合成路线1
该中间体在本合成路线中的序号:
(V) The reaction of 4-[2-(acetylamino)ethyl]phenol (I) with ethyl bromoacetate (II) by means of K2CO3 in refluxing butanone gives 4-[2-(acetylamino)ethyl]phenoxyacetic acid ethyl ester (III), which is hydrolyzed with refluxing aqueous HCl to 4-(2-aminoethyl)phenoxyacetic acid (IV). Finally, this compound is acylated with benzenesulfonyl chloride (V) by means of K2CO3 in hot water.
【1】
Witte, E.C.; Wolff, H.P.; Thiel, M.; Stegmeier, K.; Roesch, E.; Phenoxyalkylcarboxylic acid compounds and thrombocyte-aggregation inhibition. DE 2809377; EP 0004011; ES 478228; JP 54122250; US 4258058 .
|
【2】
Karup, G.L.; Preikschat, H.F. (GEA A/S Farmaceutisk Fabrik); Process for the preparation of 1,4-dihydropyridines and cpds. used in this process. WO 9925688 .
|
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) |
19989 |
N-(4-hydroxyphenethyl)acetamide
|
|
C10H13NO2 |
详情 |
详情
|
(II) |
16640 |
Ethyl 2-bromoacetate; Ethyl bromoacetate
|
105-36-2 |
C4H7BrO2 |
详情 | 详情
|
(III) |
34332 |
ethyl 2-[4-[2-(acetamido)ethyl]phenoxy]acetate
|
|
C14H19NO4 |
详情 |
详情
|
(IV) |
34333 |
2-[4-(2-aminoethyl)phenoxy]acetic acid
|
|
C10H13NO3 |
详情 |
详情
|
(V) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
合成路线2
该中间体在本合成路线中的序号:
(VIII) The hydrogenation of 4-(4-fluorophenyl)-3-(ethoxycarbonyl)-1-methylpyridinium bromide (I) with H2 over PtO2 in toluene/ethanol gives racemic (cis)-4-(4-fluorophenyl)-1-methylpiperidine-3-carboxylic acid methyl ester (rac)-(II), which is isomerized with NaOMe in refluxing toluene to yield the trans-isomer (rac)-(III). The reduction of (rac)-(III) with LiAlH4 in toluene/THF affords the hydroxymethyl compound (rac)-(IV), which is submitted to optical resolution with L-(-)-di-p-toluoyltartaric acid to provide the chiral (3S,4R)-(V).
Alternatively, the optical resolution of (cis)-(rac)-(II) with D-(+)-di-p-toluoyltartaric acid gives the ester (cis)-(3R,4R)-(VI), which is isomerized with NaOMe in refluxing toluene to yield ester (trans)-(3S,4R)-(VII). Finally, this compound is reduced with LiAlH4 in toluene/THF to afford the previously reported intermediate (3S,4R)-(V).
The reaction of (3S,4R)-(V) with benzenesulfonyl chloride (VIII) and dimethylethylamine in toluene gives the corresponding sulfonate (3S,4R)-(IX), which is condensed with 5-hydroxy-1,3-benzodioxole (X) by means of NaOMe in hot DMF to yield the adduct (3S,4R)-(XI). Finally, this compound is demethylated by reaction with phenyl chloroformate (XII) to afford the cyclic carbamate (3S,4R)-(XIII), which is hydrolyzed with KOH in refluxing toluene.
【1】
Borrett, G.T.; Ward, N.; Crowe, D.; Wells, A.S. (GlaxoSmithKline plc); Process for the preparation of paroxetine. WO 0129031 .
|
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) |
56453 |
4-(4-fluorophenyl)-3-(methoxycarbonyl)-1-methylpyridinium bromide
|
|
C14H13BrFNO2 |
详情 |
详情
|
(II) |
56454 |
(rac)-methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate
|
|
C14H18FNO2 |
详情 |
详情
|
(III) |
56455 |
(rac)-methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate
|
|
C14H18FNO2 |
详情 |
详情
|
(IV) |
43487 |
[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol; trans-(3S)-4-(4-fluorophenyl)-1-methyl-3-piperidine methanol
|
105812-81-5 |
C13H18FNO |
详情 | 详情
|
(V) |
56458 |
[(3S,4R)-4-(4-fluorophenyl)-1-methylpiperidinyl]methanol
|
|
C13H18FNO |
详情 |
详情
|
(VI) |
56456 |
methyl (3R,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate
|
|
C14H18FNO2 |
详情 |
详情
|
(VII) |
56457 |
methyl (3S,4R)-4-(4-fluorophenyl)-1-methyl-3-piperidinecarboxylate
|
|
C14H18FNO2 |
详情 |
详情
|
(VIII) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(IX) |
10986 |
[(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl benzenesulfonate
|
|
C19H22FNO3S |
详情 |
详情
|
(X) |
10985 |
1,3-Benzodioxol-5-ol; Sesamol
|
533-31-3 |
C7H6O3 |
详情 | 详情
|
(XI) |
10987 |
(3S,4R)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-methylhexahydropyridine; 1,3-Benzodioxol-5-yl [(3S,4R)-4-(4-fluorophenyl)-1-methylhexahydro-3-pyridinyl]methyl ether
|
|
C20H22FNO3 |
详情 |
详情
|
(XII) |
13580 |
1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate
|
1885-14-9 |
C7H5ClO2 |
详情 | 详情
|
(XIII) |
43489 |
phenyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate
|
|
C26H24FNO5 |
详情 |
详情
|
合成路线3
该中间体在本合成路线中的序号:
(LIII) The reaction of (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-monomethyl ester (XLIII) with ethylchloroformate and NaN3 gives the corresponding azide (XLIV), which is submitted to degradation in the presence of benzyl alcohol to afford (1R,2S,3S,4S)-3-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (XLV). The reduction of (XLV) with NaBH4 in THF gives the hydroxymethyl derivative (XLVI), which is oxidized with oxalyl chloride as before to the corresponding aldehyde (XLVII). The Wittig condensation of (XLVII) with methoxymethyl triphenylphosphonium chloride by means of t-BuOK in THF gives the vinyl ether (XLVIII), which is hydrolyzed to the corresponding aldehyde (XLIX) with formic acid. A new Wittig condensation of (XLIX) with 4-carboxybutyl triphenylphosphonium bromide as before, followed by methylation with diazomethane yields (1R,2S,3S,4S)-7-[3-(benzyloxycarbonylamino)bicyclo[2.2.1]heptan-2-yl]-5(Z)-heptenoic acid methyl ester (L). The deprotection of (L) with trifluoroacetic acid affords the 3-amino derivative (LI), which is then condensed with [14C]- or [3H]-radiolabeled benzenesulfonyl chloride (LII) to afford the radiolabeled sulfonamide ester (LIII). Finally, this compound is hydrolyzed with NaOH to the radiolabeled free acid (XIV), already obtained, which is converted to S-1452 by treatment of the Na salt with CaCl2 in methanol-water.
