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【结 构 式】

【分子编号】14790

【品名】Guanidine

【CA登记号】113-00-8

【 分 子 式 】CH5N3

【 分 子 量 】59.07092

【元素组成】C 20.33% H 8.53% N 71.14%
与该中间体有关的原料药合成路线共 56 条
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合成路线1

该中间体在本合成路线中的序号：(III)

ABPP is a phenylpyrimidinone and as such is prepared in high yield by condensation of guanidine with ethyl benzoylacetate. Ethyl benzoylacetate is commercially available and can also be prepared in high yield by condensation of dilithiomonoethylmalonate at 78 C with benzoyl chloride. Reaction of the resultant beta-ketoester with guanidine in refluxing ethanol affords its pyrimidinone in high yield. ABPP can be prepared from this pyrimidinone by bromination in acetic acid at room temperature. Similarly, iodine can be introduced at this step to afford the iodo analogue, AIPP. The overall yield of these pyrimidinones from monoethylmalonate is generally) 50%.

参考文献 中间体
合成目标
【1】 Fitzpatrick, F.A.; Wynalda, M.A.; High-perfomance liquid chromatographic determination of 5-halopyrimidinone interferon inducers. Anal Chem 1982, 17, 151.
【2】 Skulnick, H.I.; Stringfellow, D.A.; Wierenga, W.; Weed, S.D.; Antiviral and interferon induction stucture-activity relationship profile of 6-aryl-pyrimidines. Am Soc Microbiol 1980, 2, 1402-1404.
【3】 Brown, T.B.; Stevens, M.F.G.; Triazines and related products. XV. 2,4-Diaminopyrimidines and 2-aminopyrimidin-4(3H)-ones bearing 1,2,3-benzotriazinyl groups as potential dihydrofolic reductase inhibitors. J Chem Soc - Perkins Trans I 1975, 11, 1023-1028.
【4】 Wierenga, W.; Skulnick, H.I.; J Org Chem 1979, 44, 310.
【5】 Stringfellow, D.A.; Eidson, E.E.; Wierenga, W.; Skulnick, H.I.; Renis, H.E.; Weed, S.D.; 5-Substituted 2-amino-6-phenyl-4(3H)-pyrimidinones. Antiviral- and interferon-inducing agents. J Med Chem 1980, 23, 3, 237-239.
【6】 Wierenga, W.; ABPP. Drugs Fut 1984, 9, 8, 567.
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) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(II) 10004 Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester 94-02-0 C11H12O3 详情 详情
(III) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IV) 30490 2-amino-6-phenyl-4(3H)-pyrimidinone C10H9N3O 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The synthesis of [14C]-labeled piritrexim has been described: The condensation of 2,5-dimethoxybenzaldehyde (I) with acetone in aqueous NaOH gives 4-(2,5-dimethoxyphenyl)-3-(E)-buten-2-one (II), which is hydrogenated with H2 over Pd/C in methanol to give 4-(2,5-dimethoxyphenyl)-2-butanone (III). The condensation of (III) with malononitrile (IV) by means of acetic acid-sodium acetate in refluxing toluene yields 2-cyano-5-(2,5-dimethoxyphenyl)-3-methyl-2-pentenenitrile (V), which is condensed with acetic acid diethoxymethyl ester (VI) at 105 C to afford the corresponding diethoxymethyl derivative (VII). The cyclization of (VII) with 32% HBr in acetic acid affords 2-bromo-5-(2,5-dimethoxybenzyl)-4-methylpyridine-3-carbonitrile (VIII), which is finally cyclized again with [14C]-labeled guanidine (IX) by means of NaH in refluxing tert-butyl alcohol.

参考文献 中间体
合成目标
【1】 Wisowaty, J.C.; Darnofall, M.E.; Hill, J.A.; Synthesis of carbon-14 labelled piritrexim - A potential anticancer agent. J Label Compd Radiopharm 1993, 33, 12, 1119.
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) 10174 2,5-Dimethoxybenzaldehyde 93-02-7 C9H10O3 详情 详情
(II) 10175 (E)-4-(2,5-Dimethoxyphenyl)-3-buten-2-one C12H14O3 详情 详情
(III) 10176 4-(2,5-Dimethoxyphenyl)-2-butanone C12H16O3 详情 详情
(IV) 12061 Malononitrile 109-77-3 C3H2N2 详情 详情
(V) 10177 2-[3-(2,5-Dimethoxyphenyl)-1-methylpropylidene]malononitrile C15H16N2O2 详情 详情
(VI) 17661 Diethoxymethyl acetate 14036-06-7 C7H14O4 详情 详情
(VII) 10178 2-[2-(2,5-Dimethoxybenzyl)-3,3-diethoxy-1-methylpropylidene]malononitrile C20H26N2O4 详情 详情
(VIII) 10179 2-Bromo-5-(2,5-dimethoxybenzyl)-4-methylnicotinonitrile C16H15BrN2O2 详情 详情
(IX) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IX) 44601 guanidine CH5N3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(C)

The alkylation of ethyl benzoylacetate (A) with beta-ethoxyethyl bromide (B) using potassium carbonate in dimethyl formamide at 80 C gives the beta-3-keto ester (I). Condensation of (I) with guanidine hydrochloride (C) using sodium methoxide in tert-butanol at 80 C gives the pyrimidine (II). Protection of the amino group is achieved by tormylation at room temperature with the mixed anhydride (III) from formic and acetic acids. Chlorination with an excess of phosphorus oxychloride at 100 C gives a mixture of (V) and (VIII). The mixture of chloropyrimidines (V, VIII) is stirred at room temperature with excess hydrazi-ne hydrate to give the aminohydrazinopyrimidine (VI). This is heated with ethyl orthoformate in triglyme at 135 C to give the bicyclic compound (VII). This triglyme solution is then heated to 20 C to effect a Dimroth type rearrangement to give SC-33643.

参考文献 中间体
合成目标
【1】 Rorig, K.L.; Heilman, R.D.; SC-33643. Drugs Fut 1985, 10, 4, 298.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10004 Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester 94-02-0 C11H12O3 详情 详情
(D) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(B) 29132 ethyl 3-bromopropanoate 539-74-2 C5H9BrO2 详情 详情
(I) 29133 diethyl 2-benzoylpentanedioate C16H20O5 详情 详情
(II) 29134 2-amino-5-(2-ethoxyethyl)-6-phenyl-4-pyrimidinol C14H17N3O2 详情 详情
(III) 29135 Acetyl formyl mixed anhydride C3H4O3 详情 详情
(IV) 29136 5-(2-ethoxyethyl)-4-hydroxy-6-phenyl-2-pyrimidinylformamide C15H17N3O3 详情 详情
(V) 29137 4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylformamide C15H16ClN3O2 详情 详情
(VI) 29138 5-(2-ethoxyethyl)-4-hydrazino-6-phenyl-2-pyrimidinamine C14H19N5O 详情 详情
(VII) 29139 8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-5-amine C15H17N5O 详情 详情
(VIII) 29140 4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylamine C14H16ClN3O 详情 详情
(C) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线4

该中间体在本合成路线中的序号：(A)

The reaction of dimethyl 2,6-dimethoxyterphthalate (I) with hydroxylamine by means of polyphosphoric acid at 70 C gives methyl 4-(N-hydroxycarbamoyl)-3,5-dimethoxybenzoate (II), which by further reaction with PPA is converted into methyl 4-amino-3,5-dimethoxybenzoate (III). The reaction of (III) with NaNO2 and HBr affords the corresponding diazonium salt, which without isolation is treated with CuBr yielding methyl-4-bromo-3,5-dimethoxybenzoate (IV). The reduction of (IV) with diisobutylaluminum hydride in THF gives 4-bromo-3,5-dimethoxybenzaldehyde (V), which is condensed with 3-methoxypropionitrile (VI) by means of sodium methoxide in refluxing methanol to yield 4-bromo-3,5-dimethoxy-alpha-(methoxymethyl)cinnamic acid nitrile (VII). Finally, this compound is cyclized with guanidine (A) by means of sodium methoxide in hot methanol DMSO. 2) The hydrolysis of (IV) with KOH in ethanol gives 4-bromo-3,5-dimethoxybenzoic acid (VIII), which is treated with SOCl2 in refluxing benzene - DMF to afford 4-bromo-3,5-dimethoxybenzoylchloride (IX). Then the reduction of (IX) with H2 over Pd/BaSO4 in xylene yields (V), already obtained.

参考文献 中间体
合成目标
【1】 Kompis, I. (F. Hoffmann-La Roche AG); Benzylpyirimidine derivates. CA 1017743; DE 2452889; FR 2250533; GB 1449387; JP 50077378; NL 7414528 .
【2】 Sweetman, A.J.; Serradell, M.N.; Castaner, J.; Blancafort, P.; Brodimoprim. Drugs Fut 1982, 7, 2, 93.
【3】 Kompis, I.; Wick, A.; Synthesis of 4-halo-substituted analogs of trimethropin. Helv Chim Acta 1977, 60, 8, 3025-34.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(I) 31924 Methyl 4-(acetoxy)-3,5-dimethoxybenzoate; Dimethyl 2,6-dimethoxyterephthalate 16849-68-6 C12H14O6 详情 详情
(II) 31925 Methyl 4-(N-hydroxycarbamoyl)-3,5-dimethoxybenzoate; Methyl 4-[(hydroxyamino)carbonyl]-3,5-dimethoxybenzoate C11H13NO6 详情 详情
(III) 31926 Methyl 4-amino-3,5-dimethoxybenzoate C10H13NO4 详情 详情
(IV) 31927 Methyl 4-bromo-3,5-dimethoxybenzoate C10H11BrO4 详情 详情
(V) 31928 4-Bromo-3,5-dimethoxybenzaldehyde C9H9BrO3 详情 详情
(VI) 31929 3-Methoxypropanenitrile; 3-Methoxypropionitrile 110-67-8 C4H7NO 详情 详情
(VII) 31930 (E)-3-(4-bromo-3,5-dimethoxyphenyl)-2-(methoxymethyl)-2-propenenitrile C13H14BrNO3 详情 详情
(VIII) 31931 4-bromo-3,5-dimethoxybenzoic acid C9H9BrO4 详情 详情
(IX) 31932 4-bromo-3,5-dimethoxybenzoyl chloride C9H8BrClO3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(A)

The reaction of (V) with 3-morpholinopropionitrile (X) by means of sodium methoxide in methanol - DMSO gives 4-bromo-3,5-dimethoxy-alpha-(morpholinomethyliden)hydrocinnamic acid nitrile (XI), which by reaction with aniline (B) and HCl in refluxing isopropanol is converted into 4-bromo-3,5-dimethoxy-alpha-(anilinomethyliden)hydrocinnamic acid nitrile (XII). Finally, this compound is condensed with guanidine (A) as before.

参考文献 中间体
合成目标
【1】 Sweetman, A.J.; Serradell, M.N.; Castaner, J.; Blancafort, P.; Brodimoprim. Drugs Fut 1982, 7, 2, 93.
【2】 Kompis, I.; Wick, A.; Synthesis of 4-halo-substituted analogs of trimethropin. Helv Chim Acta 1977, 60, 8, 3025-34.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(A) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(V) 31928 4-Bromo-3,5-dimethoxybenzaldehyde C9H9BrO3 详情 详情
(X) 31933 3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile 4542-47-6 C7H12N2O 详情 详情
(XI) 31934 (Z)-2-(4-bromo-3,5-dimethoxybenzyl)-3-(4-morpholinyl)-2-propenenitrile C16H19BrN2O3 详情 详情
(XII) 31935 (Z)-3-anilino-2-(4-bromo-3,5-dimethoxybenzyl)-2-propenenitrile C18H17BrN2O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The cyclization of ethyl 2-(1-adamantyl)acetoacetate (I) with guanidine (II) gives 2-amino-4-hydroxy-5-(1-adamantyl)-6-methylpyrimidine (III), which by treatment with PCl5 in refluxing POCl3 is converted into 2-amino-4-chloro-5-(1-adamantyl)-6-methylpyrimidine (IV). Finally, this compound is treated with NH3 in ethanol, and with ethanesulfonic acid.

参考文献 中间体
合成目标
【1】 Jonak, J.P.; Mead, L.H.; Zakrzewski, S.F.; Synthesis and biological activity of some 5-substituted 2,4-diamino-6-alkylpyrimidines. J Med Chem 1972, 15, 6, 662-665.
【2】 Mead, L.H.; Jonak, J.P.; Zakrzewski, S.F.; Synthesis and biological activity of some 5-(1-adamantyl)pyrimidines. J Med Chem 1971, 14, 5, 408-411.
【3】 Blancafort, P.; Serradell, M.N.; Hopkins, S.J.; Castaner, J.; DAMP-ES. Drugs Fut 1983, 8, 4, 310.
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) 36013 ethyl 2-(1-adamantyl)-3-oxobutanoate C16H24O3 详情 详情
(II) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(III) 36014 5-(1-adamantyl)-2-amino-6-methyl-4-pyrimidinol C15H21N3O 详情 详情
(IV) 36015 5-(1-adamantyl)-4-chloro-6-methyl-2-pyrimidinamine; 5-(1-adamantyl)-4-chloro-6-methyl-2-pyrimidinylamine C15H20ClN3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(A)

1) By methanolysis of 2,6-dichlorophenylacetonitrile (I) by means of H2SO4 to methyl 2,6-dichlorophenylacetate (II), which is then condensed with guanidine (A) in isopropanol. 2) By condensation of S-methylisothiourea (V) with 2,6-dichlorophenylacetyl chloride (VI) in acetone to afford S-methyl-N-(2,6-dichlorophenylacetyl)isothiourea (VII); this product is then treated with ammonia in isopropanol. 3) By condensation of 2,6-dichlorophenylacetic acid (VIII) with guanidine (A) in toluene.

