-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】1-[3-[3-(Allyloxy)-3-oxo-1-propenyl]phenyl]-1,1-difluoromethylphosphonic acid diammonium salt

【CA登记号】

【分子式】C₁₃H₁₉F₂N₂O₅P

【分子量】352.27738

【开发单位】University of Waterloo (Originator)

【药理作用】Antidiabetic Drugs, Antiobesity Drugs, ENDOCRINE DRUGS, METABOLIC DRUGS, Treatment of Nutritional Disorders, Type 2 Diabetes Mellitus, Agents for, Protein Tyrosine Phosphatase PTP-1B Inhibitors

合成路线1 合成路线2

合成路线1

Condensation of dibromide (I) with allyl alcohol (II) in the presence of NaH gives rise to a mixture of mono- and diallylated compounds (III) and (IV) which, without separation, is subjected to Arbuzov reaction with triethyl phosphite, to furnish the desired phosphonate (V). Electrophilic fluorination of (V) using N-fluorobenzenesulfonimide provides the difluoro phosphonate (VI). Then, basic hydrolysis of phosphonate (VI) affords acid (VII). Compound (VII) is attached to a functionalized non-crosslinked polystyrene soluble polymer under Mitsunobu conditions to produce the polymer-bound phosphonate (VIII). Then, removal of the allyl group in the presence of p-toluenesulfinic acid and Pd(PPh3)4 yields the benzylic alcohol (IX). Oxidation of (IX) employing the Dess-Martin periodinane reagent leads to aldehyde (X) (1).

参考文献中间体

【1】 Hum, G.; Lee, J.; Taylor, S.D.; Synthesis of [difluoro-(3-alkenylphenyl)-methyl]-phosphonic acids on non-crosslinked polystyrene and their evaluation as inhibitors of PTP1B. Bioorg Med Chem Lett 2002, 12, 23, 3471.

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), (VIII)	64570	ethyl hydrogen {3-[(allyloxy)methyl]phenyl}(difluoro)methylphosphonate		C₁₃H₁₇F₂O₄P	详情	详情
(I)	64521	1,3-bis(bromomethyl)benzene		C₈H₈Br₂	详情	详情
(II)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(III)	64522	allyl 3-(bromomethyl)benzyl ether; 1-[(allyloxy)methyl]-3-(bromomethyl)benzene		C₁₁H₁₃BrO	详情	详情
(IV)	64523	1,3-bis[(allyloxy)methyl]benzene; allyl 3-[(allyloxy)methyl]benzyl ether		C₁₄H₁₈O₂	详情	详情
(V)	64524	diethyl 3-[(allyloxy)methyl]benzylphosphonate		C₁₅H₂₃O₄P	详情	详情
(VI)	64525	diethyl {3-[(allyloxy)methyl]phenyl}(difluoro)methylphosphonate		C₁₅H₂₁F₂O₄P	详情	详情
(IX)	64572	ethyl hydrogen difluoro[3-(hydroxymethyl)phenyl]methylphosphonate		C₁₀H₁₃F₂O₄P	详情	详情
(X)	64573	ethyl hydrogen difluoro(3-formylphenyl)methylphosphonate		C₁₀H₁₁F₂O₄P	详情	详情

合成路线2

Wittig condensation of aldehyde (X) with the phosphorus ylide generated from phosphonium salt (XI) provides the polymer-bound cinnamate derivative (XII). Simultaneous cleavage of the support from (XII) and phosphonate deprotection to provide phosphonic acid (XIII) is achieved using bromotrimethylsilane. Acid (XIII) is then applied to an anion exchange resin and eluted with ammonium hydroxide to furnish the corresponding ammonium salt (1).

参考文献中间体

【1】 Hum, G.; Lee, J.; Taylor, S.D.; Synthesis of [difluoro-(3-alkenylphenyl)-methyl]-phosphonic acids on non-crosslinked polystyrene and their evaluation as inhibitors of PTP1B. Bioorg Med Chem Lett 2002, 12, 23, 3471.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	64574	[2-(allyloxy)-2-oxoethyl](triphenyl)phosphonium bromide	C₂₃H₂₂BrO₂P	详情	详情
(X)	64573	ethyl hydrogen difluoro(3-formylphenyl)methylphosphonate	C₁₀H₁₁F₂O₄P	详情	详情
(XII)	64575	allyl (E)-3-{3-[[ethoxy(hydroxy)phosphoryl](difluoro)methyl]phenyl}-2-propenoate	C₁₅H₁₇F₂O₅P	详情	详情
(XIII)	64571	{3-[(E)-3-(allyloxy)-3-oxo-1-propenyl]phenyl}(difluoro)methylphosphonic acid	C₁₃H₁₃F₂O₅P	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)