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【结 构 式】

【分子编号】23540

【品名】Phenol

【CA登记号】108-95-2

【 分 子 式 】C6H6O

【 分 子 量 】94.11304

【元素组成】C 76.57% H 6.43% O 17%
与该中间体有关的原料药合成路线共 28 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24合成路线25合成路线26合成路线27合成路线28

合成路线1

该中间体在本合成路线中的序号：(IX)

Benzoylation of 2’-deoxy-2’-fluoro-2’-C-methylcytidine (I) with PhCOCl in pyridine gives the tribenzoyl fluorocytidine (II) , which by benzamide hydrolysis with AcOH at reflux gives the uridine derivative (III). Ammonolysis of the benzoate esters of protected uridine (III) with NH3 in MeOH yields the deprotected uridine (IV) , which is then coupled with isopropyl N-[chloro(phenoxy)phosphoryl]-Lalaninate (V) , optionally in the presence of 1-methylimidazole in THF or CH2Cl2 , to provide 2’-deoxy-2’-fluoro-5’-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2’-methyluridine (VI) as a diastereomeric mixture . Finally, this compound is submitted to fractional crystallization and PSI-7977 is obtained as a single diastereoisomer .
Alaninate intermediate (V) is prepared by condensation of isopropyl L-alaninate hydrochloride (VIIa) or tosylate (VIIb) with phenyl dichlorophosphate (VIII) [generated by condensation of phenol (IX) with phosphoryl chloride (X) by means of Et3N in ether ] in the presence of Et3N or 1-methylimidazole in CH2Cl2 . Benzoylation of 2’-deoxy-2’-fluoro-2’-C-methylcytidine (I) with PhCOCl in pyridine gives the tribenzoyl fluorocytidine (II) , which by benzamide hydrolysis with AcOH at reflux gives the uridine derivative (III). Ammonolysis of the benzoate esters of protected uridine (III) with NH3 in MeOH yields the deprotected uridine (IV) , which is then coupled with isopropyl N-[chloro(phenoxy)phosphoryl]-Lalaninate (V) , optionally in the presence of 1-methylimidazole in THF or CH2Cl2 , to provide 2’-deoxy-2’-fluoro-5’-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2’-methyluridine (VI) as a diastereomeric mixture . Finally, this compound is submitted to fractional crystallization and PSI-7977 is obtained as a single diastereoisomer .
Alaninate intermediate (V) is prepared by condensation of isopropyl L-alaninate hydrochloride (VIIa) or tosylate (VIIb) with phenyl dichlorophosphate (VIII) [generated by condensation of phenol (IX) with phosphoryl chloride (X) by means of Et3N in ether ] in the presence of Et3N or 1-methylimidazole in CH2Cl2 . Benzoylation of 2’-deoxy-2’-fluoro-2’-C-methylcytidine (I) with PhCOCl in pyridine gives the tribenzoyl fluorocytidine (II) , which by benzamide hydrolysis with AcOH at reflux gives the uridine derivative (III). Ammonolysis of the benzoate esters of protected uridine (III) with NH3 in MeOH yields the deprotected uridine (IV) , which is then coupled with isopropyl N-[chloro(phenoxy)phosphoryl]-Lalaninate (V) , optionally in the presence of 1-methylimidazole in THF or CH2Cl2 , to provide 2’-deoxy-2’-fluoro-5’-O-[(O-isopropyl-L-alanino)(phenoxy)phosphoryl]-2’-methyluridine (VI) as a diastereomeric mixture . Finally, this compound is submitted to fractional crystallization and PSI-7977 is obtained as a single diastereoisomer .
Alaninate intermediate (V) is prepared by condensation of isopropyl L-alaninate hydrochloride (VIIa) or tosylate (VIIb) with phenyl dichlorophosphate (VIII) [generated by condensation of phenol (IX) with phosphoryl chloride (X) by means of Et3N in ether ] in the presence of Et3N or 1-methylimidazole in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Sofia, M.J., Du, J., Wang, P., Nagarathnam, D. (Pharmasset, Inc.). Nucleoside phosphoramidate prodrugs. WO 2008121634.
【2】 Sofia, M.J. Discovery and development of 2’-F-2’-C-methyl nucleosides and nucleotides for the treatment of HCV. 240th ACS Natl Meet (Aug 22-26, Boston) 2010, Abst MEDI 259.
【3】 Sofia, M.J, Bao, D., Chang, W. et al. Discovery of a β-D-2’-deoxy-2’-α-fluoro-2’-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem 2010, 53(19): 7202-18.
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) 68217 (R)-isopropyl 2-aminopropanoate hydrochloride;isopropyl L-alaninate hydrochloride 　 C6H13NO2.HCl 详情 详情
(VIIb) 68218 (R)-isopropyl 2-aminopropanoate 4-methylbenzenesulfonate 　 C6H13NO2.C7H8O3S 详情 详情
(I) 65914 2'-Deoxy-2'-fluoro-2'-C-methylcytidine 817204-33-4 C10H14FN3O4 详情 详情
(II) 65910 (2'R)-N-Benzoyl-2'-deoxy-2'-fluoro-2'-methylcytidine 3',5'-dibenzoate 817204-32-3 C31H26FN3O7 详情 详情
(III) 68214 ((2R,3R,4S,5R)-3-(benzoyloxy)-5-(2,4-dioxo-3,4 -dihydropyrimidin-1(2H)-yl)-4-fluoro-4- methyltetrahydrofuran-2-yl)methyl benzoate 　 C24H21FN2O7 详情 详情
(IV) 68213 1-((2R,3R,4S,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione 　 C10H13FN2O5 详情 详情
(V) 68215 isopropyl N-[chloro(phenoxy)phosphoryl]- Lalaninate;(2R)-isopropyl 2-((chloro(phenoxy) phosphoryl)amino)propanoate 　 C12H17ClNO4P 详情 详情
(VI) 68216 2’-deoxy-2’-fluoro-5’-O-[(O- isopropyl-L-alanino)(phenoxy)phosphoryl]-2’- methyluridine 　 C22H29FN3O9P 详情 详情
(VIII) 39640 Phenyl dichlorophosphate;phenyl phosphorodichloridate 770-12-7 C6H5Cl2O2P 详情 详情
(IX) 23540 Phenol 108-95-2 C6H6O 详情 详情
(X) 42493 Phosphoryl chloride; Phosphorus Oxychloride; Phosphorus (V) trichloride oxide 10025-87-3 Cl3OP 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

Compound can be prepared in three different ways: 1) By nitration of 2-phenoxymethanesulfonanilide (I) with nitric acid in acetic acid. 2) By condensation of 2-phenoxy-4-nitroaniline (II) with methanesulfonyl chloride in pyridine. 3) By condensation of 2-bromo-4-nitromethanesulfonanilide (III) with phenol (A) by means of KOH and pyridine in benzene.

