合成路线1
该中间体在本合成路线中的序号:
(IV) The reaction of 2,4,6-triamino-5-methylquinazoline (I) with NaNO2 and aqueous HCl gives the corresponding diazonium salt (II), which by a Sandmeyer reaction with cuprous cyanide in hot water yields 2,4-diamino-5-methylquinazoline-6-carbonitrile (III). Finally, this compound is reductocondensed with 3,4,5-trimethoxyaniline (IV) by means of H2 over Raney-Ni in acetic acid.
【1】
Elslager, E.F.; Werbel, L.M. (Pfizer Inc.); Quinazoline compounds and processes for their production. GB 1345502 .
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【2】
Hillier, K.; Castañer, J.; Serradell, M.N.; Blancafort, P.; JB-11. Drugs Fut 1981, 6, 5, 282.
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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) |
32222 |
2,4-diamino-5-methyl-6-quinazolinylamine; 5-methyl-2,4,6-quinazolinetriamine
|
|
C9H11N5 |
详情 |
详情
|
(II) |
32223 |
2,4-diamino-5-methyl-6-quinazolinediazonium chloride
|
|
C9H9ClN6 |
详情 |
详情
|
(III) |
32224 |
2,4-diamino-5-methyl-6-quinazolinecarbonitrile
|
|
C10H9N5 |
详情 |
详情
|
(IV) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
合成路线2
该中间体在本合成路线中的序号:
(IV) The title compound has been prepared by two synthetic procedures. Condensation of 2-aminopyridine-3,5-dicarbonitrile (I) with guanidine (II) in refluxing EtOH produced the pyridopyrimidine (III). Subsequent reductive condensation of (III) with 3,4,5-trimethoxyaniline (IV) by hydrogenation over Raney Nickel provided the (arylamino)methyl derivative (V). Final reductive alkylation of (V) by means of formaldehyde and sodium cyanoborohydride then gave the target methylated amine.
【1】
Gangjee, A. (Duquesne University); Derivs. of pyrido [2,3-d] and [3,2-d] pyrimidine and methods of using these derivs.. US 5508281 .
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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) |
31544 |
2-amino-3,5-pyridinedicarbonitrile
|
|
C7H4N4 |
详情 |
详情
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(II) |
14790 |
Guanidine
|
113-00-8 |
CH5N3 |
详情 | 详情
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(III) |
14269 |
2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile
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|
C8H6N6 |
详情 |
详情
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(IV) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
(V) |
31546 |
2-amino-6-[(3,4,5-trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidin-4-ylamine; 6-[(3,4,5-trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
|
|
C17H20N6O3 |
详情 |
详情
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合成路线3
该中间体在本合成路线中的序号:
(IV) In an alternative synthesis, 2,4,6-triaminopyrimidine (VI) was condensed with bromomalonaldehyde (VII) under acidic conditions to give pyridopyrimidine (VIII), which was protected with pivaloyl anhydride in pyridine, yielding the bispivaloylamide (IX). Palladium-catalyzed Heck coupling of (IX) with styrene (X) afforded (XI). Subsequent ozonolysis of the styryl derivative (XI), followed by reductive workup with dimethyl sulfide gave aldehyde (XII). Reduction of (XII) to the corresponding alcohol with NaBH4, followed by bromination with PPh3 and Br2 provided bromide (XIII). The N-methyl aniline (XIV) was synthesized by direct alkylation of 3,4,5-trimethoxyaniline (IV) with methyl iodide. Nucleophilic displacement of the bromide (XIII) with aniline (XIV) afforded the tertiary amine (XV). The pivaloyl protecting groups of (XV) were finally removed by treatment with methanolic NaOMe.
【1】
Gangjee, A.; et al.; Synthesis and dihydrofolate reductase inhibitory activities of 2,4-diamino-5-deaza and 2,4-diamino-5, 10-dideaza lipophilic antifolates. J Med Chem 1997, 40, 4, 470.
