GW-1616A, GW-311616A, -Drug Synthesis Database

【结构式】

【药物名称】GW-1616A, GW-311616A

【化学名称】(3S,3aS,6aR)-3-Isopropyl-1-(methanesulfonyl)-4-[4-(1-piperidinyl)-2(E)-butenoyl]perhydropyrrolo[3,2-b]pyrrol-2(1H)-one hydrochloride

【CA登记号】197890-44-1, 198062-54-3 (free base), 197890-25-8 (racemate), 197893-23-5 (racemic free base)

【分子式】C₁₉H₃₂ClN₃O₄S

【分子量】434.00159

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, RESPIRATORY DRUGS, 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6

合成路线1

The reaction of D-methionine (I) with tert-butoxycarbonyl anhydride and NaOH in water gives the N-protected compound (II), which is treated with more tert-butoxycarbonyl anhydride and ammonium bicarbonate in pyridine/DMF yielding The N-protected methioninamide (III). The protection of the amide group of (III) with benzyloxycarbonyl chloride and BuLi in THF affords the fully protected methioninamidde (IV), which by reaction with methyl iodide in acetone or acetonitrile gives the dimethylsulfonium iodide (V). The cyclization of (V) by means of DOWEX 2X8-400 (hydroxide form) yields the protected 3-aminopyrrolidinone (VI), which by selective deprotection with HCl followed by acylation with methyl trifluoroacetate and NaHCO3 affords N-[1-(benzyloxycarbonyl)-2-oxopyrrolidin-3(R)-yl]trifluoroacetamide (VII). The reduction of the carbonyl group of (VII) with LiBH4 in THF provides the pyrrolidinol (VIII), which is treated with ethanol and conc. H2SO4 giving the ethyl ether (IX). The condensation of (IX) with the triisopropylsilyl derivative of ethyl 3-methylbutyrate (X) by means of BF3 ethearate in dichloromethane yields the 2-pyrrolidinylbutyrate (XI) as predominant isomer, which is destrifluoroacetylated with K2CO3 in refluxing ethanol/water affording aminopyrrolidine (XII). The cyclization of (XII) by means of tert-butylmagnesium chloride in THF gives a mixture of bicyclic pyrrolidones, from which the chiral isomer (XIII) was separated by crystallization. The mesylation of (XIII) with methanesulfonyl chloride and lithium hexamethyldisylazane in THF affords the sulfonamide (XIV), which is deprotected by hydrogenation with H2 over Pd(OH)2 in ethyl acetate/dioxane giving the bicyclic pyrrolidone (XV), which is finally acylated with 4-(1-piperidinyl)-2(E)-butenoic acid (XVI) by means of HOBT and triethylamine in acetonitrile or oxlayl chloride in dichloromethane.

参考文献中间体

【1】 Macdonald, S.J.F.; et al.; A flexible, practical, and stereoselective synthesis of enantiomerically pure trans-5-oxohexahydropyrrolo[3,2-b]pyrroles (pyrrolidine-trans-lactams), a new class of serine protease inhibitors, using acyliminium methodology. J Org Chem 1999, 64, 14, 5166.

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)	26695	D-methionine	348-67-4	C₅H₁₁NO₂S	详情	详情
(II)	26710	(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid	5241-66-7	C₁₀H₁₉NO₄S	详情	详情
(III)	26696	tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate		C₁₀H₂₀N₂O₃S	详情	详情
(IV)	26697	benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate		C₁₈H₂₆N₂O₅S	详情	详情
(V)	26698	[(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide		C₁₉H₂₉IN₂O₅S	详情	详情
(VI)	26699	benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate		C₁₇H₂₂N₂O₅	详情	详情
(VII)	26700	benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情
(VIII)	26701	benzyl (3R)-2-hydroxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₅F₃N₂O₄	详情	详情
(IX)	26702	benzyl (3R)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₆H₁₉F₃N₂O₄	详情	详情
(X)	26703	1-Ethoxy-3-methyl-1-(triisopropylsilyloxy)-1-butene		C₇H₁₃O₂Pr₃Si	详情	详情
(XI)	26704	benzyl (2S,3R)-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₂₁H₂₇F₃N₂O₅	详情	详情
(XII)	26705	benzyl (2S,3R)-3-amino-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate		C₁₉H₂₈N₂O₄	详情	详情
(XIII)	26706	benzyl (3aR,6S)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate		C₁₇H₂₂N₂O₃	详情	详情
(XIV)	26707	benzyl (3aR,6S,6aS)-6-isopropyl-4-(methylsulfonyl)-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate		C₁₈H₂₄N₂O₅S	详情	详情
(XV)	26708	(3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one		C₁₀H₁₈N₂O₃S	详情	详情
(XVI)	26709	(E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid		C₉H₁₅NO₂	详情	详情

