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【结 构 式】 
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【分子编号】23767 【品名】Methoxybenzene; Methyl phenyl ether; Anisole 【CA登记号】100-66-3 |
【 分 子 式 】C7H8O 【 分 子 量 】108.13992 【元素组成】C 77.75% H 7.46% O 14.8% |
合成路线1
该中间体在本合成路线中的序号：(A)The synthesis of GYKI-13504 is as follows: Trifluoroacetophenone (I) is reacted with triphenylbenzyl phosphonium chloride (II) in the presence of sodium methylate and this reaction yields stilbene (III). Stilbene (III) is then hydrogenized in the presence of charcoal palladium catalyzer and the yielded propane derivative (IV) is brominated with 1,2-dibromoethane. The brominated compound (V) is reacted with anizole (A) according to the Friedel Crafts' reaction. The yield (VI) is treated with pyridine hydrochloride and the phenol derivative (VII) is reacted with 2-chloroethanol tosylate (VIII) in the presence of potassium hydroxide. The chloroethoxy (IX) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the (E)-isomer (X) is obtained with fractionated crystallization. This latter product is reacted with 2-aminoethanol (B) to obtain the end product GYKI-13504.
| 【1】 Abraham, G.; Horváth, T.; Toldy, L.; Borvendeg, J.; Csányl, E.; Kiss, E.; Szente, I.; Tory, K. (Egis Pharmaceuticals Ltd.); 1,1,2-Triphenylpropane and -propene derivatives. AT 368989; BE 0884716; DD 152536; ES 494286; GB 2058061; GR 69821; HU 18253 . |
| 【2】 Borvendeg, J.; GYKI-13504. Drugs Fut 1985, 10, 5, 395. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (A) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (I) | 29349 | 2,2,2-trifluoro-1-phenyl-1-ethanone; 4-Chloro-2-fluorotrifluoroacetophenone | 434-45-7 | C8H5F3O | 详情 | 详情 |
| (II) | 42794 | Benzyl(triphenyl)phosphonium chloride | 1449-46-3 | C25H22ClP | 详情 | 详情 |
| (III) | 29351 | 1-[(Z)-3,3,3-trifluoro-2-phenyl-1-propenyl]benzene | C15H11F3 | 详情 | 详情 | |
| (IV) | 29352 | 1-(3,3,3-trifluoro-2-phenylpropyl)benzene | C15H13F3 | 详情 | 详情 | |
| (V) | 29353 | 1-(1-bromo-3,3,3-trifluoro-2-phenylpropyl)benzene | C15H12BrF3 | 详情 | 详情 | |
| (VI) | 29354 | 1-methoxy-4-(3,3,3-trifluoro-1,2-diphenylpropyl)benzene | C22H19F3O | 详情 | 详情 | |
| (VII) | 29355 | 4-(3,3,3-trifluoro-1,2-diphenylpropyl)phenol | C21H17F3O | 详情 | 详情 | |
| (VIII) | 14632 | 2-chloroethyl 4-methylbenzenesulfonate; 2-Chloroethyl-p-toluenesulfonate | 80-41-1 | C9H11ClO3S | 详情 | 详情 |
| (IX) | 29356 | 1-(2-chloroethoxy)-4-(3,3,3-trifluoro-1,2-diphenylpropyl)benzene | C23H20ClF3O | 详情 | 详情 | |
| (X) | 29357 | 1-(2-chloroethoxy)-4-[(E)-3,3,3-trifluoro-1,2-diphenyl-1-propenyl]benzene | C23H18ClF3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)Compound can be prepared in two different ways both starting from 2,4-difluoroaniline (I): 1) The diazotation of (I) with isoamyl nitrite (B) and condensation with anisole (A) gives 4-(2,4-difluorophenyl)anisole (II), which is hydrolyzed with HI in refluxing acetic acid yielding 4-(2,4-difluorophenyl)phenol (III). Finally, this compound is carbonated with K2CO3 and CO2 at 175 C and 1300 p.s.i. 2) The diazotation of (I) with isoamyl nitrite (B) and then condensation with benzene by means of powdered Cu gives 2,4-difluorobiphenyl (IV), which is acetylated with acetic anhydride by means of AlCl3 in CH2Cl2 yielding 4-(2,4-difluorophenyl)acetophenone (V). The oxidation of (V) with H2O2 in refluxing CH2Cl2 affords 4-(2,4-difluorophenyl)phenyl acetate (VI), which can be hydrolyzed with NaOH in refluxing water to give the phenol (III).
