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【结 构 式】 
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【分子编号】11720 【品名】4-Bromo-1-butene 【CA登记号】5162-44-7 |
【 分 子 式 】C4H7Br 【 分 子 量 】135.00358 【元素组成】C 35.59% H 5.23% Br 59.19% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)Benzylic bromination of 3-bromo-o-xylene (IX) with NBS in the presence of benzoyl peroxide in refluxing CCl4 or chlorobenzene at 80 °C gives 1-bromo-2,3-bis(bromomethyl)benzene (X), which then cyclizes with benzylamine in the presence of KHCO3 in acetonitrile to yield 2-benzyl-4-bromoisoindoline (XI). Alkenylation of compound (XI) with tributyl(vinyl)tin (XII) by means of Pd(PPh3)4 in toluene provides the isoindoline (XIII), which is then deprotected by means of 1-chloroethyl chloroformate (ACE-Cl) in refluxing 1,2-dichloroethane to afford 4-vinylisoindoline (XIV). Finally, coupling of 4-vinylisoindoline (XIV) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously activated with CDI, in DMF at 60 °C results in carbamate (XVI) .
Alternatively, debenzylation of 2-benzyl-4-bromoisoindoline (XI) by means of ACE-Cl in chlorobenzene at 90 °C, followed by condensation of the deprotected isoindoline (XVII) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously treated with CDI, by means of DIEA in DMF at 50 °C furnishes carbamate (XVIII). Then, alkenylation of the aryl bromide (XVIII) with potassium vinyltrifluoroborate (XIX) and Et3N in refluxing EtOH affords the vinyl isoindoline derivative (XVI) .
Finally, Boc-deprotection of proline derivative (XVI) by means of HCl in dioxane gives the corresponding amine (XX), which is then coupled with the L-tert-leucine carbamate derivative (XXI) in the presence of EDC, DIEA and HOAt or HOBt in DMF to yield the building block diene (I) .
The L-tert-leucine carbamate (XXI) is prepared by alkylation of ethyl isobutyrate (XXII) with 4-bromo-1-butene (XXIII) and LDA in HMPA, followed by ester group reduction with LiAlH4 in Et2O, affording 2,2-dimethyl-5-hexen-1-ol (XXIV) . After treatment of hexenol (XXIV) with triphosgene by means of DIEA and NaOH in 1,4-dioxane, the resulting chloroformate is condensed with L-tert-leucine (XXV) to give carbamate (XXI) .
| 【1】 Holloway, M.K., Liverton, N.J., Ludmerer, S.W. et al. (Merck & Co., Inc.). HCV NS3 protease inhibitors. EP 1910404, EP 924593, JP 2009502793, US 2007027071, WO 2007015787, WO 2007015855. |
| 【2】 McCauley, J.A., McIntyre, C.J., Rudd, M.T. et al. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. J Med Chem 2010, 53(6): 2443-63. |
| 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) | 69055 | (3S,5R)-1-(2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate | C32H45N3O7 | 详情 | 详情 | |
| (IX) | 69063 | 3-bromo-o-xylene;2,3-Dimethylbromobenzene;3-Bromo-1,2-dimethylbenzene | 576-23-8 | C8H9Br | 详情 | 详情 |
| (X) | 69064 | 1-bromo-2,3-bis(bromomethyl)benzene | C8H7Br3 | 详情 | 详情 | |
| (XI) | 69065 | 2-benzyl-4-bromoisoindoline | C15H14BrN | 详情 | 详情 | |
| (XII) | 24920 | tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane | 7486-35-3 | C14H30Sn | 详情 | 详情 |
| (XIII) | 69066 | 2-benzyl-4-vinylisoindoline | C17H17N | 详情 | 详情 | |
| (XIV) | 69067 | 4-vinylisoindoline | C10H11N | 详情 | 详情 | |
| (XV) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (XVI) | 69070 | (2S,4S)-1-tert-butyl 2-methyl 4-((4-vinylisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate | C22H28N2O6 | 详情 | 详情 | |
| (XVII) | 69068 | 4-bromoisoindoline hydrochloride;3-Bromo-1H-isoindoline Hydrochloride;4-Bromo-1H-isoindoline hydrochloride;4-Bromo-2,3-dihydro-1H-isoindole hydrochloride | 923590-95-8 | C8H8BrN.HCl | 详情 | 详情 |
| (XVIII) | 69071 | (2S,4S)-1-tert-butyl 2-methyl 4-((4-bromoisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate | C20H25BrN2O6 | 详情 | 详情 | |
| (XIX) | 69072 | potassium vinyltrifluoroborate;potassium trifluoro(vinyl)borate | C2H3BF3K | 详情 | 详情 | |
| (XX) | 69069 | (3S,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate hydrochloride | C17H20N2O4.HCl | 详情 | 详情 | |
| (XXI) | 69073 | 2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoic acid | C15H27NO4 | 详情 | 详情 | |
| (XXII) | 28650 | ethyl 2-methylpropanoate；ethyl isobutyrate | 97-62-1 | C6H12O2 | 详情 | 详情 |
| (XXIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (XXIV) | 69074 | 2,2-dimethyl-5-hexen-1-ol | C8H16O | 详情 | 详情 | |
