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【结 构 式】 
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【分子编号】12091 【品名】1-Methylhydrazine; Monomethyl hydrazine 【CA登记号】60-34-4 |
【 分 子 式 】CH6N2 【 分 子 量 】46.07212 【元素组成】C 26.07% H 13.13% N 60.8% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of methylhydrazin (I) with potassium thiocyanate (II) gives N-methyl-N-aminothiourea (III), which is cyclized with dimethyl oxalate (IV) by means of sodium methoxide in methanol to afford 2,5-dihydro-6-hydroxy-2-methyl-3-mercapto-5-oxo-1,2,4-triazine (V). The reaction of (V) with 7-aminocephalosporanic acid (VI) in a buffer solution at pH 6.5 gives 7-amino-3,4-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (VII), which is condensed with 2-(2-chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetyl chloride (VIII) at pH 2 yielding 7-]2-(2-chloroacetamido-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (IX). Finally, this compound is hydrolyzed and treated with sodium hydroxide.
| 【1】 Neuman, M.; Cefatriaxon. Drugs Fut 1981, 6, 3, 132. |
| 【2】 Reiner, R.; et al.; Ro-13-9904/001, a novel potent and long-acting parenteral cephalosporin. J Antibiot 1980, 32, 7, 783-786. |
| 【3】 Reiner, R.; Montavon, M. (F. Hoffmann-La Roche AG); Cephalosporin derivs. and process for their preparation. DE 2922036 . |
| 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) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (II) | 37410 | Potassium thiocyanate | 333-20-0 | CKNS | 详情 | 详情 |
| (III) | 37411 | 1-methyl-1-hydrazinecarbothioamide | C2H7N3S | 详情 | 详情 | |
| (IV) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
| (V) | 37413 | 6-hydroxy-2-methyl-3-sulfanyl-1,2,4-triazin-5(2H)-one | C4H5N3O2S | 详情 | 详情 | |
| (VI) | 22747 | (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C10H12N2O5S | 详情 | 详情 | |
| (VII) | 37414 | (6R,7R)-7-amino-3-[[(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C12H13N5O5S2 | 详情 | 详情 | |
| (VIII) | 32659 | 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl chloride | 75532-64-8 | C8H7Cl2N3O3S | 详情 | 详情 |
| (IX) | 37415 | (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-[[(6-hydroxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)sulfanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C20H19ClN8O8S3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The title compound has also been obtained by solid phase synthesis. Bromoacetic acid (I) is coupled to hydroxymethyl polystyrene resin by means of DIC/DMAP to produce the bromoacetyl resin (II). Bromide displacement with tert-butyl carbazate (III) leads to the N-Boc hydrazino ester (IV), which is further deprotected to (V) employing trifluoroacetic acid. The hydrazinoacetic acid-bound resin (V) is then condensed with 5-(p-nitrophenyl)furfural (VI) to furnish hydrazone (VII). Acylation of resin (VII) with p-nitrophenyl chloroformate (VIII) produces the p-nitrophenyl carbamate (IX), which upon treatment with ammonia gives rise to the semicarbazone (X). Finally, concomitant intramolecular ring closure and resin cleavage of (X) produces the target aminohydantoin derivative (XI) (4, 5).
