合成路线1
该中间体在本合成路线中的序号:
(II) The cyclization of 2-aminobenzophenone (I) with 3-amino-2-chloropyridine (II) by means of NaOH in methylene chloride-water gives 6-phenyl-11H-[2,3-b][1,4]benzodiazepine (III), which is then condensed with (3-chloropropyl)dimethylamine by means of NaH in hot DMF, followed by a treatment with fumaric acid in isopropanol.
【1】
Taylor, C.R.Jr. (A.H. Robins Co. Inc.); Pyridol [1,4] benzodiazepines phenyl-substituees et leurs intermediares, utiles comme medicaments antidepresseurs. BE 0891666; FR 2515183; JP 58065290 .
|
【2】
Serradell, M.N.; Castaner, J.; Souto, M.E.; AHR-9377. Drugs Fut 1984, 9, 3, 163.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
23808 |
Fumaric acid; (E)-2-butenedioic acid
|
110-17-8 |
C4H4O4 |
详情 | 详情
|
(I) |
21101 |
(2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone
|
2835-77-0 |
C13H11NO |
详情 | 详情
|
(II) |
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
|
(III) |
30304 |
6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine
|
|
C18H13N3 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(I) Synthesis of the intermediate 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (IV) is accomplished by condensation of 3-amino-2-chloropyridine (I) and the anthranilic ester (II) using potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene furnishes the corresponding chloroacetamide (V).
The diamine part of AF-DX 116 is prepared starting from 2-(hydroxymethyl)piperidine (VI). Reaction with thionylchloride in dichloromethane affords the pipecolylchloride hydrochloride (VII), which is converted with diethylamine to the required 2-[(diethylamino)methyl]piperidine (IX) via nucleophilic ring opening of the intermediate aziridine (VIII). Minor amounts of 3-(diethylamino)hexahydroazepine (X), formed by a side reaction, are separated by thorough fractional distillation of the diamine (IX) and/or recrystallization of its hydrochloride (XI).
Coupling of (V) and (XI) in the presence of sodium carbonate yields AF-DX 116 as its free base.
【1】
Schmidt, G.; Hammer, R.; Giachetti, A.; Engel, W.; Trummlitz, G.; Eberlein, W.; Mihm, G. (Dr. Karl Thomae GmbH); Condensed diazepinones, process for their preparation and medicines containing them. AU 8539815; EP 0156191; ES 8607282; ES 8702908; JP 1985215683; US 4550107 . |
【2】
Mattson, R.J.; Yevich, J.P.; Eison, M.S. (Bristol-Myers Squibb Co.); Cerebral function enhancing diazinylpiperidine derivs. AU 8659787; BE 0905061; CH 671579; DE 3622842; FR 2584408; GB 2177692; US 4826843 .
|
【3】
Eberlein, W.G.; Trummlitz, G.; Mihm, G.; Engel, W.W.; Hammer, R.; Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1718-24. |
【4】
Engel, W.; Doods, H.; Wetzel, B.; AF-DX 116. Drugs Fut 1990, 15, 1, 9.
|
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) |
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
|
(II) |
11161 |
methyl 2-aminobenzoate; Methyl anthranilate
|
134-20-3 |
C8H9NO2 |
详情 | 详情
|
(III) |
11162 |
2-Amino-N-(2-chloro-3-pyridinyl)benzamide
|
|
C12H10ClN3O |
详情 |
详情
|
(IV) |
11163 |
5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one
|
|
C12H9N3O |
详情 |
详情
|
(V) |
11164 |
11-(2-Chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one
|
|
C14H10ClN3O2 |
详情 |
详情
|
(VI) |
11165 |
2-Piperidinylmethanol; 2-Piperidinemethanol
|
3433-37-2 |
C6H13NO |
详情 | 详情
|
(VII) |
11166 |
2-(Chloromethyl)piperidine
|
|
C6H12ClN |
详情 |
详情
|
(VIII) |
11167 |
1-Azabicyclo[4.1.0]heptane
|
|
C6H11N |
详情 |
详情
|
(IX) |
11168 |
N-Ethyl-N-(2-piperidinylmethyl)-1-ethanamine; N-(2-Piperidylmethyl)-diethylamine; N,N-Diethyl-N-(2-piperidinylmethyl)amine
|
64168-09-8 |
C10H22N2 |
详情 | 详情
|
(X) |
11169 |
N,N-Diethyl-3-azepanamine; N-(3-Azepanyl)-N,N-diethylamine
|
|
C10H22N2 |
详情 |
详情
|
(XI) |
11170 |
N-Ethyl-N-(2-piperidinylmethyl)-1-ethanamine hydrochloride
|
|
C10H23ClN2 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(I) Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V).