参考文献 中间体
合成目标
【1】 Moore, G.; Harrington, J.K.; Substituted 2-phenoxy alkanesulfonanilides. US 3840597 .
【2】 2-Phenoxy alkyl sulphonalides. DE 2333643; FR 2190460; GB 1435755; JP 57136560; JP 57140712 .
【3】 Castaner, J.; Chatterjee, S.S.; R-805. Drugs Fut 1976, 1, 3, 145.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(I) 34063 N-(2-phenoxyphenyl)methanesulfonamide; 2-Phenoxymethanesulfonanilide 51765-51-6 C13H13NO3S 详情 详情
(II) 34064 4-nitro-2-phenoxyaniline; 4-nitro-2-phenoxyphenylamine C12H10N2O3 详情 详情
(III) 34065 N-(2-bromo-4-nitrophenyl)methanesulfonamide C7H7BrN2O4S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

By condensation of phenol (I) with propylene (II) at temperatures ranging from 230 C to 275 C and pressures up to 3000 atm. in an autoclave, using aluminum phenoxide as catalyst.

参考文献 中间体
合成目标
【1】 Napolitano, J.P.; Ecke, G.G.; Kolka, A.J.; The ortho-alkylation of phenols. J Org Chem 1956, 21, 712-713.
【2】 Kealy, T.J.; Coffman, D.D.; Thermal addition reactions of monocyclic phenols with ethylene. J Org Chem 1961, 26, 987-992.
【3】 Ecke, G.G.; Kolka, A.J.; Napolitano, J.P.; Filbey, A.H.; The ortho-alkylation of phenols. J Org Chem 1957, 22, 642-646.
【4】 Serradell, M.N.; Castaner, J.; Sneddon, J.M.; Blancafort, P.; Disoprofol. Drugs Fut 1982, 7, 3, 156.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 31974 1-propene 115-07-1 C3H6 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

1) The reaction of phenol (I) with epichlorohydrin (II) gives 1,2-epoxy-3-phenoxypropane (III), which is treated with isopropylamine (IV) to afford 3-(isopropylamino)-1-phenoxy-2-propanol (V). Cyclization of (V) with diethyl carbonate (VI) yields 3-isopropyl-5-(phenoxymethyloxazolidin-2-one) (VII), which is chloromethylated with formaldehyde - HCl giving 3-isopropyl-5-(4-chloromethylphenoxymethyl)oxazolidin-2-one (VIII). Etherification of (VIII) with ethylene glycol monoisopropyl ether (IX) yields the corresponding ether (XI), which is finally deprotected by alkaline hydrolysis.

参考文献 中间体
合成目标
【1】 Harting, J.; et al.; Pharmacodynamic profile of the selective beta1-adrenoceptor antagonist bisoprolol. Arzneim-Forsch Drug Res 1986, 36, 2, 200.
【2】 Castaner, J.; Prous, J.; Bisoprolol fumarate. Drugs Fut 1986, 11, 10, 829.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 23932 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether 122-60-1 C9H10O2 详情 详情
(IV) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(V) 23934 1-(isopropylamino)-3-phenoxy-2-propanol C12H19NO2 详情 详情
(VI) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(VII) 23936 3-isopropyl-5-(phenoxymethyl)-1,3-oxazolidin-2-one C13H17NO3 详情 详情
(VIII) 23937 5-[[4-(chloromethyl)phenoxy]methyl]-3-isopropyl-1,3-oxazolidin-2-one C14H18ClNO3 详情 详情
(IX) 23938 2-isopropoxy-1-ethanol 109-59-1 C5H12O2 详情 详情
(X) 23939 5-([4-[(2-isopropoxyethoxy)methyl]phenoxy]methyl)-3-isopropyl-1,3-oxazolidin-2-one C19H29NO5 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

3-Phenoxypyridine can be prepared by two different ways: 1) By reaction of 3-hydroxypyridine (I) with bromobenzene (II) by means of KOH and copper bronze at 150 C. 2) By reaction of 3-iodopyridine (III) with phenol (IV) by means of KOH and copper bronze at 150 C. The monosulfate salt is prepared by treating 3-phenoxypyridine with H2SO4.

参考文献 中间体
合成目标
【1】 Renshaw, R.R.; Conn, R.C.; Quaternary deivation of pyridyl ethers. Onium Compound. XVI. J Am Chem Soc 1937, 59, 297-301.
【2】 Butler, D.E. (Pfizer Inc.); 3-Phenoxypyridine monosulfate and a method for its production. BE 0861649; DE 2755016; ES 464922; FR 2392009; GB 1559918; JP 53077068; US 4128555 .
【3】 Owen, R.T.; Castaner, J.; Serradell, M.N.; CI-844. Drugs Fut 1985, 10, 4, 279.
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) 13365 Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene 108-86-1 C6H5Br 详情 详情
(II) 12911 3-Hydroxypyridine; 3-Pyridinol 109-00-2 C5H5NO 详情 详情
(III) 29108 3-iodopyridine C5H4IN 详情 详情
(IV) 23540 Phenol 108-95-2 C6H6O 详情 详情

合成路线6

该中间体在本合成路线中的序号：(B)

Reaction of 2-ethyloxazoline (A) with phenol (B) affords the propionamide (I). Treatment of (I) with phosgene yields the imino chloride (II), which is reacted with methylcarbazate to provide the amidrazone (III). Cyclodehydration of (III) gives the triazolone (IV). Alkylation of (IV) with 1-(3-chlorophenyl)-4-(3-chloropropyl) piperazine affords nefazodone, which is isolated as the hydrochloride salt.

参考文献 中间体
合成目标
【1】 Fathi, N.H.; et al.; J Heterocycl Chem 1985, 22, 10, 1121.
【2】 Eison, M.S.; Smith, D.W.; Madding, G.D.; Taylor, D.P.; Nefazodone Hydochloride. Drugs Fut 1987, 12, 8, 758.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 23540 Phenol 108-95-2 C6H6O 详情 详情
(A) 28216 2-ethyl-4,5-dihydro-1,3-oxazole 10431-98-8 C5H9NO 详情 详情
(I) 28217 N-(2-phenoxyethyl)propanamide C11H15NO2 详情 详情
(II) 28218 N-(2-phenoxyethyl)propanimidoyl chloride C11H14ClNO 详情 详情
(III) 28219 methyl 2-[(Z)-1-[(2-phenoxyethyl)amino]propylidene]-1-hydrazinecarboxylate C13H19N3O3 详情 详情
(IV) 28220 5-ethyl-4-(2-phenoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one C12H15N3O2 详情 详情
(V) 28221 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine 39577-43-0 C13H18Cl2N2 详情 详情
(C) 12556 methyl 1-hydrazinecarboxylate; methyl carbazate 6294-89-9 C2H6N2O2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

1) By condensation of phenol (I) with 1-n-butoxy-2,3-epoxypropane (VII) in presence of potassium hydroxide. 2) By condensation of phenol (I) with 1-chloro-2,3-epoxypropane (II) followed either by addition of n-butanol (VI) in presence of a Lewis acid or in presence of a base (IV).

