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【结 构 式】

【分子编号】12573

【品名】3-Bromo-1-propanol; 3-Bromopropanol

【CA登记号】627-18-9

【 分 子 式 】C3H7BrO

【 分 子 量 】138.99198

【元素组成】C 25.92% H 5.08% Br 57.49% O 11.51%
与该中间体有关的原料药合成路线共 19 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19

合成路线1

该中间体在本合成路线中的序号：(VII)

The reaction of dimethylpiperidine (IV) with 3-bromopropanol (VII) in refluxing xylene gives 1-(3-hydroxypropyl)-2,6-cis-dimethylpiperidine (VIII), which by treatment with SOCl2 in refluxing benzene is converted into 1-(3-chloropropyl)-2,6-cis-dimethylpiperidine (IX). Finally, this compound is condensed with 2-benzoylpyridine (X) by means of Li in THF.

参考文献 中间体
合成目标
【1】 Fleming, R.W. (Pfizer Inc.); Antiarrhythmic (+,-)-cis- alpha [3-(2,6-dimethyl-1-piperidinyl)propyl]-alpha-phenyl-2-pyridinemethanols. US 4112103 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Hillier, K.; Pirmenol hydrochloride. Drugs Fut 1981, 6, 4, 234.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 32229 (2R,6S)-2,6-dimethylpiperidine; cis-2,6-dimethylpiperidine C7H15N 详情 详情
(VII) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(VIII) 32231 1-(3-hydroxypropyl)-2,6-cis-dimethylpiperidine; 3-[(2R,6S)-2,6-dimethylpiperidinyl]-1-propanol C10H21NO 详情 详情
(IX) 32232 1-(3-chloropropyl)-2,6-cis-dimethylpiperidine; (2R,6S)-1-(3-chloropropyl)-2,6-dimethylpiperidine C10H20ClN 详情 详情
(X) 32233 2-Benzoylpyridine; Phenyl(2-pyridinyl)methanone 91-02-1 C12H9NO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(V)

By cyclization of 3-nitrobenzaldehyde (I) with 3-nitratopropyl-3-aminocrotonate (II) and 2-nitratopropyl acetoacetate (III) in refluxing benzene. The starting products (II) and (III) are obtained as follows: The reaction of diketene (IV) with 3-bromopropanol (V) by means of sodium acetate at 50 C gives 3-bromopropyl acetoacetate (VI), which by reaction with AgNO3 in refluxing acetonitrile is converted to 3-nitratopropyl acetoacetate (VII). Finally, this compound is treated with NH3 in THF to afford the aminocrotonic ester (II). The reaction of diketene (IV) with 2-chloropropanol (VIII) as before gives 2-chloropropyl acetoacetate (IX), which is treated with AgNO3 as before to yield acetoacetate (III).

参考文献 中间体
合成目标
【1】 Hatayama, K.; Sawada, J.; Nakazato, A.; Ogawa, T.; Ito, S. (Taisho Pharmaceutical Co., Ltd.); 1,4-Dihydropyridine derivs.. EP 0092936; US 4472411 .
【2】 Prous, J.; Castaner, J.; CD-349. Drugs Fut 1988, 13, 7, 610.
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) 12646 3-Nitrobenzaldehyde 99-61-6 C7H5NO3 详情 详情
(II) 13999 3-(nitrooxy)propyl (E)-3-amino-2-butenoate C7H12N2O5 详情 详情
(III) 22628 2-(nitrooxy)propyl 3-oxobutanoate C7H11NO6 详情 详情
(IV) 21896 4-methyl-2H-oxet-2-one C4H4O2 详情 详情
(V) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(VI) 22631 3-bromopropyl 3-oxobutanoate C7H11BrO3 详情 详情
(VII) 22632 3-(nitrooxy)propyl 3-oxobutanoate C7H11NO6 详情 详情
(VIII) 22633 2-chloro-1-propanol 78-89-7 C3H7ClO 详情 详情
(IX) 22634 2-chloropropyl 3-oxobutanoate C7H11ClO3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XVI)

5) The cyclization of D-penicillamine (X) with 2-methoxybenzaldehyde (XI) in ethanol gives (4S)-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XII), which by acetylation with hot acetic anhydride and fractional crystallization yields the chiral (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XIII). The esterification of (XIII) with the hydroxyl group of benzothiazinone (I) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) in DMF affords a diastereomeric mixture of esters, which is separated by fractional crystallization giving ester (XIV). Elimination of the chiral auxiliar by treatment with calcium borohydride in THF or sodium borohydride in ethanol (2) gives (R)-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XV), which is condensed with 3-bromopropanol (XVI) by means of triphenylphosphine and diethyl azodicarboxylate in DMF or THF yielding (R)-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XVII). Finally, this compound is condensed with the secondary amine (IV) by means of NaI and NaHCO3 as already described, and treated with fumaric acid as before.

