合成路线1
该中间体在本合成路线中的序号:
(XII) Reaction of thiophene-2-carboxylic acid (VIII) with oxalyl chloride and PPh3 gives the corresponding acyl chloride (IX), which is condensed with vinyltributylstannane, yielding 1-(2-thienyl)-2-propen-1-one (X). The addition of HCl to the double bond of (X) affords 3-chloro-1-(2-thienyl)-1-propanone (XI), which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XII) in THF to give (S)-3-chloro-1-(2-thienyl)-1-propanol (XIII) (4). Treatment of (XIII) with NaI in acetone affords the (S)-3-iodopropanol derivative (XIV), which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-1-propanol (XV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.
The Friedel-Crafts condensation of thiophene (XVI) with 3-chloropropionyl chloride (XVII) by means of SnCl4 in benzene gives the previously reported 3-chloro-1-(2-thienyl)-1-propanone (XI), which is reduced with NaBH4 in ethanol to yield the racemic alcohol (XVIII). Optical resolution of (XVIII) performed by means of immobilized CALB (Novozyme 435, Novo-Nordisk A/S) affords the previously reported (S)-alcohol (XIII).
【1】
Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907.
|
【2】
Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213.
|
【3】
Hoff, B.H.; Liu, H.; Anthonsen, T.; Chemo-enzymatic synthesis of the antidepressant duloxetine and its enantiomer. Chirality 2000, 12, 1, 26.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(V) |
40503 |
1-fluoronaphthalene
|
321-38-0 |
C10H7F |
详情 | 详情
|
(VIII) |
40505 |
2-thiophenecarboxylic acid
|
527-72-0 |
C5H4O2S |
详情 | 详情
|
(IX) |
14103 |
2-Thiophenecarbonyl chloride
|
5271-67-0 |
C5H3ClOS |
详情 | 详情
|
(X) |
40506 |
1-(2-thienyl)-2-propen-1-one
|
|
C7H6OS |
详情 |
详情
|
(XI) |
40507 |
3-chloro-1-(2-thienyl)-1-propanone
|
|
C7H7ClOS |
详情 |
详情
|
(XII) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(XIII) |
40509 |
(1S)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(XIV) |
40510 |
(1S)-3-iodo-1-(2-thienyl)-1-propanol
|
|
C7H9IOS |
详情 |
详情
|
(XV) |
40511 |
(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
|
116539-55-0 |
C8H13NOS |
详情 | 详情
|
(XVI) |
13297 |
Thiophene
|
110-02-1 |
C4H4S |
详情 | 详情
|
(XVII) |
18936 |
3-chloropropanoyl chloride
|
625-36-5 |
C3H4Cl2O |
详情 | 详情
|
(XVIII) |
40508 |
3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(XI) The reaction of thiophene-2-[14C]carboxylic acid (VII) with oxalyl chloride and PPh3 gives the corresponding labeled acyl chloride (VIII), which is condensed with vinyltributylstannane, yielding 1-(2-thienyl)-[1-14C]prop-2-en-1-one (IX). The addition of HCl to the double bond of (IX) affords 3-chloro-1-(2-thienyl)-[1-14C]propan-1-one (X), which is reduced with BH3 and the chiral (R)-oxazaborolidine catalyst (XI) in THF to give (S)-3-chloro-1-(2-thienyl)-[1-14C]propan-1-ol (XII). Treatment of (XII) with NaI in acetone affords the labeled (S)-3-iodopropanol derivative (XIII), which is condensed with methylamine in THF to provide (S)-3-(methylamino)-1-(2-thienyl)-[1-14C]propan-1-ol (XIV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA.