参考文献 中间体
合成目标
【1】 Arrigoni-Martelli, E.; Castaner, J.; BS 100-141. Drugs Fut 1976, 1, 4, 167.
【2】 Bream, J.B.; et al.; Substituted phenylacetylguanidines: A new class of antihypertensive agents. Arzneim-Forsch Drug Res 1975, 25, 10, 1477.
【3】 Bream, J.B.; et al. (Novartis AG); Substituted phenylacethyl derivatives of guanidine, O-alkylisoureas, S-alkylisothioureas and p-benzylalkylisothioureas. DE 179348; FR 1584670; GB 1235723; US 3632645 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(I) 18202 2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile 3215-64-3 C8H5Cl2N 详情 详情
(II) 40327 methyl 2-(2,6-dichlorophenyl)acetate 54551-83-6 C9H8Cl2O2 详情 详情
(V) 10272 [[Amino(imino)methyl]sulfanyl]methane 2986-19-8 C2H6N2S 详情 详情
(VI) 40329 2-(2,6-dichlorophenyl)acetyl chloride C8H5Cl3O 详情 详情
(VII) 40330 1,3-dichloro-2-(2-[[imino(methylsulfanyl)methyl]amino]-2-oxoethyl)benzene C10H10Cl2N2OS 详情 详情
(VIII) 40328 2-(2,6-dichlorophenyl)acetic acid 6575-24-2 C8H6Cl2O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(A)

4) By reaction of the nitrile (I) with ethyl formate (B) by means of NaOEt in ethanol to give alpha-formyl-2,6-dichlorophenylacetonitrile (III), which is condensed with guanidine hydrochloride (A) by means of NaOEt in ethanol to yield alpha-(guanidinomethylene)-2,6-dichlorophenylacetonitrile (IV); this product is finally hydrolyzed and rearranged by means of HCl.

参考文献 中间体
合成目标
【1】 Arrigoni-Martelli, E.; Castaner, J.; BS 100-141. Drugs Fut 1976, 1, 4, 167.
【2】 Bream, J.B.; et al.; Verfahren zur Herstellung von Acylguanidinen. CH 511816 .
【3】 Bream, J.B.; et al.; Verfahren zur Herstellung von Acylguanidinen. CH 518910 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(B) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(I) 18202 2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile 3215-64-3 C8H5Cl2N 详情 详情
(III) 40331 2-(2,6-dichlorophenyl)-2-hydroxyacetonitrile C8H5Cl2NO 详情 详情
(IV) 40332 N''-[(Z)-2-cyano-2-(2,6-dichlorophenyl)ethenyl]guanidine C10H8Cl2N4 详情 详情

合成路线9

该中间体在本合成路线中的序号：

Alternative preparation of the key intermediote (XIII)

参考文献 中间体
合成目标
【1】 Harrington, P.M.; Shih, C.; Grindey, G.B.; Gossett, L.S.; Moran, R.G.; Taylor, S.C.; Synthesis and structure-activity relationship studies of 5,10-dideazatetrahydrofolic acid (DDATHF). Chemistry and Biology of Pteridines (1989): Pteridines and Folic Acid Derivatives. H.-C. Curtius, S. Ghisla and N. Blau (Eds.). de Gruyter, New York 1990, 1035.
【2】 Taylor, E.C.; Wong, G.S.K.; Convergent and efficient palladium-effected synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). J Org Chem 1989, 54, 15, 3618.
【3】 Castaner, J.; Prous, J.; Lometrexol. Drugs Fut 1993, 18, 2, 121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14790 Guanidine 113-00-8 CH5N3 详情 详情
63827 1-iodo-2,5-pyrrolidinedione C4H4INO2 详情 详情
(XVI) 14292 methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate C7H7NO3 详情 详情
(XVII) 14293 methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate C7H6INO3 详情 详情
(XVIII) 14294 methyl 2-chloro-5-iodonicotinate C7H5ClINO2 详情 详情
(XIX) 14285 tert-butyl 4-ethynylbenzoate C13H14O2 详情 详情
(XX) 14296 methyl 5-[2-[4-(tert-butoxycarbonyl)phenyl]ethynyl]-2-chloronicotinate C20H18ClNO4 详情 详情
(XXI) 14297 tert-butyl 4-[2-(2-amino-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)ethynyl]benzoate C20H18N4O3 详情 详情
(XXII) 14298 4-[2-(2-Amino-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)ethynyl]benzoic acid C16H10N4O3 详情 详情

合成路线10

该中间体在本合成路线中的序号：

Racemic lometrexol has been prepared.

参考文献 中间体
合成目标
【1】 Taylor, E.C.; Beardsley, G.P.; Harrington, P.J.; Fletcher, S.R. (Princeton University); Pyrido[2,3-d]pyrimidin derivs. AU 8655108; EP 0215063; ES 8704167; ES 8801268; JP 1996193084; WO 8605181 .
【2】 Beardsley, G.P.; Taylor, E.C.; Shih, C.J.; Wong, G.S.K.; Fletcher, S.R.; Harrington, P.J.; Synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) and analogs. Chemistry and Biology of Pteridines (1986): Pteridines and Folic Acid Derivatives. B.A. Cooper and V.M. Whitehead (Eds.). de Gruyter, Berlin 1986, 61.
【3】 Castaner, J.; Prous, J.; Lometrexol. Drugs Fut 1993, 18, 2, 121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14790 Guanidine 113-00-8 CH5N3 详情 详情
(I) 14299 5-Methyl-2-thioxo-2,3-dihydro-3-pyridinecarbonitrile C7H6N2S 详情 详情
(II) 14300 5-Methyl-2-[(4-nitrophenyl)sulfanyl]nicotinonitrile C13H9N3O2S 详情 详情
(III) 14301 5-(Bromomethyl)-2-[(4-nitrophenyl)sulfanyl]nicotinonitrile C13H8BrN3O2S 详情 详情
(IV) 14302 ([6-[(4-Nitrophenyl)sulfanyl]-3-pyridinyl]methyl)(triphenyl)phosphonium bromide C30H24BrN2O2PS 详情 详情
(V) 14303 tert-butyl 4-formylbenzoate C12H14O3 详情 详情
(VI) 14304 tert-butyl 4-((E)-2-[5-cyano-6-[(4-nitrophenyl)sulfanyl]-3-pyridinyl]ethenyl)benzoate C25H21N3O4S 详情 详情
(VII) 14305 tert-butyl 4-[(E)-2-(6-amino-5-cyano-3-pyridinyl)ethenyl]benzoate C19H19N3O2 详情 详情
(VIII) 14306 tert-butyl 4-[(E)-2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoate C20H21N5O2 详情 详情
(IX) 14307 4-[(E)-2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoic acid C16H13N5O2 详情 详情
(X) 14273 4-[(E)-2-(2-Amino-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoic acid C16H12N4O3 详情 详情
(XI) 14309 acetic 4-[(E)-2-[2-(acetamido)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethenyl]-1-benzenecarboxylic anhydride C20H16N4O5 详情 详情
(XII) 14310 4-[(E)-2-[2-(acetamido)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethenyl]benzoic acid C18H14N4O4 详情 详情
(XIII) 11013 diethyl (2S)-2-aminopentanedioate C9H17NO4 详情 详情
(XIV) 14311 diethyl (2S)-2-[(4-[(E)-2-[2-(acetamido)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethenyl]benzoyl)amino]pentanedioate C27H29N5O7 详情 详情
(XV) 14312 diethyl (2S)-2-[(4-[2-[2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate C27H35N5O7 详情 详情
(XVI) 14313 diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate C27H35N5O7 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IV)

1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.

参考文献 中间体
合成目标
【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498.
【2】 Taylor, E.C.; Design and synthesis of inhibitors of folate-dependent enzymes as antitumor agents. Adv Exp Med Biol 1993, 338, 387-408.
【3】 Taylor, E.C.; Kuhnt, D.G.; Shih, C.; Grindey, G.B. (Eli Lilly and Company; Princeton University); N-(Pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivs. AU 9167791; EP 0432677; JP 1996003166; US 5028608 .
【4】 Jannatipour, M.; Kuhnt, D.; Shih, C.; Rinzel, S.M.; Grindey, G.B.; Taylor, E.C.; Moran, R.G.; Barredo, J.; A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 1992, 35, 23, 4450-4.
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) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(II) 12113 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal 2032-35-1 C6H13BrO2 详情 详情
(III) 14789 ethyl 2-cyano-4,4-diethoxybutanoate C11H19NO4 详情 详情
(IV) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(V) 14791 2,6-diamino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone C10H18N4O3 详情 详情
(VI) 14792 2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 7355-55-7 C6H6N4O 详情 详情
(VII) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(VIII) 14794 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide C11H14N4O2 详情 详情
(IX) 14795 N-(5,6-diiodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C11H12I2N4O2 详情 详情
(X) 14796 N-(5-iodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C11H13IN4O2 详情 详情
(XI) 14797 dimethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate C16H17NO5 详情 详情
(XII) 14798 dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl)benzoyl]amino]pentanedioate C27H29N5O7 详情 详情
(XIII) 14799 dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate C27H33N5O7 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IX)

A novel synthetic route to pemetrexed disodium has been reported: The reaction of 3,4-dimethoxybenzylamine with methyl chloroformate gives the corresponding carbamate (II), which is alkylated with 2-butenyl bromide (III) yielding the N-alkyl carbamate (IV). The cleavage of (IV) with hydrazine and KOH affords the secondary amine (V), which is condensed with dimethyl malonate to give the malonamic ester (VI). The radical cyclization of (VI) by means of manganese triacetate dihydrate/copper acetate hydrate affords the pyrrolidinone (VII), which is treated with P2S5 in THF to give the thione (VIII). The cyclization of (VIII) with guanidine (IX) yields the pyrrolopyrimidinone (X), which is condensed with N-(4-iodobenzoyl)-L-glutamic acid diethyl ester (XI) by means of palladium diacetate to afford the ethano-bridged pyrrolopyrimidine (XII). Elimination of the dimethoxybenzyl-protecting group of (XII) with TFA/H2SO4 gives the diethyl ester of pemetrexed (XIII), which is finally saponified with NaOH in THF/water.

参考文献 中间体
合成目标
【1】 Taylor, E.C.; Liu, B.; A novel synthetic route to 7-substituted derivatives of the antitumor agent LY231514 (MTA). Tetrahedron Lett 1999, 40, 29, 5291.
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) 13920 (3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine 5763-61-1 C9H13NO2 详情 详情
(II) 35244 methyl 3,4-dimethoxybenzylcarbamate C11H15NO4 详情 详情
(III) 35252 (E)-1-bromo-2-butene 29576-14-5 C4H7Br 详情 详情
(IV) 35245 methyl (E)-2-butenyl(3,4-dimethoxybenzyl)carbamate C15H21NO4 详情 详情
(V) 35246 N-[(E)-2-butenyl]-N-(3,4-dimethoxybenzyl)amine; (E)-N-(3,4-dimethoxybenzyl)-2-buten-1-amine C13H19NO2 详情 详情
(VI) 35247 methyl 3-[(E)-2-butenyl(3,4-dimethoxybenzyl)amino]-3-oxopropanoate C17H23NO5 详情 详情
(VII) 35248 methyl 1-(3,4-dimethoxybenzyl)-2-oxo-4-vinyl-3-pyrrolidinecarboxylate C17H21NO5 详情 详情
(VIII) 35249 methyl 1-(3,4-dimethoxybenzyl)-2-thioxo-4-vinyl-3-pyrrolidinecarboxylate C17H21NO4S 详情 详情
(IX) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(X) 35250 2-amino-7-(3,4-dimethoxybenzyl)-5-vinyl-3,5,6,7-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-one C17H20N4O3 详情 详情
(XI) 14283 diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate C16H20INO5 详情 详情
(XII) 35251 diethyl (2S)-2-[(4-[2-[2-amino-7-(3,4-dimethoxybenzyl)-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl)amino]pentanedioate C33H39N5O8 详情 详情
(XIII) 14807 diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate C24H29N5O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

The synthesis of pimagedine was first reported more than 100 years ago. Several other preparative methods have since been described. However, the preferred method is the nitration of guanidine nitrate (I) with concentrated sulfuric acid giving nitroguanidine (II), which is then reduced with zinc dust in acetic acid. The title compound is isolated as the bicarbonate salt.

