Sezolamide hydrochloride, MK-417, -Drug Synthesis Database

【结构式】

【药物名称】Sezolamide hydrochloride, MK-417

【化学名称】(+)-(S)-4-(2-Methylpropylamino)-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride

【CA登记号】119271-78-2, 123308-22-5 (free base)

【分子式】C₁₁H₁₉ClN₂O₄S₃

【分子量】374.93008

【开发单位】Banyu (Originator), Merck Sharp & Dohme (Originator)

【药理作用】Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Carbonic Anhydrase Inhibitors

合成路线1 合成路线2

合成路线1

A new synthesis of MK-417 has been published: The reaction of thiophene (I) with butyllithium and sulfur in THF yields thiophene-2-thiol lithium salt (II) which, without isolation, is condensed with potassium 3-bromopropionate (III) in water - THF giving 3-(2-thienylthio)propanoic acid (IV). The cyclization of (IV) with trifluoroacetic anhydride in hot toluene affords 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (V), which is oxidized with H2O2 and sodium tungstate in ethyl acetate - toluene to give the corresponding 7,7-dioxide (VI). The stereocontrolled reduction of (VI) with borane - methylsulfide and (S)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxaazaborole as catalyst in THF yields (R)-(+)-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol 7,7-dioxide (VII), which is converted to the corresponding sodium salt (VIII) with sodium acetylide in THF. This salt (VIII), without isolation, is treated with p-toluenesulfonyl chloride to afford the corresponding tosylate (IX) which, also without isolation, is condensed with isobutylamine (X) to give (S)-(-)-4-(2-methylpropylamino)-5,6-dihydro-4H-thieno[2,3-b]thiopyran 7,7-dioxide (XI). The reaction of (XI), first with oleum and then with thionyl chloride, yields the corresponding 2-sulfonyl chloride (XII), which is finally treated with aqueous ammonium hydroxide.

参考文献中间体

【1】 Reamer, R.A.; Jones, T.J.; Jones, E.T.T.; Blacklock, T.J.; Grabowski, E.J.J.; Mathre, D.J.; Roberts, F.E.; Mohan, J.J.; Xavier, L.C.; Sohar, P.; An asymmetric synthesis of MK-0417 - Observations on oxazaborolidine-catalyzed reductions. J Org Chem 1991, 56, 2, 763.

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)	13297	Thiophene	110-02-1	C₄H₄S	详情	详情
(II)	13298	2-Sulfanylthiophene lithium salt		C₄H₃LiS₂	详情	详情
(III)	13299	3-Bromopropionic acid potassium salt		C₃H₄BrKO₂	详情	详情
(IV)	13300	3-(2-Thienylsulfanyl)propionic acid		C₇H₈O₂S₂	详情	详情
(V)	13301	5,6-Dihydro-4H-thieno[2,3-b]thiopyran-4-one		C₇H₆OS₂	详情	详情
(VI)	13302	2,3-Dihydro-2H-thieno[2,3-b]thiopyran-1,1,4-trione		C₇H₆O₃S₂	详情	详情
(VII)	13303	(4R)-4-Hydroxy-3,4-dihydro-2H-thieno[2,3-b]thiopyran-1,1(2H)-dione		C₇H₈O₃S₂	详情	详情
(VIII)	13304	sodium (4R)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-4-olate		C₇H₇NaO₃S₂	详情	详情
(IX)	13305	(4R)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-4-yl 4-methylbenzenesulfonate		C₁₄H₁₄O₅S₃	详情	详情
(X)	13306	2-Methyl-1-propanamine; Isobutylamine	78-81-9	C₄H₁₁N	详情	详情
(XI)	13307	(4S)-4-(Isobutylamino)-3,4-dihydro-2H-thieno[2,3-b]thiopyran-1,1(2H)-dione		C₁₁H₁₇NO₂S₂	详情	详情
(XII)	13308	(4S)-4-(Isobutylamino)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonyl chloride		C₁₁H₁₆ClNO₄S₃	详情	详情

合成路线2

The reaction of (I) with acetonitrile in sulfuric acid provides the amide (II), which after hydrolysis in 12N HCl/methanol yields the 4-amino derivative (III). Acylation of (III) with isobutyryl chloride followed by reduction with borane-methylsulfide complex gives the racemate (V), MK-927 (2). The resolution of MK-927 is accomplished through the di-p-toluoyl-D-tartaric acid salt.

参考文献中间体

【1】 Baldwin, J.J.; Christy, M.E.; Ponticello, G.S.; Anyiglaucoma thieno-thiopyran and thieno-thiepin sulfonamide derivatives, compositions, and method of use thereof.. US 4677115 .
【2】 Baldwin, J.J.; Ponticello, G.S.; Sugrue, M.F.; MK-417. Drugs Fut 1989, 14, 7, 636.
【3】 Ponticello, G.S.; Freedman, M.B.; Habecker, C.N.; Lyle, P.A.; Schwam, H.; Varga, S.L.; Christy, M.E.; Randall, W.C.; Baldwin, J.J.; Thienothiopyran-2-sulfonamides: A novel class of water-soluble carbonic anhydrase inhibitors. J Med Chem 1987, 30, 591-7.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	14932	isobutyryl chloride; 2-methylpropanoyl chloride	79-30-1	C₄H₇ClO	详情	详情
(I)	21040	4-hydroxy-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonamide		C₇H₉NO₅S₃	详情	详情
(II)	21041	N-[6-(aminosulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-4-yl]acetamide		C₉H₁₂N₂O₅S₃	详情	详情
(III)	21042	4-amino-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonamide		C₇H₁₀N₂O₄S₃	详情	详情
(IV)	21043	N-[6-(aminosulfonyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-4-yl]-2-methylpropanamide		C₁₁H₁₆N₂O₅S₃	详情	详情
(V)	21044	4-(isobutylamino)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[2,3-b]thiopyran-6-sulfonamide		C₁₁H₁₈N₂O₄S₃	详情	详情

Extended Information