【1】
Sorbera, L.A.; Castaner, R.M.; Castaner, J.; Duloxetine oxalate. Drugs Fut 2000, 25, 9, 907.
|
【2】
Wheeler, W.J.; Kuo, F.; An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers. J Label Compd Radiopharm 1995, 36, 3, 213.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(V) |
40503 |
1-fluoronaphthalene
|
321-38-0 |
C10H7F |
详情 | 详情
|
(VII) |
40505 |
2-thiophenecarboxylic acid
|
527-72-0 |
C5H4O2S |
详情 | 详情
|
(VII) |
45145 |
2-thiophenecarboxylic acid
|
|
C5H4O2S |
详情 |
详情
|
(VIII) |
14103 |
2-Thiophenecarbonyl chloride
|
5271-67-0 |
C5H3ClOS |
详情 | 详情
|
(VIII) |
45146 |
2-thiophenecarbonyl chloride
|
|
C5H3ClOS |
详情 |
详情
|
(IX) |
40506 |
1-(2-thienyl)-2-propen-1-one
|
|
C7H6OS |
详情 |
详情
|
(IX) |
45147 |
1-(2-thienyl)-2-propen-1-one
|
|
C7H6OS |
详情 |
详情
|
(X) |
40507 |
3-chloro-1-(2-thienyl)-1-propanone
|
|
C7H7ClOS |
详情 |
详情
|
(X) |
45148 |
3-chloro-1-(2-thienyl)-1-propanone
|
|
C7H7ClOS |
详情 |
详情
|
(XI) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(XII) |
40509 |
(1S)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(XII) |
45149 |
(1S)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(XIII) |
40510 |
(1S)-3-iodo-1-(2-thienyl)-1-propanol
|
|
C7H9IOS |
详情 |
详情
|
(XIII) |
45150 |
(1S)-3-iodo-1-(2-thienyl)-1-propanol
|
|
C7H9IOS |
详情 |
详情
|
(XIV) |
40511 |
(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
|
116539-55-0 |
C8H13NOS |
详情 | 详情
|
(XIV) |
45151 |
(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
|
|
C8H13NOS |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(II) The enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (R)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (II) in THF gives 3-chloro-1-(2-thienyl)propan-1(S)-ol (III), which is treated with methylamine and NaI in acetone/THF to yield (S)-N-methyl-N-[3-(2-thienyl)propyl]amine (IV). Finally, this compound is condensed with 1-fluoronaphthalene (V) by means of NaH in DMA to provide duloxetine.
Alternatively, the enantioselective reduction of 3-chloro-1-(2-thienyl)-1-propanone (I) by means of BH3 catalyzed by (S)-1-methyl-3,3-diphenyltetrahydropyrrolo[1,2-c][1,3,2]oxazaborole (VI) in THF gives 3-chloro-1-(2-thienyl)propan-1(R)-ol (VII), which is condensed with 1-naphthol (VIII) by means of DEAD and PPh3 to yield the expected aryl ether (IX), with inversion of the configuration. Finally, this compound is treated with methylamine and NaI in acetone/THF to provide duloxetine.
【1】
Bymaster, F.P.; Beedle, E.E.; Findlay, J.; Gallagher, P.T.; Krushinski J.H.; Mitchell, S.; Robertson, D.W.; Thompson, D.C.; Wallace, L.; Wong, D.T.; Duloxetine (Cymbalta(TM)), a dual inhibitor of serotonin and norepinephrine reuptake. Bioorg Med Chem Lett 2003, 13, 24, 4477. |
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) |
40507 |
3-chloro-1-(2-thienyl)-1-propanone
|
|
C7H7ClOS |
详情 |
详情
|
(II) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(III) |
40509 |
(1S)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(IV) |
40511 |
(1S)-3-(methylamino)-1-(2-thienyl)-1-propanol
|
116539-55-0 |
C8H13NOS |
详情 | 详情
|
(V) |
40503 |
1-fluoronaphthalene
|
321-38-0 |
C10H7F |
详情 | 详情
|
(VI) |
28292 |
(S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-81-8 |
C18H20BNO |
详情 | 详情
|
(VII) |
40512 |
(1R)-3-chloro-1-(2-thienyl)-1-propanol
|
|
C7H9ClOS |
详情 |
详情
|
(VIII) |
22935 |
alpha-naphthol; 1-naphthol
|
90-15-3 |
C10H8O |
详情 | 详情
|
(IX) |
40513 |
(1S)-3-chloro-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1S)-3-chloro-1-(1-naphthyloxy)propyl]thiophene
|
|
C17H15ClOS |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
Asymmetric reduction of ketone (III) with catecholborane or boranemethyl sulfide complex and CBS-oxazaborolidene as catalyst afforded [(R)-(+)-I] or [(S)-()-I].
