyl)amino]-1-piperidinecarboxylate C28H41N3O7 详情 详情
(XXII) 61351 　 C18H30N2O5 详情 详情
(XXIII) 61352 　 C17H28N2O5 详情 详情
(XXIV) 61353 　 C18H31N3O4 详情 详情
(XXV) 61354 　 C13H23N3O2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(I)

Reductive condensation of N-Boc-4-piperidone (I) with 4-(benzyloxy)aniline (II) in the presence of NaBH(OAc)3 produced the secondary amine (III), which was further alkylated with 4-bromo-2-methyl-2-butene (IV) to afford the tertiary amine (V). Subsequent acid cleavage of the Boc protecting group of (V) furnished the intermediate piperidine (VI).

参考文献 中间体
合成目标
【1】 Ryder, T.R.; Rafferty, M.F.; Hu, L.-Y. (Pfizer Inc.); Heterocyclic substd. aniline calcium channel blockers. US 6251919; WO 9943658 .
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 22460 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine C13H13NO 详情 详情
(III) 38230 tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate C23H30N2O3 详情 详情
(IV) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(V) 38231 tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate C28H38N2O3 详情 详情
(VI) 38232 N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine C23H30N2O 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Addition of the Grignard reagent prepared from 4-bromodiphenyl ether (I) to N-Boc-4-piperidone (II) gave the 4-hydroxy-4-arylpiperidine (III). Deprotection of the Boc group of (III) with concomitant dehydration of the tertiary alcohol by means of trifluoroacetic acid afforded the tetrahydropyridine (IV), which was further hydrogenated to piperidine (V) using Pd/C as the catalyst. Condensation of pieridine (V) with phenyl glycidyl ether (VI) in refluxing isopropanol yielded the desired amino alcohol, which was finally isolated as the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Nakanishi, K.; Miyajima, A.; Annoura, H.; Uesugi, M.; Fukunaga, A.; Tamura, S.; Tamura-Horikawa, Y.; A novel class of Na+ and Ca2+ channel dual blockers with highly potent anti-ischemic effects. Bioorg Med Chem Lett 1999, 9, 20, 2999.
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) 35580 1-bromo-4-phenoxybenzene; 4-bromophenyl phenyl ether 101-55-3 C12H9BrO 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 40680 tert-butyl 4-hydroxy-4-(4-phenoxyphenyl)-1-piperidinecarboxylate C22H27NO4 详情 详情
(IV) 40681 phenyl 4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl ether; 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine C17H17NO 详情 详情
(V) 40682 phenyl 4-(4-piperidinyl)phenyl ether; 4-(4-phenoxyphenyl)piperidine C17H19NO 详情 详情
(VI) 23932 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether 122-60-1 C9H10O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

Synthesis of intermediate (XIV): Protection of 4-piperidone (I) with (Boc)2O in presence of DMAP and Et3N yields (II), which is converted into hydantoin (III) by means of NaCN in presence of (NH4)2CO3. Hydantoin (III) is then fully protected to provide (IV) by treatment with (Boc)2O and DMAP in THF. Alternatively (IV) can be obtained by treatment of 4-piperidone (I) with KCN in presence of (NH4)2CO3 to yield hydantoin (V), which is then protected with (Boc)2O and DMAP in DME. Hydrolysis of (IV) with NaOH affords aminoacid (VI) whose free amine is protected to provide carboxylic acid (VII). Treatment of (VII) with isobutyl chloroformate (IBCF) in DME in presence of NMM, followed by aqueous ammonia, yields amide (VIII), which is converted to (IX) by hydrogenation with H2 over Pd/C. Reductive amination of (IX) with aldehyde (X) affords amino amide (XI), which is treated with triethyl orthoformate to provide spirocycle (XII). Reduction of (XII) with NaBH4 in EtOH gives (XIII), which is alkylated with ethyl bromoacetate (A) followed by hydrolysis with NaOH to yield intermediate (XIV).

参考文献 中间体
合成目标
【1】 Wysong, C.L.; et al.; 4-Aminopiperidine-4-carboxamylic acid: A cyclic alpha,alpha-disubstituted amino acid for preparation of water-soluble highly helical peptides. J Org Chem 1996, 61, 22, 7650-51.
【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387.
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) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 18178 4,4-piperidinediol 73390-11-1 C5H11NO2 详情 详情
(II) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(III) 41678 tert-butyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate C12H19N3O4 详情 详情
(IV) 41679 tri(tert-butyl) 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-tricarboxylate C22H35N3O8 详情 详情
(V) 41680 1,3,8-triazaspiro[4.5]decane-2,4-dione 13625-39-3 C7H11N3O2 详情 详情
(VI) 41681 4-amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid 183673-71-4 C11H20N2O4 详情 详情
(VII) 41682 1-(tert-butoxycarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-piperidinecarboxylic acid C26H30N2O6 详情 详情
(VIII) 41683 tert-butyl 4-(aminocarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1-piperidinecarboxylate C26H31N3O5 详情 详情
(IX) 41684 tert-butyl 4-amino-4-(aminocarbonyl)-1-piperidinecarboxylate C11H21N3O3 详情 详情
(X) 18456 2-phenylacetaldehyde 122-78-1 C8H8O 详情 详情
(XI) 41685 tert-butyl 4-(aminocarbonyl)-4-(phenethylamino)-1-piperidinecarboxylate C19H29N3O3 详情 详情
(XII) 41686 tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate C20H27N3O3 详情 详情
(XIII) 41687 tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate C20H29N3O3 详情 详情
(XIV) 41688 2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid C22H31N3O5 详情 详情

合成路线18

该中间体在本合成路线中的序号：(I)

Reductive amination of N-Boc-4-piperidone (I) with allylamine (II) in the presence of sodium triacetoxyborohydride afforded aminopiperidine (III), which was acylated with 4-nitrobenzyl chloroformate (IV) to yield carbamate (V). Removal of the Boc group of (V) by means of a methanolic solution of HCl, prepared from acetyl chloride and MeOH, provided piperidine (VI).

参考文献 中间体
合成目标
【1】 Finke, P.E.; Mills, S.G.; Caldwell, C.G.; MacCoss, M.; Wang, L.; Kothandaraman, S.; Kim, D.; Oates, B. (Merck & Co., Inc.); Cyclic amine modulators of chemokine receptor activity. EP 1052992; US 6140349; WO 9938514 .
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 13672 Allylamine; 2-Propen-1-amine 107-11-9 C3H7N 详情 详情
(III) 43903 tert-butyl 4-(allylamino)-1-piperidinecarboxylate C13H24N2O2 详情 详情
(IV) 33055 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene 4457-32-3 C8H6ClNO4 详情 详情
(V) 43904 tert-butyl 4-(allyl[[(4-nitrobenzyl)oxy]carbonyl]amino)-1-piperidinecarboxylate C21H29N3O6 详情 详情
(VI) 43905 4-nitrobenzyl allyl(4-piperidinyl)carbamate C16H21N3O4 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

N-protection of the NH group of (I) with Boc2O and NaOH in Et2O yields derivative (II), which is then condensed with compound (III) by means of NaH in DMF to provide (IV). N-deprotection of (IV) by treatment with TFA in CH2Cl2 followed by reductocondensation with N-Boc-4-piperidone (V) in CH2Cl2 in the presence of Na(OAc)3BH affords compound (VI), which is oxidized with NaBO3.4H2O to provide (VII). Boc removal of (VII) by treatment with TFA in CH2Cl2, followed by reaction of the resulting secondary amine with sulfonyl chloride (VIII) in CH2Cl2 in the presence of Et3N, affords propylsulfonamide derivative (IX). Finally, treatment of (IX) with ethyleneglycol (X) in toluene in the presence of HC(OEt)3 and p-TsOH furnishes the target compound.

