合成路线1
该中间体在本合成路线中的序号:
(I) The reaction of cyclohexylamine (I) with chloroacetyl chloride (II) in water in the presence of sodium hydroxide gives N-cyclohexyl-2-chloro-acetamide (III), which by reaction with piperazine (IV) in water is converted to N-[(N-cyclohexylcarbamoyl)methyl]piperazine (V). This compound is then treated with one equivalent of HCl.
【1】
Corvi-Mora, C. (Camillo Corvi SpA); N-Cyclohexyl-piperazino acetamides and propionamides. US 4123530; US 4278796 .
|
【2】
de Angelis, L.; Esaprazole hydrochloride. Drugs Fut 1986, 11, 4, 263.
|
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) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(II) |
11296 |
2-Chloroacetyl chloride; Chloroacetic chloride
|
79-04-9 |
C2H2Cl2O |
详情 | 详情
|
(III) |
27377 |
2-chloro-N-cyclohexylacetamide
|
|
C8H14ClNO |
详情 |
详情
|
(IV) |
10355 |
Diethylenediamine; Piperazine
|
110-85-0 |
C4H10N2 |
详情 | 详情
|
(V) |
27378 |
N-cyclohexyl-2-(1-piperazinyl)acetamide
|
|
C12H23N3O |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(IX) The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).
【1】
Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
|
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) |
10722 |
1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane
|
77-76-9 |
C5H12O2 |
详情 | 详情
|
(I) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(II) |
35676 |
tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether
|
|
C9H21IOSi |
详情 |
详情
|
(III) |
35677 |
dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C14H28O5Si |
详情 |
详情
|
(IV) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(V) |
35678 |
dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C17H32O5Si |
详情 |
详情
|
(VI) |
35679 |
2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol
|
|
C15H32O3Si |
详情 |
详情
|
(VII) |
35680 |
3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane
|
|
C18H36O3Si |
详情 |
详情
|
(VIII) |
35681 |
2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde
|
|
C17H34O4Si |
详情 |
详情
|
(IX) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(X) |
35682 |
N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine
|
|
C23H45NO3Si |
详情 |
详情
|
(XI) |
35683 |
(E)-8-decenal
|
|
C10H18O |
详情 |
详情
|
(XII) |
35684 |
(2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal
|
|
C27H50O4Si |
详情 |
详情
|
(XIII) |
35685 |
tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether |
|
C35H58O4Si |
详情 |
详情
|
(XIV) |
35686 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol
|
|
C29H44O4 |
详情 |
详情
|
(XV) |
35687 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal
|
|
C29H42O4 |
详情 |
详情
|
(XVI) |
35688 |
(E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane
|
|
C13H27IOSi |
详情 |
详情
|
(XVII) |
35689 |
(E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one
|
|
C42H68O5Si |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(IX) The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X). The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with PmbCl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).
【1】
Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
|
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) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(II) |
35676 |
tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether
|
|
C9H21IOSi |
详情 |
详情
|
(III) |
35677 |
dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C14H28O5Si |
详情 |
详情
|
(IV) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(V) |
35678 |
dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C17H32O5Si |
详情 |
详情
|
(VI) |
35679 |
2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol
|
|
C15H32O3Si |
详情 |
详情
|
(VII) |
35680 |
3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane
|
|
C18H36O3Si |
详情 |
详情
|
(VIII) |
35681 |
2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde
|
|
C17H34O4Si |
详情 |
详情
|
(IX) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(X) |
35682 |
N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine
|
|
C23H45NO3Si |
详情 |
详情
|
(XI) |
35683 |
(E)-8-decenal
|
|
C10H18O |
详情 |
详情
|
(XII) |
35684 |
(2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal
|
|
C27H50O4Si |
详情 |
详情
|
(XIII) |
35685 |
tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether |
|
C35H58O4Si |
详情 |
详情
|
(XIV) |
35686 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol
|
|
C29H44O4 |
详情 |
详情
|
(XV) |
35687 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal
|
|
C29H42O4 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(II) 2-nitroaniline (III) was prepared by reaction of an excess of cyclohexylamine (II) with either 2-chloronitrobenzene (Ia) in the presence of CuI and K2CO3 at 150 C or 2-fluoronitrobenzene (Ib) in chloroform. Catalytic hydrogenation gave phenylenediamine (IV), which was selectively alkylated on the primary N atom with bromoacetylpyrrolidine (V) in the presence of K2CO3 in DMF. Condensation of the resulting (VI) with the malonic acid dichloride (VII) yielded benzodiazepine (VIII). Hydrazone function was then reduced with zinc dust in acetic acid to provide amine (IX). Separation of the racemic mixture was performed by treatment with the chiral carbonic acid derivative (X), followed by chromatographic separation to give the desired (S)-isomer (XI). Cleavage of the carbamate group of (XI) was effected by hydrogenolysis to afford chiral amine (XII). The target urea was then prepared by reaction of (XII) with 4-fluorophenylisocyanate (XIII) in dichloromethane.