【1】
Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721. |
【2】
Frigola-Constansa, J.; Torrens-Jover, A. (Laboratorios del Dr. Esteve, SA); Process for obtaining enantiomers of cizolirtine. EP 1029852; ES 2130083; US 6118009; WO 9907684 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(R)-(+)-(I) |
54587 |
(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol
|
|
C11H12N2O |
详情 |
详情
|
(III) |
54590 |
(1-methyl-1H-pyrazol-5-yl)(phenyl)methanone
|
|
C11H10N2O |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(III) The intermediate chiral epoxide (V) has been obtained as follows:
The bromination of 5-acetyl-2-benzyloxybenzoic acid methyl ester (I) with Br2 in chloroform gives the bromoacetyl derivative (II), which is submitted to a enantioselective reduction by means of BH3/THF catalyzed by the chiral oxazaborolidine (III) to yield the (R)-enantiomer (IV). Finally, this compound is cyclized by means of NaH in THF to afford the target (R)-epoxide (
【1】
Hett, R.; et al.; Enantioselective synthesis of salmeterol via asymmetric borane reduction. Tetrahedron Lett 1994, 35, 50, 9375.
|
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) |
62583 |
methyl 5-acetyl-2-(benzyloxy)benzoate
|
|
C17H16O4 |
详情 |
详情
|
(II) |
52356 |
methyl 5-(2-bromoacetyl)-2-[(phenylmethyl)oxy]benzoate
|
|
C17H15BrO4 |
详情 |
详情
|
(III) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(IV) |
62584 |
methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate
|
|
C17H17BrO4 |
详情 |
详情
|
(V) |
62585 |
methyl 2-(benzyloxy)-5-[(2R)oxiranyl]benzoate
|
|
C17H16O4 |
详情 |
详情
|
合成路线6
该中间体在本合成路线中的序号:
(VI) The activation of 5-(4-fluorophenyl)-5-oxopentanoic acid (I) with pivaloyl chloride (II) gives the mixed anhydride (III), which is condensed with the chiral oxazolidinone (IV) by means of DMAP to yield the acylated oxazolidine (V) (1). The asymmetric reduction of (V) by means of BH3/Me2S catalyzed by the chiral boron catalyst (VI) affords the chiral alcohol (VII) (1-3), which is condensed with the imine (VIII) by means of Tms-Cl, DIEA and TiCl4 to provide the adduct (IX). The cyclization of (IX) by means of bis(trimethylsilyl)acetamide and TBAF gives the protected azetidinone (X), which is finally desilylated by means of sulfuric acid in isopropanol
【1】
Fu, X.Y.; et al.; Process for preparing ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction. Tetrahedron Lett 2003, 44, 4, 801.
|
【2】
Thiruvengadam, T.K.; Tann, C.-H.; Fu, X.; McAllister, T.L. (Schering Corp.); Enantioselective synthesis of azetidinone intermediate cpds.. US 2002193607; WO 0279174 .
