合成路线1
该中间体在本合成路线中的序号:
(I) The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in chloroform gives 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (II), which is treated with NaOMe in methanol to yield 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (III). The methylation of (III) with NaH and MeI in DMF affords 3,4,4-trimethoxypiperidine-1-carboxylic acid ethyl ester (IV), which is hydrolyzed with refluxing 1% aq. H2SO4 to provide 3-methoxy-4-oxopiperidine-1-carboxylic acid ethyl ester (V). The reductocondensation of (V) with benzylamine and H2 over Pd/C in methanol in the presence of thiophene gives cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (VI), which is condensed with 4-amino-5-chloro-2-methoxybenzoic acid (VII) by means of ethyl chloroformate and TEA in chloroform to yield the benzamide (VIII). The hydrolysis of the carbamate group of (VIII) with KOH in refluxing isopropanol affords the free piperidine derivative (IX), which is finally condensed with 3-(4-fluorophenoxy)propyl chloride (X) by means of TEA and KI in hot DMF to provide the target, cisapride.
【1】
Van Daele, G. (Janssen Pharmaceutica NV); Novel N-(3-hydroxy-4-piperidinyl)benzamide derivs.. US 4962115 .
|
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) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(II) |
53112 |
ethyl 3-bromo-4-oxo-1-piperidinecarboxylate
|
95629-02-0 |
C8H12BrNO3 |
详情 | 详情
|
(III) |
49556 |
ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate
|
|
C10H19NO5 |
详情 |
详情
|
(IV) |
49569 |
ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate
|
|
C11H21NO5 |
详情 |
详情
|
(V) |
49570 |
ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate
|
|
C9H15NO4 |
详情 |
详情
|
(VI) |
49574 |
ethyl (3S,4R)-4-amino-3-methoxy-1-piperidinecarboxylate
|
|
C9H18N2O3 |
详情 |
详情
|
(VII) |
12419 |
4-Amino-5-chloro-2-methoxybenzoic acid
|
7206-70-4 |
C8H8ClNO3 |
详情 | 详情
|
(VIII) |
49575 |
ethyl (3S,4R)-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinecarboxylate
|
|
C17H24ClN3O5 |
详情 |
详情
|
(IX) |
49576 |
4-amino-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide
|
|
C14H20ClN3O3 |
详情 |
详情
|
(X) |
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2
该中间体在本合成路线中的序号:
(I) The 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (III), an intermediate in the synthesis of cisapride, has been obtained as follows: The bromination of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with Br2 in methanol followed by neutralization of the resulting HBr with NaOMe in the same solvent gives 3-bromo-4,4-dimethoxypiperidine-1-carboxylic acid ethyl ester (II), which is finally hydrolyzed with aq. 2N HBr or HCl to afford the target intermediate 3-bromo-4-oxopiperidine-1-carboxylic acid ethyl ester (III).
【1】
Serra Masia, J.; Lombardero Fernandez, J.; Montserrat, Vidal, C. (Laboratorios Salvat SA); Ethyl 3-bromo-4-oxo-1-piperidinecarboxylate, process for obtaining it and novel intermediates for its preparation. ES 2053394 .
|
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) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(II) |
53113 |
ethyl 3-bromo-4,4-dimethoxy-1-piperidinecarboxylate
|
n/a |
C10H18BrNO4 |
详情 | 详情
|
(III) |
53112 |
ethyl 3-bromo-4-oxo-1-piperidinecarboxylate
|
95629-02-0 |
C8H12BrNO3 |
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 reaction of p-chloroaniline (I) with ethyl 4-oxopiperidine-1-carboxylate (II) by means of tosyl chloride in refluxing toluene gives ethyl 4-(p-chlorophenylimino)piperidine-1-carboxylate (III), which is reduced with NaBH4 in refluxing methanol to afford ethyl 4-(p-chloroanilino)piperidine-1-carboxylate (IV). The acylation of (IV) with phenylacetyl chloride (A) in refluxing benzene yields ethyl 4-[N-(p-chlorophenyl)-N-(phenylacetyl)amino]piperidine-1-carboxylate (V), which is decarboxylated with hot aqueous HBr giving N-(p-chlorophenyl)-N-(piperidin-4-yl)phenylacetamide hydrochloride (VI). Finally, this compound is alkylated with 2-bromopropane (B) and Na2CO3 in refluxing butanol.
