合成路线1
该中间体在本合成路线中的序号:
(B) 1) The acetylation of iminodibenzyl (I) with acetyl chloride (A) in refluxing toluene gives N-acetyl-iminodibenzyl (II), which by a Friedel-Kraft's reaction with methyl oxalyl chloride (B) and AlCl3 in CH2Cl2 or CS2 is converted to N-acetyl-3-(methyloxalyl)iminodibenzyl (III). The hydrolysis of (III) with NaOH in methanol-water yields N-acetyl-5-oxalyliminodibenzyl (IV), which by treatment with NaOH in water-ethanol at high temperature affords 3-oxalyliminodibenzyl (V). The reaction of (V) with hydroxylamine and acetic acid gives 3-hydroxylaminooxalyliminodibenzyl (VI), which by heating at 100 C in water is converted into 3-cyanoiminodibenzyl (VII). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (VIII) by means of NaH in DMF.
2) Compound (VII) can also be condensed with dimethylaminopropyl N,N-dimethylcarbamate (IX) by heating at 250 C.
3) The reaction of (VII) with phosgene gives N-chlorocarbonyl-3-cyanoiminodibenzyl (X), which is condensed with 3-dimethylaminopropanol (XI) to afford 3-cyanoiminodibenzyl-N-carboxylic acid 3-dimethylaminopropyl ester (XII). Finally, this compound is heated at 250 C under reduced pressure.
【1】
Dostert, P. (Hoffmann-La Roche, Inc.); 3-Cyano-N-(N,N-dimethylaminopropyl)-iminodibenzyl and salts thereof. US 4138482 .
|
【2】
Blancafort, P.; Castaner, J.; Owen, R.T.; Serradell, M.N.; RO-11-2465. Drugs Fut 1981, 6, 1, 41.
|
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) |
19273 |
acetyl chloride
|
75-36-5 |
C2H3ClO |
详情 | 详情
|
(B) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(I) |
37165 |
10,11-dihydro-5H-dibenzo[b,f]azepine
|
494-19-9 |
C14H13N |
详情 | 详情
|
(II) |
37166 |
1-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-1-ethanone
|
|
C16H15NO |
详情 |
详情
|
(III) |
37167 |
methyl 2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetate
|
|
C19H17NO4 |
详情 |
详情
|
(IV) |
37168 |
2-(5-acetyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid
|
|
C18H15NO4 |
详情 |
详情
|
(V) |
37169 |
2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-oxoacetic acid
|
|
C16H13NO3 |
详情 |
详情
|
(VI) |
37170 |
2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-(hydroxyimino)acetic acid
|
|
C16H14N2O3 |
详情 |
详情
|
(VII) |
37171 |
10,11-dihydro-5H-dibenzo[b,f]azepine-3-carbonitrile
|
|
C15H12N2 |
详情 |
详情
|
(VIII) |
24581 |
3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine
|
5407-04-5 |
C5H12ClN |
详情 | 详情
|
(IX) |
37175 |
3-(dimethylamino)propyl dimethylcarbamate
|
|
C8H18N2O2 |
详情 |
详情
|
(X) |
37172 |
3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl chloride
|
|
C16H11ClN2O |
详情 |
详情
|
(XI) |
37173 |
3-(dimethylamino)-1-propanol
|
3179-63-3 |
C5H13NO |
详情 | 详情
|
(XII) |
37174 |
3-(dimethylamino)propyl 3-cyano-10,11-dihydro-5H-dibenzo[b,f]azepine-5-carboxylate
|
|
C21H23N3O2 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(IX) A new total synthesis of racemic epibatidine has been reported:
The benzoylation of trans-4-aminocyclohexanol (I) with benzoyl chloride gives the benzamide (II), which is treated with methanesulfonyl chloride and triethylamine to yield the mesylate (III). Cyclization of (III) by means of potassium tert-butoxide in DMF/benzene affords the 7-azanorbornane (IV), which by microbial hydroxylation using the fungus Beauveria bassiana gives stereoselectively the endo-2-hydroxy-7-azanorbornane (V). Oxidation of (V) with TPAP and NMO in dichloromethane yields the ketone (VI), which is condensed with 2-chloro-5-iodopyridine (VII) by means of butyllithium in THF affording exclusively the endo-alcohol (VIII). Reaction of (VIII) with methoxalyl chloride (IX) and DMAP/2,6-lutidine in dichloromethane gives the mixed oxalate (IX), which is reduced with tributyltin hydride and AIBN to yield exclusively the endo-isomer (XI). Isomerization of (XI) by means of potassium tert-butoxide in refluxing tert-butanol affords the exo-isomer (XII), which is finally debenzoylated by treatment with 6N HCl at 100 C.