| 【1】 Ruyle, W.V.; et al. (Merck & Co., Inc.); Phenyl benzoic acid compounds in compositions and methods for treating inflammation. US 3674870 . |
| 【2】 Howard, J.; et al. (Merck & Co., Inc.); Chemical products. DE 2532559; FR 2288729; GB 1496231; GB 1496232; JP 51034135 . |
| 【3】 Houser, R.W.; Jones, H. (Merck & Co., Inc.); Process for preparing 4-(2,4-difluorophenyl)-salicyclic acid. US 4225730 . |
| 【4】 Ruyle, W.V.; et al. (Merck & Co., Inc.); Halo-substituted 5-phenylbenzoic acids and their derivatives. GB 1175212 . |
| 【5】 Arrigoni-Martelli, E.; Castaner, J.; Diflunisal. Drugs Fut 1978, 3, 4, 28. |
| 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) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (B) | 32169 | 3-Methyl-1-nitrobutane; Isoamyl nitrite | 543-87-3 | C5H11NO2 | 详情 | 详情 |
| (I) | 19462 | 2,4-difluoroaniline; 2,4-difluorophenylamine；2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene | 367-25-9 | C6H5F2N | 详情 | 详情 |
| (II) | 33464 | 2',4'-difluoro[1,1'-biphenyl]-4-yl methyl ether; 2,4-difluoro-4'-methoxy-1,1'-biphenyl | C13H10F2O | 详情 | 详情 | |
| (III) | 14631 | 2',4'-difluoro[1,1'-biphenyl]-4-ol | C12H8F2O | 详情 | 详情 | |
| (IV) | 33465 | 2,4-difluoro-1,1'-biphenyl | C12H8F2 | 详情 | 详情 | |
| (V) | 33466 | 1-(2',4'-difluoro[1,1'-biphenyl]-4-yl)-1-ethanone | C14H10F2O | 详情 | 详情 | |
| (VI) | 33467 | 2',4'-difluoro[1,1'-biphenyl]-4-yl acetate | C14H10F2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：The condensation of 2-(tert-butoxycarbonylmethoxyimino)-2-(4 thiazolyl)acetic acid (I) with 7-amino 3-cephem-4-carboxylic acid (II) by means of the Vusmejer reagent (POCl3 and dimethylformamide) in ethyl acetate gives 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (III), which is then de protected with trifluoroacetic acid and anisole in methylene chloride. The starting acetic acid derivative (I) can be obtained by several different ways: 1) The partial hydrolysis of 2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4yl) acetic acid (IV) with concentrated HCl in methanol gives 2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (V), which is then deaminated with tert butyl nitrite in refluxing THF. 2) The preceding deamination of (IV) can be performed in a similar way with previous esterification with diphenyldiazomethane, through compounds (VI), (VII) and (VIII). Compound (VIII) is submitted to a partial hydrolysis with trifluoroacetic acid. 3) Compound (I) can also be obtained by condensation of 2-(4-thiazolylglyoxylic acid (IX) with tert-butyl-2-(aminooxy)acetate (X) by means of NaHCO3 in ethyl acetate.
| 【1】 Takaya, T.; Takasugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Cephem compounds. EP 0071891; US 4515788; US 4649136; US 4736039 . |
| 【2】 Prous, J.; Castaner, J.; FK-089. Drugs Fut 1986, 11, 2, 103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 | |
| (A) | 23003 | Diphenyldiazomethane | C13H10N2 | 详情 | 详情 | |
| (I) | 24081 | 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetic acid | C11H14N2O5S | 详情 | 详情 | |
| (II) | 24082 | 7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C7H8N2O3S | 详情 | 详情 | |
| (III) | 24083 | 7-[[2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C18H20N4O7S2 | 详情 | 详情 | |
| (IV) | 24084 | 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-[2-(formylamino)-1,3-thiazol-4-yl]acetic acid | C12H15N3O6S | 详情 | 详情 | |
| (V) | 24085 | 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetic acid | C11H15N3O5S | 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) | 24087 | benzhydryl 2-(2-amino-1,3-thiazol-4-yl)-2-[[2-(tert-butoxy)-2-oxoethoxy]imino]acetate | C24H25N3O5S | 详情 | 详情 | |
| (VIII) | 24088 | benzhydryl 2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetate | C24H24N2O5S | 详情 | 详情 | |
| (IX) | 24089 | 2-oxo-2-(1,3-thiazol-4-yl)acetic acid | C5H3NO3S | 详情 | 详情 | |
| (X) | 24090 | tert-butyl 2-(aminooxy)acetate | C6H13NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The Friedel-Crafts reaction of anisole (VI) with crotonyl chloride (VII) by means of AlCl3 in carbon disulfide gives p-methoxyphenyl propenyl ketone (VIII), which is then condensed with homoveratrylamine (IV) in toluene yielding 3-(3,4-dimethoxyphenylethylamino)-1-(4-methoxyphenyl)butan-1-one (IX). Finally, this ketone is reduced with hydrogen over Pd/C in ethanol to yield 3,4-dimethoxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]-beta-phenylethylamine (I), which by demethylation with HBr in refluxing acetic acid.