合成路线2

Synthesis of intermediate (XI) of Scheme 25142902e: Racemic 2,4-diaminobutyric acid (I) was esterified in MeOH in the presence of SOCl2. The resulting methyl ester (II) was cyclized using Dowex 2x8-400 resin to give 3-amino-2-pyrrolidinone (III), which was converted to the trifluoroacetamide (IV) using methyl trifluoroacetate in MeOH. The lactam nitrogen of (IV) was then protected with benzyl chloroformate and lithium hexamethyldisilazide yielding (V). Reduction of (V) with NaBH4, followed by treatment with ethanolic H2SO4 provided ethoxypyrrolidine (VI). Ethyl isovalerate (VII) was converted to the silyl enolate (VIII) employing lithium hexamethyldisilazide and silyl triflate. Coupling of (VIII) with ethoxypyrrolidine (VI) in the presence of BF3-Et2O provided (IX). After hydrolysis of the trifluoroacetamide group of (IX) with K2CO3 yielding (X), its cyclization by means of tert-butylmagnesium chloride yielded the pyrrolopyrrolone system. Separation of the required (3aS, 6aR)-isomer (XI) was achieved by chiral HPLC.

参考文献中间体

【1】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

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)	28222	2,4-diaminobutyric acid	1883-09-6	C₄H₁₀N₂O₂	详情	详情
(II)	28223	methyl 2,4-diaminobutanoate		C₅H₁₂N₂O₂	详情	详情
(III)	28224	3-amino-2-pyrrolidinone		C₄H₈N₂O	详情	详情
(IV)	28225	2,2,2-trifluoro-N-(2-oxo-3-pyrrolidinyl)acetamide		C₆H₇F₃N₂O₂	详情	详情
(V)	28229	benzyl 2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情
(VI)	28230	benzyl 2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₆H₁₉F₃N₂O₄	详情	详情
(VII)	28226	ethyl 3-methylbutanoate	108-64-5	C₇H₁₄O₂	详情	详情
(VIII)	28227	(Z)-1-ethoxy-3-methyl-1-butenyl triisopropylsilyl ether		C₁₆H₃₄O₂Si	详情	详情
(IX)	28231	benzyl 2-[1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₂₁H₂₇F₃N₂O₅	详情	详情
(X)	28232	benzyl 3-amino-2-[1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate		C₁₉H₂₈N₂O₄	详情	详情
(XI)	28228	benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate		C₁₇H₂₂N₂O₃	详情	详情

合成路线3

Alternative synthesis of intermediate (XI) of Scheme 25142902e: In an alternative procedure, (R)-asparagine (XII) was protected as the trifluoroacetamide (XIII) and then esterified by means of AcCl in MeOH yielding (XIV). Dehydration of the amide function of (XIV) employing tosyl chloride and pyridine produced nitrile (XV). The catalytic hydrogenation of (XV) with concomitant cyclization of the intermediate amine generated the chiral pyrrolidinone (XVI), which was protected with benzyl chloroformate and n-BuLi to give (XVII). This was converted to the intermediate (XI) by means of a sequence analogous to that for the racemic pyrrolidinone (IV).

