|
【结 构 式】 
|
【分子编号】13149 【品名】1-(Chloromethoxy)ethane; Chloromethyl ethyl ether 【CA登记号】3188-13-4 |
【 分 子 式 】C3H7ClO 【 分 子 量 】94.54068 【元素组成】C 38.11% H 7.46% Cl 37.5% O 16.92% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of diketene (I) with 2-bromoethanol (II) by means of dimethylaminopyridine (DMAP) in dichloromethane gives acetoacetic acid 2-bromoethyl ester (III), which is condensed with 3-nitrobenzaldehyde (IV) by means of piperidine acetate in isopropanol yielding the corresponding 3-nitrobenzylidene derivative (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) by heating at 80 C affords 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-bromoethyl) 5-methyl diester (VII), which is condensed with chloromethyl ethyl ether (VIII) by means of NaH in THF to afford the corresponding 1-ethoxymethyl derivative (IX). The reaction of diester (IX) with NaCN and tetrabutylammonium cyanide or sodium p-toluenesulfonate and benzyltriethylammonium chloride (BTEACl) in DMF gives 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (X). The optical resolution of (X) through the cinchonidine salt yields, after crystallization, the cinchonidine salt of the (R)-enantiomer (XI), which is treated with HCl to eliminate the cinchonidine, and esterified with 1,3-dibromopropane and K2CO3 in acetone to afford (R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-bromopropyl) 5-methyl diester (XII). Finally, this compound is condensed with 4,4-diphenylpiperidine (XIII) by means of K2CO3 in DMF at 100 C.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Dexniguldipine hydrochloride. Drugs Fut 1997, 22, 2, 114. |
| 【2】 Amschler, H.; Flockerzi, D.; Klemm, K.; Kohl, B.; Eistetter, K.; Eltze, M.; Kolassa, N.; Sanders, K.; Schudt, C. (Byk Gulden Lomberg Chemische Fabrik GmbH); 1,4-Dihydropyridine enantiomers. AU 8816264; EP 0296316; EP 0343193; WO 8807525 . |
| 【3】 Klemm, K.; Ulrich, W.-R.; Flockerzi, D.; Sanders, K.; Beller, K.-D. (Byk Gulden Lomberg Chemische Fabrik GmbH); Optically pure (R)-(-)-niguldipine and its derivs. for treating tumor diseases. WO 8907443 . |
| 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) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (III) | 13144 | 2-bromoethyl 3-oxobutanoate | C6H9BrO3 | 详情 | 详情 | |
| (IV) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 13146 | 2-bromoethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C13H12BrNO5 | 详情 | 详情 | |
| (VI) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VII) | 63539 | 3-(2-bromoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C18H19BrN2O6 | 详情 | 详情 | |
| (VIII) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (IX) | 13150 | 3-(2-bromoethyl) 5-methyl 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C21H25BrN2O7 | 详情 | 详情 | |
| (X) | 13151 | 1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (XI) | 12671 | (4S)-1-(Ethoxymethyl)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C19H22N2O7 | 详情 | 详情 | |
| (XII) | 13153 | 3-(3-bromopropyl) 5-methyl (4R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H21BrN2O6 | 详情 | 详情 | |
| (XIII) | 13154 | 4,4-Diphenylpiperidine | C17H19N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of the silylated 5-isopropylpyrimidine (I) with chloromethyl ethyl ether (II) by means of KI in dichloromethane gives 1-(ethoxymethyl)-5-isopropyl-2-thiouracil (III), which is condensed with benzaldehyde (IV) by means of lithium diisopropylamide (LDA) in THF, and desulfurized by reaction with H2O2 and NaOH in water to afford 1-(ethoxymethyl)-5-isopropyl-6-(alpha-hydroxybenzyl)uracil (V). The reaction of (V) with acetic anhydride and pyridine gives the acetate (VI), which is finally submitted to hydrogenolysis with H2 over Pd/C in acetic acid/water/dioxane.