参考文献 中间体
合成目标
【1】 Boyle, C.D.; Chackalamannil, S.; Chen, L.-Y.; et al.; Benzylidine ketal derivatives as M2 muscarinic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 24, 2727.
【2】 Chackalamannil, S.; Chen, L.-Y.; Boyle, C.D.; et al.; Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 114.
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) 21497 (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine 56346-57-7 C12H14FNO 详情 详情
(II) 45867 tert-butyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate C17H22FNO3 详情 详情
(III) 28620 1,3-benzodioxole-5-thiol C7H6O2S 详情 详情
(IV) 45868 tert-butyl 4-[4-(1,3-benzodioxol-5-ylsulfanyl)benzoyl]-1-piperidinecarboxylate C24H27NO5S 详情 详情
(V) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VI) 45869 　 C29H36N2O5S 详情 详情
(VII) 45870 　 C29H36N2O7S 详情 详情
(VIII) 45871 1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride; 10147-36-1 C3H7ClO2S 详情 详情
(IX) 45872 　 C27H34N2O7S2 详情 详情
(X) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

Reductive amination of N-Boc-4-piperidone (I) with allyl amine (II) in the presence of sodium triacetoxyborohydride gave aminopiperidine (III), which was condensed with 4-nitrobenzyl chloroformate (IV) to afford carbamate (V). The Boc group of (V) was then cleaved by treatment with methanolic HCl to produce intermediate piperidine (VI). Alternatively, the condensation of 1-Boc-piperidine-4-amine (VII) with chloroformate (IV) gives carbamate (VIII), which is allylated with allyl chloride (IX) and NaH in THF, yielding the already reported carbamate (V).

参考文献 中间体
合成目标
【1】 Chen, P.; Dorn, C.P. Jr.; Caldwell, C.G.; et al.; Synthesis and evaluation of CCR5 antagonists having potent in vitro antiviral activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 85.
【2】 Finke, P.E.; Mills, S.G.; Caldwell, C.G.; MacCoss, M.; Wang, L.; Kothandaraman, S.; Kim, D.; Oates, B. (Merck & Co., Inc.); Cyclic amine modulators of chemokine receptor activity. EP 1052992; US 6140349; WO 9938514 .
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 13672 Allylamine; 2-Propen-1-amine 107-11-9 C3H7N 详情 详情
(III) 43903 tert-butyl 4-(allylamino)-1-piperidinecarboxylate C13H24N2O2 详情 详情
(IV) 33055 1-[[(chlorocarbonyl)oxy]methyl]-4-nitrobenzene 4457-32-3 C8H6ClNO4 详情 详情
(V) 43904 tert-butyl 4-(allyl[[(4-nitrobenzyl)oxy]carbonyl]amino)-1-piperidinecarboxylate C21H29N3O6 详情 详情
(VI) 43905 4-nitrobenzyl allyl(4-piperidinyl)carbamate C16H21N3O4 详情 详情
(VII) 28414 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine 87120-72-7 C10H20N2O2 详情 详情
(VIII) 43906 tert-butyl 4-([[(4-nitrobenzyl)oxy]carbonyl]amino)-1-piperidinecarboxylate C18H25N3O6 详情 详情
(IX) 13235 Allyl chloride; 3-Chloro-1-propene 107-05-1 C3H5Cl 详情 详情

合成路线21

该中间体在本合成路线中的序号：(I)

The reductive alkylation of cyclooctylamine (II) with N-Boc-4-piperidinone (I) in the presence of sodium cyanoborohydride afforded the secondary amine (III), which was condensed with propionyl chloride, yielding amide (IV). Deprotection of the Boc group of (IV) by means of HCl in dioxan provided piperidine (V). This was finally alkylated with 1-(3-chloropropoxy)-4-fluorobenzene (VI) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Hansen, H.C.; et al.; Multistep solution-phase parallel synthesis of spiperone analogues. Bioorg Med Chem Lett 2000, 10, 21, 2435.
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 22152 cyclooctanamine; cyclooctylamine 5452-37-9 C8H17N 详情 详情
(III) 46524 tert-butyl 4-(cyclooctylamino)-1-piperidinecarboxylate C18H34N2O2 详情 详情
(IV) 46525 tert-butyl 4-[cyclooctyl(propionyl)amino]-1-piperidinecarboxylate C21H38N2O3 详情 详情
(V) 46526 N-cyclooctyl-N-(4-piperidinyl)propanamide C16H30N2O 详情 详情
(VI) 30524 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane 1716-42-3 C9H10ClFO 详情 详情

合成路线22

该中间体在本合成路线中的序号：(V)

Treatment of piperidine (I) with 9-BBN in refluxing THF followed by reaction with bromo derivative (II) by means of K2CO3, PdCl2(dppf) and Ph3As in DMF/H2O provides chlorophenylsulfonyl derivative (III), whose Boc group is removed by means of TFA in CH2Cl2/H2O to afford secondary amine (IV). Reductive amination between amine (IV) and piperidone (V) by means of NaB(OAc)3H in CH2Cl2 in the presence of HOAc furnishes compound (VI), which is then deprotected by means of TFA in CH2Cl2/H2O to yield bipiperidinyl derivative (VII). Finally, coupling of (VII) with 2-amino-3-methyl benzoic acid (VIII) by means of HOBt, DIEA and EDCI in DMF provides the target product. Alternatively, the synthesis of intermediate (VII) can be performed as follows: Protection of the piperidine moiety of (IX) by means of trifluoroacetic anhydride in CH2Cl2 followed by treatment with methanesulfonic acid and dibromodimethylhydantoin (DBDMH) affords bromo derivative (X), whose trifluoroacetate moiety is then removed by reaction with K2CO3 in MeOH/H2O to give piperidine derivative (XI). Reductive amination between (XI) and piperidone (V) by means of NaB(OAc)3H in CH2Cl2 in the presence of HOAc furnishes compound (XII), which is condensed with 3-chlorbenzenesulfonyl fluoride (XIII) by means of BuLi in THF and finally treated with TFA in CH2Cl2/H2O for Boc removal to provide the intermediate chlorophenylsulfonyl derivative (VII).