| (XXV) | 69075 | (S)-2-amino-3,3-dimethylbutanoic acid;L-tert-leucine;L-2-Amino-3,3-dimethylbutanoic acid | 20859-02-3 | C6H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)1) The microbiological oxidation of 3beta-hydroxyandrost-5-en-17-one (I) gives 1alpha,3beta-dihydroxyandrost-5-en-17-one (II), which is silylated with tert-butyldimethylsilyl (TBS) chloride and imidazole to the bis(silyloxy) compound (III). The dehydrogenation of (III) by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) yields 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androsta-5,7-dien-17-one (IV). The Wittig condensation of (IV) with ethyltriphenylphosphonium bromide (V) by means of NaH in DMS gives the corresponding ethylidene derivative (VI), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20-ol that was separated by preparative TLC. The 20(S)-isomer (VII) was condensed with 1-bromo-3-butene (VIII) by means of NaH in refluxing xylene affording 20(S)-(3-butenyloxy)-1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-diene (IX), which is oxidized with O2 gas in DMF/water catalyzed by Cu2Cl2 and PdCl2 to give the corresponding 3-oxobutoxy derivative (X). The Grignard alkylation of (X) with methylmagnesium bromide in THF afforded the 20(S)-(3-hydroxy-3-methylbutoxy) derivative (XI), which was submitted to UV irradiation with a 200 W high-pressure mercury lamp in ethanol yielding the silylated 22-oxavitamin D3 derivative (XII). Finally, this compound is desilylated by a treatment with tetrabutylammonium fluoride (TBAF) in THF. 2) The addition of ethyl acrylate (XIII) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of tetrabutylammonium hydroxide/NaOH in water/toluene gives the 2-(ethoxycarbonyl)ethoxy derivative (XIV), which by alkylation of the carbonyl function with methyllithium yields the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained. 3) The addition of N,N-dimethylacrylamide (XV) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of NaH gives the corresponding propionamide derivative (XVI), which by a Grignard alkylation with methylmagnesium bromide and CeCl3 is converted into the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.
| 【1】 Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, I.; Synthetic studies of vitamin D3 analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem Pharm Bull 1986, 34, 10, 4410-3. |
| 【2】 Kubodera, N.; Watanabe, H.; Kawanishi, T.; Matsumoto, M.; Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1alpha,25-dihydroxy-22-oxavitamin D3 analogues. Chem Pharm Bull 1992, 40, 6, 1494-9. |
| 【3】 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229. |
| 【4】 Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, I.; Murayama, E. (Chugai Pharmaceutical Co. Ltd.); Novel vitamin D derivs. and process for producing the same. EP 0184112; JP 1986267548; JP 1986267550 . |
| 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) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (II) | 11714 | (1S,3R,8R,9S,10R,13S,14S)-1,3-Dihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H28O3 | 详情 | 详情 | |
| (III) | 11715 | (1S,8R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | C31H56O3Si2 | 详情 | 详情 | |
| (IV) | 11716 | (1S,3R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C31H54O3Si2 | 详情 | 详情 | |
| (V) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (VI) | 11718 | tert-Butyl(dimethyl)silyl (1S,3R,9S,10R,13S,14S)-1-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-Butyl([(1S,3R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl]oxy)dimethylsilane | C33H58O2Si2 | 详情 | 详情 | |
| (VII) | 11719 | (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-ethanol | C33H60O3Si2 | 详情 | 详情 | |
| (VIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (IX) | 11721 | (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl 3-butenyl ether; [((1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Butenyloxy)ethyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl)oxy](tert-butyl)dimethylsilane | C37H66O3Si2 | 详情 | 详情 | |
| (X) | 11722 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-butanone | C37H66O4Si2 | 详情 | 详情 | |
| (XI) | 11723 | 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 | |
| (XII) | 11724 | 4-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]-2-methyl-2-butanol | C38H70O4Si2 | 详情 | 详情 | |
| (XIII) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (XIV) | 11726 | ethyl 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]propanoate | C38H68O5Si2 | 详情 | 详情 | |
| (XV) | 11727 | N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide | 2680-03-7 | C5H9NO | 详情 | 详情 |
| (XVI) | 11728 | 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-N,N-dimethylpropanamide | C38H69NO4Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)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4
该中间体在本合成路线中的序号：(V)Synthesis of intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII): The reaction of 3-amino-2,2-dimethyl-1-propanol (I) with Boc2 and Et3N in methanol gives the carbamate (II), which is oxidized with NaIO4 in CCl4/acetonitrile/water yielding 3-(tert-butoxycarbonylamino)-2,2-dimethylpropionic acid (III). The esterification of 2(S)-hydroxy-4-methylpentanoic acid (IV) with allyl bromide (V), NaHCO3 and tetrabutylammonium chloride in dichloromethane/water affords the corresponding allyl ester (VI). The esterification of hydroxyester (VI) with amino acid (II) by means of DCC and DMAP in dichloromethane provides the corresponding diester (VII), which is finally treated with Pd(PPh3)4 and morpholine in THF to furnish the intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII).