参考文献 中间体
合成目标
【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Sesamodil Fumarate. Drugs Fut 1997, 22, 3, 229.
【2】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 .
【3】 Iwao, J.; Iso, T.; Kawashima, Y. (Santen Pharmaceutical Co., Ltd.); Sulfur-containing polycyclic cpds. JP 1988104969 .
【4】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 12567 (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine 1113-41-3 C5H11NO2S 详情 详情
(XI) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(XII) 12569 (4S)-2-(2-Methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid C13H17NO3S 详情 详情
(XIII) 12570 (2S,4S)-3-Acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid C15H19NO4S 详情 详情
(XIV) 12571 4-methoxy-2-[(2R)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]phenyl (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate C31H32N2O6S2 详情 详情
(XV) 12572 (2R)-2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one C16H15NO3S 详情 详情
(XVI) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(XVII) 12574 (2R)-2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one C19H20BrNO3S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

Fudosteine has been obtained by two similar ways: 1) By condensation of L-cysteine (I) with 3-bromopropyl alcohol (II) by means of NaOH in water at room temperature. 2) By condensation of L-cysteine (I) with allyl alcohol (III) by means of potassium persulfate in water.

参考文献 中间体
合成目标
【1】 Castaner, J.; Leeson, P.; Wroblewski, T.; Fudosteine. Drugs Fut 1998, 23, 4, 374.
【2】 Barnsley, E.A.; The formation of 2-hydroxypropylmercapturic acid from 1-halogenopropanes in the rat. Biochem J 1996, 100, 362-72.
【3】 Itoh, Y.; Mizuno, H.; Kiyohara, C.; Sato, S.; Katori, T. (SSP Co., Ltd.); Expectorant comprising hydroxy-alkylcysteine deriv. EP 0346882; EP 0346883; JP 1990003674; US 4906665 .
【4】 Ito, Y.; Kuriyama, T.; Ogawa, M.; Sato, S.; Kuraishi, T. (SSP Co., Ltd.); Preparation method of S-hydroxypropyl-L-cysteine. JP 1996119932 .
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) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 14643 L-cysteine; (R)-2-Amino-3-mercaptopropionic acid 52-90-4 C3H7NO2S 详情 详情
(III) 14644 (2R)-2-amino-3-[(3-hydroxypropyl)sulfanyl]propionic acid C6H13NO3S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

Reaction of 6-aminobenzothiazole (I) with phosgene in refluxing tolene affords isocyanate (II). Alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-bensisoxazole hydrochloride (III) with 3-bromopropanol (IV) in the presence of potassium carbonate in acetone gave alcohol (V). Finally, condensation of this alcohol (V) with isocyanate (II) in DMF at 100 C yielded the title carbamate.

参考文献 中间体
合成目标
【1】 Hansen, J.B.; Jeppesen, L.; Gronvald, F.C. (Novo Nordisk A/S); Chemical cpds., their preparation and use. EP 0679085; JP 1995502268; US 5378714; WO 9310742 .
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) 17908 1,3-benzothiazol-6-ylamine; 1,3-benzothiazol-6-amine; 6-Aminobenzothiazole 533-30-2 C7H6N2S 详情 详情
(II) 17909 6-isocyanato-1,3-benzothiazole; 1,3-benzothiazol-6-yl isocyanate C8H4N2OS 详情 详情
(III) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情
(IV) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(V) 17912 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-1-propanol C15H19FN2O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

The reaction of 3-bromopropanol (I) with thiourea in refluxing water gives 3-sulfanylpropanol (II), which is cyclized with 2-phenylacetaldehyde (III) by means of p-toluenesulfonic acid in refluxing toluene yielding 2-benzyl-1,3-oxathiane (IV). The reductive cleavage of (IV) with Ca in liquid ammonia affords 3-(2-phenylethoxy)propanethiol (V), which is condensed with bromoacetic acid by means of NaH in DMF providing 2-[3-(2-phenylethoxy)propylsulfanyl]acetic acid (VI). The oxidation of (VI) with potassium peroxymonosulfate (oxone) gives the corresponding sulfonylacetic acid (VII), which is condensed with benzothiazolone (VIII) by means of DCC, HOBT and triethylamine in DMF yielding the correponding amide (IX). Finally, this compound is reduced with borane/THF yielding the target compound.

参考文献 中间体
合成目标
【1】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; Cheshire, D.R.; Dixon, J.; Ince, F.; Kinchin, E.C.; Lyons, A.J.; Davis, A.M.; Hallam, C.; Harper, S.T.; Unitt, J.F.; Dougall, I.G.; Jackson, D.M.; McKechnie, K.; Young, A.; Simpson, W.T.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J Med Chem 1998, 41, 25, 4915.
【2】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275.
【3】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276.
【4】 Bonnert, R.V.; Brown, R.C.; Cheshire, D.R.; Ince, F. (AstraZeneca AB); 7-(2-Aminoethyl)-benzothiazolones. EP 0649418; JP 1996503923; US 5648370; WO 9324473 .
【5】 Castañer, J.; Graul, A.; Viozan. Drugs Fut 2000, 25, 2, 165.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(I) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 25939 3-sulfanyl-1-propanol 19721-22-3 C3H8OS 详情 详情
(III) 18456 2-phenylacetaldehyde 122-78-1 C8H8O 详情 详情
(IV) 25940 2-benzyl-1,3-oxathiane C11H14OS 详情 详情
(V) 25941 3-(phenethyloxy)propylhydrosulfide; 3-(phenethyloxy)-1-propanethiol C11H16OS 详情 详情
(VI) 25942 2-[[3-(phenethyloxy)propyl]sulfanyl]acetic acid C13H18O3S 详情 详情
(VII) 25943 2-[[3-(phenethyloxy)propyl]sulfonyl]acetic acid C13H18O5S 详情 详情
(VIII) 25944 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one C9H10N2O2S 详情 详情
(IX) 25945 N-[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]-2-[[3-(phenethyloxy)propyl]sulfonyl]acetamide C22H26N2O6S2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