【1】
Narisada, M.; Katsuyama, Y.; Watanabe, F.; Hamada, Y.; Ohtani, M.; Nagasaki, T.; Synthesis of [14C]- and [3H]-labelled (+)-[1R-[1alpha,2alpha(Z),3beta,4alpha]]-7-[3-[(phenylsulfonyl)amino]
bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, ((+)-S-145) and its calcium salt (S-1452). J Label Compd Radiopharm 1992, 31, 1, 23-38. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(IL) |
14681 |
benzyl N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]carbamate
|
|
C17H21NO3 |
详情 |
详情
|
(XIV) |
14674 |
(Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
|
|
C20H27NO4S |
详情 |
详情
|
(XLIII) |
14665 |
(1S,2S,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid
|
|
C10H14O4 |
详情 |
详情
|
(XLIV) |
14704 |
methyl (1R,2S,3S,4S)-3-(azidocarbonyl)bicyclo[2.2.1]heptane-2-carboxylate
|
|
C10H13N3O3 |
详情 |
详情
|
(XLV) |
14705 |
methyl (1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]heptane-2-carboxylate
|
|
C17H21NO4 |
详情 |
详情
|
(XLVI) |
14706 |
benzyl N-[(1S,2S,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]carbamate
|
|
C16H21NO3 |
详情 |
详情
|
(XLVII) |
14707 |
benzyl N-[(1S,2S,3S,4R)-3-formylbicyclo[2.2.1]hept-2-yl]carbamate
|
|
C16H19NO3 |
详情 |
详情
|
(XLVIII) |
14708 |
benzyl N-[(1S,2S,3R,4R)-3-[(E)-2-methoxyethenyl]bicyclo[2.2.1]hept-2-yl]carbamate
|
|
C18H23NO3 |
详情 |
详情
|
(L) |
14682 |
methyl (Z)-7-((1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]hept-2-yl)-5-heptenoate
|
|
C23H31NO4 |
详情 |
详情
|
(LI) |
14683 |
methyl (Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate
|
|
C15H25NO2 |
详情 |
详情
|
(LII) |
14684 |
methyl (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoate
|
|
C21H29NO4S |
详情 |
详情
|
(LIII) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
合成路线4
该中间体在本合成路线中的序号:
The reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI).