参考文献 中间体
合成目标
【1】 Miller, M.W.; Clader, J.W.; McCombie, S.W.; Vice, S.F.; Kozlowski, J.A. (Schering Corp.); Muscarinic antagonists. WO 0121590 .
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) 48124 tert-butyl 4-methylene-1-piperidinecarboxylate C11H19NO2 详情 详情
(II) 48125 (4-bromophenyl)(3-chlorophenyl)dioxo-lambda(6)-sulfane; 4-bromophenyl 3-chlorophenyl sulfone C12H8BrClO2S 详情 详情
(III) 48126 tert-butyl 4-[4-[(3-chlorophenyl)sulfonyl]benzyl]-1-piperidinecarboxylate C23H28ClNO4S 详情 详情
(IV) 48127 3-chlorophenyl 4-(4-piperidinylmethyl)phenyl sulfone; 4-[4-[(3-chlorophenyl)sulfonyl]benzyl]piperidine C18H20ClNO2S 详情 详情
(V) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VI) 48128 　 C28H37ClN2O4S 详情 详情
(VII) 48129 　 C23H29ClN2O2S 详情 详情
(VIII) 48130 2-amino-3-methylbenzoic acid 4389-45-1 C8H9NO2 详情 详情
(IX) 26225 4-benzylpiperidine 31252-42-3 C12H17N 详情 详情
(X) 48131 1-[4-(4-bromobenzyl)-1-piperidinyl]-2,2,2-trifluoro-1-ethanone C14H15BrF3NO 详情 详情
(XI) 48132 4-(4-bromobenzyl)piperidine C12H16BrN 详情 详情
(XII) 48133 　 C22H33BrN2O2 详情 详情
(XIII) 48134 3-chlorobenzenesulfonyl fluoride C6H4ClFO2S 详情 详情

合成路线23

该中间体在本合成路线中的序号：(XV)

Condensation of piperazine (XIV) with N-Boc-4-piperidinone (XV) in the presence of titanium isopropoxide as the dehydrating reagent, followed by addition of diethylaluminum cyanide to the intermediate iminium salt, provided the alpha-aminonitrile (XVI). The cyano group of (XVI) was subsequently displaced with methylmagnesium bromide, affording the methyl derivative (XVII). After acid cleavage of the Boc protecting group of (XVII), the resulting piperidine (XVIII) was finally acylated with propanesulfonyl chloride to furnish the corresponding sulfonamide.

参考文献 中间体
合成目标
【1】 Muscarinic antagonists. WO 9805292 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 50649 (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone C20H24N2O4S 详情 详情
(XV) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XVI) 50650 tert-butyl 4-((3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methylpiperazinyl)-4-cyano-1-piperidinecarboxylate C31H40N4O6S 详情 详情
(XVII) 50651 tert-butyl 4-((3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methylpiperazinyl)-4-methyl-1-piperidinecarboxylate C31H43N3O6S 详情 详情
(XVIII) 50652 (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methyl-4-(4-methyl-4-piperidinyl)piperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methyl-4-(4-methyl-4-piperidinyl)piperazinyl]ethyl]phenyl sulfone C26H35N3O4S 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VIII)

Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.

参考文献 中间体
合成目标
【1】 Palani, A.; et al.; Discovery of 4-[(Z)-(4-bromophenyl)-(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine N-oxide (SCH 351125). An orally bioavailable human CCR5 antagonist for the treatment of HIV infection. J Med Chem 2001, 44, 21, 3339.
【2】 Palani, A.; et al.; Synthesis, SAR, and biological evaluation of oximino-piperidino-pieperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. J Med Chem 2002, 45, 14, 3143.
【3】 McCombie, S.W.; Clader, J.W.; Baroudy, B.M.; McKittrick, B.A.; Josien, H.B.; Tagat, J.R.; Vice, S.F.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Neustadt, B.R.; Palani, A. (Schering Corp.); Piperidine derivs. useful as CCR5 antagonists. EP 1175402; WO 0066559 .
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) 17402 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid 498-94-2 C6H11NO2 详情 详情
(II) 51847 1-(2,2,2-trifluoroacetyl)-4-piperidinecarboxylic acid C8H10F3NO3 详情 详情
(III) 51848 1-(2,2,2-trifluoroacetyl)-4-piperidinecarbonyl chloride C8H9ClF3NO2 详情 详情
(IV) 13365 Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene 108-86-1 C6H5Br 详情 详情
(V) 51849 1-[4-(4-bromobenzoyl)-1-piperidinyl]-2,2,2-trifluoro-1-ethanone C14H13BrF3NO2 详情 详情
(VI) 51850 1-[4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]-2,2,2-trifluoro-1-ethanone C16H17BrF3NO3 详情 详情
(VII) 51851 4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]piperidine C14H18BrNO2 详情 详情
(VIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IX) 51852 　 C25H34BrN3O4 详情 详情
(X) 51853 　 C25H37BrN2O4 详情 详情
(XI) 51854 　 C23H33BrN2O3 详情 详情
(XII) 51855 　 C25H38BrN3O3 详情 详情
(XIII) 51856 　 C20H30BrN3O 详情 详情
(XIV) 51857 3-carboxy-2,4-dimethyl-1-pyridiniumolate C8H9NO3 详情 详情

合成路线25

该中间体在本合成路线中的序号：(XIII)

The lithium derivative (II), prepared from p-bromo-alpha-methylbenzylamine (I), was added to piperonal (III) to obtain the diaryl carbinol (IV), which was further deoxygenated to (V) using triethylsilane and trifluoroacetic acid. Basic hydrolysis of the trifluoroacetamide function of (V) provided amine (VI). This was then alkylated with the chiral triflate (VII) to afford amino ester (VIII). Subsequent acylation of amine (VIII) with chloroacetyl chloride (IX), followed by cyclization of the resulting chloroacetamide (X) with ammonia, led to the diketopiperazine (XI). Reduction of the carbonyl groups of (XI), followed by reductive amination of the resulting piperazine (XII) with N-Boc-4-piperidinone (XIII), gave the piperidinyl piperazine (XIV). After acidic Boc group cleavage of (XIV), the resulting piperidine (XV) was finally condensed with 2,6-dimethylbenzoic acid (XVI) to yield the target benzamide.