【1】
Hermans, H.K.; Sanczuk, S.; N-aryl-N-(1-L-4-piperidinyl)-arylacetamides. BE 0846473; US 4151286; US 4157393; ZA 7605684 .
|
【2】
Castaner, J.; Weetman, D.F.; Lorcainide hydrochloride. Drugs Fut 1978, 3, 7, 518.
|
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) |
25890 |
2-phenylacetyl chloride;Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride |
103-80-0 |
C8H7ClO |
详情 | 详情
|
(B) |
32658 |
2-bromopropane
|
75-26-3 |
C3H7Br |
详情 | 详情
|
(I) |
12034 |
4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline
|
106-47-8 |
C6H6ClN |
详情 | 详情
|
(II) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(III) |
33565 |
ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate
|
|
C14H17ClN2O2 |
详情 |
详情
|
(IV) |
33566 |
ethyl 4-(4-chloroanilino)-1-piperidinecarboxylate
|
|
C14H19ClN2O2 |
详情 |
详情
|
(V) |
33567 |
ethyl 4-[4-chloro(2-phenylacetyl)anilino]-1-piperidinecarboxylate
|
|
C22H25ClN2O3 |
详情 |
详情
|
(VI) |
33568 |
N-(4-chlorophenyl)-2-phenyl-N-(4-piperidinyl)acetamide
|
|
C19H21ClN2O |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(I) The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound.
The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.
【1】
Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
|
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) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(II) |
49678 |
ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate
|
|
C9H13Cl2NO3 |
详情 |
详情
|
(III) |
12294 |
Aniline; Phenylamine
|
62-53-3 |
C6H7N |
详情 | 详情
|
(IV) |
49679 |
ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate
|
|
C21H25N3O3 |
详情 |
详情
|
(V) |
49680 |
ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate
|
|
C22H27N3O3 |
详情 |
详情
|
(VI) |
49681 |
4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide
|
|
C19H23N3O |
详情 |
详情
|
(VII) |
49682 |
(4-anilino-4-piperidinyl)methanol
|
|
C12H18N2O |
详情 |
详情
|
(VIII) |
14721 |
1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one
|
|
C5H9BrN4O |
详情 |
详情
|
(IX) |
32218 |
1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one
|
69048-98-2 |
C3H6N4O |
详情 | 详情
|
(X) |
10252 |
1,2-Dibromoethane; Ethylene dibromide
|
106-93-4 |
C2H4Br2 |
详情 | 详情
|
(XI) |
49683 |
1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one
|
|
C17H26N6O2 |
详情 |
详情
|
(XII) |
49684 |
1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one
|
|
C18H28N6O2 |
详情 |
详情
|
(XIII) |
15967 |
propanoyl chloride; propionyl chloride
|
79-03-8 |
C3H5ClO |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(I) The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with 2-(2-thienyl)ethyl mesylate (VIII) by means of K2CO3 in refluxing acetonitrile yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (X). Finally, this compound is acylated with propionyl chloride (XI) in chloroform to provide the target compound.
【1】
Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .
|
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) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(II) |
49678 |
ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate
|
|
C9H13Cl2NO3 |
详情 |
详情
|
(III) |
12294 |
Aniline; Phenylamine
|
62-53-3 |
C6H7N |
详情 | 详情
|
(IV) |
49679 |
ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate
|
|
C21H25N3O3 |
详情 |
详情
|
(V) |
49680 |
ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate
|
|
C22H27N3O3 |
详情 |
详情
|
(VI) |
49681 |
4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide
|
|
C19H23N3O |
详情 |
详情
|
(VII) |
49682 |
(4-anilino-4-piperidinyl)methanol
|
|
C12H18N2O |
详情 |
详情
|
(VIII) |
49685 |
2-(2-thienyl)ethyl methanesulfonate
|
|
C7H10O3S2 |
详情 |
详情
|
(IX) |
35257 |
[4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol
|
|
C18H24N2OS |
详情 |
详情
|
(X) |
49686 |
1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-N-phenyl-4-piperidinamine; N-[1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine
|
|
C21H30N2OS |
详情 |
详情
|
(XI) |
15967 |
propanoyl chloride; propionyl chloride
|
79-03-8 |
C3H5ClO |
详情 | 详情
|
合成路线6
该中间体在本合成路线中的序号:
(I) The reductocondensation of ethyl 4-oxopiperidine-1-carboxylate (I) with methylamine by means of H2 over Pd/C in thiophene gives ethyl 4-(methylamino)piperidine-1-carboxylate (II), which is then condensed with phenyl isothiocyanate (III) in diisopropyl ether to yield the substituted thiourea (IV). The cyclization of (IV) with Br2 in refluxing CCl4 affords N-[4-(ethoxycarbonyl)piperidin-l-yl]-N methylbenzo-thiazol-2-amine (V), which is decarboxylated with refluxing 48% HBr to N-methyl-N-(4-piperidyl)benzo thiazol-2-amine (VI). Finally, this compound is condensed with 1,2-epoxy-3-(4-fluorophenoxypropane) (VII) in refluxing toluene methanol.
