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【结 构 式】 
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【分子编号】23150 【品名】2-(chloromethyl)-1,3-difluorobenzene 【CA登记号】697-73-4 |
【 分 子 式 】C7H5ClF2 【 分 子 量 】162.5662064 【元素组成】C 51.72% H 3.1% Cl 21.81% F 23.37% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Aminothiophene (III) was prepared by condensation of phenylacetone (I) with ethyl cyanoacetate (II), followed by treatment with sulfur and diethylamine. Subsequent condensation of (III) with diethyl ethoxymethylenemalonate (IV) at 120 C provided the enaminomalonate (V). the partial hydrolysis of (V) with KOH in EtOH-dioxan provided monoacid (VI), which was cyclized by means of PPE to the thienopyridine (VII). Alkylation of (VII) with 2,6-difluorobenzyl chloride (VIII) and K2CO3 yielded predominantly the N-benzylated compound (IX), which was selectively nitrated at the phenyl ring to produce (X) (2). Radical bromination of the 3-methyl group of (X) gave bromomethyl compound (XI).
| 【1】 Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.; Hayase, Y.; Sasaki, S,; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo, S.; Onda, H.; Fujino, M.; Discovery of a novel, potent, and orally active no. J Med Chem 1998, 41, 22, 4190. |
| 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) | 23143 | 1-Phenylacetone; Methyl benzyl ketone; Benzyl methyl ketone; phenylacetone; Phenyl-2-propanone | 103-79-7 | C9H10O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 23145 | ethyl 2-amino-4-methyl-5-phenyl-3-thiophenecarboxylate | C14H15NO2S | 详情 | 详情 | |
| (IV) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (V) | 23147 | diethyl 2-([[3-(ethoxycarbonyl)-4-methyl-5-phenyl-2-thienyl]amino]methylene)malonate | C22H25NO6S | 详情 | 详情 | |
| (VI) | 23148 | 2-[[3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propenyl]amino]-4-methyl-5-phenyl-3-thiophenecarboxylic acid | C20H21NO6S | 详情 | 详情 | |
| (VII) | 23149 | ethyl 4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine-5-carboxylate | C17H15NO3S | 详情 | 详情 | |
| (VIII) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
| (IX) | 23151 | ethyl 7-(2,6-difluorobenzyl)-3-methyl-4-oxo-2-phenyl-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H19F2NO3S | 详情 | 详情 | |
| (X) | 23152 | ethyl 7-(2,6-difluorobenzyl)-3-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H18F2N2O5S | 详情 | 详情 | |
| (XI) | 23153 | ethyl 3-(bromomethyl)-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H17BrF2N2O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc, HOAc, S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III), which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V). Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII), which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII). Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X), which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI). Finally, this compound is treated with CDI, O-methylhydroxylamine (XII) and TEA in dichloromethane.