参考文献 中间体
合成目标
【1】 Nitroguanidine. Org Synth Coll 1967, 1, 399.
【2】 Thiele, J.; Liebigs Ann Chem 1892, 270, 1.
【3】 Anzelmi, E.; Smith, G.B.L.; J Am Chem Soc 1935, 57, 2730.
【4】 Kurzer, F.; Godfrey, L.E.A.; Chem Ind 1962, 1584-95.
【5】 Graul, A.; Castaner, J.; Prous, J.; Pimagedine. Drugs Fut 1994, 19, 8, 740.
【6】 Aminoguanidine bicarbonate. Org Synth Coll 1967, 3, 73.
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) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(II) 15496 nitroguanidine 556-88-7 CH4N4O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VII)

Cariporide has been obtained by two similar ways: 1) The oxidation of 4-isopropylbenzaldehyde (I) with sodium perborate in hot acetic acid gives 4-isopropylbenzoic acid (II), which is sulfonated with hot chlorosufonic acid yielding 3-(chlorosulfonyl)-4-isopropylbenzoic acid (III). The reduction of (III) with sodium sulfite in hot NaOH solution affords 4-isopropyl-3-sulfinobenzoic acid (IV), which is alkylated with methyl bromide and NaOH in DMF giving 4-isopropyl-3-(methylsulfonyl)benzoic acid (V). The reaction of (V) with SOCl2 in refluxing toluene yields 4-isopropyl-3-(methylsulfonyl)benzoyl chloride (VI), which is finally condensed with guanidine (VII) in DMF. 2) The iodination of 4-isopropylbenzoic acid (II) with iodine chloride or N-iodosuccinimide (NIS) gives 3-iodo-4-isopropylbenzoic acid (VIII), which is treated first with SOCl2 to afford the corresponding acyl chloride (IX), and then with methanol yielding 4-iodo-4-isopropylbenzoic methyl ester (X). The reaction of (X) with sodium methylsulfite (XI) gives 4-isopropyl-3-(methylsulfonyl)benzoic acid methyl ester (XII), which is finally treated with guanidine (VII) in refluxing THF.

参考文献 中间体
合成目标
【1】 Graul, A.; Prous, J.; Castañer, J.; Cariporide Mesylate. Drugs Fut 1997, 22, 11, 1197.
【2】 Kleemann, H.-W.; Lang, H.-J.; Weichert, A.; Crause, P.; Scholz, W.; Albus, U.; Schwark, J.-R. (Aventis SA); Diacyl substd. guanidines, process for their preparation, their use as medicament or diagnostic reagent and medicament containing them. CA 2130703; DE 4328352; EP 0640587; JP 1995082234 .
【3】 Lang, H.-J.; Weichert, A.; Kleemann, H.-W.; Englert, H.; Scholz, W.; Albus, U. (Aventis SA); Benzoylguanidines, process for their preparation and their use as antiarrhythmic agents. EP 0589336; JP 1994228082; US 5591754 .
【4】 Kleemann, H.-W. (Aventis SA); Substd. benzoic acid esters, process for their preparation and their use for the synthesis of inhibitors of the cellular Na+/H+-exchange. DE 4428480 .
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) 23109 4-isopropylbenzaldehyde 122-03-2 C10H12O 详情 详情
(II) 11698 4-Isopropylbenzoic acid 536-66-3 C10H12O2 详情 详情
(III) 16851 3-(chlorosulfonyl)-4-isopropylbenzoic acid C10H11ClO4S 详情 详情
(IV) 16852 3-(dioxo-lambda(6)-sulfanyl)-4-isopropylbenzoic acid C10H12O4S 详情 详情
(V) 16853 4-isopropyl-3-(methylsulfonyl)benzoic acid C11H14O4S 详情 详情
(VI) 16854 4-isopropyl-3-(methylsulfonyl)benzoyl chloride C11H13ClO3S 详情 详情
(VII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VIII) 16856 3-iodo-4-isopropylbenzoic acid C10H11IO2 详情 详情
(IX) 16857 3-iodo-4-isopropylbenzoyl chloride C10H10ClIO 详情 详情
(X) 16858 methyl 3-iodo-4-isopropylbenzoate C11H13IO2 详情 详情
(XI) 63963 sodium methanesulfinate CH3NaO2S 详情 详情
(XII) 16859 methyl 4-isopropyl-3-(methylsulfonyl)benzoate C12H16O4S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(V)

Two new related ways for the synthesis of cariporide mesylate have been reported: 1) The reaction of 4-isopropylbenzoic acid (I) with chlorosulfonic acid gives 3-(chlorosulfonyl)-4-isopropylbenzoic acid (II), which is reduced wth sodium sulfite/NaOH to the sorresponding sulfinic acid (III). The methylation of (III) with methyl iodide/NaOH in dimethylacetamide affords 4-isopropyl-3-(methanesulfonyl)benzoic acid methyl ester (IV), which is finally condensed with gunidine (V). 2) The hydrolysis of benzoate (IV) with NaOH in methanol/water gives the corresponding free acid (VI), which is then condensed with guanidine (V) by means of dicyclohexylcarbodiimide (DCC) in THF. 3) Benzoic ester (IV) can also be obtained by alkylation of 4-bromo-3-(methanesulfonyl)benzoic acid methyl ester with isopropylmagnesium chloride by means of CuI, ZnCl2 and a PdCl2 catalyst in THF.

参考文献 中间体
合成目标
【1】 Lang, H.J.; Scholz, W.; Faber, S.; Weichert, A.; Jansen, H.W.; Synthesis of the highly selective Na+/H+ exchange inhibitors cariporide mesylate and (3-methanesulfonyl-4-piperidino-benzoyl)guanidine methanesulfonate. Arzneim-Forsch Drug Res 1997, 47, 11, 1204.
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) 11698 4-Isopropylbenzoic acid 536-66-3 C10H12O2 详情 详情
(II) 16851 3-(chlorosulfonyl)-4-isopropylbenzoic acid C10H11ClO4S 详情 详情
(III) 16852 3-(dioxo-lambda(6)-sulfanyl)-4-isopropylbenzoic acid C10H12O4S 详情 详情
(IV) 16859 methyl 4-isopropyl-3-(methylsulfonyl)benzoate C12H16O4S 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VI) 16853 4-isopropyl-3-(methylsulfonyl)benzoic acid C11H14O4S 详情 详情
(VII) 17625 methyl 4-bromo-3-(methylsulfonyl)benzoate C9H9BrO4S 详情 详情
(VIII) 17626 chloro(isobutyl)magnesium 5674-02-2 C4H9ClMg 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XVII)

After removal of the Boc protecting group of (XIV), the resultant free amine spontaneously cyclized to the lactam (XV) in methanolic solution. Lactam (XV) was O-alkylated with trimethyloxonium fluoroborate, yielding the lactim ether (XVI), which was condensed with guanidine (XVII) to produce the pyridothiazine (XVIII). Hydrolysis of the ethyl ester of (XVIII), followed by coupling of the resultant acid (XIX) with L-glutamic acid diethyl ester (XX), furnished amide (XXI). The ester groups of (XXI) were finally hydrolyzed with NaOH to give the title compound.

参考文献 中间体
合成目标
【1】 Varney, M.D.; et al.; Protein structure-based design, synthesis, and biological evaluation of 5-thia-2, 6-diamino-4(3H)-oxopyrimidines: Potent inhibitors of glycinamide ribonucleotide transformylase with potent cell growth inhibition. J Med Chem 1997, 40, 16, 2502.
【2】 Varney, M.D.; Palmer, C.L.; Romines, W.H. (Agouron Pharmaceuticals, Inc.); Syntheses of optically pure cpds. useful as GARFT inhibitors and their intermediates. WO 9640674 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 59504 dimethyl 2-({(1S)-1-{[(tert-butoxycarbonyl)amino]methyl}-3-[5-(ethoxycarbonyl)-2-thienyl]propyl}sulfanyl)malonate C21H31NO8S2 详情 详情
(XV) 59505 methyl (6S)-6-{2-[5-(ethoxycarbonyl)-2-thienyl]ethyl}-3-oxo-2-thiomorpholinecarboxylate C15H19NO5S2 详情 详情
(XVI) 59506 methyl (6S)-6-{2-[5-(ethoxycarbonyl)-2-thienyl]ethyl}-3-methoxy-5,6-dihydro-2H-1,4-thiazine-2-carboxylate C16H21NO5S2 详情 详情
(XVII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XVIII) 59507 ethyl 5-{2-[(6S)-2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl]ethyl}-2-thiophenecarboxylate C15H18N4O3S2 详情 详情
(XIX) 59508 5-{2-[(6S)-2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl]ethyl}-2-thiophenecarboxylic acid C13H14N4O3S2 详情 详情
(XX) 11013 diethyl (2S)-2-aminopentanedioate C9H17NO4 详情 详情
(XXI) 59509 diethyl (2S)-2-{[(5-{2-[(6S)-2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]thiazin-6-yl]ethyl}-2-thienyl)carbonyl]amino}pentanedioate C22H29N5O6S2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

The condensation of dimethyl 5-aminoisophthalate (I) with 2,5-dimethoxytetrahydrofuran (II) in refluxing AcOH provided the pyrrolyl derivative (III). Partial hydrolysis of (III) with methanolic KOH then gave mono ester (IV). After activation of the carboxy group of (IV) as the corresponding mixed anhydride with isobutyl chloroformate, reduction employing NaBH4 furnished alcohol (V). The ester group of (V) was then displaced with guanidine-HCl (VI) in the presence of NaOMe to yield the title benzoyl guanidine, which was isolated as the methanesulfonate salt.

参考文献 中间体
合成目标
【1】 Kuno, A.; Inoue, Y.; Takasugi, H.; Mizuno, H.; Yamasaki, K. (Fujisawa Pharmaceutical Co., Ltd.); Guanidine derivs. as inhibitors of Na+/H+ exchange in cells. EP 0699185; JP 1996511243; US 5824691; WO 9426709 .
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) 35226 dimethyl 5-aminoisophthalate 99-27-4 C10H11NO4 详情 详情
(II) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(III) 35227 dimethyl 5-(1H-pyrrol-1-yl)isophthalate C14H13NO4 详情 详情
(IV) 35228 3-(methoxycarbonyl)-5-(1H-pyrrol-1-yl)benzoic acid C13H11NO4 详情 详情
(V) 35229 methyl 3-(hydroxymethyl)-5-(1H-pyrrol-1-yl)benzoate C13H13NO3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(VI)

Quinoline (IV) was prepared by condensation of 3,5-dimethoxyaniline (I), pyruvic acid (II) and o-tolualdehyde (III) in refluxing EtOH. After activation of (IV) as the acid chloride (V) by means of SOCl2 in benzene, its condensation with guanidine (VI) in DMF yielded the corresponding acyl guanidine.

参考文献 中间体
合成目标
【1】 Fujiwara, J.; Mori, H.; Yamashita, H.; Kitamori, T.; Hosoya, J.; Banno, H. (Mitsui Chemicals, Inc.); Quinoline-4-carbonylguanidine derivates, process for producing the same and pharmaceutical compsns. containing the cpds.. EP 0726254; JP 1996277269; US 5627193 .
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) 25780 3,5-dimethoxyaniline; 3,5-dimethoxyphenylamine 10272-07-8 C8H11NO2 详情 详情
(II) 24066 2-oxopropionic acid 127-17-3 C3H4O3 详情 详情
(III) 27085 2-methylbenzaldehyde 529-20-4 C8H8O 详情 详情
(IV) 27086 5,7-dimethoxy-2-(2-methylphenyl)-4-quinolinecarboxylic acid C19H17NO4 详情 详情
(V) 27087 5,7-dimethoxy-2-(2-methylphenyl)-4-quinolinecarbonyl chloride C19H16ClNO3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XIX)

The condensation of 4-methoxypyridine-3-carbaldehyde (I) with 2-azidoacetic acid ethyl ester (II) by means of NaOMe in ethanol gives 2-azido-3-(4-methoxypyridin-3-yl)acrylic acid ethyl ester (III), which is cyclized in refluxing o-xylene to yield the pyrrolopyridine (IV). The reaction of the NH group of (IV) with Sem-Cl and NaH in DMF affords the N-protected compound (V), whose ester group is reduced with LiAlH4 in refluxing THF to provide the carbinol (VI). The oxidation of (VI) with MnO2 in dichloromethane gives the corresponding carbaldehyde (VII), which is condensed with 2-azidoacetic acid ethyl ester (II) as before to yield the azido acrylic ester (VIII). The condensation of (VIII) with triphenylphosphine (IX) in dichloromethane affords the iminophosphorane (X), which is N-deprotected by means of TBAF in THF to provide the deprotected iminophosphorane (XI). The cyclization of (XI) with alpha-methylbenzyl isocyanate (XII) in THF gives the tricyclic pyrimidopyrrolopyridine (XIII), which is brominated with Br2 in pyridine to yield intermediate (XIV). The reaction of (XIV) with 1-ethoxyvinyl trimethyl tin (XV) by means of PdCl2(PPh3)2 in DMF affords the acetyl derivative (XVI), which is condensed with dimethylformamide di-tert-butyl acetal (XVII) in hot DMF to provide the dimethyl enaminone (XVIII). The cyclization of (XVIII) with guanidine (XIX) by means of K2CO3 in refluxing 2-methoxyethanol gives the 2-aminopyrimidine derivative (XX), with simultaneous hydrolysis of the ester group. The decarboxylation of (XX), with simultaneous demethylation, by heating at 260 C in diphenyl ether yields the N-protected precursor (XXI), which is finally treated with triflic acid to afford the target variolin B.

