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【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

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.

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.

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