(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】51591

【品名】(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid

【CA登记号】

【分子式】C₁₀H₁₈N₂O₄

【分子量】230.264

【元素组成】C 52.16% H 7.88% N 12.17% O 27.79%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IX)

(R)-Piperazine-2-carboxylic acid, obtained by resolution of the racemic piperazine (VIII) with (-)-camphorsulfonic acid, was regioselectively protected with Boc-ON at the 4-N atom, yielding the tert-butyl carbamate (IX). Subsequent treatment with cyclohexyl chloroformate (X) produced the bis-carbamate (XI), which was further subjected to selective Boc group cleavage under acidic conditions. The resultant piperazine (XII) was condensed with the tricyclic alkyl chloride (XIII), producing a diastereomeric mixture of N-alkylated adducts from which the required isomer (XIV) was isolated by flash chromatography. Finally, coupling of acid (XIV) with the intermediate amine (VII) by means of EDC and HOBt gave rise to the title compound.

参考文献中间体

合成目标

【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	51590	N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine		C₁₄H₁₉N₃	详情	详情
(VIII)	25933	2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid		C₅H₁₀N₂O₂	详情	详情
(IX)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₀H₁₈N₂O₄	详情	详情
(X)	51592	Carbonochloridic acid, cyclohexyl ester; Cyclohexyl chloroformate	13248-54-9	C₇H₁₁ClO₂	详情	详情
(XI)	51593	(2R)-4-(tert-butoxycarbonyl)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₁₇H₂₈N₂O₆	详情	详情
(XII)	51594	(2R)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₁₂H₂₀N₂O₄	详情	详情
(XIII)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine		C₁₄H₁₁Cl₂N	详情	详情
(XIV)	51595	(2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid		C₂₆H₃₀ClN₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

(S)-Piperazine-2-carboxylic acid (I) was sequentially protected as the 4-Boc derivative (II) and then as the 1-Alloc-4-Boc-piperazine (III). After conversion of (III) to benzyl ester (IV), its N-Boc group was selectively removed by treatment with trifluoroacetic acid. The resultant 4-deprotected piperazine (V) was then alkylated with 3-chloro-3-methyl-1-butyne (VI) yielding (VII). Copper-promoted coupling of 4-hydroxy-3,5-diiodopyridine (IX) prepared by halogenation of 4-hydroxypyridine (VIII) with N-iodosuccinimide with the propargyl piperazine (VII) gave rise to the furo[3,2-c]pyridine derivative (X). The N-Alloc protecting group was then replaced by the N-Boc group to yield (XII) via palladium catalyzed deprotection of (X), followed by treatment of the resultant piperazine (XI) with Boc2O. Simultaneous hydrogenolysis of the benzyl ester and the iodo substituent of (XII) led to acid (XIII). After coupling of (XIII) with 2,2,2-trifluoroethylamine, acidic cleavage of the N-Boc group furnished the piperazine-2-carboxamide (XIV).

参考文献中间体

合成目标

【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 .

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)	16266	(2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid		C₅H₁₀N₂O₂	详情	详情
(II)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₀H₁₈N₂O₄	详情	详情
(III)	56252	(2S)-1-[(allyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid		C₁₄H₂₂N₂O₆	详情	详情
(IV)	56253	1-allyl 2-benzyl 4-(tert-butyl) (2S)-1,2,4-piperazinetricarboxylate		C₂₁H₂₈N₂O₆	详情	详情
(V)	56254	1-allyl 2-benzyl (2S)-1,2-piperazinedicarboxylate		C₁₆H₂₀N₂O₄	详情	详情
(VI)	22416	3-chloro-3-methyl-1-butyne	1111-97-3	C₅H₇Cl	详情	详情
(VII)	56255	1-allyl 2-benzyl (2S)-4-(1,1-dimethyl-2-propynyl)-1,2-piperazinedicarboxylate		C₂₁H₂₆N₂O₄	详情	详情
(VIII)	56256	4-Hydroxypyridine; 4-Pyridinol; 4(1H)-Pyridone; 4-Pyridol; 4-Pyridone; gamma-Pyridone	626-64-2	C₅H₅NO	详情	详情
(IX)	56257	3,5-diiodo-4-pyridinol		C₅H₃I₂NO	详情	详情
(X)	56258	1-allyl 2-benzyl (2S)-4-[1-(7-iodofuro[3,2-c]pyridin-2-yl)-1-methylethyl]-1,2-piperazinedicarboxylate		C₂₆H₂₈IN₃O₅	详情	详情
(XI)	56259	benzyl (2S)-4-[1-(7-iodofuro[3,2-c]pyridin-2-yl)-1-methylethyl]-2-piperazinecarboxylate		C₂₂H₂₄IN₃O₃	详情	详情
(XII)	56260	2-benzyl 1-(tert-butyl) (2S)-4-[1-(7-iodofuro[3,2-c]pyridin-2-yl)-1-methylethyl]-1,2-piperazinedicarboxylate		C₂₇H₃₂IN₃O₅	详情	详情
(XIII)	56261	(2S)-1-(tert-butoxycarbonyl)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-2-piperazinecarboxylic acid		C₂₀H₂₇N₃O₅	详情	详情
(XIV)	56262	(2S)-4-(1-furo[3,2-c]pyridin-2-yl-1-methylethyl)-N-(2,2,2-trifluoroethyl)-2-piperazinecarboxamide		C₁₇H₂₁F₃N₄O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

(R)-Piperazinecarboxylic acid (I) is sequentially protected with 2-(t-butoxycarbonyloxy)imino-2-phenylacetonitrile to produce the 4N-Boc-piperazine (II), and then with cyclohexyl chloroformate, yielding the 1N-cyclohexyl carbamate (III). Selective N-Boc group cleavage in (III) under acidic conditions provides piperazine (IV). This is condensed with the tricyclic chloride (V) to furnish, after chromatographic separation of the isomers, the required intermediate (VI).

参考文献中间体

合成目标

【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 .
【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	16266	(2S)-hexahydro-2-pyrazinecarboxylic acid; (S)-Piperazine-2-carboxylic acid	C₅H₁₀N₂O₂	详情	详情
(II)	51591	(2R)-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid	C₁₀H₁₈N₂O₄	详情	详情
(III)	51593	(2R)-4-(tert-butoxycarbonyl)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₁₇H₂₈N₂O₆	详情	详情
(IV)	51594	(2R)-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₁₂H₂₀N₂O₄	详情	详情
(V)	17936	8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine	C₁₄H₁₁Cl₂N	详情	详情
(VI)	51595	(2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid	C₂₆H₃₀ClN₃O₄	详情	详情

Extended Information