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【结 构 式】 
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【分子编号】29428 【品名】1-bromo-2-butyne 【CA登记号】3355-28-0 |
【 分 子 式 】C4H5Br 【 分 子 量 】132.9877 【元素组成】C 36.13% H 3.79% Br 60.08% |
合成路线1
该中间体在本合成路线中的序号：(II)The alkylation of diethyl n-propylmalonate (I) with 1-bromo-2-butyne (II) in the presence of ethanolic NaOEt afforded the dialkyl malonate (III). Subsequent saponification of the ethyl esters of (III) with KOH gave the corresponding malonic acid (IV), which was decarboxylated at 180 C to yield the title compound.
| 【1】 Hauck, R.-S.; Elmazar, M.M.E.; Nau, H.; Bojic, U.; VPA-analogous antiepileptics. DE 4231085; US 5786380; WO 9406743 . |
合成路线2
该中间体在本合成路线中的序号：(IV)Condensation of pentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone (II) in the presence of n-butyllithium afforded the chiral N-acyl oxazolidinone (III). Subsequent asymetric alkylation of (III) with 1-bromo-2-butyne (IV) using LDA as the base produced the alkylated diastereoisomer (V). The chiral auxiliary oxazolidinone was finally removed by hydrolysis with lithium hydroperoxide to afford the required (R)-carboxylic acid.
| 【1】 Hauck, R.-S.; Elmazar, M.M.E.; Nau, H.; Bojic, U.; VPA-analogous antiepileptics. DE 4231085; US 5786380; WO 9406743 . |
| 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) | 15116 | pentanoyl chloride; valeryl chloride | 638-29-9 | C5H9ClO | 详情 | 详情 |
| (II) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (III) | 29431 | (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (IV) | 29428 | 1-bromo-2-butyne | 3355-28-0 | C4H5Br | 详情 | 详情 |
| (V) | 29432 | (4S)-4-benzyl-3-[(2R)-2-propyl-4-hexynoyl]-1,3-oxazolidin-2-one | C19H23NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)BI-1356 can be synthesized as follows. Cyclization of 2-aminoacetophenone (I) with chloroacetonitrile (II) in the presence of HCl in dioxane gives 2-(chloromethyl)-4-methylquinazoline (III) (1), which can also be prepared by reaction of 2-(chloromethyl)-4-methylquinazoline-3-oxide (IV) with PCl3 in refluxing chloroform (2). Coupling of the quinazoline derivative (III) with 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (V) –prepared by treatment of 8-bromo-3-methylxanthine (VI) with butyn-2-yl bromide (VII) in the presence of TEA or DIEA in DMF (3)–, in the presence of Na2CO3 or K2CO3 provides 1-(4-methylquinazolin-2-ylmethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (VIII). Condensation of bromoxanthine (VIII) with (R)-3-(phthalimido)piperidine D-tartrate (IX) affords the adduct (X), which is deprotected by heating with 2-aminoethanol in either toluene at 85 ºC or in THF at 65 ºC (1). Scheme 1.
The title compound can also be prepared by coupling of the bromoxanthine (VIII) with 3(R)-(tert-butoxycarbonylamino)piperidine (XI) by means of K2CO3 in DMF to give the N-protected piperidine derivative (XII), which is deprotected with TFA in CH2Cl2 (2, 3). Scheme 1.
| 【1】 Pfrengle, W., Pachur, T., Nicola, T., Duran, A. (Boehringer Ingelheim Corp.). Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)xanthines. US 2006142310. |
| 【2】 Himmelsbach, F., Langkopf, E., Eckhardt, M., Mark, M. Maier, R., Lotz, R.R.H., Tadayyon, M. (Boehringer Ingelheim Corp.). 8-[3-Amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions. US 2004097510. |
| 【3】 Eckhardt, M., Langkopf, E., Mark, M. et al. 8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem 2007, 50(26): 6450-3. |
| 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) | 65634 | 2-Aminoacetophenone;2'-Aminoacetophenone; o-Aminoacetophenone; 1-(2-Aminophenyl)ethanone | 551-93-9 | C8H9NO | 详情 | 详情 |
| (II) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (III) | 65635 | 2-(Chloromethyl)-4-methylquinazoline | 109113-72-6 | C10H9ClN2 | 详情 | 详情 |
| (IV) | 65636 | C10H9ClN2O | 详情 | 详情 | ||
| (V) | 65637 | C10H11BrN4O2 | 详情 | 详情 | ||
| (VI) | 65638 | C6H7BrN4O2 | 详情 | 详情 | ||
| (VII) | 29428 | 1-bromo-2-butyne | 3355-28-0 | C4H5Br | 详情 | 详情 |
| (VIII) | 65639 | C20H19BrN6O2 | 详情 | 详情 | ||
| (IX) | 65640 | C14H14N2O2.C4H4O6 | 详情 | 详情 | ||
| (X) | 65641 | C33H32N8O4 | 详情 | 详情 | ||
| (XI) | 65642 | (R)-3-(Boc-Amino)piperidine; (R)-(+)-3-tert-Butoxycarbonylaminopiperidine | 309956-78-3 | C10H20N2O2 | 详情 | 详情 |
| (XII) | 65643 | C30H38N8O4 | 详情 | 详情 |