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【结 构 式】

【分子编号】11263

【品名】ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate

【CA登记号】2969-81-5

【 分 子 式 】C6H11BrO2

【 分 子 量 】195.05614

【元素组成】C 36.95% H 5.68% Br 40.96% O 16.4%
与该中间体有关的原料药合成路线共 23 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20合成路线21合成路线22合成路线23

合成路线1

该中间体在本合成路线中的序号：(I)

Ethyl 4-bromobutyrate (I) is condensed with piperidine (II) in refluxing benzene to give ethyl 4-(1-piperidyl)butyrate (III), which is hydrolyzed with refluxing aqueous HCl to 4-(1-piperidyl)butyric acid (IV) . Finally, this acid is esterified with 5,5-dimethyl-8-(3-methyl-2-octyl)-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine (V) by means of dicyclohexylcarbodiimide (A) in methylene chloride.

参考文献 中间体
合成目标
【1】 Dren, A.T.; Ebert, D.M.; US 4025630 .
【2】 Razdan, R.K.; et al.; Drugs derived from cannabinoids. 2. Basic esters of nitrogen and carboxylic analogs. J Med Chem 1976, 19, 4, 454-461.
【3】 Castaner, J.; Paton, D.M.; Nabitan Hydrochloride. Drugs Fut 1980, 5, 9, 439.
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) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(II) 10158 Piperidine 110-89-4 C5H11N 详情 详情
(III) 39196 ethyl 4-(1-piperidinyl)butanoate C11H21NO2 详情 详情
(IV) 39197 4-(1-piperidinyl)butyric acid C9H17NO2 详情 详情
(V) 39198 8-(1,2-dimethylheptyl)-5,5-dimethyl-2-(2-propynyl)-1,3,4,5-tetrahydro-2H-chromeno[4,3-c]pyridin-10-ol C26H37NO2 详情 详情
(VI) 39199 N,N'-dicyclohexylcarbodiimide 538-75-0 C13H22N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butirate (III), which is cyclized in toluene by means of 2-hydroxypyridine.

参考文献 中间体
合成目标
【1】 Gobert, J.; Geerts, J.-P.; Bodson, G. (UCB SA); (S)-alpha-Ethyl-2-oxopyrrolidineacetamide. AU 8542530; EP 0162036; ES 8608485; ES 8704893; US 4696943; US 4837223 .
【2】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111.
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) 11262 (2S)-2-Aminobutanamide C4H10N2O 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 11264 ethyl 4-[[(1S)-1-(aminocarbonyl)propyl]amino]butanoate C10H20N2O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopirrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reacttion with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methythio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.

参考文献 中间体
合成目标
【1】 Cossement, E.; Motte, G.; Geerts, J.-P.; Gobert, J. (UCB SA); The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. GB 2225322 .
【2】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11265 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride 4635-59-0 C4H6Cl2O 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(IX) 11270 (2S)-2-Amino-4-(methylsulfanyl)butanamide C5H12N2OS 详情 详情
(X) 11271 ethyl 4-[[(1S)-1-(aminocarbonyl)-3-(methylsulfanyl)propyl]amino]butanoate C11H22N2O3S 详情 详情
(XI) 11272 (2S)-4-(Methylsulfanyl)-2-(2-oxo-1-pyrrolidinyl)butanamide C9H16N2O2S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XII)

This compound has been obtained by two different ways: 1) The Grignard condensation of 3-methylthiophene-2-carbaldehyde (I) with 3-methylthiophen-2-ylmagnesium bromide (II) in ethyl ether gives the carbinol (III), which is oxidized with MnO2 in dichloromethane yielding the corresponding ketone (IV). A new Grignard condensation of (IV) with cyclopropylmagnesium bromide (V) in THF affords the carbinol (VI), which is dehydrated with simultaneous cyclopropane ring opening by means of HBr or TMS-Br in acetic acid giving 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (VII).The condensation of (VII) with piperidine-2(R)-carboxylic acid ethyl ester (VIII) by means of K2CO3 and KI in acetone yields the ethyl ester (IX) of the target compound, which is finally hydrolyzed with NaOH in ethanol. 2) The reaction of 2-bromo-3-methylthiophene (X) with BuLi in ethyl ether gives the corresponding lithium derivative (XI), which is condensed with ethyl 4-bromobutyrate (XII) in the same solvent to afford the previously reported 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (VII).

参考文献 中间体
合成目标
【1】 Braestrup, C.; Gronvald, F.C. (Novo Nordisk A/S); Amino acid derivs.. AU 8661336; EP 0236342; ES 8800927; JP 1987503172; US 5010090; WO 8700171 .
【2】 Andersen, K.E.; et al.; The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4, 4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. J Med Chem 1993, 36, 12, 1716.
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) 12446 3-Methyl-2-thiophenecarboxaldehyde; 3-Methyl-2-thiophenecarbaldehyde 5834-16-2 C6H6OS 详情 详情
(II) 36973 bromo(3-methyl-2-thienyl)magnesium C5H5BrMgS 详情 详情
(III) 36974 bis(3-methyl-2-thienyl)methanol C11H12OS2 详情 详情
(IV) 36975 bis(3-methyl-2-thienyl)methanone C11H10OS2 详情 详情
(V) 12450 Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide 23719-80-4 C3H5BrMg 详情 详情
(VI) 36976 cyclopropyl[bis(3-methyl-2-thienyl)]methanol C14H16OS2 详情 详情
(VII) 36977 2-[4-bromo-1-(3-methyl-2-thienyl)-1-butenyl]-3-methylthiophene C14H15BrS2 详情 详情
(VIII) 12453 ethyl (3R)hexahydro-3-pyridinecarboxylate C8H15NO2 详情 详情
(IX) 36978 ethyl (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate C22H29NO2S2 详情 详情
(X) 12443 2-Bromo-3-methylthiophene 14282-76-9 C5H5BrS 详情 详情
(XI) 36979 (3-methyl-2-thienyl)lithium C5H5LiS 详情 详情
(XII) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

