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【结 构 式】 
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【分子编号】35778 【品名】1-(2,4-dichlorophenyl)hydrazine 【CA登记号】5446-18-4 |
【 分 子 式 】C6H6Cl2N2 【 分 子 量 】177.03252 【元素组成】C 40.71% H 3.42% Cl 40.05% N 15.82% |
合成路线1
该中间体在本合成路线中的序号：(III)Claisen condensation of 4-chloropropiophenone (I) with diethyl oxalate in the presence of lithium hexamethyldisilazide afforded the corresponding diketo ester lithium salt (II). This was condensed with 2,4-dichlorophenylhydrazine (III) to afford hydrazone (IV), which was further cyclized to pyrazole (V) in refluxing HOAc. In an improved procedure, 4-chloropropiophenone (I) was initially converted to the silyl enol ether (VI) using chlorotrimethylsilane and triethylamine. Acylation of (VI) with ethyl chloroglyoxylate in the presence of ZnCl2 produced diketo ester (VII). Condensation of (VII) with hydrazine (III), followed by acid cyclization of the intermediate hydrazone (IV), also produced pyrazole (V). Hydrolysis of ethyl ester (V) gave carboxylic acid (VIII), which was then activated as the acid chloride (IX). Finally, coupling of acid chloride (IX) with N-aminopiperidine (X) furnished the title hydrazide.
| 【1】 Rinaldi, M.; Anne-Archard, G.; Barth, F.; Casellas, P.; Congy, C.; Martinez, S. (Sanofi-Synthélabo); Substd. N-piperidino 3-pyrazolecarboxamide. CA 2136893; EP 0576357; EP 0656354; FR 2692575; FR 2713224; FR 2713225; JP 1994073014; JP 1995309841; JP 2001026541; US 5624941 . |
| 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) | 29196 | 1-(4-Chlorophenyl)-1-propanone; 4-Chloropropiophenone | 6285-05-8 | C9H9ClO | 详情 | 详情 |
| (II) | 52989 | lithium (Z)-1-(4-chlorophenyl)-4-ethoxy-2-methyl-3,4-dioxo-1-buten-1-olate | n/a | C13H12ClLiO4 | 详情 | 详情 |
| (III) | 35778 | 1-(2,4-dichlorophenyl)hydrazine | 5446-18-4 | C6H6Cl2N2 | 详情 | 详情 |
| (IV) | 52990 | ethyl 4-(4-chlorophenyl)-2-[(E)-2-(2,4-dichlorophenyl)hydrazono]-3-methyl-4-oxobutanoate | n/a | C19H17Cl3N2O3 | 详情 | 详情 |
| (V) | 52991 | ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate | n/a | C19H15Cl3N2O2 | 详情 | 详情 |
| (VI) | 52992 | (Z)-1-(4-chlorophenyl)-1-propenyl trimethylsilyl ether; {[(Z)-1-(4-chlorophenyl)-1-propenyl]oxy}(trimethyl)silane | n/a | C12H17ClOSi | 详情 | 详情 |
| (VII) | 52993 | ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate | n/a | C13H13ClO4 | 详情 | 详情 |
| (VIII) | 52994 | 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid | n/a | C17H11Cl3N2O2 | 详情 | 详情 |
| (IX) | 52995 | 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride | n/a | C17H10Cl4N2O | 详情 | 详情 |
| (X) | 35781 | 1-piperidinylamine; 1-piperidinamine | 2213-43-6 | C5H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Claisen condensation of 4'-bromopropiophenone (I) with diethyl oxalate using lithium bis(trimethylsilyl)amide provided the lithium salt of diketone (II). Subsequent condensation of (III) with 2,4-dichlorophenyl hydrazine (III), followed by cyclization of the intermediate hydrazone in refluxing AcOH yielded the desired pyrazole (IV). After hydrolysis of the ester group of (IV), the resulting carboxylic acid was converted to acid chloride (V) by treatment with SOCl2. Coupling of (V) with 1-aminopiperidine (VI) gave amide (VII). Conversion of (VII) to the tributyl-stannyl derivative (VIII) was achieved by reaction with hexabutylditin in the presence of catalytic tetrakis(triphenylphosphine)palladium. The desired iodo compound was then obtained by treatment of (VIII) with NaI and chloramine-T.
