(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol -Drug Synthesis Database

【结构式】

【分子编号】32535

【品名】(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol

【CA登记号】

【分子式】C₁₀H₁₈O₂

【分子量】170.25172

【元素组成】C 70.55% H 10.66% O 18.79%

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：(V)

The hydroboration of allyl bromide (I) with diisopinocampheylborane gives the 3-bromopropylboronic ester (II), which by treatment with acetaldehyde and water yields the boronic acid (III). The reaction of (III) with NaN3 and ethanol affords 3-azidoboronic acid ethyl ester (IV), which is transesterified with optically active pipanediol (V) giving the cyclic ester (VI). The homologation of (VI) with LDA, ZnCl2 and dichloromethane in THF yields the alpha-chlorobutylboronic ester (VII), which is aminated with hexamethyldisylazane (HMDS) and BuLi to provide the silylated alpha-aminoboronic ester (VIII). The desilylation of (VIII) with methanol, and its protection with benzyl chloroformate gives the protected alpha-aminoboronic ester (IX). The hydrogenation of the azido group of (IX) with H2 over PtO2 affords the 4-aminobutylboronic ester (X), which is treated with N,N'-bis(tert-butoxycarbonyl)thiourea (XI), HgCl2 and TEA in DMF to give the guanidine derivative (XII). Finally, this compound is hydrolyzed and deprotected with refluxing 6N HCl.

参考文献中间体

合成目标

【1】 Lebarbier, C.; Carreaux, F.; Carboni, B.; Boucher, J.L.; Synthesis of boronic acid analogs of L-arginine as alternate substrates or inhibitors of nitric oxide synthase. Bioorg Med Chem Lett 1998, 8, 18, 2573.
【2】 Lebarbier, C.; et al.; Synthesis of a boronic acid analogue of L-ornithine. Synthesis 1996, 1371.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(I)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(II)	36654	bis[[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]methyl] 3-bromopropylboronate		C₂₅H₄₄BBrO₂	详情	详情
(III)	36655	3-bromopropylboronic acid		C₃H₈BBrO₂	详情	详情
(IV)	36656	diethyl 3-azidopropylboronate		C₇H₁₆BN₃O₂	详情	详情
(V)	32535	(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol		C₁₀H₁₈O₂	详情	详情
(VI)	36657	3-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]propyl azide; (1S,2R,6S,8S)-4-(3-azidopropyl)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₃H₂₂BN₃O₂	详情	详情
(VII)	36658	(4S)-4-chloro-4-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl azide; (1S,2R,6S,8S)-4-[(1S)-4-azido-1-chlorobutyl]-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₄H₂₃BClN₃O₂	详情	详情
(VIII)	36659	N-[(1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl](trimethyl)-N-(trimethylsilyl)silanamine; N-[(1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N,N-bis(trimethylsilyl)amine		C₂₀H₄₁BN₄O₂Si₂	详情	详情
(IX)	36660	benzyl (1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate		C₂₂H₃₁BN₄O₄	详情	详情
(X)	36661	benzyl (1R)-4-amino-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate		C₂₂H₃₃BN₂O₄	详情	详情
(XI)	21843	tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate	145013-05-4	C₁₁H₂₀N₂O₄S	详情	详情
(XII)	36662	benzyl (1R)-4-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate		C₃₃H₅₁BN₄O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The preparation of the intermediate aminoboronate (VII) is shown in Scheme 27968701a. Addition of catecholborane (II) to allyl bromide (I) provided boronic ester (III). Subsequent exchange with (+)-alpha-pinanediol (IV) afforded the chiral borane (V). Insertion of dichloromethyllithium in (V) produced the alpha-chloroboronic ester (VI). The required amino compound was then obtained by displacement of the halogen with lithium hexamethyldisilazide, followed by acid-catalyzed desilylation.

参考文献中间体

合成目标

【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201.

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)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(II)	32533	1,3,2-benzodioxaborole	274-07-7	C₆H₅BO₂	详情	详情
(III)	35558	2-(3-bromopropyl)-1,3,2-benzodioxaborole		C₉H₁₀BBrO₂	详情	详情
(IV)	32535	(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol		C₁₀H₁₈O₂	详情	详情
(V)	35559	(1R,2S,6R,8R)-4-(3-bromopropyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₃H₂₂BBrO₂	详情	详情
(VI)	35560	(1R,2S,6R,8R)-4-[(1S)-4-bromo-1-chlorobutyl]-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₄H₂₃BBrClO₂	详情	详情
(VII)	35561	(1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-butanamine; (1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylamine		C₁₄H₂₅BBrNO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Coupling of 4-bromo-1-butene (I) with catecholborane (II) afforded the bromobutyl boronate (III). Subsequent exchange of (III) with alpha-pinanediol (IV) produced (V), which was regioselectively chlorinated to give (VI). Displacement of the chlorine atom of (VI) with lithium hexamethyldisilazide, followed by acid treatment furnished intermediate (VII).

参考文献中间体

合成目标

【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	34273	N,N-bis(trimethylsilyl)amine; trimethyl-N-(trimethylsilyl)silanamine	999-97-3	C₆H₁₉NSi₂	详情	详情
(I)	11720	4-Bromo-1-butene	5162-44-7	C₄H₇Br	详情	详情
(II)	32533	1,3,2-benzodioxaborole	274-07-7	C₆H₅BO₂	详情	详情
(III)	32534	2-(4-bromobutyl)-1,3,2-benzodioxaborole		C₁₀H₁₂BBrO₂	详情	详情
(IV)	32535	(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol		C₁₀H₁₈O₂	详情	详情
(V)	32536	(1R,2S,6R,8R)-4-(5-bromopentyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₅H₂₆BBrO₂	详情	详情
(VI)	32537	(1R,2S,6R,8R)-4-[(1R)-5-bromo-1-chloropentyl]-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₅H₂₅BBrClO₂	详情	详情
(VII)	32538	(1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-pentanamine; (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentylamine		C₁₅H₂₇BBrNO₂	详情	详情

Extended Information