参考文献 中间体
合成目标
【1】 Molina, P.; et al.; Synthesis of the potent antitumoral marine alkaloid variolin B. Tetrahedron Lett 2002, 43, 6, 1005.
【2】 Fresneda, P.M.; et al.; Synthetic studies towards the 2-aminopyrimidine alkaloids variolins and meridianins from marine origin. Tetrahedron Lett 2000, 41, 24, 4777.
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) 55718 4-methoxynicotinaldehyde C7H7NO2 详情 详情
(II) 32916 ethyl 2-azidoacetate 637-81-0 C4H7N3O2 详情 详情
(III) 55719 ethyl (Z)-2-azido-3-(4-methoxy-3-pyridinyl)-2-propenoate C11H12N4O3 详情 详情
(IV) 55720 ethyl 4-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate C11H12N2O3 详情 详情
(V) 55721 ethyl 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxylate C17H26N2O4Si 详情 详情
(VI) 55722 (4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol C15H24N2O3Si 详情 详情
(VII) 55723 4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde C15H22N2O3Si 详情 详情
(VIII) 55724 ethyl (Z)-2-azido-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-propenoate C19H27N5O4Si 详情 详情
(IX) 12437 Triphenylphosphine; Triphenyl phosphine 603-35-0 C18H15P 详情 详情
(X) 55725 ethyl (Z)-3-(4-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate C37H42N3O4PSi 详情 详情
(XI) 55726 ethyl (Z)-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-[(triphenylphosphoranylidene)amino]-2-propenoate C31H28N3O3P 详情 详情
(XII) 55734 (S)-(-)-1-Phenylethyl isocyanate; (S)-(-)-Phenylethyl Isocyanate; Isocyanic acid (S)-(-)-alpha-phenylethyl ester; S-(-)-alpha-Methylbenzyl isocyanate 14649-03-7 C9H9NO 详情 详情
(XIII) 55727 ethyl 4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate C22H22N4O3 详情 详情
(XIV) 55728 ethyl 5-bromo-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate C22H21BrN4O3 详情 详情
(XV) 55729 ethyl 1-(trimethylstannyl)vinyl ether; (1-ethoxyvinyl)(trimethyl)stannane C7H16OSn 详情 详情
(XVI) 55730 ethyl 5-acetyl-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate C24H24N4O4 详情 详情
(XVII) 21059 N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine 36805-97-7 C11H25NO2 详情 详情
(XVIII) 55731 ethyl 5-[(E)-3-(dimethylamino)-2-propenoyl]-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylate C27H29N5O4 详情 详情
(XIX) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XX) 55732 5-(2-amino-4-pyrimidinyl)-4-methoxy-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine-7-carboxylic acid C24H21N7O3 详情 详情
(XXI) 55733 5-(2-amino-4-pyrimidinyl)-9-{[(1S)-1-phenylethyl]amino}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol C22H19N7O 详情 详情

合成路线20

该中间体在本合成路线中的序号：(III)

The methylaion of 4-methyl-1H-indole-2-carboxylic acid (I) with NaH and methyl iodide in DMF gives of 1,4-dimethylindole-2-carboxylic acid methyl ester (II), which is condensed with guanidine at 130 C, and treated with methanesulfonic acid in isopropanol.

参考文献 中间体
合成目标
【1】 Kitano, M.; Nakano, K.; Yagi, H.; Ohashi, N.; Kojima, A.; Noguchi, T.; Miyagishi, A. (Sumitomo Pharmaceuticals Co., Ltd.); Indoloylguanidine derivs.. CA 2160600; EP 0708091; JP 1996208602 .
【2】 Kojima, A.; Kitano, M.; Miyagishi, A.; Noguchi, T.; Yagi, H.; Nakano, K.; Ohashi, N. (Sumitomo Pharmaceuticals Co., Ltd.); Indoloylguanidine derivs. as inhibitors of sodium-hydrogen exchange. CA 2121391; EP 0622356; JP 1995010839 .
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) 19960 4-methyl-1H-indole-2-carboxylic acid C10H9NO2 详情 详情
(II) 19961 methyl 1,4-dimethyl-1H-indole-2-carboxylate C12H13NO2 详情 详情
(III) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IV) 19963 N''-[(1,4-dimethyl-1H-indol-2-yl)carbonyl]guanidine C12H14N4O 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VI)

Benzoxazinone (III) was obtained by the two-step condensation of methyl 3-amino-4-hydroxybenzoate (I) and 2-bromoisobutyryl bromide (II), first with NaHCO3 in H2O-EtOAc to afford the corresponding amide, and then cyclization with K2CO3 in DMF. Subsequent N-alkylation of (III) with 2-iodopropane (IV) in the presence of NaH in DMF at 60 C provided the isopropylated compound (V). Refluxing of (V) with an excess of guanidine (VI) in MeOH yielded the desired acylguanidine, which was finally converted to the mesylate salt upon treatment with methanesulfonic acid in isopropanol.

参考文献 中间体
合成目标
【1】 Yamamoto, T.; Hori, M.; Watanabe, I.; Tsutsui, H.; Harada, K.; Ikeda, S.; Maruo, J.; Morita, T.; Ohtaka, H.; Synthesis and quantitative structure-activity relationships of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidines as Na/H exchange inhibitors. Chem Pharm Bull 1998, 46, 11, 1716.
【2】 Yamamoto, T.; et al.; An acid-catalyzed O,N-acyl migration and application to the synthesis of N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidine methanesulfonate (KB-R9032), a novel Na/H exchange inhibitor. Chem Pharm Bull 1999, 47, 1, 22.
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) 19366 methyl 3-amino-4-hydroxybenzoate 536-25-4 C8H9NO3 详情 详情
(II) 19367 2-bromo-2-methylpropanoyl bromide 20769-85-1 C4H6Br2O 详情 详情
(III) 19368 methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate C12H13NO4 详情 详情
(IV) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(V) 19370 methyl 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate C15H19NO4 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VII)

The alkylation of 3-amino-4-hydroxybenzoic acid methyl ester (I) with isopropyl iodide and NaHCO3 gives 4-hydroxy-3-(isopropylamino)benzoic acid methyl ester (II), which is esterified with 2-bromoisobutyryl bromide (III) and TEA to yield 4-(2-bromoisobutyryloxy)-3-(isopropylamino)benzoic acid methyl ester (IV). The O-N migration of the 2-bromoisobutyryl group of (IV) catalyzed by acetic acid affords the 2-bromoisobutyrylamide (V), which is cyclized by means of K2CO3 to provide 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid methyl ester (VI). Finally, this compound is condensed with guanidine and treated with MeSO3H to give the target mesylate.

参考文献 中间体
合成目标
【1】 Yamamoto, T.; et al.; An acid-catalyzed O,N-acyl migration and application to the synthesis of N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)guanidine methanesulfonate (KB-R9032), a novel Na/H exchange inhibitor. Chem Pharm Bull 1999, 47, 1, 22.
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) 19366 methyl 3-amino-4-hydroxybenzoate 536-25-4 C8H9NO3 详情 详情
(II) 36527 methyl 4-hydroxy-3-(isopropylamino)benzoate C11H15NO3 详情 详情
(III) 19367 2-bromo-2-methylpropanoyl bromide 20769-85-1 C4H6Br2O 详情 详情
(IV) 36528 methyl 4-[(2-bromo-2-methylpropanoyl)oxy]-3-(isopropylamino)benzoate C15H20BrNO4 详情 详情
(V) 36529 methyl 3-[(2-bromo-2-methylpropanoyl)(isopropyl)amino]-4-hydroxybenzoate C15H20BrNO4 详情 详情
(VI) 19370 methyl 4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate C15H19NO4 详情 详情
(VII) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VII)

Mitsunobu coupling between boronic acid (I) and 3-bromo-2,5-dichlorothiophene (II) affords the thienyl isophthalate (III). Partial hydrolysis of diester (III) using methanolic KOH gives rise to mono-acid (IV), which is further condensed with N,N-dimethyl ethylenediamine (V) to provide the amide-ester (VI). Displacement of the methyl ester function of (VI) by guanidine (VII) then produces the target acyl guanidine, which is finally converted into the corresponding dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Kuno, A.; Mizuno, H.; Yamasaki, K.; Inoue, Y. (Fujisawa Pharmaceutical Co., Ltd.); Benzoylguanidine derivs. as medicaments. JP 1998503770; WO 9604241 .
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) 58211 3,5-bis(methoxycarbonyl)phenylboronic acid C10H11BO6 详情 详情
(II) 58212 3-bromo-2,5-dichlorothiophene 60404-18-4 C4HBrCl2S 详情 详情
(III) 58213 dimethyl 5-(2,5-dichloro-3-thienyl)isophthalate C14H10Cl2O4S 详情 详情
(IV) 58214 3-(2,5-dichloro-3-thienyl)-5-(methoxycarbonyl)benzoic acid C13H8Cl2O4S 详情 详情
(V) 14881 N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine 108-00-9 C4H12N2 详情 详情
(VI) 58215 methyl 3-(2,5-dichloro-3-thienyl)-5-({[2-(dimethylamino)ethyl]amino}carbonyl)benzoate C17H18Cl2N2O3S 详情 详情
(VII) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

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.

参考文献 中间体
合成目标
【1】 Gangjee, A. (Duquesne University); Derivs. of pyrido [2,3-d] and [3,2-d] pyrimidine and methods of using these derivs.. US 5508281 .
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
(II) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(III) 14269 2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile C8H6N6 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) 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

合成路线25

该中间体在本合成路线中的序号：(X)

The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III), which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV). The condensation of (IV) with 3-hydroxy-4,5-dimethoxybenzaldehyde (V) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (VI), which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII). The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX), which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol. (1)

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castañer, J.; Rabasseda, X.; Iclaprim. Drugs Fut 2004, 29, 3, 220.
【2】 Masciadri, R. (F. Hoffmann-La Roche AG); Diaminopyrimidines, pharmaceutical compsns. containing them and their use as antibacterial. EP 0866791; JP 2000501399; US 5773446; WO 9720839 .
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) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(II) 27189 trimethyl[2-(trimethylsilyl)ethynyl]silane 14630-40-1 C8H18Si2 详情 详情
(III) 27190 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one C9H14OSi 详情 详情
(IV) 27191 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-ol C9H16OSi 详情 详情
(V) 27192 3-hydroxy-4,5-dimethoxybenzaldehyde C9H10O4 详情 详情
(VI) 27193 3-[[1-cyclopropyl-3-(trimethylsilyl)-2-propynyl]oxy]-4,5-dimethoxybenzaldehyde C18H24O4Si 详情 详情
(VII) 27194 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde C15H16O4 详情 详情
(VIII) 27195 3-anilinopropanenitrile 1075-76-9 C9H10N2 详情 详情
(IX) 27196 3-(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)-2-[(phenylimino)methyl]propanenitrile C24H24N2O3 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线26

该中间体在本合成路线中的序号：(X)

The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III), which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV). The condensation of propynol (IV) with 3-hydroxy-4,5-dimethoxybenzoic acid methyl ester (XI) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (XII), which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylic acid methyl ester (XIII). Finally, this compound is reduced with NaAlH2(OCH2CH2)2 and morpholine in toluene to give the previously described 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII). The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX), which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol.

参考文献 中间体
合成目标
【1】 Masciadri, R. (F. Hoffmann-La Roche AG); Diaminopyrimidines, pharmaceutical compsns. containing them and their use as antibacterial. EP 0866791; JP 2000501399; US 5773446; WO 9720839 .
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) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(II) 27189 trimethyl[2-(trimethylsilyl)ethynyl]silane 14630-40-1 C8H18Si2 详情 详情
(III) 27190 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one C9H14OSi 详情 详情
(IV) 27191 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-ol C9H16OSi 详情 详情
(VII) 27194 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde C15H16O4 详情 详情
(VIII) 27195 3-anilinopropanenitrile 1075-76-9 C9H10N2 详情 详情
(IX) 27196 3-(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)-2-[(phenylimino)methyl]propanenitrile C24H24N2O3 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XI) 27197 methyl 3-hydroxy-4,5-dimethoxybenzoate C10H12O5 详情 详情
(XII) 27198 methyl 3-[[1-cyclopropyl-3-(trimethylsilyl)-2-propynyl]oxy]-4,5-dimethoxybenzoate C19H26O5Si 详情 详情
(XIII) 27199 methyl 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carboxylate C16H18O5 详情 详情

合成路线27

该中间体在本合成路线中的序号：(V)

Condensation of N-(2-furanylcarbonyl)piperazine (I) with 4-chloro-3-(methylsulfonyl)benzoic acid (II) at 120 C produced the disubstituted piperazine (III). After activation of the carboxy group as the imidazolide (IV) upon treatment with 1,1'-carbonyldiimidazole and N-methylmorpholine, treatment with guanidine hydrochloride (V) and NaH in hot DMF yielded the corresponding benzoyl guanidine, which was finally isolated as the methanesulfonate salt.

