3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione -Drug Synthesis Database

【结构式】

【分子编号】41029

【品名】3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione

【CA登记号】

【分子式】C₅H₃Cl₂NO₂

【分子量】179.98976

【元素组成】C 33.37% H 1.68% Cl 39.39% N 7.78% O 17.78%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIII)

Treatment of (R)-1-chloro-2,3-propanediol (I) with either K2CO3 or Cs2CO3 in CH2Cl2, followed by O-protection with Trt-Cl and Et3N in CH2Cl2, yields (S)-trityl glycidol (II). Alternatively, derivative (II) can also be obtained either by direct O-protection of (R)-glycidol (III) by means of Trt-Cl and Et3N in refluxing CH2Cl2 or by cyclization of protected propanediol derivative (IV)--obtained from treatment of compound (I) with Trt-Cl and Et3N in CH2Cl2--by means of KOH in EtOH. Reaction of (S)-trityl glycidol (II) with vinyl magnesium bromide (V) by means of CuI in THF provides (S)-1-(triphenylmethoxy)-4-penten-2-ol (VI), which is then condensed with allyl bromide (VII) with KOtBu or NaH in THF to afford compound (VIII). Ozonolysis of (VIII) in CH2Cl2/MeOH, followed by reductive quench with NaBH4 in NaOH, gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (IX), which is then treated with MsCl/Et3N in CH2Cl2 to yield bismesylate (X). Coupling of compound (X) with 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) [obtained by treatment of dichloromaleic anhydride (XII) with methylamine hydrochloride by means of NaOMe in HOAc to furnish dichloro-N-methylmaleimide (XIII), followed by Grignard reaction of (XIII) with indole (XIV) in toluene/THF by means of EtMgBr in Et2O] by means of Cs2CO3 in DMF gives the 14-membered macrocycle (XV).

参考文献中间体

合成目标

【1】 Faul, M.M.; Sullivan, K.A.; Neel, D.A.; Krumrich, C.A.; Jirousek, M.R.; Winneroski, L.L.; Gillig, J.R.; Rito, C.J.; Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation. J Org Chem 1998, 63, 6, 1961.
【2】 Engel, G.L.; Farid, N.A.; Faul, M.M.; Jirousek, M.R.; Richardson, L.A.; Winneroski, L.L. Jr. (Eli Lilly and Company); Protein kinase C inhibitor. EP 0776895; JP 1999500149; US 5710145; WO 9718809 .
【3】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. US 5721272 .
【4】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 .
【5】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. EP 0776899 .

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)	49696	(S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol	60827-45-4	C₃H₇ClO₂	详情	详情
(II)	41006	(2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane		C₂₂H₂₀O₂	详情	详情
(III)	19241	(2S)oxiranylmethanol	60456-23-7	C₃H₆O₂	详情	详情
(IV)	51942	(2R)-1-chloro-3-(trityloxy)-2-propanol		C₂₂H₂₁ClO₂	详情	详情
(V)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(VI)	41007	(2S)-1-(trityloxy)-4-penten-2-ol		C₂₄H₂₄O₂	详情	详情
(VII)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(VIII)	41008	1-[[[(2S)-2-(allyloxy)-4-pentenyl]oxy](diphenyl)methyl]benzene; allyl (1S)-1-[(trityloxy)methyl]-3-butenyl ether		C₂₇H₂₈O₂	详情	详情
(IX)	41010	(3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol		C₂₅H₂₈O₄	详情	详情
(X)	51943	(7S)-2,11-dimethyl-2,11-dimethylene-7-[(trityloxy)methyl]-3,6,10-trioxa-2lambda(6),11lambda(6)-dithia-1,11-dodecadiene; 2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl (1S)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(trityloxy)methyl]propyl ether		C₃₁H₄₀O₄S₂	详情	详情
(XI)	51012	5-(tert-butyl) 1-(2,3,5,6-tetrafluorophenyl) (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate		C₃₂H₃₈F₄N₂O₉	详情	详情
(XII)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(XIII)	41029	3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione		C₅H₃Cl₂NO₂	详情	详情
(XIV)	15292	Indole; 1H-indole	120-72-9	C₈H₇N	详情	详情
(XV)	41016	(18S)-4-methyl-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione		C₄₆H₃₉N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXX)

The intermediate (XI), 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione, has been obtained as follows: Reaction of 2,3-dichloromaleic anhydride (XXIX) with methylamine and NaOMe in acetic acid gives 3,4-dichloro-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XXX), which is then condensed with indole (XXXI) by means of ethylmagnesium bromide in refluxing toluene/THF to the target compound (XI).

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026.
【2】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	41012	3,4-di(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione	113963-68-1	C₂₁H₁₅N₃O₂	详情	详情
(XXIX)	21947	3,4-dichloro-2,5-furandione	1122-17-4	C₄Cl₂O₃	详情	详情
(XXX)	41029	3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione		C₅H₃Cl₂NO₂	详情	详情
(XXXI)	15292	Indole; 1H-indole	120-72-9	C₈H₇N	详情	详情

Extended Information