The reaction of 3-bromopropanol (I) with thiourea in refluxing water gives 3-sulfanylpropanol (II), which is cyclized with 2-phenylacetaldehyde (III) by means of p-toluenesulfonic acid in refluxing toluene yielding 2-benzyl-1,3-oxathiane (IV). The reductive cleavage of (IV) with Ca in liquid ammonia affords 3-(2-phenylethoxy)propanethiol (V), which is condensed with bromoacetic acid by means of NaH in DMF providing 2-[3-(2-phenylethoxy)propylsulfanyl]acetic acid (VI). The oxidation of (VI) with potassium peroxymonosulfate (oxone) gives the corresponding sulfonylacetic acid (VII).The condensation of sulfonylacetic acid (VII) with dimethoxybenzothiazole derivative (X) by means of DCC, HOBT and triethylamine in DMF gives the corresponding amide (XI), which is reduced with borane/THF yielding intermediate (XII). Finally, this compound is demethylated with concentrated HBr or HCl.

参考文献 中间体
合成目标
【1】 Bonnert, R.V.; Brown, R.C.; Cage, P.A.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.275.
【2】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; et al.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airways diseases. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.276.
【3】 Bonnert, R.V.; Brown, R.C.; Chapman, D.; Cheshire, D.R.; Dixon, J.; Ince, F.; Kinchin, E.C.; Lyons, A.J.; Davis, A.M.; Hallam, C.; Harper, S.T.; Unitt, J.F.; Dougall, I.G.; Jackson, D.M.; McKechnie, K.; Young, A.; Simpson, W.T.; Dual D2-receptor and beta2-adrenoceptor agonists for the treatment of airway diseases. 1. Discovery and biological evaluation of some 7-(2-aminoethyl)-4-hydroxybenzothiazol-2(3H)-one analogues. J Med Chem 1998, 41, 25, 4915.
【4】 Bonnert, R.V.; Brown, R.C.; Cheshire, D.R.; Ince, F. (AstraZeneca AB); 7-(2-Aminoethyl)-benzothiazolones. EP 0649418; JP 1996503923; US 5648370; WO 9324473 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(I) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 25939 3-sulfanyl-1-propanol 19721-22-3 C3H8OS 详情 详情
(III) 18456 2-phenylacetaldehyde 122-78-1 C8H8O 详情 详情
(IV) 25940 2-benzyl-1,3-oxathiane C11H14OS 详情 详情
(V) 25941 3-(phenethyloxy)propylhydrosulfide; 3-(phenethyloxy)-1-propanethiol C11H16OS 详情 详情
(VI) 25942 2-[[3-(phenethyloxy)propyl]sulfanyl]acetic acid C13H18O3S 详情 详情
(VII) 25943 2-[[3-(phenethyloxy)propyl]sulfonyl]acetic acid C13H18O5S 详情 详情
(X) 25946 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethylamine; 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)-1-ethanamine C11H14N2O2S 详情 详情
(XI) 25947 N-[2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethyl]-2-[[3-(phenethyloxy)propyl]sulfonyl]acetamide C24H30N2O6S2 详情 详情
(XII) 25948 N-[2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)ethyl]-N-(2-[[3-(phenethyloxy)propyl]sulfonyl]ethyl)amine; 2-(2,4-dimethoxy-1,3-benzothiazol-7-yl)-N-(2-[[3-(phenethyloxy)propyl]sulfonyl]ethyl)-1-ethanamine C24H32N2O5S2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XXI)

In a related synthesis, (3,4-dichlorophenyl)acetonitrile (XI) was alkylated with bromide (XXII) --prepared by protection of 3-bromopropanol (XXI) with dihydropyran-- to afford (XXIII). Subsequent Michael addition of methyl acrylate (XII) to (XXIII) in the presence of Triton B® gave the cyanoacid (XXIV). This was cyclized to the glutarimide (XXV) by refluxing in HOAc in the presence of H2SO4. Reduction of (XXV) using borane-dimethylsulfide complex produced the already reported racemic piperidinoalcohol (XVI). After acylation of the amine group of (XVI) with benzoyl chloride to yield (XXVI), its hydroxyl group was converted into the target mesylate precursor (XXVII) with methanesulfonyl chloride and Et3N.

