(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin -Drug Synthesis Database

【结构式】

【分子编号】13917

【品名】(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin

【CA登记号】67843-74-7

【分子式】C₃H₅ClO

【分子量】92.5248

【元素组成】C 38.94% H 5.45% Cl 38.32% O 17.29%

与该中间体有关的原料药合成路线共 8 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1

该中间体在本合成路线中的序号：(XIb)

Esterification of 3,4-dichlorophenylacetic acid (I) with HCl/EtOH at reflux followed by radical bromination of the resulting ethyl ester (II) with NBS in the presence of HBr or (PhCOO)2 in refluxing CCl4 provides ethyl α-bromo-(3,4-dichlorophenyl)acetate (III). Tandem Michael addition and cyclization of ethyl bromoacetate (III) with ethyl acrylate (IV) by means of NaH and a catalytic amount of EtOH in ethyl ether gives diethyl cis-1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylate (V). After saponification with KOH in EtOH/H2O, the resulting diacid (VI) is cyclized with urea in refluxing xylene to yield the bicyclic imide (VII). Subsequent reduction of imide (VII) with BH3/THF or sodium bis(2-methoxyethoxy)aluminum hydride (Vitride, Red-Al) affords racemic 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) , which is finally treated with HCl in Et2O and submitted to enantiomeric separation by chiral chromatography .
Cyclocondensation of (3,4-dichlorophenyl)acetonitrile (X) with racemic epichlorohydrin (XIa) in the presence of NaNH2 in THF gives 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile as a diastereomeric mixture enriched in the cis-isomers (XIIa). Oxidation of alcohol (XIIa) with H5IO6 and CrO3 gives the carboxylic acid (XIII), which by esterification with MeOH in the presence of SOCl2 affords the methyl ester (XIV). Finally, reductive cyclization of the cyano ester (XIV) using BH3·Me2S in refluxing THF affords 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) .
In a stereospecific route, cyclization of nitrile (X) with (S)-epichlorohydrin (XIb) by means of NaHMDS in THF provides the cis-cyclopropanecarbonitrile (XIIb) as the major diastereoisomer, which is then reduced to aminoalcohol (XV) by means of BH3·Me2S. Chlorination of alcohol (XV) with SOCl2 in isopropyl acetate leads to the chlorinated amine (XVI), which is finally cyclized in the presence of NaOH, and then crystallized with HCl .

