|
【结 构 式】 
|
【分子编号】28537 【品名】3-hydroxybenzaldehyde 【CA登记号】100-83-4 |
【 分 子 式 】C7H6O2 【 分 子 量 】122.12344 【元素组成】C 68.85% H 4.95% O 26.2% |
合成路线1
该中间体在本合成路线中的序号：(I)3-Hydroxybenzaldehyde (I) was protected as the methoxyethoxymethyl ether derivative (II) by treatment with methoxyethoxymethyl chloride and diisopropyl ethyl amine. Subsequent condensation of (II) with dimethyloxosulfonium methylide, generated from oxosulfonium salt (III) and NaH, gave rise to the racemic epoxide (IV). Kinetic resolution by hydrolysis with (R,R)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt (III) acetate complex provided the (S)-diol (V) along with the unreacted (R)-epoxide (VI), which were separated by column chromatography. Opening of the desired (R)-epoxide (VI) with methanolic methylamine gave amino alcohol (VII). Finally, removal of the methoxyethoxymethyl group by refluxing in methanolic HCl furnished the title compound.
| 【1】 Gurjar, M.K.; et al.; A practical synthesis of (R)-(-)-phenylephrine hydrochloride. Org Process Res Dev 1998, 2, 6, 422. |
| 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 | |
| 40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 | |
| (I) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 36802 | 3-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H14O4 | 详情 | 详情 | |
| (III) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (IV) | 36803 | (2-methoxyethoxy)methyl 3-(2-oxiranyl)phenyl ether; 2-[3-[(2-methoxyethoxy)methoxy]phenyl]oxirane | C12H16O4 | 详情 | 详情 | |
| (V) | 36804 | (1S)-1-[3-[(2-methoxyethoxy)methoxy]phenyl]-1,2-ethanediol | C12H18O5 | 详情 | 详情 | |
| (VI) | 36805 | (2-methoxyethoxy)methyl 3-[(2R)oxiranyl]phenyl ether; (2R)-2-[3-[(2-methoxyethoxy)methoxy]phenyl]oxirane | C12H16O4 | 详情 | 详情 | |
| (VII) | 36806 | (1R)-1-[3-[(2-methoxyethoxy)methoxy]phenyl]-2-(methylamino)-1-ethanol | C13H21NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reductocondensation of piperidine (I) with 3-hydroxybenzaldehyde (II) by means of sodium borohydride in ethanol gives 3-(1-piperidylmethyl)phenol (III), which is then condensed with N-(3-bromopropyl)phthalimide (IV) by means of NaH in DMF yielding N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]phthalimide (V). The hydrolysis of (V) with hydrazine in ethanol affords 3-[3-(1-piperidylmethyl)phenoxy]propylamine (VI), which is acylated with hydroxyacetic acid (VII) at 200 C giving N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]hydroxyacetamide (VIII). Finally, this compound is acetylated with acetic anhydride at 100 C.
| 【1】 Shibata, K.; et al. (Teikoku Hormone Manufacturing Co., Ltd.); Antiulcer phenoxypropylamine derivatives. EP 0024510; JP 81115750; US 4293557 . |
| 【2】 Castaner, J.; Serradell, M.N.; TZU-0460. Drugs Fut 1985, 10, 12, 995. |
| 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) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (II) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (III) | 29854 | 3-(1-piperidinylmethyl)phenol | C12H17NO | 详情 | 详情 | |
| (IV) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (V) | 29855 | 2-[2-[3-(1-piperidinylmethyl)phenoxy]ethyl]-1H-isoindole-1,3(2H)-dione | C22H24N2O3 | 详情 | 详情 | |
| (VI) | 16105 | 3-[3-(piperidinomethyl)phenoxy]-1-propanamine; 3-[3-(piperidinomethyl)phenoxy]propylamine | C15H24N2O | 详情 | 详情 | |
| (VII) | 29856 | 2-hydroxyacetic acid;glycolic acid | 79-14-1 | C2H4O3 | 详情 | 详情 |
| (VIII) | 29857 | 2-hydroxy-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide | C17H26N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The alkylation of 3-hydroxybenzaldehyde (I) with N-(3-bromopropyl)phthalimide (II) in the presence of NaOMe leads to 3-(phthalimidopropoxy)benzaldehyde (III). The reductive alkylation of piperidine with aldehyde (III) in the presence of formic acid gives N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]phthalimide (IV), which is converted to N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amine (V) by treatment with 6N HCl. Condensation of (V) with glycolic acid in boiling xylene provides N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-hydroxyacetamide (VI), which is complexed with bismuth (+3) citrate (VII) in boiling water.