参考文献 中间体
合成目标
【1】 Giardina, G.A.M.; et al.; A reliable and efficient synthesis of SR 142801. Bioorg Med Chem Lett 1996, 6, 19, 2307.
【2】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.
【3】 Grugni, M.; Rigolio, R.; Erhard, K.F. (GlaxoSmithKline Inc.; GlaxoSmithKline SpA); Process for the preparation of 3,3-disubstd. piperidines. WO 9805640 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 26935 2-(3,4-dichlorophenyl)acetonitrile 3218-49-3 C8H5Cl2N 详情 详情
(XII) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XVI) 29465 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(XXI) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(XXII) 42252 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran C8H15BrO2 详情 详情
(XXIII) 59274 2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile C16H19Cl2NO2 详情 详情
(XXIV) 59275 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoic acid C19H23Cl2NO4 详情 详情
(XXV) 59276 3-[3-(3,4-dichlorophenyl)-2,6-dioxo-3-piperidinyl]propyl acetate C16H17Cl2NO4 详情 详情
(XXVI) 59277 [3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)-1-piperidinyl](phenyl)methanone C21H23Cl2NO2 详情 详情
(XXVII) 59278 3-[1-benzoyl-3-(3,4-dichlorophenyl)-3-piperidinyl]propyl methanesulfonate C22H25Cl2NO4S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

The cyclization of 2-methylphenyl isothiocyanate (I) with 2-aminoacetaldehyde dimethylacetal (II) in methanol gives the 1-(2-methylphenyl)imidazole-2-thiol (III), which is condensed with 3-bromopropanol (IV) by means of NaOH in refluxing water to yield the sulfide (V). The asymmetric oxidation of sulfide (V) with Ti(O-iPr)4, cumene hydroperoxide (CHP) and (R)-(-)-mandelic acid as chiral catalyst in dichloromethane affords the (S)-sulfinyl derivative (VI), which is treated with Ms-Cl to provide the expected mesylate (VII). Finally, this compound is condensed with the sodium salt of 6-hydroxy-1,2,3,4-tetrahydroquinolin-2one (VIII) to give the target compound.

参考文献 中间体
合成目标
【1】 Matsugi, M.; et al.; Catalytic asymmetric oxidation of sulfide with titanium-mandelic acid complex: Practical synthesis of (S)-3-[1-(2-methylphenyl)imidazol-2-ylsulfinyl]propan-1-ol, the key intermediate of OPC-29030. Tetrahedron 2001, 57, 14, 2739.
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) 50207 6-isothiocyanato-1-methyl-1,3-cyclohexadiene; 2-methyl-2,4-cyclohexadien-1-yl isothiocyanate C8H9NS 详情 详情
(II) 34158 aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine 22483-09-6 C4H11NO2 详情 详情
(III) 30223 1-(2-methylphenyl)-1H-imidazol-2-ylhydrosulfide; 1-(2-methylphenyl)-1H-imidazole-2-thiol C10H10N2S 详情 详情
(IV) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(V) 30239 3-[[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfanyl]-1-propanol C13H16N2OS 详情 详情
(VI) 50208 (3-hydroxypropyl)[1-(2-methylphenyl)-1H-imidazol-2-yl]sulfoniumolate C13H16N2O2S 详情 详情
(VII) 50209 [1-(2-methylphenyl)-1H-imidazol-2-yl][3-[(methylsulfonyl)oxy]propyl]sulfoniumolate C14H18N2O4S2 详情 详情
(VIII) 50210 　 C9H8NNaO2 详情 详情

合成路线10

该中间体在本合成路线中的序号：

Alkylation of isonipecotamide (I) with n-butyl bromide in the presence of potassium carbonate gives the amide (II), which is reduced with lithium aluminum hydride to afford 1-butyl-4-piperidinylmethylamine (III). Conversion of indole-3-carboxylic acid (IV) to the acid chloride (V) is carried out with oxalyl chloride in dichloromethane containing N,N-dimethylformamide (DMF). Coupling of the amine (III) with the acid chloride (V) in dichloromethane in the presence of triethylamine gives N-[(1-butyl-4-piperidinyl)methyl]indole-3-carboxamide (VI). N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a] indole-10-carboxamide (VIII) is formed by treatment of the amide (VI) with N-chlorosuccinimide in chloroform followed by reaction with 3-bromopropanol and cyclization of the intermediate ether (VII) with potassium carbonate in acetone. Conversion to N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide hydrochloride (SB-207266) is effected by treatment of (VIII) with anhydrous HCl in ethanol.

参考文献 中间体
合成目标
【1】 Gaster, L.M.; Sanger, G.J.; SB-204070: 5-HT4 receptor antagonists and their potential therapeutic utility. Drugs Fut 1994, 19, 109-21.
【2】 Ford, A.P.D.W.; Clarke, D.E.; The 5-HT4 receptor. Med Res Rev 1993, 13, 633-62.
【3】 Gaster, L.; SB-207266A. Drugs Fut 1997, 22, 12, 1325.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(I) 11762 4-Piperidinecarboxamide; Isonipecotamide 39546-32-2 C6H12N2O 详情 详情
(II) 17150 1-butyl-4-piperidinecarboxamide C10H20N2O 详情 详情
(III) 17151 (1-butyl-4-piperidinyl)methanamine; (1-butyl-4-piperidinyl)methylamine C10H22N2 详情 详情
(IV) 17152 1H-Indole-3-carboxylic acid; Indole-3-Carboxylic acid; 3-Indolecarboxylic acid 771-50-6 C9H7NO2 详情 详情
(V) 17153 1H-indole-3-carbonyl chloride C9H6ClNO 详情 详情
(VI) 17154 N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide C19H27N3O 详情 详情
(VII) 17155 2-(3-bromopropoxy)-N-[(1-butyl-4-piperidinyl)methyl]-1H-indole-3-carboxamide C22H32BrN3O2 详情 详情
(VIII) 17156 N-[(1-butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide C22H31N3O2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XIII)

Condensation of acid chloride (VIII) 3-aminotropane (IX) provided amide (X). N-Demethylation of (X) was then achieved by treatment with 1-chloroethyl chloroformate, followed by hydrolysis and decarboxylation of the intermediate carbamate (XI) with MeOH. The resulting secondary amine (XII) was then alkylated with 3-bromopropanol (XIII) to afford the target hydroxypropyl derivative.