【1】
Adhikari, S.S.; Hymavathi, L.; Sadalapure, K.; Sharma, G.V.M.; Sreenivas, P.; Mhaskar, S.V.; Lalitha, S.V.S.; Chorghade, M.S.; Murugaiah, A.M.S.; Prasad, T.R.; Reddy, B.S.; Gurjar, M.K.; Reddy, V.G.; Krishna, P.R. (LeukoSite, Inc.); Substd. oxygen alicyclic cpds., including methods for synthesis thereof. WO 0001381 . |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(I) |
19639 |
4-fluorophenol
|
371-41-5 |
C6H5FO |
详情 | 详情
|
(II) |
10146 |
Epichlorohydrin; 2-(Chloromethyl)oxirane
|
106-89-8 |
C3H5ClO |
详情 | 详情
|
(III) |
22150 |
2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether
|
18123-82-5 |
C9H9FO2 |
详情 | 详情
|
(IV) |
32985 |
(2R)-3-(4-fluorophenoxy)-1,2-propanediol
|
|
C9H11FO3 |
详情 |
详情
|
(V) |
32986 |
4-fluorophenyl (2S)oxiranylmethyl ether; (2S)-2-[(4-fluorophenoxy)methyl]oxirane
|
108648-25-5 |
C9H9FO2 |
详情 | 详情
|
(VI) |
32987 |
(2S)-3-(4-fluorophenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate
|
|
C16H17FO5S |
详情 |
详情
|
(VII) |
22150 |
2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether
|
18123-82-5 |
C9H9FO2 |
详情 | 详情
|
(VIII) |
10386 |
Allyl(bromo)magnesium
|
1730-25-2 |
C3H5BrMg |
详情 | 详情
|
(IX) |
32988 |
(2R)-1-(4-fluorophenoxy)-5-hexen-2-ol
|
|
C12H15FO2 |
详情 |
详情
|
(X) |
32989 |
(1R)-1-[(4-fluorophenoxy)methyl]-4-pentenyl benzenesulfonate
|
|
C18H19FO4S |
详情 |
详情
|
(XI) |
32990 |
(1R)-1-[(4-fluorophenoxy)methyl]-4-oxobutyl benzenesulfonate
|
|
C17H17FO5S |
详情 |
详情
|
(XII) |
14182 |
ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane
|
1099-45-2 |
C22H21O2P |
详情 | 详情
|
(XIII) |
32991 |
ethyl (E,6R)-7-(4-fluorophenoxy)-6-[(phenylsulfonyl)oxy]-2-heptenoate
|
|
C21H23FO6S |
详情 |
详情
|
(XIV) |
32992 |
(1R,4E)-1-[(4-fluorophenoxy)methyl]-6-hydroxy-4-hexenyl benzenesulfonate
|
|
C19H21FO5S |
详情 |
详情
|
(XV) |
32993 |
(1R)-1-[(4-fluorophenoxy)methyl]-3-[(2R,3S)-3-(hydroxymethyl)oxiranyl]propyl benzenesulfonate
|
|
C19H21FO6S |
详情 |
详情
|
(XVI) |
32994 |
(1R)-3-[(2R,3R)-3-(chloromethyl)oxiranyl]-1-[(4-fluorophenoxy)methyl]propyl benzenesulfonate
|
|
C19H20ClFO5S |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(VII) Protection of 3-amino-5-methylphenol (I) with phthalic anhydride (II) provided the phthalimido derivative (III), which was alkylated with ethyl 4-bromobutyrate (IV) in the presence of K2CO3 to give the corresponding ether (V). Hydrazinolysis of the phthalimido group of (V) afforded the primary amine (VI), which was condensed with benzenesulfonyl chloride (VII), yielding sulfonamide (VIII). Saponification of the ethyl ester of (VIII) gave carboxylic acid (IX). After conversion to the mixed anhydride with isobutyl chloroformate and N-methylmorpholine, treatment with methanolic ammonia furnished amide (X). This was reduced to amine (XI) using LiAlH4 in THF. Finally, reaction of (XI) with S-methylisothiouronium sulfate (XII) in refluxing EtOH provided the target guanidine.
【1】
Weber, I.R.; Neidlein, R.; von der Saal, W.; Grams, F.; Leinert, H.; Strein, K.; Engh, R.A.; Kucznierz, R.; Diarylsulfonamides as selective, non-peptidic thrombin inhibitors. Bioorg Med Chem Lett 1998, 8, 13, 1613.
|
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)) |
11900 |
2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride |
85-44-9 |
C8H4O3 |
详情 | 详情
|
(I) |
31435 |
3-amino-5-methylphenol
|
|
C7H9NO |
详情 |
详情
|
(III) |
31436 |
2-(3-hydroxy-5-methylphenyl)-1H-isoindole-1,3(2H)-dione
|
|
C15H11NO3 |
详情 |
详情
|
(IV) |
11263 |
ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate
|
2969-81-5 |
C6H11BrO2 |
详情 | 详情
|
(V) |
31437 |
ethyl 4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methylphenoxy]butanoate
|
|
C21H21NO5 |
详情 |
详情
|
(VI) |
31438 |
ethyl 4-(3-amino-5-methylphenoxy)butanoate
|
|
C13H19NO3 |
详情 |
详情
|
(VII) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(VIII) |
31439 |
ethyl 4-[3-methyl-5-[(phenylsulfonyl)amino]phenoxy]butanoate
|
|
C19H23NO5S |
详情 |
详情
|
(IX) |
31441 |
4-[3-methyl-5-[(phenylsulfonyl)amino]phenoxy]butyric acid
|
|
C17H19NO5S |
详情 |
详情
|
(X) |
31440 |
4-[3-methyl-5-[(phenylsulfonyl)amino]phenoxy]butanamide
|
|
C17H20N2O4S |
详情 |
详情
|
(XI) |
31442 |
N-[3-(4-aminobutoxy)-5-methylphenyl]benzenesulfonamide
|
|
C17H22N2O3S |
详情 |
详情
|
(XII) |
10272 |
[[Amino(imino)methyl]sulfanyl]methane
|
2986-19-8 |
C2H6N2S |
详情 | 详情
|
合成路线6
该中间体在本合成路线中的序号:
(XIV) A new, more efficient synthesis has been reported for the intermediate (XVIII). The saccharin derivative (IV) was prepared by two alternative routes. Thus, 2-sulfobenzoic acid cyclic anhydride (XII) was treated with two equivalents of 2-(trifluoromethyl)aniline (II) to give the anilinium salt (XIII), which was cyclized with POCl3 to produce (IV). Also, starting from benzenesulfonyl chloride (XIV), the corresponding sulfonamide (II) was obtained by reaction with aniline (II). Ortho lithiation with n-butyllithium at low temperature, followed by CO2 quenching, afforded carboxylic acid (XVI), which upon treatment with Ac2O and methanesulfonic acid cyclized to the saccharin (IV). Then, the saccharin ring was opened by treatment with NaOMe, and subsequent treatment with methyl bromoacetate furnished diester (XVII). Finally, Claisen cyclization promoted by TiCl4 formed the key intermediate (XVIII).