| 【1】 Petkov, O.; Lytakov, G.; Taskov, M.; Savov, E.; Kostev, V.; Tsvetkova, E.; Nikolov, G.; Atanassova, R.; Ivanov, C.; Synthesis, gastroprotective, antisecretory and anti-Helicobacter effect of +[3(3-(1-piperidinylmethyl)phenoxy)propyl]hydroxyacetamide-2-hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex (MX1). J Pharm Pharmacol 1996, 3, 3, 297-301. |
| 【2】 N-(3-(3-(1-Piperidinylmethyl)phenoxy)propyl)propenetricarboxylate bismuth (3+) complex and the method for preparation. WO 9509162 . |
| 【3】 Mondeshka, D.; Spassov, G.; Krushkov, I.; Ivanov, C.; Marazova, K.; Roxatidine Bismuth Citrate. Drugs Fut 2000, 25, 5, 462. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 | |
| (I) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 35289 | 3-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propoxy]benzaldehyde | C18H15NO4 | 详情 | 详情 | |
| (IV) | 35290 | 2-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-isoindole-1,3(2H)-dione | C23H26N2O3 | 详情 | 详情 | |
| (V) | 16105 | 3-[3-(piperidinomethyl)phenoxy]-1-propanamine; 3-[3-(piperidinomethyl)phenoxy]propylamine | C15H24N2O | 详情 | 详情 | |
| (VI) | 29857 | 2-hydroxy-N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]acetamide | C17H26N2O3 | 详情 | 详情 | |
| (VII) | 13855 | bismuth(3+) 2-hydroxy-1,2,3-propanetricarboxylate; Bismuth Citrate | 813-93-4 | C6H5BiO7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXIV)The condensation of 3-hydroxybenzaldehyde (XXXIV) with phosphonate (XXXV) by means of DBU in dichloromethane gives the propenoic ester (XXXVI), which is enanthioselectively reduced catalyzed by (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate ((S,S)-DuP-Rh+OTf-) yielding the L-phenylalanine derivative (XXXVII). The deprotection of (XXXVII) by hydrogenation as usual affords the free amino acid (XXXVIII), which is condensed with Boc-L-valine (XXXIX) by means of EDC and HOAt to afford the dipeptide (XL). Hydrolysis of the ester group of (XXXIX) with LiOH in THF/water affords the N-protected amino acid (XLI), which is condensed with the perhydropyridazine (XLII) by means of EDC and HOAt to give the protected intermediate (XLIII). Finally, this compound is deprotected with TFA in dichloromethane to afford the desired intermediate the bis(iodovinyl) compound (XXXI). The intermediate perhydropyridazine (XLII) has been obtained as follows: The reaction of the iodoaldehyde (XLIV) with iodoform and CrCl2 in dioxane/THF gives the 1,6-diiodohexadiene (XLV), which, previous desilylation with TBAF, is condensed with the protected hexahydropyridazinecarboxylic acid (XLVI) by means of EDC, 4-Ppy and DIEA in dichloromethane to provide the protected diiodo ester (XLVII). Finally, this compound is deprotected with TFA in dichloromethane to yield the desired intermediate the perhydropyridazine (XLII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXI) | 32446 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C26H36I2N4O5 | 详情 | 详情 | |
| (XXXIV) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (XXXV) | 35887 | methyl 2-[[(benzyloxy)carbonyl]amino]-2-(diethoxyphosphoryl)acetate | C15H22NO7P | 详情 | 详情 | |
| (XXXVI) | 35888 | methyl (E)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)-2-propenoate | C18H17NO5 | 详情 | 详情 | |
| (XXXVII) | 35889 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3-hydroxyphenyl)propanoate | C18H19NO5 | 详情 | 详情 | |
| (XXXVIII) | 35890 | methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate | C10H13NO3 | 详情 | 详情 | |
| (XXXIX) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XL) | 35891 | methyl (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoate | C20H30N2O6 | 详情 | 详情 | |