【1】
Bailey, N.; et al.; Novel 1,5-benzodiazepindione gastrin/CCKB antagonists. Bioorg Med Chem Lett 1997, 7, 3, 281.
|
【2】
Finch, H.; Shah, P.; Carr, R.A.E. (Glaxo Wellcome plc); 1,5-Benzodiazepine derivs. having CCK and/or gastrin antagonistic activity. US 5585376; US 5646140; WO 9424149; WO 9424151 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(Ia) |
17964 |
(2-chlorophenyl)(oxo)-lambda(5)-azanolate
|
|
C6H5ClNO2 |
详情 |
详情
|
(Ib) |
17965 |
(2-fluorophenyl)(oxo)-lambda(5)-azanolate
|
|
C6H5FNO2 |
详情 |
详情
|
(II) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(III) |
17967 |
[2-(cyclohexylamino)phenyl](oxo)-lambda(5)-azanolate
|
|
C12H17N2O2 |
详情 |
详情
|
(IV) |
17968 |
N-(2-aminophenyl)-N-cyclohexylamine; N(1)-cyclohexyl-1,2-benzenediamine
|
|
C12H18N2 |
详情 |
详情
|
(V) |
17969 |
2-bromo-1-(1-pyrrolidinyl)-1-ethanone
|
|
C6H10BrNO |
详情 |
详情
|
(VI) |
17970 |
2-[2-(cyclohexylamino)anilino]-1-(1-pyrrolidinyl)-1-ethanone
|
|
C18H27N3O |
详情 |
详情
|
(VII) |
17971 |
2-(2-phenylhydrazono)malonoyl dichloride
|
|
C9H6Cl2N2O2 |
详情 |
详情
|
(VIII) |
17972 |
1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,3,4(5H)-trione 3-(N-phenylhydrazone)
|
|
C27H31N5O3 |
详情 |
详情
|
(IX) |
17973 |
3-amino-1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione
|
|
C21H28N4O3 |
详情 |
详情
|
(X) |
17974 |
4-nitrophenyl (1S)-1-phenylethyl carbonate
|
|
C15H13NO5 |
详情 |
详情
|
(XI) |
17975 |
(1S)-1-phenylethyl (3R)-1-cyclohexyl-2,4-dioxo-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-ylcarbamate
|
|
C30H36N4O5 |
详情 |
详情
|
(XII) |
17976 |
(3R)-3-amino-1-cyclohexyl-5-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione
|
|
C21H28N4O3 |
详情 |
详情
|
(XIII) |
17977 |
1-Fluoro-4-isocyanatobenzene; 4-Fluorophenyl isocyanate
|
1195-45-5 |
C7H4FNO |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(IX) The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).
【1】
Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
|
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) |
10722 |
1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane
|
77-76-9 |
C5H12O2 |
详情 | 详情
|
(I) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(II) |
35676 |
tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether
|
|
C9H21IOSi |
详情 |
详情
|
(III) |
35677 |
dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C14H28O5Si |
详情 |
详情
|
(IV) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(V) |
35678 |
dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C17H32O5Si |
详情 |
详情
|
(VI) |
35679 |
2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol
|
|
C15H32O3Si |
详情 |
详情
|
(VII) |
35680 |
3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane
|
|
C18H36O3Si |
详情 |
详情
|
(VIII) |
35681 |
2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde
|
|
C17H34O4Si |
详情 |
详情
|
(IX) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(X) |
35682 |
N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine
|
|
C23H45NO3Si |
详情 |
详情
|
(XI) |
35683 |
(E)-8-decenal
|
|
C10H18O |
详情 |
详情
|
(XII) |
35684 |
(2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal
|
|
C27H50O4Si |
详情 |
详情
|
(XIII) |
35685 |
tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether |
|
C35H58O4Si |
详情 |
详情
|
(XIV) |
35686 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol
|
|
C29H44O4 |
详情 |
详情
|
(XV) |
35687 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal
|
|
C29H42O4 |
详情 |
详情
|
(XVI) |
35688 |
(E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane
|
|
C13H27IOSi |
详情 |
详情
|
(XVII) |
35689 |
(E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one
|
|
C42H68O5Si |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(IX) The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).