参考文献 中间体
合成目标
【1】 Tagat, J.R.; et al.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorg Med Chem Lett 2001, 11, 16, 2143.
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) 50550 N-[(1S)-1-(4-bromophenyl)ethyl]-2,2,2-trifluoroacetamide C10H9BrF3NO 详情 详情
(II) 50551 　 C10H8F3Li2NO 详情 详情
(III) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(IV) 50552 N-((1S)-1-[4-[1,3-benzodioxol-5-yl(hydroxy)methyl]phenyl]ethyl)-2,2,2-trifluoroacetamide C18H16F3NO4 详情 详情
(V) 50553 N-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2,2,2-trifluoroacetamide C18H16F3NO3 详情 详情
(VI) 50554 (1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]-1-ethanamine; (1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethylamine C16H17NO2 详情 详情
(VII) 50555 ethyl (2R)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate C6H9F3O5S 详情 详情
(VIII) 50556 ethyl (2S)-2-([(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]amino)propanoate C21H25NO4 详情 详情
(IX) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(X) 50557 ethyl (2S)-2-[[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl](2-chloroacetyl)amino]propanoate C23H26ClNO5 详情 详情
(XI) 50558 (6S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-6-methyl-2,5-piperazinedione C21H22N2O4 详情 详情
(XII) 50559 (2S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2-methylpiperazine C21H26N2O2 详情 详情
(XIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XIV) 50560 tert-butyl 4-((3S)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-3-methylpiperazinyl)-1-piperidinecarboxylate C31H43N3O4 详情 详情
(XV) 50561 (2S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2-methyl-4-(4-piperidinyl)piperazine C26H35N3O2 详情 详情
(XVI) 50562 m-Xylylic acid; 2,6-Dimethylbenzoic acid; m-Xylene-2-carboxylic acid 632-46-2 C9H10O2 详情 详情

合成路线26

该中间体在本合成路线中的序号：(IV)

Lithiation of 2,5-dibromotoluene (I) with n-butyllithium at -75 C produced a mixture of 5-lithio (II) and 2-lithio (III) toluenes. Addition of this mixture to N-Boc-4-piperidone (IV) at low temperature provided the desired carbinol (V) and the corresponding 2-tolyl regioisomer, which were separated by flash chromatography (1). Alternatively, carbinol (V) was obtained by regioselective metallation of 2-bromo-5-iodotoluene (VI) and then addition to N-Boc-4-piperidone (IV). Dehydration of carbinol (V) with concomitant N-Boc group cleavage under acidic conditions furnished the tetrahydropyridine (VII). This was sulfonylated with methyl chlorosulfonylacetate (VIII) in the presence of either N,O-bis(trimethylsilyl)acetamide or diazabicycloundecene, producing sulfonamide (IX). Suzuki coupling of aryl bromide (IX) with 3-ethoxyphenylboronic acid (X) gave biphenyl (XI). The methyl ester group of (XI) was then condensed with hydroxylamine to afford the title hydroxamic acid.

参考文献 中间体
合成目标
【1】 Dack, K.N.; et al.; Design and synthesis of a novel series of matrix metalloproteinase inhibitors with high selectivity for MMP-3. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 260.
【2】 Whitlock, G.A.; Dack, K.N. (Pfizer Inc.); Hydroxamic acid derivs. as matrix metalloprotease (MMP) inhibitors. EP 1036062; JP 2001525396; WO 9929667 .
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) 51152 2,5-Dibromotoluene 615-59-8 C7H6Br2 详情 详情
(II) 51153 (4-bromo-3-methylphenyl)lithium C7H6BrLi 详情 详情
(III) 51154 (4-bromo-2-methylphenyl)lithium C7H6BrLi 详情 详情
(IV) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(V) 51155 tert-butyl 4-(4-bromo-3-methylphenyl)-4-hydroxy-1-piperidinecarboxylate C17H24BrNO3 详情 详情
(VI) 51156 2-Bromo-5-iodotoluene C7H6BrI 详情 详情
(VII) 51157 4-(4-bromo-3-methylphenyl)-1,2,3,6-tetrahydropyridine C12H14BrN 详情 详情
(VIII) 51158 methyl 2-(chlorosulfonyl)acetate C3H5ClO4S 详情 详情
(IX) 51159 methyl 2-[[4-(4-bromo-3-methylphenyl)-3,6-dihydro-1(2H)-pyridinyl]sulfonyl]acetate C15H18BrNO4S 详情 详情
(X) 51160 3-Ethoxyphenylboronic acid C8H11BO3 详情 详情
(XI) 51151 2-(5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxyphenyl)-5-[(4-fluorobenzyl)amino]-8-(4-methoxybenzyl)-3,8-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one C38H41FN8O5S 详情 详情

合成路线27

该中间体在本合成路线中的序号：(VIII)

Enantioselective reduction of 4-trifluoromethylacetophenone (I) with borane-methyl sulfide complex in the presence of the chiral oxaborolidine (II) provided the (R)-alcohol (III) in high enantiomeric excess. Treatment of (III) with methanesulfonyl chloride and Et3N yielded the corresponding mesylate (IV). Displacement of the mesylate group of (IV) with the Boc-protected piperazine (V) produced the desired (S,S)-alpha-methylbenzyl piperazine (VI) as the major isomer. Separation from minor amounts of the (R,S)-diastereomer was effected by flash chromatography. After acid cleavage of the Boc protecting group of (VI), the resultant piperazine (VII) was subjected to a modified Strecker reaction with N-Boc-piperidone (VIII) and diethylaluminum cyanide, yielding amino nitrile (IX). A methyl group was then introduced at the 4-position of the piperidine (IX) by displacement of the cyano group with methylmagnesium bromide to yield (X). Subsequent acidic Boc group cleavage in (X) gave piperidine (XI). This was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Tagat, J.R.; Steensma, R.W.; McCombie, S.W.; Nazareno, D.V.; Lin, S.-I.; Neustadt, B.R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M.G.; Vantuno, N.; Baroudy, B.M.; Strizki, J.M.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent. J Med Chem 2001, 44, 21, 3343.
【2】 Labroli, M.A.; Smith, E.M.; Baroudy, B.M.; Gilbert, E.; Tagat, J.R.; Josien, H.B.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Clader, J.W.; McKittrick, B.A.; Neustadt, B.R.; Palani, A.; McCombie, S.W.; Vice, S.F. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. EP 1175401; WO 0066558 .
【3】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 6391865 .
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) 39907 1-[4-(trifluoromethyl)phenyl]-1-ethanone 709-63-7 C9H7F3O 详情 详情
(II) 28292 (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole 112022-81-8 C18H20BNO 详情 详情
(III) 51861 (1R)-1-[4-(trifluoromethyl)phenyl]-1-ethanol C9H9F3O 详情 详情
(IV) 51862 (1R)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate C10H11F3O3S 详情 详情
(V) 51868 tert-butyl (3S)-3-methyl-1-piperazinecarboxylate C10H20N2O2 详情 详情
(VI) 51863 tert-butyl (3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinecarboxylate C19H27F3N2O2 详情 详情
(VII) 51864 (2S)-2-methyl-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine C14H19F3N2 详情 详情
(VIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IX) 51865 tert-butyl 4-cyano-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate C25H35F3N4O2 详情 详情
(X) 51866 tert-butyl 4-methyl-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate C25H38F3N3O2 详情 详情
(XI) 51867 (2S)-2-methyl-4-(4-methyl-4-piperidinyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine C20H30F3N3 详情 详情
(XII) 51857 3-carboxy-2,4-dimethyl-1-pyridiniumolate C8H9NO3 详情 详情

合成路线28

该中间体在本合成路线中的序号：(I)

The reductocondensation of N-Boc-piperidin-4-one (I) with 3,4-dichloroaniline (II) by means of NaHB(OAc)3 in dichloroethane gives the secondary amine (III), which is acylated with chloroacetyl chloride (IV) by means of K2CO3 in dichloromethane to yield the chloroacetamide (V). The reaction of (V) with 3,5-dimethylphenol (VI) by means of Cs2CO3 in acetonitrile affords the aryl ether (VII), which is finally Boc deprotected with TFA in dichloromethane to provide the title trisubstituted acetamide.