| 【1】 Walker, R.T.; Baba, M.; De Clerq, E.; Takashima, H.; Inouye, N.; Ubasawa, M.; Miyasaka, T.; Sekiya, K.; Shigeta, S.; Tanaka, H.; Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. J Med Chem 1995, 38, 15, 2860. |
| 【2】 Ubasawa, M.; Tanaka, H.; Walker, R.T.; Yuasa, S.; Miyasaka, T.; De Clerq, E.; Baba, M.; HEPT derivatives: 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442). Nucleosides Nucleotides 1995, 14, 3-5, 575. |
| 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) | 27025 | 5-isopropyl-4-[(trimethylsilyl)methyl]-2-[(trimethylsilyl)sulfanyl]pyrimidine | C14H28N2SSi2 | 详情 | 详情 | |
| (II) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (III) | 27026 | 1-(ethoxymethyl)-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C10H16N2O2S | 详情 | 详情 | |
| (IV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (V) | 27027 | 1-(ethoxymethyl)-6-[hydroxy(phenyl)methyl]-5-isopropyl-2,4(1H,3H)-pyrimidinedione | C17H22N2O4 | 详情 | 详情 | |
| (VI) | 27028 | [3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl](phenyl)methyl acetate | C19H24N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 5-isopropyluracil (VII) with chloromethyl ethyl ether (II) by means of bis(trimethylsilyl)acetamide (BSA) and tetrabutylammonium iodide (TBI) in dichloromethane gives 1-(ethoxy-methyl)-5-isopropyluracil (VIII)(3), which is then condensed with benzaldehyde (IV) by means of LDA in THF to afford 1-(ethoxymethyl)-5-isopropyl-6-(alpha-hydroxybenzyl)uracil (V), already obtained.
| 【1】 Ubasawa, M.; Yuasa, S. (Mitsubishi Chemical Corp.); Antiviral combinations of 2',3'-dideoxyribonucleosides with 6-benzyl-1-ethoxymethyl-5-substd. uracil derivs.. EP 0631783; JP 1995097324 . |
| 【2】 Ubasawa, M.; et al. (Mitsubishi Chemical Corp.); Production of 6-aralkyl substituted pyrimidine derivative. JP 1996003143 . |
| 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) | 27029 | trimethylsilyl 4-[(trimethylsilyl)methyl]-2-pyrimidinyl sulfide | C11H22N2SSi2 | 详情 | 详情 | |
| (II) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (IV) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (V) | 27027 | 1-(ethoxymethyl)-6-[hydroxy(phenyl)methyl]-5-isopropyl-2,4(1H,3H)-pyrimidinedione | C17H22N2O4 | 详情 | 详情 | |
| (VI) | 27028 | [3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl](phenyl)methyl acetate | C19H24N2O5 | 详情 | 详情 | |
| (VII) | 27030 | 5-isopropyl-2,4(1H,3H)-pyrimidinedione | C7H10N2O2 | 详情 | 详情 | |
| (VIII) | 27031 | 1-(ethoxymethyl)-5-isopropyl-2,4(1H,3H)-pyrimidinedione | C10H16N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The condensation of ethyl 2-bromo-3-methylbutyrate (IX) with phenylacetonitrile (X) by means of activated Zn in THF gives the ethyl 2-isopropyl-3-oxo-4-phenylbutyrate (XI), which is cyclized with thiourea (XII) by means of sodium ethoxide in refluxing ethanol yielding 6-benzyl-5-isopropyl-2-thioracil (XIII). The desulfurization of (XIII) with a refluxing solution of 10% chloroacetic acid in water affords the corresponding uracil (XIV), which is finally alkylated with chloromethyl ethyl ether (II) and BSA in chloroform.