【1】
Stokbroekx, R.A.; Luyckx, M.G.M.; Janssens, F.E. (Janssen Pharmaceutica NV); Benzoxazol- and benzothiazolamine derivs.. EP 0184257; US 4861785 .
|
【2】
Prous, J.; Castaner, J.; SABELUZOLE < Rec INN >. Drugs Fut 1988, 13, 6, 529.
|
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) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(II) |
22145 |
ethyl 4-(methylamino)-1-piperidinecarboxylate
|
|
C9H18N2O2 |
详情 |
详情
|
(III) |
22146 |
1-isothiocyanatobenzene; phenyl isothiocyanate
|
103-72-0 |
C7H5NS |
详情 | 详情
|
(IV) |
22147 |
ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate
|
|
C16H23N3O2S |
详情 |
详情
|
(V) |
22148 |
ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate
|
|
C16H21N3O2S |
详情 |
详情
|
(VI) |
16742 |
N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine
|
|
C13H17N3S |
详情 |
详情
|
(VII) |
22150 |
2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether
|
18123-82-5 |
C9H9FO2 |
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 reaction of 4-fluorophenylhydrazine hydrochloride (I) with N-carbethoxy-4-piperidone (II) under Fisher's conditions affords N2-carbethoxy-8-fluoro-2,3,4,5-tetrahydro-1H-pyridol[4,3-b]indole (III). Treatment of (III) with Claisen's alkali affords the N-2 unsubstituted 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (IV), which is finally condensed with 3-pyridinylpropyl bromide hydrobromide (V) in DMF in the presence of triethyl amine (TEA). Compound (V) is obtained by refluxing 3-pyridinylpropanol with 48% hydrobromic acid.
【1】
Andree, T.H.; Webb, M.B.; Patel, U.R.; Muth, E.A.; Moyer, J.A.; Abou-Gharbia, M.; Antipsychotic activity of substituted gamma-carbol. J Med Chem 1987, 30, 1818.
|
【2】
Andree, T.; Abou-Gharbia, M.; WY-47384. Drugs Fut 1988, 13, 6, 541.
|
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) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(I) |
22135 |
1-(4-fluorophenyl)hydrazine
|
371-14-2 |
C6H7FN2 |
详情 | 详情
|
(III) |
22137 |
ethyl 8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate
|
|
C14H15FN2O2 |
详情 |
详情
|
(IV) |
14941 |
8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
|
39876-39-6 |
C11H11FN2 |
详情 | 详情
|
(V) |
22139 |
3-(3-bromopropyl)pyridine
|
|
C8H10BrN |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(IX) YM-796 can be obtained by two different ways:
1) The Wittig condensation of 1-methylpiperidin-4-one (I) with 2-(diethoxyphosphoryl)acetic acid ethyl ester (II) by means of NaH in dimethoxyethane gives 2-(1-methylpiperidin-4-ylidene) acetic acid ethyl ester (III), which is cyclized with ethyl lactate (IV) by means of NaH in DMSO yielding 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylic acid ethyl ester (V). The decarboxylation of (V) with refluxing aqueous 1N HCl affords 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (VI), which is submitted to a new Wittig condensation with methyltriphenylphosphonium iodide (or bromide) (VII) by means of NaH in DMSO to give racemic 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (VIII). Finally, this compound is submitted to optical resolution with L-tartaric acid or with di-p-toluoyl-D-tartaric acid.