【1】
Lee, C.; et al.; Synthetic studies toward a series of endothelin receptor antagonists. 1,1-Dioxo-2,4-diphenyl-2H-1,2-benzothiazine. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 058.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
12309 |
methyl 2-bromoacetate; methyl bromoacetate
|
96-32-2 |
C3H5BrO2 |
详情 | 详情
|
(II) |
25812 |
2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline
|
88-17-5 |
C7H6F3N |
详情 | 详情
|
(III) |
25813 |
methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate
|
|
C15H12F3NO4S |
详情 |
详情
|
(IV) |
25814 |
2-[2-(trifluoromethyl)phenyl]-1H-1,2-benzisothiazole-1,1,3(2H)-trione
|
|
C14H8F3NO3S |
详情 |
详情
|
(XII) |
25821 |
2-Sulfobenzoic acid anhydride; 2,1lambda(6)-benzoxathiole-1,1,3-trione
|
81-08-3 |
C7H4O4S |
详情 | 详情
|
(XIII) |
25822 |
2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid
|
|
C14H10F3NO4S |
详情 |
详情
|
(XIV) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(XV) |
25823 |
N-[2-(trifluoromethyl)phenyl]benzenesulfonamide
|
|
C13H10F3NO2S |
详情 |
详情
|
(XVI) |
25822 |
2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid
|
|
C14H10F3NO4S |
详情 |
详情
|
(XVII) |
25824 |
methyl 2-[[(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)anilino]sulfonyl]benzoate
|
|
C18H16F3NO6S |
详情 |
详情
|
(XVIII) |
25825 |
methyl 4-hydroxy-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate
|
|
C17H12F3NO5S |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(XII) The selective monoprotection of 4-(4-piperidyl)piperidine (I) gives the carbamate (II), which is condensed with the isothiocyante (III) in chloroform to yield the N-(ethoxycarbonyl)carbothioamide (IV). Decarboxylation of (IV) by means of NaOH in ethanol affords the free thioamide (V), which is cyclized with 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (VI) by means of triethylamine in ethanol to provide the thiazole derivative (VII). Hydrolysis of theester group of (VII) with NaOH in ethanol gives the carboxylic acid (VIII), which is condensed with 3-amino-2(S)-(phenylsulfonamido)propionic acid methyl ester (IX), by means of DCC, HOBT and triethylamine in DMF yielding the protected target compound (X). Finally, this compound is hydrolyzed and deprotected by a treatment with HCl in ethanol.
The intermediate 3-amino-2(S)-(phenylsulfonamido)propionic acid methyl ester (IX) has been obtained as follows: The reaction of L-asparagine (XI) with benzenesulfonyl chloride (XII) by means of NaOH in dioxane/water gives the sulfonated asparagine (XIII), which is submitted to Hofmann degradation with Br2 and NaOH in water and finally esterified with SOCl2 and methanol.
【1】
Forn, J.; Merlos, M.; Garcia-Rafanell, J.; Carceller, E.; Gomez, L.A.; Novel N-(thiazolyl-5-carbonyl)-beta-alanine derivatives as potent, orally active fibrinogen receptor antagonists. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 079.
|
【2】
Carceller, E.; Jimenez, P.J.; Salas, J. (J. Uriach & Cia., SA); Novel carboxamides as platelet aggregation inhibitors. WO 9846599 .
|
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) |
25962 |
4,4'-bipiperidine
|
|
C10H20N2 |
详情 |
详情
|
(II) |
25963 |
4,4'-bipiperidine-1-carboxylic acid tert-butyl ester
|
|
C15H28N2O2 |
详情 |
详情
|
(III) |
25964 |
1-[(isothiocyanatocarbonyl)oxy]ethane
|
16182-04-0 |
C4H5NO2S |
详情 | 详情
|
(IV) |
25965 |
N-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl-thiocarbonyl]carbamic acid ethyl ester
|
|
C19H33N3O4S |
详情 |
详情
|
(V) |
25966 |
1'-(Tert-butoxycarbonyl)-4,4'-bipiperidine-1-carbothioamide
|
|
C16H29N3O2S |
详情 |
详情
|
(VI) |
25967 |
ethyl 2-chloro-4-methyl-3-oxopentanoate
|
|
C8H13ClO3 |
详情 |
详情
|
(VII) |
25968 |
2-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]-4-isopropylthiazole-5-carboxylic acid ethyl ester
|
|
C24H39N3O4S |
详情 |
详情
|
(VIII) |
25969 |
2-[1'-(Tert-butoxycarbonyl)-4,4'-bipiperidin-1-yl]-4-isopropylthiazole-5-carboxylic acid
|
|
C22H35N3O4S |
详情 |
详情
|
(IX) |
25970 |
methyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate
|
|
C10H14N2O4S |
详情 |
详情
|
(X) |
25971 |
(2(S)-(Benzenesulfonamido)-3-[2-[4-[1-tert-butoxycarbonyl)piperidin-4-yl]piperidin-4-yl]-4-isopropylthiazol-5-ylcarboxamido]propionic acid methyl ester; (2(S)-(Benzenesulfonamido)-3-[2-[4-[1-tert-butoxycarbonyl)piperidin-4-yl]piperidin-4-yl]-4-isopropylthiazol-5-ylcarboxamido]propionic acid methyl ester |
|
C32H47N5O7S2 |
详情 |
详情
|
(XI) |
25972 |
S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine
|
70-47-3 |
C4H8N2O3 |
详情 | 详情
|
(XII) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(XIII) |
25973 |
(2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid
|
|
C10H12N2O5S |
详情 |
详情
|
合成路线8
该中间体在本合成路线中的序号:
(II) The sulfonation of 3-aminobenzonitrile (I) with benzenesulfonyl chloride (II) by means of triethylamine in dichloromethane gives the sulfonamide (III), which is nitrated with HNO3 in acetic anhydride yielding 4-nitro-3-(phenyl sulfonamido)benzonitrile (IV). The reduction of (IV) with SnCl2 in hot ethanol affords the corresponding 4-amino derivative (V), which is finally condensed with 2-bromophenyl isocyanate (VI) in hot DMF.