|
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) |
62208 |
4-(4-Fluorobenzoyl)butyric acid; 4-(4-fluorobenzoyl) butyric acid; 4-(4'-Fluorobenzoyl)butyric acid; 4-(p-Fluorobenzoyl) butyric acid; 5-(4'-Fluorophenyl)-5-oxopentanoic acid
|
149437-76-3 |
C11H11FO3 |
详情 | 详情
|
(II) |
13597 |
2,2-Dimethylpropanoyl chloride; Pivaloyl chloride
|
3282-30-2 |
C5H9ClO |
详情 | 详情
|
(III) |
62209 |
1,1-dimethylpropanoic 4-(4-fluorophenyl)-4-oxopentanoic anhydride
|
|
C16H19FO4 |
详情 |
详情
|
(IV) |
12173 |
(4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone
|
99395-88-7 |
C9H9NO2 |
详情 | 详情
|
(V) |
53476 |
1-(4-fluorophenyl)-5-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,5-pentanedione
|
n/a |
C20H18FNO4 |
详情 | 详情
|
(VI) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(VII) |
53477 |
(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one
|
n/a |
C20H20FNO4 |
详情 | 详情
|
(VIII) |
62210 |
4-fluoro-N-((Z)-{4-[(trimethylsilyl)oxy]phenyl}methylidene)aniline; N-(4-fluorophenyl)-N-((Z)-{4-[(trimethylsilyl)oxy]phenyl}methylidene)amine
|
|
C16H18FNOSi |
详情 |
详情
|
(IX) |
62211 |
(4S)-3-{(2R,5S)-2-((S)-(4-fluoroanilino){4-[(trimethylsilyl)oxy]phenyl}methyl)-5-(4-fluorophenyl)-5-[(trimethylsilyl)oxy]pentanoyl}-4-phenyl-1,3-oxazolidin-2-one
|
|
C39H46F2N2O5Si2 |
详情 |
详情
|
(X) |
62212 |
(3R,4S)-1-(4-fluorophenyl)-3-{(3S)-3-(4-fluorophenyl)-3-[(trimethylsilyl)oxy]propyl}-4-{4-[(trimethylsilyl)oxy]phenyl}-2-azetidinone
|
|
C30H37F2NO3Si2 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(XIV) The required (S)-alpha-propylpiperonyl alcohol (XV) was prepared by two alternative routes. Asymmetric addition of di-n-propyl zinc to piperonal (X) in the presence of titanium isopropoxide and the chiral bis-triflamide (XI) yielded the (S)-alcohol (XV) in high enantiomeric excess. Alternatively, ketone (XIII) was reduced with the oxazaborolidine-borane complex (XIV) to give (XV). Treatment of the (S)-alcohol (XV) with DPPA in the presence of DBU produced the (R)-azide (XVI). This was then reduced with LiAlH4 to yield amine (XVII) with some loss of optical purity. Optical enrichment was achieved by crystallization as the D-pyroglutamic acid salt. The (R)-amine (XVII) was converted to isocyanate (XVIII) by treatment with phosgene. Finally, coupling between isocyanate (XVIII) and azetidinone (IX) in the presence of DBU in acetonitrile led to the title compound.
【1】
Cvetovich, R.J.; et al.; An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of beta-lactam esters. J Org Chem 1996, 61, 19, 6575.
|
【2】
Amato, J.S.; Cvetovich, R.; Hartner, F.W. (Merck & Co., Inc.); Process for preparing substd. azetidinones. WO 9716448 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IX) |
53626 |
(4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone
|
n/a |
C19H27N3O3 |
详情 | 详情
|
(X) |
10127 |
1,3-Benzodioxole-5-carbaldehyde; Heliotropine
|
120-57-0 |
C8H6O3 |
详情 | 详情
|
(XI) |
53627 |
trifluoro-N-((1R,2R)-2-{[(trifluoromethyl)sulfonyl]amino}cyclohexyl)methanesulfonamide
|
n/a |
C8H12F6N2O4S2 |
详情 | 详情
|
(XIII) |
53629 |
1-(1,3-benzodioxol-5-yl)-1-butanone
|
63740-97-6 |
C11H12O3 |
详情 | 详情
|
(XIV) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(XV) |
53628 |
(1S)-1-(1,3-benzodioxol-5-yl)-1-butanol
|
n/a |
C11H14O3 |
详情 | 详情
|
(XVI) |
53630 |
(1R)-1-(1,3-benzodioxol-5-yl)butyl azide; 5-[(1R)-1-azidobutyl]-1,3-benzodioxole
|
n/a |
C11H13N3O2 |
详情 | 详情
|
(XVII) |
53631 |
(1R)-1-(1,3-benzodioxol-5-yl)-1-butanamine; (1R)-1-(1,3-benzodioxol-5-yl)butylamine