参考文献 中间体
合成目标
【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29.
【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
22014 1-chloro-1-[(chlorocarbonyl)oxy]ethane 50893-53-3 C3H4Cl2O2 详情 详情
(VIII) 36336 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride C13H12ClNO2 详情 详情
(IX) 12412 (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine C8H16N2 详情 详情
(X) 36337 1-isopropyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-1,2-dihydro-3-quinolinecarboxamide C21H27N3O2 详情 详情
(XI) 36338 1-chloroethyl (1R,5S)-3-[[(1-isopropyl-2-oxo-1,2-dihydro-3-quinolinyl)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate C23H28ClN3O4 详情 详情
(XII) 36339 N-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide C20H25N3O2 详情 详情
(XIII) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情

合成路线12

该中间体在本合成路线中的序号：

Reaction of vanillic acid (I) with 3-bromopropanol gave ether (II). Subsequent nitration of (II) with simultaneous oxidation of the primary alcohol employing nitric acid afforded the nitro diacid (IV), which by chemoselective esterification in the presence of a catalytic amount of p-toluenesulfonic acid yielded monoester (IV). After conversion of (IV) to the acid chloride upon treatment with oxalyl chloride, coupling with (S)-2-(hydroxymethyl)pyrrolidine (V) gave amide (VI). Catalytic hydrogenation of the nitro group of (VI), followed by protection of the intermediate aniline with 2,2,2-trichloroethyl chloroformate provided carbamate (VII). Further Swern oxidation of the alcohol group of (VII) with concomitant cyclization generated the pyrrolobenzodiazepine (VIII). The methyl ester of (VIII) was then hydrolyzed to carboxylic acid (IX).

参考文献 中间体
合成目标
【1】 Baraldi, P.G.; Cacciari, B.; Guiotto, A.; Leoni, A.; Romagnoli, R.; Spalluto, G.; Mongelli, N.; Howard, P.W.; Thurston, D.E.; Bianchi, N.; Gambari, R.; Design, synthesis and biological activity of a pyrrolo[2,1-c][1,4]benzodiazepine (PBD)-distamycin hybrid. Bioorg Med Chem Lett 1998, 8, 21, 3019.
【2】 Cacciari, B.; Baraldi, P.G.; Balboni, G.; et al.; Synthesis, in vitro antiproliferative activity, and DNA-binding properties of hybrid molecules containing pyrrolo[2,1-c][1,4]benzodiazepine and minor-groove-binding oligopyrrole carriers. J Med Chem 1999, 42, 25, 5131.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(I) 17786 4-hydroxy-3-methoxybenzoic acid; Vanillic acid 121-34-6 C8H8O4 详情 详情
(II) 26881 4-(3-hydroxypropoxy)-3-methoxybenzoic acid C11H14O5 详情 详情
(III) 26882 4-(2-carboxyethoxy)-5-methoxy-2-nitrobenzoic acid C11H11NO8 详情 详情
(IV) 26883 5-methoxy-4-(3-methoxy-3-oxopropoxy)-2-nitrobenzoic acid C12H13NO8 详情 详情
(V) 21347 (2S)pyrrolidinylmethanol 23356-96-9 C5H11NO 详情 详情
(VI) 26884 methyl 3-(4-[[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl]-2-methoxy-5-nitrophenoxy)propanoate C17H22N2O8 详情 详情
(VII) 26885 methyl 3-(4-[[(2S)-2-(hydroxymethyl)pyrrolidinyl]carbonyl]-2-methoxy-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]phenoxy)propanoate C20H25Cl3N2O8 详情 详情
(VIII) 26886 2,2,2-trichloroethyl (11S,11aS)-11-hydroxy-7-methoxy-8-(3-methoxy-3-oxopropoxy)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate C20H23Cl3N2O8 详情 详情
(IX) 26887 3-([(11S,11aS)-11-hydroxy-7-methoxy-5-oxo-10-[(2,2,2-trichloroethoxy)carbonyl]-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy)propionic acid C19H21Cl3N2O8 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.