【1】
Olivo, H.F.; Hemenway, M.S.; Total synthesis of (±)-epibatidine using a biocatalytic approach. J Org Chem 1999, 64, 24, 8968. |
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) |
19581 |
trans-4-Aminocyclohexanol;trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; |
27489-62-9 |
C6H13NO |
详情 | 详情
|
(II) |
41754 |
N-(4-hydroxycyclohexyl)benzamide
|
|
C13H17NO2 |
详情 |
详情
|
(III) |
41755 |
4-(benzoylamino)cyclohexyl methanesulfonate
|
|
C14H19NO4S |
详情 |
详情
|
(IV) |
41756 |
7-azabicyclo[2.2.1]hept-7-yl(phenyl)methanone
|
|
C13H15NO |
详情 |
详情
|
(V) |
41757 |
[(1S,2R,4R)-2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone
|
|
C13H15NO2 |
详情 |
详情
|
(VI) |
41758 |
(1S,4R)-7-benzoyl-7-azabicyclo[2.2.1]heptan-2-one
|
|
C13H13NO2 |
详情 |
详情
|
(VII) |
16423 |
2-chloro-5-iodopyridine
|
|
C5H3ClIN |
详情 |
详情
|
(VIII) |
41759 |
[(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-2-hydroxy-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone
|
|
C18H17ClN2O2 |
详情 |
详情
|
(IX) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(X) |
41760 |
(1S,2S,4R)-7-benzoyl-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-2-yl 2-methoxy-2-oxoacetate
|
|
C21H19ClN2O5 |
详情 |
详情
|
(XI) |
41761 |
[(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone
|
|
C18H17ClN2O |
详情 |
详情
|
(XII) |
41762 |
[(1S,2R,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]hept-7-yl](phenyl)methanone
|
|
C18H17ClN2O |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(II) Acylation of L-proline methyl ester (I) with methoxalyl chloride (II) afforded oxamate (III), which was condensed with 1,1-dimethylpropyl magnesium chloride to produce ketoamide (IV). Hydrolysis of the methyl ester of (IV) with LiOH gave carboxylic acid (V). This was finally coupled with 3,3-diphenylpropyl mercaptan (VI) using DCC and dimethylaminopyridine to give the title thioether.
【1】
Limburg, D.C.; et al.; Synthesis of thioester FKBP12 ligands and evaluation of their in vitro and in vivo nerve regenerative effects. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 237.
|
【2】
Hamilton, G.S.; Li, J.-H. (Guilford Pharmaceuticals Inc.); Heterocyclic thioesters and ketones. EP 0934263; US 5786378; US 5990131; WO 9813343 .
|
【3】
Hamilton, G.S.; Steiner, J.P. (Guilford Pharmaceuticals Inc.); Hair growth compsns. and uses. WO 9855090 .
|
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) |
29552 |
methyl (2S)-2-pyrrolidinecarboxylate
|
2133-40-6 |
C6H11NO2 |
详情 | 详情
|
(II) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(III) |
30780 |
methyl (2S)-1-(2-methoxy-2-oxoacetyl)-2-pyrrolidinecarboxylate
|
|
C9H13NO5 |
详情 |
详情
|
(IV) |
30781 |
methyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarboxylate
|
|
C13H21NO4 |
详情 |
详情
|
(V) |
30782 |
(2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarboxylic acid
|
|
C12H19NO4 |
详情 |
详情
|
(VI) |
30783 |
3,3-diphenyl-1-propanethiol; 3,3-diphenylpropylhydrosulfide
|
|
C15H16S |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(VI) The protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is finally deprotected and hydrolyzed with 6M HCl.
