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【结 构 式】 
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【分子编号】25087 【品名】2,6-dichlorobenzoyl chloride 【CA登记号】4659-45-4 |
【 分 子 式 】C7H3Cl3O 【 分 子 量 】209.45832 【元素组成】C 40.14% H 1.44% Cl 50.78% O 7.64% |
合成路线1
该中间体在本合成路线中的序号：(VII)The condensation of 2-fluoronitrobenzene (I) with acetone oxime (II) by means of NaH in DMF gives acetone O-(2-nitrophenyl)oxime (III), which is cyclized to 2-methyl-7-nitrobenzofuran (IV) by means of H2SO4. The Friedel Crafts acylation of (IV) with acetyl chloride and AlCl3 in dichloromethane affords 3-acetyl-2-methyl-7-nitrobenzofuran (V), which is reduced to the corresponding amino derivative (VI) with Fe and HCl in ethanol. The condensation of (VI) with 2,6-dichlorobenzoyl chloride (VII) by means of triethylamine in dichloroethane yields N-(3-acetyl-2-methylbenzofuran-7-yl)-2,6-dichlorobenzamide (VIII), which is finally submitted to a Grignard reaction with methylmagnesium bromide in THF.
| 【1】 Yamazaki, H.; et al.; Synthesis and pharmacological activities of novel benzofuran derivatives as vacuolar type H+-ATPase inhibitors. Symp Med Chem 1998, Abst 2-P-32. |
| 【2】 Kawai, Y.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K.; Yatabe, T.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Benzofuran derivs. useful as inhibitors of bone resorption. EP 0757682; JP 1997512795; US 5858995; WO 9529907 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (II) | 17791 | acetone oxime; Acetoxime | 127-06-0 | C3H7NO | 详情 | 详情 |
| (III) | 25083 | acetone O-(2-nitrophenyl)oxime | C9H10N2O3 | 详情 | 详情 | |
| (IV) | 25084 | 2-methyl-7-nitro-1-benzofuran | C9H7NO3 | 详情 | 详情 | |
| (V) | 25086 | 1-(7-amino-2-methyl-1-benzofuran-3-yl)-1-ethanone | C11H11NO2 | 详情 | 详情 | |
| (VI) | 24086 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetate | C25H25N3O6S | 详情 | 详情 | |
| (VII) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VIII) | 25088 | N-(3-acetyl-2-methyl-1-benzofuran-7-yl)-2,6-dichlorobenzamide | C18H13Cl2NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Fischer esterification of L-4-nitrophenylalanine (V) afforded nitrophenylalanine methyl ester (VI), which was then protected as the tert-butyl carbamate (VII) using (Boc)2O. Reduction of the nitro group of (VII) by catalytic hydrogenation gave aniline (VIII). Subsequent coupling of (VIII) with 2,6-dichlorobenzoyl chloride (IX) generated amide (X). Deprotection of the Boc group of (X) using HCl in dioxan provided aminoester (XI), which was coupled with camphoric acid derivative (IV) in the presence of benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate (BOP) to yield amide (XII). Deprotection of the tert-butyl ester group of (XII) by means of trifluoroacetic acid gave acid (XIII). Finally, the methyl ester group of (XIII) was hydrolyzed with LiOH to furnish the title compound.