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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 |
(IV) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
(VI) |
28977 |
2,6-diamino-4-pyrimidinylamine
|
1004-38-2 |
C4H7N5 |
详情 | 详情
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(VII) |
14278 |
2-Bromomalonaldehyde
|
|
C3H3BrO2 |
详情 |
详情
|
(VIII) |
31547 |
6-bromopyrido[2,3-d]pyrimidine-2,4-diamine; 2-amino-6-bromopyrido[2,3-d]pyrimidin-4-ylamine
|
|
C7H6BrN5 |
详情 |
详情
|
(IX) |
31548 |
N-[6-bromo-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide
|
|
C17H22BrN5O2 |
详情 |
详情
|
(X) |
19649 |
1-vinylbenzene
|
100-42-5 |
C8H8 |
详情 | 详情
|
(XI) |
31549 |
N-[2-[(2,2-dimethylpropanoyl)amino]-6-[(E)-2-phenylethenyl]pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide
|
|
C25H29N5O2 |
详情 |
详情
|
(XII) |
31550 |
N-[2-[(2,2-dimethylpropanoyl)amino]-6-formylpyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide
|
|
C18H23N5O3 |
详情 |
详情
|
(XIII) |
31554 |
3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one
|
|
C11H11BrO |
详情 |
详情
|
(XIV) |
31552 |
3,4,5-trimethoxy-N-methylaniline; N-methyl-N-(3,4,5-trimethoxyphenyl)amine
|
|
C10H15NO3 |
详情 |
详情
|
(XV) |
31553 |
N-(2-[(2,2-dimethylpropanoyl)amino]-6-[[3,4,5-trimethoxy(methyl)anilino]methyl]pyrido[2,3-d]pyrimidin-4-yl)-2,2-dimethylpropanamide
|
|
C28H38N6O5 |
详情 |
详情
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合成路线4
该中间体在本合成路线中的序号:
(VI) Condensation of 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride (I) with methyl 3-aminophenylacetate (II) leads to amide (III). Intramolecular cyclization of (III) and simultaneous hydrolysis in the presence of NaOH in MeOH/DMF provide the isoxazoloquinoline derivative (IV). After activation of acid (IV) as the corresponding acid chloride (V), coupling with 3,4,5-trimethoxyaniline (VI) furnishes the title compound
【1】
Norman, B.H.; et al.; Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1). Bioorg Med Chem Lett 2002, 12, 6, 883.
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【2】
Kroin, J.S.; Norman, B.H.; Gruber, J.M. (Eli Lilly and Company); Methods for inhibiting MRP1. EP 1067928; JP 2002510625; US 6369070; WO 9951228 .
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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) |
59641 |
3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride
|
|
C11H6Cl2FNO2 |
详情 |
详情
|
(II) |
41111 |
methyl 2-(3-aminophenyl)acetate
|
|
C9H11NO2 |
详情 |
详情
|
(III) |
62525 |
methyl 2-[3-({[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]carbonyl}amino)phenyl]acetate
|
|
C20H16ClFN2O4 |
详情 |
详情
|
(IV) |
62526 |
2-{3-[9-chloro-3-methyl-4-oxoisoxazolo[4,3-c]quinolin-5(4H)-yl]phenyl}acetic acid
|
|
C19H13ClN2O4 |
详情 |
详情
|
(V) |
62527 |
2-{3-[9-chloro-3-methyl-4-oxoisoxazolo[4,3-c]quinolin-5(4H)-yl]phenyl}acetyl chloride
|
|
C19H12Cl2N2O3 |
详情 |
详情
|
(VI) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(IV) The reaction of indoline (I) with formic acid in refluxing toluene gives N-formylindoline (II), which is treated with chlorosulfonic acid to yield 5-(chlorosulfonyl)indoline-1-carbaldehyde (III). The reaction of (III) with 3,4,5-trimethoxyaniline (IV) and pyridine in THF affords the sulfonamide (V), which is deformylated to sulfonamide (VI) with HCl in methanol. The reaction of indoline (VI) with salcomine and O2 in methanol provides the corresponding indole derivative (VII), which is finally methylated with methyl iodide and NaHMDS in THF to give the target 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.