【1】
Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(IIa) |
26964 |
benzyl 3-hydroxy-1-piperidinecarboxylate
|
|
C13H17NO3 |
详情 |
详情
|
(IIb) |
26965 |
tert-butyl 3-hydroxy-1-piperidinecarboxylate
|
|
C10H19NO3 |
详情 |
详情
|
(IIIa) |
26966 |
benzyl 3-oxo-1-piperidinecarboxylate
|
|
C13H15NO3 |
详情 |
详情
|
(IIIb) |
26967 |
1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate
|
98977-36-7 |
C10H17NO3 |
详情 | 详情
|
(Va) |
26969 |
benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate
|
|
C20H32NO7P |
详情 |
详情
|
(Vb) |
26970 |
tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate
|
|
C17H34NO7P |
详情 |
详情
|
(VIIa) |
26972 |
benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate
|
|
C23H34NO10P |
详情 |
详情
|
(VIIb) |
26973 |
tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate
|
|
C20H36NO10P |
详情 |
详情
|
(VIIIa) |
26974 |
benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate
|
|
C20H32NO6P |
详情 |
详情
|
(VIIIb) |
26975 |
tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate
|
|
C17H34NO6P |
详情 |
详情
|
(I) |
24255 |
3-piperidinol
|
6859-99-0 |
C5H11NO |
详情 | 详情
|
(IV) |
26968 |
ethyl diethoxymethylphosphinate
|
|
C7H17O4P |
详情 |
详情
|
(VI) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(VI) The protection of 3-piperidinol (I) with tert-butoxycarbonyl anhydride or benzyloxycarbonyl chloride gives the corresponding protected piperidine (II), which is oxidized with CrO3 and acetic anhydride in pyridine yielding the piperidinone (III). The condensation of (III) with phosphinate (IV) and triethylamine at 100 C affords the alpha-hydroxyphosphinate (V), which is acylated with methoxalyl chloride (VI) and DMAP giving the methoxalyl ester (VII). The reduction of (VII) with tributyl in hydride and AIBN yields the protected phophinate (VIII), which is deprotected with trifluoroacetic acid affording (IX) with its free NH group. The alkylation of (IX) with 4,4-diphenyl-3-butenyl bromide (X) provides the alkylated piperidinephosphinate (XI), which is finally hydrolyzed with refluxing 6M HCl.
【1】
Stensbol, T.B.; Kehler, J.; Krogsgaard-Larsen, P.; Piperidinyl-3-phosphinic acids as novel uptake inhibitors of the neurotransmitter gamma-aminobutyric acid (GABA). Bioorg Med Chem Lett 1999, 9, 6, 811.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
(IIa) |
26964 |
benzyl 3-hydroxy-1-piperidinecarboxylate
|
|
C13H17NO3 |
详情 |
详情
|
(IIb) |
26965 |
tert-butyl 3-hydroxy-1-piperidinecarboxylate
|
|
C10H19NO3 |
详情 |
详情
|
(IIIa) |
26966 |
benzyl 3-oxo-1-piperidinecarboxylate
|
|
C13H15NO3 |
详情 |
详情
|
(IIIb) |
26967 |
1-N-Boc-3-piperodone; tert-butyl 3-oxo-1-piperidinecarboxylate
|
98977-36-7 |
C10H17NO3 |
详情 | 详情
|
(Va) |
26969 |
benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate
|
|
C20H32NO7P |
详情 |
详情
|
(Vb) |
26970 |
tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-hydroxy-1-piperidinecarboxylate
|
|
C17H34NO7P |
详情 |
详情
|
(VIIa) |
26972 |
benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate
|
|
C23H34NO10P |
详情 |
详情
|
(VIIb) |
26973 |
tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-3-[(2-methoxy-2-oxoacetyl)oxy]-1-piperidinecarboxylate
|
|
C20H36NO10P |
详情 |
