|
【结 构 式】 
|
【分子编号】11019 【品名】(Methylimino)(oxo)methane; methyl isocyanate 【CA登记号】 |
【 分 子 式 】C2H3NO 【 分 子 量 】57.05196 【元素组成】C 42.11% H 5.3% N 24.55% O 28.04% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of khellinone (I) with hydroxylamine in refluxing ethanol gives the corresponding oxime (II), which undergoes the Beckmann rearrangement in a saturated solution of gaseous HCl in acetic acid to afford the acetamido compound (III). Treatment of (III) with gaseous HCl in ethanol under reflux yields an aminophenol (VII), which is first reacted with methyl isocyanate (IX) in chloroform, then O-alkylated by pyrrolidinoethyl chloride (IV) in refluxing acetonitrile in the presence of K2CO3 to give carocainide as the free base. Alternatively, (III) can be alkylated by pyrrolidinoethyl chloride (IV), then refluxed in aqueous 2N HCl and the resulting amino compound (VI) reacted with methyl isocyanate (IX) in dry toluene. The hydrochloride can be prepared by treatment of the free base with HCl in methylene chloride-chlorotene.
| 【1】 Ancher, J.F.; Carocainide Hydrochloride. Drugs Fut 1984, 9, 6, 410. |
| 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) | 34142 | 1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)-1-ethanone | 484-51-5 | C12H12O5 | 详情 | 详情 |
| (II) | 34143 | 1-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)-1-ethanone oxime | C12H13NO5 | 详情 | 详情 | |
| (III) | 34144 | N-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)acetamide | C12H13NO5 | 详情 | 详情 | |
| (IV) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (V) | 34145 | N-[4,7-dimethoxy-6-[2-(1-pyrrolidinyl)ethoxy]-1-benzofuran-5-yl]acetamide | C18H24N2O5 | 详情 | 详情 | |
| (VI) | 34146 | 4,7-dimethoxy-6-[2-(1-pyrrolidinyl)ethoxy]-1-benzofuran-5-ylamine; 4,7-dimethoxy-6-[2-(1-pyrrolidinyl)ethoxy]-1-benzofuran-5-amine | C16H22N2O4 | 详情 | 详情 | |
| (VII) | 34147 | 5-amino-4,7-dimethoxy-1-benzofuran-6-ol | C10H11NO4 | 详情 | 详情 | |
| (VIII) | 34148 | N-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)-N'-methylurea | C12H14N2O5 | 详情 | 详情 | |
| (IX) | 33922 | 1-(2-Chloroethyl)pyrrolidine; N-(2-Chloroethyl)pyrrolidine | C6H12ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The condensation of 5-acetamido-4,7-dimethoxy-6-hydroxybenzofuran (I) with N-(2-chloroethyl)piperidine (II) by means of K2CO3 in refluxing acetone gives 5-acetamido-4,7-dimethoxy-6-[2-(N-piperidino)ethoxy]benzofuran (III), which is hydrolyzed with refluxing 2N HCl yielding 5-amino-4,7-dimethoxy-6-[2-(N-piperidino)ethoxy]benzofuran (IV). Finally, this compound is treated with methyl isocyanate (V) in hot toluene.
| 【1】 Bourgery, G.; Lacour, A.; Pourrias, B.; Bregeon, G.C. (Laboratoires Delalande); Novel aminoalkoxybenzofurans, their process of preparation and their therapeutic use. FR 2358143 . |
| 【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Thorpe, P.J.; Murocainide. Drugs Fut 1983, 8, 8, 687. |
| 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) | 34144 | N-(6-hydroxy-4,7-dimethoxy-1-benzofuran-5-yl)acetamide | C12H13NO5 | 详情 | 详情 | |
| (II) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (III) | 36164 | N-[4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-yl]acetamide | C19H26N2O5 | 详情 | 详情 | |
| (IV) | 36165 | 4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-amine; 4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-ylamine | C17H24N2O4 | 详情 | 详情 | |
| (V) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Acetohydroxamic acid (I) is reacted with two moles of methyl isocyanate (II).
| 【1】 Reifschneider, W. (Marion Merrell Dow, Inc.); N-[(Alkylamino)carbonyl]-N-[[(alkylamino)carbonyl]. EP 0086492; US 4413009 . |
| 【2】 Eastland, G.; Caracemide. Drugs Fut 1988, 13, 11, 945. |
合成路线4
该中间体在本合成路线中的序号：(II)This compound can be obtained in two different ways: 1) By reaction of 4-oxa-5-hydroxytricyclo[5.2.1.0(2,6)]dec-8-en-3-one (I) with methyl isocyanate (II) in refluxing THF. 2) By a Diels-Alder reaction of cyclopentadiene (III) with 2-(N-methylcarbamoyloxy)-2,5-dihydrofuran-5 one (IV) in THF at 120 C in a pressure vessel.