| 【1】 WO 9640184 . |
| 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) | 42783 | 3-amino-2,2-dimethyl-1-propanol | 26734-09-8 | C5H13NO | 详情 | 详情 |
| (II) | 42784 | tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (III) | 18901 | N-(tert-butoxycarbonyl)-2,2-dimethyl-beta-alanine | C10H19NO4 | 详情 | 详情 | |
| (IV) | 42785 | (2S)-2-hydroxy-4-methylpentanoic acid | 13748-90-8 | C6H12O3 | 详情 | 详情 |
| (V) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (VI) | 18902 | allyl (2S)-2-hydroxy-4-methylpentanoate | C9H16O3 | 详情 | 详情 | |
| (VII) | 18903 | allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate | C19H33NO6 | 详情 | 详情 | |
| (VIII) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)4-Methylvaleric acid (I) was converted to acid chloride (II) and then condensed with (S)-4-benzyl-2-oxazolidinone (III) to give (IV). Subsequent alkylation of (IV) with tert-butyl bromoacetate (V) in the presence of sodium bis(trimethylsilyl)amide produced the chiral intermediate (VI), which was hydrolyzed with lithium peroxide to yield (R)-2-isobutylsuccinic acid 4-tert-butyl ester (VII). Further alkylation of (VII) with 4-bromo-1-butene (VIII) afforded a 6:1 mixture of syn/anti isobutenyl compounds (IX), which upon isomerization with LDA in THF at -20 C, followed by quenching with MeOH, provided a 1:1.5 mixture of isomers. Condensation of N-Boc-L-tyrosine (X) with methylamine in the presence of EDC and HOBt gave amide (XI). Then, removal of the Boc protecting group with HCl in dioxan yielded tyrosinamide (XII). This was coupled to succinic acid derivative (IX) using EDC and HOBt to afford the corresponding amide (XIII) as an epimeric mixture. Hydroboration of the butenyl double bond, followed by oxidative treatment with H2O2 produced alcohol (XIV).
| 【1】 Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 . |
| 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) | 25389 | 4-methylpentanoic acid | 646-07-1 | C6H12O2 | 详情 | 详情 |
| (II) | 25390 | 4-methylpentanoyl chloride | 38136-29-7 | C6H11ClO | 详情 | 详情 |
| (III) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (IV) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 25392 | tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate | C22H31NO5 | 详情 | 详情 | |
| (VII) | 25393 | (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid | C12H22O4 | 详情 | 详情 | |
| (VIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (IX) | 25394 | (2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-heptenoic acid | C16H28O4 | 详情 | 详情 | |
| (X) | 25395 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid | 3978-80-1 | C14H19NO5 | 详情 | 详情 |
| (XI) | 25396 | tert-butyl (1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethylcarbamate | C15H22N2O4 | 详情 | 详情 | |
| (XII) | 25397 | (2S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide | C10H14N2O2 | 详情 | 详情 | |
| (XIII) | 25398 | tert-butyl 2-[(1R)-1-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-5-hexenoate | C26H40N2O5 | 详情 | 详情 | |
| (XIV) | 25399 | tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate | C26H42N2O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)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).
| 【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 |
合成路线7
该中间体在本合成路线中的序号：(II)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 |
合成路线8
该中间体在本合成路线中的序号：(VII)In a related method, 4-bromo-1-butene (VII) was reacted with methylamine to produce the secondary amine (VIII). After protection of (VIII) as the tert-butyl carbamate (IX), palladium-catalyzed coupling with 3-bromo-5-ethoxypyridine (II) furnished adduct (X). The N-Boc protecting group of (X) was then cleaved under acidic conditions to afford amine precursor (VI). The title hemigalactarate salt was finally prepared by treatment of amine (VI) with D-galactaric acid in aqueous ethanol.
| 【1】 Bane, A.J.; Dull, G.M.; Bencherif, M.; Miller, C.H.; Gatto, G.J.; TC-2559: A novel orally active ligand selective at neuronal acetylcholine receptors. Eur J Pharmacol 2000, 409, 1, 45. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 48046 | 3-bromo-5-ethoxypyridine; 5-bromo-3-pyridinyl ethyl ether | C7H8BrNO | 详情 | 详情 | |
| (VI) | 48049 | N-[(E)-4-(5-ethoxy-3-pyridinyl)-3-butenyl]-N-methylamine; (E)-4-(5-ethoxy-3-pyridinyl)-N-methyl-3-buten-1-amine | C12H18N2O | 详情 | 详情 | |
| (VII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (VIII) | 48050 | N-(3-butenyl)-N-methylamine; N-methyl-3-buten-1-amine | C5H11N | 详情 | 详情 | |
| (IX) | 48051 | tert-butyl 3-butenyl(methyl)carbamate | C10H19NO2 | 详情 | 详情 | |
| (X) | 48052 | tert-butyl (E)-4-(5-ethoxy-3-pyridinyl)-3-butenyl(methyl)carbamate | C17H26N2O3 | 详情 | 详情 |