参考文献 中间体
合成目标
【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283.
【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 .
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) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 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) 26935 2-(3,4-dichlorophenyl)acetonitrile 3218-49-3 C8H5Cl2N 详情 详情
(IV) 29461 2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile C17H21Cl2NO2 详情 详情
(V) 29132 ethyl 3-bromopropanoate 539-74-2 C5H9BrO2 详情 详情
(VI) 29462 ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate C22H29Cl2NO4 详情 详情
(VII) 29463 5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone C20H27Cl2NO3 详情 详情
(VIII) 29464 3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether C20H29Cl2NO2 详情 详情
(IX) 29465 3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(X) 29466 3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol C14H19Cl2NO 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 29467 [(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone C21H23Cl2NO2 详情 详情
(XIII) 29468 3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate C22H25Cl2NO4S 详情 详情
(XIV) 29469 [(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone C21H22Cl2INO 详情 详情
(XV) 28021 4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine 40807-61-2 C11H15NO 详情 详情
(XVI) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(XVII) 24014 Phenyllithium 591-51-5 C6H5Li 详情 详情
(XVIII) 29470 1-benzyl-4-phenyl-4-piperidinol C18H21NO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

The reaction of 3-bromopropanol (I) with TBDMS-Cl, DIEA and DMAP in dichloromethane gives the silyl ether (II), which is treated with PPh3 in refluxing acetonitrile yielding the phosphonium salt (III). The Wittig reaction of (III) with 3-cholestanone (IV) by means of BuLi in DME affords 3-[3-(tert-butyldimethylsilyloxy)propylidene]cholestane (V), which is reduced with H2 over PtO2 in ethyl acetate giving 3beta-[3-(tert-butyldimethylsilyloxy)propyl]cholestane (VI). The reaction of (VI) with TBAF in THF gives the 3-hydroxypropyl derivative (VII), which is treated with CBr4 and PPh3 in dichloromethane yielding the 3-bromopropyl derivative (VIII). The reaction of (VIII) with PPh3 in refluxing chlorobenzene affords the phosphonium salt (IX), which is submitted to a Wittig condensation with 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) by means of NaN(SiMe3)2 in THF giving the expected condensation intermediate (XI). The intermediate 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) has been obtained as follows: The dimerization of 3-chloro-2-hydroxybenzoic acid (XII) with H2CO and H2SO4 in methanol gives 5,5'-methylenebis(3-chloro-2-hydroxybenzoic acid) (XIII), which is fully methylated with SO4Me2 or CO3Me2 and K2CO3 yielding 5,5'-methylenebis(3-chloro-2-methoxybenzoic acid methyl ester) (XIV). Finally, this compound is oxidized with CrO3 in acetic anhydride to afford the desired intermediate (X).

参考文献 中间体
合成目标
【1】 Bader, J.P.; Cushman, M.; Golebiewski, W.M.; Design and synthesis of cosalane, a novel anti-HIV agent. Bioorg Med Chem Lett 1993, 3, 8, 1739.
【2】 Golebiewski, W.M.; McMahon, J.B.; Cushman, M.; et al.; Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. J Med Chem 1994, 37, 19, 3040.
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) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 30994 3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane C9H21BrOSi 详情 详情
(III) 30995 (3-[[tert-butyl(dimethyl)silyl]oxy]propyl)(triphenyl)phosphonium bromide C27H36BrOPSi 详情 详情
(IV) 30996 (10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one 15600-08-5 C27H46O 详情 详情
(V) 30997 tert-butyl(3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propyl ether C36H66OSi 详情 详情
(VI) 30998 tert-butyl(dimethyl)silyl 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl ether; tert-butyl(3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propoxy)dimethylsilane C36H68OSi 详情 详情
(VII) 30999 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-propanol C30H54O 详情 详情
(VIII) 31000 (3R,10S,13R,17R)-3-(3-bromopropyl)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene C30H53Br 详情 详情
(IX) 31001 (3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl)(trimethyl)phosphonium bromide C33H62BrP 详情 详情
(X) 26176 methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzoyl]-2-methoxybenzoate C19H16Cl2O7 详情 详情
(XI) 31002 methyl 3-chloro-5-(1-[3-chloro-4-methoxy-5-(methoxycarbonyl)phenyl]-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-butenyl)-2-methoxybenzoate C49H68Cl2O6 详情 详情
(XII) 31003 3-chloro-2-hydroxybenzoic acid C7H5ClO3 详情 详情
(XIII) 31004 5-(3-carboxy-5-chloro-4-hydroxybenzyl)-3-chloro-2-hydroxybenzoic acid C15H10Cl2O6 详情 详情
(XIV) 31005 methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzyl]-2-methoxybenzoate C19H18Cl2O6 详情 详情

合成路线15

该中间体在本合成路线中的序号：(I)

The reaction of 3-bromopropanol (I) with TBDMS-Cl, DIEA and DMAP in dichloromethane gives the silyl ether (II), which is treated with PPh3 in refluxing acetonitrile yielding the phosphonium salt (III). The Wittig reaction of (III) with 3-cholestanone (IV) by means of BuLi in DME affords 3-[3-(tert-butyldimethylsilyloxy)propylidene]cholestane (V), which is reduced with H2 over PtO2 in ethyl acetate giving 3beta-[3-(tert-butyldimethylsilyloxy)propyl]cholestane (VI). The reaction of (VI) with TBAF in THF gives the 3-hydroxypropyl derivative (VII), which is treated with CBr4 and PPh3 in dichloromethane yielding the 3-bromopropyl derivative (VIII). The reaction of (VIII) with PPh3 in refluxing chlorobenzene affords the phosphonium salt (IX), which is submitted to a Wittig condensation with 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) by means of NaN(SiMe3)2 in THF giving the expected condensation intermediate (XI). The intermediate 5,5'-carbonylbis(3-chloro-2-methoxybenzoic acid methyl ester) (X) has been obtained as follows: The dimerization of 3-chloro-2-hydroxybenzoic acid (XII) with H2CO and H2SO4 in methanol gives 5,5'-methylenebis(3-chloro-2-hydroxybenzoic acid) (XIII), which is fully methylated with SO4Me2 or CO3Me2 and K2CO3 yielding 5,5'-methylenebis(3-chloro-2-methoxy-benzoic acid methyl ester) (XIV). Finally, this compound is oxidized with CrO3 in acetic anhydride to afford the desired intermediate (X).