详情
|
(VIIIa) |
26974 |
benzyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate
|
|
C20H32NO6P |
详情 |
详情
|
(VIIIb) |
26975 |
tert-butyl 3-[(diethoxymethyl)(ethoxy)phosphoryl]-1-piperidinecarboxylate
|
|
C17H34NO6P |
详情 |
详情
|
(I) |
24255 |
3-piperidinol
|
6859-99-0 |
C5H11NO |
详情 | 详情
|
(IV) |
26968 |
ethyl diethoxymethylphosphinate
|
|
C7H17O4P |
详情 |
详情
|
(VI) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(IX) |
27066 |
1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinic acid
|
|
C21H26NO2P |
详情 |
详情
|
(X) |
24116 |
1-(4-bromo-1-phenyl-1-butenyl)benzene
|
|
C16H15Br |
详情 |
详情
|
(XI) |
27067 |
ethyl 1-(4,4-diphenyl-3-butenyl)-3-piperidinylphosphinate
|
|
C23H30NO2P |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(XI) Acylation of tetrachloroaniline (X) with methyl oxalyl chloride (XI) provided the oxamate ester (XII), which was further hydrolyzed to the N-(tetrachlorophenyl)oxamic acid (XIII) by using LiOH. Coupling of acid (XIII) with the intermediate amine (IX) in the presence of HATU furnished the oxalic diamide (XIV). The alcohol function of (XIV) was then reoxidized to ketone (XV) employing the Dess-Martin periodinane reagent. Finally, the tert-butyl ester group of (XV) was cleaved by treatment with trifluoroacetic acid.
【1】
Ternansky, R.J.; et al.; Structure-activity relationship of a series of oxamyl dipeptide caspase inhibitors developed for the treatment of stroke. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 75.
|
【2】
Karanewsky, D.S.; Ternansky, R.J. (Idun Pharmaceuticals, Inc.); C-Terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases. EP 1091930; WO 0001666 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IX) |
49989 |
tert-butyl (3S)-3-[[(2S)-2-amino-3-methylbutanoyl]amino]-4-hydroxy-5-(2,3,5,6-tetrafluorophenoxy)pentanoate
|
|
C20H28F4N2O5 |
详情 |
详情
|
(X) |
49990 |
2,3,5,6-Tetrachloroaniline
|
3481-20-7 |
C6H3Cl4N |
详情 | 详情
|
(XI) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(XII) |
49991 |
methyl 2-oxo-2-(2,3,5,6-tetrachloroanilino)acetate
|
|
C9H5Cl4NO3 |
详情 |
详情
|
(XIII) |
49992 |
2-oxo-2-(2,3,5,6-tetrachloroanilino)acetic acid
|
|
C8H3Cl4NO3 |
详情 |
详情
|
(XIV) |
49993 |
tert-butyl (3S)-4-hydroxy-3-[((2S)-3-methyl-2-[[2-oxo-2-(2,3,5,6-tetrachloroanilino)acetyl]amino]butanoyl)amino]-5-(2,3,5,6-tetrafluorophenoxy)pentanoate
|
|
C28H29Cl4F4N3O7 |
详情 |
详情
|
(XV) |
49994 |
tert-butyl (3S)-3-[((2S)-3-methyl-2-[[2-oxo-2-(2,3,5,6-tetrachloroanilino)acetyl]amino]butanoyl)amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoate
|
|
C28H27Cl4F4N3O7 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(VII) This compound has been obtained by two similar ways:
The condensation of 6-iodo-1-methyl-1H-indole (I) with imidazole (II) by means of copper trifluoromethanesulfonate, 1,10-phenanthroline, Cs2CO3 and dibenzylideneacetone gives 6-(1-imidazolyl)-1-methyl-1H-indole (III), which is condensed with oxalyl chloride (IV) in dichloromethane to yield the adduct (V). Finally, this compound is cyclized with 2-(1-methyl-1H-indol-3-yl)acetimidic acid isopropyl ester (VI) by means of TEA in dichloromethane to afford the target pyrrolinedione.
