5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine -Drug Synthesis Database

【结构式】

【分子编号】68102

【品名】5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine

【CA登记号】402960-38-7

【分子式】C₁₀H₁₆BN₃O₂

【分子量】221.067

【元素组成】C 54.33% H 7.30% B 4.89% N 19.01% O 14.47%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIII)

Cyclocondensation of ethyl 3-amino-4-methyl-2-thiophenecarboxylate (I) with urea (II) at 190 °C gives 7-methylthieno[3,2-d]pyrimidine-2,4-dione (III), which is chlorinated with POCl3 at reflux to yield 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (IV). Condensation of compound (IV) with morpholine (V) in MeoH affords 2-chloro-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidine (VI) , which, after metalation with BuLi in THF, is formylated with DMF, providing the thieno[3,2-d]pyrimidine-6-carbaldehyde derivative (VII) . Reductive amination of aldehyde (VII) with N-Boc-piperazine (VIII) in the presence of HC(oMe)3, AcoH and naBH(oAc)3 in dichloroethane gives the piperazinylmethyl derivative (IX) , which by cleavage of the Boc moiety by means of HCl in CH2Cl2 produces the N-deprotected piperazine derivative (X). N-Acylation of compound (X) with (S)-lactic acid (XI) in the presence of HATU and DIEA in DMF generates the corresponding amide (XII), which is finally submitted to Suzuki coupling with the boronate ester (XIII) in the presence of PdCl2(PPh3)4 and Na2CO3 or K2CO3 in acetonitrile .
Alternatively, Suzuki coupling of chloro intermediate (IX) with boronate ester (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in acetonitrile under microwave irradiation produces the 2-aminopyrimidine derivative (XIV), which is then N-deprotected by means of HCl in CH2Cl2 to yield the free piperazine derivative (XV). Finally, piperazine derivative (XV) is condensed with (S)-lactic acid (XI) in the presence of DIEA and HATU in DMF .

参考文献中间体

合成目标

【1】 Belvin, M., Friedman, L., Hoeflich, K. et al. (Genentech, Inc.; F. Hoffmann-La Roche AG). Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use. Cn 101939006, EP 2205242, JP 2010539177, KR 2010085912, US 2011223619, US 8247397, Wo 2009036082.
【2】 Ebens, A.J. Jr., Friedman, L. (Genentech, Inc.). Combination of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic a gents for the treatment of hematopoietic malignancies. Cn 102369011, EP 2405916, JP 2012520313, KR 2011132442, US 2010233164, US 8536161, Wo 2010105008.
【3】 Sutherlin, D.P., Bao, L., Berry, M. et al. Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/Mammalian target of rapamycin (mTOR) kinase inhibitor. J Med Chem 2011, 54(21): 7579-87.
【4】 Bayliss, T., Chuckowree, I., Folkes, A. et al. (Genentech, Inc.; F. Hoffmann-La Roche AG). Phosphoinositide 3-kinase inhibitor compounds and methods of use. CA 2671782, EP 2114949, EP 2518074, JP 2010512338, US 2008242665, US 7888352, US 8383620, US 2013129820, WO 2008070740.

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)	68092	ethyl 3-amino-4-methyl-2-thiophenecarboxylate		C₈H₁₁NO₂S	详情	详情
(II)	19310	urea	57-13-6	CH₄N₂O	详情	详情
(III)	68093	7-methylthieno[3,2-d]pyrimidine-2,4-dione	35265-81-7	C₇H₆N₂O₂S	详情	详情
(IV)	68094	2,4-dichloro-7-methylthieno[3,2-d]pyrimidine	35265-83-9	C₇H₄Cl₂N₂S	详情	详情
(V)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(VI)	68095	4-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)morpholine;2-chloro-7-methyl-4-(4-morpholinyl)thieno[3,2-d]pyrimidine		C₁₁H₁₂ClN₃OS	详情	详情
(VII)	68096	2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde		C₁₂H₁₂ClN₃O₂S	详情	详情
(VIII)	68097	tert-butyl piperazine-1-carboxylate	143238-38-4	C₉H₁₈NO₂	详情	详情
(IX)	68098	tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate		C₂₁H₃₀ClN₅O₃S	详情	详情
(X)	68099	4-(2-chloro-7-methyl-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine hydrochloride		C₁₆H₂₂ClN₅OS.HCl	详情	详情
(XI)	68100	(S)-lactic acid;(S)-2-hydroxypropanoic acid		C₃H₆O₃	详情	详情
(XII)	68101	(S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one		C₁₉H₂₆ClN₅O₃S	详情	详情
(XIII)	68102	5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine	402960-38-7	C₁₀H₁₆BN₃O₂	详情	详情
(XIV)	68103	tert-butyl 4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate		C₂₅H₃₄N₈O₃S	详情	详情
(XV)	68104	5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine		C₂₀H₂₆N₈OS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

The key intermediate (XIII) is prepared by N-protection of 5-bromopyrimidin-2-amine (XVI) with Boc2o by means of DMAP in DMF to give N,N-di-Boc-5-bromopyrimidin-2-amine (XVII), which by metalation with BuLi in THF, followed by borylation with (i-Pro)3B provides the pyrimidin-5-ylboronic acid derivative (XVIII). Hydrolysis of protected amine (XVIII) with methanolic HCl affords 2-aminopyrimidin-5-ylboronic acid (IV), which is finally cyclized with pinacol (XX) in refluxing toluene or xylene .

参考文献中间体

合成目标

【1】 Xu, J., Lai, W., Yang, B., Gu, S. (Jiangsu ChemFuture Pharma Tech. Co., Ltd.). Synthesis method of 2-amino-5-pyridineboronic acid pinacol ester. Cn 102399235

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	68102	5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine	402960-38-7	C₁₀H₁₆BN₃O₂	详情	详情
(XVI)	34822	5-bromo-2-pyrimidinamine; 5-bromo-2-pyrimidinylamine	7752-82-1	C₄H₄BrN₃	详情	详情
(XVII)	68105	N,N-di-Boc-5-bromopyrimidin-2-amine;Imidodicarbonicacid, 2-(5-bromo-2-pyrimidinyl)-, 1,3-bis(1,1-dimethylethyl) ester;Imidodicarbonicacid, (5-bromo-2-pyrimidinyl)-, bis(1,1-dimethylethyl) ester (9CI);(5-Bromopyrimidin-2-yl)bis(tert-butoxycarbonyl)amine	209959-33-1	C₁₄H₂₀BrN₃O₄	详情	详情
(XVIII)	68106			C₁₄H₂₂BN₃O₆	详情	详情
(XIX)	68107	(2-aminopyrimidin-5-yl)boronic acid		C₄H₆BN₃O₂	详情	详情
(XX)	68108	2,3-Dimethyl-2,3-butanediol;2,3-Dimethylbutane-2,3-diol;Tetramethylethylene glycol;pinacol	76-09-5	C₆H₁₄O₂	详情	详情

Extended Information