| (XLI) | 32444 | (2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propionic acid | C19H28N2O6 | 详情 | 详情 | |
| (XLII) | 32443 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)hexahydro-3-pyridazinecarboxylate | C12H18I2N2O2 | 详情 | 详情 | |
| (XLIII) | 32445 | (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl (3S)-1-[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-3-(3-hydroxyphenyl)propanoyl]hexahydro-3-pyridazinecarboxylate | C31H44I2N4O7 | 详情 | 详情 | |
| (XLIV) | 32438 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-4-methyl-4-pentenal | C12H23IO2Si | 详情 | 详情 | |
| (XLV) | 32439 | tert-butyl([(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl ether | C13H24I2OSi | 详情 | 详情 | |
| (XLVI) | 32441 | (3S)-1,2-bis(tert-butoxycarbonyl)hexahydro-3-pyridazinecarboxylic acid | C15H26N2O6 | 详情 | 详情 | |
| (XLVII) | 32442 | 1,2-di(tert-butyl) 3-[(1S,3E)-4-iodo-1-[(E)-2-iodo-1-methylethenyl]-3-butenyl] (3S)tetrahydro-1,2,3-pyridazinetricarboxylate | C22H34I2N2O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Basic treatment of 3-hydroxybenzyl alcohol (I) with either NaOH in dichloromethane, Et3N in toluene or K2CO3 in acetone, followed by reaction with acetylsalicyloyl chloride (II) in the respective solvents, gives 2-acetoxybenzoic acid 3-(hydroxymethyl)phenyl ester (III). NCX-4016 is obtained by nitration of compound (III) with steaming nitric acid in dichloromethane in the presence of either sulfuric acid, acetic anhydride or methanesulfonic acid.
| 【1】 Benedini, F.; Razzetti, G.; Castaldi, G.; Oldani, E. (NicOx SA); A process for obtaining (nitroxymethyl)phenyl esters of salicylic acid derivs.. WO 0104082 . |
合成路线6
该中间体在本合成路线中的序号：(I)Alternatively, coupling of 3-hydroxybenzaldehyde (I) with acetylsalicyloyl chloride (II) by means of Et3N in dichloromethane affords 2-acetoxybenzoic acid 3-formyl-phenyl ester (IV), which is then reduced by hydrogenation over Pd/C in ethyl acetate to provide alcohol (III). Chlorination of alcohol (III) by treatment with thionyl chloride in DMF gives the chloromethyl derivative (V), which is finally converted to NCX-4016 by treatment with AgNO3 in refluxing acetonitrile.
| 【1】 Garufi, M.; Del Soldato, P. (NicOx SA); Synthesis method of nitroxymethylphenyl esters of aspirin derivs.. WO 0044705 . |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 16900 | 2-(chlorocarbonyl)phenyl acetate; Acetylsalicyloyl chloride | 5538-51-2 | C9H7ClO3 | 详情 | 详情 |
| (III) | 51713 | 3-(hydroxymethyl)phenyl 2-(acetoxy)benzoate | C16H14O5 | 详情 | 详情 | |
| (IV) | 51714 | 3-formylphenyl 2-(acetoxy)benzoate | C16H12O5 | 详情 | 详情 | |
| (V) | 51715 | 3-(chloromethyl)phenyl 2-(acetoxy)benzoate | C16H13ClO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Ethyl 2-(3-formylphenoxy)acetate (III) was prepared by alkylation of 3-hydroxybenzaldehyde (I) with ethyl bromoacetate (II) in the presence of K2CO3 and KI. Reduction of aldehyde (III) with NaBH4 provided the benzyl alcohol (IV), which was further protected as the silyl ether (V) by treatment with tert-butyldimethylsilyl chloride and imidazole. Addition of methylmagnesium bromide to the ester function of (V) yielded the tertiary alcohol (VI). Condensation of the sodium alkoxide of (VI) with 3-(bromomethyl)thiophene (VII) furnished ether (VIII). After desilylation of (VIII) employing tetrabutylammonium fluoride, the resultant benzyl alcohol (IX) was treated with methanesulfonyl chloride and triethylamine to afford mesylate (X). Alkylation of amine (XI) with mesylate (X) furnished the target tertiary amine, which was finally treated with HCl in EtOAc to afford the corresponding hydrochloride salt.