| 【1】 Castaner, J.; Thorpe, P.; Dobutamine. Drugs Fut 1977, 2, 9, 579. |
| 【2】 Tuttle, R.R.; Mills, J. (Eli Lilly and Company); Dopamine derivatives. DE 2317710; ES 413639; FR 2182947; GB 1392674; JP 49007237 . |
| 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) | 40177 | N-(3,4-dimethoxyphenethyl)-4-(4-methoxyphenyl)-2-butanamine; N-(3,4-dimethoxyphenethyl)-N-[3-(4-methoxyphenyl)-1-methylpropyl]amine | C21H29NO3 | 详情 | 详情 | |
| (IV) | 10098 | 2-(3,4-Dimethoxyphenyl)-1-ethanamine; 3,4-Dimethoxyphenethylamine; 2-(3,4-Dimethoxyphenyl)ethylamine | 120-20-7 | C10H15NO2 | 详情 | 详情 |
| (VI) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (VII) | 40178 | (E)-2-Butenoyl chloride; (E)-Crotonyl chloride | 625-35-4 | C4H5ClO | 详情 | 详情 |
| (VIII) | 40179 | (E)-1-(4-methoxyphenyl)-2-buten-1-one | C11H12O2 | 详情 | 详情 | |
| (IX) | 40180 | 3-[(3,4-dimethoxyphenethyl)amino]-1-(4-methoxyphenyl)-1-butanone | C21H27NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) has also been obtained as follows: The Friedel Crafts condensation of anisole (XV) with N-trifluoroacetyl-L-aspartic acid anhydride (XVI) by means of AlCl3 in dichloromethane gives 4-(4-methoxyphenyl)-4-oxo-2(S)-(trifluoro-acetamido)butyric acid (XVII), which is hydrogenated with H2 over Pd/C in ethanol/H2SO4 yielding 4-(4-methoxyphenyl)-2(S)-(trifluoroacetamido)butyric acid (XVIII). The cyclization of (XVIII) by its reaction with PCl5, followed by a treatment with SnCl4 provides the tetralone (XIX), which is hydrogenated as before to give N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-yl)trifluoro-acetamide (XX). Finally, this compound is deacetylated with HCl in ethanol to provide the chiral intermediate the amine (IV).
| 【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551. |
| 【2】 Cecchi, R.; et al.; Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers. Eur J Med Chem 1994, 29, 4, 259. |
| 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) | 32820 | (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
| (XV) | 18410 | N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | 777-33-3 | C6H4F3NO4 | 详情 | 详情 |
| (XVI) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (XVII) | 32827 | (2S)-4-(4-methoxyphenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C13H12F3NO5 | 详情 | 详情 | |
| (XVIII) | 32828 | (2S)-4-(4-methoxyphenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C13H14F3NO4 | 详情 | 详情 | |
| (XIX) | 32829 | 2,2,2-trifluoro-N-[(2S)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H12F3NO3 | 详情 | 详情 | |
| (XX) | 32830 | 2,2,2-trifluoro-N-[(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H14F3NO2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：Liarozole fumarate is prepared as shown in Scheme 20970301a. Anisol is reacted with 3-chlorobenzoyl chloride (I) under Friedel-Craft conditions to give (3-chlorophenyl)(4-methoxyphenyl)methanone (II). Nitration of (II) is carried out in dichloromethane at 10 C to yield (III). The methoxy group in (III) is replaced by the amino group by means of NH3 in 2-propanol at 100 C under pressure, giving (IV). By reduction of the keto function of (IV) with sodium borohydride in 2-propanol, the corresponding alcohol (V) is obtained, which upon treatment with 1,1'-carbonyldiimidazole in refluxing dichloromethane yields the imidazolyl compound (VI). Hydrogenation of the nitro group in (VI), followed by cyclization of (VII) in a refluxing mixture of formic acid and 4N hydrochloric acid, gives the benzimidazole derivative (VIII). Finally, the treatment of (VIII) with fumaric acid in ethanol yields liarozole fumarate (IX).