参考文献 中间体
合成目标
【1】 Pirlot, N.; Balançon, L.; Berton, O.; Genicot, C.; Lamberty, Y.; Quéré, L.; Pasau, P.; Lallemand, B.; Talaga, P.; Ryckmans, T.; First dual NK1 antagonists-serotonin reuptake inhibitors: Synthesis and SAR of a new class of potential antidepressants. Bioorg Med Chem Lett 2002, 12, 2, 261.
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(III) 54455 tert-butyl 4-(3,4-dichloroanilino)-1-piperidinecarboxylate C16H22Cl2N2O2 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 54456 tert-butyl 4-[3,4-dichloro(2-chloroacetyl)anilino]-1-piperidinecarboxylate C18H23Cl3N2O3 详情 详情
(VI) 46786 3,5-dimethylphenol 108-68-9 C8H10O 详情 详情
(VII) 54457 tert-butyl 4-{3,4-dichloro[2-(3,5-dimethylphenoxy)acetyl]anilino}-1-piperidinecarboxylate C26H32Cl2N2O4 详情 详情

合成路线29

该中间体在本合成路线中的序号：(VII)

N-Boc-4-Piperidone (VII) is converted into the enol triflate (VIII) upon treatment with N-phenyl trifluoromethanesulfonimide and LDA. Subsequent Suzuki coupling of (VIII) with 3-acetamidophenylboronic acid (IX) yields the 4-aryl tetrahydropyridine (X). Removal of the N-Boc group of (X) under acidic conditions furnishes the deprotected tetrahydropyridine (XI). Optionally, catalytic hydrogenation of (X) gives rise to piperidine (XII), which is then deprotected by acidic treatment to produce (XIII).

参考文献 中间体
合成目标
【1】 Gluchowski, C.; Chiu, G.; Marzabadi, M.R.; Nagarathnam, D.; Lagu, B.; Noble, S.; Wetzel, J.; Deleon, J.E. (Synaptic Pharmaceutical Corp.); Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof. EP 1299362; WO 0206245 .
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VIII) 32972 tert-butyl 4-[[(trifluoromethyl)sulfonyl]oxy]-3,6-dihydro-1(2H)-pyridinecarboxylate C11H16F3NO5S 详情 详情
(IX) 60992 3-(acetylamino)phenylboronic acid C8H10BNO3 详情 详情
(X) 60993 tert-butyl 4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate C18H24N2O3 详情 详情
(XI) 60994 N-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide C13H16N2O 详情 详情
(XII) 60995 tert-butyl 4-[3-(acetylamino)phenyl]-1-piperidinecarboxylate C18H26N2O3 详情 详情
(XIII) 60996 N-[3-(4-piperidinyl)phenyl]acetamide C13H18N2O 详情 详情

合成路线30

该中间体在本合成路线中的序号：(XI)

The reaction of 4-fluoroacetophenone (I) with sodium hydrogensulfide in hot DMF gives 4-sulfanylacetophenone (II), which is condensed with 5-iodo-1,3-benzodioxole (III) by means of CuI and K2CO3 in hot DMF to yield the thioether (IV). The oxidation of (IV) with MCPBA in dichloroethane affords the sulfone (V), which is enantioselectively reduced by means of BH3/SMe2 and Corey's oxoborolidine catalyst in THF to provide the chiral (R)-alcohol (VI). The reaction of (VI) with Ms-Cl in dichloromethane gives the mesylate (VII), which is condensed with the monoprotected 2(R)-methylpiperazine (VIII) by means of tetramethylpiperidine (TMP) in refluxing acetonitrile to yield the expected benzylic (S)-methyl compound (IX). The elimination of the Boc protecting group of (IX) with refluxing 6N HCl affords the piperazine derivative (X), which is reductocondensed with 1-(Boc)piperidin-4-one (XI) by means of NaBH(OAc)3 to provide adduct (XII). Elimination of the Boc protecting group of (XII) as before gives the piperidine derivative (XIII), which is finally sulfonated with ethylsulfonyl chloride and TEA to provide the target ethylsufonyl piperidine.

参考文献 中间体
合成目标
【1】 Kozlowski, J.A.; Zhou, G.; Tagat, J.R.; et al.; Substituted 2-(R)-methyl piperazines as muscarinic M2 selective ligands. Bioorg Med Chem Lett 2002, 12, 5, 791.
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) 37684 1-(4-fluorophenyl)-1-ethanone 403-42-9 C8H7FO 详情 详情
(II) 54059 1-(4-sulfanylphenyl)-1-ethanone n/a C8H8OS 详情 详情
(III) 54060 1-Iodo-3,4-methylenedioxybenzene 5876-51-7 C7H5IO2 详情 详情
(IV) 54061 1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanone n/a C15H12O5S 详情 详情
(V) 50643 1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanone C15H12O3S 详情 详情
(VI) 50645 (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanol C15H14O5S 详情 详情
(VII) 50646 (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl methanesulfonate C16H16O7S2 详情 详情
(VIII) 51868 tert-butyl (3S)-3-methyl-1-piperazinecarboxylate C10H20N2O2 详情 详情
(IX) 54062 tert-butyl (3R)-4-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate n/a C25H32N2O6S 详情 详情
(X) 50649 (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone C20H24N2O4S 详情 详情
(XI) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XII) 54063 tert-butyl 4-((3R)-4-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-3-methylpiperazinyl)-1-piperidinecarboxylate n/a C30H41N3O6S 详情 详情
(XIII) 54064 (2R)-1-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-2-methyl-4-(4-piperidinyl)piperazine; 1,3-benzodioxol-5-yl 4-{(1S)-1-[(2R)-2-methyl-4-(4-piperidinyl)piperazinyl]ethyl}phenyl sulfone n/a C25H33N3O4S 详情 详情
(XIV) 54065 Ethanesulfonyl chloride; Ethylsulfonyl chloride 594-44-5 C2H5ClO2S 详情 详情

合成路线31

该中间体在本合成路线中的序号：(I)

Knoevenagel condensation between N-Boc-4-piperidinone (I) and ethyl cyanoacetate (II) produced the piperidinylidene cyanoacetate (III), which was further converted to the thienopyridine derivative (IV) upon treatment with sulfur and morpholine. Acylation of amine (IV) with ethyl oxalyl chloride (V) furnished the oxalamide (VI). Subsequent hydrolysis of the ester groups of (VI) under basic conditions led to diacid (VII). The title compound was finally obtained by trifluoroacetic acid-promoted Boc group cleavage.