参考文献中间体

合成目标

【1】 Epstein, J.W., Brabander, H.J., Osterberg, A.C. (Wyeth, LLC). Method of treating depression using azabicyclohexanes. US 4435419.
【2】 Epstein, J.W., Brabander, H.J., Fanshawe, W.J. et al. 1-Aryl-3-azabicyclo[3.1.0]hexanes, a new series of nonnarcotic analgesic agents. J Med Chem 1981, 24(5): 481-90.
【3】 Epstein, J.W., Lippa, A.S. (Euthymics Bioscience, Inc.). (+)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as an anti-depressant agent. CA 2434616, EP 1349835, JP 2005500983, JP 2009280605, US 6372919, WO 2002066427.
【4】 Phil, S., Chen, Z. (Euthymics Bioscience, Inc.). Methods and compositions for production, formulation and use of 1-aryl-3-azabicyclo[3.1.0]hexanes. US 2008058535, WO 2008013856.
【5】 Corley, E.G., Feng, X., Murry, J.A., Simmons, B. (Euthymics Bioscience, Inc.). Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. EP 2012777, EP 061318, JP 2010500972, US 2008045725, WO 2007127396, WO 2008024143.
【6】 Murry, J.A., Corely, E.G., Xu, F., Simmons, B. Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. US 2010298574.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIa)	68227	racemic epichlorohydrin		C₃H₅ClO	详情	详情
(XIb)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XIIa)	68228	racemic 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile		C₁₁H₉Cl₂NO	详情	详情
(XIIb)	68229	cis-cyclopropanecarbonitrile;(1S,2R)-1-(3,4-dichlorophenyl)-2-(hydroxymethyl);cyclopropanecarbonitrile		C₁₁H₉Cl₂NO	详情	详情
(XV)	68231	((1S,2R)-2-(aminomethyl)-2-(3,4-dichlorophenyl)cyclopropyl)methanol		C₁₁H₁₂Cl₃N	详情	详情
(I)	30414	2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid	5807-30-7	C₈H₆Cl₂O₂	详情	详情
(II)	68220	ethyl 2-(3,4-dichlorophenyl)acetate	6725-45-7	C₁₀H₁₀Cl₂O₂	详情	详情
(III)	68221	ethyl 2-bromo-2-(3,4-dichlorophenyl)acetate；ethyl α-bromo-(3,4-dichlorophenyl)acetate	41204-08-4	C₁₀H₉BrCl₂O₂	详情	详情
(IV)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(V)	68222	(1R,2S)-diethyl 1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylate;diethyl cis-1-(3,4-dichlorophenyl)-1,2- cyclopropanedicarboxylate		C₁₅H₁₆Cl₂O₄	详情	详情
(VI)	68223	(1R,2S)-1-(3,4-dichlorophenyl)cyclopropane-1,2-dicarboxylic acid		C₁₁H₈Cl₂O₄	详情	详情
(VII)	68226	(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione		C₁₁H₇Cl₂NO₂	详情	详情
(VIII)	68225	1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane;(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane		C₁₁H₁₁Cl₂N	详情	详情
(IX)	68224	(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride		C₁₁H₁₁Cl₂N.HCl	详情	详情
(X)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(XIII)	68233	racemic (1S,2R)-2-cyano-2-(3,4-dichlorophenyl)cyclopropanecarboxylic acid		C₁₁H₇Cl₂NO₂	详情	详情
(XIV)	68232	racemic (1S,2R)-methyl 2-cyano-2-(3,4-dichlorophenyl)cyclopropanecarboxylate		C₁₂H₉Cl₂NO₂	详情	详情
(XVI)	68230	((1S,2R)-2-(chloromethyl)-1-(3,4-dichlorophenyl)cyclopropyl)methanamine hydrochloride		C₁₁H₁₂Cl₃N.HCl	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The compound can be prepared in the following way: The reaction of a large excess of epichlorohydrin (II) with cyanuric acid (I) at a temperature above 60 C leads to the 1,3,5-tris(oxiranylmethyl)-substituted derivative (III). Thus, epichlorohydrin functions both as alkylating agent and base. The addition of sodium hydroxide accelerates and completes the hydrogen chloride abstraction after the first step of the reaction. Fractional crystallization of the product gives the alpha and beta stereoisomers.

参考文献中间体

合成目标

【1】 Budnowski, M.; Preparation and properties of the diastereoisomeic 1,3,5-triglycidyl-s-triazinetriones. Angew Chem 1968, 7, 827.
【2】 Schnegelberger, H.; Budnowski, M. (Henkel KgA); Therapeutic compsns. with a cytostatic action. GB 2044614 .
【3】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Teroxirone. Drugs Fut 1983, 8, 11, 936.

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)	36210	1,3,5-triazinane-2,4,6-trione		C₃H₃N₃O₃	详情	详情
(II)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The synthesis of the (+)-(R)-isomer of OPC-18790 has been published: The condensation of 6-hydroxyquinolin-2(1H)-one (I) with (S)-(+)-epichlorohydrin (II) by means of triethylamine in methanol gives (S)-(+)-6-(3-chloro-2-hydroxypropoxy)quinolin-2(1H)-one (III), which by reaction with KOH in isopropanol/water yields the (R)-(-)-epoxide (IV). Finally, this compound is condensed with 3,4-dimethoxybenzylamine (V) by heating its mixture at 80 C. The (+)-(R)-isomer is about 10-fold more potent than the (-)-(S)-isomer.