参考文献 中间体
合成目标
【1】 Burger, E.; Eickmeier, C.; Roos, O. (Boehringer Ingelheim GmbH); Novel benzoyl guanidine derivs., process for their preparation and their use in the preparation of medicines. DE 19601303; EP 0882031; JP 2000503309; US 6114335; WO 9726253 .
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) 30751 2-furyl(1-piperazinyl)methanone; 2-Furoyl-1-piperazine 40172-95-0 C9H12N2O2 详情 详情
(II) 37884 4-chloro-3-(methylsulfonyl)benzoic acid C8H7ClO4S 详情 详情
(III) 37885 4-[4-(2-furoyl)-1-piperazinyl]-3-(methylsulfonyl)benzoic acid C17H18N2O6S 详情 详情
(IV) 37886 2-furyl[4-[4-(1H-imidazol-1-ylcarbonyl)-2-(methylsulfonyl)phenyl]-1-piperazinyl]methanone C20H20N4O5S 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线28

该中间体在本合成路线中的序号：(II)

Cyclization of ethyl 4-methyl-3-oxopentanoate (I) with guanidine carbonate (II) in boiling EtOH gave 2-amino-4-hydroxy-6-isopropylpyrimidine (III), which was converted to the corresponding chloropyrimidine (IV) by means of POCl3. Boronic ester (VI) was prepared by lithiation of 1-bromo-4-fluoronaphthalene (V) with n-butyllithium, followed by reaction with trimethyl borate. Subsequent coupling of chloropyrimidine (IV) with boronic ester (VI) in the presence of tetrakis(triphenylphosphine)palladium yielded the target naphthylpyrimidine.

参考文献 中间体
合成目标
【1】 Berger, J.; Flippin, L.A.; Greenhouse, R.; Jaime-Figueroa, S.; Liu, Y.; Miller, A.K.; Putman, D.G.; Weinhardt, K.K.; Zhao, S.-H. (F. Hoffmann-La Roche AG); Aryl pyrimidine derivs.. EP 0901474; US 5863924; WO 9744326 .
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) 19408 ethyl 4-methyl-3-oxopentanoate 7152-15-0 C8H14O3 详情 详情
(II) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(III) 30387 2-amino-6-isopropyl-4-pyrimidinol C7H11N3O 详情 详情
(IV) 30388 4-chloro-6-isopropyl-2-pyrimidinylamine; 4-chloro-6-isopropyl-2-pyrimidinamine C7H10ClN3 详情 详情
(V) 30389 1-bromo-4-fluoronaphthalene 341-41-3 C10H6BrF 详情 详情
(VI) 30390 dimethyl 4-fluoro-1-naphthylboronate C12H12BFO2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(IV)

2-Indolecarboxylic acid (I) was esterified with MeOH and SOCl2 to provide methyl ester (II). Subsequent N-alkylation of (II) using methyl iodide and NaH afforded N-methyl indole (III). Guanidine, liberated by treatment of the hydrochloride salt with NaOMe, was finally condensed with indole ester (III) at 130 C to produce the corresponding acylguanidine, which was isolated as the mesylate salt.

参考文献 中间体
合成目标
【1】 Kojima, A.; Kitano, M.; Miyagishi, A.; Noguchi, T.; Yagi, H.; Nakano, K.; Ohashi, N. (Sumitomo Pharmaceuticals Co., Ltd.); Indoloylguanidine derivs. as inhibitors of sodium-hydrogen exchange. CA 2121391; EP 0622356; JP 1995010839 .
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) 25226 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid 1477-50-5 C9H7NO2 详情 详情
(II) 27750 Indole-2-carboxylic acid methyl ester; 1H-indole-2-carboxylic acid methyl ester 1202-04-6 C10H9NO2 详情 详情
(III) 27751 methyl 1-methyl-1H-indole-2-carboxylate C11H11NO2 详情 详情
(IV) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线30

该中间体在本合成路线中的序号：(V)

The condensation of 2-(2,6-dichlorophenyl)acetonitrile (I) with ethyl acetate (II) by means of sodium ethoxide in refluxing ethanol gives 2-(2,6-dichlorophenyl)-3-oxobutyronitrile (III), which is methylated with diazomethane in ether yielding the enol ether (IV). Finally, this compound is cyclized with guanidine (V) by means of sodium ethoxide in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Miller, A.A.; Nobbs, M.S.; Hyde, R.M.; Leach, M.J. (Glaxo Wellcome plc); Pharmacologically active CNS cpds.. AU 8945964; EP 0372934; EP 0713703; EP 0715851; EP 0727212; EP 0727213; EP 0727214; JP 1990202876; US 5587380; US 5597828; US 5635507; US 5684005 .
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) 18202 2-(2,6-dichlorophenyl)acetonitrile; 2,6-Dichlorophenylacetonitrile 3215-64-3 C8H5Cl2N 详情 详情
(II) 17491 ethyl acetate 141-78-6 C4H8O2 详情 详情
(III) 28609 2-(2,6-dichlorophenyl)-3-oxobutanenitrile C10H7Cl2NO 详情 详情
(IV) 28610 (Z)-2-(2,6-dichlorophenyl)-3-methoxy-2-butenenitrile C11H9Cl2NO 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线31

该中间体在本合成路线中的序号：(VIII)

2,3,5-Trichlorobenzaldehyde (I) was reduced with NaBH4 to the benzyl alcohol (II) and then converted to the corresponding bromide (III) by means of PBr3 in benzene. Displacement of bromide group of (III) with KCN gave 2,3,5-trichlorophenylacetonitrile (IV), which was condensed with ethyl diethoxyacetate (V) in the presence of NaOEt to provide keto nitrile (VI). Subsequent treatment of (VI) with ethereal diazomethane generated the enol ether (VII). This was cyclized with guanidine (VIII) in boiling EtOH to produce pyrimidine (IX). After ketal hydrolysis of (IX), the resulting aldehyde (X) was reduced with NaBH4 to alcohol (XI). Finally, treatment of (XI) with diethylaminosulfur trifluoride in cold CH2Cl2 provided the desired fluoromethyl compound.

参考文献 中间体
合成目标
【1】 Miller, A.A.; Nobbs, M.S.; Hyde, R.M.; Leach, M.J. (Glaxo Wellcome plc); Pharmacologically active CNS cpds.. AU 8945964; EP 0372934; EP 0713703; EP 0715851; EP 0727212; EP 0727213; EP 0727214; JP 1990202876; US 5587380; US 5597828; US 5635507; US 5684005 .
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) 25670 2,3,5-trichlorobenzaldehyde 56961-75-2 C7H3Cl3O 详情 详情
(II) 25671 (2,3,5-trichlorophenyl)methanol C7H5Cl3O 详情 详情
(III) 25672 1-(bromomethyl)-2,3,5-trichlorobenzene C7H4BrCl3 详情 详情
(IV) 25673 2-(2,3,5-trichlorophenyl)acetonitrile C8H4Cl3N 详情 详情
(V) 25674 ethyl 2,2-diethoxyacetate 6065-82-3 C8H16O4 详情 详情
(VI) 25675 4,4-diethoxy-3-oxo-2-(2,3,5-trichlorophenyl)butanenitrile C14H14Cl3NO3 详情 详情
(VII) 25676 (E)-4,4-diethoxy-3-methoxy-2-(2,3,5-trichlorophenyl)-2-butenenitrile C15H16Cl3NO3 详情 详情
(VIII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IX) 25677 2-amino-6-(diethoxymethyl)-5-(2,3,5-trichlorophenyl)-4-pyrimidinylamine C15H17Cl3N4O2 详情 详情
(X) 25678 2,6-diamino-5-(2,3,5-trichlorophenyl)-4-pyrimidinecarbaldehyde C11H7Cl3N4O 详情 详情
(XI) 25679 [2,6-diamino-5-(2,3,5-trichlorophenyl)-4-pyrimidinyl]methanol C11H9Cl3N4O 详情 详情

合成路线32

该中间体在本合成路线中的序号：(VIII)

In the original procedure, pyruvic aldehyde dimethyl acetal (VI) was condensed with N,N-dimethylformamide dimethyl acetal to give enaminoketone (VII). Subsequent reaction of (VII) with guanidine (VIII) provided 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (IX), which was hydrolyzed to the corresponding aldehyde (X) with 3 N HCl at 48 C. This was condensed with 4-amino-2,2,6,6-tetramethylpiperidine (XI) to produce imine (XII). Finally, reaction between imine (XII) and tosyl isonitrile (V) in the presence of K2CO3 generated the target imidazole.

参考文献 中间体
合成目标
【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 .
【2】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 .
【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 25595 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide C15H12FNO2S 详情 详情
(VI) 25433 1,1-dimethoxyacetone 6342-56-9 C5H10O3 详情 详情
(VII) 25434 (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one C8H15NO3 详情 详情
(VIII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IX) 25435 4-(dimethoxymethyl)-2-pyrimidinylamine C7H11N3O2 详情 详情
(X) 25436 2-amino-4-pyrimidinecarbaldehyde C5H5N3O 详情 详情
(XI) 25596 2,2,6,6-tetramethyl-4-piperidinamine 36768-62-4 C9H20N2 详情 详情
(XII) 25597 4-[[(2,2,6,6-tetramethyl-4-piperidinyl)imino]methyl]-2-pyrimidinamine C14H23N5 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VIII)

A new procedure, which avoided the unstable pyrimidine aldehye (X), started by condensing pyruvic aldehyde (XIII) with aminopiperidine (XI). The resulting imine (XIV) was reacted with tosyl isonitrile (V) to form the acetyl imidazole (XV). Subsequent treatment of (XV) with N,N-dimethylformamide dimethyl acetal gave enaminoketone (XVI), which was then condensed with guanidine (VIII) to produce the required pyrimidine ring.

参考文献 中间体
合成目标
【1】 Sisko, J.; A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)imidazole: A potent inhibitor of P38 MAP kinase. J Org Chem 1998, 63, 13, 4529.
【2】 Sisko, J. (SmithKline Beecham plc); Novel synthesis. US 5917043; WO 9723479 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 25595 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide C15H12FNO2S 详情 详情
(VIII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XI) 25596 2,2,6,6-tetramethyl-4-piperidinamine 36768-62-4 C9H20N2 详情 详情
(XIII) 25598 2-oxopropanal 78-98-8 C3H4O2 详情 详情
(XIV) 25599 1-[(2,2,6,6-tetramethyl-4-piperidinyl)imino]acetone C12H22N2O 详情 详情
(XV) 25600 1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-1-ethanone C20H26FN3O 详情 详情
(XVI) 25601 (E)-3-(dimethylamino)-1-[4-(4-fluorophenyl)-1-(2,2,6,6-tetramethyl-4-piperidinyl)-1H-imidazol-5-yl]-2-propen-1-one C23H31FN4O 详情 详情

合成路线34

该中间体在本合成路线中的序号：(VI)

Quinoline (IV) was prepared by condensation of 2-(2-methoxyethyl)aniline (I), pyruvic acid (II) and benzaldehyde (III) in refluxing EtOH. After activation of (IV) as the imidazolide (V) by means of 1,1'-carbonyldiimidazole in DMF, its condensation with guanidine (VI) in the same solvent yielded the corresponding acyl guanidine.

参考文献 中间体
合成目标
【1】 Doebner, O.; Ueber alpha-alkylcinchoninsauren. Ber 1887, 20, 277-80.
【2】 Pfitzinger, W.; Chinolinederivate aus isatinsaure. J Prakt Chem 1886, 33, 100.
【3】 Kitamori, T.; Hosoya, J.; Mori, H.; Banno, H.; Kibayashi, K.; Yamashita, H.; Fujiwara, J.; MS-31-038. Drugs Fut 1999, 24, 12, 1306.
【4】 Fujiwara, J.; Mori, H.; Yamashita, H.; Kitamori, T.; Hosoya, J.; Banno, H. (Mitsui Chemicals, Inc.); Quinoline-4-carbonylguanidine derivates, process for producing the same and pharmaceutical compsns. containing the cpds.. EP 0726254; JP 1996277269; US 5627193 .
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) 27088 2-(2-methoxyethoxy)aniline C9H13NO2 详情 详情
(II) 24066 2-oxopropionic acid 127-17-3 C3H4O3 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 27089 8-(2-methoxyethoxy)-2-phenyl-4-quinolinecarboxylic acid C19H17NO4 详情 详情
(V) 27090 1H-imidazol-1-yl[8-(2-methoxyethoxy)-2-phenyl-4-quinolinyl]methanone C22H19N3O3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线35

该中间体在本合成路线中的序号：(IV),(V)

Condensation of 2-formylcycloheptanone (I) with ethyl 3-aminocrotonate (II) provides ethyl carboxylate (III), which is then converted into carbonylguanidine (VI) by reaction with free guanidine (V) (obtained from guanidine hydrochloride (IV) by treatment with Na/MeOH) in refluxing isopropanol. Alternatively, carbonylguanidine (VI) can also be obtained by saponification of ethyl ester (III) with refluxing NaOH to yield carboxylic acid (VII), which is then activated with oxalyl chloride (A) in CH2Cl2 or with CDI in THF to allow condensation with guanidine (V) in THF. Finally, the corresponding maleate can be obtained by reaction of carbonylguanidine (VI) with maleic acid (VIII) in MeOH.

