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【结 构 式】 
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【分子编号】15488 【品名】1-bromo-2,4-difluorobenzene 【CA登记号】348-57-2 |
【 分 子 式 】C6H3BrF2 【 分 子 量 】192.9906264 【元素组成】C 37.34% H 1.57% Br 41.4% F 19.69% |
合成路线1
该中间体在本合成路线中的序号：(XIII)By condensation of 3-[2(E)-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)vinyl]-1H-1,2,4-triazole (I) with (+)-(R)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane (II) by means of anhydrous K2CO3 in hot DMF. The starting products (I) and (II) are obtained as follows: a) The condensation of 4-chlorobenzonitrile (III) with 2,2,3,3-tetrafluoropanol (IV) by means of NaH in DMF gives 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile (V), which is reduced to the corresponding benzaldehyde (VI) with diisobutylaluminum hydride in toluene. The condensation of diethoxyphosphorylacetic acid ethyl ester (VII) with aldehyde (VI) by means of KOH in THF yields (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamic acid ethyl ester (VIII), which is saponified to the corresponding acid (IX) with NaOH in ethanol-water. The reaction of (IX) first with refluxing SOCl2 and then with aqueous ammonia in toluene affords the corresponding amide (X), which is finally condensed with formyl hydrazide (XI) by means of trimethyloxonium tetrafluoroborate in CH2Cl2 to give (I). b) The reaction of 1,3-dichloroacetone (XII) with 2,4-difluorobromobenzene (XIII) by means of butyllithium in ether gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into 3-chloro-2-(2,4-difluorophenyl)-1,2-epoxypropane (XV) by treatment with NaH in DMF. The reaction of (XV) with tellurium and sodium hydroxymethylsulfinate in water yields 2-(2,4-difluorophenyl)allyl alcohol (XVI), which by stereoselective epoxidation with titanium tetraisopropoxide and diethyl (+)-tartrate in methylene chloride is converted into (R)-(-)-2-(2,4-difluorophenyl)-2,3-epoxypropanol (XVII). The reaction of (XVII) with 1,2,4-triazole (XVIII) by means of K2CO3 in THF affords (S)-(-)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazole-1-yl)-propane-1,2-diol (XIX), which is finally treated with methanesulfonyl chloride and triethylamine in ether to give (II).
| 【1】 Murakami, K.; Mochizuki, H. (AstraZeneca plc; Mochida Pharmaceutical Co., Ltd.); Optically active triazole derivs. and compsns. EP 0472392; JP 1993009183 . |
| 【2】 Fromtling, R.A.; Castaner, J.; ICI-D0870. Drugs Fut 1993, 18, 5, 424. |
| 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) | 15476 | 2,2,3,3-tetrafluoropropyl 4-[(E)-2-(1H-1,2,4-triazol-3-yl)ethenyl]phenyl ether; 3-[(E)-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethenyl]-1H-1,2,4-triazole | C13H11F4N3O | 详情 | 详情 | |
| (II) | 15477 | 1-[[(2R)-2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole | C11H9F2N3O | 详情 | 详情 | |
| (III) | 15478 | 4-methylcyclohexanecarbonitrile | C8H13N | 详情 | 详情 | |
| (IV) | 15479 | 2,2,3,3-tetrafluoro-1-propanol | 76-37-9 | C3H4F4O | 详情 | 详情 |
| (V) | 15480 | 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile | C10H7F4NO | 详情 | 详情 | |
| (VI) | 15481 | 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde | C10H8F4O2 | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 15483 | ethyl (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoate | C14H14F4O3 | 详情 | 详情 | |
| (IX) | 15484 | (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenoic acid | C12H10F4O3 | 详情 | 详情 | |
| (X) | 15485 | (E)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-propenamide | C12H11F4NO2 | 详情 | 详情 | |
| (XI) | 15486 | formic hydrazide; Formylhydrazine | 624-84-0 | CH4N2O | 详情 | 详情 |
| (XII) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XIV) | 15489 | 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol | C9H8Cl2F2O | 详情 | 详情 | |
| (XV) | 15490 | 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane | C9H7ClF2O | 详情 | 详情 | |
