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【结 构 式】 
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【分子编号】12314 【品名】1-Naphthaldehyde 【CA登记号】66-77-3 |
【 分 子 式 】C11H8O 【 分 子 量 】156.18392 【元素组成】C 84.59% H 5.16% O 10.24% |
合成路线1
该中间体在本合成路线中的序号：(IV)1) Synthesis of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine: The condensation of diethyl succinate (III) with 1-naphthaldehyde (IV) by means of sodium ethoxide in refluxing methanol gives 2-(1-naphthylmethylene)succinic acid diethyl ester (V), which is hydrolyzed to the corresponding acid (VI) with NaOH. The cyclization of (VI) with refluxing SOCl2 affords the anhydride (VII), which is treated with morpholine (VIII) in ethyl acetate, yielding 2-(morpholinocarbonylmethyl)-3-(1-naphthyl)acrylic acid (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding propionic acid (X), which is then condensed with histidine methyl ester (XI) by means of DCC and HONB as before, giving a racemic mixture that is submitted to optical resolution by repeated crystallization of its salycylic acid salt, thus yielding N-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine methyl ester (XII). Finally, this compound is hydrolyzed with NaOH and protected with tert-butoxycarbonyl anhydride to give (I).
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 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) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (III) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 12315 | diethyl 2-[(Z)-1-naphthylmethylidene]succinate | C19H20O4 | 详情 | 详情 | |
| (VI) | 12316 | 2-[(Z)-1-Naphthylmethylidene]succinic acid | C15H12O4 | 详情 | 详情 | |
| (VII) | 12317 | 3-[(Z)-1-Naphthylmethylidene]-2,5(4H)-furandione | C15H10O3 | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IX) | 12319 | (Z)-2-(2-Morpholino-2-oxoethyl)-3-(1-naphthyl)-2-propenoic acid | C19H19NO4 | 详情 | 详情 | |
| (X) | 12320 | 4-Morpholino-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (XI) | 12321 | methyl (2S)-2-amino-3-(1H-imidazol-5-yl)propanoate; Methyl-L-histidine | 1499-46-3 | C7H11N3O2 | 详情 | 详情 |
| (XII) | 12322 | methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2R)-4-morpholino-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VII) with HCl in cold EtOAc furnished the required intermediate (IX).
| 【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 . |
| 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) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 34734 | methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 34735 | methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate | C25H36N2O4 | 详情 | 详情 | |
| (VI) | 34736 | 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid | C24H34N2O4 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VIII) | 34737 | methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate | C30H45N3O5S | 详情 | 详情 | |
| (IX) | 34738 | methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate | C25H37N3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VIII) with HCl in cold EtOAc furnished the required intermediate (IX).
| 【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 . |
| 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) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 34734 | methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 34735 | methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate | C25H36N2O4 | 详情 | 详情 | |
| (VI) | 34736 | 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid | C24H34N2O4 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VIII) | 34737 | methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate | C30H45N3O5S | 详情 | 详情 | |
| (IX) | 34738 | methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate | C25H37N3O3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Horner-Emmons reaction of 1-naphthaldehyde (I) with triethyl phosphonoacetate (II) gave naphthyl propenoate (III), which was hydrogenated over Pd/C to afford propanoate (IV), and further reduced to alcohol (V) with LiAlH4. The required naphthyl propylamine (VIII) was then obtained by the sequence of conversion of (V) to mesylate (VI), displacement by NaN3, and reduction of the resulting azide (VII) with LiAlH4. After coupling of (VIII) with N-Boc-L-asparagine N-hydroxysuccinimidyl ester (IX) to give (X), the N-Boc group was deprotected using trifluoroacetic acid in CH2Cl2 to afford amine (XI). Subsequent coupling of (XI) with N-Boc-1-amino-1-cyclohexanecarboxylic acid (XII) by means of DCC and HOBt gave (XIII).
