Freselestat, ONO-PO-736, ONO-6818, -Drug Synthesis Database

【结构式】

【药物名称】Freselestat, ONO-PO-736, ONO-6818

【化学名称】2-(5-Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[1-(5-tert-butyl-1,3,4-oxadiazol-2-ycarbonyl)-2-methylpropyl]acetamide

【CA登记号】208848-19-5

【分子式】C₂₃H₂₈N₆O₄

【分子量】452.51741

【开发单位】Ono (Originator)

【药理作用】Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, Leukocyte Elastase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

The reaction of methyl pivalate (I) with hydrazine gives the expected hydrazide (II), which is cyclized with methyl or ethyl orthoformate and Ts-OH, yielding the 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N-(tert-butoxycarbonyl)-L-valinal (IV) by means of BuLi and MgBr2 in THF affords the alcohol (V), which is treated with HCl in dioxane to provide the amino alcohol (VI). The condensation of (VI) with 2-[5-(benzyloxycarbonyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetic acid (VII) by means of EDC, HOBT and NMM in DMF gives the corresponding amide (VIII), which is treated with DMP or (COCl)2 in order to oxidize the secondary OH group to the ketone (IX). Finally, this compound is deprotected by means of AlCl3 and anisole or HBr in HOAc to afford the target compound.

参考文献中间体

【1】 Yamamoto, T.; Okuma, M.; Ohmoto, K.; et al.; Development of orally active nonpeptidic inhibitors of human neutrophil elastase. J Med Chem 2001, 44, 8, 1268.
【3】 Spruce, L.W.; Gyorkos, A. (Cortech, Inc.); Serine protease inhibitors. JP 2001192398; JP 2001507679; WO 9824806 .
【2】 Ohmoto, K.; Matsuoka, S.; Sekioka, T.; Imanishi, H.; Hirota, Y.; Kawabata, K.; Nakai, H.; Yamamoto, T.; Horiuchi, T.; Odagaki, Y.; Toda, M.; Design and synthesis of new orally active nonpeptide inhibitors of human neutrophil elastase. J Med Chem 2000, 43, 26, 4927.

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)	47802	Trimethylacetic acid methyl ester; 2,2-Dimethylpropionic acid methyl ester; Methyl Trimethylacetate; pivalic acid methyl ester; methyl pivalate	598-98-1	C₆H₁₂O₂	详情	详情
(II)	47803	Pivalic acid hydrazide; 2,2-dimethylpropanohydrazide		C₅H₁₂N₂O	详情	详情
(III)	47804	2-(tert-butyl)-1,3,4-oxadiazole		C₆H₁₀N₂O	详情	详情
(IV)	47805	tert-butyl (1S)-1-formyl-2-methylpropylcarbamate		C₁₀H₁₉NO₃	详情	详情
(V)	47806	tert-butyl (1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate		C₁₆H₂₉N₃O₄	详情	详情
(VI)	47807	(2S)-2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanol		C₁₁H₂₁N₃O₂	详情	详情
(VII)	47808	2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid		C₂₀H₁₇N₃O₅	详情	详情
(VIII)	47809	benzyl 1-[2-([(1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropyl]amino)-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₃₁H₃₆N₆O₆	详情	详情
(IX)	47810	benzyl 1-[2-[((1S)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₃₁H₃₄N₆O₆	详情	详情

合成路线2

The intermediate 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid (IV) has been obtained by several related ways: 1. The cyclization of N-(tert-butoxycarbonylmethyl)benzamidine (I) with 3-methoxy-2-nitro-2-propenoic acid methyl ester (II) by means of Na2CO3 gives 2-(5-nitro-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetic acid tert-butyl ester (III), which is hydrolyzed by means of TFA to the target intermediate acid (IV). 2. The direct cyclization of N-(carboxymethyl)benzamidine (V) with propenoic ester (II) by means of NaOH gives the target intermediate (IV). 3. The cyclization of N-allylbenzamidine (VI) with propenoic ester (II) by means of HCl in methanol gives the allyl pyrimidinone (VII), which is oxidized with NaIO4 and RhCl3 to afford the target intermediate acid (IV). 4. The cyclization of N-(2-furylmethyl)benzamidine (VIII) with propenoic ester (II) by means of HCl in toluene/methanol gives the furylmethyl pyrimidinone (IX), with is treated with ozone, NaIO4 and RhCl3 in acetonitrile to yield the target intermediate acid (IV). 5. The cyclization of N-(2,2-dimethoxyethyl(benzamidine (X) with propenoic ester (II) in methanol gives the pyrimidinone acetaldehyde dimethylacetal (XI), which is hydrolyzed with TFA to the corresponding aldehyde (XII). Finally, this compound is oxidized with NaClO2 to afford the target intermediate acid (IV).