| (XVI) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (XVII) | 64587 | [(2R)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (XVIII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XIX) | 15494 | (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The intermediate (XIX) can be obtained by two related ways: 1. The condensation of 1,3-dichloroacetone (XIII) with 2,4-difluorobromobenzene (XII) by means of n-BuLi gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into the epoxide (XV) by reaction with KOH in toluene. The reaction of (XV) with isobutyric anhydride (XXII) yields the diester (XX), which is stereoselectively hydrolyzed with Lipase D in an acetate buffer to afford the (R)-monoester (XXIV). The reaction of (XXIV) with Ms-Cl and pyridine provides the monomesylate (XXV), which is treated with KOH in toluene to give the hydroxymethyl epoxide (XVII). Finally, this compound is treated with 1,2,4-triazole (XVIII) and K2CO3 in refluxing THF to afford the target intermediate. Alternatively, the mesylate (XXV) can be treated with 1,2,4-triazole (XVIII) and Na2CO3 in refluxing methanol to yield directly the target intermediate (XIX). 2. The acylation of 1,3-dihydroxypropanone (XXI) with butyric anhydride (XXII), pyridine and DMAP gives the diester (XXIII), which is submitted to a Grignard condensation with 2,4-difluorobromobenzene (XIII) by means of Mg to afford the already described intermediate, the diester (XIX).
| 【1】 Yasohara, Y.; et al.; A practical chemoenzymatic synthesis of a key intermediate of antifungal agents. Tetrahedron Lett 2001, 42, 19, 3331. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XIV) | 15489 | 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol | C9H8Cl2F2O | 详情 | 详情 | |
| (XV) | 15490 | 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane | C9H7ClF2O | 详情 | 详情 | |
| (XVII) | 17058 | [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (XVIII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XIX) | 15494 | (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 | |
| (XX) | 50741 | 2-(2,4-difluorophenyl)-2-hydroxy-3-(isobutyryloxy)propyl 2-methylpropanoate | C17H22F2O5 | 详情 | 详情 | |
| (XXI) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (XXII) | 22334 | 1-methylpropionic anhydride | 97-72-3 | C8H14O3 | 详情 | 详情 |
| (XXIII) | 50742 | 3-(isobutyryloxy)-2-oxopropyl 2-methylpropanoate | C11H18O5 | 详情 | 详情 | |
| (XXIV) | 50743 | (2R)-2-(2,4-difluorophenyl)-2,3-dihydroxypropyl 2-methylpropanoate | C13H16F2O4 | 详情 | 详情 | |
| (XXV) | 50744 | (2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-[(methylsulfonyl)oxy]propyl 2-methylpropanoate | C14H18F2O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.
| 【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42. |
| 【2】 Kitazaki, T.; et al.; Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone and its analogs. Chem Pharm Bull 1999, 47, 3, 360. |
| 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) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (VII) | 43502 | 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C11H9F4N3O2 | 详情 | 详情 | |
| (XIII) | 43507 | 2-[(1R)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C20H15F6N3O3 | 详情 | 详情 | |
| (XIV) | 43508 | propyl (2S)-2-hydroxypropanoate | 616-09-1 | C6H12O3 | 详情 | 详情 |
| (XV) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XVI) | 41498 | (2S)-2-hydroxy-1-(4-morpholinyl)-1-propanone | C7H13NO3 | 详情 | 详情 | |
| (XVII) | 43509 | (2S)-1-(4-morpholinyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C12H21NO4 | 详情 | 详情 | |
| (XVIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XIX) | 43511 | (2S)-1-(2,4-difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (XX) | 43510 | (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl trifluoromethanesulfonate | C10H7F5O4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The acylation of m-difluorobenzene (I) with 2-bromoacetyl bromide (II) by means of AlCl3 gives the phenacyl bromide (III), which is treated with ethylmercaptan (IV) and K2CO3 to yield the sulfanyl derivative (V). The fluorination of (V) with N-fluoro-4-methylpyridinium-2-sulfonate affords the difluoroacetyl derivative (VI). The methylenation of the carbonyl group of (VI) with trimethylsulfoxonium iodide provides the oxiranyl derivative (VII), which is opened with 1,2,4-triazole (VIII) and K2CO3, furnishing the propanol derivative (IX). The oxidation of the sulfanyl group of (IX) by means of H2O2 or MCPBA gives the corresponding sulfonyl derivative (X). Finally, the racemic mixture (X) is submitted to optical resolution by crystallization of the (+)-3-bromocamphorsulfonic acid. Alternatively, intermediate (VI) can be obtained as follows: The reaction of 2-chloro-2,2-difluoroacetic acid ethyl ester (XI) with ethylmercaptan (IV) by means of NaH gives the sulfanyl derivative (XII), which is finally condensed with 2,4-difluorobromobenzene (XIII) by means of BuLi to afford the desired intermediate (VI).