参考文献 中间体
合成目标
【1】 Modulators of protein tyrosine phosphatases. WO 9946237 .
【2】 Jones, T.K.; Ripka, W.C.; Andersen, H.S.; Olsen, O.H.; Bakir, F.; Branner, S.; Iversen, L.F.; Holsworth, D.D.; Axe, F.U.; Ge, Y.; Uyeda, R.T.; Judge, L.M.; Moeller, N.P.H. (Novo Nordisk A/S; Ontogen Corp.); Modulators of protein tyrosine phosphatases (PTPases). JP 2002506072; US 6410586; WO 9946267 .
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(III) 58781 tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)-1-piperidinecarboxylate C15H22N2O4 详情 详情
(IV) 58782 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate C15H22N2O4S 详情 详情
(V) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(VI) 58783 6-(tert-butyl) 3-ethyl 2-[(2-ethoxy-2-oxoacetyl)amino]-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate C19H26N2O7S 详情 详情
(VII) 58784 6-(tert-butoxycarbonyl)-2-[(carboxycarbonyl)amino]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid C15H18N2O7S 详情 详情

合成路线32

该中间体在本合成路线中的序号：(III)

Condensation of 3,4-dichlorobenzyl bromide (I) with triphenylphosphine affords the phosphonium salt (II). The ylide obtained from (II) and butyllithium is then subjected to a Wittig reaction with N-Boc-4-piperidinone (III) to provide the benzylidene piperidine (IV). Catalytic hydrogenation of (IV) over PtO2 gives rise to the corresponding benzylpiperidine (V). After acidic Boc group cleavage in (V), the deprotected piperidine (VI) is coupled with N-Boc-D-valine (VII) in the presence of EDC to furnish amide (VIII). Further N-Boc group cleavage in (VIII) employing trifluoroacetic acid yields amino amide (IX), which is then reduced to diamine (X) by means of borane in THF. Coupling of amine (X) with 3,4,5-trimethoxyphenyl isocyanate (XI) leads to urea (XII). Finally, quaternization of the piperidine N of (XII) with iodomethane provides the title piperidinium salt.

参考文献 中间体
合成目标
【1】 Kertesz, D.J.; Smith, D.B.; Hirschfeld, D.R. (F. Hoffmann-La Roche AG); Piperidine CCR-3 receptor antagonists. DE 19955793; EP 1131290; GB 2343894; JP 2002530375; US 6342509; WO 0031033 .
【2】 Wilhelm, R.S.; Smith, D.B.; Talamas, F.X.; Gong, L.; tesz, D.J. (Syntex (USA) LLC); Cyclic amine derivs.-CCR-3 receptor antagonists. US 6339087 .
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) 42911 4-(bromomethyl)-1,2-dichlorobenzene 18880-04-1 C7H5BrCl2 详情 详情
(II) 58924 (3,4-dichlorobenzyl)(triphenyl)phosphonium bromide C25H20BrCl2P 详情 详情
(III) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IV) 58925 tert-butyl 4-(3,4-dichlorobenzylidene)-1-piperidinecarboxylate C17H21Cl2NO2 详情 详情
(V) 58926 tert-butyl 4-(3,4-dichlorobenzyl)-1-piperidinecarboxylate C17H23Cl2NO2 详情 详情
(VI) 58927 4-(3,4-dichlorobenzyl)piperidine C12H15Cl2N 详情 详情
(VII) 48375 (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VIII) 58928 tert-butyl (1R)-1-{[4-(3,4-dichlorobenzyl)-1-piperidinyl]carbonyl}-2-methylpropylcarbamate C22H32Cl2N2O3 详情 详情
(IX) 58929 (2R)-2-amino-1-[4-(3,4-dichlorobenzyl)-1-piperidinyl]-3-methyl-1-butanone C17H24Cl2N2O 详情 详情
(X) 58930 (2R)-1-[4-(3,4-dichlorobenzyl)-1-piperidinyl]-3-methyl-2-butanamine; (1R)-1-{[4-(3,4-dichlorobenzyl)-1-piperidinyl]methyl}-2-methylpropylamine C17H26Cl2N2 详情 详情
(XI) 58931 3,4,5-trimethoxyphenyl isocyanate; 5-isocyanato-1,2,3-trimethoxybenzene C10H11NO4 详情 详情
(XII) 58933 7-Octene-1,2-diol C8H16O2 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VIII)

The enantioselective reduction of 4-(trifluoromethyl)acetophenone (I) with BH3/Me2S in the presence of the chiral borane (II) gives the (R) alcohol (III), which is treated with MsCl and TEA to yield the corresponding mesylate (IV). The displacement of the Ms group of (V) by means of the 1-Boc-3(S)-methylpiperazine (V) produced the protected (S,S)-alpha-methylbenzyl piperazine (VI) as the major isomer, which is purified by flash chromatography. After cleavage of the Boc group of (VI) with TFA in dichloromethane, the resulting piperazine (VII) is subjected to a modified Strecker reaction with 1-Boc-piperidin-4-one (VIII) and diethylaluminum cyanide to yield the aminonitrile (IX). A methyl group is then introduced by displacement of the cyano group of (IX) by means of MeMgBr to afford the protected 4-methylpiperidine derivative (X). Subsequent acidic Boc group cleavage in (X) with TFA provides the piperidine (XI), which is finally condensed with 2,4-dimethylpyridine-3-carboxylic acid (XII) by means of EDC and HOBT to furnish the target amide (1-3).

参考文献 中间体
合成目标
【1】 Tagat, J.R.; Steensma, R.W.; McCombie, S.W.; Nazareno, D.V.; Lin, S.-I.; Neustadt, B.R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M.G.; Vantuno, N.; Baroudy, B.M.; Strizki, J.M.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent. J Med Chem 2001, 44, 21, 3343.
【2】 Labroli, M.A.; Smith, E.M.; Baroudy, B.M.; Gilbert, E.; Tagat, J.R.; Josien, H.B.; Steensma, R.; Laughlin, M.A.; Miller, M.W.; Clader, J.W.; McKittrick, B.A.; Neustadt, B.R.; Palani, A.; McCombie, S.W.; Vice, S.F. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. EP 1175401; WO 0066558 .
【3】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 6391865 .
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) 17145 1-(4-methylphenyl)-1-ethanone; p-methylacetophenone; 4-methylacetophenone; 4-methylphenylethanone 122-00-9 C9H10O 详情 详情
(II) 10624 (3aS)-1,3,3-Trimethyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole C8H16BNO 详情 详情
(III) 51861 (1R)-1-[4-(trifluoromethyl)phenyl]-1-ethanol C9H9F3O 详情 详情
(IV) 51862 (1R)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate C10H11F3O3S 详情 详情
(V) 51868 tert-butyl (3S)-3-methyl-1-piperazinecarboxylate C10H20N2O2 详情 详情
(VI) 51863 tert-butyl (3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinecarboxylate C19H27F3N2O2 详情 详情
(VII) 51864 (2S)-2-methyl-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine C14H19F3N2 详情 详情
(VIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(IX) 51865 tert-butyl 4-cyano-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate C25H35F3N4O2 详情 详情
(X) 51866 tert-butyl 4-methyl-4-((3S)-3-methyl-4-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazinyl)-1-piperidinecarboxylate C25H38F3N3O2 详情 详情
(XI) 51867 (2S)-2-methyl-4-(4-methyl-4-piperidinyl)-1-[(1S)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazine C20H30F3N3 详情 详情
(XII) 64432 2,4-dimethylnicotinic acid C8H9NO2 详情 详情