The Grignard condensation of phenylethynylmagnesium bromide with acetic anhydride in THF gives 4-phenyl-3-butyn-2-one (II), which is cyclized with 1-aminopyridinium iodide (III) by means of KOH in dichloromethane yielding the pyrazolopyridine (IV). The reaction of (IV) with 2-oxoacetic acid (V) by means of acetic acid in dimethoxyethane (DME) affords the butyric acid derivative (VI), which is cyclized with hydrazine in hot DMA to give the pyridazinone (VII). The condensation of (VII) with 4-bromobutyric acid ethyl ester (VIII) by means of benzyltriethylammonium chloride in hot DME/methanol provides the butyric ester intermediate (IX), which is finally hydrolyzed with NaOH.

参考文献 中间体
合成目标
【1】 Zanka, A.; et al.; Pilot-scale synthesis of a novel non-xanthine adenosine A1 receptor antagonist. 1,3-dipolar cycloaddition of pyridine N-immine to an acetylene. Org Process Res Dev 1998, 2, 5, 320.
【2】 Zanka, A.; Efficient large-scale synthesis of 4-phenyl-3-butyn-2-one, a key intermediate for a novel potent adenosine antagonist. Org Process Res Dev 1998, 2, 1, 60.
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) 32758 bromo(2-phenylethynyl)magnesium；phenylacetylenyl magnesium bromide;(phenylethynyl)magnesium bromide C8H5BrMg 详情 详情
(II) 32759 4-phenyl-3-butyn-2-one 1817-57-8 C10H8O 详情 详情
(III) 32760 1-aminopyridinium iodide C5H7IN2 详情 详情
(IV) 32760 1-aminopyridinium iodide C5H7IN2 详情 详情
(V) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(VI) 32761 2-hydroxy-4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)butyric acid C17H14N2O4 详情 详情
(VII) 17984 6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone C17H12N4O 详情 详情
(VIII) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(IX) 32762 ethyl 4-[6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinyl]butanoate C23H22N4O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

Alkylation of 5-hydroxy-2-nitrobenzaldehyde (I) with ethyl 4-bromobutyrate (II) in the presence of potassium carbonate at 110 C in DMF provided the aldehyde (III). Coupling of (III) with the phosphonate (IV) using triethylamine as the base afforded the unsaturated hydantoin derivative (V) as a mixture of geometrical isomers. Exhaustive catalytic hydrogenation of (V) over palladium on charcoal in DMF furnished the saturated aniline (VI), which underwent acid-catalyzed cyclization-dehydration in methanol at reflux, followed by oxidation upon addition of a molar equivalent of iodine to give the imidazo[4,5-b]quinoline derivative (VII). Alkaline hydrolysis of (VII) provided acid (VIII), which was coupled with N-cyclohexylmethylpiperazine, using diphenylphosphoryl azide in DMF at room temperature, to furnish BMY 43351 (IX). The dihydrochloride salt of (IX) was prepared by dissolution of the free base in a solution of 10% hydrogen chloride in methanol and subsequent precipitation with diethyl ether.

参考文献 中间体
合成目标
【1】 Wedding, D.L.; Meanwell, N.A.; Roth, H.R.; Wright, J.J.K.; Smith, E.C.R.; Diethyl 2,4-dioxoimidazolidine-5-phosphonates: Horner-Wadsworth-Emmons reagents for the mild and efficient preparations of C-5 unsaturated hydantoin derivatives. J Org Chem 1991, 56, 6897-904.
【2】 Russell, J.W.; Seiler, S.M.; Meanwell, N.A.; Fleming, J.S.; BMY 43351. Drugs Fut 1992, 17, 1, 15.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63929 1-(cyclohexylmethyl)piperazine C11H22N2 详情 详情
(I) 14942 5-hydroxy-2-nitrobenzaldehyde 42454-06-8 C7H5NO4 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 14944 ethyl 4-(3-formyl-4-nitrophenoxy)butanoate C13H15NO6 详情 详情
(IV) 14945 Diethyl 5-hydantoylphosphonate; diethyl 2,5-dioxo-4-imidazolidinylphosphonate 95378-36-2 C7H13N2O5P 详情 详情
(V) 14946 ethyl 4-[3-[(2,5-dioxotetrahydro-4H-imidazol-4-ylidene)methyl]-4-nitrophenoxy]butanoate C16H17N3O7 详情 详情
(VI) 14947 ethyl 4-[4-amino-3-[(2,5-dioxo-4-imidazolidinyl)methyl]phenoxy]butanoate C16H21N3O5 详情 详情
(VII) 14948 methyl 4-[(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoate C15H15N3O4 详情 详情
(VIII) 14949 4-[(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid C14H13N3O4 详情 详情
(IX) 14950 7-[4-[4-(cyclohexylmethyl)piperazino]-4-oxobutoxy]-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one C25H33N5O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IV)

The Friedel-Crafts condensation of indole (I) with 3-nitrobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3-(3-nitrobenzoyl)indole (III), which is allowed to react with ethyl 4-bromobutyrate (IV) by means of K2CO3 in DMF to yield 4-[3-(3-nitrobenzoyl)indol-1-yl]butyric acid ethyl ester (V). The hydrolysis of (V) with NaOH in dioxane/water affords the corresponding butyric acid (VI), which is hydrogenated with H2 over Pd/C in methanol/dioxane yielding 3-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (VII). Finally, this compound is condensed with bis(4-isobutylphenyl)chloromethane (VIII) by means of ethyldiisopropylamine in dichloromethane.

