diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate -Drug Synthesis Database

【结构式】

【分子编号】68705

【品名】diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate

【CA登记号】　

【分子式】C₁₆H₁₉FNO₃P

【分子量】323.304

【元素组成】C 59.44% H 5.92% F 5.88% N 4.33% O 14.85% P 9.58%

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：(XII)

In one strategy, Horner–Emmons condensation of tetracyclic aldehyde (I) with pyridylmethyl phosphonate (II) by means of BuLi in THF gives the olefin adduct (III), which, after desilylation to the corresponding hydroxypyridine with TBAF in THF, is treated with Tf2O in pyridine to afford the pyridyl triflate (IV). Suzuki coupling of triflate (IV) with 3-fluorophenylboronic acid (V) by means of Pd(PPh3)4 and K2CO3 in toluene/EtOH/H2O at 100 °C gives the phenylpyridine derivative (VI). After hydrolysis of the ethylene ketal group in compound (VI) by means of HCl in acetone at 50 °C, the resulting tricyclic ketone is reductively aminated with NH3 and NaBH3CN in the presence of Ti(O-i-Pr)4 and TiCl4 in EtOH/CH2Cl2 to yield a diastereomeric mixture of primary amines that are separated by preparative TLC, providing the 6(R)-amine (VII). Finally, amine (VII) is acylated with ethyl chloroformate (VIII) in the presence of Et3N in CH2Cl2 .
In another strategy, N-acylation of the tricyclic amino acid (IX) with ethyl chloroformate (VIII) yields the carbamate (X), which, after reduction of the carboxyl group to the corresponding aldehyde (XI), is subjected to Wittig reaction with phosphonate (XII) .

参考文献中间体

合成目标

【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4.
【2】 Chackalamannil, S., Greenlee, W.J., Xia, Y., Chelliah, M., Clasby, M.C., Wang, Y., Veltri, E.P. (Schering Corp.). Tricyclic thrombin receptor antagonists. EP 1495018, EP 1860106, EP 1982984, EP 2062890, EP 2065384, JP 2005528406, JP 2010132710, US 2003216437, US 7304078, WO 200308928.
【3】 Sudhakar, A., Kwok, D.-I., Wu, G.G., Green, M.D., Thiruvengadam, T.K., Lim, N.K., Wang, T., Huang, M. (Schering Corp.). An exo-selective synthesis of himbacine analogs. EP 1846385, JP 2008526974, US 2006217422, US 7772276, WO 2006076452.
【4】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.

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)	68713	(1'R,3a'R,4a'R,8a'R,9a'S)-1'-methyl-3'- oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho [2,3-c]furan]-9'-carbaldehyde		C₁₆H₂₂O₅	详情	详情
(II)	68703	diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate		C₁₉H₃₆NO₄PSi	详情	详情
(III)	68712	(1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-9'-((E)-2-(5-((triisopropylsilyl)oxy)pyridin-2-yl)vinyl)octahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-3'(7'H)-one		C₃₁H₄₇NO₅Si	详情	详情
(IV)	68711	6-((E)-2-((1'R,3a'R,4a'R,8a'R,9'S,9a'S)-1'-methyl-3'-oxodecahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-9'-yl)vinyl)pyridin-3-yl trifluoromethanesulfonate		C₂₃H₂₆F₃NO₇S	详情	详情
(V)	68704	3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid	768-35-4	C₆H₆BFO₂	详情	详情
(VI)	68710	(1'R,3a'R,4a'R,8a'R,9'S,9a'S)-9'-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1'-methyloctahydro-1'H-spiro[[1,3]dioxolane-2,6'-naphtho[2,3-c]furan]-3'(7'H)-one		C₂₈H₃₀FNO₄	详情	详情
(VII)	68709	7-amino-4-((E)-2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one		C₂₆H₂₉FN₂O₂	详情	详情
(VIII)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(IX)	68708	(3S,3aS,4R,4aS,7S,8aS,9aS)-7-amino-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid		C₁₄H₂₁NO₄	详情	详情
(X)	68707	(3S,3aS,4R,4aS,7S,8aS,9aS)-7-((ethoxycarbonyl)amino)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-carboxylic acid		C₁₇H₂₅NO₆	详情	详情
(XI)	68706	ethyl ((1S,3aS,4aS,6S,8aS,9R,9aR)-9-formyl-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl)carbamate		C₁₇H₂₅NO₅	详情	详情
(XII)	68705	diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate		C₁₆H₁₉FNO₃P	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