| 【1】 Okumura, H.; Washizuka, K.; Fujii, N.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Substd. amine derivs.. JP 2000517314; WO 9808838 . |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 56003 | ethyl 2-(3-formylphenoxy)acetate | C11H12O4 | 详情 | 详情 | |
| (IV) | 56004 | ethyl 2-[3-(hydroxymethyl)phenoxy]acetate | C11H14O4 | 详情 | 详情 | |
| (V) | 56005 | ethyl 2-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenoxy]acetate | C17H28O4Si | 详情 | 详情 | |
| (VI) | 56006 | 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenoxy]-2-methyl-2-propanol | C17H30O3Si | 详情 | 详情 | |
| (VII) | 56007 | 3-(bromomethyl)thiophene | 34846-44-1 | C5H5BrS | 详情 | 详情 |
| (VIII) | 56008 | tert-butyl(dimethyl)silyl 3-[2-methyl-2-(3-thienylmethoxy)propoxy]benzyl ether; tert-butyl(dimethyl)({3-[2-methyl-2-(3-thienylmethoxy)propoxy]benzyl}oxy)silane | C22H34O3SSi | 详情 | 详情 | |
| (IX) | 56009 | {3-[2-methyl-2-(3-thienylmethoxy)propoxy]phenyl}methanol | C16H20O3S | 详情 | 详情 | |
| (X) | 56010 | 3-[2-methyl-2-(3-thienylmethoxy)propoxy]benzyl methanesulfonate | C17H22O5S2 | 详情 | 详情 | |
| (XI) | 56011 | (E)-N-ethyl-6,6-dimethyl-2-hepten-4-yn-1-amine; N-[(E)-6,6-dimethyl-2-hepten-4-ynyl]-N-ethylamine | C11H19N | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Protection of 3-hydroxybenzaldehyde (I) with methoxymethyl chloride afforded the corresponding methoxymethyl ether (II). Subsequent addition of 4-tert-butylphenylmagnesium bromide (III) produced the diarylcarbinol (IV), which was converted to chloride (V) by means of CCl4 and PPh3. Condensation of (V) with 1-benzylpiperazine (VI) yielded the disubstituted piperazine (VII). The methoxymethyl ether of (VII) was finally deprotected with aqueous HCl to provide the title compound.
| 【1】 Liao, S.; Alfaro-Lopez, J.; Shenderovich, M.D.; Hosohata, K.; Lin, J.; Li, X.; Stropova, D.; Davis, P.; Jernigan, K.A.; Porreca, F.; Yamamura, H.I.; Hruby, V.J.; De novo design, synthesis, and biological activities of high-affinity and selective non-peptide agonists of the delta-opioid receptor. J Med Chem 1998, 41, 24, 4767. |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 28538 | 3-(methoxymethoxy)benzaldehyde | C9H10O3 | 详情 | 详情 | |
| (III) | 28539 | bromo[4-(tert-butyl)phenyl]magnesium | C10H13BrMg | 详情 | 详情 | |
| (IV) | 28540 | [4-(tert-butyl)phenyl][3-(methoxymethoxy)phenyl]methanol | C19H24O3 | 详情 | 详情 | |
| (V) | 28541 | 1-[[4-(tert-butyl)phenyl](chloro)methyl]-3-(methoxymethoxy)benzene | C19H23ClO2 | 详情 | 详情 | |
| (VI) | 28542 | N-Benzylpiperazine; 1-Benzylpiperazine | 2759-28-6 | C11H16N2 | 详情 | 详情 |
| (VII) | 28543 | (3-[(4-benzyl-1-piperazinyl)[4-(tert-butyl)phenyl]methyl]phenoxy)methyl methyl ether | C30H38N2O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Strecker condensation of 3-hydroxybenzaldehyde (I) with trimethylsilyl cyanide in the presence of (S)-2-phenylglycine (II) yielded the chiral aminonitrile (III) as the major diastereoisomer. Oxidative cleavage of the chiral auxiliary of (III) with lead tetraacetate, followed by acid hydrolysis of the nitrile group provided the (S)-amino acid (IV), which was esterified with MeOH and Me3SiCl. The resulting aminoester (V) was coupled with carboxylic acid (VI) using diphenylphosphoryl azide to form amide ester (VII). Finally, saponification of the methyl ester of (VIII) afforded the target carboxylic acid.