| 【1】 Wiersdorff, W.W.; Wilsmann, K.; DE 2510714 . |
| 【2】 Ammann, A.; et al. (BASF AG); Carbamates and their use as pharmaceuticals. US 3965119 . |
| 【3】 Blancafort, P.; Neuman, M.; Serradell, M.N.; Castaner, J.; LU-253. Drugs Fut 1981, 6, 2, 89. |
合成路线5
该中间体在本合成路线中的序号：(III)The synthesis of several forms of [13C]- and [15N]-labeled temozolomide has been reported: 1) The diazotation of 3-aminopyrazole-4-carboxamide (I) with [15N]-labeled sodium nitrite and HCl gives the corresponding labeled diazonium salt (II), which is cyclized with methyl isocyanate (II) at room temperature, yielding temozolomide labeled at the N in the 2-position.
| 【1】 Wilman, D.E.V.; Thomson, W.; Wheelhouse, R.T.; Stevens, M.F.G.; Antitumour imidazotetrazines. 31. The synthesis of isotopically labelled temozolomide and a multinuclear (H-1, C-13, N-15) magnetic resonance investigation of temozolomide and mitozolomide. J Chem Soc - Perkins Trans I 1995, 3, 3, 249. |
| 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) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
| (II) | 11018 | 5-Carbamoylimidazolidin-4-yldiazonium salt | C4H3N5O | 详情 | 详情 | |
| (II) | 45040 | 5-(aminocarbonyl)-4-imidazolidinediazonium | C4H8N5O | 详情 | 详情 | |
| (III) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII),(XII)2) The condensation of N,N-diphenylcarbamoyl chloride (IV) with [13C]-labeled methylamine (V) gives the corresponding urea (VI), which by heating at 240 C is converted to the [13C]-labeled methyl isocyanate (VII). Finally, this compound is cyclized with the diazonium salt (VIII) (obtained by diazotation of 3-aminopyrazole-4-carbonitrile with NaNO2-HCl in the usual way) to afford temozolomide labeled at the methyl in the 3-position. 3) The preceding sequence performed with [15N]-labeled methylamine (X) gives urea (XI), isocyanate (XII) and finally temozolomide labeled at the N in the 3-position.
| 【1】 Wilman, D.E.V.; Thomson, W.; Wheelhouse, R.T.; Stevens, M.F.G.; Antitumour imidazotetrazines. 31. The synthesis of isotopically labelled temozolomide and a multinuclear (H-1, C-13, N-15) magnetic resonance investigation of temozolomide and mitozolomide. J Chem Soc - Perkins Trans I 1995, 3, 3, 249. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII),(XII) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (V),(X) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (VI),(XI) | 11022 | 1-Methyl-3,3-diphenylurea; N'-Methyl-N,N-diphenylurea | 13114-72-2 | C14H14N2O | 详情 | 详情 |
| (IV) | 11020 | N,N-Diphenylcarbamic chloride; Diphenylcarbamyl chloride | 83-01-2 | C13H10ClNO | 详情 | 详情 |
| (V) | 45041 | methylamine; methanamine | CH5N | 详情 | 详情 | |
| (VI) | 45042 | N'-methyl-N,N-diphenylurea | C14H14N2O | 详情 | 详情 | |
| (VII) | 45043 | (methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (VIII) | 11016 | 1-[5-(Aminocarbonyl)-4-imidazolidinyl]diazonium | C4H3N5O | 详情 | 详情 | |
| (IX) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
| (X) | 45044 | methylamine; methanamine | CH5N | 详情 | 详情 | |
| (XI) | 45045 | N'-methyl-N,N-diphenylurea | C14H14N2O | 详情 | 详情 | |
| (XII) | 45046 | methyl isocyanate; (methylimino)(oxo)methane | C2H3NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)This compound has been obtained by two related ways: 1. The reaction of 5-diazoimidazole (I) with methylamine gives the triazene (II), which is then cyclized with 11C-phosgene (III) to yield the target 11C-carbonyl labeled compound. 2. The cyclization of 5-diazoimidazole-4-carboxamide (I) with 11C-carbonyl labeled methyl isocyanate (IV) gives the target 11C carbonyl labeled compound.
