【结 构 式】 |
【分子编号】18192 【品名】ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate 【CA登记号】2356-16-3 |
【 分 子 式 】C8H16FO5P 【 分 子 量 】242.1842052 【元素组成】C 39.68% H 6.66% F 7.84% O 33.03% P 12.79% |
合成路线1
该中间体在本合成路线中的序号:(II)The Horner-Emmons condensation of 3-quinuclidinone (I) with triethyl 2-fluoro-2-phosphonoacetate (II) produced the unsaturated ester (III). The amino-borane complex (IV) was then obtained by treatment of (III) with borane in THF. Ester group of (IV) reduction by means of sodium bis(2-methoxyethoxy)aluminium hydride gave the allylic alcohol (V), which was converted into chloride (VI) by treatment with mesyl chloride in the presence of LiCl. Condensation of chloride (VI) with 2-hydroxycarbazole (VII) yielded ether (VIII). After acid cleavage of the amino-borane complex (VIII), the title compound was isolated as the hydrochloride salt.
【1】 Isaka, M.; Ishihara, T.; Matsuda, K.; Kakuta, H.; Moritani, H. (Yamanouchi Pharmaceutical Co., Ltd.); Novel quinuclidine derivs. having tricyclic fused hetero ring. EP 0812840; WO 9626938 . |
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) | 16925 | 3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one | 1193-65-3 | C7H11NO | 详情 | 详情 |
(II) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
(III) | 44999 | ethyl 2-(1-azabicyclo[2.2.2]oct-3-ylidene)-2-fluoroacetate | C11H16FNO2 | 详情 | 详情 | |
(IV) | 45000 | C11H19BFNO2 | 详情 | 详情 | ||
(V) | 45001 | C9H17BFNO | 详情 | 详情 | ||
(VI) | 45002 | C9H16BClFN | 详情 | 详情 | ||
(VII) | 45003 | 9H-carbazol-2-ol | C12H9NO | 详情 | 详情 | |
(VIII) | 45004 | C21H24BFN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(V)Formylation of tetrahydroquinoline (I) with N,N-dimethylformamide and POCl3 afforded aldehyde (II), which was condensed with ethylmagnesium bromide to give alcohol (III), and then oxidized to ketone (IV) with activated MnO2 in acetone. Coupling with triethyl 2-fluoro-2-phosphonoacetate (V) in the presence of NaH in DMF produced a mixture of olefins, from which the desired E isomer (VI) was separated by column chromatography. Ester reduction with DIBAL-H at -70 C provided the E-alcohol (VII), which was oxidized to aldehyde (VIII) with MnO2 in acetone. Horner-Emmons condensation with phosphonate (IX) afforded heptatrienoic ester (X), which was finally hydrolyzed with NaOH to the target heptatrienoic acid.
【1】 Hibi, S.; Kikuchi, K.; Yoshimura, H.; Nagai, M.; Tai, K.; Hida, T.; Syntheses and structure-activity relationships of novel retinoid X receptor agonists. J Med Chem 1998, 41, 17, 3245. |
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) | 18188 | 1-isopropyl-1,2,3,4-tetrahydroquinoline | C12H17N | 详情 | 详情 | |
(II) | 18189 | 1-isopropyl-1,2,3,4-tetrahydro-6-quinolinecarbaldehyde | C13H17NO | 详情 | 详情 | |
(III) | 18190 | 1-(1-isopropyl-1,2,3,4-tetrahydro-6-quinolinyl)-1-propanol | C15H23NO | 详情 | 详情 | |
(IV) | 18191 | 1-(1-isopropyl-1,2,3,4-tetrahydro-6-quinolinyl)-1-propanone | C15H21NO | 详情 | 详情 | |
(V) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
(VI) | 18193 | ethyl (E)-2-fluoro-3-(1-isopropyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-pentenoate | C19H26FNO2 | 详情 | 详情 | |
(VII) | 18194 | (E)-2-fluoro-3-(1-isopropyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-penten-1-ol | C17H24FNO | 详情 | 详情 | |
(VIII) | 18195 | (E)-2-fluoro-3-(1-isopropyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-pentenal | C17H22FNO | 详情 | 详情 | |
(IX) | 18196 | methyl (E)-4-(diethoxyphosphoryl)-3-methyl-2-butenoate | C10H19O5P | 详情 | 详情 | |