| 【1】 Huggins, C.; Hodges, C.V.; Studies on prostatic cancer. I. The effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941, 1, 5, 293-7. |
| 【2】 Raeymaekers, A.H.M.; Freyne, E.J.E.; Sanz, G.C. (Janssen Pharmaceutica NV); Novel (1H-imidazol-1-ylmethyl) substd. benzimidazole derivs. AU 8778385; EP 0260744; JP 1989085975; US 4859684 . |
| 【3】 Mahler, C.; De Coster, R.; Freyne, E.; Bruynseels, J.; Denis, L.; De Porre, P.; Verhelst, J.; Liarozole Fumarate. Drugs Fut 1994, 19, 6, 552. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13297 | Thiophene | 110-02-1 | C4H4S | 详情 | 详情 | |
| 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 | |
| (I) | 16687 | 3-chlorobenzoyl chloride | 618-46-2 | C7H4Cl2O | 详情 | 详情 |
| (II) | 16688 | (3-chlorophenyl)(4-methoxyphenyl)methanone | C14H11ClO2 | 详情 | 详情 | |
| (III) | 16689 | (3-Chlorophenyl)(4-methoxy-3-nitrophenyl)-methanone; (3-chlorophenyl)(4-methoxy-3-nitrophenyl)methanone | 66938-41-8 | C14H10ClNO4 | 详情 | 详情 |
| (IV) | 16690 | (4-amino-3-nitrophenyl)(3-chlorophenyl)methanone | C13H9ClN2O3 | 详情 | 详情 | |
| (V) | 16691 | (4-amino-3-nitrophenyl)(3-chlorophenyl)methanol | C13H11ClN2O3 | 详情 | 详情 | |
| (VI) | 16692 | 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-nitroaniline; 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-nitrophenylamine | C16H13ClN4O2 | 详情 | 详情 | |
| (VII) | 16693 | 2-amino-4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]phenylamine; 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine | C16H15ClN4 | 详情 | 详情 | |
| (VIII) | 16694 | 5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole | C17H13ClN4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Condensation of (4-methoxyphenyl)acetic acid (I) with anisole (II) in hot PPA produced ketone (III). Subsequent treatment of (III) with the Vilsmeier reagent afforded chloroaldehyde (IV). The required thiophene (VI) was then obtained by cyclization with ethyl mercaptoacetate (V) in the presence of NaOEt. After basic hydrolysis of the ester group of (VI), the resulting acid (VII) was decarboxylated by means of copper in quinoline at 180 C, yielding thiophene (VIII). Stannic chloride-promoted Friedel-Crafts acylation of (VIII) with 3-(methoxycarbonyl)propionyl chloride (IX) gave ketoester (X). The keto group of (X) was further reduced employing triethylsilane in trifluoroacetic acid to afford (XI). Hydrolysis of the methyl ester of (XI), followed by treatment with oxalyl chloride furnished acid chloride (XII). The title hydroxamic acid was then obtained by coupling of (XII) with O-(tert-butyldimethylsilyl)-N-methylhydroxylamine and subsequent acid-catalyzed desilylation.