参考文献中间体

【1】 Yamamoto, T.; Okuma, M.; Ohmoto, K.; et al.; Development of orally active nonpeptidic inhibitors of human neutrophil elastase. J Med Chem 2001, 44, 8, 1268.
【2】 Okada, T.; Hachiya, K.; Motoi, T.; Kojima, T.; Hashimoto, S. (Ono Pharmaceutical Co., Ltd.); Pyrimidine derivs., process for preparing the derivs. and drugs containing the same as the active ingredient. WO 0123361 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	47811	tert-butyl 2-[[imino(phenyl)methyl]amino]acetate	C₁₃H₁₈N₂O₂	详情	详情
(II)	47812	methyl (E)-3-methoxy-2-nitro-2-propenoate	C₅H₇NO₅	详情	详情
(III)	47813	tert-butyl 2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetate	C₁₆H₁₇N₃O₅	详情	详情
(IV)	47814	2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid	C₁₂H₉N₃O₅	详情	详情
(V)	47815	2-[[imino(phenyl)methyl]amino]acetic acid	C₉H₁₀N₂O₂	详情	详情
(VI)	47816	N-allylbenzenecarboximidamide	C₁₀H₁₂N₂	详情	详情
(VII)	47817	3-allyl-5-nitro-2-phenyl-4(3H)-pyrimidinone	C₁₃H₁₁N₃O₃	详情	详情
(VIII)	47818	N-(2-furylmethyl)benzenecarboximidamide	C₁₂H₁₂N₂O	详情	详情
(IX)	47819	3-(2-furylmethyl)-5-nitro-2-phenyl-4(3H)-pyrimidinone	C₁₅H₁₁N₃O₄	详情	详情
(X)	47820	N-(2,2-dimethoxyethyl)benzenecarboximidamide	C₁₁H₁₆N₂O₂	详情	详情
(XI)	47821	3-(2,2-dimethoxyethyl)-5-nitro-2-phenyl-4(3H)-pyrimidinone	C₁₄H₁₅N₃O₅	详情	详情
(XII)	47822	2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetaldehyde	C₁₂H₉N₃O₄	详情	详情

合成路线3

The condensation of intermediate acetic acid (IV) with 2-tert-butyl-5-(DL-valyl)-1,3,4-oxadiazole (XIII) by means of methyl chloroformate and NMM gives the corresponding amide (XIV), which is finally reduced with H2 over Pd/C in MeOH.

参考文献中间体

【1】 Yamamoto, T.; Okuma, M.; Ohmoto, K.; et al.; Development of orally active nonpeptidic inhibitors of human neutrophil elastase. J Med Chem 2001, 44, 8, 1268.
【2】 Okada, T.; Hachiya, K.; Motoi, T.; Kojima, T.; Hashimoto, S. (Ono Pharmaceutical Co., Ltd.); Pyrimidine derivs., process for preparing the derivs. and drugs containing the same as the active ingredient. WO 0123361 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	47814	2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid	C₁₂H₉N₃O₅	详情	详情
(XIII)	47823	2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone	C₁₁H₁₉N₃O₂	详情	详情
(XIV)	47824	N-(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)-2-[5-nitro-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetamide	C₂₃H₂₆N₆O₆	详情	详情

合成路线4

The intermediate oxadiazole (VIII) has been obtained as follows: The reaction of methyl pivalate (I) with refluxing hydrazine hydrate gives the corresponding hydrazide (II), which is cyclized with methyl orthoformate catalyzed by Ts-OH to yield 2-tert-butyl-1,3,4-oxadiazole (III). The condensation of (III) with N2-(tert-butoxycarbonyl)-N1-methoxy-N1-methyl-DL-valinamide (VI) by means of LDA in THF affords the acylated oxadiazole (VII), which is finally deprotected with HCl in ethyl acetate to provide the target intermediate (VIII).