参考文献 中间体
合成目标
【1】 Golebiewski, W.M.; McMahon, J.B.; Cushman, M.; et al.; Design, synthesis, and biological evaluation of cosalane, a novel anti-HIV agent which inhibits multiple features of virus reproduction. J Med Chem 1994, 37, 19, 3040.
【2】 Bader, J.P.; Cushman, M.; Golebiewski, W.M.; Design and synthesis of cosalane, a novel anti-HIV agent. Bioorg Med Chem Lett 1993, 3, 8, 1739.
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) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(II) 30994 3-bromopropyl tert-butyl(dimethyl)silyl ether; (3-bromopropoxy)(tert-butyl)dimethylsilane C9H21BrOSi 详情 详情
(III) 30995 (3-[[tert-butyl(dimethyl)silyl]oxy]propyl)(triphenyl)phosphonium bromide C27H36BrOPSi 详情 详情
(IV) 30996 (10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one 15600-08-5 C27H46O 详情 详情
(V) 30997 tert-butyl(3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-[(10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-ylidene]propyl ether C36H66OSi 详情 详情
(VI) 30998 tert-butyl(dimethyl)silyl 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl ether; tert-butyl(3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propoxy)dimethylsilane C36H68OSi 详情 详情
(VII) 30999 3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-propanol C30H54O 详情 详情
(VIII) 31000 (3R,10S,13R,17R)-3-(3-bromopropyl)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene C30H53Br 详情 详情
(IX) 31001 (3-[(3R,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]propyl)(trimethyl)phosphonium bromide C33H62BrP 详情 详情
(X) 26176 methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzoyl]-2-methoxybenzoate C19H16Cl2O7 详情 详情
(XI) 31002 methyl 3-chloro-5-(1-[3-chloro-4-methoxy-5-(methoxycarbonyl)phenyl]-4-[(3S,10S,13R,17R)-17-[(1R)-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl]-1-butenyl)-2-methoxybenzoate C49H68Cl2O6 详情 详情
(XII) 31003 3-chloro-2-hydroxybenzoic acid C7H5ClO3 详情 详情
(XIII) 31004 5-(3-carboxy-5-chloro-4-hydroxybenzyl)-3-chloro-2-hydroxybenzoic acid C15H10Cl2O6 详情 详情
(XIV) 31005 methyl 3-chloro-5-[3-chloro-4-methoxy-5-(methoxycarbonyl)benzyl]-2-methoxybenzoate C19H18Cl2O6 详情 详情

合成路线16

该中间体在本合成路线中的序号：(A)

Acetonitrile derivative (I) is treated with BuLi and alkylated with 3-bromopropanol (A) to yield alcohol (II), which is further alkylated by means of LICKOR (n-BuLi/t-BuOK) and 1-chloro-3-bromopropane (B) to afford (III). Reaction of derivative (III) with secondary amine (VIII) in acetonitrile gives (IV). Amine (VIII) is obtained by trifluoroacetylation of azide (VI) with trifluoroacetic anhydride to yield (VII), which is then N-methylated by means of MeI and hydrolyzed with KOH. Finally, alcohol (IV) reacts with succinimido biotinate (V) in DMSO to provide the desired product.

参考文献 中间体
合成目标
【1】 Teodori, E.; et al.; Synthesis and binding properties of photoactivable biotin-conjugated verapamil derivatives for the study of P-170 glycoprotein. Bioorg Med Chem 1999, 7, 9, 1873.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(B) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(I) 25857 2-(3,4-dimethoxyphenyl)acetonitrile 93-17-4 C10H11NO2 详情 详情
(II) 42244 2-(3,4-dimethoxyphenyl)-5-hydroxypentanenitrile C13H17NO3 详情 详情
(III) 42245 5-chloro-2-(3,4-dimethoxyphenyl)-2-(3-hydroxypropyl)pentanenitrile C16H22ClNO3 详情 详情
(IV) 42249 5-[(2-azidophenethyl)(methyl)amino]-2-(3,4-dimethoxyphenyl)-2-(3-hydroxypropyl)pentanenitrile C25H33N5O3 详情 详情
(V) 42250 1-([5-[(3aS,4S,6aR)-3a,4,6a-trimethyl-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoyl]oxy)-2,5-pyrrolidinedione C17H25N3O5S 详情 详情
(VI) 42246 2-azidophenethylamine; 2-(2-azidophenyl)-1-ethanamine C8H10N4 详情 详情
(VII) 42247 N-(2-azidophenethyl)-2,2,2-trifluoroacetamide C10H9F3N4O 详情 详情
(VIII) 42248 N-(2-azidophenethyl)-N-methylamine; 2-(2-azidophenyl)-N-methyl-1-ethanamine C9H12N4 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IV)

