Ragaglitazar, NNC-61-0029, (-)-DRF-2725, NN-622, -Drug Synthesis Database

【结构式】

【药物名称】Ragaglitazar, NNC-61-0029, (-)-DRF-2725, NN-622

【化学名称】(-)-2(S)-Ethoxy-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]propionic acid

【CA登记号】222834-30-2, 222834-21-1 (racemate)

【分子式】C₂₅H₂₅NO₅

【分子量】419.4817

【开发单位】Dr. Reddy's Research Foundation (Originator), Novo Nordisk (Licensee)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists

合成路线1 合成路线2 合成路线3

合成路线1

Several related procedures have been described for the synthesis of the title compound. The Horner-Emmons reaction of 4-benzyloxybenzaldehyde (I) with triethyl 2-ethoxyphosphonoacetate (II) afforded the unsaturated ester (IIIa-b) as a mixture of E/Z isomers. Simultaneous double-bond hydrogenation and benzyl group hydrogenolysis in the presence of Pd/C furnished phenol (IV). Alternatively, double-bond reduction by means of magnesium in MeOH was accompanied by transesterification, yielding the saturated methyl ester (V). Further benzyl group hydrogenolysis of (V) over Pd/C gave phenol (VI). The alkylation of phenols (IV) and (VI) with the phenoxazinylethyl mesylate (VII) provided the corresponding ethers (VIII) and (IX), respectively. The racemic carboxylic acid (X) was then obtained by hydrolysis of either ethyl- (VIII) or methyl- (IX) esters under basic conditions.

参考文献中间体

【1】 Kalchar, S.; Lohray, V.B.; Lohray, B.B.; Chakrabarti, R.; Bajji, A.C.; Ramanujam, R. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsns. containing them. EP 1049684; JP 2001519422; WO 9919313 .
【2】 Rajagopalan, R.; Ashok, C.B.; Shivaramayya, K.; Gurram, R.M.; Lohray, B.B.; Paraselli, B.R.; Rajan, C.; Lohray, V.B. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsn. containing them. EP 1155006; WO 0050414 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	50411	ethyl (E)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate		C₂₀H₂₂O₄	详情	详情
(IIIb)	51683	ethyl (Z)-3-[4-(benzyloxy)phenyl]-2-ethoxy-2-propenoate		C₂₀H₂₂O₄	详情	详情
(I)	29179	4-(Benzyloxy)benzaldehyde	4397-53-9	C₁₄H₁₂O₂	详情	详情
(II)	51675	ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate		C₁₀H₂₁O₆P	详情	详情
(IV)	51682	ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate		C₁₃H₁₈O₄	详情	详情
(V)	51676	methyl 3-[4-(benzyloxy)phenyl]-2-ethoxypropanoate		C₁₉H₂₂O₄	详情	详情
(VI)	51677	methyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate		C₁₂H₁₆O₄	详情	详情
(VII)	51678	2-(10H-phenoxazin-10-yl)ethyl methanesulfonate		C₁₅H₁₅NO₄S	详情	详情
(VIII)	51679	ethyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate		C₂₇H₂₉NO₅	详情	详情
(IX)	51680	methyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate		C₂₆H₂₇NO₅	详情	详情
(X)	51681	2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid		C₂₅H₂₅NO₅	详情	详情

合成路线2

In a related method, 4-(2-bromoethoxy)benzaldehyde (XI) was subjected to a Horner-Emmons reaction with phosphonate (II) to produce the unsaturated ester (XIIa-b), which was further hydrogenated to afford (XIII). Alkylation of phenoxazine (XIV) with bromide (XIII) gave adduct (VIII) (1,2). In a different reaction sequence, bromoaldehyde (XI) was initially condensed with phenoxazine (XIV), producing adduct (XV). This was subjected to Horner-Emmons condensation with (II) to give the unsaturated ester (XVIa-b), which was then hydrogenated to (VIII). Alternatively, double-bond reduction of (XVI) by means of Mg in MeOH gave rise to the transesterified methyl ester (IX). Ester hydrolysis as above provided acid (X).

