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【结 构 式】 
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【分子编号】29012 【品名】1-bromo-4-fluorobenzene 【CA登记号】460-00-4 |
【 分 子 式 】C6H4BrF 【 分 子 量 】175.0001632 【元素组成】C 41.18% H 2.3% Br 45.66% F 10.86% |
合成路线1
该中间体在本合成路线中的序号：(V)By condensation of 4-(4-fluorobenzoyl)piperidine (IX) with 6-(2-bromo ethyl)-7-methyl-2,3-dihydro-5H-thiazolo[2,3-a]pyrimidin-5-one (IV) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting products are obtained as follows: The cyclization of 4-hydroxy-5-(2-hydroxyethyl)-6-methyl-2-mercaptopyrimidine (I) with 1,2-dibromo ethane (II) by means of K2CO3 in hot dimethylacetamide gives 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (II), which by reaction with HBr in refluxing acetic acid is converted to the corresponding 6-(2-bromoethyl) derivative (IV). The Grignard reaction of 4-bromofluorobenzene (V) with N benzyl-4 cyanopiperidine (VI) by means of Mg in dimethoxyethane gives 4-(4-fluorobenzoyl)-N-benzylpiperidine (VII), which is treated with ethyl chlorocarbo-nate in refluxing toluene to afford ethyl 4-(4-fluorobenzoyl)piperidine-1-carboxylate (VIII). Finally, this compound is treated with HBr in refluxing 48% HBr to give (IX).
| 【1】 Kennis, L.; Mertens, J.C. (Janssen Pharmaceutica NV); Bicyclic pyrimidin-5-one derivatives. DD 215553; EP 0070053; US 4443451 . |
| 【2】 Serradell, M.N.; Castaner, J.; Setoperone. Drugs Fut 1985, 10, 1, 40. |
| 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) | 29009 | 5-(2-hydroxyethyl)-6-methyl-2-sulfanyl-4-pyrimidinol | C7H10N2O2S | 详情 | 详情 | |
| (II) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (III) | 29010 | 6-(2-hydroxyethyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one | C9H12N2O2S | 详情 | 详情 | |
| (IV) | 29011 | 6-(2-bromoethyl)-7-methyl-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one | C9H11BrN2OS | 详情 | 详情 | |
| (V) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (VI) | 29013 | 1-benzyl-4-piperidinecarbonitrile | C13H16N2 | 详情 | 详情 | |
| (VII) | 29014 | (1-benzyl-4-piperidinyl)(4-fluorophenyl)methanone | C19H20FNO | 详情 | 详情 | |
| (VIII) | 29015 | ethyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate | C15H18FNO3 | 详情 | 详情 | |
| (IX) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(C)The synthesis of bervastatin is outlined: Heating of 2-hydroxyacetophenone (A) with cyclopentanone (B) and pyrrolidine in toluene gave 3,4-dihydrospiro[1-benzopyran-2(2H),1'-cyclopentan]-4-one (I). 1,2-Addition of 4-fluorophenylmagnesium bromide (D) on (I) followed by dehydration of the intermediate alcohol (II) upon treatment with p-toluenesulfonic acid yielded 4-(4-fluorophenyl)spiro[1-benzopyran-2(2H),1'-cyclopentane] (III). Vilsmeier reaction on (III) using 3-morpholinoacrolein (E) gave the corresponding prop-2-enal (IV). Addition of the dianion of ethyl acetoacetate to aldehyde (IV) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (V) with diethylmethoxyborane and sodium borohydride yielded bervastatin.