The title compound was prepared by solid-phase synthesis on a Sasrin resin. The silylated m-hydroxyphenylacetic acid (I) was attached to the resin using DCC and DMAP to yield the acid-bound resin (II). The silyl group of (II) was then removed by treatment of resin (II) with tetrabutylammonium fluoride in THF. The resultant phenol (III) was coupled to 3-bromo-1-propanol (IV) under Mitsunobu conditions to afford the bromide functionalized resin (V). Displacement of the bromide ion of (V) with 2,2-diphenylethylamine (VI) furnished the secondary amine (VII), which was subjected to reductive alkylation with aldehyde (VIII) in the presence of NaBH(OAc)3 to produce the resin-bound product (IX). Cleavage from the solid support employing trifluoroacetic acid in CH2Cl2 provided the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Collins, J.L.; et al.; Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 2002, 45, 10, 1963.
【2】 Willson, T.M.; Collins, J.L.; Maloney, P.R.; Fivush, A.M.; Stewart, E.L. (GlaxoSmithKline plc); Chemical cpds.. WO 0224632 .
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),(II) 58560 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetic acid C14H22O3Si 详情 详情
(III) 58561 2-(3-hydroxyphenyl)acetic acid C8H8O3 详情 详情
(IV) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(V) 58562 2-[3-(3-bromopropoxy)phenyl]acetic acid C11H13BrO3 详情 详情
(VI) 38962 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine 3963-62-0 C14H15N 详情 详情
(VII) 58563 2-(3-{3-[(2,2-diphenylethyl)amino]propoxy}phenyl)acetic acid C25H27NO3 详情 详情
(VIII) 58564 2-chloro-3-trifluoromethyl benzaldehyde 93118-03-7 C8H4ClF3O 详情 详情
(IX) 58565 2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetic acid C33H31ClF3NO3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

In a solution-phase synthesis, 2,2-diphenylethylamine (VI) was reductively condensed with 2-chloro-3-(trifluoromethyl)benzaldehyde (VIII) using a polymer-supported borohydride resin to give the secondary amine (X). Mitsunobu coupling of methyl 3-hydroxyphenylacetate (XI) with 3-bromo-1-propanol (IV) afforded the bromopropyl ether (XII). Condensation of bromide (XII) with amine (X) in refluxing acetonitrile furnished amino ester (XIII). This was finally hydrolyzed with LiOH to the title carboxylic acid.

参考文献 中间体
合成目标
【1】 Willson, T.M.; Collins, J.L.; Maloney, P.R.; Fivush, A.M.; Stewart, E.L. (GlaxoSmithKline plc); Chemical cpds.. WO 0224632 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(VI) 38962 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine 3963-62-0 C14H15N 详情 详情
(VIII) 58564 2-chloro-3-trifluoromethyl benzaldehyde 93118-03-7 C8H4ClF3O 详情 详情
(X) 58566 N-[2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenyl-1-ethanamine; N-[2-chloro-3-(trifluoromethyl)benzyl]-N-(2,2-diphenylethyl)amine C22H19ClF3N 详情 详情
(XI) 58567 methyl 2-(3-hydroxyphenyl)acetate C9H10O3 详情 详情
(XII) 58568 methyl 2-[3-(3-bromopropoxy)phenyl]acetate C12H15BrO3 详情 详情
(XIII) 58569 methyl 2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate C34H33ClF3NO3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(III)

Demethylation of N-[2-(7-methoxynaphth-1-yl)ethyl]acetamide (I) with boron tribromide-dimethyl sulfide complex affords phenol (II). This is then alkylated with 3-bromopropanol (III) in the presence of K2CO3 to provide the hydroxypropyl derivative (IV). After conversion of alcohol (IV) into the corresponding mesylate (V), condensation with a further equivalent of phenol (II) in hot DMF furnishes the target dimeric compound

参考文献 中间体
合成目标
【1】 Guillaumet, G.; Renard, P.; Lesieur, D.; Yous, S.; Descamps-Francois, C.; Lefoulon, F.; Viaud, M.-C.; Delagrange, P.; Bennejean, C. (ADIR et Cie.); Substd. dimeric cpds., process for their preparation and pharmaceutical compsns. thereof. EP 1038863; FR 2791344; JP 2000319242; US 2002035114; US 6319930; US 6635650 .
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) 63525 N-{2-[7-(methyloxy)-1-naphthalenyl]ethyl}acetamide C15H17NO2 详情 详情
(II) 63526 N-[2-(7-hydroxy-1-naphthalenyl)ethyl]acetamide C14H15NO2 详情 详情
(III) 12573 3-Bromo-1-propanol; 3-Bromopropanol 627-18-9 C3H7BrO 详情 详情
(IV) 63527 N-(2-{7-[(3-hydroxypropyl)oxy]-1-naphthalenyl}ethyl)acetamide C17H21NO3 详情 详情
(V) 63528 3-({8-[2-(acetylamino)ethyl]-2-naphthalenyl}oxy)propyl methanesulfonate C18H23NO5S 详情 详情
Extended Information