【2】
Barr, K.J.; Steiner, B.A.; Qun, L.; Rosenberg, S.; Sham, H.; Gwaltney, S.L. II; Imade, H.M.; Woods, K.W. (Abbott Laboratories Inc.); Cell proliferation inhibitors. WO 0073264 .
|
【1】
Li, Q.; Woods, K.W.; Steiner, A.; et al.; Synthesis and biological evaluation of biarylsulfonamides as tubulin polymerization inhibitors. Discovery of A-318315 and A-293620 as orally and intravenously active antimitotic agents. Proc Am Assoc Cancer Res 2002, 43, Abst 1313. |
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) |
19652 |
indoline
|
496-15-1 |
C8H9N |
详情 | 详情
|
(II) |
55546 |
1-Formylindoline
|
2861-59-8 |
C9H9NO |
详情 | 详情
|
(III) |
55547 |
1-formyl-5-indolinesulfonyl chloride
|
|
C9H8ClNO3S |
详情 |
详情
|
(IV) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
(V) |
55548 |
1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide
|
|
C18H20N2O6S |
详情 |
详情
|
(VI) |
55549 |
N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide
|
|
C17H20N2O5S |
详情 |
详情
|
(VII) |
55550 |
N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide
|
|
C17H18N2O5S |
详情 |
详情
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合成路线6
该中间体在本合成路线中的序号:
(IV) The reaction of indoline (I) with formic acid in refluxing toluene gives N-formylindoline (II), which is treated with chlorosulfonic acid to yield 5-(chlorosulfonyl)indoline-1-carbaldehyde (III). The reaction of (III) with 3,4,5-trimethoxyaniline (IV) and pyridine in THF affords the sulfonamide (V), which is deformylated to sulfonamide (VI) with HCl in methanol. The reaction of indoline (VI) with salcomine and O2 in methanol provides the corresponding indole derivative (VII), which is methylated with methyl iodide and NaHMDS in THF to give 1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide (VIII). Finally, this compound is condensed with N,N-dimethylglycine (IX) by means of DCC and 4-(1-pyrrolidinyl)pyridine (pypyr) in dichloromethane.
【1】
Li, Q.; Woods, K.W.; Steiner, A.; et al.; Synthesis and biological evaluation of biarylsulfonamides as tubulin polymerization inhibitors. Discovery of A-318315 and A-293620 as orally and intravenously active antimitotic agents. Proc Am Assoc Cancer Res 2002, 43, Abst 1313. |
【2】
Barr, K.J.; Steiner, B.A.; Qun, L.; Rosenberg, S.; Sham, H.; Gwaltney, S.L. II; Imade, H.M.; Woods, K.W. (Abbott Laboratories Inc.); Cell proliferation inhibitors. WO 0073264 .
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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) |
19652 |
indoline
|
496-15-1 |
C8H9N |
详情 | 详情
|
(II) |
55546 |
1-Formylindoline
|
2861-59-8 |
C9H9NO |
详情 | 详情
|
(III) |
55547 |
1-formyl-5-indolinesulfonyl chloride
|
|
C9H8ClNO3S |
详情 |
详情
|
(IV) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
(V) |
55548 |
1-formyl-N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide
|
|
C18H20N2O6S |
详情 |
详情
|
(VI) |
55549 |
N-(3,4,5-trimethoxyphenyl)-5-indolinesulfonamide
|
|
C17H20N2O5S |
详情 |
详情
|
(VII) |
55550 |
N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide
|
|
C17H18N2O5S |
详情 |
详情
|
(VIII) |
55569 |
1-methyl-N-[3,4,5-tris(methyloxy)phenyl]-1H-indole-5-sulfonamide
|
|
C18H20N2O5S |
详情 |
详情
|
(IX) |
16765 |
2-(dimethylamino)acetic acid; N,N-Dimethylglycine
|
1118-68-9 |
C4H9NO2 |
详情 | 详情
|
合成路线7
该中间体在本合成路线中的序号:
(V) Chlorination of 5-fluorouracil (I) by means of POCl3 gives 2,4-dichloro-5-fluoropyrimidine (II), which is condensed with the pyrido-[3,2-b][1,4]oxazin-3-one derivative (III) to afford the secondary amine (IV). Then, subsequent displacement of the remaining chlorine of pyrimidine (IV) with 3,4,5-trimethoxyaniline (V) yields the substituted pyrimidine-2,4-diamine (VI) . Condensation of pyridooxazinone derivative (VI) with di-tert-butyl chloromethyl phosphate (VII) prepared by chlorination of potassium di-tert-butylphosphate (VIII) with ClSO3CH2Cl by means of Bu4NHSO4 in CH2Cl2/H2O – in the presence of Cs2CO3 in acetone or DMF gives a mixture of three N-substituted regioisomers, which are then subjected to either column chromatography or crystallization on MTBE to provide the major N-substituted oxazinone (IX). Hydrolysis of the t-butyl ester groups of (IX) by means of AcOH in H2O or TFA in CH2Cl2 affords free acid (X) , which is finally treated with aqueous or IPA/H2O NaOH .