| 【1】 Larsen, D.K.; et al.; Synthesis and potent anti-HIV-1 activity of novel 6-benzyluracil analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J Med Chem 1996, 39, 12, 2427. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (IX) | 27032 | 2-Bromoisovalerianic acid ethyl ester; ethyl 2-bromo-3-methylbutanoate | 609-12-1 | C7H13BrO2 | 详情 | 详情 |
| (X) | 17046 | Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide | 140-29-4 | C8H7N | 详情 | 详情 |
| (XI) | 27033 | ethyl 2-isopropyl-3-oxo-4-phenylbutanoate | C15H20O3 | 详情 | 详情 | |
| (XII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (XIII) | 27034 | 6-benzyl-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C14H16N2OS | 详情 | 详情 | |
| (XIV) | 27035 | 6-benzyl-5-isopropyl-2,4(1H,3H)-pyrimidinedione | C14H16N2O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXV)In a different approach, the precursor aldehyde (XVII) was obtained by addition of the Grignard reagent prepared from chloromethyl ethyl ether (XXV) to acetophenone (XIV), and then rearrangement of the resultant ethoxy alcohol (XXVI) in refluxing AcOH
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 62689 | 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone | C13H12OS | 详情 | 详情 | |
| (XVIII) | 62692 | 2-[4-(3-methyl-2-thienyl)phenyl]propanal | C14H14OS | 详情 | 详情 | |
| (XXV) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (XXVI) | 62699 | 1-ethoxy-2-[4-(3-methyl-2-thienyl)phenyl]-2-propanol | C16H20O2S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)Coupling of 4(S)-amino-4-carboxybutyric acid methyl ester (I) to acyl chloride (II) by means of Et3N in CH2Cl2 provides derivative (III), which is then converted into hydroxy derivative (IV) by means of N-hydroxysuccinimide (A) and DCC in THF followed by reduction with NaBH4 in H2O. Treatment of (IV) with ethoxymethylchloride (V) and DIEA in CH2Cl2 affords compound (VI), which is then methylated by means of lithium bis(trimethylsilyl)amide and methyl iodide in THF to give derivative (VII). Saponification of methyl ester (VII) by treatment with aqueous NaOH in THF affords carboxylic acid (VIII), which is then coupled to N-(1-methoxy-1,1-dimethyloxy)amine (IX) by means of HOBt and EDC in DMF and finally hydrolyzed with HCl in MeOH to furnish the target compound.
| 【1】 Sugiura, T.; Takahashi, K. (Ono Pharmaceutical Co., Ltd.); Aminobutanoic acid derivs.. EP 1024134; WO 9919296 . |
| 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) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (I) | 44795 | (2S)-2-amino-5-methoxy-5-oxopentanoic acid | 1499-55-4 | C6H11NO4 | 详情 | 详情 |
| (II) | 44796 | 4-phenoxybenzoyl chloride | C13H9ClO2 | 详情 | 详情 | |
| (III) | 44797 | (2S)-5-methoxy-5-oxo-2-[(4-phenoxybenzoyl)amino]pentanoic acid | C19H19NO6 | 详情 | 详情 | |
| (IV) | 44798 | methyl (4S)-5-hydroxy-4-[(4-phenoxybenzoyl)amino]pentanoate | C19H21NO5 | 详情 | 详情 | |
| (V) | 13149 | 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether | 3188-13-4 | C3H7ClO | 详情 | 详情 |
| (VI) | 44799 | methyl (4S)-5-(ethoxymethoxy)-4-[(4-phenoxybenzoyl)amino]pentanoate | C22H27NO6 | 详情 | 详情 | |
| (VII) | 44800 | methyl (2S,4S)-5-(ethoxymethoxy)-2-methyl-4-[(4-phenoxybenzoyl)amino]pentanoate | C23H29NO6 | 详情 | 详情 | |
| (VIII) | 44801 | (2S,4S)-5-(ethoxymethoxy)-2-methyl-4-[(4-phenoxybenzoyl)amino]pentanoic acid | C22H27NO6 | 详情 | 详情 | |
| (IX) | 44802 | 2-(aminooxy)-2-methoxypropane; O-(1-methoxy-1-methylethyl)hydroxylamine | C4H11NO2 | 详情 | 详情 |