| 【1】 Brock, C.S.; Brady, F.; Stevens, M.F.G.; Brown, G.D.; Price, P.M.; Luthra, S.K.; Antitumor imidazotetrazines. 40.(1) Radiosyntheses of [4-11C-carbonyl]- and 3-N-11C-methyl]-8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies. J Med Chem 2002, 45, 25, 5448. |
| 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) | 56930 | 4-diazo-4H-imidazole-5-carboxamide | C4H3N5O | 详情 | 详情 | |
| (II) | 56931 | 4-[(E)-3-methyl-2-triazenyl]-4H-imidazole-5-carboxamide | C5H8N6O | 详情 | 详情 | |
| (III) | 56932 | Carbonyl chloride | CCl2O | 详情 | 详情 | |
| (III) | 56933 | carbonic dichloride | CCl2O | 详情 | 详情 | |
| (IV) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (IV) | 56934 | (methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The cyclization of 5-diazoimidazole-4-carboxamide (I) with 11C-methyl isocyanate (II) gives the target 11C methyl labelled compound.
| 【1】 Brock, C.S.; Brady, F.; Stevens, M.F.G.; Brown, G.D.; Price, P.M.; Luthra, S.K.; Antitumor imidazotetrazines. 40.(1) Radiosyntheses of [4-11C-carbonyl]- and 3-N-11C-methyl]-8-carbamoyl-3- methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies. J Med Chem 2002, 45, 25, 5448. |
合成路线9
该中间体在本合成路线中的序号：(X)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10
该中间体在本合成路线中的序号：(X)Synthesis of sildenafil: Reaction of 5-(chlorosulfonyl)-2-hydroxybenzoic acid (XIV) with 1-methylpiperazine (XV) by means of DIEA gives the sulfonamide (XVI), which is treated with diethyl sulfate yielding 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (XVII). The activation of (XVII) with a polymer-supported 1-hydroxybenzotriazole (HOBt) variant (XVIII) and bromotris(pyrrolidino)phosphonium (PyBrOP) as catalyst affords the activated ester (XIX), which is condensed with the aminopyrazole intermediate (XIII), and treated with the methyl isocyanate resin (X) in order to eliminate the excess of aminopyrazole (XIII), to provide the diamide (XX). Finally, the cyclization and dehydration to sildenafil are performed by microwave irradiation of an ethanolic solution of compound (XX) containig a catalytic amount of NaOEt.
| 【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 |
|---|---|---|---|---|---|---|
| (X) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 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 |
| (XIV) | 44346 | 5-(chlorosulfonyl)-2-hydroxybenzoic acid | C7H5ClO5S | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVI) | 44347 | 2-hydroxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid | C12H16N2O5S | 详情 | 详情 | |
| (XVII) | 21188 | 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid | 194602-23-8 | C14H20N2O5S | 详情 | 详情 |
| (XVIII) | 44348 | 1-hydroxy-1H-1,2,3-benzotriazole-6-carbaldehyde | C7H5N3O2 | 详情 | 详情 | |
| (XIX) | 44349 | 1-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]oxy)-1H-1,2,3-benzotriazole-6-carbaldehyde | C21H23N5O6S | 详情 | 详情 | |
| (XX) | 21191 | 4-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]amino)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide | C22H32N6O5S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)The reaction of (2-hydroxyethyl)hydrazine (I) with MsCl in pyridine gives the trimesylated compound (II), which is treated with LiCl in refluxing acetone to yield 1-(2-chloroethyl)-1,2-bis(methanesulfonyl)hydrazine (III) (1). Finally, this compound is condensed with methyl isocyanate (IV) by means of TEA in acetonitrile to afford the target semicarbazide.
| 【1】 Shyam, K.; et al.; Antitumor 2-(aminocarbonyl)-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines. J Med Chem 1996, 39, 3, 796. |
| 【2】 Satorelli, A.C.; Shyam, K.; Penketh, P.G. (Yale University); Antitumor 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-(substd.)hydrazines. EP 0841912; JP 1999508898; WO 9702029 . |
| 【3】 Shyam, K.; et al.; Synthesis and evaluation of 1,2, 2-tris(sulfonyl)hydrazines as antineoplastic and trypanocidal agents. J Med Chem 1990, 33, 8, 2259. |
| 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) | 24951 | 2-hydrazino-1-ethanol | 109-84-2 | C2H8N2O | 详情 | 详情 |
| (II) | 48610 | 2-[1,2-bis(methylsulfonyl)hydrazino]ethyl methanesulfonate | C5H14N2O7S3 | 详情 | 详情 | |
| (III) | 48611 | N-(2-chloroethyl)-N'-(methylsulfonyl)methanesulfonohydrazide | C4H11ClN2O4S2 | 详情 | 详情 | |
| (IV) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 |