(X) | 18197 | methyl (2E,4E,6E)-6-fluoro-7-(1-isopropyl-1,2,3,4-tetrahydro-6-quinolinyl)-3-methyl-2,4,6-nonatrienoate | C23H30FNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(II)L-Glyceraldehyde acetonide (I) was subjected to Horner-Emmons reaction with triethyl alpha-fluorophosphonoacetate (II) in the presence of sodium bis(trimethylsilyl)amide to yield a mixture of Z (III) and E (IV) unsaturated esters. Acidic treatment of this mixture, followed by silylation with tert-butyldimethylsilyl chloride gave the desired fluorobutyrolactone (V) along with the open-chain silylated dihydroxyester (VI), which were separated by column chromatography. Reduction of lactone (V) with DIBAL provided an anomeric mixture of lactols (VIIa-b), which was further acetylated to afford (VIIIa-b). N-Glycosylation of the silylated N(4)-benzoylcytosine (IX) using trimethylsilyl triflate gave rise to the mixture of furanosylcytosines (Xa-b). After chromatographic isolation of the desired beta-anomer, deprotection of the silyl ether by means of tetrabutylammonium fluoride yielded (XI). Finally, ammonolysis of the N-benzoyl group of (XI) furnished the title compound.
【1】 Schinazi, R.F.; Choi, Y.; Chu, C.K.; Gullen, E.; Lee, K.; Schlueter-Wirtz, S.; Cheng, Y.-C.; Synthesis and anti-HIV and anti-HBV activities of 2'-fluoro-2',3'-unsaturated L-nucleosides. J Med Chem 1999, 42, 7, 1320. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIIa) | 36279 | (2R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2,5-dihydro-2-furanol | C11H21FO3Si | 详情 | 详情 | |
(VIIb) | 36280 | (2S,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2,5-dihydro-2-furanol | C11H21FO3Si | 详情 | 详情 | |
(VIIIa) | 36281 | (2S,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2,5-dihydro-2-furanyl acetate | C13H23FO4Si | 详情 | 详情 | |
(VIIIb) | 36282 | (2R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2,5-dihydro-2-furanyl acetate | C13H23FO4Si | 详情 | 详情 | |
(Xa) | 36284 | N-[1-[(2R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2,5-dihydro-2-furanyl]-5-fluoro-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C22H27F2N3O4Si | 详情 | 详情 | |
(Xb) | 36285 | N-[1-[(2S,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2,5-dihydro-2-furanyl]-5-fluoro-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C22H27F2N3O4Si | 详情 | 详情 | |
(I) | 14969 | (4S)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 22323-80-4 | C6H10O3 | 详情 | 详情 |
(II) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
(III) | 36276 | ethyl (E)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate | C10H15FO4 | 详情 | 详情 | |
(IV) | 36287 | ethyl (Z)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate | C10H15FO4 | 详情 | 详情 | |
(V) | 36277 | (5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2(5H)-furanone | C11H19FO3Si | 详情 | 详情 | |
(VI) | 36278 | ethyl (Z,4R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-fluoro-2-pentenoate | C19H39FO4Si2 | 详情 | 详情 | |
(IX) | 36283 | N-(5-fluoro-2-oxo-1,2-dihydro-4-pyrimidinyl)benzamide | C11H8FN3O2 | 详情 | 详情 | |
(XI) | 36286 | N-[5-fluoro-1-[(2S,5R)-3-fluoro-5-(hydroxymethyl)-2,5-dihydro-2-furanyl]-2-oxo-1,2-dihydro-4-pyrimidinyl]benzamide | C16H13F2N3O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(VII)Coupling of ethyl phenylsulfinylfluoro acetate (I) with bromo derivative (II) by means of NaH in DMF yields ethyl hexenoate (III), which is then oxidized by means of Jones reagent in acetone to provide 5-carboxy pentenoate derivative (IV). Alternatively, compound (IV) can be obtained as follows: eduction of gamma-butyrolactone (V) in THF with aluminum diisobutylhydride in toluene affords gamma-butyrolactol (VI), which is treated with ethyl (diethoxyphosphoryl)fluoroacetate (VII) and sodium bis(trimethylsilyl)amide in THF to provide an isomeric mixture of hexenoates (VIII). O-Protection of (VIII) by means of tert-butyldiphenylchlorosilane and imidazole in DMF followed by chromatographic separation of the geometrical isomers furnishes hexenoate (Z)-(IX), which is finally oxidized with Jones reagent in acetone. Conversion of carboxylic acid (IV) into bicycle (±)-(X) is then performed by first reaction with oxalyl chloride in refluxing hexane to form the corresponding acid chloride, followed by treatment with diazomethane in ether and subsequent reaction with cooper(II) bis(N-tert-butylsalicylaldiimidate) in refluxing benzene. Treatment of oxobicycle (±)-(X) with LiHMDS and chlorotrimethylsilane in THF followed by reaction with palladium acetate in acetonitrile gives 6-fluoro-2-oxobicyclo[3.1.0]hex-3-en-6-carboxylate (±)-(XI), from which epoxide (±)-(XII) is obtained by reaction in toluene with tert-butyl hydroxyperoxide (TBHP) and benzyltrimethylammoniumhydroxide (Triton B) in MeOH or EtOH. Epoxide reduction of (±)-(XII) using diphenyl diselenide (PhSe)2 and sodium borohydride in the presence of HOAc in EtOH, or by means of (PhSe)2, N-acetyl-L-cysteine and sodium tetraborate decahydrate in H2O:EtOH, yields hydroxy derivative (±)-(XIII), which is converted into ethylenedithio derivative (±)-(XV) by first protection of the hydroxyl group with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole, followed by thioketalization with 1,2-ethanedithiol (XIV) and boron trifluoride-diethylether complex in CHCl3 (with subsequent TBS group removal during work-up). Oxidation of the hydroxyl group of (±)-(XV) with DMSO and dicyclohexylcarbodiimide (DCC) in the presence of pyridine and TFA gives ketone (±)-(XVI), which is then hydrolyzed with NaOH in EtOH and subjected to reaction with KCN and ammonium carbonate (Bucherer-Bergs conditions) to yield hydantoin (±)-(XVII). Coupling of (±)-(XVII) with (R)-(+)-1-phenylethylamine using EDC-HCl and HOBt followed by chromatographic separation of the two resulting diastereomers furnishes (1R,2S,5R,6S)-(XIX), which is finally converted into the desired product after hydrolysis with H2SO4.
【4】 Kumagai, T.; Sakagami, K.; Nakazato, A.; Tomisawa, K. (Taisho Pharmaceutical Co., Ltd.); 6-Fluorobicyclo[3.1.0]hexane derivs.. EP 1110943; JP 2000336071; WO 0012464 . |
【1】 Nakazato, A.; et al.; Synthesis, SAR, and biological activities of potent and selective group II mGluR agonists, novel 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 104. |
【2】 Nakazato, A.; et al.; Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylix acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J Med Chem 2000, 43, 25, 4893. |
【3】 Yoshikawa, R.; Kumagai, T.; Suzuki, Y.; Nakazato, A.; Sakagami, K.; Chaki, S.; Okuyama, S.; Synthesis SAR and biological activities of potent and selective group II metabotropic glutamate receptor antagonists, novel 2-amino-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-104. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(rac)-(XIV) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
(rac)-(X) | 49005 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO3 | 详情 | 详情 | |
(rac)-(XI) | 49006 | ethyl (rac)-(1S*,5S*,6S*)-6-fluoro-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate | C9H9FO3 | 详情 | 详情 | |
(rac)-(XII) | 49007 | ethyl (rac)-(1R*,2S*,4S*,6S*,7S*)-7-fluoro-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate | C9H9FO4 | 详情 | 详情 | |
(rac)-(XIII) | 49008 | ethyl (rac)-(1R*,2R*,5S*,6S*)-6-fluoro-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H11FO4 | 详情 | 详情 | |
(rac)-(XV) | 49009 | C11H15FO3S2 | 详情 | 详情 | ||
(rac)-(XVI) | 49010 | C11H13FO3S2 | 详情 | 详情 | ||
(rac)-(XVII) | 49011 | C11H11FN2O4S2 | 详情 | 详情 | ||
(VIIIa) | 49014 | ethyl (Z)-2-fluoro-6-hydroxy-2-hexenoate | C8H13FO3 | 详情 | 详情 | |
(VIIIIb) | 49015 | ethyl (E)-2-fluoro-6-hydroxy-2-hexenoate | C8H13FO3 | 详情 | 详情 | |
(I) | 49002 | ethyl 2-fluoro-2-(phenylsulfinyl)acetate | C10H11FO3S | 详情 | 详情 | |