| 【1】 Wilson, L.J.; Li, M.; Portlock, D.E.; Solid phase synthesis of 1-aminohydantoin libraries. Tetrahedron Lett 1998, 39, 29, 5135. |
| 【2】 Portlock, D.E.; Li, M.; Wilson, L.J. (The Procter & Gamble Co.); Solid phase synthesis of 1-aminohydantoins. WO 9942450 . |
| 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) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (II) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (III) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (IV) | 63589 | 2-[2-(tert-butoxycarbonyl)hydrazino]acetic acid | C7H14N2O4 | 详情 | 详情 | |
| (V) | 63590 | 2-hydrazinoacetic acid | C2H6N2O2 | 详情 | 详情 | |
| (VI) | 63583 | 5-(4-nitrophenyl)-2-furaldehyde | C11H7NO4 | 详情 | 详情 | |
| (VII) | 63591 | 2-(2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid | C13H11N3O5 | 详情 | 详情 | |
| (VIII) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (IX) | 63592 | 2-(1-[(4-nitrophenoxy)carbonyl]-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid | C20H14N4O9 | 详情 | 详情 | |
| (X) | 63593 | 2-(1-(aminocarbonyl)-2-{(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}hydrazino)acetic acid | C14H12N4O6 | 详情 | 详情 | |
| (XI) | 63586 | 1-({(E)-[5-(4-nitrophenyl)-2-furyl]methylidene}amino)-2,4-imidazolidinedione | C14H10N4O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of methyl hydrazine (I) and methyl isothiocyanate (II) in either ethanol or THF afforded 2,4-dimethylthiosemicarbazide (III). Acylation of (III) with 3-fluorobenzoyl chloride in either pyridine or THF/N(Et)3 yielded 1-(3-fluorobenzoyl)-2,4-dimethylthiosemicarbazide (IV), which was easily cyclized to MDL 26,479 by warming in 1 M aqueous NaOH.
| 【1】 Miller, J.A.; Dudley, M.W.; Kehne, J.H.; Sorensen, S.M.; Wenstrup, D.L.; Kane J.M.; MDL 26,479. Drugs Fut 1992, 17, 1, 21. |
| 【2】 Dudley, M.W.; Baron, B.M.; Sorensen, S.M.; Miller, F.P.; MDL 26,479: A potential antidepressant whose mechanism of action involves interaction at the GABAA receptor complex. 29th Annu Meet Amer Coll Neuropsychopharmacol (Dec 10-14, San Juan) 1990, Abst. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63420 | 3-fluorobenzoyl chloride | C7H4ClFO | 详情 | 详情 | ||
| (I) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (II) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (III) | 12093 | 2,4-Dimethylthiosemicarbazide; N,1-Dimethyl-1-hydrazinecarbothioamide | 6621-75-6 | C3H9N3S | 详情 | 详情 |
| (IV) | 12094 | 2-(3-Fluorobenzoyl)-N,1-dimethyl-1-hydrazinecarbothioamide | C10H12FN3OS | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Synthesis of the aminopyrazole intermediate (XIII): The reaction of butanal (I) with methylhydrazine (II) in dichloromethane in the presence of MgSO4 gives the corresponding hydrazide (III), which is alkylated with ethyl bromoacetate (IV) by means of the polymer-supported base 2-(tert-butylimino)-2-(diethylamino)-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (V) and polymer-supported methylamine (VI) to yield the hydrazino ester (VII). Treatment of compound (VII) with an ion exchange tetramethylammonium cyanide resin (VIII) in refluxing ethanol containing a catalytic amount of HOAc affords the adduct (IX), which is dehydrogenated with Pd/C/cyclopentene or MnO2 and treated with a polymer-supported ethyl isocyanate resin (X) in order to eliminate the unreacted product, providing the hydrazone (XI). Cyclization of (XI) by means of PS-BEMP (V) in ethanol gives 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid ethyl ester (XII), which is finally treated with ammonia in methanol to afford the desired pyrazolecarboxamide intermediate (XIII).
