3αR-苄基-1-(叔丁基)氧羰基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶-3-(3H)-酮的合成
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摘要
在O-烯丙基-N-9-蒽甲基溴化辛可宁的催化下,1-苄基-3-乙氧羰基-4-哌啶酮与溴化苄经不对称苄基化反应制得(R)-1,3-二苄基-4-氧代哌啶-3-甲酸乙酯(3);3脱除Bn保护基并经Boc保护转化为(R)-3-苄基-1-(叔丁基)氧羰基-4-氧代哌啶-3-甲酸乙酯(5);5与甲基肼在乙醇中经环化反应合成了Capromorelin的关键中间体3αR-苄基-1-(叔丁基)氧羰基-2-甲基-4,5,6,7-四氢-2H-吡唑并[4,3-c]吡啶-3-(3H)-酮,收率70%,ee值69.1%,其结构经~1H NMR,~(13)C NMR和HR-MS(ESI)确证。
Under the catalysis of O-allyl-N-9-anthracenemethylcindexnine bromide,(R)-1,3-dibenzyl-4-oxopiperidine-3-carboxylic acid ethyl ester(3) was obtained by the asymmetric benzylation of 1-benzyl-3-ethoxycarbonyl-4-piperidone with benzyl bromide. Then 3 was converted into ethyl(R)-3-benzyl-1-(tert-butyl)oxycarbonyl-4-oxopiperidine-3-carboxylate(5) through two steps of protecting group change. 3αR-Benzyl-1-(tert-butyl)oxycarbonyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-(3H)-one(6), a key intermediate for Capromorelin, was obtained with 70% yield and ee 69.1% by cyclization of 5 with methyl hydrazine in EtOH. The structure was confirmed by ~1H NMR, ~(13)C NMR and HR-MS(ESI).
Under the catalysis of O-allyl-N-9-anthracenemethylcindexnine bromide,(R)-1,3-dibenzyl-4-oxopiperidine-3-carboxylic acid ethyl ester(3) was obtained by the asymmetric benzylation of 1-benzyl-3-ethoxycarbonyl-4-piperidone with benzyl bromide. Then 3 was converted into ethyl(R)-3-benzyl-1-(tert-butyl)oxycarbonyl-4-oxopiperidine-3-carboxylate(5) through two steps of protecting group change. 3αR-Benzyl-1-(tert-butyl)oxycarbonyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-(3H)-one(6), a key intermediate for Capromorelin, was obtained with 70% yield and ee 69.1% by cyclization of 5 with methyl hydrazine in EtOH. The structure was confirmed by ~1H NMR, ~(13)C NMR and HR-MS(ESI).
引文
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[2] CAPRPINO P A,LEFKER B A,TOLER S M,et al.Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs):Discovery of Capromorelin[J].Bioorg Med Chem,2003,11(4):581-590.
[3] PAN L C,CAPRPINO P A,LEFKER B A,et al.Preclinical pharmacology of CP-424,391,an orally active pyrazolinone-piperidine growth hormone secretagogue[J].Endocrine,2001,14(1):121-131.
[4] YANG L H,MORRIELLO G,PATCHETT A A,et al.1-[2(R)-(2-Amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]-3-benzylpiperidine-3(S)-carboxylic acid ethyl ester(L-163,540):A potent,orally bioavailable,and short-duration growth hormone secretagogue[J].J Med Chem,1998,41(14):2339-2441.
[5] MALIGRES P E,CHARTRAIN M M,UPADHYAY V,et al.Preparation of (S)-3-carbethoxy-3- benzylpiperidine and the growth hormone secretagogue L-163,540[J].J Org Chem,1998,63(25):9548-9551.
[6] LACHERETZ R,PARDO D G,COSSY J.Daucus carota mediated-reduction of cyclic 3-oxo-amines[J].Org Lett,2009,11(6):1245-1248.
[7] ROSE C R,ZAWISTOSKI M P,LEFKER B A,et al.Practical synthesis of capromorelin,a growth hormone secretagogue,via a crystallization-induced dynamic resolution[J].Bioorg Med Chem,2017,25(3):1000-1003.
[8] PAIXAO M W,NIELSEN M,JACOBSEN C B,et al.Organocatalytic asymmetric ring-opening of aziridines[J].Org Biomol Chem,2008,6(19):3467-3470.
[9] O'DOMMELL M J,WU S D,HUFFMAN J C.A new active catalyst species for enantioselective alkylation by phase-transfer catalysis [J]Tetrahedron,1994,50(15):4507-4518.
[10] BASCJHIERI A,BERNARDI L,RICCI A,et al.Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro-5-styrylisoxazoles[J].Angew Chem Int Ed,2009,48(49):9342-9345.
[11] MINAKATA S,MURAKAMI Y,TSURUOKA R,et al.Catalytic aziridination of electron-deficient olefins with an N-chloro-N-sodio carbamate and application of this novel method to asymmetric synthesis[J].Chem Commun,2008,47:6363-6365.
[12] WANG X,LV J,LIU L,et al.A novel N-acetophenone cinchona ammonium salts as chiral phase transfer catalysts for the alkylation of Schiff base in water[J].J Mol Catal A,2007,276:102-109.
[13] HE W,WANG Q J,WANG Q F,et al.Synthesis of novel chiral phase-transfer catalysts and their application to asymmetric synthesis of α-amino acid derivatives[J].Synlett,2009,8:1311-1314.