The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.
【1】
Eberlein, W.; Engel, W.; Trummlitz, G.; Mihm, G.; Mayer, N.; Doods, H. (Dr. Karl Thomae GmbH); Condensed diazepinones, process for their preparation and medicines containing them. AU 8824122; DE 3735895; EP 0312895; JP 1989230580; US 5175158 .
|
【2】
Eberlein, W.; Doods, H.; Wetzel, B.; AQ-RA-741. Drugs Fut 1990, 15, 8, 786.
|
【3】
LaMontagne, M.P.; et al.; Tricyclic compounds as selective muscarinic receptor antagonists. 3.
Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1728-32.
|
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) |
11296 |
2-Chloroacetyl chloride; Chloroacetic chloride
|
79-04-9 |
C2H2Cl2O |
详情 | 详情
|
(I) |
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
|
(II) |
11161 |
methyl 2-aminobenzoate; Methyl anthranilate
|
134-20-3 |
C8H9NO2 |
详情 | 详情
|
(III) |
11162 |
2-Amino-N-(2-chloro-3-pyridinyl)benzamide
|
|
C12H10ClN3O |
详情 |
详情
|
(IV) |
11163 |
5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one
|
|
C12H9N3O |
详情 |
详情
|
(V) |
11164 |
11-(2-Chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one
|
|
C14H10ClN3O2 |
详情 |
详情
|
(VI) |
31150 |
4-methylpyridine
|
108-89-4 |
C6H7N |
详情 | 详情
|
(VII) |
31151 |
N-(3-chloropropyl)-N,N-diethylamine; 3-chloro-N,N-diethyl-1-propanamine
|
|
C7H16ClN |
详情 |
详情
|
(VIII) |
31152 |
N,N-diethyl-N-[4-(4-pyridinyl)butyl]amine; N,N-diethyl-4-(4-pyridinyl)-1-butanamine
|
|
C13H22N2 |
详情 |
详情
|
(IX) |
31153 |
N,N-diethyl-N-[4-(4-piperidinyl)butyl]amine; N,N-diethyl-4-(4-piperidinyl)-1-butanamine
|
|
C13H28N2 |
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 3-amino-2-chloropyridine (I) with triethyl orthoacetate (II) catalyzed by TsOH gives the acetimidate (III), which is reduced to 3-(ethylamino)-2-chloropyridine (IV) by means of DIBAL in toluene. The reaction of (IV) with piperazine (V) by means of Na2CO3 by heating at 144 C affords 3-(ethylamino)-2-(1-piperazinyl)pyridine (VI), which is finally condensed with 5-methoxy-1H-indole-2-carboxylic acid (II) by means of CDI in dichloromethane and treated with CH3SO3H in methanol to provide the target mesylate.
【1】
Perrault, W.R.; et al.; Production scale synthesis of the non-nucleoside recverse transcriptase inhibitor atervirdine mesylate (U-87,201E). Org Process Res Dev 1997, 1, 2, 106.
|
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) |
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
|
(II) |
36531 |
1,1,1-trimethoxypropane; 1,1-dimethoxypropyl methyl ether
|
|
C6H14O3 |
详情 |
详情
|
(III) |
36532 |
methyl N-(2-chloro-3-pyridinyl)ethanimidoate
|
|
C8H9ClN2O |
详情 |
详情
|
(IV) |
36533 |
N-(2-chloro-3-pyridinyl)-N-ethylamine; 2-chloro-N-ethyl-3-pyridinamine
|
|
C7H9ClN2 |
详情 |
详情
|
(V) |
10355 |
Diethylenediamine; Piperazine
|
110-85-0 |
C4H10N2 |
详情 | 详情
|
(VI) |
36534 |
N-ethyl-N-[2-(1-piperazinyl)-3-pyridinyl]amine; N-ethyl-2-(1-piperazinyl)-3-pyridinamine
|
|
C11H18N4 |
详情 |
详情
|
(VII) |
28885 |
5-methoxy-1H-indole-2-carboxylic acid
|
4382-54-1 |
C10H9NO3 |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(IV) In an alternative procedure, the reductive alkylation of 3-amino-2-chloropyridine (IV) with 2-methoxy-5-trifluoromethoxybenzaldehyde (III) in the presence of NaBH(OAc)3 produced the 3-(benzylamino)pyridine (V). The 2-phenyl pyridine derivative (VII) was then prepared by chloride displacement with phenylmagnesium bromide (VI) in the presence of bis(triphenylphosphino)nickel(II) chloride. Catalytic hydrogenation of pyridine (VII) produced the racemic cis-piperidine, which was finally resolved into the enantiomers by using (S)-mandelic acid.
