合成路线1
该中间体在本合成路线中的序号:
(II) The reaction of 2-iodo-5-methylbenzoic acid (I) with 4-hydroxyacetophenone (II) by means of K2CO3 in nitrobenzene at 150 C gives 2-(4-acetylphenoxy)-5-methylbenzoic acid (III), which by reduction with LiAlH4 in refluxing THF is converted into 2-[4-(1-hydroxyethyl)phenoxy]-5-methylbenzyl alcohol (IV). The reaction of (IV) with SOCl2 in refluxing CHCl3 affords 2-[4-(1-chloroethyl)phenoxy]-5-methylbenzyl chloride (V), which is treated with NaCN in refluxing dioxane ethanol-water yielding the dinitrile (VI). The hydrolysis of (VI) with KOH in refluxing ethanol-water gives 2-[4-[2-(carboxymethyl)-4-methylphenoxy]phenyl]propionic acid (VII), which is finally cyclized by treatment with polyphosphoric acid (PPA) at 120 C.
【1】
Uno, H.; Nagai, Y.; Nakamura, H.; Dibenz[b,f]oxepin and dibenzo[b,f]thiepin derivatives, process for preparation thereof, method of using the same, and compositions thereof. EP 0003893; ES 477791; JP 1393170C; JP 54122284; US 4238620 .
|
【2】
Serradell, M.N.; Arrigoni-Martelli, E.; Castaner, J.; AD-1590. Drugs Fut 1984, 9, 6, 399.
|
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) |
34151 |
2-iodo-5-methylbenzoic acid
|
52548-14-8 |
C8H7IO2 |
详情 | 详情
|
(II) |
18123 |
1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone
|
99-93-4 |
C8H8O2 |
详情 | 详情
|
(III) |
34152 |
2-(4-acetylphenoxy)-5-methylbenzoic acid
|
|
C16H14O4 |
详情 |
详情
|
(IV) |
34153 |
1-[4-[2-(hydroxymethyl)-4-methylphenoxy]phenyl]-1-ethanol
|
|
C16H18O3 |
详情 |
详情
|
(V) |
34154 |
1-[4-(1-chloroethyl)phenoxy]-2-(chloromethyl)-4-methylbenzene; 4-(1-chloroethyl)phenyl 2-(chloromethyl)-4-methylphenyl ether
|
|
C16H16Cl2O |
详情 |
详情
|
(VI) |
34155 |
2-[4-[4-methyl-2-(2-nitriloethyl)phenoxy]phenyl]propanenitrile
|
|
C18H16N2O |
详情 |
详情
|
(VII) |
34156 |
2-[4-[2-(2-hydroxy-2-oxoethyl)-4-methylphenoxy]phenyl]propionic acid
|
|
C18H18O5 |
详情 |
详情
|
合成路线2
该中间体在本合成路线中的序号:
(V) The chloromethylation of 4-hydroxyacetophenone (V) with formaldehyde and HCl in hot water gives 3-chloromethyl-4-hydroxyacetophenone (VI), which is treated with acetic anhydride-sodium acetate in refluxing acetic acid to afford 3-acetoxymethyl-4-acetoxyacetophenone (VII). The bromination of (VII) with Br2 in chloroform yields after hydrolysis 3-hydroxymethyl-4-hydroxyphenacyl bromide (VIII), which is condensed with benzyl tert-butylamine (II) in refluxing benzene giving alpha-(N-benzyl-N-tert-butylamino)-4-hydroxy-3-hydroxymethylacetophenone (IX). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol.
An alternative method of hydrogenation of (IX) is its reduction with NaBH4 - ethanol, to afford the previously obtained product (IV), which is reduced with H2 over Pd/C in ethanol.
【1】
Lunts, L.H.C.; et al.; GB 1200886 .
|
【2】
Castaner, J.; Blancafort, P.; Serradell, M.N.; Hopkins, S.J.; Albuterol. Drugs Fut 1979, 4, 9, 629.