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) |
28662 |
3-aminobenzonitrile
|
2237-30-1 |
C7H6N2 |
详情 | 详情
|
(II) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(III) |
28663 |
N-(3-cyanophenyl)benzenesulfonamide
|
|
C13H10N2O2S |
详情 |
详情
|
(IV) |
28664 |
N-(5-cyano-2-nitrophenyl)benzenesulfonamide
|
|
C13H9N3O4S |
详情 |
详情
|
(V) |
28665 |
N-(2-amino-5-cyanophenyl)benzenesulfonamide
|
|
C13H11N3O2S |
详情 |
详情
|
(VI) |
28666 |
1-bromo-2-isocyanatobenzene
|
1592-00-3 |
C7H4BrNO |
详情 | 详情
|
合成路线9
该中间体在本合成路线中的序号:
(II) The sulfonation of 3-aminobenzonitrile (I) with benzenesulfonyl chloride (II) by means of triethylamine in dichloromethane gives the sulfonamide (III), which is nitrated with HNO3 in acetic anhydride yielding 4-nitro-3-(phenyl sulfonamido)benzonitrile (IV). The reduction of (IV) with SnCl2 in hot ethanol affords the corresponding 4-amino derivative (V), which is finally condensed with 2,3-dichlorophenyl isocyanate (VI) in hot DMF.
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) |
28662 |
3-aminobenzonitrile
|
2237-30-1 |
C7H6N2 |
详情 | 详情
|
(II) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(III) |
28663 |
N-(3-cyanophenyl)benzenesulfonamide
|
|
C13H10N2O2S |
详情 |
详情
|
(IV) |
28664 |
N-(5-cyano-2-nitrophenyl)benzenesulfonamide
|
|
C13H9N3O4S |
详情 |
详情
|
(V) |
28665 |
N-(2-amino-5-cyanophenyl)benzenesulfonamide
|
|
C13H11N3O2S |
详情 |
详情
|
(VI) |
28667 |
1,2-dichloro-3-isocyanatobenzene
|
41195-90-8 |
C7H3Cl2NO |
详情 | 详情
|
合成路线10
该中间体在本合成路线中的序号:
(II) The condensation of L-asparagine (I) with benzenesulfonyl chloride (II) in the presence of NaOH gave sulfonamide (III). Subsequent Hofmann rearrangement of (III) employing sodium hypobromite produced the diaminopropionic acid derivative (IV), which was protected as the tert-butyl ester (V) using isobutylene in the presence of H2SO4. Condensation of methyl 4-aminobenzoate (VI) with bis(2-chloroethyl)amine (VII) in refluxing butanol yielded the arylpiperazine (VIII), which was protected with di tert-butyl dicarbonate to give the corresponding carbamate (IX). Basic hydrolysis of the methyl ester of (IX) provided carboxylic acid (X). This was then coupled with amine (V) using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) to afford amide (XI). Finally, deprotection of the tert-butyl ester and BOC group of (XI) with trifluoroacetic acid furnished the title compound.
【1】
Egbertson, M.S.; Turchi, L.M.; Hartman, G.D.; Halczenko, W.; Whitman, D.B.; Perkins, J.J.; Krause, A.E.; Ihle, N.; Claremon, D.A.; Hoffman, W.; Duggan, M.E. (Merck & Co., Inc.); Fibrinogen receptor antagonists. EP 0673247; JP 1996504194; WO 9412181 . |
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) |
25972 |
S-(+)-Asparagine; S-(+)-2-Aminosuccinamic acid; L-Asparagine
|
70-47-3 |
C4H8N2O3 |
详情 | 详情
|
(II) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(III) |
25973 |
(2S)-4-amino-4-oxo-2-[(phenylsulfonyl)amino]butyric acid
|
|
C10H12N2O5S |
详情 |
详情
|
(IV) |
31422 |
(2S)-3-amino-2-[(phenylsulfonyl)amino]propionic acid
|
|
C9H12N2O4S |
详情 |
详情
|
(V) |
31423 |
tert-butyl (2S)-3-amino-2-[(phenylsulfonyl)amino]propanoate
|
|
C13H20N2O4S |
详情 |
详情
|
(VI) |
20537 |
methyl 4-aminobenzoate
|
619-45-4 |
C8H9NO2 |
详情 | 详情
|
(VII) |
21583 |
2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine
|
821-48-7 |
C4H9Cl2N |
详情 | 详情
|
(VIII) |
31424 |
methyl 4-(1-piperazinyl)benzoate
|
|
C12H16N2O2 |
详情 |
详情
|
(IX) |
31425 |
tert-butyl 4-[4-(methoxycarbonyl)phenyl]-1-piperazinecarboxylate
|
|
C17H24N2O4 |
详情 |
详情
|
(X) |
31426 |
4-[4-(tert-butoxycarbonyl)-1-piperazinyl]benzoic acid
|
|
C16H22N2O4 |
详情 |
详情
|
(XI) |
31427 |
tert-butyl 4-[4-[([(2S)-3-(tert-butoxy)-3-oxo-2-[(phenylsulfonyl)amino]propyl]oxy)carbonyl]phenyl]-1-piperazinecarboxylate
|
|
C29H39N3O8S |
详情 |
详情
|
合成路线11
该中间体在本合成路线中的序号:
Ethyl 6-azaindole-3-carboxylate (I) was formylated using dichloromethyl methyl ether and AlCl3 to provide aldehyde (II). Nitrogen protection in (II) with benzenesulfonyl chloride and NaH gave sulfonyl derivative (III). Subsequent Wittig condensation of (III) with (ethoxycarbonylmethylene)triphenyl phosphorane produced the unsaturated ester (IV). Finally, removal of the benzenesulfonyl protecting group of (IV) was effected by treatment with ethanolic NaOEt.