Rearrangement of 5-bromo-2-methylpyridine 1-oxide (LXVII) with trifluoroacetic anhydride gives (5-bromopyridin-2-yl)methyl trifluoroacetate (LXVIII), which, without isolation, is hydrolyzed in MeOH solution, yielding (5-bromopyridin-2-yl)methanol trifluoroacetate salt (LXIX). Basification of compound (LXIX) with K2CO3 followed by chlorination with SOCl2 affords 5-bromo-2-(chloromethyl)pyridine (LXX), which is subsequently condensed with diethyl phosphite in the presence of LiHMDS, affording phosphonate (LXXI). Finally, Suzuki coupling of bromopyridine derivative (LXXI) with 3-fluorophenylboronic acid (V) by means of Na2CO3 and Pd/C in H2O at 75 °C provides the phenylpyridine compound (XII) .
O-Protection of 6-methyl-3-pyridinol (LXXII) with TIPSCl in DMF gives the corresponding silyl ether (LXXIII), which is then condensed with diethyl chlorophosphate (LXXIV) in the presence of BuLi and DIEA in THF, yielding diethyl phosphonate (II) .

参考文献中间体

合成目标

【1】 Chackalamannil, S., Wang, Y., Greenlee, W.J. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008, 51(11): 3061-4.
【2】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.

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)	68703	diethyl ((5-((triisopropylsilyl)oxy)pyridin-2-yl)methyl)phosphonate		C₁₉H₃₆NO₄PSi	详情	详情
(V)	68704	3-fluorophenylboronic acid;3-Fluorobenzeneboronic acid	768-35-4	C₆H₆BFO₂	详情	详情
(XII)	68705	diethyl ((5-(3-fluorophenyl)pyridin-2-yl)methyl)phosphonate		C₁₆H₁₉FNO₃P	详情	详情
(LXVII)	68760	5-bromo-2-methylpyridine 1-oxide；5-bromo-2-Picoline-1-oxide；3-Bromo-6-methylpyridine 1-oxide;5-bromo-2-methylpyridine N-oxide;5-Bromo-2-picoline N-oxide	31181-64-3	C₆H₆BrNO	详情	详情
(LXVIII)	68761	(5-bromopyridin-2-yl)methyl trifluoroacetate；(5-bromopyridin-2-yl)methyl 2,2,2-trifluoroacetate		C₈H₅BrF₃NO₂	详情	详情
(LXIX)	68762	(5-bromopyridin-2-yl)methanol 2,2,2-trifluoroacetate		C₆H₆BrNO.C₂HF₃O₂	详情	详情
(LXX)	68763	5-bromo-2-(chloromethyl)pyridine	168823-76-5	C₆H₅BrClN	详情	详情
(LXXI)	68764	diethyl ((5-bromopyridin-2-yl)methyl)phosphonate		C₁₀H₁₅BrNO₃P	详情	详情
(LXXII)	25748	6-methyl-3-pyridinol; 5-Hydroxy-2-methylpyridine	1121-78-4	C₆H₇NO	详情	详情
(LXXIV)	68765	2-methyl-5-((triisopropylsilyl)oxy)pyridine		C₁₅H₂₇NOSi	详情	详情
(LXXV)	23623	Chlorophosphoric acid ethyl ester；Phosphorochloridic acid diethyl ester；Diethyl chlorophosphate;diethyl phosphorochloridate	814-49-3	C₄H₁₀ClO₃P	详情	详情

Extended Information