参考文献中间体

合成目标

【1】 Fujioka, T.; Teramoto, S.; Tominaga, M.; Mori, T.; Sumida, T.; Yabuuchi, Y.; Tsujimi, S.; Takemoto, K.; Hosokawa, T.; Synthesis and biological activities of optically active 6-[3-(3,4-dimethox ybenzylamino)-2 hydroxypropoxy]-2(1H)-quinolinone (OPC-18790). Chem Pharm Bull 1996, 44, 8, 1596.

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)	13913	6-Hydroxy-2(1H)-quinolinone		C₉H₇NO₂	详情	详情
(II)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(III)	13918	6-[[(2S)-3-Chloro-2-hydroxypropyl]oxy]-2(1H)-quinolinone		C₁₂H₁₂ClNO₃	详情	详情
(IV)	13919	6-[(2R)Oxiranylmethoxy]-2(1H)-quinolinone		C₁₂H₁₁NO₃	详情	详情
(V)	13920	(3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine	5763-61-1	C₉H₁₃NO₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XXXIII)

4) Lactone form: The condensation of 2(S)-(chloromethyl)oxirane (XXXIII) with trimethylsilylacetylene (XXXIV) by means of butyllithium and BF3 ethearate in THF gives 5-chloro-4(S)-hydroxy-1-(trimethylsilyl)-1-pentyne (XXXV), which is cyclized with KOH in THF to the chiral epoxide (XXXVI). The condensation of (XXXVI) with 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII, see Scheme 5) by means of butyllithium in THF affords the silylated heptynol (XXXVIII), which is desilylated with K2CO3 in methanol to the terminal acetylene (XXXIX). The carboxylation of (XXXIX) with CO by means of PdCl2/CuCl2 in methanol yields the heptynoic acid ester (XL), which is selectively reduced with H2 over the Lindlar catalyst in methanol to the cis-heptenoic ester (XLI). The cyclization of (XLI) with PPTS in refluxing toluene affords the (S)-unsaturated lactone (XLII), which is oxidized with m-chloroperbenzoic acid to the corresponding sulfinyl derivative (XLIII).

参考文献中间体

合成目标

【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859.
【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IL)	17460	1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-[(2R)oxiranyl]ethyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[2-[(2R)oxiranyl]-1-(phenylsulfanyl)ethyl]quinoline		C₂₈H₂₄FNOS	详情	详情
(XXXIII)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XXXIV)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(XXXV)	17449	(2S)-1-chloro-5-(trimethylsilyl)-4-pentyn-2-ol		C₈H₁₅ClOSi	详情	详情
(XXXVI)	17450	trimethyl[3-[(2S)oxiranyl]-1-propynyl]silane		C₈H₁₄OSi	详情	详情
(XXXVII)	17451	[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline		C₂₅H₂₀FNS	详情	详情
(XXXVIII)	17452	(3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-6-(trimethylsilyl)-5-hexyn-3-ol		C₃₃H₃₄FNOSSi	详情	详情
(XXXIX)	17453	(3S)-1-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-1-(phenylsulfanyl)-5-hexyn-3-ol		C₃₀H₂₆FNOS	详情	详情
(XL)	17454	methyl (5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptynoate		C₃₂H₂₈FNO₃S	详情	详情
(XLI)	17455	methyl (Z,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-5-hydroxy-7-(phenylsulfanyl)-2-heptenoate		C₃₂H₃₀FNO₃S	详情	详情
(XLII)	17456	(6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfanyl)ethyl]-5,6-dihydro-2H-pyran-2-one		C₃₁H₂₆FNO₂S	详情	详情
(XLIII)	17457	(6S)-6-[2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-2-(phenylsulfinyl)ethyl]-5,6-dihydro-2H-pyran-2-one		C₃₁H₂₆FNO₃S	详情	详情
(XLVII)	38067	(2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin	51594-55-9	C₃H₅ClO	详情	详情
(XLVIII)	17459	(2R)-1-chloro-4-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-4-(phenylsulfanyl)-2-butanol		C₂₈H₂₅ClFNOS	详情	详情
(L)	17461	ethynyllithium		C₂HLi	详情	详情

合成路线5

该中间体在本合成路线中的序号：(V)

(S)-Epichlorhydrin (V) was treated with benzylamine to afford aminoalcohol (VI). After protection of the amino group of (VI) as the tert-butyl carbamate (VII) with Boc2O, displacement of the chlorine of (VII) with arylpiperazine (I) furnished (VIII). Deprotection of the N-Boc group of (VIII) by means of trifluoroacetic acid gave (IX). Then, the N-benzyl group of (IX) was removed by transfer hydrogenolysis employing ammonium formate and Pd/C to provide the intermediate amine (IV).