【1】
Rosen, T.J.; Godek, D.M.; Ruggeri, S.G.; Wint, L.T. (Pfizer Inc.); Preparation of substd. piperidines. WO 9311110 .
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(III) |
59236 |
2-methoxy-5-(trifluoromethoxy)benzaldehyde
|
|
C9H7F3O3 |
详情 |
详情
|
(IV) |
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
|
(V) |
59237 |
N-(2-chloro-3-pyridinyl)-N-[2-methoxy-5-(trifluoromethoxy)benzyl]amine; 2-chloro-N-[2-methoxy-5-(trifluoromethoxy)benzyl]-3-pyridinamine
|
|
C14H12ClF3N2O2 |
详情 |
详情
|
(VI) |
17616 |
bromo(phenyl)magnesium; Phenyl Magnesium Bromide
|
100-58-3 |
C6H5BrMg |
详情 | 详情
|
(VII) |
59238 |
N-[2-methoxy-5-(trifluoromethoxy)benzyl]-2-phenyl-3-pyridinamine; N-[2-methoxy-5-(trifluoromethoxy)benzyl]-N-(2-phenyl-3-pyridinyl)amine
|
|
C20H17F3N2O2 |
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 2-phenylpyridine-3-amine (V), an intermediate in the synthesis of 235944, has been obtained with better yields by three related ways:
1. The acylation of 2-chloropyridine-3-amine (I) with Ac2O and TEA in dichloromethane gives the corresponding acetamide (II), which is condensed with phenylboronic acid (III) by means of Pd(PPh3)4 and Na2CO3 in ethanol/toluene, yielding N-(2-phenylpyridin-3-yl)acetamide (IV). Finally, this compound is hydrolyzed with HCl in methanol to afford the target 2-phenylpyridine-3-amine (V) intermediate.
2. The condensation of 2-chloropyridine-3-amine (I) with benzaldehyde (VI) in refluxing toluene gives the corresponding imine (VII), which is condensed with phenylboronic acid (III) as before to yield the 2-phenylpyridine derivative (VIII). Finally, the imino group of (VIII) is hydrolyzed with aqueous HCl to afford the target intermediate (V).
3. The one-pot condensation of 2-chloropyridine-3-amine (I), boronic acid (III) and benzaldehyde (VI) by means of Pd(PPh3)2Cl2 and Na2CO3 in hot toluene gives the already reported 2-phenylpyridine derivative (VIII), which is hydrolyzed as before to afford the target intermediate (V).
【1】
Caron, S.; et al.; An efficient and cost-effective synthesis of 2-phenyl-3-aminopyridine. Org Process Res Dev 2001, 5, 3, 254.