参考文献 中间体
合成目标
【1】 Hoffmann, H.; et al.; Procedimiento de fabricacion de sustancias medicinalmente activas y metodo de preparacion de medicamentos de accion coleretica. ES 402799; FR 2134389; GB 1393451; US 3839587 .
【2】 Janiak, P. St.; Febuprol. Drugs Fut 1978, 3, 3, 191.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(III) 33456 1-chloro-3-phenoxy-2-propanol C9H11ClO2 详情 详情
(IV) 33457 sodium 1-butanolate; Sodium butoxide; Sodium n-butoxide 2372-45-4 C4H9NaO 详情 详情
(V) 23932 2-(phenoxymethyl)oxirane; oxiranylmethyl phenyl ether 122-60-1 C9H10O2 详情 详情
(VI) 29766 butanol; n-butanol; 1-butanol 71-36-3 C4H10O 详情 详情
(VII) 33458 2-(butoxymethyl)oxirane; butyl 2-oxiranylmethyl ether 2426-08-6 C7H14O2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(I)

The reaction of phenol (I) with ethyl 4-chloroacetoacetate (II) by means of KOH in DMSO gives ethyl 4 phenoxyacetoacetate (III), which by treatment with NH3 is converted into ethyl 3-amino-4-phenoxycrotonate (IV). The cyclization of (IV) with propargyl aldehyde (V) in hot toluene affords ethyl 2-(phenoxymethyl)nicotinate (VI), which is cyclized again by means of polyphosphoric acid (PPA) to yield 5,11-dihydro[1]benzoxepino[3,4-b)pyridin-5-one (VII). The reduction of (VII) with NaBH4 in ethanol gives the corresponding alcohol (VIII), which is finally condensed with N,N-diethylethylene diamine (IX) by means of SOCl2 in dichloromethane.

参考文献 中间体
合成目标
【1】 Harakawa, H.; Kumazawa, T.; Tanaka, H.; Oijo, Y.; Shuto, K.; Ishii, A.; Nakamizo, N.; Obase, H.; Oka, T.; Synthesis and antiulcer activity of 5,11-dihydro[1. J Med Chem 1988, 31, 4, 779.
【2】 Kumazawa, T.; Oiji, Y.; Shuto, K.; Tanaka, H. (Kyowa Hakko Kogyo Co., Ltd.); Benzepino[3,4-b]pyridine derivs.. EP 0129879; JP 1985006690; JP 1985078985; JP 1985089419; US 4547496 .
【3】 Castaner, J.; Prous, J.; KW-5805. Drugs Fut 1988, 13, 11, 954.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 23541 ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(III) 23542 ethyl 3-oxo-4-phenoxybutanoate C12H14O4 详情 详情
(IV) 23543 ethyl (Z)-3-amino-4-phenoxy-2-butenoate C12H15NO3 详情 详情
(V) 23544 propiolaldehyde C3H2O 详情 详情
(VI) 23545 ethyl 2-(phenoxymethyl)nicotinate C15H15NO3 详情 详情
(VII) 23546 [1]benzoxepino[3,4-b]pyridin-5(11H)-one C13H9NO2 详情 详情
(VIII) 23547 5,11-dihydro[1]benzoxepino[3,4-b]pyridin-5-ol C13H11NO2 详情 详情
(IX) 23548 N-(5,11-dihydro[1]benzoxepino[3,4-b]pyridin-5-yl)-N-[2-(dimethylamino)ethyl]amine; N(1)-(5,11-dihydro[1]benzoxepino[3,4-b]pyridin-5-yl)-N(2),N(2)-dimethyl-1,2-ethanediamine C17H21N3O 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

The reaction of phenol (I) with ethyl bromoacetate (II) by means of NaH in dimethoxyethane gives ethyl phenoxyacetate (III), which is condensed with dimethyl methylphosphonate (IV) by means of n-butyllithium in THF to afford dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy-5'beta-ormylcyclopent-1'alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in dimethoxyethane yields the ketonic lactone (VII), which is reduced with aluminum isopropoxide in refluxing toluene to give the hydroxy lactone (VIII). The hydrolysis of the protecting group of (VIII) with K2CO3 in methanol yields the dihydroxy lactone (IX), which is then protected with dihydropyran affording the bis(tetrahydropyranyloxy) compound (X). The reduction of the lactone group of (X) with diisobutylaluminum hydride in toluene yields the protected hemiacetal (XI), which is condensed with 4-pentinoic acid (XII) by means of LiCH3 in HMPT affording 6,9alpha-dihy-droxy-11alpha,15alpha-bistetrahydropyranyloxy-16-phenoxy-17,18,19,20-tetranorprost-4-yn-13-trans-enoic acid methyl ester (XIII) resulting from the methylation with CH2N2 of the acid intermediate.

参考文献 中间体
合成目标
【1】 Van Horn, A.R.; Garay, G.; Edwards, J.A. (Syntex (USA), Inc.); (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof. DE 2927715; EP 0008003; ES 482330; FR 2430939; GB 2025413; US 4178457 .
【2】 Muchowski, J.M.; Fried, J.H. (Syntex (USA), Inc.); 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives. DE 2627910; ES 449162; FR 2315263; US 3985791 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hillier, K.; RS-84,135. Drugs Fut 1982, 7, 11, 812.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 32040 ethyl 2-phenoxyacetate 2555-49-9 C10H12O3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 32041 dimethyl 2-oxo-3-phenoxypropylphosphonate 40665-68-7 C11H15O5P 详情 详情
(VI) 32042 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C21H18O5 详情 详情
(VII) 32043 (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H26O6 详情 详情
(VIII) 32044 (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H28O6 详情 详情
(IX) 32045 (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one C17H20O5 详情 详情
(X) 32046 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one C29H40O7 详情 详情
(XI) 32047 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C29H42O7 详情 详情
(XII) 32048 4-pentynoic acid 6089-09-4 C5H6O2 详情 详情
(XIII) 32049 methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate C35H50O9 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

This compound has been obtained by two related ways: 1) The reaction of phenol (I) with formaldehyde gives 4-(hydroxymethyl)phenol (II), which is treated with NaCN in hot DMF to yield 2-(4-hydroxyphenyl)acetonitrile (III). The hydrolysis of (III) in refluxing ethanol/water, catalyzed by a Pt catalyst affords the corresponding acetamide (IV), which is condensed with an excess of hot epichlorohydrin (V) by means of piperidine gives 2-[4-(2-oxiranylmethoxy)phenyl]acetamide (VI). Finally, the oxirane ring of (VI) is opened with isopropylamine in methanol. 2)The condensation of acetonitrile (III) with epichlorohydrin (V) as before gives the 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile (VIII), which is treated with isopropylamine (VII) in methanol yielding 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile (IX). Finally, this compound is hydrolyzed with refluxing ethanol/water catalyzed by a Pt catalyst as before to afford the target acetamide.

