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【结 构 式】

【分子编号】15116

【品名】pentanoyl chloride; valeryl chloride

【CA登记号】638-29-9

【 分 子 式 】C5H9ClO

【 分 子 量 】120.57856

【元素组成】C 49.81% H 7.52% Cl 29.4% O 13.27%

与该中间体有关的原料药合成路线共 10 条

合成路线1

该中间体在本合成路线中的序号:(II)

By acylation of 9-(2-hydroxyethoxymethyl)guanine (I) with pentanoyl chloride (II) or pentanoyl anhydride (III).

1 Beauchamp, L.M.; Krenitsky, T.A.; Acyclovir prodrugs: The road to valaciclovir. Drugs Fut 1993, 18, 7, 619.
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) 28279 2-amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro-6H-purin-6-one 59277-89-3 C8H11N5O3 详情 详情
(II) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(III) 27683 pentanoic anhydride 2082-59-9 C10H18O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IV)

The reaction of cyclopentanone (I) with sodium cyanide, NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II), which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III). The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V), which, without isolation, is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI). This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene. The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X). Cyclization of (X) with tributyltin azide in refluxing xylene, followed by reaction with trityl chloride in DMF, affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI). Finally, this compound is hydrolyzed to irbesartan with HCl in methanol/THF. The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.

1 Casas, A.; Merlos, M.; Castaner, J.; Irbesartan. Drugs Fut 1997, 22, 5, 481.
2 Bernhart, C.; Breliere, J.-C.; Clement, J.; Nisato, D.; Perreaut, P. (Sanofi-Synthélabo ); Heterocyclic N-substd. derivs., their preparation and the pharmaceutical compsns. containing them. EP 0454511; FR 2659967; FR 2665702; JP 1992506222; JP 1998279566; US 5270317; WO 9114679 .
3 Caron, A.; Chantreux, D.; Bouloumie, C. (Sanofi-Synthelabo ); Method for the preparation of a tetrazole deriv. under two crystalline forms and novel crystalline form of this deriv. EP 0708103 .
4 Bernhart, C.A.; Perreaut, P.M.; Ferrari, B.P.; et al.; A new series of imidazolones: Highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem 1993, 36, 22, 3371-80.
5 Bernhart, C.; Clement, J.; Ferrari, B.; et al.; Spiro-dihydro-imidazolones, a new class of non-peptide angiotensin II receptor antagonists. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-084.A..
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) 15113 cyclopentanone 120-92-3 C5H8O 详情 详情
(II) 15114 1-aminocyclopentanecarbonitrile C6H10N2 详情 详情
(III) 15115 1-Amino-1-cyclopentane carboxamide; 1-Aminocyclopentanecarboxamide 17193-28-1 C6H12N2O 详情 详情
(IV) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(V) 15117 N-[1-(aminocarbonyl)cyclopentyl]pentanamide; 1-(pentanoylamino)cyclopentanecarboxamide C11H20N2O2 详情 详情
(VI) 15118 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 1,3-Diazaspirol[4,4]non-1-en-4-one,2-butyl 151257-01-1 C11H18N2O 详情 详情
(VII) 15119 ethyl 1-aminocyclopentanecarboxylate C8H15NO2 详情 详情
(VIII) 15120 ethyl pentanimidoate C7H15NO 详情 详情
(IX) 15332 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl 114772-54-2 C14H10BrN 详情 详情
(X) 15122 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl][1,1'-biphenyl]-2-carbonitrile C25H27N3O 详情 详情
(XI) 15121 2-butyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one C44H42N6O 详情 详情

合成路线3

该中间体在本合成路线中的序号:(VI)

This compound has been obtained by two related ways: 1) The hydrolysis of 4'-(bromomethyl)biphenyl-2-carbonitrile (I) with NaOAc in refluxing acetic acid gives the corresponding carbinol (II), which is oxidized with oxalyl chloride in DMSO/dichloromethane yielding the aldehyde (III). The reductocondensation of (III) with L-valine methyl ester (IV) by means of NaBH4CN in THF affords the N-alkylated valine (V), which is acylated with pentanoyl chloride (VI) and TEA in dichloromethane providing the pentanamide (VII). The reaction of the CN group of (VII) with tributyltin azide in refluxing xylene gives the tetrazol derivative (VIII). Finally, the ester group of (VIII) is hydrolyzed with NaOH to furnish the target compound. 2) L-valine methyl ester (IV) can be condensed directly with the bromo-methyl derivative (I) by means of DIEA in dichloromethane giving the N-alkylated valine (V) already reported.