【1】
Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
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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 |
(I) |
19373 |
dimethyl malonate;Methyl malonate;Propanedioic acid dimethyl ester |
108-59-8 |
C5H8O4 |
详情 | 详情
|
(II) |
35676 |
tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether
|
|
C9H21IOSi |
详情 |
详情
|
(III) |
35677 |
dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C14H28O5Si |
详情 |
详情
|
(IV) |
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(V) |
35678 |
dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate
|
|
C17H32O5Si |
详情 |
详情
|
(VI) |
35679 |
2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol
|
|
C15H32O3Si |
详情 |
详情
|
(VII) |
35680 |
3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane
|
|
C18H36O3Si |
详情 |
详情
|
(VIII) |
35681 |
2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde
|
|
C17H34O4Si |
详情 |
详情
|
(IX) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(X) |
35682 |
N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine
|
|
C23H45NO3Si |
详情 |
详情
|
(XI) |
35683 |
(E)-8-decenal
|
|
C10H18O |
详情 |
详情
|
(XII) |
35684 |
(2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal
|
|
C27H50O4Si |
详情 |
详情
|
(XIII) |
35685 |
tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether |
|
C35H58O4Si |
详情 |
详情
|
(XIV) |
35686 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol
|
|
C29H44O4 |
详情 |
详情
|
(XV) |
35687 |
3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal
|
|
C29H42O4 |
详情 |
详情
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合成路线7
该中间体在本合成路线中的序号:
(V) This compound can be obtained by several related ways:
1.- The cyclization of 3-aminothiophene-2-carboxamide (I) with pentanoyl anhydride (II) by means of DCC, DMAP and pyridine in DMF and NaOH gives 2-butylthieno[3,2-d]pyrimidin-4(3H)-one (III), which by reaction with POCl3 or SOCl2 affords 2-butyl-4-chlorothieno[3,2-d]pyrimidine (IV). Finally, this compound is condensed with cyclohexylamine (V) by means of triethylamine in in THF.
2.- The intermediate 2-butylthieno[3,2-d]pyrimidin-4-(3H)-one (III) can be obtained by other ways:
a.- By cyclization of amide (I) with pentanoic acid (VI) by means of DCC, DMAP and pyridine in DMF and NaOH.
b.- By cyclization of 3-aminothiophene-2-carboxylic acid methyl ester (VII) with pentanoic acid (VI) by means of DCC, DMAP and ammonia in dichloromethane.
c.- By cyclization of 3-aminothiophene-2-carboxylic acid methyl ester (VII) with pentanoyl chloride (VIII) by means of pyridine and ammonia.
d.- By cyclization of 3-aminothiophene-2-carboxylic acid (IX) with pentanoic anhydride (II) and ammonia.
【1】
Crespo, M. I.; Pages, L.; Vega, A.; Segarra, V.; Lopez, M.; Domenech, T.; Miralpeix, M.; Beleta, J.; Ryder, H.; Palacios, J.M.; Design, synthesis, and biological activities of new thieno[3,2-d]pyrimidines as selective type 4 phosphodiesterase inhibitors. J Med Chem 1998, 41, 21, 4021. |
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) |
27682 |
3-amino-2-thiophenecarboxamide
|
147123-47-5 |
C5H6N2OS |
详情 | 详情
|
(II) |
27683 |
pentanoic anhydride
|
2082-59-9 |
C10H18O3 |
详情 | 详情
|
(III) |
27684 |
2-butylthieno[3,2-d]pyrimidin-4(3H)-one
|
|
C10H12N2OS |
详情 |
详情
|
(IV) |
27685 |
2-butyl-4-chlorothieno[3,2-d]pyrimidine
|
|
C10H11ClN2S |
详情 |
详情
|
(V) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(VI) |
19682 |
pentanoic acid
|
109-52-4 |
C5H10O2 |
详情 | 详情
|
(VII) |
27686 |
3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate
|
22288-78-4 |
C6H7NO2S |
详情 | 详情
|
(VIII) |
15116 |
pentanoyl chloride; valeryl chloride
|
638-29-9 |
C5H9ClO |
详情 | 详情
|
(IX) |
27687 |
3-amino-2-thiophenecarboxylic acid
|
|
C5H5NO2S |
详情 |
详情
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合成路线8
该中间体在本合成路线中的序号:
(II) Title compound was synthesized by condensation of ethyl 6-fluoro-4-quinolone-3-carboxylate (I) with cyclohexylamine (II) in pyridine at 120 C under pressure.
