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【结 构 式】 
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【分子编号】12642 【品名】Trimethyl phosphite 【CA登记号】121-45-9 |
【 分 子 式 】C3H9O3P 【 分 子 量 】124.076422 【元素组成】C 29.04% H 7.31% O 38.68% P 24.96% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of chlorobenzoyl chloride (I) with trimethyl phosphite gives dimethyl p-chlorobenzoylphosphonate (II). Addition of dimethyl phosphite to (II) in the presence of 80% molar amount of an organic base (e.g., di-n-butylamine) in diethyl ether or toluene at 0 C produces the final compound.
| 【1】 Bentzen, C.L.; Nguyen, M.L.; Niesor, E.; US 4309364 . |
| 【2】 Nguyen, M.L.; Bentzen, C.L.; SR-202. Drugs Fut 1982, 7, 4, 271. |
合成路线2
该中间体在本合成路线中的序号：(VI)The condensation of 2-pyrrolidinone (I) with 2-oxoacetic acid (II) in ethyl ether gives 2-hydroxy-2-(2-oxopyrrolidin-1-yl)acetic acid (III), which is fully methylated with methanol and conc. sulfuric acid to yield 2-methoxy-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (IV). The reaction of (IV) with PCl3 in hot toluene affords 2-chloro-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (V), which is condensed with triethyl phosphite (VI), also in hot toluene, to provide the dimethyl phosphonate (VII). The condensation of (VII) with acetaldehyde (VIII) in THF by means of tetramethylguanidine gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid methyl ester (IX), which is reduced with H2 and a chiral Rhodium catalyst in THF to yield 2(S)-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (X). Finally, this ester is treated with ammonia in methanol to afford the target chiral amide.
| 【1】 Boaz, N.W.; Debenham, S.D.; Highly enantiomerically pure lactam-substd. propanoic acid derivs. and methods of making and using same. WO 0226705 . |
| 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) | 27397 | 2-Pyrrolidinone | 616-45-5 | C4H7NO | 详情 | 详情 |
| (II) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (III) | 61966 | 2-hydroxy-2-(2-oxo-1-pyrrolidinyl)acetic acid | C6H9NO4 | 详情 | 详情 | |
| (IV) | 61967 | methyl 2-methoxy-2-(2-oxo-1-pyrrolidinyl)acetate | C8H13NO4 | 详情 | 详情 | |
| (V) | 61968 | methyl 2-chloro-2-(2-oxo-1-pyrrolidinyl)acetate | C7H10ClNO3 | 详情 | 详情 | |
| (VI) | 12642 | Trimethyl phosphite | 121-45-9 | C3H9O3P | 详情 | 详情 |
| (VII) | 61969 | methyl 2-(dimethoxyphosphoryl)-2-(2-oxo-1-pyrrolidinyl)acetate | C9H16NO6P | 详情 | 详情 | |
| (VIII) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (IX) | 61970 | methyl (E)-2-(2-oxo-1-pyrrolidinyl)-2-butenoate | C9H13NO3 | 详情 | 详情 | |
| (X) | 61971 | methyl (2S)-2-(2-oxo-1-pyrrolidinyl)butanoate | C9H15NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)A new synthesis of efonidipine has been described: The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III), which, by treatment with iodoacetone (IV) in refluxing ether, yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII), which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.
