合成路线1
该中间体在本合成路线中的序号:
(XII) 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).
【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.
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【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 .
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【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 .
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【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 .
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【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 .
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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:
(XXIX) 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).
【1】
Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026.
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【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 .
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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
|
合成路线3
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded a dihydroxynaphthoquinone, assumed to exist as an equilibrium mixture between posicional isomers (III) and (IV). Subsequent methylation with CH3I in the presence of Ag2O yielded a mixture of dimethoxy quinones (V) and (VI) from which the target compound (V) was isolated by column chromatography.
【1】
Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
(IV) |
21949 |
6,7-dichloro-5,8-dihydroxynaphthoquinone
|
|
C10H4Cl2O4 |
详情 |
详情
|
(VI) |
21950 |
6,7-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded a dihydroxynaphthoquinone, assumed to exist as an equilibrium mixture between posicional isomers (III) and (IV). Subsequent methylation with CH3I in the presence of Ag2O yielded a mixture of dimethoxy quinones (V) and (VI), which were separated by column chromatography. Treatment of isomer (V) with NaOMe in MeOH then produced the target trimethoxy quinone.
【1】
Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
(IV) |
21949 |
6,7-dichloro-5,8-dihydroxynaphthoquinone
|
|
C10H4Cl2O4 |
详情 |
详情
|
(V) |
21951 |
2,3-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
(VI) |
21950 |
6,7-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded a dihydroxynaphthoquinone, assumed to exist as an equilibrium mixture between posicional isomers (III) and (IV). Subsequent methylation with CH3I in the presence of Ag2O yielded a mixture of dimethoxy quinones (V) and (VI) from which the target compound (VI) was isolated by column chromatography.
【1】
Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
(IV) |
21949 |
6,7-dichloro-5,8-dihydroxynaphthoquinone
|
|
C10H4Cl2O4 |
详情 |
详情
|
(V) |
21951 |
2,3-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dihydroxynaphthoquinone (III). Subsequent acetylation with Ac2O and AcOH furnished the target diacetate.
【1】
Huang, L.-J.; Chang, F.C.; Lee, K.H.; Wang, J.P; Teng, C.M.; Kuo, S.C.; Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds. Bioorg Med Chem 1998, 6, 12, 2261. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
合成路线7
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Finally, treatment of (III) with resorcinol (IV) and Na2CO3 in DMSO at room temperature furnished the target compound.
【1】
Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
(IV) |
10361 |
1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol
|
108-46-3 |
C6H6O2 |
详情 | 详情
|
合成路线8
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Subsequent methylation of (III) with CH3I in the presence of Ag2O in CHCl3 gave a mixture of dimethoxy naphthoquinones (IV) and (V), from which the desired isomer (IV) was isolated by recrystallization from CHCl3-CCl4. Finally, treatment of (IV) with 3-methoxyphenol (VI) and Na2CO3 in DMSO at room temperature furnished the target compound.
【1】
Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
(IV) |
21951 |
2,3-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
(V) |
21950 |
6,7-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
(VI) |
22389 |
3-Methoxyphenol
|
150-19-6 |
C7H8O2 |
详情 | 详情
|
合成路线9
该中间体在本合成路线中的序号:
(II) Friedel Crafts condensation of p-dimethoxybenzene (I) with dichloromaleic anhydride (II) in a molten mixture of AlCl3 and NaCl yielded dichloronaphthazarin (III). Subsequent methylation of (III) with CH3I in the presence of Ag2O in CHCl3 gave a mixture of dimethoxy naphthoquinones (IV) and (V), from which the desired isomer (IV) was isolated by recrystallization from CHCl3-CCl4. Finally, treatment of (IV) with 3,5-dimethoxyphenol (VI) and Na2CO3 in DMSO at room temperature furnished the target compound.
【1】
Chang, H.-X.; Chou, T.C.; Savaraj, N.; Liu, L.F.; Yu, C.; Cheng, C.C.; Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1,4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones. J Med Chem 1999, 42, 3, 405. |
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) |
21946 |
1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether
|
150-78-7 |
C8H10O2 |
详情 | 详情
|
(II) |
21947 |
3,4-dichloro-2,5-furandione
|
1122-17-4 |
C4Cl2O3 |
详情 | 详情
|
(III) |
21948 |
2,3-dichloro-5,8-dihydroxynaphthoquinone
|
14918-69-5 |
C10H4Cl2O4 |
详情 | 详情
|
(IV) |
21951 |
2,3-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
(V) |
21950 |
6,7-dichloro-5,8-dimethoxynaphthoquinone
|
|
C12H8Cl2O4 |
详情 |
详情
|
(VI) |
22390 |
3,5-dimethoxyphenol
|
500-99-2 |
C8H10O3 |
详情 | 详情
|