参考文献 中间体
合成目标
【1】 Mealy, N.; Castaner, J.; FK-143. Drugs Fut 1996, 21, 5, 473.
【2】 Golden, P.; Hashimoto, M.; Tanaka, H.; Sawada, Y.; Okada, S.; Sawada, K.; Kayakiri, N.; 4-(1-Benzoylindol-3-yl)butyric acids and FK143: Novel nonsteroidal inhibitors of steroid 5alpha-reductase (II). Chem Pharm Bull 1999, 47, 4, 481.
【3】 Okada, S.; Sawada, K.; Kayakiri, N.; Saitoh, Y.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Indole derivs. EP 0458207; JP 1992244061; US 5212320; US 5312829 .
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) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(II) 15293 3-nitrobenzoyl chloride; m-nitrobenzoyl chloride 121-90-4 C7H4ClNO3 详情 详情
(III) 15294 1H-indol-3-yl(3-nitrophenyl)methanone C15H10N2O3 详情 详情
(IV) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(V) 15296 ethyl 4-[3-(3-nitrobenzoyl)-1H-indol-1-yl]butanoate C21H20N2O5 详情 详情
(VI) 15297 4-[3-(3-nitrobenzoyl)-1H-indol-1-yl]butyric acid C19H16N2O5 详情 详情
(VII) 15298 4-[3-(3-aminobenzoyl)-1H-indol-1-yl]butyric acid C19H18N2O3 详情 详情
(VIII) 15299 1-[chloro(4-isobutylphenyl)methyl]-4-isobutylbenzene C21H27Cl 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 reaction of 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) with ethyl 4-bromobutyrate (II) by means of K2CO3 in refluxing acetone gives the corresponding condensation product (III), which is then hydrolyzed with NaOH in ethanol/water yielding compound (IV).

参考文献 中间体
合成目标
【1】 Castaner, J.; Graul, A.; Betotastine besilate. Drugs Fut 1998, 23, 3, 256.
【2】 Koda, A.; Kuroki, Y.; Fujiwara, H.; Takamura, S.; Yamano, K. (Ube Industries, Ltd.); Piperidine and piperazine derivs., process for preparing the same and pharmaceutical compsns. containing them. EP 0335586; JP 1989242574; JP 1990025465; JP 1993294929; US 4929618 .
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) 16053 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether C17H19ClN2O 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 16055 ethyl 4-[4-[(4-chlorophenyl)(2-pyridinyl)methoxy]piperidino]butanoate C23H29ClN2O3 详情 详情
(IV) 16056 4-[4-[(4-chlorophenyl)(2-pyridinyl)methoxy]piperidino]butyric acid C21H25ClN2O3 详情 详情

合成路线9

该中间体在本合成路线中的序号：(III)

A new synthesis of betotastine has been developed: The racemic 4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidine (I) is submitted to optical resolution with N-acyl amino acids such as N-acetyl-L-phenylalanine (preferred), N-acetyl-L-leucine, N-(benzyloxycarbonyl)-L-phenylalanine, N-(benzyloxycarbonyl)-L-valine, N-(benzyloxycarbonyl)-L-threonine, N-(benzyloxycarbonyl)-L-serine or with (2R,3R)-3-(5-chloro-2-nitrophenylsulfanyl)-2-hydroxy-3-(4-methoxyphenyl)propionic acid (preferred) or (2R,3R)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylsulfanyl)propionic acid as chiral intermediates, yielding the (S)-isomer (II). The condensation of (II) with ethyl 4-bromobutyrate (III) by means of a base such as Na2CO3, NaHCO3, K2CO3 or KHCO3 gives the expected 4-(1-piperidinyl)butyric acid ester (IV), which is finally hydrolyzed with NaOH or KOH in aqueous ethanol or methanol.

参考文献 中间体
合成目标
【1】 Kita, J.; Yoshioka, R.; Ozaki, Y.; Takemura, S.; Fujiwara, H.; Yamada, S. (Tanabe Seiyaku Co., Ltd.; Ube Industries, Ltd.); Acid-addition salts of optically active piperidine cpd. and process for producing the same. JP 1998237070; JP 2000198784; WO 9829409 .
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) 16053 2-[(4-chlorophenyl)(4-piperidinyloxy)methyl]pyridine; (4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether C17H19ClN2O 详情 详情
(II) 22441 (S)-(4-chlorophenyl)(2-pyridinyl)methyl 4-piperidinyl ether C17H19ClN2O 详情 详情
(III) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(IV) 22443 ethyl 4-(4-[[(S)-(4-chlorophenyl)(2-pyridinyl)methyl]oxy]-1-piperidinyl)butanoate C23H29ClN2O3 详情 详情

合成路线10

该中间体在本合成路线中的序号：(III)

Fischer esterification of 1-aminocyclohexanecarboxylic acid (I) provided the ethyl ester (II), which was alkylated with ethyl 4-bromobutyrate (III) in the presence of K2CO3 at 100 C to give aminodiester (IV). Dieckmann cyclization of (IV) using NaOEt afforded the azaspiro ketoester (V), which was decarboxylated under acidic conditions to yield ketone (VI). Addition of 4-chlorophenylmagnesium bromide (VII) to (VI) produced the tertiary acohol (VIII). This was dehydrated with concentrated H2SO4 to give the corresponding olefin as the sulfate salt, which was further treated with NaOH and then with HCl to furnish the corresponding hydrochloride.