参考文献中间体

合成目标

【1】 Prouty, C.; Wang, J.; Kuo, G.-H.; Pulito, V.; Murray, W.V.; Cheung, P.; Jolliffe, L.; Varga, S.; Evangelisto, M.; Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: A novel series of potent and selective alpha1a-adrenergic receptor antagonists. J Med Chem 2000, 43, 11, 2183.
【2】 Murray, W.V.; Kuo, G.-H.; Prouty, C.P. (Ortho-McNeil Pharmaceutical, Inc.); Phthalimido arylpiperazines as alpha 1a receptor antagonists useful in the treatment of benign prostatic hyperplasia. US 6063785; WO 9942445 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(I)	35066	isopropyl 2-(1-piperazinyl)phenyl ether; 1-(2-isopropoxyphenyl)piperazine		C₁₃H₂₀N₂O	详情	详情
(IV)	35069	(2S)-1-amino-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol		C₁₆H₂₇N₃O₂	详情	详情
(V)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(VI)	35070	(2S)-1-(benzylamino)-3-chloro-2-propanol		C₁₀H₁₄ClNO	详情	详情
(VII)	35071	tert-butyl benzyl[(2S)-3-chloro-2-hydroxypropyl]carbamate		C₁₅H₂₂ClNO₃	详情	详情
(VIII)	35072	tert-butyl benzyl[(2R)-2-hydroxy-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]propyl]carbamate		C₂₈H₄₁N₃O₄	详情	详情
(IX)	35073	(2S)-1-(benzylamino)-3-[4-(2-isopropoxyphenyl)-1-piperazinyl]-2-propanol		C₂₃H₃₃N₃O₂	详情	详情

合成路线6

该中间体在本合成路线中的序号：(XIV)

Intermediate (XIb) is prepared by condensation of 4-chlorobenzaldehyde (XIII) with NH4OH and (S)-(+)-epichlorohydrin (XIV) in MTBE or MeOH to yield imine (XV). Then imine (XV) is condensed with carbamate (VI) using t-BuOLi to give the 2-oxazolidinone derivative (XVI), which is finally hydrolyzed with HCl in EtOAc/H2O .

参考文献中间体

合成目标

【1】 Brickner, S.J., Nuermberger, E., Stover, C.K. (Pfizer, Inc.). Combination therapy for tuberculosis. CN 102143748, EP 2340022, JP 20122502017, KR 2011063518, US 2011190199, WO 2010026526.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIb)	68067	(R)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one hydrochloride		C₁₄H₁₈FN₃O₂S.HCl	详情	详情
(VI)	68062	benzyl (3-fluoro-4-thiomorpholinophenyl)carbamate		C₁₈H₁₉FN₂O₂S	详情	详情
(XIII)	29029	4-chlorobenzaldehyde	104-88-1	C₇H₅ClO	详情	详情
(XIV)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XV)	68068	(R,E)-1-chloro-3-((4-chlorobenzylidene)amino)propan-2-ol		C₁₀H₁₁Cl₂NO	详情	详情
(XVI)	68069	(R,E)-5-(((4-chlorobenzylidene)amino)methyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one		C₂₁H₂₁ClFN₃O₂S	详情	详情

合成路线7

该中间体在本合成路线中的序号：(X)

Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .

参考文献中间体

合成目标

【1】 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350.
【2】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355.
【3】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637.
【4】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889.
【5】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519.
【6】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979.
【7】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640.
【8】 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127.
【9】 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976.