| 【1】 Baxendale, I.R.; Ley, S.V.; Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil. Bioorg Med Chem Lett 2000, 10, 17, 1983. |
| 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) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (II) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (III) | 44339 | butanal N-methylhydrazone | C5H12N2 | 详情 | 详情 | |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 44344 | N-(tert-butyl)-N-[2-(diethylamino)-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-ylidene]amine; 2-(tert-butylimino)-N,N-diethyl-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-amine | C13H31N4P | 详情 | 详情 | |
| (VI) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (VII) | 44340 | ethyl 2-[2-[(E)butylidene]-1-methylhydrazino]acetate | C9H18N2O2 | 详情 | 详情 | |
| (VIII) | 44345 | N,N,N-trimethylmethanaminium cyanide | C5H12N2 | 详情 | 详情 | |
| (IX) | 44341 | ethyl 2-[2-(1-cyanobutyl)-1-methylhydrazino]acetate | C10H19N3O2 | 详情 | 详情 | |
| (X) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (XI) | 44342 | ethyl 2-[2-[(Z)-1-cyanobutylidene]-1-methylhydrazino]acetate | C10H17N3O2 | 详情 | 详情 | |
| (XII) | 44343 | ethyl 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylate | C10H17N3O2 | 详情 | 详情 | |
| (XIII) | 15627 | 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide | 139756-02-8 | C8H14N4O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：Methyl 4-oxopiperidine-3-carboxylate (IX) was protected as the tert-butyl carbamate (X) with Boc2O. This was alkylated with benzyl bromide in the presence of NaH to provide the racemic benzyl derivative (XI). Subsequent cyclization of (XI) with methylhydrazine produced the pyrazolopyridine (XII), which was deprotected with trifluoroacetic acid. The resulting amine (XIII) was then coupled with dipeptide (VI) using EDC and HOBt to afford the diastereomeric amides (XIV). After chromatographic isolation of the (R,R)-diastereoisomer, acid deprotection of the Boc group furnished the title compound.
| 【1】 Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.; Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 276. |
| 【2】 Carpino, P.A.; Jardine, D.P.A.; Lefker, B.A.; Ragan, J.A. (Pfizer Inc.); Growth-hormone secretagogues. EP 0869968; JP 1999501945; WO 9724369 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 | |
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (VI) | 28103 | (2R)-3-(benzyloxy)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (IX) | 28106 | methyl 4-oxo-3-piperidinecarboxylate | 56026-52-9 | C7H11NO3 | 详情 | 详情 |
| (X) | 28107 | 1-(tert-butyl) 3-methyl 4-oxo-1,3-piperidinedicarboxylate | C12H19NO5 | 详情 | 详情 | |
| (XI) | 28108 | 1-(tert-butyl) 3-methyl 3-benzyl-4-oxo-1,3-piperidinedicarboxylate | C19H25NO5 | 详情 | 详情 | |
| (XII) | 28109 | tert-butyl 3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate | C19H25N3O3 | 详情 | 详情 | |
| (XIII) | 28110 | 3a-benzyl-2-methyl-2,3a,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one | C14H17N3O | 详情 | 详情 | |
| (XIV) | 28111 | tert-butyl 2-([(1R)-2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-1-[(benzyloxy)methyl]-2-oxoethyl]amino)-1,1-dimethyl-2-oxoethylcarbamate | C33H43N5O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The cyclization of 2-pivaloylacetonitrile (I) with methylhydrazine (II) in refluxing ethanol gives 5-amino-3-tert-butyl-1-methylpyrazole (III), which is finally condensed with 4-(4-pyridylmethyl)aniline (IV) and carbonyldimidazole (CDI) in dichloromethane to afford the target urea. The aniline (IV) has been obtained by reduction of the corresponding nitro derivative (V) with H2 over Pd/C in ethanol.
| 【1】 Dumas, J.; et al.; Synthesis and pharmacological characterization of a potent, orally active p38 kinase inhibitor. Bioorg Med Chem Lett 2002, 12, 12, 1559. |
| 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) | 44248 | 4,4-dimethyl-3-oxopentanenitrile | 59997-51-2 | C7H11NO | 详情 | 详情 |
| (II) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (III) | 51506 | 5-Amino-3-tert-butyl-1-methylpyrazole | 118430-73-2 | C8H15N3 | 详情 | 详情 |
| (IV) | 51504 | 4-(4-pyridinylmethyl)aniline; 4-(4-pyridinylmethyl)phenylamine | C12H12N2 | 详情 | 详情 | |
| (V) | 51503 | 4-(4-Nitrobenzyl)pyridine; 4-(p-nitrobenzyl) pyridine | 1083-48-3 | C12H10N2O2 | 详情 | 详情 |