Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene -Drug Synthesis Database

【结构式】

【分子编号】16643

【品名】Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene

【CA登记号】7785-26-4

【分子式】C₁₀H₁₆

【分子量】136.23704

【元素组成】C 88.16% H 11.84%

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：(I)

The required chiral auxiliary hydroxyketone (II) was prepared from (S)-alpha-pinene (I) either by dihydroxylation with K2OsO4 and NMO, followed by Swern oxidation of the secondary alcohol, or by direct oxidation using KMnO4 under phase-transfer conditions. Condensation of (II) with 2-(aminomethyl)pyridine (III) in the presence of titanium isopropoxide or thionyl chloride as the dehydrating reagents provided the chiral imine (IV), which was estereoselectively alkylated with cyclohexylmethyl bromide (V) and n-BuLi, yielding (VI). Cleavage of the chiral auxiliary of (VI) was carried out by treatment with hydroxylamine hydrochloride. Enantiomeric enrichment of the resulting (S)-pyridylamine was achieved by recrystallization of the corresponding L-tartrate salt (VII). Finally, the amine was condensed with chlorobenzoxazole (VIII) in the presence of NaOAc and Na2CO3 in refluxing methylcyclohexane.

参考文献中间体

合成目标

【1】 Roth, G.P.; et al.; Optimization and scale-up of an asymetric route to the LTB4 inhibitor ontazolast. Org Process Res Dev 1997, 1, 5, 331.

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)	16643	Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene	7785-26-4	C₁₀H₁₆	详情	详情
(II)	31762	(1S,2R,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one		C₁₀H₁₆O₂	详情	详情
(III)	13582	2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine	3731-51-9	C₆H₈N₂	详情	详情
(IV)	31763	(1S,2R,5S)-2,6,6-trimethyl-3-[(2-pyridinylmethyl)imino]bicyclo[3.1.1]heptan-2-ol		C₁₆H₂₂N₂O	详情	详情
(V)	31767	1-(bromomethyl)cyclohexane	2550-36-9	C₇H₁₃Br	详情	详情
(VI)	31764	(1S,2R,5S)-3-[[(1S)-2-cyclohexyl-1-(2-pyridinyl)ethyl]imino]-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol		C₂₃H₃₄N₂O	详情	详情
(VII)	31765	(1S)-2-cyclohexyl-1-(2-pyridinyl)ethylamine; (1S)-2-cyclohexyl-1-(2-pyridinyl)-1-ethanamine		C₁₃H₂₀N₂	详情	详情
(VIII)	31766	2-chloro-5-methyl-1,3-benzoxazole		C₈H₆ClNO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

1) The isomerization of (-)-beta-pinene (I) with potassium 3-aminopropylamide (KAPA) gives (-)-alpha-pinene (II), which is dihydroxylated with OsO4, trimethylamine oxide and NaHSO3 in tert-butanol/pyridine/water yielding (1R,2R,3S,5R)-(-)-pinanediol (III) that is used as chiral director. The trans-esterification of (III) with 4-bromobutylboronic acid dimethyl ester (IV) [obtained by treatment of 4-bromo-1-butene (V) with BCl3, methanol and triethylsilane] affords the pinane boronic ester (VI), which is treated with dichloromethane and butyllithium in THF forming the intermediate lithium salt (VII). This salt, without isolation, is treated with anhydrous ZnCl2 to give 5-bromo-1(S)-chloropentylboronic acid pinanediol ester (VIII), which is then treated with methylmagnesium bromide in THF affording 5-bromo-1(S)-methylpentylboronic acid pinanediol ester (IX). The reaction of (IX) with 3,7-dimethylxanthine (X) by means of NaH in DMSO gives the corresponding condensation product (XI), which is finally treated with KOH and H2O2 in THF/water to eliminate the boronic group yielding the desired lisofylline.

参考文献中间体

合成目标

【1】 Graul, J.; Casas, A.; Castañer, J.; Lisofylline. Drugs Fut 1997, 22, 5, 492.
【2】 Bianco, J.A.; Woodson, P.; Porubek, D.; Singer, J. (Cell Therapeutics, Inc.); Enantiomeric hydroxylated xanthine cpds. JP 1994509584; JP 1996259565; WO 9317684 .

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)	16642	(1S,5S)-6,6-dimethyl-2-methylenebicyclo[3.1.1]heptane; (+)-Beta-Pinene	18172-67-3	C₁₀H₁₆	详情	详情
(II)	16643	Poly-alpha-pinene; (1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene	7785-26-4	C₁₀H₁₆	详情	详情
(III)	16644	(-)-Pinanediol; (1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol	20536-52-1	C₁₀H₁₈O₂	详情	详情
(IV)	16645	dimethyl 4-bromobutylboronate		C₆H₁₄BBrO₂	详情	详情
(V)	11720	4-Bromo-1-butene	5162-44-7	C₄H₇Br	详情	详情
(VI)	16647	(1R,2R,6S,8R)-4-(4-bromobutyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₄H₂₄BBrO₂	详情	详情
(VII)	16648			C₁₅H₂₅BBrCl₂LiO₂	详情	详情
(VIII)	16649	(1R,2R,6S,8R)-4-[(1S)-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
(IX)	16650	(1R,2R,6S,8R)-4-[(1S)-5-bromo-1-methylpentyl]-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₆H₂₈BBrO₂	详情	详情
(X)	16651	theobromine; 3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione	83-67-0	C₇H₈N₄O₂	详情	详情
(XI)	16652	3,7-dimethyl-1-[(5S)-5-[(1R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]hexyl]-3,7-dihydro-1H-purine-2,6-dione		C₂₃H₃₅BN₄O₄	详情	详情

Extended Information