| 【1】 Festal, D.; Bervastatin. Drugs Fut 1995, 20, 12, 1217. |
| 【2】 Festal, D.; Nioche, J.-Y.; Descours, D.; Bellemin, R.; Decerprit, J. (Lipha Santé); Derivs. of benzocycloalkenyldihydroxyalkanoic acids, inhibitors of HMG-CoA reductase, antagonists of thromboxane A2 receptors and antifungals. AU 9048797; EP 0380392; FR 2642065; JP 1990258738; US 5082859; US 5183924 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (B) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (A) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (E) | 44198 | (E)-3-(4-morpholinyl)-2-propenal | C7H11NO2 | 详情 | 详情 | |
| (I) | 14114 | 3,4-Dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-one | C13H14O2 | 详情 | 详情 | |
| (II) | 14115 | 4-(4-Fluorophenyl)-3,4-dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-ol | C19H19FO2 | 详情 | 详情 | |
| (III) | 14116 | 4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentane] | C19H17FO | 详情 | 详情 | |
| (IV) | 14117 | 3-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-2(E)-propenal | C22H19FO2 | 详情 | 详情 | |
| (V) | 14118 | 5-Hydroxy-7-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-3-oxo-6(E)-heptenoic acid ethyl ester | C28H29FO5 | 详情 | 详情 | |
| (C) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Ethyl isonipecotate (I) was protected as the N-trityl derivative (II) using triphenylmethyl chloride and triethylamine. Addition of Grignard reagent (IV) (prepared from 1-bromo-4-fluorobenzene (III) and magnesium in Et2O) to (II) produced the diaryl carbinol (V). Alcohol dehydration with simultaneous trityl group cleavage under acidic conditions yielded 4-[bis(4-fluorophenyl)methylene]piperidine (VI). 4-Chlorobutyrylpyrrolidine (IX), prepared by coupling of 4-chlorobutyryl chloride (VII) and pyrrolidine (VIII), was then condensed with piperidine (VI) to yield the target compound.
| 【1】 Rae, D.R.; Jaap, D.R. (Akzo Nobel N.V.); Diphenylmethylene piperidine derivs.. EP 0842170; JP 1999508907; US 5935974; WO 9703065 . |
| 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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (II) | 33780 | ethyl 1-trityl-4-piperidinecarboxylate | C27H29NO2 | 详情 | 详情 | |
| (III) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (IV) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (V) | 33781 | bis(4-fluorophenyl)(1-trityl-4-piperidinyl)methanol | C37H33F2NO | 详情 | 详情 | |
| (VI) | 24706 | 4-[bis(4-fluorophenyl)methylene]piperidine | C18H17F2N | 详情 | 详情 | |
| (VII) | 11265 | 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride | 4635-59-0 | C4H6Cl2O | 详情 | 详情 |
| (VIII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IX) | 33782 | 4-chloro-1-(1-pyrrolidinyl)-1-butanone | C8H14ClNO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The CuI-assisted coupling between methyl N-(4-fluorophenyl)carbamate (I) and 1-bromo-4-fluorobenzene (II) produced the N,N-bis(4-fluorophenyl)carbamate (III), which was subsequently hydrolyzed to bis(4-fluorophenyl)amine (IV) using ethanolic KOH. Acylation of diarylamine (IV) with 3-bromopropionyl chloride (V) gave bromopropionamide (VI). This was then condensed with cis-2,6-dimethylpiperazine (VII) to yield the 3-piperazinylpropionamide (VIII). Amide reduction with LiAlH4 provided the triamino compound (IX). Acid chloride (XI), prepared from hydrocinnamic acid (X), was then coupled with piperazine (IX) to furnish amide (XII). The amide function was finally reduced to the corresponding amine by using LiAlH4.