| 【1】 Rishton, G.; Chrusciel, R.A.; Yamagishi, M.; Polinsky, A.; Thomas, E.W.; Lobl, T.J.; Tanis, S.P.; Teegarden, B.; Fisher, J.F. (Pharmacia Corp.; Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4beta1 mediated cell adhesion. EP 0991619; WO 9858902 . |
| 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) | 32572 | (1S,3R)-3-(tert-butoxycarbonyl)-2,2,3-trimethylcyclopentanecarboxylic acid | C14H24O4 | 详情 | 详情 | |
| (V) | 15341 | (2S)-2-amino-3-(4-nitrophenyl)propionic acid; 4-nitro-L-phenylalanine | 949-99-5 | C9H10N2O4 | 详情 | 详情 |
| (VI) | 15342 | methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate | C10H12N2O4 | 详情 | 详情 | |
| (VII) | 32574 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propanoate | C15H20N2O6 | 详情 | 详情 | |
| (VIII) | 32575 | methyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (IX) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (X) | 32576 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate | C22H24Cl2N2O5 | 详情 | 详情 | |
| (XI) | 32578 | methyl (2S)-2-amino-3-[4-[(2,6-dichlorobenzoyl)amino]phenyl]propanoate | C17H16Cl2N2O3 | 详情 | 详情 | |
| (XII) | 32573 | tert-butyl (1R,3S)-3-[[((1S)-1-[4-[(2,6-dichlorobenzoyl)amino]benzyl]-2-methoxy-2-oxoethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylate | C31H38Cl2N2O6 | 详情 | 详情 | |
| (XIII) | 32577 | (1R,3S)-3-[[((1S)-1-[4-[(2,6-dichlorobenzoyl)amino]benzyl]-2-methoxy-2-oxoethyl)amino]carbonyl]-1,2,2-trimethylcyclopentanecarboxylic acid | C27H30Cl2N2O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Treatment of N-Boc-4-bromo-L-phenylalanine (I) with ethanolic or methanolic HCl gave aminoester (II). Subsequent condensation of (II) with 2,6-dichlorobenzoyl chloride (III) produced amide (IV). Lithiation of 1,3-dimethoxybenzene (V) with n-butyllithium, followed by reaction with trimethyl borate and aqueous hydrolysis yielded boronic acid (VI). Suzuki coupling of bromide (IV) with boronic acid (VI) in the presence of palladium catalyst furnished biphenyl derivative (VII). Finally, hydrolysis of the ethyl ester of (VII) with LiOH provided the title carboxylic acid.
| 【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051. |
| 【2】 Gudmundsson, K.S.; Sircar, I.; Martin, R. (Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4 mediated cell adhesion. WO 9936393 . |
| 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) | 32546 | (2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H18BrNO4 | 详情 | 详情 | |
| (II) | 32547 | ethyl (2S)-2-amino-3-(4-bromophenyl)propanoate | C11H14BrNO2 | 详情 | 详情 | |
| (III) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (IV) | 32548 | ethyl (2S)-3-(4-bromophenyl)-2-[(2,6-dichlorobenzoyl)amino]propanoate | C18H16BrCl2NO3 | 详情 | 详情 | |
| (V) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (VI) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (VII) | 32550 | ethyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C26H25Cl2NO5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)In an alternative procedure, N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX). Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X). After deprotection of the Boc group of (X) with trifluoroacetic acid, the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII). The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.
| 【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051. |
| 【2】 Hattfield, L.D.; Sircar, I.; McNutly, A.; Naubauer, B.; Discovery of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 59. |
| 【3】 Sircar, I.; Liang, J.T.; Martin, R.; et al.; SAR of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (VI) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (VIII) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (IX) | 32551 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate | C16H20F3NO7S | 详情 | 详情 | |
| (X) | 32552 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C23H29NO6 | 详情 | 详情 | |
| (XI) | 32553 | methyl (2S)-2-amino-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C11H16N2O4S | 详情 | 详情 | |
| (XII) | 32554 | methyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C25H23Cl2NO5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Ethylenediamine (I) was selectively monoprotected as the N-Boc derivative (II) and then coupled with sulfonyl chloride (III), yielding sulfonamide (IV). After deprotection of the Boc group of (IV) with HCl in dioxan, the resulting amine (V) was condensed with hydroxyacid (VI) by means of BOP reagent to give amide (VII). Acid deprotection of the Boc group of (VII), followed by condensation with 2,6-dichlorobenzoyl chloride (IX), provided (X). Finally, the hydroxyl group of (X) was oxidized to the title ketone employing the Dess-Martin periodinane reagent in CH2Cl2.