【1】
Le Hyaric, M.; Doisy, X.; Dekhane, M.; et al.; Synthesis and benzodiazepine receptor (omega receptor) affinities of 3-substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of omega1 selective ligands. Bioorg Med Chem 1999, 7, 5, 921. |
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
14182 |
ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane
|
1099-45-2 |
C22H21O2P |
详情 | 详情
|
|
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
|
40668 |
dichloro(methoxy)methane; dichloromethyl methyl ether
|
4885-02-3 |
C2H4Cl2O |
详情 | 详情
|
(I) |
26182 |
ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate
|
|
C10H10N2O2 |
详情 |
详情
|
(II) |
26183 |
ethyl 3-formyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
|
|
C11H10N2O3 |
详情 |
详情
|
(III) |
26184 |
ethyl 3-formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
|
|
C17H14N2O5S |
详情 |
详情
|
(IV) |
26185 |
ethyl 3-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate
|
|
C21H20N2O6S |
详情 |
详情
|
合成路线12
该中间体在本合成路线中的序号:
(I) Reaction of benzenesulfonyl chloride (I) with methylamine afforded sulfonamide (II). Regioselective ortho lithiation of (II) with n-butyllithium, followed by condensation with 3-methylbenzaldehyde (III) gave carbinol (IV), which was cyclized to the sultam (V) by treatment with concentrated H2SO4. The desired (S)-enantiomer was finally isolated by chiral HPLC.
【1】
Johnson, S.C.; Yan, S.; Mayasundari, A.; Mao, J.; Baker, D.C. (University of Tennessee, Knoxville); Methods of synthesizing sultams and anti-viral compsns.. WO 0004004 .
|
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) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(II) |
41076 |
N-methylbenzenesulfonamide
|
5183-78-8 |
C7H9NO2S |
详情 | 详情
|
(III) |
41077 |
3-methylbenzaldehyde
|
620-23-5 |
C8H8O |
详情 | 详情
|
(IV) |
41078 |
2-[hydroxy(3-methylphenyl)methyl]-N-methylbenzenesulfonamide
|
|
C15H17NO3S |
详情 |
详情
|
(V) |
41079 |
2-methyl-3-(3-methylphenyl)-2,3-dihydro-1H-1,2-benzisothiazole-1,1-dione
|
|
C15H15NO2S |
详情 |
详情
|
合成路线13
该中间体在本合成路线中的序号:
(VI) The alkylation of 2-phenyl-4-pentenenitrile (I) with 2-(trimethylsilyl)ethoxymethyl chloride (II) in the presence of LDA afforded (III), which was reduced to aldehyde (IV) by means of DIBAL. Reductive amination of (III) with methylamine and NaBH(OAc)3 produced amine (V) and subsequent condensation with benzenesulfonyl chloride (VI) yielded sulfonamide (VII). A two-step oxidation of (VII) with osmium tetroxide and N-methylmorpholine-N-oxide, followed by sodium periodate cleavage of the resulting diol (VIII) generated aldehyde (IX). Further reductive amination of (IX) with piperidine derivative (X) gave adduct (XI). The (trimethylsilyl)ethoxy protecting group of (XI) was finally cleaved by means of trifluoroacetic acid to furnish the title compound.
【1】
Cladwell, C.G.; Chen, P.; Donnelly, K.F.; et al.; Discovery of potent human CCR5 antagonists for the treatment of HIV-1 infection-IV. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 120.