| 【1】 Cao, J.; Husbands, S.M.; Kopajtic, T.; Newman, A.H.; Katz, J.L.; [3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel for the dopamine transporter. Bioorg Med Chem Lett 2001, 11, 24, 3169. |
| 【2】 Ca, J.; Newman, A.H.; Kopajtic, T.; Katz, J.L.; Husbands, S.M.; [3-cis-3,5-Dimethyl-1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amines analogs as novel probes for the dopamine transporter. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 96. |
| 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) | 49174 | methyl 4-fluorophenylcarbamate | C8H8FNO2 | 详情 | 详情 | |
| (II) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (III) | 49175 | methyl bis(4-fluorophenyl)carbamate | C14H11F2NO2 | 详情 | 详情 | |
| (IV) | 49176 | 4-fluoro-N-(4-fluorophenyl)aniline; N,N-bis(4-fluorophenyl)amine | C12H9F2N | 详情 | 详情 | |
| (V) | 49177 | 3-Bromopropionyl chloride; beta-Bromopropionyl chloride | 15486-96-1 | C3H4BrClO | 详情 | 详情 |
| (VI) | 49178 | 3-bromo-N,N-bis(4-fluorophenyl)propanamide | C15H12BrF2NO | 详情 | 详情 | |
| (VII) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (VIII) | 49179 | 3-[(3R,5S)-3,5-dimethylpiperazinyl]-N,N-bis(4-fluorophenyl)propanamide | C21H25F2N3O | 详情 | 详情 | |
| (IX) | 49180 | N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N,N-bis(4-fluorophenyl)amine; N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-4-fluoro-N-(4-fluorophenyl)aniline | C21H27F2N3 | 详情 | 详情 | |
| (X) | 49181 | Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid | 501-52-0 | C9H10O2 | 详情 | 详情 |
| (XI) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (XII) | 49182 | 1-((2R,6S)-4-[3-[bis(4-fluorophenyl)amino]propyl]-2,6-dimethylpiperazinyl)-3-phenyl-1-propanone | C30H35F2N3O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The cyclization of p-fluorophenylhydrazine (I) with 1-carbethoxy-4-piperidinone (II) in refluxing ethanol gives 2-carbethoxy-8-fluoro-1,2,3,4-tetrahydro-gamma-carboline (III), which is arylated with p-fluorobromobenzene (IV), by means of Na2CO3 - Cu2Br2 in N-methyl-2-pyrrolidinone heated at 200 C to yield 2-carbethoxy-8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-gamma-carboline (V). The hydrolytic decarboxylation of (V) with KOH in refluxing ethanol affords 8-fluoro-5-(p-fluorophenyl)-1,2,3,4-tetrahydro-gamma-carboline (VI), which is alkylated with p-fluoro-gamma-bromobutyrophenone (VII) by means of Na2CO3 in hot DMF to give 8-fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-4-oxobutyl]-1,2,3,4-tetrahydro-gamma-carboline (VIII). Finally this compound is reduced with NaBH4 in ethanol - THF
| 【1】 Harbert, C.A.; et al.; Neuroleptic activity in 5-aryl-tetrahydro-gamma-carbolines. J Med Chem 1980, 23, Suppl. 3, 635. |
| 【2】 Plattner, J.J.; et al. (Pfizer Inc.); US 4001263 . |
| 【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Leeson, P.A.; Mealy, N.E.; Flutroline. Drugs Fut 1981, 6, 2, 84. |
| 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) | 22135 | 1-(4-fluorophenyl)hydrazine | 371-14-2 | C6H7FN2 | 详情 | 详情 |
| (II) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (III) | 22137 | ethyl 8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate | C14H15FN2O2 | 详情 | 详情 | |
| (IV) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (V) | 60777 | ethyl 8-fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate | C20H18F2N2O2 | 详情 | 详情 | |
| (VI) | 60775 | 8-fluoro-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole | C17H14F2N2 | 详情 | 详情 | |
| (VII) | 60778 | 4-bromo-1-(4-fluorophenyl)-1-butanone | C10H10BrFO | 详情 | 详情 | |
| (VIII) | 60779 | 4-[8-fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-1-(4-fluorophenyl)-1-butanone | C27H23F3N2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XI)In one method, metalation of 1-bromo-4-fluorobenzene (XI) with Mg in 2-MeTHF at 90 °C gives 4-fluorophenyl magnesium bromide (XII), which then couples with 2-bromothiophene (XIII) in the presence of NiCl2·dppe and AcOH in 2-MeTHF at 22 °C or in the presence of Pd(OAc)2 and DPPP in THF to yield 2-(4-fluorophenyl)thiophene (XIV). Finally, this compound undergoes Friedel–Crafts acylation with 5-iodo-2-methylbenzoic acid (XV) (initially chlorinated with SOCl2 in CH2Cl2) using AlCl3 in CH2Cl2, and subsequent reduction with (Me2SiH)2O in refluxing acetonitrile .