参考文献 中间体
合成目标
【1】 Harris, P.J.; Kerrigan, F. (The Boots Company plc); Aza spiro alkanes derivs. as therapeutic agents. EP 0667860; JP 1996502985; US 5610161; WO 9411346 .
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) 31282 1-aminocyclohexanecarboxylic acid 2756-85-6 C7H13NO2 详情 详情
(II) 31283 ethyl 1-aminocyclohexanecarboxylate C9H17NO2 详情 详情
(III) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(IV) 31284 ethyl 1-[(4-ethoxy-4-oxobutyl)amino]cyclohexanecarboxylate C15H27NO4 详情 详情
(V) 31285 ethyl 5-oxo-1-azaspiro[5.5]undecane-4-carboxylate C13H21NO3 详情 详情
(VI) 31286 1-azaspiro[5.5]undecan-5-one C10H17NO 详情 详情
(VII) 25127 bromo(4-chlorophenyl)magnesium 873-77-8 C6H4BrClMg 详情 详情
(VIII) 31287 5-(4-chlorophenyl)-1-azaspiro[5.5]undecan-5-ol C16H22ClNO 详情 详情

合成路线11

该中间体在本合成路线中的序号：

Title compound was prepared by two synthetic ways. Friedel-Crafts acylation of N-(phenylsulfonyl)indole (II) with acid chloride (I) with concomitant O-debenzylation in the presence of AlCl3 yielded ketone (III). Then, hydroxyl group alkylation of (III) with alpha-bromo-p-xylene (IV) provided p-methylbenzyl ether (V). Subsequent displacement of the chloro group in (IV) by 1-(2-ethoxyphenyl)piperazine (VI) furnished (VII). After hydrolysis of sulfonyl group of (VII) with KOH, the resulting deprotected indole (VIII) was alkylated with ethyl 4-bromobutyrate to give (IX). Finally, hydrolysis of the ethyl ester of (IX) by means of ethanolic KOH provided the title carboxylic acid potassium salt.

参考文献 中间体
合成目标
【1】 Sato, H.; et al.; Dual-acting agents with alpha1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory activities. Synthesis and evaluation of arylpiperazine derivatives. Bioorg Med Chem Lett 1999, 9, 11, 1553.
【2】 Yoshida, K.; Kurimoto, T.; Takei, M.; Sato, H. (Zeria Pharmaceutical Co., Ltd.); Indole deriv. and medicine containing the same. EP 0753511; US 5760040; WO 9526955 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(I) 26120 4-(benzyloxy)-3-(3-chloropropoxy)benzoyl chloride C17H16Cl2O3 详情 详情
(II) 26121 1-(phenylsulfonyl)-1H-indole 40899-71-6 C14H11NO2S 详情 详情
(III) 26122 [3-(3-chloropropoxy)-4-hydroxyphenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone C24H20ClNO5S 详情 详情
(IV) 24623 1-(bromomethyl)-4-methylbenzene 104-81-4 C8H9Br 详情 详情
(V) 26123 [3-(3-chloropropoxy)-4-[(4-methylbenzyl)oxy]phenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone C32H28ClNO5S 详情 详情
(VI) 23055 ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine C12H18N2O 详情 详情
(VII) 26124 [3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]phenyl][1-(phenylsulfonyl)-1H-indol-3-yl]methanone C44H45N3O6S 详情 详情
(VIII) 26125 [3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]phenyl](1H-indol-3-yl)methanone C38H41N3O4 详情 详情
(IX) 26126 ethyl 4-(3-[3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate C44H51N3O6 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

2-Naphtalenethiol (I) was treated with ethyl 4-bromobutyrate (II) and NaH to give thioether (III). Alkylation of (III) with isobutyl iodide (IV) in the presence of LDA afforded racemic (V), which was then hydrolyzed to the acid (VI) on treatment with litium hydroxide. Coupling of racemic acid (VI) with (S)-leucinol (VII) yielded a mixture of diastereomeric amides, which were separated by column chromatography. Diastereoisomer (VIII) was oxidized with m-chloroperbenzoic acid to give sulfone (IX), and was further oxidized with DMSO and sulfur trioxide-pyridine complex to produce the target aldehyde.

参考文献 中间体
合成目标
【1】 Chatterjee, S.; et al.; Nonpeptidic inhibitors of recombinant human calpain; I. Bioorg Med Chem Lett 1997, 7, 3, 287-290.
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) 15234 2-Naphthalenethiol; 2-Naphthylhydrosulfide 91-60-1 C10H8S 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 18167 ethyl 4-(2-naphthylsulfanyl)butanoate C16H18O2S 详情 详情
(IV) 18168 1-iodo-2-methylpropane 513-38-2 C4H9I 详情 详情
(V) 18169 ethyl 4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanoate C20H26O2S 详情 详情
(VI) 18170 4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanoic acid C18H22O2S 详情 详情
(VII) 18171 L-(+)-leucinol; (S)-2-amino-4-methyl-1-pentanol; (2S)-2-amino-4-methyl-1-pentanol 7533-40-6 C6H15NO 详情 详情
(VIII) 18172 (2R)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-methyl-2-[2-(2-naphthylsulfanyl)ethyl]pentanamide C24H35NO2S 详情 详情
(IX) 18173 (2R)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-methyl-2-[2-(2-naphthylsulfonyl)ethyl]pentanamide C24H35NO4S 详情 详情

合成路线13

该中间体在本合成路线中的序号：(V)