合成路线34

该中间体在本合成路线中的序号：(XXII)

Reductive amination of N-Boc-4-piperidone (XXII) with benzylamine, followed by benzyl group hydrogenolysis of the resultant secondary amine (XXIII) gives rise to N-Boc-4-aminopiperidine (XXIV). This is then condensed with 2-chloro-5-trifluoromethylpyrimidine (XXV) to furnish adduct (XXVI). Subsequent alkylation of amine (XXVI) with allyl bromide in the presence of sodium hexamethyldisilazide affords the N-allyl amine (XXVII), which is further hydrogenated to the N-propyl analogue (XXVIII). Acidic hydrolysis of (XXVIII) then removes the N-Boc protecting group, providing piperidine (XXIX). (1,2)

参考文献 中间体
合成目标
【1】 1,3,4 Trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorg Med Chem Lett 2003, 13, 3, 427.
【2】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Kim, R.M. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6498161; WO 0059498 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XXIII) 63999 tert-butyl 4-(benzylamino)-1-piperidinecarboxylate C17H26N2O2 详情 详情
(XXIV) 28914 benzyl 4-ethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate C16H19N3O2 详情 详情
(XXV) 64000 2-chloro-5-(trifluoromethyl)pyrimidine C5H2ClF3N2 详情 详情
(XXVI) 64001 tert-butyl 4-{[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate C15H21F3N4O2 详情 详情
(XXVII) 64002 tert-butyl 4-{allyl[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate C18H25F3N4O2 详情 详情
(XXVIII) 64003 tert-butyl 4-{propyl[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate C18H27F3N4O2 详情 详情
(XXIX) 64004 N-(4-piperidinyl)-N-propyl-5-(trifluoromethyl)-2-pyrimidinamine; N-(4-piperidinyl)-N-propyl-N-[5-(trifluoromethyl)-2-pyrimidinyl]amine C13H19F3N4 详情 详情

合成路线35

该中间体在本合成路线中的序号：(IX)

The reaction of 4-(trifluoromethyl)styrene (I) with mCPBA in dichloromethane gives the epoxide (II), which is treated with MeONa in methanol to yield the benzyl alcohol (III). The reaction of (III) with MsCl and TEA affords the mesylate (IV), which is condensed with the monoprotected piperazine (V) in refluxing acetonitrile to provide a diastereomeric mixture of compounds (VI) + (VII) that is resolved by flash chromatography. The desired isomer (VII) is deprotected by means of HCl or TFA to give piperazine (VIII), which is condensed with N-Boc-4-piperidone (IX) with simultaneous alkylation by means of Ti(OiPr)4 and Et2Al-CN in refluxing dichloromethane to yield the intermediate (X). The reaction of (X) with MeMgBr in THF affords the methylated compound (XI), which is deprotected by means of TFA to provide the substituted piperidine derivative (XII). Finally, this compound is acylated by means of 4,6-dimethylpyrimidine-5-carbonyl chloride (XIII) and aqueous NaOH in dichloromethane to provide the target compound. (1-3)

参考文献 中间体
合成目标
【1】 Imamura, S.; Baba, M.; Ishihara, Y.; Hashiguchi, S.; Kanzaki, N.; Nishimura, O. (Takeda Chemical Industries, Ltd.); Cyclic amide cpds., process for the preparation of the same and uses thereof. EP 1180513; JP 2001011073; WO 0066551 .
【2】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 6391865 .
【3】 Neustadt, B.R.; Smith, E.M.; McKittrick, B.A.; McCombie, S.W.; Tagat, J.R.; Clader, J.W.; Vice, S.F.; Laughlin, M.A.; Baroudy, B.M.; Josien, H.B.; Miller, M.W.; Palani, A.; Steensma, R.; Gilbert, E.; Labroli, M.A. (Schering Corp.); Piperazine derivs. useful as CCR5 antagonists. US 2003069252; US 6689765 .
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) 64940 1-ethenyl-4-(trifluoromethyl)benzene C9H7F3 详情 详情
(II) 64941 2-[4-(trifluoromethyl)phenyl]oxirane C9H7F3O 详情 详情
(III) 64942 2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]-1-ethanol C10H11F3O2 详情 详情
(IV) 64943 2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl methanesulfonate C11H13F3O4S 详情 详情
(V) 51868 tert-butyl (3S)-3-methyl-1-piperazinecarboxylate C10H20N2O2 详情 详情
(VI) 64944 1,1-dimethylethyl 3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinecarboxylate C20H29F3N2O3 详情 详情
(VII) 64945 1,1-dimethylethyl 3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinecarboxylate C20H29F3N2O3 详情 详情
(VIII) 64946 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether C15H21F3N2O 详情 详情
(IX) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(X) 64947 1,1-dimethylethyl 4-cyano-4-(3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinecarboxylate C26H37F3N4O3 详情 详情
(XI) 64948 1,1-dimethylethyl 4-methyl-4-(3-methyl-4-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinecarboxylate C26H40F3N3O3 详情 详情
(XII) 64949 methyl 2-[2-methyl-4-(4-methyl-4-piperidinyl)-1-piperazinyl]-2-[4-(trifluoromethyl)phenyl]ethyl ether; 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-4-(4-methyl-4-piperidinyl)piperazine C21H32F3N3O 详情 详情
(XIII) 64950 4,6-dimethyl-5-pyrimidinecarbonyl chloride C7H7ClN2O 详情 详情

合成路线36

该中间体在本合成路线中的序号：(V)

MK-0974 (I) can be prepared by condensation of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (II) with aminoazepinone (III) using either p-nitrophenyl chloroformate (1) or carbonyl diimidazole (CDI) (2-5) in the presence of Et3N. Treatment of (I) with potassium tert-butoxide in ethanol gives the corresponding potassium salt ethanolate (2-5). The intermediate imidazopyridine (II) can be prepared by two related methods. Reductive alkylation of 2,3-diaminopyridine (IV) with 1-Boc-4-piperidone (V) in the presence of NaBH(OAc)3 in CH2Cl2 gives the piperidinylamino pyridine (VI), which on treatment with CDI in CH3CN yields the pyridoimidazolone derivative (VII). Acidic Boc group cleavage in (VII) then provides the target intermediate (II) (1). In a related method, 3-amino-2-chloropyridine (VIII) is reductively alkylated with 1-(ethoxycarbonyl)-4-piperidone (IX) using either NaBH(OAc)3 or NaBH4 in the presence of trifluoroacetic acid to provide (X), which is converted to the N-carbamoyl derivative (XI) upon treatment with chlorosulfonyl isocyanate. Then, cyclization of (XI) by means of palladium diacetate and bis(diphenylphosphino)butane leads to the protected imidazopyridinone (XII), from which the N-carbethoxy group is removed by hydrolysis under alkaline conditions to furnish intermediate (II) (2-5). Scheme 1.