参考文献 中间体
合成目标
【1】 Akisanya, J.; et al.; A synthesis of atenolol using a nitrile hydration catalyst. Org Process Res Dev 1998, 2, 4, 274.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 29474 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol 623-05-2 C7H8O2 详情 详情
(III) 32753 2-(4-hydroxyphenyl)acetonitrile; 4-Hydroxybenzyl cyanide 14191-95-8 C8H7NO 详情 详情
(IV) 32754 p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide 17194-82-0 C8H9NO2 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(VI) 32755 2-[4-(2-oxiranylmethoxy)phenyl]acetamide C11H13NO3 详情 详情
(VII) 23933 2-Propanamine; Isopropylamine 75-31-0 C3H9N 详情 详情
(VIII) 32756 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile C11H11NO2 详情 详情
(IX) 32757 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile C14H20N2O2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(I)

The reaction of uniformly 14C-labeled phenol (I) with acetylenedicarboxylic acid dimethyl ester (II) gives the adduct (III), which is reduced with ammonium formate and Pd/C to yield the 2-phenoxysuccinic acid dimethyl ester (IV). The hydrolysis of (IV) in acidic medium (HCl) affords the succinic acid derivative (V), which is cyclized by means of P2O5 to provide 4-oxo-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VI). The reduction of (VI) by means of Ph3SiH and TFA gives 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (VII), which is condensed with 1(R)-phenylethylamine (VIII) by means of CDI to yield the corresponding amide (IX) as a diastereomeric mixture. The reduction of (IX) by means of NaAlH2(OC2H4OMe)2 affords the secondary amine (X), also as a diastereomeric mixture, which is resolved by chromatography. The desired isomer (XI) is condensed with the butyl bromide derivative (XII) by means of NaHCO3 and KI to provide the tertiary amine (XIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to furnish the target labeled Repinotan.

参考文献 中间体
合成目标
【1】 Seidel, D.; et al.; Synthesis of [14C]-labelled repinotan hydrochloride and its major metabolite M-6. J Label Compd Radiopharm 2002, 45, 13, 1115.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 24551 Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester 762-42-5 C6H6O4 详情 详情
(III) 62010 dimethyl (E)-2-phenoxy-2-butenedioate C12H12O5 详情 详情
(IV) 62011 dimethyl 2-phenoxysuccinate C12H14O5 详情 详情
(V) 62012 2-phenoxysuccinic acid C10H10O5 详情 详情
(VI) 62013 4-oxo-2-chromanecarboxylic acid C10H8O4 详情 详情
(VII) 17037 2-chromanecarboxylic acid C10H10O3 详情 详情
(VIII) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(IX) 17040 (2R)-N-[(1S)-1-phenylethyl]-3,4-dihydro-2H-chromene-2-carboxamide C18H19NO2 详情 详情
(X) 17041 (1S)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1S)-1-phenylethyl]amine C18H21NO 详情 详情
(XI) 62014 (1R)-N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-1-phenyl-1-ethanamine; N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-N-[(1R)-1-phenylethyl]amine C18H21NO 详情 详情
(XII) 17043 2-(4-bromobutyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione C11H12BrNO3S 详情 详情
(XIII) 62015 2-(4-{[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl][(1R)-1-phenylethyl]amino}butyl)-1H-1,2-benzisothiazole-1,1,3(2H)-trione C29H32N2O4S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IX)

1) The esterification of D-penicillamine (I) with trimethylsilyl chloride and DBU in DMF gives the expected ester (II), which is cyclized with 1,2-dibromoethane by means of DBU and DIEA in DMF and protected at the amino group with Fmoc-Cl and NMM to afford 4-(9-fluorenylmethoxycarbonyl)-2,2-dimethylthiomorpholine-3(S)-carboxylic acid (III), which by treatment with O-[tert-butyl(diphenyl)silyl]hydroxylamine (TBDPSO-NH2) and EDC in dichloro-methane yields the silylated carbohydroxamic acid (IV). The removal of the Fmoc group of (IV) with diethylamine in THF affords (V), which is sulfonated with 4-(4-pyridyloxy)phenylsulfonyl chloride (VI) and NMM in dichloroethane to give the protected prinomastat (VII). Finally, this compound is desilylated with concentrated HCl in methanol. The intermediate (VI) is obtained by condensation of 4-chloropyridine (VIII) with phenol (IX) at 150 C to give 4-phenoxypyridine (X), which is then sulfonated with chlorosulfonic acid and treated with oxalyl chloride to afford the desired sulfonyl chloride (VI).

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150.
【2】 Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses. US 5753653 .
【3】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .
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) 12567 (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine 1113-41-3 C5H11NO2S 详情 详情
(II) 32883 trimethylsilyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate C8H19NO2SSi 详情 详情
(III) 32884 (3S)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2,2-dimethyl-3-thiomorpholinecarboxylic acid C22H23NO4S 详情 详情
(IV) 32885 9H-fluoren-9-ylmethyl (3S)-3-[([[tert-butyl(diphenyl)silyl]oxy]amino)carbonyl]-2,2-dimethyl-4-thiomorpholinecarboxylate C38H42N2O4SSi 详情 详情
(V) 32886 (3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-3-thiomorpholinecarboxamide C23H32N2O2SSi 详情 详情
(VI) 32887 4-(4-pyridinyloxy)benzenesulfonyl chloride C11H8ClNO3S 详情 详情
(VII) 32888 (3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxamide C34H39N3O5S2Si 详情 详情
(VIII) 32889 4-chloropyridine 7379-35-3 C5H4ClN 详情 详情
(IX) 23540 Phenol 108-95-2 C6H6O 详情 详情
(X) 32890 4-phenoxypyridine; phenyl 4-pyridinyl ether 4783-86-2 C11H9NO 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 reaction of phenol (I) with 4-oxopentanoic acid (II) by means of H2SO4 gives 4,4-bis(4-hydroxyphenyl)pentanoic acid (III), which is esterified with MeOH and H2SO4 to yield the methyl pentanoate (IV). The condensation of (IV) with 2-(chloromethyl)quinoline (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally hydrolyzed with NaOH in methanol/dioxane to provide the target sodium salt. Alternatively, the intermediate methyl pentanoate (IV) can also be obtained by direct condensation of phenol (I) with methyl 4-oxopentanoate (VII) by means of H2SO4 as before.