| 【1】 Sorbera, L.A.; Castaner, J.; Leeson, P.A.; TAK-013. Drugs Fut 2003, 28, 2, 121-124. |
| 【5】 Suzuki, N.; Furuya, S.; Choh, N.; Nara, Y. (Takeda Chemical Industries, Ltd.); Thienopyrimidine cpds., their production and use. EP 1163244; JP 2001278884; JP 2001278885; US 6340682; WO 0056739 . |
| 【6】 Kimura, K.; Yamamoto, H.; Miki, S.; Kawakami, J.; Fukuoka, K. (Takeda Chemical Industries, Ltd.); Processes for the production of thienopyrimidine derivs.. EP 1266898; JP 2001316391; WO 0164683 . |
| 【2】 Suzuki, N.; Nara, Y.; Harada, M.; Endo, S.; Fujino, M.; Sasaki, S.; Furuya, S.; Cho, N.; Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: A highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor. J Med Chem 2003, 46, 1, 113. |
| 【3】 Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.; Furuya, S.; Fujino, M.; Suzuki, N.; Synthesis of orally active nonpeptide LHRH (GnRH) antagonists [II]: Discovery of the thieno[2,3-b]pyrimidine-2,4-dione derivative TAK-013. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 2P-26. |
| 【4】 Harada, M.; Nara, Y.; Endo, S.; Suzuki, N.; Cho, N.; Fujino, M.; Sasaki, S.; Furuya, S.; Discovery of the thieno[2,3-d]pyrimidine-2,4-dione derivative TAK-013: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (II). 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 354. |
| 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) | 59515 | 1-(4-Nitrophenyl)-2-propanone; 4-Nitrophenylacetone | 5332-96-7 | C9H9NO3 | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 59516 | ethyl 2-amino-4-methyl-5-(4-nitrophenyl)-3-thiophenecarboxylate | C14H14N2O4S | 详情 | 详情 | |
| (IV) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (V) | 59517 | 5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C19H13N3O4S | 详情 | 详情 | |
| (VI) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
| (VII) | 59518 | 1-(2,6-difluorobenzyl)-5-methyl-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C26H17F2N3O4S | 详情 | 详情 | |
| (VIII) | 59519 | 5-(bromomethyl)-1-(2,6-difluorobenzyl)-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C26H16BrF2N3O4S | 详情 | 详情 | |
| (IX) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (X) | 59520 | 5-{[benzyl(methyl)amino]methyl}-1-(2,6-difluorobenzyl)-6-(4-nitrophenyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C34H26F2N4O4S | 详情 | 详情 | |
| (XI) | 59521 | 6-(4-aminophenyl)-5-{[benzyl(methyl)amino]methyl}-1-(2,6-difluorobenzyl)-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione | C34H28F2N4O2S | 详情 | 详情 | |
| (XII) | 15455 | (aminooxy)methane; O-methylhydroxylamine | 67-62-9 | CH5NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)Benzaldehyde (I) is converted into the corresponding hydrazone (II) upon treatment with methylhydrazine in toluene. Condensation of hydrazone (II) with ethyl (ethoxymethylene)cyanoacetate (III) produces the hydrazinomethylene cyanoacetate (IV), which is further cyclized to the pyrazole (V) under acidic conditions (1). Heating of amino ester (V) with formamide gives rise to the pyrazolopyrimidinone (VI). This is finally alkylated with 2,6-difluorobenzyl chloride (VII) to furnish the title compound
| 【1】 Unverferth, K.; Lankau, H-J.; Arnold, T.; Synthesis and anticonvulsant activity of AWD 34-176. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Lankau, H.-J.; Unverferth, K.; Tober, C.; Rundfeldt, C.; Arnold, T.; Dost, R.; Gasparic, A.; Bernöster, K. (AWD.pharma GmbH & Co. KG); 2,5-Dihydro-pyrazolo[3,4-d]pyrimidin-4-ones with an anticonvulsive action and methods for producing the same. WO 0218387 . |
| 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) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 62055 | benzaldehyde N-methylhydrazone | C8H10N2 | 详情 | 详情 | |
| (III) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (IV) | 62056 | ethyl (E)-2-cyano-3-{1-methyl-2-[(E)-phenylmethylidene]hydrazino}-2-propenoate | C14H15N3O2 | 详情 | 详情 | |
| (V) | 62057 | ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate | C7H11N3O2 | 详情 | 详情 | |
| (VI) | 62058 | 2-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one | C6H6N4O | 详情 | 详情 | |
| (VII) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The cyclization of phenylacetone (I) with ethyl cyanoacetate (II) by means of HOAc and AcONH4 in refluxing benzene, followed by a treatment with sulfur in hot ethanol gives 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl ester (III). The condensation of (III) with diethyl ethoxymethylene malonate (IV) by heating at 120 C yields the adduct (V), which is submitted to a selective hydrolysis with KOH in hot ethanol to afford the carboxylic acid (VI). The cyclization of (VI) by means of PPE at 120 C provides the thienopyridine (VII), which is nitrated with NaNO3 and H2SO4 to give the 4-nitrophenyl derivative (VIII). The alkylation of the hydroxy-thienopyridine (VIII) with 2,6-difluorobenzyl chloride (IX) by means of NaH in DMF yields the benzylated thienopyridinone (X), which is brominated with NBS and AIBN in refluxing CCl4 to afford the bromomethyl derivative (XI). The condensation of (XI) with N-benzyl-N-methylamine (XII) by means of TEA in DMF provides the tertiary amine (XIII). The reduction of the nitro group of (XIII) by means of Fe and HCl in ethanol gives the 4-aminophenyl derivative (XIV), which is acylated with trifluoroacetic anhydride and TEA to yield the acetamide (XV). The reaction of (XV) with N,O-dimethylhydroxylamine (XVI) and TEA in CH2Cl2 affords the methoxyamide (XVII).