| 【1】 Kaneko, Y.; Takeda, S.; Eto, H.; et al.; New antifungal 1,2,4-triazoles with difluoro(substituted sulfonyl)methyl moiety. Chem Pharm Bull 2001, 49, 2, 173. |
| 【2】 Sato, S.; Kaneko, Y.; Takeda, S.; Eto, H.; Tokizawa, M.; SS750, a new triazole agent: Structure-activity relationship of novel triazole-containing gem-difluoromethylsulfonyl moiety. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1080. |
| 【3】 Matsumoto, M.; Kaneko, Y.; Maebashi, K.; Takeda, S.; Sato, S.; Tokizawa, M.; Ishida, K.; Eto, H.; Asaoka, T. (SSP Co., Ltd.); Triazole deriv. or salt thereof, preparation process thereof as well as pharmaceutical containing said cpd.. CA 2256060; EP 0927719; JP 1999240871; US 6083968 . |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (III) | 47646 | 2-bromo-1-(2,4-difluorophenyl)-1-ethanone | C8H5BrF2O | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 47647 | 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-1-ethanone | C10H10F2OS | 详情 | 详情 | |
| (VI) | 47648 | 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-2,2-difluoro-1-ethanone | C10H8F4OS | 详情 | 详情 | |
| (VII) | 47649 | 2-(2,4-difluorophenyl)-2-[(ethylsulfanyl)(difluoro)methyl]oxirane; [2-(2,4-difluorophenyl)-2-oxiranyl](difluoro)methyl ethyl sulfide | C11H10F4OS | 详情 | 详情 | |
| (VIII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (IX) | 47650 | 2-(2,4-difluorophenyl)-1-(ethylsulfanyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol | C13H13F4N3OS | 详情 | 详情 | |
| (X) | 47651 | 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol | C13H13F4N3O3S | 详情 | 详情 | |
| (XI) | 47652 | Chlorodifluoroacetic acid ethyl ester; Difluorochloroacetic acid ethyl ester; Ethyl chlorodifluoroacetate; ethyl 2-chloro-2,2-difluoroacetate | 383-62-0 | C4H5ClF2O2 | 详情 | 详情 |
| (XII) | 47653 | ethyl 2-(ethylsulfanyl)-2,2-difluoroacetate | C6H10F2O2S | 详情 | 详情 | |
| (XIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Aromatic hydroxylation of 1-bromo-2,4-difluorobenzene (I) using tert-butyl hydroperoxide and LDA afforded phenol (II), which was methylated with iodomethane and K2CO3 to give methyl ether (III). The required benzoic acid (IV) was then obtained from (III) by lithium-bromine exchange with n-butyllithium, followed by carboxylation with CO2 gas at -70 C. Treatment of (IV) with oxalyl chloride and DMF gave acid chloride (V). This was condensed with the lithium salt of monoethyl malonate to yield, after acid decarboxylation, ketoester (VI). Subsequent condensation of (VI) with triethyl orthoformate in refluxing Ac2O provided methoxyacrylate (VII), and further treatment with cyclopropylamine (VIII) furnished aminoacrylate (IX). Cyclization of (IX) by means of NaH in THF generated the quinolone system (X). Acid hydrolysis of the ethyl ester group of (X) gave quinolinecarboxylic acid (XI), which was converted to the boron difluoride complex (XII) by treatment with BF3-Et2O in hot THF. Displacement of the aromatic fluorine of (XII) with 3R-(1S-tert-butoxycarbonylaminoethyl)pyrrolidine (XIII) in the presence of DIEA, followed by boron complex cleavage with Et3N in EtOH provided the pyrrolidinylquinoline (XIV). Finally, the Boc protecting group of (XIV) was removed by hydrolysis with ethanolic HCl.