参考文献 中间体
合成目标
【1】 Gunn, D.E.; Bhatia, P.; Kolasa, T.; et al.; Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis. J Med Chem 2000, 43, 17, 3322.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 36170 4-oxopentanoic acid 123-76-2 C5H8O3 详情 详情
(III) 22391 4,4-bis(4-hydroxyphenyl)pentanoic acid 126-00-1 C17H18O4 详情 详情
(IV) 22392 methyl 4,4-bis(4-hydroxyphenyl)pentanoate C18H20O4 详情 详情
(V) 13162 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine 4377-41-7 C10H8ClN 详情 详情
(VI) 22394 methyl 4,4-bis[4-(2-quinolinylmethoxy)phenyl]pentanoate C38H34N2O4 详情 详情
(VII) 50960 Methyl levulinate C6H10O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(XVI)

The reaction of adipic acid monomethyl ester (XIII) with SOCl2 gives the acyl chloride (XIV), which is brominated with NBS in carbon tetrachloride to yield 5-bromo-5-(chloroformyl)pentanoic acid methyl ester (XV). The reaction of (XV) with phenol (XVI) by means of DIEA in ethyl ether affords the mixed diester (XVII), which is reduced with tri-tert-butoxylithiumaluminum hydride in THF to provide 5-bromo-5-formylpentanoic acid methyl ester (XVIII). The cyclization of (XVIII) with chiral ethanone (XIX) by means of DIEA in hot dioxane gives the methyl ester (XX) of the target compound, which is finally hydrolyzed with NaOH in ethanol/water to obtain the target acid . The intermediate chiral ethanone (XIX) has been obtained as follows: The reaction of the chiral alcohol (VIII) with 4-hydroxybenzoic acid methyl ester (XXI) under Mitsunobu conditions (DEAD, PPh3) gives the chiral ether (XXII), which is then condensed with 2-methylpyridine (XXIII) by means of LiHMDS in THF to yield the target ethanone.

参考文献 中间体
合成目标
【1】 Sawada, K.; Tanaka, H.; Watanabe, S.; Kuroda, A.; Okada, S. (Fujisawa Pharmaceutical Co., Ltd.); Process for the preparation of indolizine derivs.. WO 9507279 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 49223 (1R)-1-(4-isobutylphenyl)-1-butanol C14H22O 详情 详情
(XIII) 49227 6-methoxy-6-oxohexanoic acid C7H12O4 详情 详情
(XIV) 49228 methyl 6-chloro-6-oxohexanoate C7H11ClO3 详情 详情
(XV) 49229 methyl 5-bromo-6-chloro-6-oxohexanoate C7H10BrClO3 详情 详情
(XVI) 23540 Phenol 108-95-2 C6H6O 详情 详情
(XVII) 49230 6-methyl 1-phenyl 2-bromohexanedioate C13H15BrO4 详情 详情
(XVIII) 49231 methyl 5-bromo-6-oxohexanoate C7H11BrO3 详情 详情
(XIX) 49232 1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]phenyl)-2-(2-pyridinyl)-1-ethanone C27H31NO2 详情 详情
(XX) 49233 methyl 4-[1-(4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoyl)-3-indolizinyl]butanoate C34H39NO4 详情 详情
(XXI) 10251 methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate 99-76-3 C8H8O3 详情 详情
(XXII) 49234 methyl 4-[[(1S)-1-(4-isobutylphenyl)butyl]oxy]benzoate C22H28O3 详情 详情
(XXIII) 17590 2-methylpyridine; 2-picoline 109-06-8 C6H7N 详情 详情

合成路线15

该中间体在本合成路线中的序号：

Further coupling and deprotection cycles with N(epsilon)-Boc-lysine (I), and O-tert-butyl-tyrosine (XVIII), yielded the peptide resins (XVII) and (XIX), respectively. Then, acetylation of the free amino group of peptide resin (XIX) with Ac2O, and final deprotection and cleavage from the resin by means of moist trifluoroacetic acid, phenol and triisopropylsilane furnished the title peptide amide.

参考文献 中间体
合成目标
【1】 Aldrich, J.V.; Murray, T.F.; Wan, Q.; A novel acetylated analogue of dynorphin A-(1-11) amide as a kappa-opioid receptor antagonist. J Med Chem 1999, 42, 16, 3011.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
23540 Phenol 108-95-2 C6H6O 详情 详情
(I) 18854 (2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid C26H32N2O6 详情 详情
(XVI) 34772 　 C114H166N22O24S3 详情 详情
(XVII) 34773 　 C125H186N24O27S3 详情 详情
(XVIII) 34774 (2S)-2-[tert-butyl[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid C28H29NO5 详情 详情
(XIX) 34775 　 C138H203N25O29S3 详情 详情

合成路线16

该中间体在本合成路线中的序号：

Alkylation of 4-fluorothiophenol (I) with 3-chloropropanol (II) in the presence of K2CO3 in DMF provided thioether (III), which was oxidized to sulfone (IV) using Oxone(R). Fluorine displacement in (IV) with phenol and K2CO3 gave phenoxy derivative (V). Subsequent Mitsunobu condensation of (V) with thioacetic acid afforded thioacetate ester (VI), which by further hydrolysis with NaOMe furnished the target thiol.

参考文献 中间体
合成目标
【1】 Freskos, J.N.; Abbas, Z.S.; Decrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. (Pharmacia Corp.); Thiol sulfone metalloprotease inhibitors. EP 0939628; WO 9803164 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
23540 Phenol 108-95-2 C6H6O 详情 详情
(I) 22971 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 371-42-6 C6H5FS 详情 详情
(II) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(III) 27076 3-[(4-fluorophenyl)sulfanyl]-1-propanol C9H11FOS 详情 详情
(IV) 27077 3-[(4-fluorophenyl)sulfonyl]-1-propanol C9H11FO3S 详情 详情
(V) 27078 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol C15H16O4S 详情 详情
(VI) 27079 S-[3-[(4-phenoxyphenyl)sulfonyl]propyl] ethanethioate C17H18O4S2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords the title product as a mixture of two diastereomeric racemates that are separated by column chromatography.

参考文献 中间体
合成目标
【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.
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) 53530 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione 606-23-5 C9H6O2 详情 详情
(II) 23540 Phenol 108-95-2 C6H6O 详情 详情
(III) 53531 2-Benzylidene-1,3-indandione n/a C16H10O2 详情 详情
(IV) 53532 　 n/a C16H10O3 详情 详情
(V) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(VI) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(VII) 53533 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione 19844-27-0 C10H5Cl2NO2 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 condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords the title product as a mixture of two diastereomeric racemates that are separated by column chromatography.

参考文献 中间体
合成目标
【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.
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) 53530 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione 606-23-5 C9H6O2 详情 详情
(II) 23540 Phenol 108-95-2 C6H6O 详情 详情
(III) 53531 2-Benzylidene-1,3-indandione n/a C16H10O2 详情 详情
(IV) 53532 　 n/a C16H10O3 详情 详情
(V) 53533 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione 19844-27-0 C10H5Cl2NO2 详情 详情
(VI) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(VII) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

Condensation of phenol (I) with acetone (II) in refluxing HOAc/HCl affords diol (III), which is finally converted into the desired compound by first reaction with chlorosulfonic acid in pyridine followed by treatment with aqueous KOH.