| 【1】 Yao, Z.-J.; King, C.R.; Cao, T.; Kelley, J.; Milne, G.W.; Voigt, J.H.; Burke, T.R. Jr.; Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. J Med Chem 1999, 42, 1, 25. |
| 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) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (III) | 25405 | ethyl (E)-3-(1-naphthyl)-2-propenoate | C15H14O2 | 详情 | 详情 | |
| (IV) | 25406 | ethyl 3-(1-naphthyl)propanoate | C15H16O2 | 详情 | 详情 | |
| (V) | 25407 | 3-(1-naphthyl)-1-propanol | C13H14O | 详情 | 详情 | |
| (VI) | 25408 | 3-(1-naphthyl)propyl methanesulfonate | C14H16O3S | 详情 | 详情 | |
| (VII) | 25409 | 3-(1-naphthyl)propyl azide; 1-(3-azidopropyl)naphthalene | C13H13N3 | 详情 | 详情 | |
| (VIII) | 25410 | 3-(1-naphthyl)-1-propanamine; 3-(1-naphthyl)propylamine | C13H15N | 详情 | 详情 | |
| (IX) | 25411 | tert-butyl (1S)-3-amino-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]-3-oxopropylcarbamate | C13H19N3O7 | 详情 | 详情 | |
| (X) | 25412 | tert-butyl (1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropylcarbamate | C22H29N3O4 | 详情 | 详情 | |
| (XI) | 25413 | (2S)-2-amino-N(1)-[3-(1-naphthyl)propyl]butanediamide | C17H21N3O2 | 详情 | 详情 | |
| (XII) | 25414 | 1-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid | C12H21NO4 | 详情 | 详情 | |
| (XIII) | 25415 | tert-butyl 1-([[(1S)-3-amino-1-([[3-(1-naphthyl)propyl]amino]carbonyl)-3-oxopropyl]amino]carbonyl)cyclohexylcarbamate | C29H40N4O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Horner-Emmons condensation of 1-naphthaldehyde (VI) with triethyl phosphonoacetate (VII) using DBU as the base afforded naphthylacrylate (VIII). This was reacted with tosylmethylisocyanide and potassium tert-butoxide to produce pyrrole (IX). Hydrolysis of the ester group of (IX) with KOH gave rise to the carboxylic acid (X), which was coupled with N-methylpiperazine (XI) employing EDC and HOBt or, alternatively, by previous conversion to the corresponding acid chloride with SOCl2. The resulting amide (XII) was finally alkylated at the pyrrole N atom with chloride (V) in the presence of NaH.
| 【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210. |
| 【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 . |
| 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) | 33672 | 1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole | C12H11ClN2O2 | 详情 | 详情 | |
| (VI) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 25405 | ethyl (E)-3-(1-naphthyl)-2-propenoate | C15H14O2 | 详情 | 详情 | |
| (IX) | 33673 | ethyl 4-(1-naphthyl)-1H-pyrrole-3-carboxylate | C17H15NO2 | 详情 | 详情 | |
| (X) | 33674 | 4-(1-naphthyl)-1H-pyrrole-3-carboxylic acid | C15H11NO2 | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XII) | 33675 | (4-methyl-1-piperazinyl)[4-(1-naphthyl)-1H-pyrrol-3-yl]methanone | C20H21N3O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The intermediate naphthylmethyl amine (IV) was prepared from 1-naphthaldehyde (I) by two related procedures. Reduction of (II) with NaBH4 gave alcohol (II), which was converted to the corresponding chloride with SOCl2 and then condensed with methylamine. Alternatively, condensation of aldehyde (I) with methylamine using TiCl4 as the dehydrating reagent produced aldimine (III), which was then reduced to amine (IV) by means of NaBH4.
| 【1】 Zhou, Y.; Zhang, W.; Li, K.; Jiang, Y.; Li, Y.; Wang, X.; The synthesis and antifungal activity of the substituted naphthalenemethanamines. Chin Journal of Medicinal Chemistry 1999, 9, 7, 7. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (I) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (II) | 35129 | 1-naphthylmethanol | 4780-79-4 | C11H10O | 详情 | 详情 |
| (III) | 35130 | N-[(Z)-1-naphthylmethylidene]methanamine; N-methyl-N-[(Z)-1-naphthylmethylidene]amine | C12H11N | 详情 | 详情 | |
| (IV) | 10108 | N-Methyl(1-naphthyl)methanamine; N-Methyl-N-(1-naphthylmethyl)amine; 1-Methyl-1-naphthalenemethylamine | 65473-13-4 | C12H13N | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)Solid phase synthesis: Attachment of 8-Fmoc-3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (I) to Wang resin by means of 2,6-dichlorobenzoyl chloride (A) in DMF in the presence of pyridine, followed by treatment with benzoyl chloride (B) in dichloromethane in the presence of pyridine, provides resin-anchored derivative (II). Treatment of resin (II) with piperidine in DMF allows Fmoc removal to yield deprotected piperidine derivative (III), which is then converted into the target compound by alkylation with 1-(bromomethyl)naphthalene (IV) by heating in DMSO in the presence of DIEA, followed by cleavage of the molecule from the resin by heating with NaOMe in THF/MeOH. Alternatively, the conversion of (III) into the desired compound can be achieved by reductive amination between resin (III) and aldehyde (V) by means of NaBH3CN in THF in the presence of HOAc to afford anchored derivative (VI), followed by cleavage from the resin by heating with NaOMe in THF/MeOH.
| 【1】 Watson, B.; Thomsen, C.; Hohlweg, R. (Novo Nordisk A/S); Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes. EP 1080091; WO 9959997 . |
| 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) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (A) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (I),(II) | 47322 | 2-[8-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid | C30H29N3O5 | 详情 | 详情 | |
| (III) | 47323 | 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl)acetic acid | C15H19N3O3 | 详情 | 详情 | |
| (IV) | 47324 | 1-(bromomethyl)naphthalene | 3163-27-7 | C11H9Br | 详情 | 详情 |
| (V) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (VI) | 47325 | 2-[8-(1-naphthylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid | C26H27N3O3 | 详情 | 详情 |