| 【1】 Sakoda, R.; Kamikawaji, Y.; Seto, K.; Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium antagonistic and antihypertensive activities: Novel calcium-antagonist NZ-105 and its crystal structure. Chem Pharm Bull 1992, 40, 9, 2362. |
| 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) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (II) | 12642 | Trimethyl phosphite | 121-45-9 | C3H9O3P | 详情 | 详情 |
| (III) | 12643 | 2-Methoxy-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one | C6H13O4P | 详情 | 详情 | |
| (IV) | 12644 | 1-Iodoacetone | C3H5IO | 详情 | 详情 | |
| (V) | 12645 | 5,5-Dimethyl-2-(2-oxopropyl)-1,3,2lambda(5)-dioxaphosphinan-2-one | C8H15O4P | 详情 | 详情 | |
| (VI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (VII) | 12647 | 2-[(Z)-1-Acetyl-2-(3-nitrophenyl)ethenyl]-5,5-dimethyl-1,3,2lambda(5)-dioxaphosphinan-2-one | C15H18NO6P | 详情 | 详情 | |
| (VIII) | 12648 | 2-(benzylanilino)ethyl (E)-3-amino-2-butenoate | C19H22N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)The reaction of the already reported amide (VIII) with phosphonate salt (XV) gives the succinimide ammonium salt (XVI), which is finally treated with HCl in acetone to yield the target quaternary ammonium chloride derivative. The phosphonate salt (XV) is obtained by reaction of trimethyl phosphite (XVII) with N-chlorosuccinimide (XVIII) in trimethyl phosphate.
| 【1】 Ikemoto, T.; et al.; Convenient efficient synthesis of TAK-779, a nonpeptide CCR5 antagonist: Development of preparation of various ammonium salts using trialkylphosphite and N-halogenosuccinimide. Tetrahedron 2001, 57, 8, 1525. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 55371 | C2H6ClO3P | 详情 | 详情 | |||
| (VIII) | 31567 | 2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C32H36N2O2 | 详情 | 详情 | |
| (XV) | 55369 | C7H13ClNO5P | 详情 | 详情 | ||
| (XVI) | 55370 | C37H43N3O4 | 详情 | 详情 | ||
| (XVII) | 12642 | Trimethyl phosphite | 121-45-9 | C3H9O3P | 详情 | 详情 |
| (XVIII) | 40429 | Succinchlorimide; N-Chlorosuccinimide; 1-chloro-2,5-pyrrolidinedione | 128-09-6 | C4H4ClNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)Bromination of acrylate derivative (I) by means of NBS and AIBN in CCl4 affords (II), which is then converted into (III) by reaction with trimethyl phosphite (A) in toluene. Wittig oxopropenylation of aldehyde (IV) with phosphonium bromide derivative (V) and NaOMe or NaOEt in DMF provides benzaldehyde derivative (VI), which finally reacts with phosphonate (III) and NaH by a Wittig-Horner reaction in THF.
| 【1】 McCoy, R.K.; Spangler, C.W.; Preparation of conjugated aromatic polyenals by witting oxopropenylation. Synth Commun 1988, 18, 1, 51. |
| 【2】 Alzeer, J.; Chollet, J.; Matile, H.; Ridley, R.G.; Hubschwerlen, C.; Heinze-Krauss, I.; Phenyl beta-methoxyacrylates: A new antimalarial pharmacophore. J Med Chem 2000, 43, 4, 560. |
| 【3】 Matile, H.; Chollet, J.; Alzeer, J.; Ridley, R.G.; Hubschwerlen, C. (F. Hoffmann-La Roche AG); beta-Alkoxyacrylates against malaria. EP 0996439; WO 9902150 . |
| 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) | 12642 | Trimethyl phosphite | 121-45-9 | C3H9O3P | 详情 | 详情 |
| (I) | 43523 | methyl (E)-3-methoxy-2-(2-methylphenyl)-2-propenoate | C12H14O3 | 详情 | 详情 | |
| (II) | 43524 | methyl (E)-2-[2-(bromomethyl)phenyl]-3-methoxy-2-propenoate | C12H13BrO3 | 详情 | 详情 | |
| (III) | 43525 | methyl (E)-2-[2-[(dimethoxyphosphoryl)methyl]phenyl]-3-methoxy-2-propenoate | C14H19O6P | 详情 | 详情 | |
| (IV) | 22196 | 2,4-dichlorobenzaldehyde | 874-42-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 43526 | tributyl(1,3-dioxolan-2-ylmethyl)phosphonium bromide | C16H34BrO2P | 详情 | 详情 | |
| (VI) | 43527 | (E)-3-(2,4-dichlorophenyl)-2-propenal | C9H6Cl2O | 详情 | 详情 |