|
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) |
39738 |
2-phenyl-3-butenenitrile
|
|
C10H9N |
详情 |
详情
|
(II) |
27243 |
[2-(chloromethoxy)ethyl](trimethyl)silane
|
76513-69-4 |
C6H15ClOSi |
详情 | 详情
|
(III) |
39739 |
2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]-3-butenenitrile
|
|
C16H23NOSi |
详情 |
详情
|
(IV) |
39740 |
2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]-4-pentenal
|
|
C17H26O2Si |
详情 |
详情
|
(V) |
39741 |
N-methyl-N-(2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]-4-pentenyl)amine; N-methyl-2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]-4-penten-1-amine
|
|
C18H31NOSi |
详情 |
详情
|
(VI) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(VII) |
39742 |
N-methyl-N-(2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]-4-pentenyl)benzenesulfonamide
|
|
C24H35NO3SSi |
详情 |
详情
|
(VIII) |
39743 |
N-(4,5-dihydroxy-2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]pentyl)-N-methylbenzenesulfonamide
|
|
C24H37NO5SSi |
详情 |
详情
|
(IX) |
39744 |
N-methyl-N-(4-oxo-2-phenyl-2-[[2-(trimethylsilyl)ethoxy]methyl]butyl)benzenesulfonamide
|
|
C23H33NO4SSi |
详情 |
详情
|
(X) |
39745 |
benzyl ethyl(4-piperidinyl)carbamate
|
|
C15H22N2O2 |
详情 |
详情
|
(XI) |
39746 |
benzyl ethyl[1-(4-[methyl(phenylsulfonyl)amino]-3-phenyl-3-[[2-(trimethylsilyl)ethoxy]methyl]butyl)-4-piperidinyl]carbamate
|
|
C38H55N3O5SSi |
详情 |
详情
|
合成路线14
该中间体在本合成路线中的序号:
(XII) Reductive amination of 2,5-dimethyl-2-phenylhex-4-enal (X) with methylamine and NaBH3 gives the expected secondary amine as a racemic mixture that is separated by means of mandelic acid, yielding the desired isomer (XI). The sulfonylation of the resulting amine (XI) with benzenesulfonyl chloride (XII) provided sulfonamide (XIII). Dihydroxylation with N-methylmorpholine-N-oxide in the presence of a catalytic amount of osmium tetroxide gave rise to diol (XIV), which was oxidatively cleaved to aldehyde (XV) by means of sodium periodate. Finally, reductive condensation between aldehyde (XV) and piperidine (VI) furnished the title compound.
【1】
Chen, P.; Dorn, C.P. Jr.; Caldwell, C.G.; et al.; Synthesis and evaluation of CCR5 antagonists having potent in vitro antiviral activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 85.
|
【2】
Finke, P.E.; Mills, S.G.; Caldwell, C.G.; MacCoss, M.; Wang, L.; Kothandaraman, S.; Kim, D.; Oates, B. (Merck & Co., Inc.); Cyclic amine modulators of chemokine receptor activity. EP 1052992; US 6140349; WO 9938514 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VI) |
43905 |
4-nitrobenzyl allyl(4-piperidinyl)carbamate
|
|
C16H21N3O4 |
详情 |
详情
|
(X) |
43906 |
tert-butyl 4-([[(4-nitrobenzyl)oxy]carbonyl]amino)-1-piperidinecarboxylate
|
|
C18H25N3O6 |
详情 |
详情
|
(XI) |
43907 |
2,5-dimethyl-2-phenyl-4-hexenal
|
|
C14H18O |
详情 |
详情
|
(XII) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(XIII) |
43908 |
(2S)-N,2,5-trimethyl-2-phenyl-4-hexen-1-amine; N-[(2S)-2,5-dimethyl-2-phenyl-4-hexenyl]-N-methylamine
|
|
C15H23N |
详情 |
详情
|
(XIV) |
43909 |
N-[(2S)-2,5-dimethyl-2-phenyl-4-hexenyl]-N-methylbenzenesulfonamide
|
|
C21H27NO2S |
详情 |
详情
|
(XV) |
43910 |
N-[(2S)-4,5-dihydroxy-2,5-dimethyl-2-phenylhexyl]-N-methylbenzenesulfonamide
|
|
C21H29NO4S |
详情 |
详情
|
合成路线15
该中间体在本合成路线中的序号:
(II) Protection of 5-methoxyindole (I) with benzenesulfonyl chloride (II) in the presence of NaH affords the N-sulfonyl indole (III). Acylation of the 2-lithio derivative of (III) with benzoyl chloride (IV) gives rise to ketone (V). Finally, removal of the phenylsulfonyl protecting group of (V) is achieved by either basic hydrolysis or by treatment with tetrabutylammonium fluoride.
【1】
Hufsky, H.; Pongratz, H.; Mahboobi, S.; et al.; Synthetic 2-aroylindole derivatives as a new class of potent tubulin-inhibitory, antimitotic agents. J Med Chem 2001, 44, 26, 4535.
|
【2】
Teller, S.; Pongratz, H.; Mahboobi, S.; et al.; Bis(1H-2-indolyl) methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase. J Med Chem 2002, 45, 5, 1002.
|
【3】
Burger, A.; Mahboobi, S.; Pongratz, H.; Hufsky, H.; Böhmer, F.-D.; Beckers, T.; Klenner, T.; Baasner, S.; Frieser, M.; Hockemeyer, J.; Fiebig, H.-H. (Asta Medica AG); 2-Acyl indol derivs. and their use as anti-tumour agents. DE 10020852; WO 0182909 . |
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) |
25902 |
1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole
|
1006-94-6 |
C9H9NO |
详情 | 详情
|
(II) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(III) |
57928 |
5-methoxy-1-(phenylsulfonyl)-1H-indole; methyl 1-(phenylsulfonyl)-1H-indol-5-yl ether
|
|
C15H13NO3S |
详情 |
详情
|
(IV) |
10463 |
Benzoyl chloride
|
98-88-4 |
C7H5ClO |
详情 | 详情
|
(V) |
57929 |
[5-methoxy-1-(phenylsulfonyl)-1H-indol-2-yl](phenyl)methanone
|
|
C22H17NO4S |
详情 |
详情
|
合成路线16
该中间体在本合成路线中的序号:
(V) N-Boc-pyrrolidine-3-carboxylic acid (II) was obtained by saponification of the corresponding methyl ester (I) with NaOH. Curtius rearrangement of acid (II) using diphenyl phosphoazidate, followed by trapping the resultant isocyanate with benzyl alcohol, produced carbamate (III). Deprotection of the benzyl carbamate (III) by hydrogenation over Pd/C gave amine (IV), which was acylated with benzenesulfonyl chloride (V) to form sulfonamide (VI). Removal of the Boc group of (VI) was then effected by treatment with trifluoroacetic acid. The resulting amine (VII) was converted to the title cyanamide by treatment with cyanogen bromide.
