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【结 构 式】 
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【分子编号】25964 【品名】1-[(isothiocyanatocarbonyl)oxy]ethane 【CA登记号】16182-04-0 |
【 分 子 式 】C4H5NO2S 【 分 子 量 】131.15524 【元素组成】C 36.63% H 3.84% N 10.68% O 24.4% S 24.45% |
合成路线1
该中间体在本合成路线中的序号：(III)The selective monoprotection of 4-(4-piperidyl)piperidine (I) gives the carbamate (II), which is condensed with the isothiocyante (III) in chloroform to yield the N-(ethoxycarbonyl)carbothioamide (IV). Decarboxylation of (IV) by means of NaOH in ethanol affords the free thioamide (V), which is cyclized with 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (VI) by means of triethylamine in ethanol to provide the thiazole derivative (VII). Hydrolysis of theester group of (VII) with NaOH in ethanol gives the carboxylic acid (VIII), which is condensed with 3-amino-2(S)-(phenylsulfonamido)propionic acid methyl ester (IX), by means of DCC, HOBT and triethylamine in DMF yielding the protected target compound (X). Finally, this compound is hydrolyzed and deprotected by a treatment with HCl in ethanol. The intermediate 3-amino-2(S)-(phenylsulfonamido)propionic acid methyl ester (IX) has been obtained as follows: The reaction of L-asparagine (XI) with benzenesulfonyl chloride (XII) by means of NaOH in dioxane/water gives the sulfonated asparagine (XIII), which is submitted to Hofmann degradation with Br2 and NaOH in water and finally esterified with SOCl2 and methanol.
| 【1】 Forn, J.; Merlos, M.; Garcia-Rafanell, J.; Carceller, E.; Gomez, L.A.; Novel N-(thiazolyl-5-carbonyl)-beta-alanine derivatives as potent, orally active fibrinogen receptor antagonists. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 079. |
| 【2】 Carceller, E.; Jimenez, P.J.; Salas, J. (J. Uriach & Cia., SA); Novel carboxamides as platelet aggregation inhibitors. WO 9846599 . |
| 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) | 25962 | 4,4'-bipiperidine | C10H20N2 | 详情 | 详情 | |
| (II) | 25963 | 4,4'-bipiperidine-1-carboxylic acid tert-butyl ester | C15H28N2O2 | 详情 | 详情 | |
| (III) | 25964 | 1-[(isothiocyanatocarbonyl)oxy]ethane | 16182-04-0 | C4H5NO2S | 详情 | 详情 |
| (IV) | 25965 | N-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl-thiocarbonyl]carbamic acid ethyl ester | C19H33N3O4S | 详情 | 详情 | |
| (V) | 25966 | 1'-(Tert-butoxycarbonyl)-4,4'-bipiperidine-1-carbothioamide | C16H29N3O2S | 详情 | 详情 | |
| (VI) | 25967 | ethyl 2-chloro-4-methyl-3-oxopentanoate | C8H13ClO3 | 详情 | 详情 | |
| (VII) | 25968 | 2-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]-4-isopropylthiazole-5-carboxylic acid ethyl ester | C24H39N3O4S | 详情 | 详情 | |
| (VIII) | 25969 | 2-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]-4-isopropylthiazole-5-carboxylic acid | C22H35N3O4S | 详情 | 详情 | |
| (IX) | 25970 | methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate | C10H14N2O4S | 详情 | 详情 | |
| (X) | 25971 | (2(S)-(Benzenesulfonamido)-3-[2-[4-[1-tert-butoxycarbonyl)piperidin-4-yl]piperidin-4-yl]-4-isopropylthiazol-5-ylcarboxamido]propionic acid methyl ester; (2(S)-(Benzenesulfonamido)-3-[2-[4-[1-tert-butoxycarbonyl)piperidin-4-yl]piperidin-4-yl]-4-isopropylthiazol-5-ylcarboxamido]propionic acid methyl ester | C32H47N5O7S2 | 详情 | 详情 | |
| (XI) | 25972 | S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine | 70-47-3 | C4H8N2O3 | 详情 | 详情 |
| (XII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (XIII) | 25973 | (2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid | C10H12N2O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of 2-amino-6-bromopyridine (I) with ethoxycarbonyl isothiocyanate (II) in CH2Cl2 gives 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl) thiourea (III), which by cyclization with hydroxylamine hydrochloride (IV) in the presence of DIEA in EtOH/MeOH yields 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine (V). N-Acylation of amine (V) with cyclopropanecarbonyl chloride (VI) using Et3N in acetonitrile, and subsequent treatment with methanolic ammonia, results in the carboxamide (VII) . Suzuki coupling of compound (VII) with 4-(hydroxymethyl)phenylboronic acid (VIII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C, followed by bromination with PBr3 in CHCl3, affords the benzyl bromide intermediate (IX), which is finally condensed with thiomorpholine-1,1-dioxide (X) using DIEA in CH2Cl2/MeOH .
Alternatively, condensation of (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (XI) with thiomorpholine 1,1-dioxide (X) by means of DIEA in CH2Cl2/MeOH gives intermediate (XII), which finally undergoes Suzuki coupling with aryl bromide (VII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C .
| 【1】 Menet, C.J.M., Smits, K.K. (Galapagos NV). 5-Phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl carboxamides as JAK inhibitors. CN 102482273, EP 2445911, JP 2012530766, KR 2012107919, US 201331319, US 8088764, WO 2010149769. |
| 【2】 Menet, C.J.M., Smits, K.K. (Galapagos NV). Novel compound useful for the treatment of degenerative and inflammatory diseases. US 2012142678, US 8563545. |
| 【3】 Van ‘t Klooster, G.A.E., Brys, R.C.X., Van Rompaey, L.J.C., Namour, F.S. (Galapagos NV). Aminotriazolopyridine for use in the treatment of inflammation, and pharmaceutical composition thereof. US 2013345209, WO 2013189771. |
| 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) | 41341 | 2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine | 19798-81-3 | C5H5BrN2 | 详情 | 详情 |
| (II) | 25964 | 1-[(isothiocyanatocarbonyl)oxy]ethane | 16182-04-0 | C4H5NO2S | 详情 | 详情 |
| (III) | 67818 | 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea | C9H10BrN3O2S | 详情 | 详情 | |
| (IV) | 65957 | Hydroxylamine hydrochloride; Hydroxylammonium chloride; Oxammonium hydrochloride | 5470-11-1 | H3NO.HCl | 详情 | 详情 |
| (V) | 67819 | 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine | C6H5BrN4 | 详情 | 详情 | |
| (VI) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (VII) | 67820 | N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide | C10H9BrN4O | 详情 | 详情 | |
| (VIII) | 67821 | 4-(hydroxymethyl)phenylboronic acid | 59016-93-2 | C7H9BO3 | 详情 | 详情 |
| (IX) | 67822 | N-(5-(4-(bromomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide | C17H15BrN4O | 详情 | 详情 | |
| (X) | 67823 | thiomorpholine-1,1-dioxide | 39093-93-1 | C4H9NO2S | 详情 | 详情 |
| (XI) | 67824 | (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane | 138500-85-3 | C13H18BBrO2 | 详情 | 详情 |
| (XII) | 67825 | 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1-dioxide | C17H26BNO4S | 详情 | 详情 |