2) The Wittig condensation of 4-oxopiperidine-1-carboxylic acid ethyl ester (IX) with phosphorane (VII) as before gives the corresponding methylene derivative (X), which is submitted to alkoxybromination with N-bromosuccinimide (NBS) and (S)-3-butyn-2-ol (XI) yielding (S)-4-(bromomethyl)-4-(1-methyl-2-propynyloxy)piperidine-1-carboxylic acid ethyl ester (XII). The radical cyclization of (XII) with NaBH4 catalyzed by bis(dimethylglyoximato)(pyridine)cobalt(III) chloride [chlorocobaloxime(III)] affords (S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (XIII), which is finally reduced with sodium bis(2-methoxyethoxy)aluminum hydride (vitride) in toluene and treated with fumaric acid to obtain the sesquifumarate salt.
【1】
Ngo, J.; Martel, A.M.; Castaner, J.; YM-796. Drugs Fut 1997, 22, 2, 144.
|
【2】
Tsukamoto, S.; Kondo, Y.; Igarashi, S.; An efficient synthesis of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane by cobaloxime(I)-mediated radical cyclization. Heterocycles 1995, 41, 8, 1771-1778.
|
【3】
Tsukamoto, S.; Fujii, M.; Yasunaga, T.; Matsuda, K.; Wanibuchi, F.; Hidaka, K.; Furuya, T.; Tamura, T.; Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists. Chem Pharm Bull 1995, 43, 5, 842-852. |
【4】
Tsukamoto, S.-I.; Nagaoka, H.; Usuda, S.; Harada, M.; Tamura, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic spiro cpds. and their preparation. AU 8823449; EP 0311313; JP 1990036183; US 4996210 .
|
【5】
Tsukamoto, S.; Kohinata, T.; Fujii, M.; Tomisawa, S. (Yamanouchi Pharmaceutical Co., Ltd.); (-)-(S)-2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate. EP 0590150; JP 1993508699; WO 9220683 .
|
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) |
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
|
(II) |
10019 |
Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate
|
867-13-0 |
C8H17O5P |
详情 | 详情
|
(III) |
13480 |
ethyl 2-(1-methyl-4-piperidinylidene)acetate
|
|
C10H17NO2 |
详情 |
详情
|
(IV) |
13481 |
ethyl lactate; ethyl 2-hydroxypropanoate
|
97-64-3 |
C5H10O3 |
详情 | 详情
|
(V) |
13482 |
ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylate
|
|
C13H21NO4 |
详情 |
详情
|
(VI) |
13483 |
2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one
|
|
C10H17NO2 |
详情 |
详情
|
(VII) |
13484 |
Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide
|
2065-66-9 |
C19H18IP |
详情 | 详情
|
(VIII) |
13485 |
2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane
|
|
C11H19NO |
详情 |
详情
|
(IX) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(X) |
13487 |
ethyl 4-methylene-1-piperidinecarboxylate
|
|
C9H15NO2 |
详情 |
详情
|
(XI) |
13488 |
(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol
|
2914-69-4 |
C4H6O |
详情 | 详情
|
(XII) |
13489 |
ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate
|
|
C13H20BrNO3 |
详情 |
详情
|
(XIII) |
13490 |
ethyl (2S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylate
|
|
C13H21NO3 |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(IV) The condensation of 2-chlorobenzoyl chloride (I) with cyanacetic acid (II) by means of butyllithium in THF gives 2-(2-chlorobenzoyl)acetonitrile (III), which is cyclized with N-(ethoxycarbonyl)piperidin-4-one (IV) by means of S and morpholine in refluxing methanol yielding the bicyclic ethyl ester (V). The acylation of (V) with bromoacetyl bromide (VI) in chloroform affords the corresponding 2-(bromoacetamido) derivative (VII), which by reaction with dry ammonia in THF is converted into the 2-glycinamido derivative (VIII). The cyclization of (VIII) in refluxing pyridine gives the tricyclic ethyl ester (IX), which by reaction with P2S5 in refluxing pyridine is converted into the corresponding thioketone (X). The reaction of (X) with hydrazine in methanol yields the 2-hydrazino derivative (XI), which is acylated with acetyl chloride (XII) and NaHCO3 in THF affording the 2-(acetylhydrazino) derivative (XIII). The cyclization of (XIII) in refluxing acetic acid gives the tetracyclic ethyl ester (XIV), which is decarboxylated with 30% HBr yielding the tetracyclic precursor (XV). The acylation of (XV) with 2-(3,4-dimethoxyphenylthio)acetic acid (XVI) by means of dicyclohexylcarbodiimide (DCC) in DMF affords the acylated compound (XVII), which is finally treated with P2S5 or Lawesson's reagent.