参考文献 中间体
合成目标
【1】 Bushman, F.D.; Rubins, K.; Molteni, V.; Hansen, M.; Rhodes, D.; Siegel, J.S.; A new class of HIV-1 integrase inhibitors: The 3,3,3',3'-tetramethyl-1,1'-spirobi (indan)-5',5',6,6'-tetrol family. J Med Chem 2000, 43, 10, 2031.
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 23199 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether 67-64-1 C3H6O 详情 详情
(III) 45615 　 C21H24O2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(I)

Friedel-Crafts acylation of phenol (I) with nonanoyl chloride (II) in the presence of AlCl3 afforded ketone (III). Aminosulfonyl chloride (V) was prepared by decarboxylation of chlorosulfonyl isocyanate (IV) upon treatment with formic acid. Finally, condensation of the sodium phenolate of (III) with aminosulfonyl chloride (V) furnished the title sulfamate.

参考文献 中间体
合成目标
【1】 Ahmed, S.; et al.; Novel inhibitors of the enzyme estrone sulfatase (ES). Bioorg Med Chem Lett 2001, 11, 6, 841.
【2】 Ahmed, S.; James, K.; Owen, C.P.; Patel, C.K.; Synthesis and biochemical evaluation of novel and potent inhibitors of the enzyme oestrone sulphatase (ES). J Steroid Biochem Mol Biol 2002, 80, 4-5, 419.
【3】 Ahmed, S. (Kingston University); Sulphamate cpds.. WO 0104086 .
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 30296 nonanoyl chloride 764-85-2 C9H17ClO 详情 详情
(III) 50915 4-n-Nonanoylphenol; 4-Hydroxynonanophenone 14392-69-9 C15H22O2 详情 详情
(IV) 14101 Chlorosulfonyl isocyanate 1189-71-5 CClNO3S 详情 详情
(V) 40598 amidosulfonoyl chloride 7778-42-9 H2ClNO2S 详情 详情

合成路线21

该中间体在本合成路线中的序号：(III)

Treatment of N-Boc-prolinol (I) with p-toluenesulfonyl chloride and pyridine afforded tosylate (II), which was condensed with the sodium salt of phenol (III) to produce ether (IV). Acid cleavage of the Boc protecting group of (IV) then gave pyrrolidine (V). Sulfonyl chloride (VII) was prepared by chlorination of the sodium salt of 5-isatinsulfonic acid (VI) with POCl3 in tetramethylenesulfone. Acylation of pyrrolidine (V) with acid chloride (VII) gave sulfonamide (VIII). Finally, the isatin nitrogen atom was methylated employing iodomethane in the presence of K2CO3.

参考文献 中间体
合成目标
【1】 Lee, D.; et al.; Potent and selective nonpeptide inhibitors of caspases 3 and 7. J Med Chem 2001, 44, 12, 2015.
【2】 Long, S.A.; Lee, D. (SmithKline Beecham Corp.); Caspases and apoptosis. EP 1001933; JP 2001512100; WO 9906367 .
【3】 Lee, D.; Long, S.A.; Elliott, J.D.; Gleason, J.G. (SmithKline Beecham Corp.); Caspases and apoptosis. WO 0122966 .
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) 49819 (S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinenemethanol C10H19NO3 详情 详情
(II) 49813 tert-butyl (2S)-2-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1-pyrrolidinecarboxylate C17H25NO5S 详情 详情
(III) 23540 Phenol 108-95-2 C6H6O 详情 详情
(IV) 49814 tert-butyl (2S)-2-(phenoxymethyl)-1-pyrrolidinecarboxylate C16H23NO3 详情 详情
(V) 49815 phenyl (2S)pyrrolidinylmethyl ether; (2S)-2-(phenoxymethyl)pyrrolidine C11H15NO 详情 详情
(VI) 49816 sodium 2,3-dioxo-5-indolinesulfonate C8H4NNaO5S 详情 详情
(VII) 49817 2,3-dioxo-5-indolinesulfonyl chloride C8H4ClNO4S 详情 详情
(VIII) 49818 5-[[(2S)-2-(phenoxymethyl)pyrrolidinyl]sulfonyl]-1H-indole-2,3-dione C19H18N2O5S 详情 详情

合成路线22

该中间体在本合成路线中的序号：(I)

The condensation of phenol (I) with ethyl bromoacetate (II) by means of NaH in refluxing dimethoxyethane gives phenoxyacetate (III), which by condensation with dimethyl methylphosphonate (IV) by means of butyllithium in THF is converted into dimethyl 2-oxo-3-phenoxypropylphosphonate (V). The Wittig condensation of (V) with (2'alpha-hydroxy-4'alpha-p-phenylbenzoyloxy)-5'beta-formylcyclopent-1’alpha-yl)acetic acid 1,2'-lactone (VI) by means of NaH in methoxyethane affords the phenoxylactone (VII), which is reduced witl aluminium isopropoxide in refluxing toluene to yield the hydroxylactone (VIII). The hydrolysis of (VIII) with K2CO3 in methanol gives the dihydroxylactone (IX), which is protected with dihydropyran and p-toluenesulfonic acid in methylene chloride giving the bis-tetrahydropyranyloxylactone (X). The reduction of (X) with diisobutylaluminium hydride in toluene yields [2'alpha-hydroxy-4'alpha-tetrahydropyranyloxy-5'beta-(3''alpha-tetrapyranyloxy-4''-phenoxybut-1''-trans-en-1''-yl)cyclopent-1'alpha-yl]acetaldehyde 1,2-hemiacetal (XI), which is condensed with 4-pentynoate (XII) by means of methyllithium and diisopropylamine in ether to afford the acetylenic prostaglandin derivative (XIII). The acetylation of (XIII) with acetic anhydride - triethylamine and dimethylaminopyridine in methylene chloride gives the diacetoxy compound (XIV), which by treatment with Cu2I2 and methyllithium in ether is converted into the cumulenic prostaglandin (XV). The elimination of the tetrahydropyran groups with acetic acid yields the dihydroxy-acetoxy ester (XVI), which is fully hydrolyzed with K2ClO3 in MeOH affording 8R-9alpha,11alpha,15alpha-trihydroxy-16-phenoxy-17,18,19,20-tetranorprosta-4,5,13-trans-trienoic acid (XVII). Finally this compound is methylated with diazomethane in ether