5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Silvestre, J.S.; Castañer, J.; Bayes, M.; Tolvaptan. Drugs Fut 2002, 27, 4, 350.
【2】 Kondo, K.; Yamashita, H.; Ogawa, H.; et al.; 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem 1999, 7, 8, 1743.
【3】 Yabuuchi, Y.; Kora, S.; Tanaka, M.; Miyamoto, H.; Komatsu, H.; Kondo, K.; Yamashita, H.; Tominaga, M.; Ogawa, H.; Nakaya, K. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. US 5985869 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIa) 33001 methyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate C19H18ClNO5S 详情 详情
(VIIb) 33002 ethyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate C20H20ClNO5S 详情 详情
(I) 32996 5-chloro-2-nitrobenzoic acid 2516-95-2 C7H4ClNO4 详情 详情
(II) 32997 methyl 5-chloro-2-nitrobenzoate 51282-49-6 C8H6ClNO4 详情 详情
(III) 32998 methyl 2-amino-5-chlorobenzoate 5202-89-1 C8H8ClNO2 详情 详情
(IV) 32999 methyl 5-chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoate C15H14ClNO4S 详情 详情
(V) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(VI) 33000 methyl 5-chloro-2-[(4-ethoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino]benzoate C21H24ClNO6S 详情 详情
(VIII) 33003 7-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C17H16ClNO3S 详情 详情
(IX) 33004 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C10H10ClNO 详情 详情
(X) 33005 2-methyl-4-nitrobenzoyl chloride C8H6ClNO3 详情 详情
(XI) 33006 7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C18H15ClN2O4 详情 详情
(XII) 33007 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one C18H17ClN2O2 详情 详情
(XIII) 14770 2-methylbenzoyl chloride; o-Toluoyl chloride 933-88-0 C8H7ClO 详情 详情
(XIV) 33008 N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide C26H23ClN2O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IV)

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.

参考文献 中间体
合成目标
【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15

该中间体在本合成路线中的序号：(III)

Condensation of 7-methoxytetralone (I) with diethyl carbonate in the presence of NaH afforded ketoester (II), which was alkylated with ethyl 4-bromobutyrate (III) to give (IV). Hydrolysis and decarboxylation of (IV) using KOH in boiling MeOH provided ketoacid (V). Subsequent addition of thiophenol to (V) with concomitant esterification in the presence of ethanolic HCl, followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave rise to the (phenylthio)naphthalene (VI). Addition of methylmagnesium bromide to the ester function of (VI) yielded carbinol (VII), which was cyclized to the tetrahydroanthracene (VIII) employing ethereal H2SO4. After reductive removal of the phenylthio group of (VIII) by means of Raney Ni yielding (IX), its methyl ether group was cleaved with BBr3, providing phenol (X). Treatment with trifluoromethanesulfonic anhydride gave triflate (XI).

参考文献 中间体
合成目标
【1】 Ericsson, A.; Marinier, A.; Lapointe, P.; et al.; Synthesis and SAR of novel dihydroanthracene derivatives as retinoid analogs. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 43.
【2】 Starrett, J.E. Jr.; Tramposch, K.M.; Martel, A.; Nair, X.; Zusi, F.C.; Reczek, P.R.; Marinier, A.; Ericsson, A. (Bristol-Myers Squibb Co.); Retinoid-like cpds.. WO 9849136 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(I) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(II) 32514 ethyl 7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate C14H16O4 详情 详情
(III) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(IV) 32515 ethyl 2-(4-ethoxy-4-oxobutyl)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate C20H26O6 详情 详情
(V) 32516 4-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)butyric acid C15H18O4 详情 详情
(VI) 32517 ethyl 4-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]butanoate C23H24O3S 详情 详情
(VII) 32518 5-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]-2-methyl-2-pentanol C23H26O2S 详情 详情
(VIII) 32519 5,5-dimethyl-9-(phenylsulfanyl)-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-10-(phenylsulfanyl)-1,2,3,4-tetrahydroanthracene C23H24OS 详情 详情
(IX) 32520 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydroanthracene C17H20O 详情 详情
(X) 32521 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenol C16H18O 详情 详情
(XI) 32522 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl trifluoromethanesulfonate C17H17F3O3S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(III)

Condensation of 7-methoxytetralone (I) with diethyl carbonate in the presence of NaH afforded ketoester (II), which was alkylated with ethyl 4-bromobutyrate (III) to give (IV). Hydrolysis and decarboxylation of (IV) using KOH in boiling MeOH provided ketoacid (V). Subsequent addition of thiophenol to (V) with concomitant esterification in the presence of ethanolic HCl, followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave rise to the (phenylthio)naphthalene (VI). Addition of methylmagnesium bromide to the ester function of (VI) yielded carbinol (VII), which was cyclized to the tetrahydroanthracene (VIII) employing ethereal H2SO4. After reductive removal of the phenylthio group of (VIII) by means of Raney-Ni yielding (IX), its methyl ether group was cleaved with BBr3, providing phenol (X). Treatment with trifluoromethanesulfonic anhydride gave triflate (XI).

参考文献 中间体
合成目标
【1】 Ericsson, A.; Marinier, A.; Lapointe, P.; et al.; Synthesis and SAR of novel dihydroanthracene derivatives as retinoid analogs. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 43.
【2】 Starrett, J.E. Jr.; Tramposch, K.M.; Martel, A.; Nair, X.; Zusi, F.C.; Reczek, P.R.; Marinier, A.; Ericsson, A. (Bristol-Myers Squibb Co.); Retinoid-like cpds.. WO 9849136 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(I) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(II) 32514 ethyl 7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate C14H16O4 详情 详情
(III) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(IV) 32515 ethyl 2-(4-ethoxy-4-oxobutyl)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenecarboxylate C20H26O6 详情 详情
(V) 32516 4-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)butyric acid C15H18O4 详情 详情
(VI) 32517 ethyl 4-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]butanoate C23H24O3S 详情 详情
(VII) 32518 5-[7-methoxy-1-(phenylsulfanyl)-2-naphthyl]-2-methyl-2-pentanol C23H26O2S 详情 详情
(VIII) 32519 5,5-dimethyl-9-(phenylsulfanyl)-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-10-(phenylsulfanyl)-1,2,3,4-tetrahydroanthracene C23H24OS 详情 详情
(IX) 32520 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl methyl ether; 6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydroanthracene C17H20O 详情 详情
(X) 32521 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenol C16H18O 详情 详情
(XI) 32522 5,5-dimethyl-5,6,7,8-tetrahydro-2-anthracenyl trifluoromethanesulfonate C17H17F3O3S 详情 详情

合成路线17

该中间体在本合成路线中的序号：(IV)

Condensation of 5-nitroanthranilic acid (I) with formamidine hydrochloride (II) at 210 C generated the quinazolinone (III). Subsequent alkylation of (III) at the 3-N atom with ethyl 4-bromobutyrate (IV) in the presence of K2CO3 in DMF produced the quinazoline-3-butyrate ester (V). Finally, catalytic hydrogenation of the nitro group of (V) using Pd/C yielded the corresponding 6-aminoquinazoline.