| 【1】 Imada, T.; Fujino, M.; Suzuki, N.; Harada, M.; Kasai, S.; Sasaki, S.; Endo, S.; Hayase, Y.; Furuya, S.; Cho, N.; Discovery of the thieno[2,3-b]pyridin-4-one derivative TAK-810: Highly potent and orally active nonpeptide LHRH (GnRH) antagonist (I). 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 353. |
| 【2】 Suzuki, N.; Furuya, S.; Choh, N.; Imada, T. (Takeda Chemical Industries, Ltd.); Thienopyridine cpds., their production and use. EP 1090010; JP 2000219690; JP 2000219691; US 6262267; US 6329388; WO 0000493 . |
| 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) | 23143 | 1-Phenylacetone; Methyl benzyl ketone; Benzyl methyl ketone; phenylacetone; Phenyl-2-propanone | 103-79-7 | C9H10O | 详情 | 详情 |
| (II) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (III) | 23145 | ethyl 2-amino-4-methyl-5-phenyl-3-thiophenecarboxylate | C14H15NO2S | 详情 | 详情 | |
| (IV) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (V) | 23147 | diethyl 2-([[3-(ethoxycarbonyl)-4-methyl-5-phenyl-2-thienyl]amino]methylene)malonate | C22H25NO6S | 详情 | 详情 | |
| (VI) | 23148 | 2-[[3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propenyl]amino]-4-methyl-5-phenyl-3-thiophenecarboxylic acid | C20H21NO6S | 详情 | 详情 | |
| (VII) | 23149 | ethyl 4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine-5-carboxylate | C17H15NO3S | 详情 | 详情 | |
| (VIII) | 58691 | ethyl 4-hydroxy-3-methyl-2-(4-nitrophenyl)thieno[2,3-b]pyridine-5-carboxylate | C17H14N2O5S | 详情 | 详情 | |
| (IX) | 23150 | 2-(chloromethyl)-1,3-difluorobenzene | 697-73-4 | C7H5ClF2 | 详情 | 详情 |
| (X) | 23152 | ethyl 7-(2,6-difluorobenzyl)-3-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H18F2N2O5S | 详情 | 详情 | |
| (XI) | 23153 | ethyl 3-(bromomethyl)-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C24H17BrF2N2O5S | 详情 | 详情 | |
| (XII) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (XIII) | 23155 | ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C32H27F2N3O5S | 详情 | 详情 | |
| (XIV) | 23156 | ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C32H29F2N3O3S | 详情 | 详情 | |
| (XV) | 58692 | ethyl 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate | C34H28F5N3O4S | 详情 | 详情 | |
| (XVI) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XVII) | 58693 | 3-{[benzyl(methyl)amino]methyl}-7-(2,6-difluorobenzyl)-N-methoxy-N-methyl-4-oxo-2-{4-[(2,2,2-trifluoroacetyl)amino]phenyl}-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide | C34H29F5N4O4S | 详情 | 详情 |