|
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) |
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
|
(II) |
51952 |
N-(2-Chloropyridin-3-yl)acetamide
|
|
C7H7ClN2O |
详情 |
详情
|
(III) |
16593 |
Phenylboronic acid;Benzeneboronic acid;Phenylboron dihydroxide |
98-80-6 |
C6H7BO2 |
详情 | 详情
|
(IV) |
51953 |
N-(2-phenyl-3-pyridinyl)acetamide
|
|
C13H12N2O |
详情 |
详情
|
(V) |
51954 |
2-phenyl-3-pyridinylamine; 2-phenyl-3-pyridinamine
|
|
C11H10N2 |
详情 |
详情
|
(VI) |
10498 |
Benzaldehyde;Benzoic aldehyde;Phenylmethanal |
100-52-7 |
C7H6O |
详情 | 详情
|
(VII) |
51955 |
N-(2-chloro-3-pyridinyl)-N-[(E)-benzylidene]amine; 2-chloro-N-[(E)-benzylidene]-3-pyridinamine
|
|
C12H9ClN2 |
详情 |
详情
|
(VIII) |
51956 |
2-phenyl-N-[(E)-benzylidene]-3-pyridinamine; N-[(E)-benzylidene]-N-(2-phenyl-3-pyridinyl)amine
|
|
C18H14N2 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(I) Reductive condensation of 3-amino-2-chloropyridine (I) with 5-isopropylbenzofuran-7-carbaldehyde (II) in the presence of sodium triacetoxyborohydride provided secondary amine (III). Displacement of the chlorine atom of (III) with phenylmagnesium bromide (IV) using NiCl2 produced phenylpyridine (V), which was hydrogenated with hydrogen over PtO2 in acetic acid to give racemic piperidine (VI). Resolution of (VI) with (R)-(-)-mandelic acid yielded the (2S,3S)-isomer, which was finally isolated as the dihydrochloride salt.
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) |
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
|
(II) |
26501 |
5-isopropyl-2,3-dihydro-1-benzofuran-7-carbaldehyde
|
|
C12H14O2 |
详情 |
详情
|
(III) |
26502 |
2-chloro-N-[(5-isopropyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3-pyridinamine
|
|
C17H19ClN2O |
详情 |
详情
|
(IV) |
17616 |
bromo(phenyl)magnesium; Phenyl Magnesium Bromide
|
100-58-3 |
C6H5BrMg |
详情 | 详情
|
(V) |
26503 |
N-[(5-isopropyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-phenyl-3-pyridinamine
|
|
C23H24N2O |
详情 |
详情
|
(VI) |
26504 |
N-[(5-isopropyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-phenyl-3-piperidinamine
|
|
C23H30N2O |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(V) Bromination of 2-amino-5-methylpyrazine (I) with Br2 in CHCl3 affords the bromopyrazine (II). Subsequent bromide displacement in (II) by means of sodium methoxide gives rise to the methoxypyrazine (III). The amino group of (III) is then protected by acylation with isobutyl chloroformate, to produce carbamate (IV). Diazotization of 3-amino-2-chloropyridine (V), followed by treatment with sulfur dioxide in the presence of CuCl furnishes sulfonyl chloride (VI). Carbamate (IV) is then acylated by means of NaH and sulfonyl chloride (VI) in DMF to furnish the N-sulfonyl carbamate (VII). Esterification of 4-carboxyphenylboronic acid (VIII) with H2SO4 in MeOH gives 4-(methoxycarbonyl)phenylboronic acid (IX). Mitsunobu coupling between boronic acid (IX) and chloropyridine (VII) furnishes adduct (X). Methyl ester (X) is converted into hydrazide (XI) by treatment with hydrazine hydrate in refluxing methanol. Then, cyclization of the acyl hydrazide (XI) with boiling triethyl orthoformate gives rise to the target oxadiazole derivative.
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) |
64109 |
5-methyl-2-pyrazinamine; 5-methyl-2-pyrazinylamine
|
|
C5H7N3 |
详情 |
详情
|
(II) |
64110 |
3-bromo-5-methyl-2-pyrazinamine; 3-bromo-5-methyl-2-pyrazinylamine
|
|
C5H6BrN3 |
详情 |
详情
|
(III) |
64111 |
5-methyl-3-(methyloxy)-2-pyrazinamine; 5-methyl-3-(methyloxy)-2-pyrazinylamine
|
|
C6H9N3O |
详情 |
详情
|
(IV) |
64112 |
2-methylpropyl 5-methyl-3-(methyloxy)-2-pyrazinylcarbamate
|
|
C11H17N3O3 |
详情 |
详情
|
(V) |
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
|
(VI) |
64113 |
2-chloro-3-pyridinesulfonyl chloride
|
|
C5H3Cl2NO2S |
详情 |
详情
|
(VII) |
64115 |
2-methylpropyl (2-chloro-3-pyridinyl)sulfonyl[5-methyl-3-(methyloxy)-2-pyrazinyl]carbamate
|
|
C16H19ClN4O5S |
详情 |
详情
|
(VIII) |
32841 |
4-(dihydroxyboryl)benzoic acid;4-Boronobenzoic acid;4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid |
14047-29-1 |
C7H7BO4 |
详情 | 详情
|
(IX) |
64114 |
4-[(methyloxy)carbonyl]phenylboronic acid
|
|
C8H9BO4 |
详情 |
详情
|
(X) |
64116 |
methyl 4-{3-[([5-methyl-3-(methyloxy)-2-pyrazinyl]{[(2-methylpropyl)oxy]carbonyl}amino)sulfonyl]-2-pyridinyl}benzoate
|
|
C24H26N4O7S |
详情 |
详情
|
(XI) |
64117 |
2-[4-(hydrazinocarbonyl)phenyl]-N-[5-methyl-3-(methyloxy)-2-pyrazinyl]-3-pyridinesulfonamide
|
|
C18H18N6O4S |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(I) Condensation between 3-amino-2-chloropyridine (I) and 3,4-diethoxycyclobut-3-ene-1,2-dione (II) in refluxing EtOH affords the (pyridylamino)cyclobutenedione (III). The remaining ethoxy group of (III) is then displaced with methanolic ammonia to furnish the diamino cyclobutenedione (IV).