|
n/a |
C11H15NO2 |
详情 | 详情
|
(XVIII) |
53632 |
5-[(1R)-1-isocyanatobutyl]-1,3-benzodioxole; (1R)-1-(1,3-benzodioxol-5-yl)butyl isocyanate
|
n/a |
C12H13NO3 |
详情 | 详情
|
合成路线8
该中间体在本合成路线中的序号:
(VII) Nitration of 4-hydroxyacetophenone with KNO3 in cold H2SO4 gave the 3-nitro derivative (II), which was protected as the benzyl ether (III) with benzyl bromide in DMF. Hydrogenation of the nitro group of (III) over PtO2 afforded aniline (IV), and further treatment of (IV) with methanesulfonyl chloride in pyridine provided sulfonamide (V). Subsequent alpha-bromination of the acetophenone (V) was achieved using CuBr2 in a refluxing mixture of EtOAc and CHCl3. Asymmetric reduction of the ketone with borane in the presence of the chiral oxazaborolidine (VII), (prepared in situ from (R)-a,a-diphenyl-2-pyrrolidinemethanol (VIII) and trimethylboroxine (IX) in boiling toluene), provided the (R)-alcohol (X). The bromo group of (X) was then substituted for a iodo group upon treatment with NaI in acetone, and the resulting (IX) was protected as the triethylsilyl ether (XII) with Et3SiCl in the presence of imidazole and dimethylaminopyridine. Reaction of 4,4'-dihydroxybenzophenone (XIII) with chlorodifluoromethane and t-BuOK yielded the bis(difluoromethyl) ether (XIV). The benzhydryl amine (XV) was then obtained by reductive amination with ammonium formate at 160 C, followed by acid hydrolysis of the intermediate formamide. Condensation of iodide (XII) with benzhydryl amine (XV) in the presence of diisopropyl ethylamine in THF at 110 C in a sealed flask provided the secondary amine (XVI). Finally, the target compound was obtained by desilylation with tetrabutylammonium fluoride, followed by hydrogenolysis of the benzyl protecting group.
【1】
Washburn, W.N.; Girotra, R.N.; Sher, P.M.; Mikkilineni, A.B.; Poss, K.M.; Mathur, A.; Gavai, A.; Bisacchi, G.S. (Bristol-Myers Squibb Co.); Catecholamine surrogates useful as B3 agonists. CA 2138675; EP 0659737; JP 1995206806; US 5776983 .
|
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) |
18123 |
1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone
|
99-93-4 |
C8H8O2 |
详情 | 详情
|
(II) |
20626 |
1-(4-hydroxy-3-nitrophenyl)-1-ethanone
|
6322-56-1 |
C8H7NO4 |
详情 | 详情
|
(III) |
20627 |
1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanone
|
|
C15H13NO4 |
详情 |
详情
|
(IV) |
20628 |
1-[3-amino-4-(benzyloxy)phenyl]-1-ethanone
|
|
C15H15NO2 |
详情 |
详情
|
(V) |
20629 |
N-[5-acetyl-2-(benzyloxy)phenyl]methanesulfonamide
|
|
C16H17NO4S |
详情 |
详情
|
(VI) |
20630 |
N-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]methanesulfonamide
|
|
C16H16BrNO4S |
详情 |
详情
|
(VII) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(VIII) |
20632 |
diphenyl[(2R)pyrrolidinyl]methanol
|
|
C17H19NO |
详情 |
详情
|
(IX) |
20633 |
2,4,6-trimethylboroxin
|
823-96-1 |
C3H9B3O3 |
详情 | 详情
|
(X) |
20634 |
N-[2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl]methanesulfonamide
|
|
C16H18BrNO4S |
详情 |
详情
|
(XI) |
20635 |
N-[2-(benzyloxy)-5-[(1R)-1-hydroxy-2-iodoethyl]phenyl]methanesulfonamide
|
|
C16H18INO4S |
详情 |
详情
|
(XII) |
20636 |
N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide
|
|
C22H32INO4SSi |
详情 |
详情
|
(XIII) |
20637 |
bis(4-hydroxyphenyl)methanone
|
611-99-4 |
C13H10O3 |
详情 | 详情
|
(XIV) |
20638 |
bis[4-(difluoromethoxy)phenyl]methanone
|
|
C15H10F4O3 |
详情 |
详情
|
(XV) |
20639 |
bis[4-(difluoromethoxy)phenyl]methylamine; bis[4-(difluoromethoxy)phenyl]methanamine
|
|
C15H13F4NO2 |
详情 |
详情
|
(XVI) |
20640 |
