SDZ-242-484, PKF-242-484, -Drug Synthesis Database

【结构式】

【药物名称】SDZ-242-484, PKF-242-484

【化学名称】N1-[2,2-Dimethyl-1(S)-(N-methylcarbamoyl)propyl]-N4-hydroxy-3(R)-(hydroxymethyl)-2(S)-(4-methoxyphenyl)succinamide

【CA登记号】205807-59-6

【分子式】C₁₉H₂₉N₃O₆

【分子量】395.45948

【开发单位】Novartis (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Antiarthritic Drugs, Asthma Therapy, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, MMP-1 (Interstitial Collagenase) Inhibitors, MMP-13 (Collagenase 3) Inhibitors, MMP-2 (Gelatinase A) Inhibitors, MMP-3 (Stromelysin 1) Inhibitors, MMP-9 (Gelatinase B) Inhibitors, TNF-alpha-Converting Enzyme (TACE) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The intermediate phenylacetic acid allyl ester (IV) is prepared by two methods. Reaction of trans-1,4-dibromo-2-butene (I) with benzyl alcohol under phase-transfer conditions provides the benzyl ether (II). Subsequent DBU-mediated coupling of (II) with (4-methoxyphenyl)acetic acid (III) yields ester (IV).

参考文献中间体

【1】 Kottirsch, G.; et al.; beta-Aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme. J Med Chem 2002, 45, 11, 2289.
【2】 Kottirsch, G.; Neumann, U. (Novartis AG); Hydroxamic acid derivs.. EP 0929517; JP 2000508338; US 2002003804; US 6500983; WO 9814424 .

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)	18349	(E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene	821-06-7	C₄H₆Br₂	详情	详情
(II)	61680	benzyl (E)-4-bromo-2-butenyl ether; 1-({[(E)-4-bromo-2-butenyl]oxy}methyl)benzene		C₁₁H₁₃BrO	详情	详情
(III)	34794	(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal		C₁₇H₁₅ClO₃	详情	详情
(IV)	61681	(E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate		C₂₀H₂₂O₄	详情	详情

合成路线2

In an alternative synthesis of (IV), alkylation of propargyl alcohol (V) with benzyl bromide in a two-phase system gives ether (VI). Subsequent addition of paraformaldehyde to the lithium acetylide derived from (VI) furnishes alcohol (VII). Selective reduction of acetylene (VII) to the trans olefin (VIII) is accomplished by means of Red-Al in cold THF. The allylic alcohol (VIII) is then esterified with (4-methoxyphenyl)acetic acid (III) in the presence of DCC to form ester (IV).

参考文献中间体

【1】 Koch, G.; Kottirsch, G.; Wietfeld, B.; Kusters, E.; Process development of a dual MMP/TNF inhibitor (SDZ 242-484). Org Process Res Dev 2002, 6, 5, 652.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	34794	(E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal		C₁₇H₁₅ClO₃	详情	详情
(IV)	61681	(E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate		C₂₀H₂₂O₄	详情	详情
(V)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(VI)	16663	benzyl 2-propynyl ether; 1-[(2-propynyloxy)methyl]benzene		C₁₀H₁₀O	详情	详情
(VII)	61682	4-(benzyloxy)-2-butyn-1-ol		C₁₁H₁₂O₂	详情	详情
(VIII)	61683	(E)-4-(benzyloxy)-2-buten-1-ol		C₁₁H₁₄O₂	详情	详情

合成路线3

Allyl ester (IV) is subjected to Claisen-Ireland rearrangement in the presence of strong bases to produce a diastereomeric mixture of pentenoic acids, from which the desired isomer (IX) can be isolated via crystallization of its (S)-phenylethylamine salt. Subsequent coupling of acid (IX) with tert-leucine methylamide (X) provides amide (XI). Oxidative cleavage of the terminal olefin of (XI) to aldehyde (XII) is performed by either treatment with NaIO4 or by ozonolysis. Aldehyde (XII) is further oxidized to the carboxylic acid (XIII) employing NaClO2. Coupling of acid (XIII) with O-benzyl hydroxylamine yields the benzyl-protected hydroxamate (XIV). The title compound is finally obtained by hydrogenolysis of the benzyl groups of (XIV) in the presence of Pd/BaSO4.

参考文献中间体

【1】 Koch, G.; Kottirsch, G.; Wietfeld, B.; Kusters, E.; Process development of a dual MMP/TNF inhibitor (SDZ 242-484). Org Process Res Dev 2002, 6, 5, 652.
【2】 Kottirsch, G.; et al.; beta-Aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme. J Med Chem 2002, 45, 11, 2289.
【3】 Kottirsch, G.; Neumann, U. (Novartis AG); Hydroxamic acid derivs.. EP 0929517; JP 2000508338; US 2002003804; US 6500983; WO 9814424 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	61681	(E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate		C₂₀H₂₂O₄	详情	详情
(IX)	61684	(2S,3R)-3-[(benzyloxy)methyl]-2-(4-methoxyphenyl)-4-pentenoic acid		C₂₀H₂₂O₄	详情	详情
(X)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(XI)	61685	(2S,3R)-3-[(benzyloxy)methyl]-N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-2-(4-methoxyphenyl)-4-pentenamide		C₂₇H₃₆N₂O₄	详情	详情
(XII)	61686	(2S)-2-{[(2S,3R)-4-(benzyloxy)-3-formyl-2-(4-methoxyphenyl)butanoyl]amino}-N,3,3-trimethylbutanamide		C₂₆H₃₄N₂O₅	详情	详情
(XIII)	61687	(2R,3S)-2-[(benzyloxy)methyl]-4-({(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}amino)-3-(4-methoxyphenyl)-4-oxobutanoic acid		C₂₆H₃₄N₂O₆	详情	详情
(XIV)	61688	(2R,3S)-N~1~-(benzyloxy)-2-[(benzyloxy)methyl]-N~4~-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-3-(4-methoxyphenyl)butanediamide		C₃₃H₄₁N₃O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)