| 【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 | |
| (I) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (II) | 34648 | 3-bromo-2,6-difluorophenol | 221220-99-1 | C6H3BrF2O | 详情 | 详情 |
| (III) | 34649 | 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene | 221221-00-7 | C7H5BrF2O | 详情 | 详情 |
| (IV) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (V) | 34650 | 2,4-difluoro-3-methoxybenzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (VI) | 34651 | ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate | C12H12F2O4 | 详情 | 详情 | |
| (VII) | 34652 | ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate | C15H16F2O5 | 详情 | 详情 | |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 34653 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate | C16H17F2NO4 | 详情 | 详情 | |
| (X) | 34654 | ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H16FNO4 | 详情 | 详情 | |
| (XI) | 34655 | 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 221221-16-5 | C14H12FNO4 | 详情 | 详情 |
| (XII) | 34656 | C14H11BF3NO4 | 详情 | 详情 | ||
| (XIII) | 34657 | tert-butyl (1S)-1-[(3R)pyrrolidinyl]ethylcarbamate | C11H22N2O2 | 详情 | 详情 | |
| (XIV) | 34658 | 7-((3R)-3-[(1S)-1-[(tert-butoxycarbonyl)amino]ethyl]pyrrolidinyl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C25H33N3O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The copper-promoted coupling between 2-iodothiophene (I) and ethyl bromodifluoroacetate (II) produced ethyl 2,2-difluoro-2-(2-thienyl)acetate (III). Addition of the organolithium reagent derived from 2,4-difluorobromobenzene (IV) to ester (III) yielded ketone (V). This was converted into the oxirane (VI) by reaction with dimethyloxosulfonium methylide in DMSO. Finally, oxirane ring opening with 1,2,4-triazole (VII) provided the title compound.
| 【1】 Sakamoto, T.; Eto, H.; Kaneko, Y.; New antifungal 1,2,4-triazoles with difluro(heteroaryl)methyl moiety. Chem Pharm Bull 2000, 48, 7, 982. |
| 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) | 43394 | 2-iodothiophene | 3437-95-4 | C4H3IS | 详情 | 详情 |
| (II) | 43395 | ethyl 2,2-difluoro-2-(2-thienyl)acetate | C8H8F2O2S | 详情 | 详情 | |
| (III) | 43396 | 1-(2,4-difluorophenyl)-2,2-difluoro-2-(2-thienyl)-1-ethanone | C12H6F4OS | 详情 | 详情 | |
| (IV) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (V) | 43397 | 2-(2,4-difluorophenyl)-2-[difluoro(2-thienyl)methyl]oxirane | C13H8F4OS | 详情 | 详情 | |
| (VI) | 43398 | 2-(2,4-difluorophenyl)-1,1-difluoro-1-(2-thienyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol | C15H11F4N3OS | 详情 | 详情 | |
| (VII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Metalation of 1-bromo-2,4-difluorobenzene (I) by means of LDA, followed by treatment with tert-butyl hydroperoxide gave rise to phenol (II), which was further converted to methyl ether (III) by alkylation with iodomethane and K2CO3. Lithium halogen exchange of (III) with n-butyllithium, and subsequent quenching with CO2 produced 3-methoxy-2,4-difluorobenzoic acid (IV). After activation of (IV) as the acid chloride (V), condensation with the lithium derivative of monoethyl malonate (A) led to the benzoyl acetate ester (VI). The benzoyl ethoxyacrylate (VII), obtained by condensation of ketoester (VI) with triethyl orthoformate, was then reacted with cyclopropylamine (VIII) to afford enamine (IX). This was cyclized to the quinolone compound (X) upon treatment with NaH in THF. Acidic hydrolysis of ester (X) gave a keto acid, which was subsequently converted to the boron chelate (XI) by treatment with boron trifluoride etherate. Fluoride displacement of quinolone (XI) with the amino piperidine (XII) produced the piperidino quinolone (XIII). The boron difluoride complex of (XIII) was finally removed by means of triethylamine in boiling EtOH.