| 【1】 Ator, M.A.; Mallamo, J.P.; Chatterjee, S.; Tao, M.; Wells, G.; Dunn, D.; Bihovsky, R.; Siman, R.; Gu, Z.-Q; P2-Achiral, P'-extended alpha-ketoamide inhibitors of calpain I. Bioorg Med Chem Lett 1999, 9, 16, 2371. |
| 【2】 Wells, G.J.; Mallamo, J.P.; Chatterjee, S.; Bihovsky, R. (Cephalon, Inc.); Peptidyl-containing alpha-ketoamide cysteine and serine protease inhibitors. US 6150378 . |
| 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) | 14574 | 3-methoxy-3-oxo-2-(2-thienylmethyl)propionic acid | C9H10O4S | 详情 | 详情 | |
| (II) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (III) | 43065 | 5-(3-cyanophenyl)-2-thiophenesulfonyl chloride | C11H6ClNO2S2 | 详情 | 详情 | |
| (IV) | 43066 | tert-butyl 2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethylcarbamate | C18H21N3O4S2 | 详情 | 详情 | |
| (V) | 43067 | N-(2-aminoethyl)-5-(3-cyanophenyl)-2-thiophenesulfonamide | C13H13N3O2S2 | 详情 | 详情 | |
| (VI) | 43071 | (3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyric acid | C15H21NO5 | 详情 | 详情 | |
| (VII) | 43068 | tert-butyl (1S)-1-benzyl-3-[[2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethyl]amino]-2-hydroxy-3-oxopropylcarbamate | C28H32N4O6S2 | 详情 | 详情 | |
| (VIII) | 43069 | (3S)-3-amino-N-[2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethyl]-2-hydroxy-4-phenylbutanamide | C23H24N4O4S2 | 详情 | 详情 | |
| (IX) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (X) | 43070 | N-((1S)-1-benzyl-3-[[2-([[5-(3-cyanophenyl)-2-thienyl]sulfonyl]amino)ethyl]amino]-2-hydroxy-3-oxopropyl)-2,6-dichlorobenzamide | C30H26Cl2N4O5S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Condensation of 3-nitro-1,2-phenylenediamine (I) with trifluoroacetic acid provided benzimidazole (II). Reduction of the nitro group of (II) by means of hydrazine in the presence of FeCl3 and activated carbon gave amine (III), which was coupled with 2,6-dichlorobenzoyl chloride (IV) yielding amide (V). Alkylation of (V) with tert-butyl bromoacetate afforded benzimidazoleacetic acid tert-butyl ester (VI). After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VI) the resulting carboxylic acid (VII) was coupled with morpholine (VIII) using EDC to furnish the title morpholide.
| 【1】 Oku, T.; Kawai, Y.; Yatabe, T.; Sato, S.; Yamazaki, H.; Kayakiri, N.; Yoshihara, K. (Fujisawa Pharmaceutical Co., Ltd.); Benzimidazole derivs. and their use in the prevention and/or the treatment of bone diseases. EP 0863881; JP 1999513364; WO 9710219 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 | |
| (I) | 38446 | 2-amino-3-nitrophenylamine; 3-nitro-1,2-benzenediamine | 3694-52-8 | C6H7N3O2 | 详情 | 详情 |
| (II) | 38447 | 4-nitro-2-(trifluoromethyl)-1H-benzimidazole | C8H4F3N3O2 | 详情 | 详情 | |
| (III) | 38448 | 2-(trifluoromethyl)-1H-benzimidazol-4-ylamine; 2-(trifluoromethyl)-1H-benzimidazol-4-amine | C8H6F3N3 | 详情 | 详情 | |
| (IV) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (V) | 38449 | 2,6-dichloro-N-[2-(trifluoromethyl)-1H-benzimidazol-4-yl]benzamide | C15H8Cl2F3N3O | 详情 | 详情 | |
| (VI) | 38450 | tert-butyl 2-[4-[(2,6-dichlorobenzoyl)amino]-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetate | C21H18Cl2F3N3O3 | 详情 | 详情 | |
| (VII) | 38451 | 2-[4-[(2,6-dichlorobenzoyl)amino]-2-(trifluoromethyl)-1H-benzimidazol-1-yl]acetic acid | C17H10Cl2F3N3O3 | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(A)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 |