【1】
Srivastava S; Srivastava, S.K.; Shukla, A.; Chauhan, P.M.; Puri, S.K.; Bhaduri, A.P.; Pandey, V.C.; Synthesis and methemoglobin toxicity of the amides of 6/7 mono or disubstituted quinolone. Bioorg Med Chem Lett 1999, 9, 1, 25.
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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 |
(I) |
19903 |
ethyl 6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate
|
|
C12H10FNO3 |
详情 |
详情
|
(II) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
合成路线9
该中间体在本合成路线中的序号:
(II) Title compound was synthesized by condensation of ethyl 7-chloro-6-fluoro-4-quinolone-3-carboxylate (I) with cyclohexylamine (II) in pyridine at 120 C under pressure.
【1】
Srivastava S; Srivastava, S.K.; Shukla, A.; Chauhan, P.M.; Puri, S.K.; Bhaduri, A.P.; Pandey, V.C.; Synthesis and methemoglobin toxicity of the amides of 6/7 mono or disubstituted quinolone. Bioorg Med Chem Lett 1999, 9, 1, 25.
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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 |
(I) |
19904 |
ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate
|
|
C12H9ClFNO3 |
详情 |
详情
|
(II) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
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合成路线10
该中间体在本合成路线中的序号:
(IV) Diazotization of 2-chloro-5-nitroaniline (I), followed by quenching with a solution of SO2 in HOAc in the presence of CuCl2, furnished the sulfonyl chloride (II). Treatment of (II) with aqueous ammonia gave rise to the corresponding sulfonamide (III). The chloro group of (III) was then displaced with cyclohexylamine (IV) in refluxing 3-chlorotoluene to afford the cyclohexylamino benzenesulfonamide (V). Finally, condensation of sulfonamide (V) with pentyl isocyanate (VI) produced the target sulfonylurea.
【1】
Delarge, J.; Masereel, B.; Dogne, J.-M. (University of Liege); Benzenic sulphonamide derivs. and their uses. WO 0042004 .
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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 |
(I) |
43033 |
2-chloro-5-nitroaniline; 2-chloro-5-nitrophenylamine
|
6283-25-6 |
C6H5ClN2O2 |
详情 | 详情
|
(II) |
43034 |
2-chloro-5-nitrobenzenesulfonyl chloride;2-Chloro-5-nitro-benzenesulfonyl chloride;2-Chloro-5-nitrophenylsulfonyl chloride;6-Chloro-3-nitrobenzenesulfonyl chloride |
4533-95-3 |
C6H3Cl2NO4S |
详情 | 详情
|
(III) |
43035 |
2-chloro-5-nitrobenzenesulfonamide
|
96-72-0 |
C6H5ClN2O4S |
详情 | 详情
|
(IV) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(V) |
47439 |
2-(cyclohexylamino)-5-nitrobenzenesulfonamide
|
|
C12H17N3O4S |
详情 |
详情
|
(VI) |
47440 |
1-isocyanatopentane; pentyl isocyanate
|
3954-13-0 |
C6H11NO |
详情 | 详情
|
合成路线11
该中间体在本合成路线中的序号:
(I)
【1】
K.ankan RN, Rao DR, et aL 2005. Preparation of cilostazol. IN 2003MU00444 |
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) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(II) |
66194 |
delta-Valerolactone;Tetrahydro-2H-2-pyranone |
|
C5H8O2 |
详情 | 详情
|
(II) |
66193 |
(Z)-5-chloro-N-cyclohexylpentanimidoyl chloride |
|
C11H19Cl2N |
详情 | 详情
|
(III) |
66195 |
5-Hydroxypentanoic acid cyclohexylamide |
84996-93-0 |
C10H19NO2 |
详情 | 详情
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合成路线12