| 【1】 Lan, R.; et al.; Preparation of iodine-123 labeled AM251: A potential SPECT radioligand for the brain cannabinoid CB1 receptor. J Label Compd Radiopharm 1996, 38, 10, 875. |
| 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) | 35776 | 1-(4-bromophenyl)-1-propanone | 10342-83-3 | C9H9BrO | 详情 | 详情 |
| (II) | 35777 | C13H12BrLiO4 | 详情 | 详情 | ||
| (III) | 35778 | 1-(2,4-dichlorophenyl)hydrazine | 5446-18-4 | C6H6Cl2N2 | 详情 | 详情 |
| (IV) | 35779 | ethyl 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate | C19H15BrCl2N2O2 | 详情 | 详情 | |
| (V) | 35780 | 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride | C17H10BrCl3N2O | 详情 | 详情 | |
| (VI) | 35781 | 1-piperidinylamine; 1-piperidinamine | 2213-43-6 | C5H12N2 | 详情 | 详情 |
| (VII) | 35782 | 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide | C22H21BrCl2N4O | 详情 | 详情 | |
| (VIII) | 35783 | 1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(tributylstannyl)phenyl]-1H-pyrazole-3-carboxamide | C34H48Cl2N4OSn | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Propiophenone (IX) was condensed with diethyl oxalate to give diketone (X). Reaction with hydrazine (III) afforded pyrazole (XI). Nitration of (XI) by nitronium tetrafluoborate in acetonitrile gave a mixture of para- and ortho-nitrated compounds (XIIa-b), which were used without separation. Ester hydrolysis, followed by chlorination to (XIIIa-b) and condensation with 1-aminopiperidine (VI) gave the corresponding mixture of para- and ortho-nitro amides, which were separated by flash chromatography. The required para-isomer (XIV) was reduced by hydrazine and Raney Nickel to aniline (XV). This was finally converted to the title iodide via the reaction of the diazonium salt with NaI.
| 【1】 Fan, P.; Liu, Q.; Lan, R.; et al.; Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 1999, 42, 4, 769. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIa) | 35786 | ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(2-nitrophenyl)-1H-pyrazole-3-carboxylate | C19H15Cl2N3O4 | 详情 | 详情 | |
| (XIIb) | 35787 | ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate | C19H15Cl2N3O4 | 详情 | 详情 | |
| (XIIIa) | 35788 | 1-(2,4-dichlorophenyl)-4-methyl-5-(2-nitrophenyl)-1H-pyrazole-3-carbonyl chloride | C17H10Cl3N3O3 | 详情 | 详情 | |
| (XIIIb) | 35789 | 1-(2,4-dichlorophenyl)-4-methyl-5-(4-nitrophenyl)-1H-pyrazole-3-carbonyl chloride | C17H10Cl3N3O3 | 详情 | 详情 | |
| (III) | 35778 | 1-(2,4-dichlorophenyl)hydrazine | 5446-18-4 | C6H6Cl2N2 | 详情 | 详情 |
| (VI) | 35781 | 1-piperidinylamine; 1-piperidinamine | 2213-43-6 | C5H12N2 | 详情 | 详情 |
| (IX) | 33531 | propiophenone | 93-55-0 | C9H10O | 详情 | 详情 |
| (X) | 35784 | C13H13LiO4 | 详情 | 详情 | ||
| (XI) | 35785 | ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-phenyl-1H-pyrazole-3-carboxylate | C19H16Cl2N2O2 | 详情 | 详情 | |
| (XIV) | 35790 | 1-(2,4-dichlorophenyl)-4-methyl-5-(4-nitrophenyl)-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide | C22H21Cl2N5O3 | 详情 | 详情 | |
| (XV) | 35791 | 5-(4-aminophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide | C22H23Cl2N5O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Claisen condensation of the lithium enolate of 4-methoxypropiophenone (I) with diethyl oxalate leads to diketo ester (II). Treatment of (II) with 2,4-dichlorophenyl hydrazine (III), followed by cyclization of the resultant hydrazone (IV) in boiling AcOH furnishes the pyrazolecarboxylate (V). Alkaline hydrolysis of ester (V) yields carboxylic acid (VI), which is further activated as the acid chloride (VII) with SOCl2 in refluxing toluene. Finally, coupling of acid chloride (VII) with 1-aminopiperidine (VIII) produces the target hydrazide derivative.
| 【1】 Katoch-Rouse, R.; Pavlova, O.A.; Caulder, T.; Hoffman, A.F.; Mukhin, A.G.; Horti, A.G.; Synthesis, structure-activity relationship, and evaluation of SR141716 analogues: Development of central cannabinoid receptor ligands with lower lipophilicity. J Med Chem 2003, 46, 4, 642. |
| 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) | 64383 | 1-[4-(methyloxy)phenyl]-1-propanone | C10H12O2 | 详情 | 详情 | |
| (II) | 64384 | ethyl 3-methyl-4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate | C14H16O5 | 详情 | 详情 | |
| (III) | 35778 | 1-(2,4-dichlorophenyl)hydrazine | 5446-18-4 | C6H6Cl2N2 | 详情 | 详情 |
| (IV) | 64385 | ethyl 2-[2-(2,4-dichlorophenyl)hydrazono]-3-methyl-4-[4-(methyloxy)phenyl]-4-oxobutanoate | C20H20Cl2N2O4 | 详情 | 详情 | |
| (V) | 64386 | ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(methyloxy)phenyl]-1H-pyrazole-3-carboxylate | C20H18Cl2N2O3 | 详情 | 详情 | |
| (VI) | 64387 | 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(methyloxy)phenyl]-1H-pyrazole-3-carboxylic acid | C18H14Cl2N2O3 | 详情 | 详情 | |
| (VII) | 64388 | 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(methyloxy)phenyl]-1H-pyrazole-3-carbonyl chloride | C18H13Cl3N2O2 | 详情 | 详情 | |
| (VIII) | 35781 | 1-piperidinylamine; 1-piperidinamine | 2213-43-6 | C5H12N2 | 详情 | 详情 |