参考文献中间体

【1】 Kojima, T.; Hachiya, K.; Ohmoto, K. (Ono Pharmaceutical Co., Ltd.); 1,3,4-Oxadiazole derivs. and process for producing the same. EP 1162199; WO 0055145 .

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)	47802	Trimethylacetic acid methyl ester; 2,2-Dimethylpropionic acid methyl ester; Methyl Trimethylacetate; pivalic acid methyl ester; methyl pivalate	598-98-1	C₆H₁₂O₂	详情	详情
(II)	47803	Pivalic acid hydrazide; 2,2-dimethylpropanohydrazide		C₅H₁₂N₂O	详情	详情
(III)	47804	2-(tert-butyl)-1,3,4-oxadiazole		C₆H₁₀N₂O	详情	详情
(IV)	51959	N-(tert-butoxycarbonyl)valine		C₁₀H₁₉NO₄	详情	详情
(V)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(VI)	51958	tert-butyl 1-[[methoxy(methyl)amino]carbonyl]-2-methylpropylcarbamate		C₁₂H₂₄N₂O₄	详情	详情
(VII)	51957	tert-butyl 1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropylcarbamate		C₁₆H₂₇N₃O₄	详情	详情
(VIII)	47823	2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone		C₁₁H₁₉N₃O₂	详情	详情

合成路线5

The reaction of 3-(2,2-dimethoxyethyl)-2-phenyl-4-oxo-3,4-dihydropyrimidine-5-carboxylic acid (IX) with isobutyl chloroformate and hydroxylamine gives the corresponding hydroxamic acid (X), which is acylated with Ac2O in pyridine to yield the acetoxy compound (XI). The degradation of (XI) by reaction with DBU in refluxing THF affords the amine (XII), which is protected with benzyl chloroformate (XIII) and NaHCO3, providing the carbamate (XIV). The hydrolysis of the dimethylacetal group of (XIV) with HCl in hot acetic acid gives the acetaldehyde derivative (XV), which is oxidized with NaClO2 in tert-butanol/water yielding the corresponding acetic acid derivative (XVI). The condensation of (XVI) with the intermediate amine (VIII) by means of ethyl chloroformate and NMM in THF affords the amide (XVII), which is hydrogenolyzed with H2 over Pd/C in order to eliminate its carbamate protecting group and provide the target racemic 285811.

参考文献中间体

【1】 Kojima, T.; Hachiya, K.; Ohmoto, K. (Ono Pharmaceutical Co., Ltd.); 1,3,4-Oxadiazole derivs. and process for producing the same. EP 1162199; WO 0055145 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	47823	2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanone		C₁₁H₁₉N₃O₂	详情	详情
(IX)	51960	1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxylic acid		C₁₅H₁₆N₂O₅	详情	详情
(X)	51961	1-(2,2-dimethoxyethyl)-N-hydroxy-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarboxamide		C₁₅H₁₇N₃O₅	详情	详情
(XI)	51962	5-[[(acetoxy)amino]carbonyl]-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone		C₁₇H₁₉N₃O₆	详情	详情
(XII)	51963	5-amino-3-(2,2-dimethoxyethyl)-2-phenyl-4(3H)-pyrimidinone		C₁₄H₁₇N₃O₃	详情	详情
(XIII)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(XIV)	51964	benzyl 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₂₂H₂₃N₃O₅	详情	详情
(XV)	51965	benzyl 6-oxo-1-(2-oxoethyl)-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₂₀H₁₇N₃O₄	详情	详情
(XVI)	47808	2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid		C₂₀H₁₇N₃O₅	详情	详情
(XVII)	51966	benzyl 1-[2-[(1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate		C₃₁H₃₄N₆O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)