N-Benzoyl-2'-C-methyl-D-cytidine -Drug Synthesis Database

【结构式】

【分子编号】65908

【品名】N-Benzoyl-2'-C-methyl-D-cytidine

【CA登记号】　

【分子式】C₁₇H₁₉N₃O₆

【分子量】361.35448

【元素组成】C 56.51% H 5.3% N 11.63% O 26.57%

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：(XVI)

Reaction of cytidine (XII) with benzoyl anhydride in DMF gives Nbenzoylcytidine (XIII), which is selectively protected with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2) in pyridine to yield the silylated cytidine (XIV). Oxidation of the remaining OH group of (XIV) by means of DMSO, TFAA and TEA produces the ketone (XV), which by a Grignard condensation with MeLi, followed by a desilylation with AcOH provides the tertiary alcohol (XVI). Selective benzoylation of the primary and secondary OH groups of compound (XVI) with benzoyl chloride and pyridine results in tribenzoate (XVII) with a remaining free tertiary OH group. Finally, benzoate (XVII) is fluorinated with DAST to yield the tribenzoylated fluorocytidine (II) .

参考文献中间体

合成目标

【1】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues, WO 2005003147.
【2】 Clark, J.L., Hollecker, L., Mason, J.C. et al. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 45(17): 5504-8.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	65909	N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine		C₃₁H₂₇N₃O₈	详情	详情
(II)	65910	(2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate	817204-32-3	C₃₁H₂₆FN₃O₇	详情	详情
(XII)	27920	Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone	65-46-3	C₉H₁₃N₃O₅	详情	详情
(XIII)	61580	N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide	13089-48-0	C₁₆H₁₇N₃O₆	详情	详情
(XIV)	65906	N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide	69304-43-4	C₂₈H₄₃N₃O₇Si₂	详情	详情
(XV)	65907	N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine	119411-03-9	C₂₈H₄₁N₃O₇Si₂	详情	详情
(XVI)	65908	N-Benzoyl-2'-C-methyl-D-cytidine		C₁₇H₁₉N₃O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Acylation of cytidine (I) with benzoic anhydride in DMF provides N4-benzoylcytidine (II), which is regioselectively protected at the 3’- and 5’-hydroxyl groups with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine, giving the cyclic siloxane derivative (III). Subsequent Swern oxidation of the 2’-alcohol group of compound (III) using DMSO, TFAA and Et3N followed by addition of methyllithium to the obtained ketone (IV) and desilylation with AcOH leads to the 2’-C-methylcytidine derivative (V). After reprotection of the primary and secondary hydroxyl groups of the cytidine (V) with benzoyl chloride in pyridine, the tertiary hydroxyl of compound (VI) is fluorinated using DAST in cold toluene to give the benzoyl-protected 2’-deoxy-2’-fluoro-2’-methylcytidine (VII) (1-3). In a different strategy, the nucleoside derivative (VII) is prepared by coupling of the methyl (VIIIa) (1-3) or acetyl (VIIIb) glycosides (4) or the glycosyl chloride (VIIIc) (5) with silylated N4-benzoylcytosine (IX) by means of either trimethylsilyl triflate or tin tetrachloride. The tribenzoylated precursor (VII) is then deprotected with methanolic NaOMe (1, 2) or ammonia (3, 4) to obtain PSI-6130 (X), which is finally esterified with isobutyryl chloride (XI) in the presence of DMAP and Et3N in THF/H2O (6). Scheme 1.

参考文献中间体

合成目标

【1】 Clark, J. (Pharmasset Ltd.). Modified fluorinated nucleoside analogues. WO 2005003147.
【2】 Clark, J.L., Hollecker, L., Mason, J.C. Design, synthesis, and antiviral activity of 2’-deoxy-2’-fluoro-2’-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem 2005, 48(17): 5504-8.
【3】 Clark, J. (Pharmasset, Inc.). Modified fluorinated nucleoside analogues. US 20080070861.
【4】 Chun, B.-K., Wang, P. (Pharmasset, Inc.). Preparation of 2’-fluoro-2’-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives. WO 2006031725.
【5】 Axt, S.D., Sarma, K., Vitale, J. et al. (Pharmasset, Inc.; F. Hoffmann La Roche AG). Preparation of nucleosides ribofuranosyl pyrimidines. WO 2008045419.
【6】 Chun, B.-K., Clark, J., Sarma, K., Wang, P. (F. Hoffmann-La Roche AG; Pharmasset, Inc.). Antiviral nucleosides. WO 2007065829.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIA)	65911	((2S,3S,4S)-3-(benzoyloxy)-4-fluoro-5-methoxy-4-methyltetrahydrofuran-2-yl)methyl benzoate		C₂₁H₂₁FO₆	详情	详情
(VIIIB)	65912			C₂₂H₂₁FO₆	详情	详情
(VIIIC)	65913			C₂₀H₁₇ClFO₅	详情	详情
(I)	27920	Cytidine; 4-amino-1-((2S,3S,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one;4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2(1H)-pyrimidinone	65-46-3	C₉H₁₃N₃O₅	详情	详情
(II)	61580	N-Benzoylcytidine;N-[1-[3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]benzamide;N-{1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl}benzamide	13089-48-0	C₁₆H₁₇N₃O₆	详情	详情
(III)	65906	N-Benzoyl-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine; N-[1-[(6aR,8R,9R,9aS)-9-hydroxy-2,2,4,4-tetra(propan-2-yl)-6a,8,9,9a-tetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-2-oxopyrimidin-4-yl]benzamide	69304-43-4	C₂₈H₄₃N₃O₇Si₂	详情	详情
(IV)	65907	N-Benzoyl-2'-deoxy-2'-oxo-3',5'-O-[1,1,3,3-tetrakis(1-methylethyl)-1,3-disiloxanediyl]cytidine	119411-03-9	C₂₈H₄₁N₃O₇Si₂	详情	详情
(V)	65908	N-Benzoyl-2'-C-methyl-D-cytidine		C₁₇H₁₉N₃O₆	详情	详情
(VI)	65909	N-Benzoyl-3',5'-di-O-benzoyl-2'-C-methyl-D-cytidine		C₃₁H₂₇N₃O₈	详情	详情
(VII)	65910	(2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate	817204-32-3	C₃₁H₂₆FN₃O₇	详情	详情
(IX)	12715	N-(2-Oxo-1,2-dihydro-4-pyrimidinyl)benzamide; N-Benzoylcytosine	26661-13-2	C₁₁H₉N₃O₂	详情	详情
(X)	65914	2'-Deoxy-2'-fluoro-2'-C-methylcytidine	817204-33-4	C₁₀H₁₄FN₃O₄	详情	详情
(XI)	14932	isobutyryl chloride; 2-methylpropanoyl chloride	79-30-1	C₄H₇ClO	详情	详情

Extended Information