Alternatively, indole (I) and imidazole (II) are condensed by means of Pd2(dba)3, BINAP and tBu-ONa to give 6-(1-imidazolyl)-1-methyl-1H-indole (III), which is condensed with methoxalyl chloride (VII) in dichloromethane to yield the adduct (VIII). The reduction of (VIII) with NaH2PO2 affords the methyl acetate derivative (IX), which is treated with NH4OH to provide the acetamide derivative (X). Finally, this compound is cyclized with the methoxalyl derivative (XI) (obtained by condensation of 1-methyl-1H-indole (XII) with methoxalyl chloride (VII)) by means of tBu-ONa in THF to afford the target pyrrolinedione.
【1】
Kong, N.; Lovey, A.; Specian, A.; et al.; Design and synthesis of novel orally bioavailable, water soluble bisindolylmaleimides as cell cycle inhibitors. Proc Am Assoc Cancer Res 2002, 43.
|
【2】
Lovey, A.J.; Fotouhi, N.; Kong, N. (F. Hoffmann-La Roche AG); Substd. pyrroles. WO 0146178 .
|
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) |
55752 |
6-iodo-1-methyl-1H-indole
|
|
C9H8IN |
详情 |
详情
|
(II) |
10255 |
Imidazole; 1H-Imidazole
|
288-32-4 |
C3H4N2 |
详情 | 详情
|
(III) |
55753 |
6-(1H-imidazol-1-yl)-1-methyl-1H-indole
|
|
C12H11N3 |
详情 |
详情
|
(IV) |
29841 |
Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride
|
79-37-8 |
C2Cl2O2 |
详情 | 详情
|
(V) |
55754 |
2-[6-(1H-imidazol-1-yl)-1-methyl-1H-indol-3-yl]-2-oxoacetyl chloride
|
|
C14H10ClN3O2 |
详情 |
详情
|
(VI) |
55755 |
isopropyl 2-(1-methyl-1H-indol-3-yl)ethanimidoate
|
|
C14H18N2O |
详情 |
详情
|
(VII) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(VIII) |
55756 |
methyl 2-[6-(1H-imidazol-1-yl)-1-methyl-1H-indol-3-yl]-2-oxoacetate
|
|
C15H13N3O3 |
详情 |
详情
|
(IX) |
55757 |
methyl 2-[6-(1H-imidazol-1-yl)-1-methyl-1H-indol-3-yl]acetate
|
|
C15H15N3O2 |
详情 |
详情
|
(X) |
55758 |
2-[6-(1H-imidazol-1-yl)-1-methyl-1H-indol-3-yl]acetamide
|
|
C14H14N4O |
详情 |
详情
|
(XI) |
55759 |
methyl 2-(1-methyl-1H-indol-3-yl)-2-oxoacetate
|
|
C12H11NO3 |
详情 |
详情
|
(XII) |
14119 |
1-Methylindole; 1-Methyl-1H-indole
|
603-76-9 |
C9H9N |
详情 | 详情
|
合成路线8
该中间体在本合成路线中的序号:
(II) Acylation of methyl pipecolinate (I) with methyl oxalyl chloride (II) provides oxamate (III). Subsequent addition of 1,1-dimethylpropylmagnesium chloride (IV) to oxamate (III) gives rise to keto amide (V). The methyl ester group of (V) is then hydrolyzed by means of LiOH, yielding the intermediate carboxylic acid (VI)
【1】
Hamilton, G.S.; Wu, Y.-Q.; Limburg, D.C.; Wilkinson, D.E.; Vaal ,M.J.; Li, J.-H.; Thomas, C.; Huang, W.; Sauer, H.; Ross, D.T.; Soni, R.; Chen, Y.; Guo, H.; Howorth, P.; Valentine, H.; Liang, S.; Spicer, D.; Fuller, M.; Steiner, J.P; Synthesis of N-glyoxyl prolyl and pipecolyl amides and thioesters and evaluation of their in vitro and in vivo nerve regenerative effects. J Med Chem 2002, 45, 16, 3549. |
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) |
25354 |
methyl (2S)-2-piperidinecarboxylate
|
|
C7H13NO2 |
详情 |
详情
|
(II) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(III) |
60287 |
methyl 1-[2-(methyloxy)-2-oxoacetyl]-2-piperidinecarboxylate
|
|
C10H15NO5 |
详情 |
详情
|
(IV) |
60288 |
chloro(1,1-dimethylpropyl)magnesium
|
|
C5H11ClMg |
详情 |
详情
|
(V) |
60289 |
methyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate
|
|
C14H23NO4 |
详情 |
详情
|
(VI) |
60290 |
1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylic acid
|
|
C13H21NO4 |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(VI) Cyclocondensation of formic hydrazide (I) with thioacetamide (II) at 150 °C gives 3-methyl-1,2,4-triazole (III), which by condensation with 7-chloro-4-methoxy-pyrrolo[2,3-c]pyridine (IV) in the presence of CuI and K2CO3 at 173 °C provides 4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine (V). Friedel-Crafts acylation of compound (V) with methyl chloro(oxo)acetate (VI) using AlCl3 in CH2Cl2/MeNO2 affords the keto ester (VII), which is hydrolyzed using NaOH in MeOH to yield the carboxylic acid (VIII). Condensation of acid (VIII) with 1-benzoylpiperazine (IX) by means of EDC and Et3N in DMF gives piperazinamide (X). Treatment of intermediate (X) with NaH and I2 in THF followed by N-alkylation of di-tert-butyl chloromethyl phosphate (XI) (obtained by the chloromethylation of the tetrabutylammonium salt of di-tert-butyl hydrogen phosphate (XII) with chloroiodomethane (XIII) optionally in benzene) in acetone/H2O, or the direct condensation of intermediate (X) with chloromethyl phosphate (XI) in the presence of CsCO3 and KI in NMP affords the di-tert-butyl phosphate ester (XIV). Finally, O-deprotection of intermediate (XIV) is performed by treatment with TFA in CH2Cl2, or by heating in acetone/H2O at 40 °C .
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) |
15486 |
formic hydrazide; Formylhydrazine
|
624-84-0 |
CH4N2O |
详情 | 详情
|
(II) |
19170 |
ethanethioamide
|
62-55-5 |
C2H5NS |
详情 | 详情
|
(III) |
67601 |
3-methyl-1,2,4-triazole;3-Methyltriazole;3-Methyl-1H-1,2,4-triazole;3-Methyl-4H-1,2,4-triazole |
7170-01-6 |
C3H5N3 |
详情 | 详情
|
(IV) |
67602 |
7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine |
|
C8H7ClN2O |
详情 | 详情
|
(V) |
67603 |
4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridine |
|
C11H11N5O |
详情 | 详情
|
(VI) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(VII) |
67604 |
methyl 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate |
|
C14H13N5O4 |
详情 | 详情
|
(VIII) |
67605 |
2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid |
|
C13H11N5O4 |
详情 | 详情
|
(IX) |
67606 |
1-benzoylpiperazine;4-Benzoylpiperazine;N-Benzoylpiperazine;(Phenyl)(piperazin-1-yl)methanone |
13754-38-6 |
C11H14N2O |
详情 | 详情
|
(X) |
67607 |
1-(4-benzoylpiperazin-1-yl)-2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione |
|
C24H23N7O4 |
详情 | 详情
|
(XI) |
42239 |
di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate;PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER |
229625-50-7 |
C9H20ClO4P |
详情 | 详情
|
(XII) |
67608 |
tetra-tert-butylammonium di-tert-butyl phosphate |
|
C8H18O4P.C16H36N |
详情 | 详情
|
(XIII) |
42238 |
chloro(iodo)methane
|
593-71-5 |
CH2ClI |
详情 | 详情
|
(XIV) |
67609 |
(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)methyl di-tert-butyl phosphate |
|
C33H42N7O8P |
详情 | 详情
|
合成路线10
该中间体在本合成路线中的序号:
(VI) Friedel-Crafts acylation of 1-(phenylsulfonyl)pyrrole (XV) with chloroacetyl chloride (XVI) by means of AlCl3 in CH2Cl2 gives 2-chloro-1-[1-(phenylsulfonyl)pyrrol-3-yl]ethanone (XVII), which by condensation with sodium N-tosyl formamide (XVIII) (obtained by treatment of tosylamide (XIX) with NaOMe in MeOH to afford sodium tosylamide (XX), which is then formylated with HCOOEt in MeOH) using Bu4NBr in THF at 60 °C affords the corresponding keto amide (XXI). Decarbonylation of intermediate (XXI) by means of H2SO4 in MeOH at 60 °C followed by protection of the keto group with (CH2OH)2 using HC(OMe)3 produces acetal (XXII). Pictet-Spengler cyclization of protected amine (XXII) with (HCHO)n in the presence of TFA in CH2Cl2 affords the 1,5,6,7-tetrahydro-4H-pyrrolo[2,3-c]pyridin-4-one derivative (XXIII) , which by O-methylation with HC(OMe)3 using MsOH and CMNOOH in MeOH yields the enol ether (XXIV). Redox elimination of the tosyl group in compound (XXIV) by means of Na2S2O3 and Et3N gives the pyrrolo[2,3-c]pyridine derivative (XXV) , which can also be prepared by treatment of N-protected amine (XXIII) with HC(OMe)3 in the presence of MsOH or Tf2O and CMNOOH or AIBN . Oxidation of intermediate (XXV) with H2O2 using MeReO3 or phthalic anhydride in CH2Cl2 results in the pyridine-N-oxide (XXVI). Bromination of compound (XXVI) with PyBroP and K3PO4 in trifluorotoluene, followed by treatment with NaOH in i-PrOH at 80 °C yields the bromopyridine (XXVII), which by Friedel-Crafts C-3-acylation with methyl oxalyl chloride (VI) using AlCl3 in CH2Cl2/MeNO2 at 0 °C produces the keto ester (XXVIII). Hydrolysis of the methyl ester (XXVIII) with aqueous NaOH and subsequent treatment with HBr affords (7-bromo-4-methoxypyrrolo[2,3-c]pyridin-3-yl)(oxo)acetic acid hydrobromide salt (XXIX) .
【1】
Ueda, Y., Connolly, T.P., Kadow, J.F. et al. (Bristol-Myers Squibb Co.). Prodrugs of piperazine and substituted piperidine antiviral agents. CN 101941990; US 7745625; EP 1725569; JP 2007529519; US 2005209246; WO 2005090367. |
【3】
Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038709. |
【4】
Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038710. |
【5】
Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038711. |
【6】
Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038712. |
【7】
Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038716. |
【8】
Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038717. |
【2】
Chen, K., Risatti, C., Bultman, M. et al. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J Org Chem 2014, 79(18): 8757-67. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(XV) |
67610 |
1-(phenylsulfonyl)pyrrole;N-(Benzenesulfonyl)pyrrole;N-Phenylsulfonylpyrrole;1-(Benzenesulfonyl)-1H-pyrrole |
16851-82-4 |
C10H9NO2S |
详情 | 详情
|
(XVI) |
11296 |
2-Chloroacetyl chloride; Chloroacetic chloride
|
79-04-9 |
C2H2Cl2O |
详情 | 详情
|
(XVII) |
67611 |
2-chloro-1-[1-(phenylsulfonyl)pyrrol-3-yl]ethanone |
|
C12H10ClNO3S |
详情 | 详情
|
(XVIII) |
67612 |
sodium N-tosyl formamide |
|
C8H8NNaO3S |
详情 | 详情
|
(XIX) |
59937 |
4-methylbenzenesulfonamide
|
70-55-3 |
C7H9NO2S |
详情 | 详情
|
(XX) |
67613 |
sodium tosylamide |
|
C7H8NNaO2S |
详情 | 详情
|
(XXI) |
67614 |
N-(2-oxo-2-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethyl)-N-tosylformamide |
|
C20H18N2O6S2 |
详情 | 详情
|
(XXII) |
67615 |