参考文献 中间体
合成目标
【1】 Burgey, C.S., Deng, Z.J., Williams, T.M., Paone, D.V., Shaw, A.W., Nguyen, D.N. (Merck & Co., Inc.). CGRP receptor antagonists. EP 1638969, JP 2006523697, US 2004229861, US 6953790, WO 2004092166, WO 2004092168.
【2】 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589.
【3】 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590.
【4】 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591.
【5】 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592.
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) 65554 Telcagepant; MK-0974; N-[(3R,6S)-6-(2,3-Difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepin-3-yl]-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxamide 781649-09-0 C26H27F5N6O3 详情 详情
(II) 65555 1-(Piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; 1-Piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one 185961-99-3 C11H14N4O 详情 详情
(III) 65556 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine 　 C14H15F5N2O 详情 详情
(IV) 54816 2,3-Diaminopyridine 452-58-4 C5H7N3 详情 详情
(V) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(VI) 65557 　 　 C15H24N4O2 详情 详情
(VII) 65558 tert-Butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; 4-(2,3-Dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester 781649-87-4 C16H22N4O3 详情 详情
(VIII) 11160 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine 6298-19-7 C5H5ClN2 详情 详情
(IX) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(X) 65559 　 　 C13H18ClN3O2 详情 详情
(XI) 65560 　 　 C14H19ClN3O3 详情 详情
(XII) 65561 　 　 C14H18N4O3 详情 详情

合成路线37

该中间体在本合成路线中的序号：(XXXVI)

The thiazolopyridine derivatives (II) and (III) can be obtained in several ways. Treatment of N-Boc-4-piperidinone (XXXVI) with pyrrolidine in the presence of p-TsOH·H2O in refluxing cyclohexane, followed by cyclization of the resulting enamine with cyanamide and elemental sulfur in MeOH gives 2-amino-5-Boc-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XXXVII), which by Sandmeyer reaction with CuBr2 and t-BuONO in DMF at 40 °C affords the 2-bromo compound (XXXVIII). After removal of the N-Boc-protecting group of intermediate (XXXVIII) with TFA, reductive methylation of the deprotected amine (XXXIX) with formaldehyde and NaBH(OAc)3 in the presence of AcOH and Et3N in CH2Cl2 yields 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XL) , optionally isolated as the corresponding tosylate salt (1). Alternatively, cyclization of 1-methyl-4-piperidinone (XLI) with cyanamide and sulfur in the presence of pyrrolidine in i-PrOH at 50 °C yields 2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XLII), which is converted to the corresponding bromide (XL) by diazotization with NaNO2 in the presence of HBr in H2O. Metalation of the bromo derivative (XL) with BuLi in THF at –78 °C, followed by quenching with CO2 affords the lithium carboxylate (II) , which is converted to the carboxylic acid (III) by treatment with HCl in EtOH. Alternatively, cyanation of bromide (XL) with NaCN/CuCN in DMAc at 150 °C yields nitrile (XLIII), which is hydrolyzed to carboxylate (II) using LiOH in EtOH . In one further method, deamination of intermediate (XXXVII) by diazotization with NaNO2 and H2SO4 in the presence of hypophosphorous acid in H2O gives 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XLIV) , which is carboxylated to compound (II) by metalation with BuLi in THF at –78 °C and subsequent quenching with CO2 , or by acylation with trichloroacetyl chloride and Et3N in toluene, followed by haloform reaction of the resultant trichloromethyl ketone in the presence of LiOH .
The tetrahydrothiazolopyridine intermediate (XLIV) can also be prepared by a different procedure. After protection of 4-aminopyridine (XLV) as the N-Boc derivative (XLVI) with Boc2O in THF, treatment with BuLi in cold THF, followed by elemental sulfur yields the 3-sulfanylpyridine (XLVI). Cyclization of the Boc-protected amino thiol (XLVI) with formic acid at reflux, followed by KOH in H2O or Et2O leads to thiazolo[5,4-c]pyridine (XLVII), which is converted to the target intermediate (XLIV) by quaternization with iodomethane in DMF at 80 °C and then reduction with NaBH4 in MeOH .

参考文献 中间体
合成目标
【1】 Nagasawa, Sato, K., Yagi, T., H., Kitani, Y. (Daiichi Sankyo Co., Ltd.).Process for producing thiazole derivative. CA 2545730, EP 1683800, US 7547786, US 2007135476, US 2009192313.
【2】 Ohta, T., Komoyira, S., Yoshimo, T. et al. (Daiichi Sankyo Co., Ltd.).Diamine derivatives. CA 2451605, CA 2456841, EP 1405852, EP 1415992, JP 2008143905, US 2005020645, US 2005119486, US 2005245565, US 2008015215, US 2009270446, US 7342014, US 7365205, WO 2003000657, WO 2003000680, WO 2003016302.
【3】 Ohta, T., Komoriya, S., Yoshino, T. et al. (Daiichi Sankyo Co., Ltd.). Diamine derivatives. CA 2511493, EP 1577301, JP 2007070369, JP 2008138011, US 2006252837, US 2009281074, US 7576135, WO 2004058715.
【4】 Schwartz, H.M., Wu, W.-S., Marr, P.W., Jones, J.B. Predicting the enantiomeric selectivity of chymotrypsin. Homologous series of ester substances. J Am Chem Soc 1978, 100(16): 5199-203.
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) 69421 lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate C8H9LiN2O2S 详情 详情
(III) 69422 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride C8H10N2O2S.HCl 详情 详情
(XVIII) 69458 tert-butyl (3-mercaptopyridin-4-yl)carbamate C10H14N2O2S 详情 详情
(XXXVI) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XXXVII) 69450 2-amino-5-Boc-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine；tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate；Thiazolo[5,4-c]pyridine-5(4H)-carboxylicacid, 2-amino-6,7-dihydro-, 1,1-dimethylethyl ester;2-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester;2-Amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butylester 365996-05-0 C11H17N3O2S 详情 详情
(XXXVIII) 69451 tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate；Thiazolo[5,4-c]pyridine-5(4H)-carboxylicacid, 2-bromo-6,7-dihydro-, 1,1-dimethylethyl ester;2-Bromo-5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine；2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butylester;2-Bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylic acidtert-butyl ester 365996-06-1 C11H15BrN2O2S 详情 详情
(XXXIX) 69452 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2,2,2-trifluoroacetate C8H8BrF3N2O2S 详情 详情
(XL) 69453 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine C7H9BrN2S 详情 详情
(XLI) 10919 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one 1445-73-4 C6H11NO 详情 详情
(XLII) 69454 2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine;5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine C7H11N3S 详情 详情
(XLIII) 69455 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonitrile C8H9N3S 详情 详情
(XLIV) 69456 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 259809-24-0 C7H10N2S 详情 详情
(XLV) 25661 4-pyridinamine; 4-aminopyridine 5044-74-5 C5H6N2 详情 详情
(XLVI) 69457 tert-butyl pyridin-4-ylcarbamate;4-(Boc-amino)pyridine;4-(tert-Butoxycarbonylamino)pyridine 98400-69-2 C10H14N2O2 详情 详情
(XLVII) 69459 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine C6H8N2S 详情 详情
Extended Information