参考文献中间体

【2】 Kalchar, S.; Lohray, V.B.; Lohray, B.B.; Chakrabarti, R.; Bajji, A.C.; Ramanujam, R. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsns. containing them. EP 1049684; JP 2001519422; WO 9919313 .
【3】 Rajagopalan, R.; Ashok, C.B.; Shivaramayya, K.; Gurram, R.M.; Lohray, B.B.; Paraselli, B.R.; Rajan, C.; Lohray, V.B. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsn. containing them. EP 1155006; WO 0050414 .
【1】 Lohray, B.B.; et al.; (-)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid[(-)DRF 2725]: A dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J Med Chem 2001, 44, 16, 2675.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIa)	51686	ethyl (E)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxy-2-propenoate		C₁₅H₁₉BrO₄	详情	详情
(XIIb)	51687	ethyl (Z)-3-[4-(2-bromoethoxy)phenyl]-2-ethoxy-2-propenoate		C₁₅H₁₉BrO₄	详情	详情
(XVIa)	51689	ethyl (E)-2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]-2-propenoate		C₂₇H₂₇NO₅	详情	详情
(XVba)	51690	ethyl (Z)-2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]-2-propenoate		C₂₇H₂₇NO₅	详情	详情
(II)	51675	ethyl 2-(diethoxyphosphoryl)-2-ethoxyacetate		C₁₀H₂₁O₆P	详情	详情
(VIII)	51679	ethyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate		C₂₇H₂₉NO₅	详情	详情
(IX)	51680	methyl 2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanoate		C₂₆H₂₇NO₅	详情	详情
(X)	51681	2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid		C₂₅H₂₅NO₅	详情	详情
(XI)	18799	4-(2-bromoethoxy)benzaldehyde	52191-15-8	C₉H₉BrO₂	详情	详情
(XIII)	51688	ethyl 3-[4-(2-bromoethoxy)phenyl]-2-ethoxypropanoate		C₁₅H₂₁BrO₄	详情	详情
(XIV)	51684	2,3,5,6-Dibenzo-1,4-oxazine; Phenoxazine	135-67-1	C₁₂H₉NO	详情	详情
(XV)	51685	4-[2-(10H-phenoxazin-10-yl)ethoxy]benzaldehyde		C₂₁H₁₇NO₃	详情	详情

合成路线3

Resolution of the racemic acid (X) was carried out via activation as the mixed anhydride (XVIII) upon treatment with pivaloyl chloride (XVII) and triethylamine. Anhydride (XVIII) was then condensed with (S)-2-phenylglycinol (XIX), producing a separable mixture of diastereomeric amides. Isolation of the desired (S,S)-isomer (XX) by silica gel chromatography, followed by amide hydrolysis under acidic conditions, furnished the target (S)-enantiomer.

参考文献中间体

【2】 Kalchar, S.; Lohray, V.B.; Lohray, B.B.; Chakrabarti, R.; Bajji, A.C.; Ramanujam, R. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsns. containing them. EP 1049684; JP 2001519422; WO 9919313 .
【3】 Rajagopalan, R.; Ashok, C.B.; Shivaramayya, K.; Gurram, R.M.; Lohray, B.B.; Paraselli, B.R.; Rajan, C.; Lohray, V.B. (Dr. Reddy's Research Foundation); Novel tricyclic cpds. and their use in medicine; process for their preparation and pharmaceutical compsn. containing them. EP 1155006; WO 0050414 .
【1】 Lohray, B.B.; et al.; (-)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid[(-)DRF 2725]: A dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. J Med Chem 2001, 44, 16, 2675.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	51681	2-ethoxy-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic acid		C₂₅H₂₅NO₅	详情	详情
(XVII)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(XVIII)	51691	1,1-dimethylpropionic 1-ethoxy-2-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propionic anhydride		C₃₀H₃₃NO₆	详情	详情
(XIX)	10973	(2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol	20989-17-7	C₈H₁₁NO	详情	详情
(XX)	51692	(2S)-2-ethoxy-N-[(1S)-2-hydroxy-1-phenylethyl]-3-[4-[2-(10H-phenoxazin-10-yl)ethoxy]phenyl]propanamide		C₃₃H₃₄N₂O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)