|
【3】
Collin, D.T.; et al.; Saligenin analogs of sympathomimetic catecholamines. J Med Chem 1970, 13, 4, 674-680.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
24700 |
N-benzyl-2-methyl-2-propanamine
|
3378-72-1 |
C11H17N |
详情 | 详情
|
(IV) |
39614 |
4-[2-[benzyl(tert-butyl)amino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol
|
|
C20H27NO3 |
详情 |
详情
|
(V) |
18123 |
1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone
|
99-93-4 |
C8H8O2 |
详情 | 详情
|
(VI) |
39615 |
1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone
|
|
C9H9ClO2 |
详情 |
详情
|
(VII) |
39616 |
5-acetyl-2-(acetoxy)benzyl acetate
|
|
C13H14O5 |
详情 |
详情
|
(VIII) |
39617 |
2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-1-ethanone
|
|
C9H9BrO3 |
详情 |
详情
|
(IX) |
39618 |
2-[benzyl(tert-butyl)amino]-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-1-ethanone
|
|
C20H25NO3 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(I) The cyclization of 4-hydroxyacetophenone (I) with 3-chloro-3-methyl-1-butyne (II) gives 6-acetyl-2,2-dimethyl-2H-1-benzopyran (III), which is enantioselectively epoxidized by means of Mn+3 salen catalysts, yielding the chiral epoxide (IV). The cleavage of the epoxide ring of (IV) with ammonia in ethanol affords the (3R,4S)-trans-aminoalcohol (V). The acylation of (V) with 3-chloro-4-fluorobenzoyl chloride (VI) and triethylamine yields the (3R,4S)-trans-amide (VII). The cyclization of (VII) by means of diethylaminosulfur trifluoride (DAST) in dichloromethane affords the (3aS-cis)-oxazoline (VIII), which is finally treated with 5N H2SO4.
【1】
Chan, W.N.; et al.; Synthesis of novel trans-4-(substituted-benzamido)-3, 4-dihydro-2H-benzo[b]-pyran-3-ol derivatives as potential anticonvulsant agents with a distinctive binding profile. J Med Chem 1996, 39, 23, 4537.
|
【2】
Castañer, J.; Leeson, P.; Rabasseda, X.; Tonabersat. Drugs Fut 1999, 24, 10, 1078.
|
【3】
Chan, W.N.; Morgan, H.K.A.; Thompson, M.; Evans, J.M. (SmithKline Beecham plc); Benzopyrans and their use as therapeutic agents. EP 0764157; JP 1998501251; US 5760074; WO 9534545 .
|
【4】
Thompson, M.; Evans, J.M.; Upton, N.; Chan, W.N.; Vong, K.K.; Willette, R.N. (SmithKline Beecham plc); Bicyclic cpds. with pharmaceutical activity. EP 0673373; JP 1996505132; US 5908860; WO 9413656 .
|
【5】
Attrill, R.P.; Bell, D.; Miller, D. (SmithKline Beecham plc); Chiral catalysts and epoxidation reactions catalyzed thereby. WO 9403271 .
|
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) |
22416 |
3-chloro-3-methyl-1-butyne
|
1111-97-3 |
C5H7Cl |
详情 | 详情
|
(III) |
28706 |
1-(2,2-dimethyl-2H-chromen-6-yl)-1-ethanone
|
|
C13H14O2 |
详情 |
详情
|
(IV) |
28707 |
1-[(1aR,7bR)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-1-ethanone
|
|
C13H14O3 |
详情 |
详情
|
(V) |
28708 |
1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone
|
|
C13H17NO3 |
详情 |
详情
|
(VI) |
24370 |
3-chloro-4-fluorobenzoyl chloride
|
65055-17-6 |
C7H3Cl2FO |
详情 | 详情
|
(VII) |
28709 |
N-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-chloro-4-fluorobenzamide
|
|
C20H19ClFNO4 |
详情 |
详情
|
(VIII) |
28713 |
1-[(3aS,9bS)-2-(3-chloro-4-fluorophenyl)-4,4-dimethyl-3a,9b-dihydro-4H-chromeno[4,3-d][1,3]oxazol-8-yl]-1-ethanone
|
|
C20H17ClFNO3 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(I) The cyclization of 4-hydroxyacetophenone (I) with 3-chloro-3-methyl-1-butyne (II) gives 5-acetyl-2,2-dimethyl-2H-1-benzopyran (III), which is enantioselectively epoxidized catalyzed by chiral salen Mn(III) catalysts to yield the (3R,4R)-epoxide (IV). The reaction of (IV) with ammonia in ethanol affords the (3R,4S)-aminoalcohol (V), which is finally acylated with 4-fluorobenzoyl chloride (VI) and TEA in dichloromethane to provide the target amide.
Alternatively, the target amide can also be obtained by direct cleavage of the epoxide ring of (IV) with 4-fluorobenzamide (VII) by means of tBu-OK in tert-butanol.