该中间体在本合成路线中的序号:
(III) Substitution of chlorine with iodine in potassium tetrachloroplatinate (I) by treatment with KI in water results in potassium tetraiodoplatinate (II), which by reaction with cyclohexylamine (III) yields cis-di(cyclohexylamine)diiodoplatinium (IV). Reaction of complex (IV) with HClO4 in H2O/EtOH furnishes dimer (V), which is then treated with NH4OH in H2O affording cis-ammine(cyclohexylamine) diiodoplatinium (VI). Nitration of complex (VI) with AgNO3 in H2O followed by chlorination with HCl gives cis-amminechloro-(cyclohexylamine)platinium (VII) . Alternatively, treatment of cisplatin (VIII) with Et4NCl in dimethylacetamide at 100 °C followed by ion exchange by DOWEX 50WX8 and HCl leads to amminetrichloroplatinum (IX), which is then treated with KCl, giving potassium(SP-4-2)-amminetrichloroplatinate (X). Subsequent reaction of compound (X) with cyclohexylamine (III) in the presence of NaI in water furnishes (SP-4-3)-amminechloro(cyclohexanamine)iodoplatinum (XI), which by subsequent nitration and chlorination with AgNO3 in water and treatment with HCl affords complex (VII) . Then, compound (VII) is submitted to hydroxylation with H2O2 in water to give (OC-6-43)-amminedichloro(cyclohexylamine)dihydroxyplatinum (XII), which is finally acetylated with Ac2O in CH2Cl2 .
【1】
Khokhar, A.R., Deng, Y., Al-Baker, S., Yoshida, M., Siddik, Z.H. Synthesis and antitumor activity of ammine/amine platinum (II) and (IV) complexes. J Inorg Biochem 1993, 51(3): 677-87. |
【2】
Ciandomenico, C.M., Abrams, M.J., Murrer, B.A. et al. Carboxylation of kinetically inert platinum (IV) hydroxy complexes. An entr.acte.ee into orally active platinum (IV) antitumor agents. Inorg Chem 1995, 34(5): 1015-21. |
【3】
Abrams, M.J., Giandomenico, C.M., Murrer, B.A., Vollano, J.F. (Johnson Matthey plc). Pt(IV) complexes. AU 8928971, EP 0328274, JP 1989294684. |
【4】
Abrams, M.J., Giandomenico, C., Murrer, B.A., Vollano, J.F. (Johnson &Johnson). Pt(IV) complexes. US 5072011. |
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) |
51693 |
dipotassium tetrachloroplatinate(2-);potassium tetrachloroplatinate(II);potassium tetrachloroplatinate |
10025-99-7 |
Cl4K2Pt |
详情 | 详情
|
(II) |
51694 |
dipotassium tetraiodoplatinate(2-);potassium tetraiodoplatinate(II);Potassium tetraiodoplatinate |
14708-56-6 |
I4K2Pt |
详情 | 详情
|
(III) |
17966 |
cyclohexanamine; cyclohexyl amine; cyclohexylamine
|
108-91-8 |
C6H13N |
详情 | 详情
|
(IV) |
69489 |
cis-di(cyclohexylamine)diiodoplatinium |
|
C12H26I2N2Pt |
详情 |
详情
|
(V) |
69490 |
(cyclohexylamino)platinum(III) iodide |
|
C12H26I4N2Pt2 |
详情 |
详情
|
(VI) |
69491 |
cis-ammine(cyclohexylamine)diiodoplatinium |
|
C6H16I2N2Pt |
详情 |
详情
|
(VII) |
69492 |
cis-amminechloro-(cyclohexylamine)platinium |
|
C6H16Cl2N2Pt |
详情 |
详情
|
(VIII) |
51698 |
dichloroplatinum diammoniate
|
|
H6Cl2N2Pt |
详情 |
详情
|
(IX) |
69493 |
amminetrichloroplatinum |
|
H4Cl3NPt |
详情 |
详情
|
(X) |
69494 |
potassium (SP-4-2)-amminetrichloroplatinate |
|
H3Cl3KNPt |
详情 |
详情
|
(XI) |
69495 |
(SP-4-3)-amminechloro(cyclohexanamine)iodoplatinum |
|
C6H16ClIN2Pt |
详情 |
详情
|
(XII) |
69496 |
(OC-6-43)-amminedichloro(cyclohexylamine)dihydroxyplatinum |
|
C6H18Cl2N2O2Pt |
详情 |
详情
|