参考文献 中间体
合成目标
【1】 Shih, H.; Deng, L.; Genini, D.; Cottam, H.B.; Leoni, L.M.; Chao, Q.; Carson, D.A.; Substituted isoquinolines and quinazolines as potential antiinflammatory agents. Synthesis and biological of inhibitors of tumor necrosis factor alpha. J Med Chem 1999, 42, 19, 3860.
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) 34443 2-amino-5-nitrobenzoic acid 616-79-5 C7H6N2O4 详情 详情
(II) 15369 Iminoformamide; Methanimidamide 463-52-5 CH4N2 详情 详情
(III) 34444 6-nitro-4(3H)-quinazolinone C8H5N3O3 详情 详情
(IV) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(V) 34445 ethyl 4-[6-nitro-4-oxo-3(4H)-quinazolinyl]butanoate C14H15N3O5 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Alkylation of 2-hydroxy-1-naphthaldehyde (I) with ethyl 4-bromobutyrate (II) in the presence of K2CO3 and tris[2-(2-methoxyethoxy)ethyl]amine furnished the naph-thoxybutyrate ester (III), which was hydrolyzed to the corresponding carboxylic acid (IV) using NaOH in aqueous dioxan. Condensation of (IV) with N-methyl rhodanine (V) by means of NaOAc in refluxing AcOH gave rise to the title compound.

参考文献 中间体
合成目标
【1】 Fujitani, B.; Mizuta, H.; Murata, M.; Synthesis and aldose reductase inhibitory activity of a new series of 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives. Eur J Med Chem 1999, 34, 12, 1061.
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) 38150 2-hydroxy-1-naphthaldehyde 708-06-5 C11H8O2 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 38151 ethyl 4-[(1-formyl-2-naphthyl)oxy]butanoate C17H18O4 详情 详情
(IV) 38152 4-[(1-formyl-2-naphthyl)oxy]butyric acid C15H14O4 详情 详情
(V) 38153 3-methyl-2-thioxo-1,3-thiazolidin-4-one C4H5NOS2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

Reaction of (S)-2-aminobutyramide (I) with ethyl 4-bromobutyrate (II) in the presence of triethylamine in toluene gives ethyl (S)-4-[1-(carbamoyl)propylamino]butyrate (III), which is cyclized in toluene by means of 2-hydroxypyridine. Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamoyl)propyl]-4-chlorobutyramide (V). An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)butyrate (VI) with sodium hydroxide to give racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane. A third procedure involves Ni-Raney desulfurization of (S)-4-(methylthio)-2-(2-oxopyrrolidin-1-yl)butyramide (XI), prepared from (S)-2-amino-4-(methylthio)butyramide (IX) by reaction with 4-chlorobutyryl chloride (IV). Compound (XI) can also be obtained by treatment of (IX) with ethyl 4-bromobutyrate (II) to give ethyl (S)-4-[1-(carbamoyl)-3-(methylthio)propylamino]butyrate (X), which is cyclized in toluene by means of 2-hydroxypyridine.

参考文献 中间体
合成目标
【1】 Gobert, J.; Geerts, J.-P.; Bodson, G. (UCB SA); (S)-alpha-Ethyl-2-oxopyrrolidineacetamide. AU 8542530; EP 0162036; ES 8608485; ES 8704893; US 4696943; US 4837223 .
【2】 Cossement, E.; Motte, G.; Geerts, J.-P.; Gobert, J. (UCB SA); The preparation of S-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. GB 2225322 .
【3】 Castaner, J.; Prous, J.; Mealy, N.; Levetiracetam. Drugs Fut 1994, 19, 2, 111.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(VII)-rac 11268 2-(2-Oxo-1-pyrrolidinyl)butyric acid 67118-31-4 C8H13NO3 详情 详情
(I) 11262 (2S)-2-Aminobutanamide C4H10N2O 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 11264 ethyl 4-[[(1S)-1-(aminocarbonyl)propyl]amino]butanoate C10H20N2O3 详情 详情
(IV) 11265 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride 4635-59-0 C4H6Cl2O 详情 详情
(V) 11266 (2S)-2-[(4-Chlorobutanoyl)amino]butanamide C8H15ClN2O2 详情 详情
(VI) 11267 ethyl 2-(2-oxo-1-pyrrolidinyl)butanoate C10H17NO3 详情 详情
(VIII) 11269 (2S)-2-(2-Oxo-1-pyrrolidinyl)butyric acid 102849-49-0 C8H13NO3 详情 详情
(IX) 11270 (2S)-2-Amino-4-(methylsulfanyl)butanamide C5H12N2OS 详情 详情
(X) 11271 ethyl 4-[[(1S)-1-(aminocarbonyl)-3-(methylsulfanyl)propyl]amino]butanoate C11H22N2O3S 详情 详情
(XI) 11272 (2S)-4-(Methylsulfanyl)-2-(2-oxo-1-pyrrolidinyl)butanamide C9H16N2O2S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

3,5-Dimethylphenol (I) was alkylated with ethyl 4-bromobutyrate (II) to provide the (dimethylphenoxy)butyrate ester (III), which was hydrolyzed under basic conditions to yield acid (IV). This was sulfonated with chlorosulfonic acid, and the resultant sulfonyl chloride (V) was condensed with Boc-diaminopropanoic acid (VI) to afford sulfonamide (VII). Coupling of (VII) with mono-benzyloxycarbonyl ethylenediamine (VIII) furnished amide (IX). Then, acid cleavage of the Boc protecting group of (IX) provided amine (X).