| 【1】 Baek, D.-J.; Park, Y.-K.; Heo, H.I.; Lee, M.; Yang, Z.; Choi, M.; Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro. Bioorg Med Chem Lett 1998, 8, 23, 3287. |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 10973 | (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol | 20989-17-7 | C8H11NO | 详情 | 详情 |
| (III) | 29636 | (2S)-2-(3-hydroxyphenyl)-2-[[(1R)-2-hydroxy-1-phenylethyl]amino]ethanenitrile | C16H16N2O2 | 详情 | 详情 | |
| (IV) | 29637 | (2S)-2-amino-2-(3-hydroxyphenyl)ethanoic acid | C8H9NO3 | 详情 | 详情 | |
| (V) | 29638 | methyl (2S)-2-amino-2-(3-hydroxyphenyl)ethanoate | C9H11NO3 | 详情 | 详情 | |
| (VI) | 29639 | 4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoic acid | C16H13N3O3S | 详情 | 详情 | |
| (VII) | 29640 | methyl (2S)-2-([4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5-quinazolinyl)sulfanyl]benzoyl]amino)-2-(3-hydroxyphenyl)ethanoate | C25H22N4O5S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(IV)In a related procedure, indomethacin chloride (III) was coupled with 3-hydroxybenzaldehyde (IV) to yield ester (V). Catalytic hydrogenation of the formyl group of (V) over Pd/C produced alcohol (VI), which was further converted to chloride (VII) upon treatment with SOCl2. The chloride group of (VII) was finally displaced with silver nitrate to furnish the corresponding nitrate ester.
| 【1】 Garufi, M.; Del Soldato, P. (NicOx SA); Synthesis method of nitroxymethylphenyl esters of aspirin derivs.. WO 0044705 . |
| 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) | 24047 | 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl chloride | C19H15Cl2NO3 | 详情 | 详情 | |
| (IV) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (V) | 48379 | 3-formylphenyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate | C26H20ClNO5 | 详情 | 详情 | |
| (VI) | 48380 | 3-(hydroxymethyl)phenyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate | C26H22ClNO5 | 详情 | 详情 | |
| (VII) | 48381 | 3-(chloromethyl)phenyl 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetate | C26H21Cl2NO4 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Condensation of the (chloromethyl)oxazole (I) with 3-hydroxybenzaldehyde (II) in the presence of K2CO3 afforded ether (III). The aldehyde group of (III) was then converted to oxime (IV) upon treatment with hydroxylamine hydrochloride and sodium acetate. Reduction of oxime (IV) with NaBH3CN produced the hydroxylamine (V). This was finally condensed with N-(chlorocarbonyl)isocyanate to produce the target oxadiazolidine dione.
| 【1】 Malamas, M.S.; et al.; Antihyperglycemic activity of new 1,2,4-oxadiazolidine-3,5-diones. Eur J Med Chem 2001, 36, 1, 31. |
| 【2】 Malamas, M.S.; Palka, C.L.; Gunawan, I. (American Home Products Corp.); Aralkyl-1,2,4-oxadiazolidine-3,5-diones as antihyperglycemic agents. US 5480896 . |
| 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) | 49144 | 4-(chloromethyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole; 4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]phenyl trifluoromethyl ether | C12H9ClF3NO2 | 详情 | 详情 | |
| (II) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (III) | 49145 | 3-([5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-4-yl]methoxy)benzaldehyde | C19H14F3NO4 | 详情 | 详情 | |
| (IV) | 49146 | 3-([5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-4-yl]methoxy)benzaldehyde oxime | C19H15F3N2O4 | 详情 | 详情 | |
| (V) | 49147 | N-[3-([5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-4-yl]methoxy)benzyl]hydroxylamine; 4-([3-[(hydroxyamino)methyl]phenoxy]methyl)-5-methyl-2-[4-(trifluoromethoxy)phenyl]-1,3-oxazole | C19H17F3N2O4 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)Alkylation of 3-hydroxybenzaldehyde (I) with t-butyl bromoacetate (II) affords t butyl (3-formylphenoxy)acetate (III). Aldehyde (III) is then converted to oxime (IV) upon treatment with hydroxylamine in MeOH. Reduction of oxime (IV) to the benzylic amine (V) is carried out by catalytic hydrogenation in the presence of Raney nickel. Subsequent reductive alkylation of amine (V) with 4-t-butylbenzaldehyde (VI) furnishes the secondary amine (VII). This is then acylated by pyridine-3-sulfonyl chloride (VIII) producing sulfonamide (IX). The t-butyl ester group of (IX) is finally cleaved with trifluoroacetic acid to give the corresponding carboxylic acid.