参考文献 中间体
合成目标
【1】 Serradell, M.N.; Castaner, J.; Adaikan, P.G.; Kottegoda, S.R.; Fenprostalene. Drugs Fut 1984, 9, 11, 817.
【2】 Muchowski, J.M.; et al. (Syntex (USA) Inc.); US 3985791 .
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) 23540 Phenol 108-95-2 C6H6O 详情 详情
(II) 10640 (1S,3R,4S,7S,8S,10R,13S)-7-(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2,5-trihydroxy-8,12,15,15-tetramethyl-9-oxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-10-yl acetate C41H58O8SSi 详情 详情
(III) 32040 ethyl 2-phenoxyacetate 2555-49-9 C10H12O3 详情 详情
(IV) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(V) 32041 dimethyl 2-oxo-3-phenoxypropylphosphonate 40665-68-7 C11H15O5P 详情 详情
(VI) 32042 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C21H18O5 详情 详情
(VII) 32043 (3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H26O6 详情 详情
(VIII) 32044 (3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate C30H28O6 详情 详情
(IX) 32045 (3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one C17H20O5 详情 详情
(X) 32046 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one C29H40O7 详情 详情
(XI) 32047 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol C29H42O7 详情 详情
(XII) 51633 methyl 4-pentynoate C6H8O2 详情 详情
(XIII) 32049 methyl 6-hydroxy-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate C35H50O9 详情 详情
(XIV) 32050 methyl 6-(acetoxy)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4-heptynoate C39H54O11 详情 详情
(XV) 32051 methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-4,5-heptadienoate C37H52O9 详情 详情
(XVI) 32052 methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoate C25H32O7 详情 详情
(XVII) 32053 7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]cyclopentyl]-4,5-heptadienoic acid C22H28O6 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (II), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords a mixture of two diastereomeric racemates from which the desired isomer (VIII) is separated by column chromatography (1-3). Finally, (VIII) is reduced with NaBH4 in methanol to provide a diastereomeric mixture from which the title product is separated by chromatography.

参考文献 中间体
合成目标
【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.
【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Tetracyclic heterocycles as antimicrobial agents. US 6153645; WO 0017206 .
【3】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
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) 53530 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione 606-23-5 C9H6O2 详情 详情
(II) 23540 Phenol 108-95-2 C6H6O 详情 详情
(III) 53531 2-Benzylidene-1,3-indandione n/a C16H10O2 详情 详情
(IV) 53532 　 n/a C16H10O3 详情 详情
(V) 53533 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione 19844-27-0 C10H5Cl2NO2 详情 详情
(VI) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(VII) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(VIII) 53598 　 n/a C26H15Cl2NO5 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

The condensation of indane-1,3-dione (I) with benzaldehyde (II) by means of piperidine in refluxing benzene gives 2-benzylideneindane-1,3-dione (III), which is treated with H2O2 and NaOH in methanol to yield the epoxide (IV). The condensation of (IV) with N-(3,4-dichlorophenyl)maleimide (V) (obtained by condensation of 3,4-dichloroaniline (VI) with maleic anhydride (VII) in diethyl ether) in refluxing benzene affords a mixture of two diastereomeric racemates from which the desired isomer (VIII) is separated by column chromatography (1-3). Finally, (VIII) is reduced with NaBH4 in methanol to provide a diastereomeric mixture from which the title product is separated by chromatography.

参考文献 中间体
合成目标
【1】 Hill, J.M.; Oliver, N.; Yu, X.; Wang, Z.; Finn, J.; Silverman, J.; Gallant, P.; Wendler, P.; Keith, D.; Synthesis and activity of spirocyclic tetrahydrofurans as inhibitors of phenylalanine tRNA synthetase. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1707.
【2】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Condensed imidazolidinones as tRNA synthetase inhibitors. WO 0018772 .
【3】 Wang, Z.; Hill, J.; Finn, J.; Yu, X.Y.; Keith, D.; Gallant, P.; Wendler, P. (Cubist Pharmaceuticals, Inc.); Tetracyclic heterocycles as antimicrobial agents. US 6153645; WO 0017206 .
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) 53530 1,3-Diketohydrindene; 1,3-Indandione; 1,3-Indanedione 606-23-5 C9H6O2 详情 详情
(II) 23540 Phenol 108-95-2 C6H6O 详情 详情
(III) 53531 2-Benzylidene-1,3-indandione n/a C16H10O2 详情 详情
(IV) 53532 　 n/a C16H10O3 详情 详情
(V) 53533 1-(3,4-dichlorophenyl)-1H-pyrrole-2,5-dione 19844-27-0 C10H5Cl2NO2 详情 详情
(VI) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(VII) 11182 2,5-Furandione; Maleic anhydride 108-31-6 C4H2O3 详情 详情
(VIII) 53598 　 n/a C26H15Cl2NO5 详情 详情

合成路线25

该中间体在本合成路线中的序号：(XII)

An alternative route to the intermediate bromide (IX) has been reported. Condensation of phenol (XII) with 1,1,1-trichloro-2-methyl-2-propanol (V) led to 2-phenoxyisobutyric acid (XIII), which was further esterified by treatment with SOCl2 in EtOH to yield (XIV). Friedel-Crafts acylation of (XIV) with bromoacetyl bromide (XV) in the presence of AlCl3 provided the phenacyl bromide (XVI). The corresponding phenethyl bromide (IX) was then obtained by reduction of ketone (XVI) with triethylsilane in trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 25975 1,1,1-trichloro-2-methyl-2-propanol 57-15-8 C4H7Cl3O 详情 详情
(IX) 56067 ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate C14H19BrO3 详情 详情
(XII) 23540 Phenol 108-95-2 C6H6O 详情 详情
(XIII) 56069 2-methyl-2-phenoxypropanoic acid C10H12O3 详情 详情
(XIV) 56070 ethyl 2-methyl-2-phenoxypropanoate C12H16O3 详情 详情
(XV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XVI) 56071 ethyl 2-[4-(2-bromoacetyl)phenoxy]-2-methylpropanoate C14H17BrO4 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VII)

Alkylation of adenine (I) by means of (R)-propylene carbonate (II) in the presence of NaOH in hot DMF provided (R)-9-(2-hydroxypropyl)adenine (III). This was condensed with tosylate (IV) using magnesium tert-butoxide to furnish the alkoxymethylphosphonate (V). Phosphonic acid (VI) was then obtained by hydrolysis of the phosphate ester groups with bromotrimethylsilane. Monophenyl phosphonate (IX) was prepared by either coupling of acid (VI) with phenol (VII) in the presence of DCC or by previous activation of (VI) with SOCl2, and then coupling with phenoxytrimethylsilane (VIII). Further activation of (IX) with SOCl2 to give (X), followed by its condensation with L-alanine isopropyl ester (XI), yielded phosphonamide (XII) as a mixture of diastereomers. The title isomer was then isolated by several alternative procedures, including column chromatography over various supports and fractional crystallization.