【1】
Rodan, S.B.; Falgueyret, J.-P.; Wesolowski, G.; Oballa, R.M.; Rydzewski, R.M.; Okamoto, O.; Prasit, P.; Riendeau, D.; Aubin, Y.; Percival, M.D.; Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L. J Med Chem 2001, 44, 1, 94. |
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) |
46931 |
1-(tert-butyl) 3-methyl 1,3-pyrrolidinedicarboxylate
|
|
C11H19NO4 |
详情 |
详情
|
(II) |
46932 |
1-(tert-butoxycarbonyl)-3-pyrrolidinecarboxylic acid
|
|
C10H17NO4 |
详情 |
详情
|
(III) |
46933 |
tert-butyl 3-[[(benzyloxy)carbonyl]amino]-1-pyrrolidinecarboxylate
|
|
C17H24N2O4 |
详情 |
详情
|
(IV) |
46934 |
3-amino-1-N-Boc-pyrrolidine; tert-butyl 3-amino-1-pyrrolidinecarboxylate
|
|
C9H18N2O2 |
详情 |
详情
|
(V) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(VI) |
46935 |
tert-butyl 3-[(phenylsulfonyl)amino]-1-pyrrolidinecarboxylate
|
|
C15H22N2O4S |
详情 |
详情
|
(VII) |
46936 |
N-(3-pyrrolidinyl)benzenesulfonamide
|
|
C10H14N2O2S |
详情 |
详情
|
合成路线17
该中间体在本合成路线中的序号:
(VII) Treatment of aniline (I) with hexafluoroacetone trihydrate (II) and p-toluenesulfonic acid affords derivative (III), which is then derivatized with trifluoroacetic anhydride (IV) to provide trifluoroacetanilide derivative (V). Reduction of (V) by means of LiAlH4 in refluxing THF yields N-trifluoroethylaniline derivative (VI), which is finally converted into the target sulfonamide by reaction with benzenesulfonyl chloride (VII) in pyridine.
【1】
Shan, B. (Tularik Inc.); Compsns. and methods for raising HDL cholesterol levels. WO 0103705 .
|
【2】
Liu, J.; Li, L.; Cutler, S.T.; Zhu, L.; Shan, B.; Medina, J.C.; Hasegawa, H.; Lustig, K. (Tularik Inc.); LXR modulators. EP 1161233; WO 0054759 .
|
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) |
12294 |
Aniline; Phenylamine
|
62-53-3 |
C6H7N |
详情 | 详情
|
(II) |
44260 |
1,1,1,3,3,3-hexafluoroacetone
|
684-16-2 |
C3F6O |
详情 | 详情
|
(III) |
50005 |
2-(4-Aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 4-(Hexafluoro-2-hydroxyisopropyl)aniline
|
722-92-9 |
C9H7F6NO |
详情 | 详情
|
(IV) |
33862 |
trifluoroacetic anhydride
|
407-25-0 |
C4F6O3 |
详情 | 详情
|
(V) |
50006 |
2,2,2-trifluoro-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide
|
|
C11H6F9NO2 |
详情 |
详情
|
(VI) |
50007 |
1,1,1,3,3,3-hexafluoro-2-[4-[(2,2,2-trifluoroethyl)amino]phenyl]-2-propanol
|
|
C11H8F9NO |
详情 |
详情
|
(VII) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
合成路线18
该中间体在本合成路线中的序号:
(II) The target compound is obtained by sulfonylation of aniline (I) with benzenesulfonyl chloride (II) in MeOH.
【1】
Shan, B. (Tularik Inc.); Compsns. and methods for raising HDL cholesterol levels. WO 0103705 .
|
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) |
49999 |
1,1,1,3,3,3-hexafluoro-2-[4-(methylamino)phenyl]-2-propanol
|
|
C10H9F6NO |
详情 |
详情
|
(II) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
合成路线19
该中间体在本合成路线中的序号:
(I)
【1】
Lara Ochoa JMF, De La Torre Guria JA, Franco Andrade F.2000. Improved procedure for the prepration of 4—hydroxy- 2-methyl-N-(5-methyl-2-thiazolyl )-2 H-l,2-benaothiazinr3-carboxamide l,l-choxide(mdoxiatm).
MX 9908522 |
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) |
66517 |
diethyl 2-(N-methylphenylsulfonamido)malonate |
|
C14H19NO6S |
详情 | 详情
|
(I) |
14713 |
benzenesulfonyl chloride
|
98-09-9 |
C6H5ClO2S |
详情 | 详情
|
(II) |
41076 |
N-methylbenzenesulfonamide
|
5183-78-8 |
C7H9NO2S |
详情 | 详情
|
(IV) |
19537 |
methyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate
|
|
C11H11NO5S |
详情 |
详情
|