【1】
Braquet, P.; Esanu, A.; Laurent, J.-P.; Pommier, J. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Thieno-triazolo-diazepine derivs. and process for their preparation. BE 1004122; CH 681009; DE 4015137; FR 2646774; FR 2646851; GB 2231330; JP 1991005484; US 5049559 . |
【2】
Braquet,P.; Castaner, J.; Duverger, D.; Koltai, M.; Spinnewyn, B.; Pirotzky, E.; Esanu, A.; BN 50739. Drugs Fut 1991, 16, 5, 413.
|
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) |
14000 |
o-Chlorobenzoyl chloride; 2-Chlorobenzoyl chloride
|
609-65-4 |
C7H4Cl2O |
详情 | 详情
|
(II) |
12591 |
Cyanoacetic Acid; 2-Cyanoacetic acid
|
372-09-8 |
C3H3NO2 |
详情 | 详情
|
(III) |
12923 |
3-(2-Chlorophenyl)-3-oxopropanenitrile
|
40018-25-5 |
C9H6ClNO |
详情 | 详情
|
(IV) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(V) |
14004 |
ethyl 2-amino-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
|
|
C17H17ClN2O3S |
详情 |
详情
|
(VI) |
14005 |
2-Bromoacetyl bromide; Bromoacetyl bromide
|
598-21-0 |
C2H2Br2O |
详情 | 详情
|
(VII) |
14006 |
ethyl 2-[(2-bromoacetyl)amino]-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
|
|
C19H18BrClN2O4S |
详情 |
详情
|
(VIII) |
14007 |
ethyl 2-[(2-aminoacetyl)amino]-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate
|
|
C19H20ClN3O4S |
详情 |
详情
|
(IX) |
14008 |
ethyl 5-(2-chlorophenyl)-2-oxo-1,2,3,6,7,9-hexahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate
|
|
C19H18ClN3O3S |
详情 |
详情
|
(X) |
14009 |
ethyl 5-(2-chlorophenyl)-2-thioxo-1,2,3,6,7,9-hexahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate
|
|
C19H18ClN3O2S2 |
详情 |
详情
|
(XI) |
14010 |
ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate
|
|
C19H20ClN5O2S |
详情 |
详情
|
(XII) |
14011 |
1-(Chlorooxy)-1-oxoethane
|
|
C2H3ClO2 |
详情 |
详情
|
(XIII) |
14012 |
ethyl 2-(2-acetylhydrazino)-5-(2-chlorophenyl)-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate
|
|
C21H22ClN5O3S |
详情 |
详情
|
(XIV) |
14013 |
ethyl 6-(2-chlorophenyl)-1-methyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-9(8H)-carboxylate
|
|
C21H20ClN5O2S |
详情 |
详情
|
(XV) |
14014 |
6-(2-Chlorophenyl)-1-methyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
|
|
C18H16ClN5S |
详情 |
详情
|
(XVI) |
14015 |
2-[(3,4-Dimethoxyphenyl)sulfanyl]acetic acid
|
95735-63-0 |
C10H12O4S |
详情 | 详情
|
(XVII) |
14016 |
1-[6-(2-Chlorophenyl)-1-methyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-9(8H)-yl]-2-[(3,4-dimethoxyphenyl)sulfanyl]-1-ethanone
|
|
C28H26ClN5O3S2 |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(VII) A new synthesis of lubeluzole has been reported: The condensation of 3,4-difluorophenol (I) with racemic glycidol (II) by means of PPh3 and DEAD in THF gives 2-(3,4-difluorophenoxymethyl)oxirane (III), which is opened by means of Li2CuCl4 in THF yielding racemic 1-chloro-3-(3,4-difluorophenoxy)-2-propanol (IV). Racemic compound (IV) is kinetically resolved by transesterification with vinyl butyrate using Rhizomucor miehei lipase (RML) as catalyst, providing a mixture of (R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol (V) and the (S)-butyrate (VI). This mixture is easily separated by column chromatography. Finally, the (R)-alcohol (V) is condensed with N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) by means of NaHCO3 in hot DMF. The key intermediate N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) has been obtained as follows: Reductive amination of 4-oxopiperidine-1-carboxylic acid ethyl ester (VIII) with methylamine and borane/pyridine complex in methanol gives 4-(methylamino)piperidine-1-carboxylic acid ethyl ester (IX), which is condensed with isothiocyanatobenzene (X) in isopropyl ether to yield the thiourea (XI). Cyclization of compound (XI) by means of Br2 in refluxing CCl4 affords the benzothiazole derivative (V), which is finally decarboxylated by means of HBr in refluxing water, followed by treatment with NaOH.