参考文献 中间体
合成目标
【1】 Prisbe, E.J.; Lee, W.A.; Rohloff, J.C.; Becker, M.W.; Chapman, H.H.; Cihlar, T.; Eisenberg, E.J.; He, G.-X.; Kernan, M.R.; Sparacino, M.L. (Gilead Sciences Inc.); Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same. WO 0208241 .
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) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(II) 19244 (4S)-4-methyl-1,3-dioxolan-2-one C4H6O3 详情 详情
(III) 19232 (2S)-1-(6-amino-9H-purin-9-yl)-2-propanol C8H11N5O 详情 详情
(IV) 12072 Dibromoneopentyl glycol; 2,2-Bis(bromomethyl)-1,3-propanediol 3296-90-0 C5H10Br2O2 详情 详情
(V) 19246 diethyl [[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonate C13H22N5O4P 详情 详情
(VI) 19252 [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy]methylphosphonic acid C9H14N5O4P 详情 详情
(VII) 23540 Phenol 108-95-2 C6H6O 详情 详情
(VIII) 58583 Trimethylsilylphenoxide; Phenoxytrimethylsilane 1529-17-5 C9H14OSi 详情 详情
(IX) 58584 phenyl hydrogen {[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy}methylphosphonate C15H18N5O4P 详情 详情
(X) 58585 phenyl {[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy}methylphosphonate chloride C15H17ClN5O3P 详情 详情
(XI) 58586 isopropyl (2S)-2-aminopropanoate C6H13NO2 详情 详情
(XII) 58587 isopropyl (2S)-2-{[({[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethyl]oxy}methyl)(phenoxy)phosphoryl]amino}propanoate C21H29N6O5P 详情 详情

合成路线27

该中间体在本合成路线中的序号：(XIII)

Condensation of 4-nitro-ortho-phthalonitrile (XII) with phenol (XIII) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (XIV) , which by hydrolysis with NaOH or KOH in refluxing MeOH yields 4-phenoxyphthalic acid (I) . Dehydration of dicarboxylic acid (I) using Ac2O and AcOH at reflux provides the phthalic anhydride (XV), which is then condensed with methyl 2-isocyanoacetate (XVI) using DBU in THF to generate the oxazole derivative (XVII). Rearrangement of intermediate (XVII) with HCl in MeOH at 60 °C leads to the isoquinoline derivative (XVIII), which is partially chlorinated by means of POCl3 at 70 °C to afford the 1-chloro-isoquinoline derivative (XIX). Substitution of chlorine in intermediate (XIX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (XX), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (IX). Coupling of carboxylic acid (IX) with methyl glycinate hydrochloride (XXI) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields the methyl ester (XXII), which is finally hydrolyzed with aqueous NaOH in THF .

参考文献 中间体
合成目标
【1】 Arend, M.P., Flippin, L.A., Du, X., Ho, W.-B., Turtle, E.D., Guenzler-Pukall, V. (FibroGen, Inc.). Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin. WO 2004108681.
【2】 Kang, X., Long, W., Zhang, J., Hu, Y., Wang, Y. (Zhejiang Beta Pharma, Inc.). Polymorphic forms of compounds as prolyl hydroxylase inhibitor, and uses thereof. EP 2734504; CN 104024227; WO 2013013609.
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) 67865 4-phenoxyphthalic acid 　 C14H10O5 详情 详情
(IX) 67872 4-(benzyloxy)-1-methyl-6-phenoxyisoquinoline-3-carboxylic acid 　 C21H21NO4 详情 详情
(XII) 67875 4-nitro-ortho-phthalonitrile 31643-49-9 C8H3N3O2 详情 详情
(XIII) 23540 Phenol 108-95-2 C6H6O 详情 详情
(XIV) 67876 4-phenoxy-ortho-phthalonitrile 38791-62-7 C14H8N2O 详情 详情
(XV) 67878 5-phenoxyisobenzofuran-1,3-dione 　 C14H8O4 详情 详情
(XVI) 67877 methyl 2-isocyanoacetate 39687-95-1 C4H5NO2 详情 详情
(XVII) 67879 2-(4-(methoxycarbonyl)oxazol-5-yl)-5-phenoxybenzoic acid 　 C18H13NO6 详情 详情
(XVIII) 67880 methyl 4-hydroxy-1-oxo-7-phenoxy-1,2-dihydroisoquinoline-3-carboxylate 　 C17H13NO5 详情 详情
(XIX) 67881 methyl 1-chloro-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C17H12ClNO4 详情 详情
(XX) 67882 methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate 　 C18H15NO4 详情 详情
(XXI) 67884 methyl glycinate hydrochloride 5680-79-5 C3H7NO2.HCl 详情 详情
(XXII) 67883 methyl 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetate 　 C20H18N2O5 详情 详情

合成路线28

该中间体在本合成路线中的序号：(XIII)

Condensation of 5-bromophthalide (XXIII) with phenol (XIII) by means of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (XXIV), which is submitted to lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene to yield 2-(chloro-methyl)-4-phenoxybenzoyl chloride (XXV). Esterification of acid chloride (XXV) with MeOH at 50 °C provides the methyl ester (XXVI), which is then condensed with methyl N-tosylglycinate (XXVII) in the presence of K2CO3 and NaI in DMF at 50 °C to afford the N-substituted amino ester (XXVIII). Cyclization of diester (XXVIII) with NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXIX), which is submitted to Mannich reaction with bis(dimethylamino)methane (XXX) by means of AcOH at 57 °C to provide the 1-(dimethylaminomethyl)isoquinoline derivative (XXXI). Treatment of compound (XXXI) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XXXII). Hydrogenolysis of benzylic acetate (XXXII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XX), which is finally condensed with glycine (II) by means of NaOMe in MeOH at 110 °C .

参考文献 中间体
合成目标
【1】 Thompson, M.D., Park, J.M., Arend, M.P. (FibroGen, Inc.). Process for making isoquinoline compounds. CN 103435546; WO 2014014834.
【2】 Witschi, C., Park, J.M., Thompson, M.D., Martinelli, M.J., Yeowell, D.A.,Arend, M.P. (FibroGen, Inc.). Crystalline forms of a prolyl hydroxylase inhibitor. WO 2014014835, US 2014024675.
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) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XIII) 23540 Phenol 108-95-2 C6H6O 详情 详情
(XX) 67882 methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate 　 C18H15NO4 详情 详情
(XXIII) 33229 5-bromophthalide; 5-bromo-2-benzofuran-1(3H)-one 64169-34-2 C8H5BrO2 详情 详情
(XXIV) 67885 5-phenoxyphthalide 57830-14-5 C14H10O3 详情 详情
(XXV) 67886 2-(chloromethyl)-4-phenoxybenzoyl chloride 　 C14H10Cl2O2 详情 详情
(XXVI) 67887 methyl 2-(chloromethyl)-4-phenoxybenzoate 　 C15H13ClO3 详情 详情
(XXVII) 57744 methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate 2645-02-5 C10H13NO4S 详情 详情
(XXVIII) 67888 methyl 2-((N-(2-methoxy-2-oxoethyl)-4-methylphenylsulfonamido)methyl)-4-phenoxybenzoate 　 C25H25NO7S 详情 详情
(XXIX) 67889 methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C17H13NO4 详情 详情
(XXX) 14349 N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine 51-80-9 C5H14N2 详情 详情
(XXXI) 67890 methyl 1-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C20H20N2O4 详情 详情
(XXXII) 67891 methyl 1-(acetoxymethyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate 　 C20H17NO6 详情 详情
Extended Information