Alternatively, condensation of pyridooxazinone (VI) and chloromethyl phosphate (VII) with Cs2CO3 in DMAC at 40 °C affords the N-substituted oxazinone (IX), which is directly hydrolyzed by means of AcOH in H2O, and the phosphoric acid (X) is submitted to purification by crystallization on DMF .
【1】
Singh, R., Atuegbu, A., Ramphal, J. et al. (Rigel Pharmaceuticals, Inc.).Pyrimidinediamine kinase inhibitors. US 2010179134, WO 2010078369. |
【2】
Felfer, U., Giselbrecht, K.-H., Wolberg, M. (Rigel Pharmaceuticals, Inc.). Synthesis of N4-(2,2-dimethyl-4-[dihydrogen phosphonoxy]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine disodium salt. US 2011003986, WO 2011002999. |
【3】
Bhamidipati, S., Singh, R., Sun, T., Masuda, E. (Rigel Pharmaceuticals, Inc.). Prodrug salts of 2,4-pyrimidinediamine compounds and their uses. EP 2078026, JP 2010510322, WO 2008064274. |
【4】
Singh, R., Bhamidipati, S., Masuda, E., Stella, V.J., Sun, T. (Rigel Pharmaceuticals, Inc.). Prodrugs of 2,4-pyrimidinediamine compounds and their uses. CA 2591948, EP 1856135, EP 2161275, JP 2008527048, US 2006211657, US 7449458, WO 2006078846. |
【5】
Singh, R., Bhamidipati, S., Stella, V.J., Sun, T. (Rigel Pharmaceuticals, Inc.). Prodrugs of 2,4-pyrimidinediamine compounds and their uses. US 7563892. |
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) |
29241 |
5-fluoro-2,4(1H,3H)-pyrimidinedione;5-fluorouracil;5-Fluoro-2,4-pyrimidinedione;5-Fluoropyrimidine-2,4-dione |
51-21-8 |
C4H3FN2O2 |
详情 | 详情
|
(II) |
45722 |
2,4-dichloro-5-fluoropyrimidine;2,4-Dichloro-5-fluorouracil |
|
C4HCl2FN2 |
详情 |
详情
|
(III) |
68776 |
6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one |
1002726-62-6 |
C9H11N3O2 |
详情 | 详情
|
(IV) |
68777 |
6-((2-chloro-5-fluoropyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one |
|
C13H11ClFN5O2 |
详情 | 详情
|
(V) |
31545 |
3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine;3,4,5-Trimethoxybenzenamine;[3,4,5-Tris(methyloxy)phenyl]amine |
24313-88-0 |
C9H13NO3 |
详情 | 详情
|
(VI) |
68778 |
6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one |
|
C22H23FN6O5 |
详情 | 详情
|
(VII) |
42239 |
di(tert-butyl) chloromethyl phosphate;di-tert-butyl chloromethyl phosphate;PHOSPHORIC ACI DI-T-BUTYL EXTER CHLOROMETHYL ESTER |
229625-50-7 |
C9H20ClO4P |
详情 | 详情
|
(VIII) |
68779 |
potassium di-tert-butyl phosphate |
|
C8H18KO4P |
详情 | 详情
|
(IX) |
68780 |
di-tert-butyl ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl) phosphate |
|
C31H42FN6O9P |
详情 | 详情
|
(X) |
68781 |
(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl dihydrogen phosphate |
|
C23H26FN6O9P |
详情 | 详情
|