In another method, hydrolysis of methyl 5-bromo-2-methylbenzoate (XVI) with NaOH in MeOH at 50 °C gives rise to the benzoic acid (XVII) , which is then chlorinated with (COCl)2 in the presence of DMF in CH2Cl2 to yield 5-bromo-2-methylbenzoyl chloride (XVIII). Friedel–Crafts reaction of acyl chloride (XVIII) with 2-(4-fluorophenyl) thiophene (XIV) in the presence of AlCl3 in CH2Cl2 affords ketone (XIX), which is then reduced by means of Et3SiH and BF3·Et2O in CH2Cl2/acetonitrile to afford 2-(5-bromo-2-methylbenzoyl)-5-(4-fluorophenyl)thiophene (III) . Finally, compound (III) is iodinated with NaI and CuI in the presence of (MeNHCH2)2 in refluxing toluene/diglyme (IV) .
Alternatively, coupling of 4-fluorophenylboronic acid (XX) with either 2-bromothiophene (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in dimethoxyethane at 75-80 °C or with 2-iodothiophene (XXI) in the presence of PdCl2(PPh3)2 at 50 °C affords 2-(4-fluorophenyl) thiophene (XIV) .
| 【1】 Abdel-Magid, A.F., Chisholm, M., Mehrman, S. et al. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. CN 101801371, EP 2200606, JP 2010539092, WO 2009035969. |
| 【2】 Nomura, S., Ueta, K., Kawanishi, E. (Mitsubishi Tanabe Pharma Corp.). Novel compounds having inhibitory activity against sodium-dependant transporter. EP 1651658, JP 2007518683, JP 2008266328, WO 2005012326. |
| 【3】 Nomura, S., Sakamaki, S., Hongu, M. et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010, 53(17): 6355-60. |
| 【4】 Filliers, W.F.M., Broeckx, R.L.M., Nieste, P.H.J., Hatsuda, M., Yoshinaga, M., Yada, M. (Janssen Pharmaceutica NV; Mitsubishi Tanabe Pharma Corp.). Process for the preparation of compounds useful as inhibitors of SGLT. US 2010099883, WO 2010043682. |
| 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) | 68782 | 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene | 1030825-20-7 | C18H14BrFS | 详情 | 详情 |
| (IV) | 68783 | 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene | 898566-17-1 | C18H14FIS | 详情 | 详情 |
| (XI) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (XII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XIII) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
| (XIV) | 68790 | 2-(4-fluorophenyl)thiophene | 58861-49-7 | C10H7FS | 详情 | 详情 |
| (XV) | 68791 | 5-iodo-2-methylbenzoic acid;2-Methyl-5-iodobenzoicacid | 54811-38-0 | C8H7IO2 | 详情 | 详情 |
| (XVI) | 68792 | methyl 5-bromo-2-methylbenzoate;methyl 5-bromo-o-toluate | 79669-50-4 | C9H9BrO2 | 详情 | 详情 |
| (XVII) | 68793 | 5-bromo-2-methylbenzoic acid;2-Methyl-5-bromobenzoic acid | 79669-49-1 | C8H7BrO2 | 详情 | 详情 |
| (XVIII) | 68794 | 5-bromo-2-methylbenzoyl chloride | C8H6BrClO | 详情 | 详情 | |
| (XIX) | 68795 | (5-bromo-2-methylphenyl)(5-(4-fluorophenyl)thiophen-2-yl)methanone | C18H12BrFOS | 详情 | 详情 | |
| (XX) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (XXI) | 43394 | 2-iodothiophene | 3437-95-4 | C4H3IS | 详情 | 详情 |