【1】
Liu, H.L.; Helgehoff, B.; Berg, T.C.; Anthonsen, T.; Synthesis of the antistroke drug lubeluzole and its enantiomer. Lipase-catalyzed resolution of chiral building block. Chirality 2001, 13, 3, 135.
|
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) |
16739 |
3,4-difluorophenol
|
2713-33-9 |
C6H4F2O |
详情 | 详情
|
(II) |
29648 |
2-oxiranylmethanol
|
556-52-5 |
C3H6O2 |
详情 | 详情
|
(III) |
47537 |
2-[(3,4-difluorophenoxy)methyl]oxirane; 3,4-difluorophenyl 2-oxiranylmethyl ether
|
|
C9H8F2O2 |
详情 |
详情
|
(IV) |
47534 |
1-chloro-3-(3,4-difluorophenoxy)-2-propanol
|
|
C9H9ClF2O2 |
详情 |
详情
|
(V) |
47535 |
(1S)-2-chloro-1-[(3,4-difluorophenoxy)methyl]ethyl butyrate
|
|
C13H15ClF2O3 |
详情 |
详情
|
(VI) |
47536 |
(2R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol
|
|
C9H9ClF2O2 |
详情 |
详情
|
(VII) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(VIII) |
22145 |
ethyl 4-(methylamino)-1-piperidinecarboxylate
|
|
C9H18N2O2 |
详情 |
详情
|
(IX) |
22146 |
1-isothiocyanatobenzene; phenyl isothiocyanate
|
103-72-0 |
C7H5NS |
详情 | 详情
|
(X) |
22147 |
ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate
|
|
C16H23N3O2S |
详情 |
详情
|
(XI) |
22148 |
ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate
|
|
C16H21N3O2S |
详情 |
详情
|
(XII) |
16742 |
N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine
|
|
C13H17N3S |
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 cyclization of p-fluorophenylhydrazine (I) with 1-carbethoxy-4-piperidinone (II) in refluxing ethanol gives 2-carbethoxy-8-fluoro-1,2,3,4-tetrahydro-gamma-carboline (III), which is arylated with p-fluorobromobenzene (IV), by means of Na2CO3 - Cu2Br2 in N-methyl-2-pyrrolidinone heated at 200 C to yield 2-carbethoxy-8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-gamma-carboline (V). The hydrolytic decarboxylation of (V) with KOH in refluxing ethanol affords 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-gamma-carboline (VI), which is alkylated with p-fluoro-gamma-bromobutyrophenone (VII) by means of Na2CO3 in hot DMF to give 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-oxobutyl]-1,2,3,4-tetrahydro-gamma-carboline (VIII). Finally this compound is reduced with NaBH4 in ethanol - THF
【1】
Harbert, C.A.; et al.; Neuroleptic activity in 5-aryl-tetrahydro-gamma-carbolines. J Med Chem 1980, 23, Suppl. 3, 635.
|
【2】
Plattner, J.J.; et al. (Pfizer Inc.); US 4001263 .
|
【3】
Blancafort, P.; Serradell, M.N.; Castaner, J.; Leeson, P.A.; Mealy, N.E.; Flutroline. Drugs Fut 1981, 6, 2, 84.
|
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) |
22135 |
1-(4-fluorophenyl)hydrazine
|
371-14-2 |
C6H7FN2 |
详情 | 详情
|
(II) |
13486 |
Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone
|
29976-53-2 |
C8H13NO3 |
详情 | 详情
|
(III) |
22137 |
ethyl 8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate
|
|
C14H15FN2O2 |
详情 |
详情
|
(IV) |
29012 |
1-bromo-4-fluorobenzene
|
460-00-4 |
C6H4BrF |
详情 | 详情
|
(V) |
60777 |
ethyl 8-fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate
|
|
C20H18F2N2O2 |
详情 |
详情
|
(VI) |
60775 |
8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
|
|
C17H14F2N2 |
详情 |
详情
|
(VII) |
60778 |
4-bromo-1-(4-fluorophenyl)-1-butanone
|
|
C10H10BrFO |
详情 |
详情
|
(VIII) |
60779 |
4-[8-fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-1-(4-fluorophenyl)-1-butanone
|
|
C27H23F3N2O |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(IX) 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.
【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
|