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【结 构 式】 
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【分子编号】16644 【品名】(-)-Pinanediol; (1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol 【CA登记号】20536-52-1 |
【 分 子 式 】C10H18O2 【 分 子 量 】170.25172 【元素组成】C 70.55% H 10.66% O 18.79% |
合成路线1
该中间体在本合成路线中的序号：(XIV)The optical resolution of racemic pagoclone (VII) can also be performed by reaction with (-)-(1R,2R,3S,5R)-pinanediol (XIV) by means of PPTS in refluxing dichloroethane to give the ketal (XV) as a diastereomeric mixture separated by crystallization. Finally, hydrolysis of the desired diastereomer (XVI) with 12N HCl affords the (+)-enantiomer, pagoclone.
| 【1】 Silvestre, J.S.; Castaner, J.; Leeson, P.A.; Sorbera, L.A.; Pagoclone. Drugs Fut 2001, 26, 7, 651. |
| 【2】 Barreau, M.; Cotrel, C.; Dubroeucq, M.-C.; Manfre, F. (Aventis Pharma SA); Method for preparing enantiomers of an isoindolinone deriv.. WO 9313098 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 47678 | 2-(7-chloro[1,8]naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone | C23H22ClN3O2 | 详情 | 详情 | |
| (XIV) | 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 |
| (XV) | 47685 | (rac)-2-(7-chloro[1,8]naphthyridin-2-yl)-3-[[(1R,2R,6S,8R)-4-isopentyl-2,9,9-trimethyl-3,5-dioxatricyclo[6.1.1.0(2,6)]dec-4-yl]methyl]-1-isoindolinone | C33H38ClN3O3 | 详情 | 详情 | |
| (XVI) | 47686 | (+)-2-(7-chloro[1,8]naphthyridin-2-yl)-3-[[(1R,2R,6S,8R)-4-isopentyl-2,9,9-trimethyl-3,5-dioxatricyclo[6.1.1.0(2,6)]dec-4-yl]methyl]-1-isoindolinone | C33H38ClN3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |
合成路线3
该中间体在本合成路线中的序号：(VI)The protected glutamic acid (I) is converted to the mixed anhydride (II) using ethyl chloroformate, and subsequently reduced to alcohol (III) by means of NaBH4. Swern oxidation of (III) provides aldehyde (IV), which is subjected to a Wittig condensation with triphenyl methylenephosphorane to afford olefin (V). Hydroboration of (V), followed by reaction with (+)-pinanediol (VI) leads to the boronate (VII). Finally, complete deprotection of (VII) with BCl3 yields the desired boronic acid.
| 【1】 Ash, D.E.; Carroll, P.J.; Baggio, R.; Cavalli, R.C.; Christianson, D.W.; Kanyo, Z.F.; Elbaum, D.; Inhibition of Mn2+2-arginase by borate leads to the design of a transition state analogue inhibitor, 2(S)-amino-6-boronohexanoic acid. J Am Chem Soc 1997, 119, 34, 8107. |
| 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) | 57915 | (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | C14H25NO6 | 详情 | 详情 | |
| (II) | 57916 | C17H29NO8 | 详情 | 详情 | ||
| (III) | 57917 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-hydroxypentanoate | C14H27NO5 | 详情 | 详情 | |
| (IV) | 57918 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoate | C14H25NO5 | 详情 | 详情 | |
| (V) | 57919 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-hexenoate | C15H27NO4 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 57920 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]hexanoate | C25H44BNO6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The enantioselective alkylation of the nickel complex (I) of the Schiff base derived from glycine and (S)-2-[N'-(N-benzylprolyl)amino]benzophenone with 4-bromo-1-butene (II) affords the corresponding complex (III) of (S)-2-amino-5-hexenoic acid, which is subsequently hydrolyzed to the free aminoacid (IV) under mild acidic conditions. Esterification of (IV) by means of SOCl2 in methanol leads to amino ester (V), and further protection with di-tert-butyl dicarbonate provides the N-Boc derivative (VI). Hydroboration of the double bond of (VI) with diisopinocampheylborane, followed by in situ oxidation with acetaldehyde gives rise to the diethyl boronate (VII). This is then converted to the isolable pinanediol boronate (IX) upon treatment with (+)-pinanediol (VIII). Finally, total deprotection of (IX) by refluxing with 12 M HCl furnishes the title compound.
| 【1】 Collet, S.; et al.; Synthesis and evaluation of omega-borono-alpha-amino acids as active-site probes of arginase and nitric oxide synthases. J Chem Soc - Perkins Trans I 2000, 2, 177. |
| 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) | 57921 | C27H25N3NiO3 | 详情 | 详情 | ||
| (II) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (III) | 57922 | C31H31N3NiO3 | 详情 | 详情 | ||
| (IV) | 57923 | (2S)-2-amino-5-hexenoic acid | C6H11NO2 | 详情 | 详情 | |
| (V) | 57924 | methyl (2S)-2-amino-5-hexenoate | C7H13NO2 | 详情 | 详情 | |
| (VI) | 57925 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-hexenoate | C12H21NO4 | 详情 | 详情 | |
| (VII) | 57926 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-(diethoxyboryl)hexanoate | C16H32BNO6 | 详情 | 详情 | |
| (VIII) | 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 |
| (IX) | 57927 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-6-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]hexanoate | C22H38BNO6 | 详情 | 详情 |