【1】
Basha, F.Z.; Carroll, W.A.; Kort, M.E.; Gregg, R.J.; Dinges, J.; Perez Medrano, A. (Abbott Laboratories Inc.); Aminal diones as potassium channel openers. US 2002165264; US 6495576; WO 0262761 .
|
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) |
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
|
(II) |
30975 |
3,4-diethoxy-3-cyclobutene-1,2-dione
|
5231-87-8 |
C8H10O4 |
详情 | 详情
|
(III) |
57596 |
3-[(2-chloro-3-pyridinyl)amino]-4-ethoxy-3-cyclobutene-1,2-dione
|
|
C11H9ClN2O3 |
详情 |
详情
|
(IV) |
57597 |
3-amino-4-[(2-chloro-3-pyridinyl)amino]-3-cyclobutene-1,2-dione
|
|
C9H6ClN3O2 |
详情 |
详情
|
合成路线10
该中间体在本合成路线中的序号:
(VIII) 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
|
合成路线11
该中间体在本合成路线中的序号:
(XVI) Bromination of 2-amino-5-methylpyrazine (X) with Br2 in CHCl3 affords the bromopyrazine (XI), which by subsequent bromide displacement by means of sodium methoxide in refluxing methanol gives the methoxypyrazine (XII). Then, the amino group of (XII) is protected by acylation with isobutyl chloroformate (XIII) in the presence of pyridine in CH2Cl2 to provide carbamate (XIV), which finally, after being pretreated with NaH, is sulfonylated with 2-chloropyridine-3-sulfonyl chloride (XV) in DMF. Compound (XV) is prepared from 3-amino-2-chloropyridine (XVI) by diazotization and subsequent treatment with sulfur dioxide in the presence of CuCl in AcOH .
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IV) |
69329 |
isobutyl (2-chloropyridin-3-yl)sulfonyl(3-methoxy-5-methyl-4,5-dihydropyrazin-2-yl)carbamate |
|
C16H21ClN4O5S |
详情 |
详情
|
(X) |
64109 |
5-methyl-2-pyrazinamine; 5-methyl-2-pyrazinylamine
|
|
C5H7N3 |
详情 |
详情
|
(XI) |
64110 |
3-bromo-5-methyl-2-pyrazinamine; 3-bromo-5-methyl-2-pyrazinylamine
|
|
C5H6BrN3 |
详情 |
详情
|
(XII) |
64111 |
5-methyl-3-(methyloxy)-2-pyrazinamine; 5-methyl-3-(methyloxy)-2-pyrazinylamine
|
|
C6H9N3O |
详情 |
详情
|
(XIII) |
13423 |
1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate |
543-27-1 |
C5H9ClO2 |
详情 | 详情
|
(XIV) |
64112 |
2-methylpropyl 5-methyl-3-(methyloxy)-2-pyrazinylcarbamate
|
|
C11H17N3O3 |
详情 |
详情
|
(XV) |
64113 |
2-chloro-3-pyridinesulfonyl chloride
|
|
C5H3Cl2NO2S |
详情 |
详情
|
(XVI) |
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
|