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)	18619	(2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol	5344-90-1	C₇H₉NO	详情	详情
(II)	36334	[2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol		C₁₀H₁₅NO	详情	详情
(III)	36335	2-(isopropylamino)benzaldehyde		C₁₀H₁₃NO	详情	详情
(IV)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(V)	36333	1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid		C₁₃H₁₃NO₃	详情	详情
(VI)	68799	(1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate		C₁₂H₂₂N₂O₂	详情	详情
(VII)	68803	(1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate		C₂₅H₃₃N₃O₄	详情	详情
(VIII)	68804	N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate		C₂₀H₂₅N₃O₂.C₂HF₃O₂	详情	详情
(IX)	68807	1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate		C₉H₁₈ClNO₃	详情	详情
(X)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XI)	68808	(S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol		C₁₁H₁₆ClNO	详情	详情
(XII)	68805	tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate		C₂₉H₄₂N₄O₅	详情	详情
(XIII)	68806	N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate		C₂₄H₃₄N₄O₃.C₂HF₃O₂	详情	详情
(XIV)	13467	Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride	124-63-0	CH₃ClO₂S	详情	详情
(XV)	68802	N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide		C₅H₁₁NO₃S	详情	详情
(XVI)	67859	N-methylmethanesulfonamide	1184-85-6	C₂H₇NO₂S	详情	详情
(XVII)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XVIII)	12132	2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether	696-59-3	C₆H₁₂O₃	详情	详情
(XIX)	15530	1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid	542-05-2	C₅H₆O₅	详情	详情
(XX)	68801	(1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one		C₁₄H₁₇NO	详情	详情
(XXI)	68800	N-Boc-8-azabicyclo[3.2.1]octan-3-one		C₁₂H₁₉NO₃	详情	详情

合成路线8

该中间体在本合成路线中的序号：(XVII)

参考文献中间体

合成目标

【1】 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350.
【2】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355.
【3】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637.
【4】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889.
【5】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519.
【6】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979.
【7】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640.
【8】 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127.
【9】 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976.

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)	18619	(2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol	5344-90-1	C₇H₉NO	详情	详情
(II)	36334	[2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol		C₁₀H₁₅NO	详情	详情
(III)	36335	2-(isopropylamino)benzaldehyde		C₁₀H₁₃NO	详情	详情
(IV)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(V)	36333	1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid		C₁₃H₁₃NO₃	详情	详情
(VI)	68799	(1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate		C₁₂H₂₂N₂O₂	详情	详情
(VII)	68803	(1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate		C₂₅H₃₃N₃O₄	详情	详情
(VIII)	68804	N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate		C₂₀H₂₅N₃O₂.C₂HF₃O₂	详情	详情
(IX)	68807	1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate		C₉H₁₈ClNO₃	详情	详情
(X)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XI)	68808	(S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol		C₁₁H₁₆ClNO	详情	详情
(XII)	68805	tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate		C₂₉H₄₂N₄O₅	详情	详情
(XIII)	68806	N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate		C₂₄H₃₄N₄O₃.C₂HF₃O₂	详情	详情
(XIV)	13467	Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride	124-63-0	CH₃ClO₂S	详情	详情
(XV)	68802	N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide		C₅H₁₁NO₃S	详情	详情
(XVI)	67859	N-methylmethanesulfonamide	1184-85-6	C₂H₇NO₂S	详情	详情
(XVII)	13917	(S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin	67843-74-7	C₃H₅ClO	详情	详情
(XVIII)	12132	2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether	696-59-3	C₆H₁₂O₃	详情	详情
(XIX)	15530	1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid	542-05-2	C₅H₆O₅	详情	详情
(XX)	68801	(1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one		C₁₄H₁₇NO	详情	详情
(XXI)	68800	N-Boc-8-azabicyclo[3.2.1]octan-3-one		C₁₂H₁₉NO₃	详情	详情

Extended Information