4-methyl-N-((2-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-1,3-dioxolan-2-yl)methyl)benzenesulfonamide |
|
C21H22N2O6S2 |
详情 | 详情
|
(XXIII) |
67616 |
1-(phenylsulfonyl)-6-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4(5H)-one |
|
C20H18N2O5S2 |
详情 | 详情
|
(XXIV) |
67617 |
4-methoxy-1-(phenylsulfonyl)-6-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine |
|
C21H20N2O5S2 |
详情 | 详情
|
(XXV) |
67618 |
4-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine |
|
C14H12N2O3S |
详情 | 详情
|
(XXVI) |
67619 |
4-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide |
|
C14H12N2O4S |
详情 | 详情
|
(XXVII) |
67620 |
7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride hydrate |
|
C8H7BrN2O.HCl.H2O |
详情 | 详情
|
(XXVIII) |
67621 |
methyl 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate |
|
C11H9BrN2O4 |
详情 | 详情
|
(XXIX) |
67622 |
2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid hydrobromide |
|
C10H7BrN2O4.HBr |
详情 | 详情
|
合成路线11
该中间体在本合成路线中的序号:
(XXIX) Aminocyclohexanecarboxylic acid ethyl ester (IV) and some synthetic precursors are prepared as follows. Acylation of 2-amino-5-chloropyridine (XXVII) with either potassium ethyl oxalate (XXVIII) by means of EDC and HOBt in DMF or with methyl oxalyl chloride (XXIX) in the presence of NaHCO3 in THF or CH2Cl2 or Et3N in CH2Cl2 provides the corresponding N-(5-chloro-2-pyridyl)-oxamic acid esters (XXI) and (XXX), respectively. The lithium oxamate (VI) has been prepared by hydrolysis of the methyl ester (XXX) with LiOH in aqueous THF . Coupling of the ehtyl pyridyloxamate (XXI) with the monoprotected diamine (XV) (previously derivatized as the corresponding malate or oxalate salt) in the presence of Et3N in acetonitrile at 65-70 ℃ yields oxamide (XXXI), which is finally deprotected to give intermediate (IV) by removing the N-Boc-protecting group by means of methanesulfonic acid in acetonitrile .
【1】
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. |
【2】
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. |
【3】
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 |
(IV) |
69423 |
(1S,2R,4S)-ethyl 3-amino-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate |
|
C16H21ClN4O4 |
详情 |
详情
|
(VI) |
69425 |
N-(5-chloro-2-pyridyl)oxamic acid lithium salt;lithium 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate |
|
C7H4ClLiN2O3 |
详情 |
详情
|
(XV) |
69432 |
(1R,3R,4S)-ethyl 4-amino-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate |
|
C14H26N2O4 |
详情 |
详情
|
(XXI) |
69438 |
ethyl N-(5-chloro-2-pyridyl)oxamate;ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate |
|
C9H9ClN2O3 |
详情 |
详情
|
(XXVII) |
18559 |
5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine
|
1072-98-6 |
C5H5ClN2 |
详情 | 详情
|
(XXVIII) |
69444 |
potassium 2-ethoxy-2-oxoacetate;potassium ethyl oxalate;Oxalic acid 1-ethyl 2-potassium salt |
1906-57-6 |
C4H6KO4 |
详情 | 详情
|
(XXIX) |
26971 |
2-methoxy-2-oxoacetyl chloride
|
5781-53-3 |
C3H3ClO3 |
详情 | 详情
|
(XXX) |
69446 |
methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate |
|
C8H7ClN2O3 |
详情 |
详情
|
(XXXI) |
69445 |
(1R,3S,4R)-ethyl 3-((tert-butoxycarbonyl)amino)-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate |
|
C21H29ClN4O6 |
详情 |
详情
|