| 【1】 Wierzbicki, M.; Sauveur, F.; Bonnet, J.; Tordjman, C. (ADIR et Cie.); Thiophene cpds., process for their preparation and pharmaceutical compsns. containing them. EP 0728755; FR 2730996; JP 1996253470 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40600 | tert-butyl(dimethyl)[(methylamino)oxy]silane; O-[tert-butyl(dimethyl)silyl]-N-methylhydroxylamine | C7H19NOSi | 详情 | 详情 | ||
| (I) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (II) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (III) | 22991 | 1,2-bis(4-methoxyphenyl)-1-ethanone | 120-44-5 | C16H16O3 | 详情 | 详情 |
| (IV) | 34794 | (E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal | C17H15ClO3 | 详情 | 详情 | |
| (V) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VI) | 34795 | ethyl 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylate | C21H20O4S | 详情 | 详情 | |
| (VII) | 34796 | 4,5-bis(4-methoxyphenyl)-2-thiophenecarboxylic acid | C19H16O4S | 详情 | 详情 | |
| (VIII) | 34797 | 2,3-bis(4-methoxyphenyl)thiophene; 4-[2-(4-methoxyphenyl)-3-thienyl]phenyl methyl ether | C18H16O2S | 详情 | 详情 | |
| (IX) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (X) | 34798 | methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]-4-oxobutanoate | C23H22O5S | 详情 | 详情 | |
| (XI) | 34799 | methyl 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoate | C23H24O4S | 详情 | 详情 | |
| (XII) | 34800 | 4-[4,5-bis(4-methoxyphenyl)-2-thienyl]butanoyl chloride | C22H21ClO3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Condensation of anisole (I) with gamma,gamma-dimethylbutyrolactone (II) in the presence of AlCl3 in 1-nitropropane gave 4-(4-methoxyphenyl)-4-methylpentanoic acid (III), which was cyclized to the tetralone (V) using polyphosphoric acid. Subsequent treatment of (V) with refluxing N,N-dimethylformamide dimethyl acetal provided the dimethylamino-methylene compound (VI). This was cyclized with guanidinium carbonate in boiling isopropanol to furnish the benzoquinazoline (VII). Then, diazotization of (VII) in aqueous sulfuric acid generated the quinazolinone (VIII), which was subsequently converted to chloroquinazoline (IX) with phosphoryl chloride in the presence of DMF. Condensation of (IX) with aniline (X) in refluxing ethoxyethanol gave (XI). Finally, the hydroxyl group of (XI) was alkylated with (diethylamino)ethyl chloride (XII) in the presence of Cs2CO3 in DMF at 110 C to yield the title compound.
| 【1】 Davis, J.M.; Hutchings, M.C.; Moffat, D.; Batchelor, M.; Parry, D.M.; Johnson, J.; Berg, D.A.; Davis, P.D.; Benzo[h]-5,6-dihydroquinazoline-2-amines as potent. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.234. |
| 【2】 Moffat, D.F.C.; Davis, J.M.; Batchelor, M.J.; Davis, P.D. (Celltech Chiroscience plc); Fused polycyclic 2-aminopyrimidine derivs., their . EP 0946523; US 6057329; WO 9828281 . |
| 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) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (II) | 23768 | 5,5-dimethyldihydro-2(3H)-furanone | C6H10O2 | 详情 | 详情 | |
| (III) | 23769 | 4-(4-methoxyphenyl)-4-methylpentanoic acid | 23203-48-7 | C13H18O3 | 详情 | 详情 |
| (V) | 23770 | 7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (VI) | 23771 | 2-[(E)-(dimethylamino)methylidene]-7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C16H21NO2 | 详情 | 详情 | |
| (VII) | 23772 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-ylamine; 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-amine | C15H17N3O | 详情 | 详情 | |
| (VIII) | 23773 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one | C15H16N2O2 | 详情 | 详情 | |
| (IX) | 23774 | 2-chloro-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-9-yl methyl ether; 2-chloro-9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazoline | C15H15ClN2O | 详情 | 详情 | |
| (X) | 23775 | 5-amino-2,3-dimethoxyphenol | C8H11NO3 | 详情 | 详情 | |
| (XI) | 23776 | 2,3-dimethoxy-5-[(9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-yl)amino]phenol | C23H25N3O4 | 详情 | 详情 | |
| (XII) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Condensation of anisole (I) with gamma,gamma-dimethylbutyrolactone (II) in the presence of AlCl3 in 1-nitropropane gave 4-(4-methoxyphenyl)-4-methylpentanoic acid (III), which was cyclized to the tetralone (V) using polyphosphoric acid. Subsequent treatment of (V) with refluxing N,N-dimethylformamide dimethyl acetal provided the dimethylamino-methylene compound (VI). This was cyclized with guanidinium carbonate in boiling isopropanol to furnish the benzoquinazoline (VII). Then, diazotization of (VII) in aqueous sulfuric acid generated the quinazolinone (VIII), which was subsequently converted to the chloroquinazoline (IX) using phosphoryl chloride and DMF. Aniline (XIII) was obtained by alkylation of 2,6-dimethoxy-4-nitrophenol (X) with (diethylamino)ethyl chloride (XI) in the presence of Cs2CO3 to give (XII), followed by catalytic transfer hydrogenation of the nitro group of (XII) with ammonium formate and Pd/C. Finally, condensation of chloroquinazoline (IX) with aniline (XIII) in refluxing ethoxyethanol yielded the title compound.