N-(2-(benzyloxy)-5-[(1R)-2-([bis[4-(difluoromethoxy)phenyl]methyl]amino)-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide
|
|
C37H44F4N2O6SSi |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(VIII)
【1】
Wu GZ. Chen X,Wong YS et al.1999.3-hydroxy gamma-lactone based enaptiolelective synthesis of azetidinones. US 5886171 |
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) |
20651 |
N-[(E)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(E)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine
|
|
C20H16FNO |
详情 |
详情
|
(II) |
37681 |
(4S)-4-hydroxydihydro-2(3H)-furanone; (S)-3-Hydroxy-gamma-butyrolactone
|
7331-52-4 |
C4H6O3 |
详情 | 详情
|
(III) |
20653 |
3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl]propionic acid
|
|
C25H22FNO4 |
详情 |
详情
|
(IV) |
37683 |
(2S,3S)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxo-3-azetidinecarbaldehyde
|
|
C23H18FNO3 |
详情 |
详情
|
(V) |
37685 |
[[1-(4-fluorophenyl)vinyl]oxy](trimethyl)silane; 1-(4-fluorophenyl)vinyl trimethylsilyl ether
|
|
C11H15FOSi |
详情 |
详情
|
(VI) |
20656 |
(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone
|
|
C31H25F2NO3 |
详情 |
详情
|
(VII) |
37688 |
(3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-2-azetidinone
|
|
C24H19F2NO3 |
详情 |
详情
|
(VIII) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
合成路线10
该中间体在本合成路线中的序号:
(III)
【1】
Wu GZ, Chen X,Wong YS et a1.1999. 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones. US 5886171 |
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) |
20656 |
(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone
|
|
C31H25F2NO3 |
详情 |
详情
|
(II) |
20656 |
(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-2-azetidinone
|
|
C31H25F2NO3 |
详情 |
详情
|
(III) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|
(IV) |
20657 |
(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone
|
|
C31H27F2NO3 |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
(IX)
【1】
Rosenblum SB, Dugar S,Bumett DA et al.1995. Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents.W0 9508532(本专利属于Schering Corporation. USA) |
【2】
Shankar BB. 1999. Process for preparing l-(4-fluorophenyD-3(R),[3(S)-hydroxy-3-[(phenylor 4-flu-orophenyl)]-propyll-4 (S) -(4-hydroxyphenyD-2-azetidinone US 5856473(本专利属于Scherirra: Corporation, USA) |
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) |
37692 |
(E)-5-(4-fluorophenyl)-4-pentenoic acid
|
190595-67-6 |
C11H11FO2 |
详情 | 详情
|
(II) |
37693 |
(E)-5-(4-fluorophenyl)-4-pentenoyl chloride
|
|
C11H10ClFO |
详情 |
详情
|
(III) |
12173 |
(4S)-4-Phenyl-1,3-oxazolan-2-one; (4S)-4-Phenyl-2-oxazolidinone; (S)-(+)-4-Phenyl-2-oxazolidinone
|
99395-88-7 |
C9H9NO2 |
详情 | 详情
|
(IV) |
37694 |
(4S)-3-[(E)-5-(4-fluorophenyl)-4-pentenoyl]-4-phenyl-1,3-oxazolidin-2-one
|
|
C20H18FNO3 |
详情 |
详情
|
(V) |
37689 |
N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-4-fluoroaniline; N-[(Z)-[4-(benzyloxy)phenyl]methylidene]-N-(4-fluorophenyl)amine
|
|
C20H16FNO |
详情 |
详情
|
(VI) |
37695 |
(4S)-3-[(2R,4E)-2-[(S)-[4-(benzyloxy)phenyl](4-fluoroanilino)methyl]-5-(4-fluorophenyl)-4-pentenoyl]-4-phenyl-1,3-oxazolidin-2-one
|
|
C40H34F2N2O4 |
详情 |
详情
|
(VII) |
37696 |
(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(E)-3-(4-fluorophenyl)-2-propenyl]-2-azetidinone
|
|
C31H25F2NO2 |
详情 |
详情
|
(VIII) |
37688 |
(3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-2-azetidinone
|
|
C24H19F2NO3 |
详情 |
详情
|
(IX) |
20631 |
(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole
|
112022-83-0 |
C18H20BNO |
详情 | 详情
|