(II) | 29460 | 2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether | C9H17BrO2 | 详情 | 详情 | |
(III) | 49003 | ethyl (Z)-2-fluoro-6-(tetrahydro-2H-pyran-2-yloxy)-2-hexenoate | C13H21FO4 | 详情 | 详情 | |
(IV) | 49004 | (Z)-6-ethoxy-5-fluoro-6-oxo-4-hexenoic acid | C8H11FO4 | 详情 | 详情 | |
(V) | 20576 | dihydro-2(3H)-furanone | 96-48-0 | C4H6O2 | 详情 | 详情 |
(VI) | 49013 | tetrahydro-2-furanol | C4H8O2 | 详情 | 详情 | |
(VII) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
(IX) | 49016 | ethyl (Z)-6-[[tert-butyl(diphenyl)silyl]oxy]-2-fluoro-2-hexenoate | C24H31FO3Si | 详情 | 详情 | |
(XVIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
(XIX) | 49012 | C19H20FN3O3S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(II)Horner-Emmons condensation of 2,3-isopropylidene-D-glyceraldehyde (I) with phosphonate (II) produced the unsaturated ester (IIIa-b). Ketal deprotection and lactone ring closure of (II) under acidic conditions, followed by O-silylation afforded (IV). The lactone function of (IV) was reduced with DIBAL and then with NaBH4-CeCl3 to produce the corresponding diol. Further silylation of the primary hydroxyl group furnished (V). Condensation of (V) with triethyl orthoacetate followed by Claisen rearrangement gave rise to the gamma,delta-unsaturated ester (VI). This was reduced to alcohol with LiAlH4 and then alkylated with benzyl bromide to yield benzyl ether (VII). Ozonization of (VII) in methanol at -78 C, followed by decomposition of the ozonide with dimethyl sulfide gave aldehyde (VIII). Horner-Emmons condensation of (VIII) with the sodium salt of triethyl phosphonoacetate (IX) produced the alpha,beta-unsaturated ester (X). Double bond hydrogenation in (X) with simultaneous benzyl group cleavage afforded hydroxy ester (XI), which was then converted to mesylate (XII). This was cyclized to the cyclopentane (XIIIa-b) by means of NaH in refluxing THF.
【1】 Hong, J.H.; et al.; Enantiomeric synthesis of 3'-fluoro-apionucleosides using claisen rearrangement. Tetrahedron Lett 1998, 39, 21, 3443. |
【2】 Gumina, G.; et al.; Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine. Org Lett 2000, 2, 9, 1229. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
(XIIIa) | 36757 | ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
(XIIIb) | 36758 | ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
(IIIa) | 36760 | ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate | C10H15FO4 | 详情 | 详情 | |
(IIIb) | 36761 | ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate | C10H15FO4 | 详情 | 详情 | |
(I) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
(II) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
(IV) | 36762 | (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2(5H)-furanone | C11H19FO3Si | 详情 | 详情 | |
(V) | 36750 | (6S,7E)-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-7-tridecen-6-ol | C17H37FO3Si2 | 详情 | 详情 | |
(VI) | 36751 | ethyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenoate | C21H43FO4Si2 | 详情 | 详情 | |
(VII) | 36752 | benzyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenyl ether; (E,8S)-8-[2-(benzyloxy)ethyl]-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-6-tridecene | C26H47FO3Si2 | 详情 | 详情 | |
(VIII) | 36753 | (2R)-4-(benzyloxy)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-fluorobutanal | C18H29FO3Si | 详情 | 详情 | |
(IX) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(X) | 36754 | ethyl (E,4S)-6-(benzyloxy)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-2-hexenoate | C22H35FO4Si | 详情 | 详情 | |
(XI) | 36755 | ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-hydroxyhexanoate | C15H31FO4Si | 详情 | 详情 | |
(XII) | 36756 | ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-[(methylsulfonyl)oxy]hexanoate | C16H33FO6SSi | 详情 | 详情 |