[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol -Drug Synthesis Database

【结构式】

【分子编号】51423

【品名】[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol

【CA登记号】

【分子式】C₁₀H₁₆O

【分子量】152.23644

【元素组成】C 78.9% H 10.59% O 10.51%

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：(VI)

In an alternative method, (-)-myrtenol (VI) was heated with triethyl orthoacetate to produce an intermediate allyl vinyl ether (VII), which underwent Claisen rearrangement to the unsaturated ester (VIII). Ozonization of the olefin (VIII), followed by reductive treatment with trimethyl phosphite, furnished ketone (IX). Conversion of ketone (IX) into the required amine (XI) was effected via previous formation of either the oxime (XII) or the O-methyl oxime (X). Simultaneous reduction of the O-methyl oxime and ester functions of (X) was carried out by using NaBH4 in the presence of AlCl3 or, alternatively, with sodium metal and n-propanol, to produce the desired (2R,3R)-amino alcohol (XI) as the major diastereoisomer. Isolation of (XI) from the reaction mixture was achieved through formation of the corresponding benzoate salt. Amino alcohol (XI) was also obtained by reduction of oxime (XII) with NaBH4 in the presence of either boron trifluoride ethearate or TiCl4. Optionally, (X) was reduced in a two-step process by first conversion to alcohol (XIII) and subsequent reduction of the oxime function. Acid chloride (XIV) was prepared from 5-hydroxybenzothiophene-3-carboxylic acid (I) by sulfonylation of the phenolic hydroxyl with benzenesulfonyl chloride, followed by treatment with SOCl2. Condensation of acid chloride (XIV) with amine (XI) produced the corresponding amide (XV). The alcohol function of (XV) was oxidized to aldehyde (XVI) using NaOCl in the presence of catalytic amounts of TEMPO and KBr. Then Wittig condensation of aldehyde (XVI) with (4-carboxybutyl)triphenylphosphonium bromide (XVII), followed by basic hydrolysis of the phenylsulfonyl protecting group, gave rise to the title compound.

参考文献中间体

合成目标

【1】 Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.; Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem 1997, 40, 22, 3504.
【2】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 .
【3】 Arimura, A. (Shionogi & Co. Ltd.); Remedies for itching containing PGD2 antagonists. EP 1084711; WO 9962555 .
【4】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 .

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)	52240	5-hydroxy-1-benzothiophene-3-carboxylic acid		C₉H₆O₃S	详情	详情
(VI)	51423	[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol		C₁₀H₁₆O	详情	详情
(VII)	52245	(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl 1-(ethyloxy)ethenyl ether; 2-({[1-(ethyloxy)ethenyl]oxy}methyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene		C₁₄H₂₂O₂	详情	详情
(VIII)	52246	ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate		C₁₄H₂₂O₂	详情	详情
(IX)	52247	ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate		C₁₃H₂₀O₃	详情	详情
(X)	52248	ethyl 2-{6,6-dimethyl-2-[(methyloxy)imino]bicyclo[3.1.1]hept-3-yl}acetate		C₁₄H₂₃NO₃	详情	详情
(XI)	52250	2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol		C₁₁H₂₁NO	详情	详情
(XII)	52251	ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate		C₁₃H₂₁NO₃	详情	详情
(XIII)	52249	3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime		C₁₂H₂₁NO₂	详情	详情
(XIV)	52252	3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate		C₁₅H₉ClO₄S₂	详情	详情
(XV)	52253	3-({[3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate		C₂₆H₂₉NO₅S₂	详情	详情
(XVI)	52254	3-({[6,6-dimethyl-3-(2-oxoethyl)bicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate		C₂₆H₂₇NO₅S₂	详情	详情
(XVII)	37404	(3-carboxypropyl)(triphenyl)phosphonium bromide	17857-14-6	C₂₂H₂₂BrO₂P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIII)

The precursor amino alcohol (XXVIII) was prepared by the following synthetic routes. Claisen orthoester rearrangement of (-)-myrtenol (XXIII) with triethyl orthoacetate at 165-195 C afforded the gamma,delta-unsaturated ester (XXIV). Subsequent ozonolysis of the exocyclic double bond gave rise to keto ester (XXV). Alternatively, keto ester (XXV) was obtained as the major diastereoisomer by alkylation of the lithium enolate of (R)-(+)-nopinone (XXVI) with ethyl bromoacetate in the presence of 1,3-dimethyl-2-imidazolidinone (DMI). Ketone (XXV) was either converted to oxime (XXVI) or to O-methyl oxime (XXVII) by treatment with hydroxylamine or O-methyl hydroxylamine, respectively. Reduction of the hydroxyimino and ester groups of (XXVI) to the key amino alcohol intermediate (XXVIII) was performed by using the combination LiAlH4/AlCl3 or with NaBH4 in the presence of several Lewis acids. The O-methyl oxime (XXVII) was directly reduced to amino alcohol (XXVIII) employing NaBH4 in the presence of boron trifluoride etherate or AlCl3 or, alternatively, with sodium metal in n-propanol. Optionally, the oxime ester (XXVII) was converted to (XXVIII) in a two step procedure, by first reduction of the ester group to alcohol (XXIX) with sodium bis(2-methoxyethoxy)aluminium hydride, and then reduction of the O-methyl oxime with sodium in n-propanol.

参考文献中间体

合成目标

【1】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 .
【2】 Hiramatsu, Y.; Honma, T.; Mitsumori, S. (Shionogi & Co. Ltd.); Novel process for producing bicyclic amino alcohol. EP 1193243; WO 0102334 .
【3】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(A)	60678	(1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one		C₉H₁₄O	详情	详情
(XXIII)	51423	[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol		C₁₀H₁₆O	详情	详情
(XXIV)	52246	ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate		C₁₄H₂₂O₂	详情	详情
(XXV)	52247	ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate		C₁₃H₂₀O₃	详情	详情
(XXVI)	52251	ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate		C₁₃H₂₁NO₃	详情	详情
(XXVII)	52246	ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate		C₁₄H₂₂O₂	详情	详情
(XXVIII)	52250	2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol		C₁₁H₂₁NO	详情	详情
(XXIX)	60679	(1R,3R,5R)-3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime		C₁₂H₂₁NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XV)

The intermediate 4-hydroxy-myrtenyl pivalate (XIII) has been obtained as follows: The reaction of (1R,5S)-myrtenol (XV) with pivaloyl chloride (XVI) and pyridine in dichloromethane gives the pivalate ester (XVII), which by an allylic oxidation with CrO3 and 3,5-dimethylpyrazole in dichloromethane yields 4-oxo-myrtenyl pivalate (XVIII). Finally, this compound is reduced with LiAlH(OBu)3 in THF to afford the target 4-hydroxy-myrtenyl pivalate (XIII) intermediate.

参考文献中间体

合成目标

【1】 Huffman, J.W.; Liddle, J.; Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC, a very potent CB1 agonist. Tetrahedron 2001, 57, 36, 7607.

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)	24407	[(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₄O₃	详情	详情
(XV)	51423	[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol		C₁₀H₁₆O	详情	详情
(XVI)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(XVII)	51424	[(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₄O₂	详情	详情
(XVIII)	51425	[(1R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate		C₁₅H₂₂O₃	详情	详情

Extended Information