| 【1】 Rosati, R.L.; Lefker, B.A.; Cameron, K.O. (Pfizer Inc.); Prostaglandin agonists and their use to treat bone disorders. EP 1021410; JP 2001519414; US 6498172; WO 9919300 . |
| 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) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (III) | 64442 | tert-butyl 2-(3-formylphenoxy)acetate | C13H16O4 | 详情 | 详情 | |
| (IV) | 64443 | tert-butyl 2-{3-[(hydroxyimino)methyl]phenoxy}acetate | C13H17NO4 | 详情 | 详情 | |
| (V) | 64444 | tert-butyl 2-[3-(aminomethyl)phenoxy]acetate | C13H19NO3 | 详情 | 详情 | |
| (VI) | 16638 | 4-(tert-butyl)benzaldehyde; 4-tert-Butyl-benzaldehyde | 939-97-9 | C11H14O | 详情 | 详情 |
| (VII) | 64445 | tert-butyl 2-[3-({[4-(tert-butyl)benzyl]amino}methyl)phenoxy]acetate | C24H33NO3 | 详情 | 详情 | |
| (VIII) | 64446 | 3-pyridinesulfonyl chloride | C5H4ClNO2S | 详情 | 详情 | |
| (IX) | 64447 | tert-butyl 2-(3-{[[4-(tert-butyl)benzyl](3-pyridinylsulfonyl)amino]methyl}phenoxy)acetate | C29H36N2O5S | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XI)Mitsunobu reaction of 3-hydroxybenzaldehyde (XI) with cyclohexylmethanol (XII) using PPh3 and DEAD in THF or condensation of 3-hydroxybenzaldehyde (XI) with cyclohexylmethyl bromide (IX) using K2CO3 and NMP in DMF at 75 °C give ether (XIII), which by reaction with acetonitrile (II) by means of LDA in THF at –78 °C or t-BuOK in THF yields the b-hydroxynitrile (XIV). Reduction of nitrile (XIV) with LiAlH4 or BH3·Me2S in THF affords the primary amine (XV), which by N-protection with Fmoc-Cl and DIEA in CH2Cl2 provides carbamate (XVI). Oxidation of secondary alcohol (XVI) with MnO2 in CH2Cl2 leads to the ketone (XVII), which is finally submitted to enantioselective reduction using (–)-DIP-Cl (prepared in situ by treating (–)-a-pinene with chloroborane-methyl sulfide complex in hexane) and DIEA in THF, followed by deprotection of the obtained N-Fmoc protected compound with DBU in THF. Alternatively, resolution of racemic emixustat (XV) can be performed using D-mandelic acid .
| 【1】 Scott, I.L., Kuksa, V.A. Orme, M.W., Little, T., gall, A., Hong, f. (Acucela, Inc.). Alkoxy compounds for disease treatment. CN 103553945, EP 2091955, JP 2011512321, US 2009326074, US 7982071, US 2012122938, US 2012214852, US 2013197096, US 8829244, WO 2009045479. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IX) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (XI) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (XII) | 28360 | cyclohexylmethanol | 100-49-2 | C7H14O | 详情 | 详情 |
| (XIII) | 67839 | 3-(cyclohexylmethoxy)benzaldehyde | C14H18O2 | 详情 | 详情 | |
| (XIV) | 67840 | 3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropanenitrile | C16H21NO2 | 详情 | 详情 | |
| (XV) | 67841 | 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol | C16H25NO2 | 详情 | 详情 | |
| (XVI) | 67842 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-hydroxypropyl)carbamate | C31H35NO4 | 详情 | 详情 | |
| (XVII) | 67843 | (9H-fluoren-9-yl)methyl (3-(3-(cyclohexylmethoxy)phenyl)-3-oxopropyl)carbamate | C31H33NO4 | 详情 | 详情 |