| 【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 . |
| 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) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (I) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (II) | 34648 | 3-bromo-2,6-difluorophenol | 221220-99-1 | C6H3BrF2O | 详情 | 详情 |
| (III) | 34649 | 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene | 221221-00-7 | C7H5BrF2O | 详情 | 详情 |
| (IV) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (V) | 34650 | 2,4-difluoro-3-methoxybenzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (VI) | 34651 | ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate | C12H12F2O4 | 详情 | 详情 | |
| (VII) | 34652 | ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate | C15H16F2O5 | 详情 | 详情 | |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 34653 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate | C16H17F2NO4 | 详情 | 详情 | |
| (X) | 34654 | ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H16FNO4 | 详情 | 详情 | |
| (XI) | 59792 | 1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-7-fluoro-8-methoxy-4(1H)-quinolinone | C14H11BF3NO4 | 详情 | 详情 | |
| (XII) | 59793 | (3S,4R)-4-ethyl-3-piperidinamine; (3S,4R)-4-ethylpiperidinylamine | C7H16N2 | 详情 | 详情 | |
| (XIII) | 59794 | 7-[(3S,4R)-3-amino-4-ethylpiperidinyl]-1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-8-methoxy-4(1H)-quinolinone | C21H26BF2N3O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XXIII)In an alternative route to the quinolone precursor (XX), deprotonation of 2,4-difluorobromobenzene (XXIII) with LDA in THF followed by addition of tert-butyl hydroperoxide gives 3-bromo-2,6-difluorophenol (XXIV), which is converted to the corresponding methyl ether (XXV) by treatment with iodomethane and K2CO3. Metalation of the aryl bromide (XXV) with butyl lithium in cold diethyl ether and subsequent addition of CO2 gas leads to 3-methoxy-2,4-difluorobenzoic acid (XXVI). After chlorination of acid (XXVI) with oxalyl chloride and catalytic DMF, the obtained acid chloride (XXVII) is condensed with monoethyl malonate (XXVIII) in the presence of butyl lithium in THF at –50 °C to yield the 2-(benzoyl)acetate (XVII). Subsequent reaction of keto ester (XVII) with triethyl orthoformate in boiling Ac2O provides the enol ether (XXIX), which is then condensed with cyclopropylamine (XIX) in EtOH to give the key enamine (XX) (3). Scheme 3.
| 【3】 Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 34651 | ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate | C12H12F2O4 | 详情 | 详情 | |
| (XIX) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XX) | 34653 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate | C16H17F2NO4 | 详情 | 详情 | |
| (XXIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XXIV) | 34648 | 3-bromo-2,6-difluorophenol | 221220-99-1 | C6H3BrF2O | 详情 | 详情 |
| (XXV) | 34649 | 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene | 221221-00-7 | C7H5BrF2O | 详情 | 详情 |
| (XXVI) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (XXVII) | 34650 | 2,4-difluoro-3-methoxybenzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (XXVIII) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (XXIX) | 34652 | ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate | C15H16F2O5 | 详情 | 详情 |