参考文献中间体

【1】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

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)	28227	(Z)-1-ethoxy-3-methyl-1-butenyl triisopropylsilyl ether		C₁₆H₃₄O₂Si	详情	详情
(XI)	28228	benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate		C₁₇H₂₂N₂O₃	详情	详情
(XII)	28237	R-(-)-Asparagine; S-(-)-2-Aminosuccinamic acid; D-asparagine	5794-13-8	C₄H₈N₂O₃	详情	详情
(XIII)	28233	(2R)-4-amino-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid		C₆H₇F₃N₂O₄	详情	详情
(XIV)	28234	methyl (2R)-4-amino-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butanoate		C₇H₉F₃N₂O₄	详情	详情
(XV)	28235	methyl (2R)-3-cyano-2-[(2,2,2-trifluoroacetyl)amino]propanoate		C₇H₇F₃N₂O₃	详情	详情
(XVI)	28236	2,2,2-trifluoro-N-[(3R)-2-oxopyrrolidinyl]acetamide		C₆H₇F₃N₂O₂	详情	详情
(XVII)	26700	benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情
(XVIII)	26702	benzyl (3R)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₆H₁₉F₃N₂O₄	详情	详情
(XIX)	26704	benzyl (2S,3R)-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₂₁H₂₇F₃N₂O₅	详情	详情
(XX)	28238	benzyl (2S,3R)-3-amino-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate		C₁₉H₂₈N₂O₄	详情	详情

合成路线4

Alternative synthesis of intermediate (XVII) of Scheme 25142902b: In a further procedure, (R)-methionine (XXI), was protected as the Boc derivative (XXII). Subsequent treatment of (XXII) with Boc2O and then with ammonium bicarbonate yielded amide (XXIII), which was condensed with benzyl chloroformate to produce imide (XXIV). The S-alkylation with CH3I yielded sulfonium salt (XXV), which was then cyclized to pyrrolidinone (XXVI) in the presence of Dowex 2x8-400 resin. Acid deprotection of the Boc group of (XXVI), followed by condensation with methyl trifluoroacetate furnished intermediate (XVII) already described in Scheme 25142902b.

参考文献中间体

【1】 Dowle, M.D.; Harrison, L.A.; Macdonald, S.J.F.; Inglis, G.G.A.; Johnson, M.R.; Shah, P.; Clarke, G.D.E.; The discovery and synthesis of some bicyclic trans-lactams having potent neutrophil elastase inhibitory properties. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.215.
【2】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	26700	benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情
(XXI)	26695	D-methionine	348-67-4	C₅H₁₁NO₂S	详情	详情
(XXII)	26710	(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid	5241-66-7	C₁₀H₁₉NO₄S	详情	详情
(XXIII)	26696	tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate		C₁₀H₂₀N₂O₃S	详情	详情
(XXIV)	26697	benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate		C₁₈H₂₆N₂O₅S	详情	详情
(XXV)	26698	[(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide		C₁₉H₂₉IN₂O₅S	详情	详情
(XXVI)	26699	benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate		C₁₇H₂₂N₂O₅	详情	详情

合成路线5

Synthesis of intermediate (XXX) of Scheme 25142902e: Alkylation of piperidine (XXVII) with ethyl 4-bromocrotonate (XXVIII) afforded tertiary amine (XXIX). Acid hydrolysis of the ethyl ester of (XXIX) then provided carboxylic acid (XXX).

参考文献中间体

【1】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXVII)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(XXVIII)	28239	ethyl (E)-4-bromo-2-butenoate	37746-78-4	C₆H₉BrO₂	详情	详情
(XXIX)	28240	ethyl (E)-4-(1-piperidinyl)-2-butenoate		C₁₁H₁₉NO₂	详情	详情
(XXX)	26709	(E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid		C₉H₁₅NO₂	详情	详情

合成路线6

The intermediate pyrrolopyrrolone (XI) was converted to the methanesulfonamide (XXXI) upon treatment with mesyl chloride and lithium hexamethyldisilazide. Removal of the benzyloxycarbonyl group of (XXXI) by hydrogenolysis over Pd(OH)2 produced amine (XXXII). This was coupled with piperidinylbutenoic acid (XXX) using EDC and HOBt to yield the target compound, which was finally converted to the hydrochloride salt.

参考文献中间体

【1】 Dowle, M.D.; Harrison, L.A.; Macdonald, S.J.F.; Inglis, G.G.A.; Johnson, M.R.; Shah, P.; Clarke, G.D.E.; The discovery and synthesis of some bicyclic trans-lactams having potent neutrophil elastase inhibitory properties. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.215.
【2】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	28228	benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate	C₁₇H₂₂N₂O₃	详情	详情
(XXX)	26709	(E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid	C₉H₁₅NO₂	详情	详情
(XXXI)	26707	benzyl (3aR,6S,6aS)-6-isopropyl-4-(methylsulfonyl)-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate	C₁₈H₂₄N₂O₅S	详情	详情
(XXXII)	26708	(3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one	C₁₀H₁₈N₂O₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)