参考文献 中间体
合成目标
【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88.
【2】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 .
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) 46786 3,5-dimethylphenol 108-68-9 C8H10O 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 50998 ethyl 4-(3,5-dimethylphenoxy)butanoate C14H20O3 详情 详情
(IV) 50999 4-(3,5-dimethylphenoxy)butyric acid C12H16O3 详情 详情
(V) 51000 4-[4-(chlorosulfonyl)-3,5-dimethylphenoxy]butyric acid C12H15ClO5S 详情 详情
(VI) 25095 methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate C9H18N2O4 详情 详情
(VII) 51001 4-(4-[[((1S)-1-[[(tert-butoxycarbonyl)amino]methyl]-2-methoxy-2-oxoethyl)amino]sulfonyl]-3,5-dimethylphenoxy)butyric acid C21H32N2O9S 详情 详情
(VIII) 51002 benzyl 2-aminoethylcarbamate C10H14N2O2 详情 详情
(IX) 51003 methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate C31H44N4O10S 详情 详情
(X) 51004 methyl (2S)-3-amino-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]propanoate C26H36N4O8S 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

Vanillic acid (I) was alkylated with ethyl bromobutyrate (II) to afford ether (III). The ester function of (III) was then subjected to saponification, yielding diacid (IV). Nitration of (IV) gave the nitro compound (V). Selective esterification of the aliphatic carboxyl group of (V) was achieved employing p-toluenesulfonic acid in methanol, and the resultant mono-acid was further converted to the corresponding acid chloride (VI) upon treatment with oxalyl chloride. Coupling of acid chloride (VI) with (S)-pyrrolidine-2-carbaldehyde diethyl dithioketal (VII) provided amide (VIII). After the reduction of the nitro group of (VIII) by means of SnCl2, the resultant amino compound (IX) was protected as the N-Fmoc derivative (X). Thioketal deprotection of (X) with concomitant cyclization in the presence of HgCl2 and CaCO3 gave rise to the pyrrolobenzodiazepinone system (XI). The methyl ester of (XI) was then hydrolyzed under acidic conditions to furnish acid (XII).

参考文献 中间体
合成目标
【1】 Zhou, Q.; et al.; Design and synthesis of a novel DNA-DNA interstrand adenine-guanine cross-linking agent. J Am Chem Soc 2001, 123, 20, 4865.
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) 17786 4-hydroxy-3-methoxybenzoic acid; Vanillic acid 121-34-6 C8H8O4 详情 详情
(II) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(III) 52255 4-{[4-(ethyloxy)-4-oxobutyl]oxy}-3-(methyloxy)benzoic acid C14H18O6 详情 详情
(IV) 52256 4-[(3-carboxypropyl)oxy]-3-(methyloxy)benzoic acid C12H14O6 详情 详情
(V) 52257 4-[(3-carboxypropyl)oxy]-5-(methyloxy)-2-nitrobenzoic acid C12H13NO8 详情 详情
(VI) 52258 methyl 4-{[4-(chlorocarbonyl)-2-(methyloxy)-5-nitrophenyl]oxy}butanoate C13H14ClNO7 详情 详情
(VII) 52259 2-[bis(ethylsulfanyl)methyl]pyrrolidine; ethyl (ethylsulfanyl)(2-pyrrolidinyl)methyl sulfide C9H19NS2 详情 详情
(VIII) 52260 methyl 4-{[4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-2-(methyloxy)-5-nitrophenyl]oxy}butanoate C22H32N2O7S2 详情 详情
(IX) 52261 methyl 4-{[5-amino-4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-2-(methyloxy)phenyl]oxy}butanoate C22H34N2O5S2 详情 详情
(X) 52263 methyl 4-{[4-({2-[bis(ethylsulfanyl)methyl]-1-pyrrolidinyl}carbonyl)-5-({[(9H-fluoren-9-ylmethyl)oxy]carbonyl}amino)-2-(methyloxy)phenyl]oxy}butanoate C37H44N2O7S2 详情 详情
(XI) 52262 9H-fluoren-9-ylmethyl 11-hydroxy-7-(methyloxy)-8-{[4-(methyloxy)-4-oxobutyl]oxy}-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate C33H34N2O8 详情 详情
(XII) 52264 4-{[10-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-11-hydroxy-7-(methyloxy)-5-oxo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yl]oxy}butanoic acid C32H32N2O8 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VII)

The reaction of perhydroazepinone (I) with ethyl 2-bromoacetate (II) by means of LiHMDS in THF, followed by hydrolysis with KOH in methanol/water, gives the perhydroazepinylacetic acid (III), which is condensed with the pyrrolidine derivative (IV) by means of HOBt, WSCl and DIEA in dichloromethane to yield the adduct (V). The cleavage of the carbamate group of (V) with TFA in dichloromethane affords the 3-aminoperhydroazepinone (VI), which is condensed with ethyl 4-bromobutyrate (VII) by means of DIEA in acetonitrile to provide the 4-aminobutyrate derivative (VIII). The reaction of the cyano group of (VIII) with HCl in ethanol, followed by amonolysis with NH3 in the same solvent, gives the carboxamidine derivative (IX), which is hydrolyzed with KOH in ethanol/water to yield the target butyric acid derivative.