参考文献 中间体
合成目标
【1】 Kogi, K.; Takahashi, A.; Gengyou, K.; Aihara, K.; Yoneyama, F.; Sasamori, J.; Yoneyama, S.; Satoh, T.; Yamada, S.; Kimura, T. (Toa Eiyo Ltd.); Cycloalka[b]pyridine-3-carbonylguanidine derivs., process for producing the same, and drugs containing the same. EP 0972767; WO 9839300 .
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),(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(A) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(I) 45624 2-oxocycloheptanecarbaldehyde 641-70-3 C8H12O2 详情 详情
(II) 45628 Ethyl (Z)-3-amino-2-butenoate; 3-amino-2-butenoic acid ethyl ester; Ethyl 3-aminocrotonate; 3-Aminocrotonic acid ethyl ester 626-34-6 C6H11NO2 详情 详情
(III) 45625 ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate C14H19NO2 详情 详情
(VI) 45626 N-[(2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl)carbonyl]guanidine C13H18N4O 详情 详情
(VII) 45627 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylic acid C12H15NO2 详情 详情
(VIII) 37495 Maleic acid; (Z)-2-Butenedioic acid 110-16-7 C4H4O4 详情 详情

合成路线36

该中间体在本合成路线中的序号：(VI)

Condensation of malononitrile (I) with triethyl orthoacetate (II) in pyridine produced the intermediate (III), which was cyclized to pyridine (IV) by acidic treatment. Reductive dechlorination of (IV) by hydrogenation over Pd/BaCO3 afforded 2-aminopyridine-3,5-dicarbonitrile (V). Subsequent condensation of (V) with guanidine (VI) gave rise to the pyridopyrimidine system (VII). Finally, reductive amination of (VII) with 2-chloroaniline (VIII) by means of H2 and Raney-Ni afforded the title compound.

参考文献 中间体
合成目标
【1】 Boutli, F.; Mourellou, O.; Avgoustinaki, N.; Zioga, M.; Rammnos, C.H.; Chin Journal of Medicinal Chemistry 1995, 5, 2, 79-85.
【2】 Gangjee, A.; Adair, O.; Queener, S.F.; Pneumocystis carinii Toxoplasma gondii dihydrofolate reductase inhibitors and antitumor agents: Synthesis and biological activities of 2,4-diamino-5-methyl-6-[(monosubstituted anilino)methyl]-pyrido[2,3-d]pyrimidines. J Med Chem 1999, 42, 13, 2447.
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) 12061 Malononitrile 109-77-3 C3H2N2 详情 详情
(II) 12940 1,1-Diethoxyethyl ethyl ether; 1,1,1-Triethoxyethane; Triethyl orthoacetate 78-39-7 C8H18O3 详情 详情
(III) 35800 　 C13H9N5 详情 详情
(IV) 35801 2-amino-6-chloro-4-methyl-3,5-pyridinedicarbonitrile C8H5ClN4 详情 详情
(V) 35802 2-amino-4-methyl-3,5-pyridinedicarbonitrile C8H6N4 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VII) 35803 2,4-diamino-5-methylpyrido[2,3-d]pyrimidine-6-carbonitrile C9H8N6 详情 详情
(VIII) 35804 2-chloroaniline; 2-chlorophenylamine 95-51-2 C6H6ClN 详情 详情

合成路线37

该中间体在本合成路线中的序号：(VI)

Alkylation of ethyl 4-chloroindole-2-carboxylate (I) with ethyl 5-bromovalerate (II) in the presence of NaH in DMF afforded diester (III). Regioselective hydrolysis of the aliphatic ester group employing sulfuric acid and acetic acid at 75 C produced the mono-carboxylic acid (IV). The intramolecular cyclization of acid (IV) by means of phosphoric acid and phosphorus pentoxide furnished the tricyclic system (V). The ethyl ester group of (V) was then treated with guanidine (VI) to yield the target acyl guanidine derivative, which was finally converted to the title methanesulfonate salt.

参考文献 中间体
合成目标
【1】 Kitano, M.; Ohashi, N. (Sumitomo Pharmaceuticals Co., Ltd.); Substd. guanidine derivs., process for production thereof, and pharmaceutical uses thereof. EP 0787728; JP 1998237073; US 5834454; US 5977100; US 6271251 .
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) 47754 ethyl 4-chloro-1H-indole-2-carboxylate C11H10ClNO2 详情 详情
(II) 37151 ethyl 5-bromopentanoate 14660-52-7 C7H13BrO2 详情 详情
(III) 47755 ethyl 4-chloro-1-(5-ethoxy-5-oxopentyl)-1H-indole-2-carboxylate C18H22ClNO4 详情 详情
(IV) 47756 5-[4-chloro-2-(ethoxycarbonyl)-1H-indol-1-yl]pentanoic acid C16H18ClNO4 详情 详情
(V) 47757 ethyl 11-chloro-8-oxo-5,6,7,8-tetrahydro-4H-azocino[3,2,1-hi]indole-2-carboxylate C16H16ClNO3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线38

该中间体在本合成路线中的序号：(V)

Methylation of 5-iodovanillin (I) with dimethyl sulfate and K2CO3 afforded dimethoxy derivative (II). This was condensed with 3-anilinopropionitrile (III) in the presence of potassium tert-butoxide yielding the enamino nitrile (IV). Subsequent cyclization of (IV) with guanidine hydrochloride (V) produced diaminopyrimidine (VI).

参考文献 中间体
合成目标
【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800.
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) 12758 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin 5438-36-8 C8H7IO3 详情 详情
(II) 40641 3-iodo-4,5-dimethoxybenzaldehyde 32024-15-0 C9H9IO3 详情 详情
(III) 27195 3-anilinopropanenitrile 1075-76-9 C9H10N2 详情 详情
(IV) 40642 (Z)-3-anilino-2-(3-iodo-4,5-dimethoxybenzyl)-2-propenenitrile C18H17IN2O2 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VI) 40643 5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine C13H15IN4O2 详情 详情

合成路线39

该中间体在本合成路线中的序号：(V)

Methylation of 5-iodovanillin (I) with dimethyl sulfate and K2CO3 afforded dimethoxy derivative (II). This was condensed with 3-anilinopropionitrile (III) in the presence of potassium tert-butoxide yielding the enamino nitrile (IV). Subsequent cyclization of (IV) with guanidine hydrochloride (V) produced diaminopyrimidine (VI). Cinnamate derivative (VIII) was then obtained by palladium-catalyzed coupling of (VI) with ethyl acrylate (VII).

参考文献 中间体
合成目标
【1】 Guerry, P.; Locher, H.H.; Hubschwerlen, C.; Wyss, P.C.; Jolidon, S.; Hartman, P.G.; Stalder, H.; Specklin, J.L.; Anti-MRSA dihydrofolate reductase inhibitors: Synthesis and SAR. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F1800.
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) 12758 4-Hydroxy-3-iodo-5-methoxybenzaldehyde; 5-Iodovanillin 5438-36-8 C8H7IO3 详情 详情
(II) 40641 3-iodo-4,5-dimethoxybenzaldehyde 32024-15-0 C9H9IO3 详情 详情
(III) 27195 3-anilinopropanenitrile 1075-76-9 C9H10N2 详情 详情
(IV) 40642 (Z)-3-anilino-2-(3-iodo-4,5-dimethoxybenzyl)-2-propenenitrile C18H17IN2O2 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VI) 40643 5-(3-iodo-4,5-dimethoxybenzyl)-2,4-pyrimidinediamine; 2-amino-5-(3-iodo-4,5-dimethoxybenzyl)-4-pyrimidinylamine C13H15IN4O2 详情 详情
(VII) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(VIII) 40649 ethyl (E)-3-[5-[(2,4-diamino-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl]-2-propenoate C18H22N4O4 详情 详情

合成路线40

该中间体在本合成路线中的序号：(X)

Diazotization of ethyl 3-amino-2-(3-ethoxycarbonylpropoxy)benzoate (I), followed by treatment of the resultant diazonium salt with potassium xanthogenate, afforded the aryl xanthate (II). Basic hydrolysis of (II) furnished the mercapto diacid (III). The methylthio analogue (IV) was prepared by alkylation of the thiol group with iodomethane and K2CO3. Subsequent Fischer esterification of the carboxyl groups produced diester (V), which was subjected to a Dieckmann cyclization to furnish the benzoxepin derivative (VI). Ketone (VI) reduction with NaBH4 gave hydroxyester (VII). This was dehydrated to the unsaturated ester (VIII) upon heating with p-toluenesulfonic acid in toluene. Oxidation of sulfide (VIII) with m-chloroperbenzoic acid yielded sulfone (IX). Then, displacement of the ester group of (IX) with guanidine (X) provided the title acyl guanidine, which was isolated as the mesylate salt. Alternatively, ester (VIII) was first treated with guanidine (X), producing the acyl guanidine (XI), and the sulfide group of (XI) was further oxidized to sulfone with m-chloroperbenzoic acid .

参考文献 中间体
合成目标
【1】 Takenaka, K.; et al.; Synthesis and structure activity relationships on benzoxepine derivatives as novel Na+/H+ exchange inhibitors. 21st Symp Med Chem (Nov 28 2001, Kyoto) 2001, Abst 1P-14.
【2】 Inoue, Y.; Akahane, A.; Takenaka, K.; Minagawa, M. (Fujisawa Pharmaceutical Co., Ltd.); Guanidine derivs.. EP 1073650; US 6346527; WO 9955690 .
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) 53032 ethyl 3-amino-2-(4-ethoxy-4-oxobutoxy)benzoate n/a C15H21NO5 详情 详情
(II) 53033 ethyl 3-[(ethoxycarbothioyl)sulfanyl]-2-(4-ethoxy-4-oxobutoxy)benzoate n/a C18H24O6S2 详情 详情
(III) 53034 2-(3-carboxypropoxy)-3-sulfanylbenzoic acid n/a C11H12O5S 详情 详情
(IV) 53035 2-(3-carboxypropoxy)-3-(methylsulfanyl)benzoic acid n/a C12H14O5S 详情 详情
(V) 53036 ethyl 2-(4-ethoxy-4-oxobutoxy)-3-(methylsulfanyl)benzoate n/a C16H22O5S 详情 详情
(VI) 53037 ethyl 9-(methylsulfanyl)-5-oxo-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate n/a C14H16O4S 详情 详情
(VII) 53038 ethyl 5-hydroxy-9-(methylsulfanyl)-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxylate n/a C14H18O4S 详情 详情
(VIII) 53039 ethyl 9-(methylsulfanyl)-2,3-dihydro-1-benzoxepine-4-carboxylate n/a C14H16O3S 详情 详情
(IX) 53041 N''-{[9-(methylsulfanyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl}guanidine n/a C13H15N3O2S 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线41

该中间体在本合成路线中的序号：(V)

The alkylation of 1H-indole-2-carboxylic acid methyl ester (I) with 2-phenylethyl bromide (II) by means of NaH in DMF gives 1-(2-phenylethyl)-1H-indole-2-carboxylic acid methyl ester (II), with is hydrolyzed with NaOH in methanol/water yielding the corresponding free acid (IV). Finally, this compound is condensed with guanidine by means of CDI and TEA in THF/DMF.

参考文献 中间体
合成目标
【1】 Kitano, M.; Miyagishi, A.; Ohashi, N.; Noguchi, T.; Nakano, K.; Kojima, A.; Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors. Chem Pharm Bull 1999, 47, 11, 1538.
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) 27750 Indole-2-carboxylic acid methyl ester; 1H-indole-2-carboxylic acid methyl ester 1202-04-6 C10H9NO2 详情 详情
(II) 20730 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide 103-63-9 C8H9Br 详情 详情
(III) 40402 methyl 1-phenethyl-1H-indole-2-carboxylate C18H17NO2 详情 详情
(IV) 40403 1-phenethyl-1H-indole-2-carboxylic acid C17H15NO2 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线42

该中间体在本合成路线中的序号：(III)

3-Formylchromen-4-one (II) was prepared by Vilsmeier formylation of 2'-hydroxyacetophenone (I) with POCl3 and DMF. Cyclization of (II) with guanidine carbonate (III) in refluxing EtOH gave rise to the benzopyranopyrimidine (IV). This was finally condensed with piperidine (V) in the presence of TiCl4 to furnish the title compound.

参考文献 中间体
合成目标
【1】 Barocelli, E.; Bertoni, S.; Bruno, O.; Ranise, A.; Schenone, S.; Chiavarini, M.; Ballabeni, V.; Synthesis and pharmacological screening of novel non-acidic gastroprotective antipyretic anti-inflammatory agents with anti-platelet properties. 5-Alkyl/cycloalkylamino substituted 2-amino-5H-[1]benzopyrano[4,3-d]pyrimidines. Arzneim-Forsch Drug Res 2000, 50, 2, 140.
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) 29654 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone 118-93-4 C8H8O2 详情 详情
(II) 47086 4-oxo-4H-chromene-3-carbaldehyde 17422-74-1 C10H6O3 详情 详情
(III) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IV) 47087 2-amino-5H-chromeno[4,3-d]pyrimidin-5-ol C11H9N3O2 详情 详情
(V) 10158 Piperidine 110-89-4 C5H11N 详情 详情

合成路线43

该中间体在本合成路线中的序号：(XIII)

An alternative route involved a Wittig reaction between aldehyde (IV) and ylide (XI), generated from 2-amino-3-cyanopyrazin-5-ylmethyltriphenylphosphonium chloride (X). The resulting adduct (XII) was then cyclized and partly hydrolyzed to pteridine (XIV) upon refluxing with guanidine (XIII) in MeOH. Catalytic hydrogenation and further reoxidation of (XIV) yielded (XV). The methyl ester group of (XV) was finally hydrolyzed by treatment with NaOH in DMSO.