| 【1】 Davis, J.M.; Hutchings, M.C.; Moffat, D.; Batchelor, M.; Parry, D.M.; Johnson, J.; Berg, D.A.; Davis, P.D.; Benzo[h]-5,6-dihydroquinazoline-2-amines as potent. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.234. |
| 【2】 Moffat, D.F.C.; Davis, J.M.; Batchelor, M.J.; Davis, P.D. (Celltech Chiroscience plc); Fused polycyclic 2-aminopyrimidine derivs., their . EP 0946523; US 6057329; WO 9828281 . |
| 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) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (II) | 23768 | 5,5-dimethyldihydro-2(3H)-furanone | C6H10O2 | 详情 | 详情 | |
| (III) | 23769 | 4-(4-methoxyphenyl)-4-methylpentanoic acid | 23203-48-7 | C13H18O3 | 详情 | 详情 |
| (V) | 23770 | 7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (VI) | 23771 | 2-[(E)-(dimethylamino)methylidene]-7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C16H21NO2 | 详情 | 详情 | |
| (VII) | 23772 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-ylamine; 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-amine | C15H17N3O | 详情 | 详情 | |
| (VIII) | 23773 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one | C15H16N2O2 | 详情 | 详情 | |
| (IX) | 23774 | 2-chloro-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-9-yl methyl ether; 2-chloro-9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazoline | C15H15ClN2O | 详情 | 详情 | |
| (X) | 23778 | 2,6-dimethoxy-4-nitrophenol | C8H9NO5 | 详情 | 详情 | |
| (XI) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (XII) | 23779 | N-[2-(2,6-dimethoxy-4-nitrophenoxy)ethyl]-N,N-diethylamine; 2-(2,6-dimethoxy-4-nitrophenoxy)-N,N-diethyl-1-ethanamine | C14H22N2O5 | 详情 | 详情 | |
| (XIII) | 23780 | 4-[2-(diethylamino)ethoxy]-3,5-dimethoxyaniline; N-[2-(4-amino-2,6-dimethoxyphenoxy)ethyl]-N,N-diethylamine | C14H24N2O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：The 2-aminobenzophenone derivative (III) was prepared by condensation of L-tyrosine methyl ester (I) with 2-benzoylcyclohexanone (II) in refluxing anisole, with concomitant dehydrogenation in the presence of Pd/C. Subsequent Mitsunobu coupling of (III) with 2-(N-Boc-N-methylamino)ethanol (V), prepared from aminoalcohol (IV) and Boc2O, afforded the Boc-protected aminoethyl ether (VI). After removal of the Boc group of (VI) by treatment with trifluoroacetic acid, condensation of the resulting secondary amine (VII) with 2-fluoropyridine (VIII) yielded the 2-aminopyridine derivative (IX). Finally, the methyl ester group of (IX) was hydrolyzed to the title carboxylic acid using LiOH.
| 【1】 N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel serieis of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998, 41, 25, 5020. |
| 【2】 Willson, T.M.; Mook, R.A. Jr.; Kaldor, I.; Henke, B.R.; Deaton, D.N.; Collins, J.L.; Cobb, J.E.; Brackeen, M.; Sharp, M.J.; O'Callaghan, J.M.; Erickson, G.A.; Boswell, G.E. (Glaxo Wellcome plc); Substd. 4-hydroxy-phenylalkanoic acid derivs. with agonist activity to PPAR-gamma. EP 0888317; JP 2000507216; WO 9731907 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 | |
| (I) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (II) | 21432 | 2-benzoylcyclohexanone | 3580-38-9 | C13H14O2 | 详情 | 详情 |
| (III) | 21434 | methyl (2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoate | C23H21NO4 | 详情 | 详情 | |
| (IV) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (V) | 34509 | tert-butyl 2-hydroxyethyl(methyl)carbamate | C8H17NO3 | 详情 | 详情 | |
| (VI) | 34510 | methyl (2S)-2-(2-benzoylanilino)-3-(4-[2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy]phenyl)propanoate | C31H36N2O6 | 详情 | 详情 | |
| (VII) | 34511 | methyl (2S)-2-(2-benzoylanilino)-3-[4-[2-(methylamino)ethoxy]phenyl]propanoate | C26H28N2O4 | 详情 | 详情 | |
| (VIII) | 34512 | 2-fluoropyridine | 372-48-5 | C5H4FN | 详情 | 详情 |
| (IX) | 34513 | methyl (2S)-2-(2-benzoylanilino)-3-(4-[2-[methyl(2-pyridinyl)amino]ethoxy]phenyl)propanoate | C31H31N3O4 | 详情 | 详情 |