【1】
Chan, W.N.; et al.; Synthesis of novel trans-4-(substituted-benzamido)-3, 4-dihydro-2H-benzo[b]-pyran-3-ol derivatives as potential anticonvulsant agents with a distinctive binding profile. J Med Chem 1996, 39, 23, 4537.
|
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) |
22416 |
3-chloro-3-methyl-1-butyne
|
1111-97-3 |
C5H7Cl |
详情 | 详情
|
(III) |
28706 |
1-(2,2-dimethyl-2H-chromen-6-yl)-1-ethanone
|
|
C13H14O2 |
详情 |
详情
|
(IV) |
28707 |
1-[(1aR,7bR)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-1-ethanone
|
|
C13H14O3 |
详情 |
详情
|
(V) |
28708 |
1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone
|
|
C13H17NO3 |
详情 |
详情
|
(VI) |
17263 |
4-fluorobenzoyl chloride
|
403-43-0 |
C7H4ClFO |
详情 | 详情
|
(VII) |
37090 |
4-fluorobenzamide
|
824-75-9 |
C7H6FNO |
详情 | 详情
|
合成路线5
该中间体在本合成路线中的序号:
(I) 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6
该中间体在本合成路线中的序号:
(I) 4-Hydroxyacetophenone (I) was nitrated with KNO3 in H2SO4 to give (II). Alkylation of the phenolic hydroxyl of (II) with benzyl bromide afforded benzyl ether (III). The nitro group of (III) was then reduced by catalytic hydrogenation to yield aniline (IV), which was converted to sulfonamide (V) upon treatment with mesyl chloride and pyridine. Bromination of (V) with CuBr2 produced the bromoacetophenone (VI), which by reduction with BH3-Me2S in the presence of the chiral auxiliary agent (VII) furnished the (R)-alcohol (VIII). After displacement of the bromo group of (VIII) with NaI, the resulting iodoalcohol (IX) was protected as the silyl ether (X) by treatment with triethyl chlorosilane and imidazole.
【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) |
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
|
(VIII) |
20634 |
N-[2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenyl]methanesulfonamide
|
|
C16H18BrNO4S |
详情 |
详情
|
(IX) |
20635 |
N-[2-(benzyloxy)-5-[(1R)-1-hydroxy-2-iodoethyl]phenyl]methanesulfonamide
|
|
C16H18INO4S |
详情 |
详情
|
(X) |
20636 |
N-(2-(benzyloxy)-5-[(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl]phenyl)methanesulfonamide
|
|
C22H32INO4SSi |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(II) Aldol condensation between 3,4-dichlorobenzaldehyde (I) and 4'-hydroxyacetophenone (II) in hydroalcoholic NaOH yielded chalcone (III). Then, Mannich reaction of (III) with N,N-dimethylmethyleneammonium chloride (IV) in refluxing acetonitrile provided the bis(dimethylamino) compound as the dihydrochloride.
【1】
Dimmock, J.R.; et al.; Cytotoxic activities of Mannich bases of chalcones and related compounds. J Med Chem 1998, 41, 7, 1014-1026.
|
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) |
18122 |
3,4-Dichlorobenzaldehyde
|
6287-38-3 |
C7H4Cl2O |
详情 | 详情
|
(II) |
18123 |
1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone
|
99-93-4 |
C8H8O2 |
详情 | 详情
|
(III) |
18124 |
(E)-3-(3,4-dichlorophenyl)-1-(4-hydroxyphenyl)-2-propen-1-one
|
|
C15H10Cl2O2 |
详情 |
详情
|
(IV) |
18125 |
dimethyl(methylene)-lambda(5)-azane
|
|
C3H9N |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(VI) Urocanic acid (I) was hydrogenated to imidazolepropionic acid (II) and then esterified with EtOH and H2SO4. The resulting imidazole ester (III) was protected as the N-trityl derivative (IV) and then reduced to alcohol (V) by means of LiAlH4 (1). Coupling of (V) with 4'-hydroxyacetophenone (VI) under Mitsunobu conditions furnished ether (VII). The trityl protecting group of (VII) was then cleaved by acidic treatment to give (VIII). Finally, condensation of (VIII) with hydroxylamine provided the target E-oxime.