参考文献 中间体
合成目标
【1】 Rosowsky, A.; Vaidya, C.M.; Wright, J.E.; Forsch, R.A.; Bader, H.; Analogues of the potent nonpolyglutamatable antifolate Nalpha-(4-amino-4-deoxypteroyl)-Ndelta-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity. J Med Chem 2000, 43, 8, 1620.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIIa) 42883 methyl (2S)-2-([4-[(E)-2-(5-amino-6-cyano-2-pyrazinyl)ethenyl]benzoyl]amino)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanoate C28H24N6O5 详情 详情
(XIVa) 42885 2-([[(4S)-4-([4-[(E)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid C29H28N8O6 详情 详情
(XIVb) 42886 2-([[(4S)-4-([4-[(Z)-2-(2,4-diamino-6-pteridinyl)ethenyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid C29H28N8O6 详情 详情
(XIIb) 42887 2-([[(4S)-4-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid C29H30N8O6 详情 详情
(IV) 42876 methyl (2S)-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate C22H20N2O6 详情 详情
(X) 42881 [(5-amino-6-cyano-2-pyrazinyl)methyl](triphenyl)phosphonium chloride C24H20ClN4P 详情 详情
(XI) 42882 3-amino-6-[(triphenylphosphoranylidene)methyl]-2-pyrazinecarbonitrile C24H19N4P 详情 详情
(XIII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XV) 42887 2-([[(4S)-4-([4-[2-(2,4-diamino-6-pteridinyl)ethyl]benzoyl]amino)-5-methoxy-5-oxopentyl]amino]carbonyl)benzoic acid C29H30N8O6 详情 详情

合成路线44

该中间体在本合成路线中的序号：(VIII)

4-Fluoro-3-trifluoromethylbenzoic acid (I) is esterified employing MeOH and SOCl2 to afford the methyl ester (II). Displacement of the 4-fluoride of (II) with N-benzylpiperazine (III) in hot DMSO yields the piperazinyl benzoate (IV). The N-benzyl group of (IV) is then removed by hydrogenolysis over Pd/C to yield the deprotected piperazine (V), which is further coupled with 2-pyrrolecarboxylic acid (VI) by means of CDI producing amide (VII). Finally, displacement of the methyl ester of (VII) with guanidine (VIII) gives rise to the target acyl guanidine, which is converted to the corresponding mesylate salt

参考文献 中间体
合成目标
【1】 Roos, O.; Eickmeier, C.; Blech, S.-M.; Búrger, E. (Boehringer Ingelheim Pharma GmbH & Co. KG); Benzoylguanidine derivs. with advantageous properties, method for producing them and their use in the production of medicaments. DE 19843489; JP 2002538077; US 6323207; WO 0017176 .
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) 62343 4-fluoro-3-(trifluoromethyl)benzoic acid C8H4F4O2 详情 详情
(II) 62344 methyl 4-fluoro-3-(trifluoromethyl)benzoate C9H6F4O2 详情 详情
(III) 28542 N-Benzylpiperazine; 1-Benzylpiperazine 2759-28-6 C11H16N2 详情 详情
(IV) 62345 methyl 4-(4-benzyl-1-piperazinyl)-3-(trifluoromethyl)benzoate C20H21F3N2O2 详情 详情
(V) 62346 methyl 4-(1-piperazinyl)-3-(trifluoromethyl)benzoate C13H15F3N2O2 详情 详情
(VI) 31796 Pyrrole-2-carboxylic acid; 1H-pyrrole-2-carboxylic acid 634-97-9 C5H5NO2 详情 详情
(VII) 62347 methyl 4-[4-(1H-pyrrol-2-ylcarbonyl)-1-piperazinyl]-3-(trifluoromethyl)benzoate C18H18F3N3O3 详情 详情
(VIII) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线45

该中间体在本合成路线中的序号：(III)

The known benzazepinone (I) was reacted with dimethylformamide dimethylacetal in DMF to furnish enamino ketone (II). Subsequent cyclization of (II) with guanidine in the presence of sodium methoxide produced the title pyrimido-benzazepine.

参考文献 中间体
合成目标
【1】 Trybulski, E.J.; et al.; 2-Benzazepines. 5.Synthesis of pyrimido[5,4-d][2] benzazepines and their evaluation as anxiolytic agents. J Med Chem 1983, 26, 11, 1589.
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) 41391 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one C16H11ClFNO 详情 详情
(II) 41392 8-chloro-4-[(E)-(dimethylamino)methylidene]-1-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one C19H16ClFN2O 详情 详情
(III) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线46

该中间体在本合成路线中的序号：(IX),(XII)

Malonic acid monoethyl ester (I) is converted into beta-ketoester (III) by formation of the corresponding trimethylsilyl ester with TMSCl and pyridine in ether followed by deprotonation with n-BuLi and acylation with cyclopropanecarbonyl chloride (II) in DME. Treatment of (III) with refluxing N,N-dimethylformamide dimethyl acetal (IV) affords enamine (V). Quinoline-5-amine (VI) is first subjected to diazotation by treatment with NaNO2 in H2O/HCl, reduced with SnCl2.2H2O in HCl and isolated as the corresponding dihydrochloride salt (VII) by treatment with HCl. Condensation of enamine (V) with hydrazine (VII) in the presence of Et3N in refluxing EtOH yields pyrazole ester (VIII), which is converted into acylguanidine (X) either by direct heating with guanidine (IX) in EtOH or by first transformation into the corresponding carboxylic acid (XI) by saponification with NaOH in refluxing MeOH, followed by treatment with refluxing thionyl chloride and reaction with guanidine hydrochloride (XII) under Schotten-Baumann conditions in refluxing THF/NaOH. Finally, treatment of the free base (X) with HCl in THF allows isolation of the corresponding monohydrochloride-monohydrate salt .

参考文献 中间体
合成目标
【1】 Wester, R.T.; Allen, M.C.; Guzman-Perez, A.; et al.; Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. Bioorg Med Chem Lett 2001, 11, 6, 803.
【2】 Guzman-Perez, A.; Ruggeri, R.B.; Wester, R.T.; Hamanaka, E.S.; Mularski, C.J. (Pfizer Inc.); N-[(Substd. five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivs. for the treatment of ischemia. EP 1056729; WO 9943663 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX),(XII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(I) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(II) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(III) 15949 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate 24922-02-9 C8H12O3 详情 详情
(IV) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(V) 48913 ethyl (Z)-3-amino-2-(cyclopropylcarbonyl)-2-propenoate C9H13NO3 详情 详情
(VI) 26799 5-Aminoquinoline; 5-quinolinamine 611-34-7 C9H8N2 详情 详情
(VII) 48914 5-hydrazinoquinoline C9H9N3 详情 详情
(VIII) 48915 ethyl 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate C18H17N3O2 详情 详情
(X) 48917 N''-[[5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazol-4-yl]carbonyl]guanidine C17H16N6O 详情 详情
(XI) 48916 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid C16H13N3O2 详情 详情

合成路线47

该中间体在本合成路线中的序号：(X)

Preparation of the title compound has been reported by two procedures. Catalytic hydrogenation of benzofuran-4-carboxylic acid (I) over Pd/C afforded the dihydrobenzofuran (II). Carboxyl group reduction in (II) with LiAlH4 and further Swern oxidation of the resulting alcohol (III) furnished aldehyde (IV). Knoevenagel condensation of aldehyde (IV) with dimethyl malonate provided the benzylidenemalonate (V), which was converted to the key cyclopropane derivative (VII) upon treatment with 2-nitropropane (VI) and potassium tert-butoxide. Hydrolysis and decarboxylation of the malonate ester (VII) was performed using NaCN in hot DMSO to yield acid (VIIIa-b) as a diastereomeric mixture. Recrystallization of (VIIIa-b) from acetonitrile-water allowed the separation of the major (+/-)-trans-isomer, which was then resolved by preparative chiral HPLC. The desired (R,R)-isomer (IX) was finally coupled with guanidine (X) via activation with CDI

参考文献 中间体
合成目标
【1】 Ahmad, S.; et al.; Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1. J Med Chem 2001, 44, 20, 3302.
【2】 Wu, S.C.; Atwal, K.S.; Dugar, S.; Ahmad, S. (Bristol-Myers Squibb Co.); Acyl guanidine sodium/proton exchange inhibitors and method. EP 1041980; JP 2001527042; US 6011059; WO 9933460 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIIa) 51881 (1R)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid C14H16O3 详情 详情
(VIIIb) 51882 (1S)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid C14H16O3 详情 详情
(I) 51875 1-benzofuran-4-carboxylic acid C9H6O3 详情 详情
(II) 51876 2,3-dihydro-1-benzofuran-4-carboxylic acid C9H8O3 详情 详情
(III) 51877 2,3-dihydro-1-benzofuran-4-ylmethanol C9H10O2 详情 详情
(IV) 51878 2,3-dihydro-1-benzofuran-4-carbaldehyde C9H8O2 详情 详情
(V) 51879 dimethyl 2-(2,3-dihydro-1-benzofuran-4-ylmethylene)malonate C14H14O5 详情 详情
(VI) 21819 2-nitropropane 79-46-9 C3H7NO2 详情 详情
(VII) 51880 dimethyl 3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethyl-1,1-cyclopropanedicarboxylate C17H20O5 详情 详情
(IX) 51883 (1R,3R)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid C14H16O3 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线48

该中间体在本合成路线中的序号：(X)

In a different procedure, the previously reported acetal (XI) was hydrolyzed under acidic conditions to give triol (XII). Oxidative cleavage of the cyclic diol function of (XII) by means of NaIO4 gave rise to the dialdehyde (XIII), which was further subjected to a reductive treatment with NaBH4, yielding triol (XIV). Tosylation of the aliphatic hydroxyl groups of (XIV) produced the ditosylate (XV) which, upon treatment with K2CO3 in MeOH, underwent intramolecular cyclization to the dihydrobenzofuran (XVI). Elimination of the remaining tosylate group of (XVI) in the presence of potassium tert-butoxide afforded the styrene derivative (XVII). Subsequent cycloaddition between styrene (XVII) and the enol triflate generated from N,N-dimethylisobutyramide (XVIII) produced the cyclobutanone (XIX). Halogenation of the lithium enolate of ketone (XIX) with N-bromosuccinimide in cold THF yielded the bromo ketone (XX). This underwent a Favorskii rearrangement in the presence of NaOH, producing the corresponding racemic cyclopropanecarboxylic acid, which was resolved by formation of the diastereomeric salts with (+)-alpha-methylbenzylamine. The desired (R,R)-acid (IX) was finally coupled with guanidine (X) via activation with CDI as above.

参考文献 中间体
合成目标
【1】 Wu, S.C.; Atwal, K.S.; Dugar, S.; Ahmad, S. (Bristol-Myers Squibb Co.); Acyl guanidine sodium/proton exchange inhibitors and method. EP 1041980; JP 2001527042; US 6011059; WO 9933460 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 51883 (1R,3R)-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclopropanecarboxylic acid C14H16O3 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XI) 51884 (3aS,9aR)-2,2-dimethyl-3a,4,9,9a-tetrahydronaphtho[2,3-d][1,3]dioxol-5-ol C13H16O3 详情 详情
(XII) 40442 (6R,7S)-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol C10H12O3 详情 详情
(XIII) 51885 2-[2-hydroxy-6-(2-oxoethyl)phenyl]acetaldehyde C10H10O3 详情 详情
(XIV) 51886 2,3-bis(2-hydroxyethyl)phenol C10H14O3 详情 详情
(XV) 51887 3-hydroxy-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)phenethyl 4-methylbenzenesulfonate C24H26O7S2 详情 详情
(XVI) 51888 2-(2,3-dihydro-1-benzofuran-4-yl)ethyl 4-methylbenzenesulfonate C17H18O4S 详情 详情
(XVII) 51889 4-vinyl-2,3-dihydro-1-benzofuran C10H10O 详情 详情
(XVIII) 51890 N,N,2-Trimethylpropionamide; N,N-Dimethylisobutyramide 21678-37-5 C6H13NO 详情 详情
(XIX) 51891 3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclobutanone C14H16O2 详情 详情
(XX) 51892 4-bromo-3-(2,3-dihydro-1-benzofuran-4-yl)-2,2-dimethylcyclobutanone C14H15BrO2 详情 详情

合成路线49

该中间体在本合成路线中的序号：(VI)

The title compound was isolated from the fermentation broth of Streptomyces sp. strain HC-21. A synthetic method for the preparation of the title compound was also reported. Asymmetric dihydroxylation of ethyl crotonate (I) using commercial AD-mix-beta produced diol (II). This was converted to the (2S,3R)-epoxide (III) by bromination with HBr in HOAc followed by cyclization of the resultant bromohydrin in the presence of DBU. Epoxide ring opening with the organomagnesium reagent generated from indole (IV) and methylmagnesium bromide furnished the chiral indolylbutanoate (V). Cyclization of the hydroxy ester (V) with guanidine hydrochloride (VI) in the presence of potassium tert-butoxide yielded the amino oxazolone (VII). Finally, displacement of the amino- by a methylamino group was achieved by treatment with aqueous methylamine.

