Olopatadine hydrochloride, AL-4943A, ALO-4943A, KW-4679, Opatanol, Allelock, Patanol, -Drug Synthesis Database

【结构式】

【药物名称】Olopatadine hydrochloride, AL-4943A, ALO-4943A, KW-4679, Opatanol, Allelock, Patanol

【化学名称】(Z)-11-[3-(Dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride

【CA登记号】140462-76-6, 113806-05-6 (free base)

【分子式】C₂₁H₂₄ClNO₃

【分子量】373.88333

【开发单位】Kyowa Hakko (Originator), Alcon (Licensee)

【药理作用】Allergic Skin Disorders, Treatment for, Antiallergic Ophthalmic Agents, Antipruritics, Antipsoriatics, Asthma Therapy, Atopic Dermatitis, Agents for, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, Eczema, Treatment of, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists, Mediator Release Inhibitors

合成路线1 合成路线2

合成路线1

Reaction of the sodium salt of p-hydroxyphenylacetic acid methyl ester (I) with phthalide (II) gives 2-(4-carboxymethylphenoxymethyl)benzoic acid methyl ester (III), which is cyclized with trifluoroacetic anhydride followed by borontrifluoride etherate to yield 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (IV). Wittig reaction of compound (IV) with 3-(dimethylaminopropyl)triphenylphosphonium bromide hydrobromide (V) yields (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (VIII), which is hydrolyzed with NaOH and treated with p-toluenesulfonic acid in isopropanol to afford the p-toluenesulfonate salt (IX), from which the free base is finally liberated. Compound (V) is obtained from (3-bromopropyl)triphenylphosphonium bromide hydrobromide (VI), previously prepared from 1,3-dibromopropane (VII) and triphenylphosphine in toluene.

参考文献中间体

【1】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 .
【2】 Oshiam, E.; Kumazawa, T.; Otaki, S.; Obase, H.; Ohmori, K.; Ishii, H.; Manabe, H.; Tamura, T.; Shuto, K. (Kyowa Hakko Kogyo Co., Ltd.); Dibenz[b,e]oxepin deriv. and antiallergic and antiinflammatory agent. EP 0235796; JP 1988010784; US 5116863 .
【3】 Sano, T.; et al.; Process improvement in the production of a pharmaceutical intermediate using a reaction calorimeter for studies on the reaction kinetics of amination of a bromopropyl compound. Org Process Res Dev 1998, 2, 3, 169.
【4】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905.
【5】 Otaki, S.; Sato, H.; Ohshima, E.; et al.; Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives. J Med Chem 1992, 35, 11, 2074.
【6】 Prous, J.; Castaner, J.; Graul, A.; KW-4679. Drugs Fut 1993, 18, 9, 794.

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)	12575	sodium 4-(2-methoxy-2-oxoethyl)benzenolate		C₉H₉NaO₃	详情	详情
(II)	12576	2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one	87-41-2	C₈H₆O₂	详情	详情
(III)	12577	2-[[4-(2-Methoxy-2-oxoethyl)phenoxy]methyl]benzoic acid		C₁₇H₁₆O₅	详情	详情
(IV)	12578	methyl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate		C₁₇H₁₄O₄	详情	详情
(V)	12579	[3-(Dimethylamino)propyl](triphenyl)phosphonium bromide		C₂₃H₂₇BrNP	详情	详情
(VI)	12580	(3-Bromopropyl)(triphenyl)phosphonium bromide; (3-Bromopropyl)triphenylphosphonium bromide	3607-17-8	C₂₁H₂₁Br₂P	详情	详情
(VII)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(VIII)	12582	1-[11-[(Z)-3-(Dimethylamino)propylidene]dibenzo[b,e]oxepin-2(6H)-yl]acetone		C₂₂H₂₅NO₂	详情	详情
(IX)	12583	2-[11-[(Z)-3-(Dimethylamino)propylidene]dibenzo[b,e]oxepin-2(6H)-yl]acetic acid		C₂₁H₂₃NO₃	详情	详情

合成路线2

Reduction of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid methyl ester (IV) with lithium aluminum hydride gives 11-hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin (X), whose primary hydroxyl group is protected with triphenylchloromethane in pyridine to yield 11-hydroxy-2-(2-triphenylmethoxyethyl)-6,11-dihdrodibenz[b,e]oxepin (XI). Oxidation of (XI) with potassium permanganate affords 11-oxo-2-(2-triphenylmethoxyethyl)-6,11-dihydrodibenz[b,e]oxepin (XII), which is treated with 3-(dimethylamino)propylmagnesium chloride (XIII) to give 11-[3-(dimethylamino)propyl]-11-hydroxy-2-(2-triphenylmethoxyethyl)-6,11-dihydrodibenz[b,e]oxepin (XIV). Elimation of water with phosphorous oxychloride yields 11-[3-(dimethylamino)propylidene]-2-(2-triphenylmethoxyethyl)-6,11-dihydrodibenz[b,e]oxepin (XV), which is deprotected with p-toluenesulfonic acid to 11-[3-(dimethylamino)propylidene]- 2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin (XVI). Finally, compound (XVI) is oxidized with Jones reagent.

参考文献中间体

【1】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 .
【2】 Oshiam, E.; Kumazawa, T.; Otaki, S.; Obase, H.; Ohmori, K.; Ishii, H.; Manabe, H.; Tamura, T.; Shuto, K. (Kyowa Hakko Kogyo Co., Ltd.); Dibenz[b,e]oxepin deriv. and antiallergic and antiinflammatory agent. EP 0235796; JP 1988010784; US 5116863 .
【3】 Iwao, J.; Iso, T.; Kawashima, Y. (Santen Pharmaceutical Co., Ltd.); Sulfur-containing polycyclic cpds. JP 1988104969 .
【4】 Prous, J.; Castaner, J.; Graul, A.; KW-4679. Drugs Fut 1993, 18, 9, 794.
【5】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	12584	2-(2-Hydroxyethyl)-6,11-dihydrodibenzo[b,e]oxepin-11-ol	C₁₆H₁₆O₃	详情	详情
(XI)	12585	2-[2-(Trityloxy)ethyl]-6,11-dihydrodibenzo[b,e]oxepin-11-ol	C₃₅H₃₀O₃	详情	详情
(XII)	12586	2-[2-(Trityloxy)ethyl]dibenzo[b,e]oxepin-11(6H)-one	C₃₅H₂₈O₃	详情	详情
(XIII)	12587	Chloro[3-(dimethylamino)propyl]magnesium	C₅H₁₂ClMgN	详情	详情
(XIV)	12588	11-[3-(Dimethylamino)propyl]-2-[2-(trityloxy)ethyl]-6,11-dihydrodibenzo[b,e]oxepin-11-ol	C₄₀H₄₁NO₃	详情	详情
(XV)	12589	N,N-Dimethyl-N-[3-[2-[2-(trityloxy)ethyl]dibenzo[b,e]oxepin-11(6H)-ylidene]propyl]amine; N,N-Dimethyl-3-[2-[2-(trityloxy)ethyl]dibenzo[b,e]oxepin-11(6H)-ylidene]-1-propanamine	C₄₀H₃₉NO₂	详情	详情
(XVI)	12590	2-[11-[(Z)-3-(Dimethylamino)propylidene]dibenzo[b,e]oxepin-2(6H)-yl]-1-ethanol	C₂₁H₂₅NO₂	详情	详情

Extended Information