【1】
Derrick, I.; et al.; 3-Deoxyclocinnamox: The first high-affinity, nonpeptide mu-opioid antagonist lacking a phenolic hydroxyl group. J Med Chem 2000, 43, 17, 3348.
|
【2】
Imidazole derivs. as histamine receptor H3 (ant)agonists. EP 0760811; FR 2732017; JP 1998501001; WO 9629315 .
|
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) |
27420 |
Urocanic acid; (E)-3-(1H-imidazol-4-yl)-2-propenoic acid
|
104-98-3 |
C6H6N2O2 |
详情 | 详情
|
(II) |
27421 |
3-(1H-imidazol-4-yl)propionic acid
|
|
C6H8N2O2 |
详情 |
详情
|
(III) |
27422 |
ethyl 3-(1H-imidazol-4-yl)propanoate
|
|
C8H12N2O2 |
详情 |
详情
|
(IV) |
27423 |
ethyl 3-(1-trityl-1H-imidazol-4-yl)propanoate
|
|
C27H26N2O2 |
详情 |
详情
|
(V) |
27424 |
3-(1-trityl-1H-imidazol-4-yl)-1-propanol
|
|
C25H24N2O |
详情 |
详情
|
(VI) |
18123 |
1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone
|
99-93-4 |
C8H8O2 |
详情 | 详情
|
(VII) |
44104 |
1-[4-[3-(1-trityl-1H-imidazol-4-yl)propoxy]phenyl]-1-ethanone
|
|
C33H30N2O2 |
详情 |
详情
|
(VIII) |
44105 |
1-[4-[3-(1H-imidazol-4-yl)propoxy]phenyl]-1-ethanone
|
|
C14H16N2O2 |
详情 |
详情
|
合成路线9
该中间体在本合成路线中的序号:
(XII) An alternative method, suitable for large-scale synthesis, has been described: The chloromethylation of 4'-hydroxyacetophenone (XII) using formaldehyde and HCl gave (XIII). Displacement of the chloride group with NaCN provided nitrile (XIV), which was further hydrolyzed to the carboxylic acid (XV). Esterification of (XV) with methanol and sulfuric acid yields (XVI), whose phenolic hydroxyl group was protected as the benzyl ether (XVII) by alkylation with benzyl chloride. Subsequent bromination of ketone (XVII) yielded the phenacyl bromide (XVIII). The chiral amino alcohol (XX) was prepared from (-)-camphor (XIX) by ketone oxidation in position alpha with SeO2, followed by condensation with hydroxylamine and reduction with LiAlH4. Asymmetric reduction of the bromo ketone (XVIII) with borane in the presence of aluminum triethoxide and the chiral auxiliary (XX) provided the desired (R)-bromohydrin (XXI). The hydroxyl groups of (XXI) were then protected by silylation with tert-butyldimethylsilyl chloride, yielding (XXII). Condensation of the silyl-protected bromide (XXII) with (S)-2[(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)oxy]-N,N-dimethylacetamide (XXIII) furnished adduct (XXIV).
【1】
Yanagi, T.; et al.; The practical synthesis of a uterine relaxant, bis (2-{[2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)sulfate (KUR-1246). Chem Pharm Bull 2001, 49, 8, 1018. |
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) |
18123 |
1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone
|
99-93-4 |
C8H8O2 |
详情 | 详情
|
(XIII) |
39615 |
1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone
|
|
C9H9ClO2 |
详情 |
详情
|
(XIV) |
50683 |
2-(5-acetyl-2-hydroxyphenyl)acetonitrile
|
|
C10H9NO2 |
详情 |
详情
|
(XV) |
50684 |
2-(5-acetyl-2-hydroxyphenyl)acetic acid
|
|
C10H10O4 |
详情 |
详情
|
(XVI) |
50685 |
methyl 2-(5-acetyl-2-hydroxyphenyl)acetate
|
|
C11H12O4 |
详情 |
详情
|
(XVII) |
50686 |
methyl 2-[5-acetyl-2-(benzyloxy)phenyl]acetate
|
|
C18H18O4 |
详情 |
详情
|
(XVIII) |
50687 |
methyl 2-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]acetate
|
|
C18H17BrO4 |
详情 |
详情
|
(XIX) |
17415 |
(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
|
464-49-3 |
C10H16O |
详情 | 详情
|
(XX) |
50688 |
(1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol
|
|
C10H19NO |
详情 |
详情
|
(XXI) |
50689 |
(1R)-1-[4-(benzyloxy)-3-(2-hydroxyethyl)phenyl]-2-bromo-1-ethanol
|
|
C17H19BrO3 |
详情 |
详情
|
(XXII) |
50690 |
([(1R)-1-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-bromoethyl]oxy)(tert-butyl)dimethylsilane; benzyl 4-((1R)-2-bromo-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl ether
|
|
C29H47BrO3Si2 |
详情 |
详情
|
(XXIII) |
50691 |
2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]-N,N-dimethylacetamide
|
|
C14H20N2O2 |
详情 |
详情
|
(XXIV) |
50692 |
2-([(7S)-7-[((2R)-2-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)-N,N-dimethylacetamide
|
|
C43H66N2O5Si2 |
详情 |
详情
|