参考文献 中间体
合成目标
【1】 Kanamaru, T.; Nakao, M.; Tawada, H.; Kamiyama, K. (Takeda Chemical Industries, Ltd.); Oxazolone derivs. and their use as anti-Helicobacter pylori agent. EP 0923577; JP 1998279579; US 6169102; WO 9749703 .
【2】 Kamiyama, K.; Nakayama, Y. (Takeda Chemical Industries, Ltd.); Process for producing indolmycins. WO 9952905 .
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) 52087 Ethyl crotonate; trans-Ethyl crotonate; Crotonic acid ethyl ester 623-70-1 C6H10O2 详情 详情
(II) 52088 ethyl (2S,3R)-2,3-dihydroxybutanoate C6H12O4 详情 详情
(III) 52089 ethyl (2S,3R)-3-methyl-2-oxiranecarboxylate C6H10O3 详情 详情
(IV) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(V) 52090 ethyl (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoate C14H17NO3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VII) 52091 (5S)-2-amino-5-[(1R)-1-(1H-indol-3-yl)ethyl]-1,3-oxazol-4(5H)-one C13H13N3O2 详情 详情

合成路线50

该中间体在本合成路线中的序号：(V)

The condensation of the chiral epoxide (I) with indole (II) by means of methylmagnesium bromide in ethyl ether/dichloromethane gives the indolylbutyric ester (III), which is hydrolyzed with NaOH in ethanol/water and purified by crystallization to yield the corresponding butyric acid (IV). The esterification of (IV) with ethanol/HCl regenerates pure ester (III), which is cyclized with guanidine (V) by means of tBu-OK in tert-butanol to afford the oxazolone (VI). Finally the amino group of (VI) is methylated by means of methylamine in water to provide the target indolmycin.

参考文献 中间体
合成目标
【1】 Hasuoka, A.; et al.; Development of a stereoselective practical synthetic route to indolmycin, a candidate anti-H. pylori agent. Chem Pharm Bull 2001, 49, 12, 1604.
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) 52089 ethyl (2S,3R)-3-methyl-2-oxiranecarboxylate C6H10O3 详情 详情
(II) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(III) 52090 ethyl (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoate C14H17NO3 详情 详情
(IV) 58332 (rac)-2-hydroxy-3-(1H-indol-3-yl)butanoic acid C12H13NO3 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VI) 52091 (5S)-2-amino-5-[(1R)-1-(1H-indol-3-yl)ethyl]-1,3-oxazol-4(5H)-one C13H13N3O2 详情 详情

合成路线51

该中间体在本合成路线中的序号：(VI)

N-Benzoylisonipecotic acid (I) was chlorinated with SOCl2 to produce the corresponding acid chloride (II). Acylation of the lithium enolate of (4-methoxyphenyl)acetone (III) with acid chloride (II) provided a mixture of diketone regioisomers (IV) and (V); these were separated by column chromatography. The desired diketone (IV) was then cyclized with guanidine (VI) in hot pyridine to afford the pyrimidine (VII). Basic hydrolysis of the benzamide function of (VII) gave the piperidine derivative (VIII). The target amide was finally prepared by acylation of (VIII) with 3,4-methylenedioxybenzoic acid (IX) in the presence of EDC.

参考文献 中间体
合成目标
【1】 Kawakami, H.; Kurimoto, A.; Murata, S.; Fujita, H.; Iwai, K.; Fujiwara, N.; Synthesis and bioactivities of novel piperidylpyrimidine derivatives: Inhibitors of tumor necrosis factor-alpha production. Bioorg Med Chem Lett 2000, 10, 12, 1317.
【2】 Fujiwara, N.; Ueda, Y.; Murata, S.; Hirota, F.; Kawakami, H.; Fujita, H. (Sumitomo Pharmaceuticals Co., Ltd.); Piperidinylpyramidine derivs.. EP 0892795; JP 2001511764; US 5948786; WO 9738992 .
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) 52892 1-benzoyl-4-piperidinecarboxylic acid C13H15NO3 详情 详情
(II) 52893 1-benzoyl-4-piperidinecarbonyl chloride C13H14ClNO2 详情 详情
(III) 10038 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone 122-84-9 C10H12O2 详情 详情
(IV) 52894 1-(1-benzoyl-4-piperidinyl)-4-(4-methoxyphenyl)-1,3-butanedione C23H25NO4 详情 详情
(V) 52895 1-(1-benzoyl-4-piperidinyl)-2-(4-methoxyphenyl)-1,3-butanedione C23H25NO4 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VII) 52896 {4-[2-amino-6-(4-methoxybenzyl)-4-pyrimidinyl]-1-piperidinyl}(phenyl)methanone C24H26N4O2 详情 详情
(VIII) 52897 4-(4-methoxybenzyl)-6-(4-piperidinyl)-2-pyrimidinamine; 4-(4-methoxybenzyl)-6-(4-piperidinyl)-2-pyrimidinylamine C17H22N4O 详情 详情
(IX) 10125 1,3-Benzodioxole-5-carboxylic acid 94-53-1 C8H6O4 详情 详情

合成路线52

该中间体在本合成路线中的序号：(V)

Pyridine (III) was prepared by condensation of malononitrile (I) with triethyl orthoformate (II) in refluxing pyridine, followed by treatment with concentrated HCl. Dechlorination of (III) was effected by hydrogenolysis in the presence of Pd on BaCO3. The dechlorinated pyridine dinitrile (IV) was cyclized with guanidine (V), yielding the pyridopyrimidine (VI). Reduction of the nitrile function of (VI) to aldehyde (VII) was carried out using formic acid and Raney-Ni. This was further reduced to alcohol (VIII) with NaBH4. Bromination of the alcohol (VIII) by means of HBr resulted in bromide (IX). Nucleophilic displacement of the bromide group of (IX) with the sodium salt of 1-naphthalenethiol (X) afforded the target sulfide.

参考文献 中间体
合成目标
【1】 Gangjee, A.; et al.; Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido [2,3-d]pyrimidines as dihydrofolate reductase inhibitors. Bioorg Med Chem 2001, 9, 11, 2929.
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) 12061 Malononitrile 109-77-3 C3H2N2 详情 详情
(II) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(III) 50364 2-amino-6-chloro-3,5-pyridinedicarbonitrile C7H3ClN4 详情 详情
(IV) 31544 2-amino-3,5-pyridinedicarbonitrile C7H4N4 详情 详情
(V) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(VI) 14269 2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile C8H6N6 详情 详情
(VII) 14270 2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbaldehyde C8H7N5O 详情 详情
(VIII) 50365 (2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)methanol C8H9N5O 详情 详情
(IX) 50366 2-amino-6-(bromomethyl)pyrido[2,3-d]pyrimidin-4-ylamine; 6-(bromomethyl)pyrido[2,3-d]pyrimidine-2,4-diamine C8H8BrN5 详情 详情
(X) 50367 1-Naphthalenethiol 529-36-2 C10H8S 详情 详情

合成路线53

该中间体在本合成路线中的序号：(XI)

Protection of 4-methoxyphenol (I) with methyl chloroformate in the presence of pyridine affords the carbonate ester (II), which is condensed with dichloromethyl methyl ether and TiCl4 to yield alpha-chloro ether (III). Acidic hydrolysis of (III) with HCl furnishes aldehyde (IV), which is converted into the sodium phenoxide (V) by methanolysis of the carbonate ester (IV). Subsequent alkylation of (V) with p-methoxybenzyl bromide (VI) produces the p-methoxybenzyl ether (VII), which is condensed with 3-morpholinopropionitrile (VIII) employing a catalytic amount of NaOMe to give the morpholino acrylonitrile (IX). After conversion of (IX) to the 3-anilino acrylonitrile (X) upon heating with aniline hydrochloride, condensation with guanidine (XI) produces the diaminopyrimidine (XII). The p-methoxybenzyl group of (XII) is then cleaved by treatment with p-toluenesulfonic acid in MeOH, producing phenol (XIII). The sodium salt generated from phenol (XIII) and NaOEt is then alkylated with ethyl 5-bromopentanoate (XIV) to furnish ether (XV). Finally, alkaline hydrolysis of the ethyl ester group of (XV) leads to the title compound.

参考文献 中间体
合成目标
【1】 Rosowsky, A.; Queener, S.F.; Forsch, R.A.; Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity. J Med Chem 2002, 45, 1, 233.
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) 32744 4-methoxyphenol 150-76-5 C7H8O2 详情 详情
(II) 59058 4-methoxyphenyl methyl carbonate C9H10O4 详情 详情
(III) 59059 3-[chloro(methoxy)methyl]-4-methoxyphenyl methyl carbonate C11H13ClO5 详情 详情
(IV) 59060 3-formyl-4-methoxyphenyl methyl carbonate C10H10O5 详情 详情
(V) 59061 sodium 3-formyl-4-methoxybenzenolate C8H7NaO3 详情 详情
(VI) 27490 1-(bromomethyl)-4-methoxybenzene C8H9BrO 详情 详情
(VII) 59062 2-methoxy-5-[(4-methoxybenzyl)oxy]benzaldehyde C16H16O4 详情 详情
(VIII) 31933 3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile 4542-47-6 C7H12N2O 详情 详情
(IX) 59063 (Z)-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-3-(4-morpholinyl)-2-propenenitrile C23H26N2O4 详情 详情
(X) 59064 (Z)-3-anilino-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2-propenenitrile C25H24N2O3 详情 详情
(XI) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XII) 59065 2-amino-5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-4-pyrimidinylamine; 5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2,4-pyrimidinediamine C20H22N4O3 详情 详情
(XIII) 59066 3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenol C12H14N4O2 详情 详情
(XIV) 37151 ethyl 5-bromopentanoate 14660-52-7 C7H13BrO2 详情 详情
(XV) 59067 ethyl 5-{3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenoxy}pentanoate C19H26N4O4 详情 详情

合成路线54

该中间体在本合成路线中的序号：(III)

Fischer esterification of 2-aminonicotinic acid (I) leads to methyl ester (II). Subsequent treatment of ester (II) with a methanolic solution of guanidine (III) provides (2-aminonicotinoyl)guanidine (IV). Finally, bromination of (IV) employing Br2/HBr affords the title compound.

参考文献 中间体
合成目标
【1】 Cragoe, E.J. Jr. (Merck & Co., Inc.); Certain aminopyridinecarbonyl guanidines. DE 1963317; FR 2026469; US 3586688 .
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) 55933 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid 5345-47-1 C6H6N2O2 详情 详情
(II) 55934 methyl 2-aminonicotinate 14667-47-1 C7H8N2O2 详情 详情
(III) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(IV) 62994 　 C7H9N5O 详情 详情

合成路线55

该中间体在本合成路线中的序号：(IV)

Glycosylation of dimethyl 2-phenylimidazole-4,5-dicarboxylate (I) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (II) in the presence of hexamethyldisilazane, chlorotrimethylsilane and trifluoromethanesulfonic acid leads to the imidazole ribofuranoside (III). Then, cyclization of the imidazoledicarboxylate (III) with guanidine (IV), and simultaneous alcoholysis of the ribose ester groups in the presence of methanolic NaOMe gives rise to the target imidazodiazepine ribofuranoside

参考文献 中间体
合成目标
【1】 Zhang, N.; Chen, H.-M.; Sood, R.; Kalicharran, K.; Fattom, A.I.; Naso, R.B.; Barnard, D.L.; Sidwell, R.W.; Hosmane, R.S.; In vitro inhibition of the measles virus by novel ring-expanded ('fat') nucleoside analogues containing the imidazo[4,5-e]diazepine ring system. Bioorg Med Chem Lett 2002, 12, 23, 3391.
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) 62724 4-ethyl 5-methyl 2-phenyl-1H-imidazole-4,5-dicarboxylate C14H14N2O4 详情 详情
(II) 62725 [(2R,3R,4R)-5-(acetyloxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate C28H24O9 详情 详情
(III) 62726 4-ethyl 5-methyl 1-{(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl}-2-phenyl-1H-imidazole-4,5-dicarboxylate C40H34N2O11 详情 详情
(IV) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线56

该中间体在本合成路线中的序号：(I)

Condensation of guanidine nitrate (I) with (ethoxymethylene)malononitrile (II) in the presence of NaOEt yields 2,4-diaminopyrimidine-5-carbonitrile (III). Reduction of nitrile (III) by means of Raney nickel in formic acid leads to aldehyde (IV), which is further reduced to alcohol (V) by means of NaBH4. Treatment of alcohol (V) with HBr in AcOH gives the bromide (VI), which is condensed with pyridine in DMF to form the crystalline pyridinium salt (VII). Finally, displacement of compound (VII) with the tetrahydroisoquinoline (VIII), followed by resolution by chiral HPLC, furnishes the title compound.

参考文献 中间体
合成目标
【1】 Gerber, P.; Wyss, P.C.; Hartman, P.G.; Hubschwerlen, C.; Locher, H.; Marty, H.-P.; Stahl, M.; Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003, 46, 12, 2304.
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) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(II) 13017 Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile 123-06-8 C6H6N2O 详情 详情
(III) 64871 2,4-diamino-5-pyrimidinecarbonitrile C5H5N5 详情 详情
(IV) 26525 2,4-diamino-5-pyrimidinecarbaldehyde C5H6N4O 详情 详情
(V) 64872 (2,4-diamino-5-pyrimidinyl)methanol C5H8N4O 详情 详情
(VI) 64873 5-(bromomethyl)-2,4-pyrimidinediamine C5H7BrN4 详情 详情
(VII) 64874 1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide C10H12BrN5 详情 详情
(VIII) 64875 methyl 9-methyl-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinolin-4-yl ether; 9-methyl-4-(methyloxy)-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinoline C12H15NO3 详情 详情
Extended Information