参考文献 中间体
合成目标
【1】 Park, C.-H.; Koo, B.-A.; Nam, W.-H. (C & C Research Laboratories); Substd. aromatic amidine deriv. and medicinal compsn. comprising the same. WO 0055156 .
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) 54736 2,2-dimethyl-N-[(3R)-2-oxoazepanyl]propanamide C11H20N2O2 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 54737 2-{(3R)-3-[(2,2-dimethylpropanoyl)amino]-2-oxoazepanyl}acetic acid C13H22N2O4 详情 详情
(IV) 50438 1-ethyl-2-[2-[(2S)pyrrolidinyl]ethyl]-1H-indole-6-carbonitrile C17H21N3 详情 详情
(V) 54738 N-[(3R)-1-(2-{(2R)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl}-2-oxoethyl)-2-oxoazepanyl]-2,2-dimethylpropanamide C30H41N5O3 详情 详情
(VI) 54739 2-[2-((2R)-1-{2-[(3R)-3-amino-2-oxoazepanyl]acetyl}pyrrolidinyl)ethyl]-1-ethyl-1H-indole-6-carbonitrile C25H33N5O2 详情 详情
(VII) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(VIII) 54740 ethyl 4-{[(3R)-1-(2-{(2R)-2-[2-(6-cyano-1-ethyl-1H-indol-2-yl)ethyl]pyrrolidinyl}-2-oxoethyl)-2-oxoazepanyl]amino}butanoate C31H43N5O4 详情 详情
(IX) 54741 ethyl 4-[((3R)-1-{2-[(2R)-2-(2-{6-[amino(imino)methyl]-1-ethyl-1H-indol-2-yl}ethyl)pyrrolidinyl]-2-oxoethyl}-2-oxoazepanyl)amino]butanoate C31H46N6O4 详情 详情

合成路线23

该中间体在本合成路线中的序号：(XIIb)

Reduction of 2-fluoro-6-(trifluoromethyl)benzonitrile (I) with BH3/THF in refluxing THF gives the benzylamine derivative (II), which by treatment with urea in the presence of HCl in refluxing water yields N-[2-fluoro-6-(trifluoromethyl)benzyl]urea (III). Cyclization of the urea (III) with diketene (IV) by means of NaI and TMSCl in acetonitrile provides the pyrimidine-2,4-dione derivative (V), which is then brominated with Br2 in AcOH to afford the 5-bromopyrimidine-2,4-dione derivative (VI). N-Alkylation of intermediate (VI) with N-Boc-D-phenylglycinol (VII) by means of PPh3 and DBAD in THF gives the 3-[2(R)-amino-2-phenylethyl]pyrimidine-2,4-dione derivative (VIII), which upon Suzuki condensation with 2-fluoro-3-methoxyphenylboronic acid (IX) in the presence of Na2CO3 and Pd(PPh3)4 in H2O/dioxane at 90 °C yields the 5-(2-fluoro-3-methoxyphenyl)pyrimidine-2,4-dione derivative (X). Deprotection of the N-protected benzylamine (X) by means of TFA in CH2Cl2 affords the benzylamine derivative (XI), which is finally N-alkylated with methyl (XIIa) or ethyl (XIIb) 4-bromobutyrate and DIEA or Et3N, respectively, in refluxing acetonitrile and the resulting methyl or ethyl esters, (XIIIa) or (XIIIb), saponified with NaOH or LiOH in THF/H2O or MeOH/H2O at 45-50 °C .

参考文献 中间体
合成目标
【1】 Chen, C., Wu, D., Guo, Z. et al. Discovery of sodium R-(+)-4-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylaminobutyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem 2008, 51(23):7478-85.
【2】 Guo, Z., Chen, Y., Chen, C. et al. (Neurocrine Biosciences, Inc.). Pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists. EP 1646389, JP 2007521309, JP 2011088902, US 2005038057, US 7056927, WO 200500765.
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) 68008 (R)-3-(2-amino-2-phenylethyl)-5- (2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- (trifluoromethyl)benzyl)-6-methylpyrimidine-2,4 (1H,3H)-dione 　 C28H24F5N3O3 详情 详情
(XIIa) 68011 methyl 4-bromobutanoate 4897-84-1 C5H9BrO2 详情 详情
(XIIb) 11263 ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate 2969-81-5 C6H11BrO2 详情 详情
(XIIIa) 68009 (R)-methyl 4-((2-(5-(2- fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3- dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amino) butanoate 　 C33H32F5N3O5 详情 详情
(XIIIb) 68010 (R)-ethyl 4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-yl)-1-phenylethyl)amino)butanoate 　 C34H34F5N3O5 详情 详情
(I) 67999 2-fluoro-6-(trifluoromethyl)benzonitrile 133116-83-3 C8H3F4N 详情 详情
(II) 68000 (2-fluoro-6-(trifluoromethyl)phenyl)methanamine 239087-06-0 C8H7F4N 详情 详情
(III) 68001 1-(2-fluoro-6-(trifluoromethyl)benzyl)urea;N-[2-fluoro-6-(trifluoromethyl)benzyl]urea 830346-46-8 C9H8F4N2O 详情 详情
(IV) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(V) 68002 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione 　 C13H10F4N2O2 详情 详情
(VI) 68003 5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione 　 C13H9BrF4N2O2 详情 详情
(VII) 68004 （R）－tert-butyl (2-hydroxy-1-phenylethyl)carbamate 102089-74-7 C13H19NO3 详情 详情
(VIII) 68006 (R)-tert-butyl (2-(5-bromo-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3- dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate 　 C26H26BrF4N3O4 详情 详情
(IX) 68005 2-fluoro-3-methoxyphenylboronic acid 352303-67-4 C7H8BFO3 详情 详情
(X) 68007 (R)-tert-butyl (2-(5-(2-fluoro-3- methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1 (6H)-yl)-1-phenylethyl)carbamate 　 C33H32F5N3O5 详情 详情
Extended Information