CP-265298, -Drug Synthesis Database

【结构式】

【药物名称】CP-265298

【化学名称】(3S-cis)-N-[3-[6-(5,6-Difluoro-2-benzothiazolylmethoxy)-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ylmethyl]-4-methoxyphenyl]trifluoromethanesulfonamide

【CA登记号】158103-79-8, 158190-19-3 (cis-isomer)

【分子式】C₂₈H₂₅F₅N₂O₆S₂

【分子量】644.64125

【开发单位】Pfizer (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Leukotriene CysLT1 (LTD4) Antagonists

合成路线1 合成路线2

合成路线1

Condensation of 5-(benzyloxy)-2-hydroxyacetophenone (I) with acetone in the presence of pyrrolidine in toluene with azeotropical removal of water yielded chromanone (II). Subsequent aldol condensation of (II) with 2-methoxy-5-nitrobenzaldehyde (III), promoted by tetramethyl orthosilicate and KF, produced the benzylidenechromanone (IV). Palladium-catalysed hydrogenation of the benzylidene double bond of (IV) with concomitant benzyl ether cleavage and nitro group reduction, gave benzylchromanone (V). Then, the phenolic hydroxyl group of (V) was alkylated with 2-(chloromethyl)-5,6-difluorobenzothiazole (VI) in the presence of NaH in DMF to afford ether (VII). Treatment of (VII) with trifluoromethanesulfonic anhydride and Et3N produced the bis(sulfonamide) (VIII), which after basic hydrolysis yielded the mono-trifluoromethylsulfonamide (IX). Subsequent reduction of (IX) with Super Hydride(R) afforded the racemic cis alcohol (X).

参考文献中间体

【1】 Chambers, R.J.; Antognoli, G.W.; Cheng, J.B.; Kuperman, A.V.; Liston, T.C.; Marfat, A.; Owens, B.S.; Pillar, J.S.; Shirley, J.T.; Watson, J.W.; Development of 2,2-dimethylchromanol cysteinyl LT1 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3577.
【2】 Chambers, R.J.; et al.; Development of 2,2-dimethylchromanol antagonists of leukotriene D4. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 036.
【3】 Marfat, A.; Chambers, R.J.; Aldol condensation of 6-alkoxy-2,2-dimethylchroman-4-ones with substituted benzaldehydes using tetramethylorthosilicate and potassium fluoride. J Heterocycl Chem 1995, 32, 4, 1401.
【4】 Marfat, A. (Pfizer Inc.); Sulfonamide derivs. of benzenefused hydroxy substd. cycloalkyl and heterocyclic ring cpds.. EP 0665842; JP 1995508534; US 5641789; WO 9408996 .

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)	20133	1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone		C₁₅H₁₄O₃	详情	详情
(II)	20134	6-(benzyloxy)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₁₈H₁₈O₃	详情	详情
(II)	23199	2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether	67-64-1	C₃H₆O	详情	详情
(III)	20135	2-methoxy-5-nitrobenzaldehyde		C₈H₇NO₄	详情	详情
(IV)	20136	6-(benzyloxy)-3-[(E)-(2-methoxy-5-nitrophenyl)methylidene]-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₂₆H₂₃NO₆	详情	详情
(V)	20137	3-(5-amino-2-methoxybenzyl)-6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₁₉H₂₁NO₄	详情	详情
(VI)	20150	2-(chloromethyl)-5,6-difluoro-1,3-benzothiazole		C₈H₄ClF₂NS	详情	详情
(VII)	20151	3-(5-amino-2-methoxybenzyl)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one		C₂₇H₂₄F₂N₂O₄S	详情	详情
(VIII)	20152	N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide		C₂₉H₂₂F₈N₂O₈S₃	详情	详情
(IX)	20153	N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₂₈H₂₃F₅N₂O₆S₂	详情	详情
(X)	20154	N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₂₈H₂₅F₅N₂O₆S₂	详情	详情
(XI)	23214	N-[3-([(3S,4R)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₂₈H₂₅F₅N₂O₆S₂	详情	详情
(XII)	20156	(3S,4R)-6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-3-(2-methoxy-5-[[(trifluoromethyl)sulfonyl]amino]benzyl)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoate		C₄₄H₄₃F₅N₄O₉S₂	详情	详情

合成路线2

Resolution of (X) was then achieved by esterification with Boc-D-tryptophan (XI), followed by isolation of the desired diastereoisomer (XII) by chromatography, and final saponification with NaOH to give the target dextrorotatory enantiomer.

参考文献中间体

【1】 Chambers, R.J.; et al.; Development of 2,2-dimethylchromanol antagonists of leukotriene D4. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 036.
【2】 Chambers, R.J.; Antognoli, G.W.; Cheng, J.B.; Kuperman, A.V.; Liston, T.C.; Marfat, A.; Owens, B.S.; Pillar, J.S.; Shirley, J.T.; Watson, J.W.; Development of 2,2-dimethylchromanol cysteinyl LT1 receptor antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3577.
【3】 Marfat, A.; Chambers, R.J.; Aldol condensation of 6-alkoxy-2,2-dimethylchroman-4-ones with substituted benzaldehydes using tetramethylorthosilicate and potassium fluoride. J Heterocycl Chem 1995, 32, 4, 1401.
【4】 Marfat, A. (Pfizer Inc.); Sulfonamide derivs. of benzenefused hydroxy substd. cycloalkyl and heterocyclic ring cpds.. EP 0665842; JP 1995508534; US 5641789; WO 9408996 .

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)	20154	N-[3-([6-[(5,6-difluoro-1,3-benzothiazol-2-yl)methoxy]-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-3-yl]methyl)-4-methoxyphenyl](trifluoro)methanesulfonamide		C₂₈H₂₅F₅N₂O₆S₂	详情	详情
(XI)	16114	N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid	13139-14-5	C₁₆H₂₀N₂O₄	详情	详情

Extended Information