1 Buhlmayer, P.; Ostermayer, F.; Schmidlin, T. (Novartis AG); Acyl cpds.. EP 0443983; JP 1992235149; US 5399578; US 5965592 .
2 Buhlmayer, P.; et al.; Valsartan, a potent, orally active angiotensin II antagonist developed from the structurally new amino acid series. Bioorg Med Chem Lett 1994, 4, 1, 29.
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) 15332 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl 114772-54-2 C14H10BrN 详情 详情
(II) 37265 4'-(hydroxymethyl)[1,1'-biphenyl]-2-carbonitrile C14H11NO 详情 详情
(III) 37266 4'-formyl[1,1'-biphenyl]-2-carbonitrile C14H9NO 详情 详情
(IV) 16613 methyl (2S)-2-amino-3-methylbutanoate C6H13NO2 详情 详情
(V) 37267 methyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate C20H22N2O2 详情 详情
(VI) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(VII) 37268 methyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate C25H30N2O3 详情 详情
(VIII) 37269 methyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C25H31N5O3 详情 详情

合成路线4

该中间体在本合成路线中的序号:(VI)

The reaction of 2-bromo-4'-methylbiphenyl (I) with 14C labeled cuprous cyanide in refluxing DMF gives 4'-methylbiphenyl-2-carbonitrile (II), which is brominated with NBS and AIBN in refluxing CCl4 to yield the bromomethyl derivative (III). The condensation of (III) with L-valine benzyl ester (IV) by means of DIEA in hot DMF affords the N-substituted valine (V), which is acylated with pentanoyl chloride (VI) and DIEA to provide the N-acylated valine (VII). The cyclization of the cyano group of (VII) with tributyltin azide at 140 C furnishes the tetrazol derivative (VIII) which is finally debenzylated by hydrogenation with H2 over Pd/C in dioxane.

1 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245.
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) 41935 2-bromo-4'-methyl-1,1'-biphenyl C13H11Br 详情 详情
(II) 13929 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile 114772-53-1 C14H11N 详情 详情
(II) 45264 4'-methyl[1,1'-biphenyl]-2-carbonitrile C14H11N 详情 详情
(III) 15332 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl 114772-54-2 C14H10BrN 详情 详情
(III) 45265 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile C14H10BrN 详情 详情
(IV) 41936 benzyl (2S)-2-amino-3-methylbutanoate C12H17NO2 详情 详情
(V) 41937 benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate; N-[(2'-cyanobiphenyl-4-yl)methyl]-L-valine benzyl ester 137864-23-4 C26H26N2O2 详情 详情
(V) 45266 benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl]amino]-3-methylbutanoate C26H26N2O2 详情 详情
(VI) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(VII) 41938 benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate C31H34N2O3 详情 详情
(VII) 45267 benzyl (2S)-2-[[(2'-cyano[1,1'-biphenyl]-4-yl)methyl](pentanoyl)amino]-3-methylbutanoate C31H34N2O3 详情 详情
(VIII) 41939 benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C31H35N5O3 详情 详情
(VIII) 45268 benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C31H35N5O3 详情 详情

合成路线5

该中间体在本合成路线中的序号:(XIII)

The reaction of 14C labeled chiral bromoacetyl sultam (I) with benzophenoneimine (II) in hot acetonitrile gives the substituted benzophenoneimine (III), which is estereoselectively alkylated with isopropyl iodide (IV) and n-BuLi in THF yielding the labeled L-valine derivative (V). The hydrolysis of (V) with HCl in THF affords the valine derivative (VI) with a free amino group that is protected with Boc2O in THF providing the carbamate (VII). The basic hydrolysis of (VII) with LiOH in THF gives the labeled N-(tert-butoxycarbonyl)-L-valine (VIII), which is esterified with Bn-OH, EDC and DMAP in dichloromethane yielding the protected benzyl ester (IX). Treatment of (IX) with TFA in dichloromethane affords L-valine benzyl ester (X), which is condensed with the bromomethylbiphenyl (XI) by means of DIEA in hot DMF to give the N-alkylated valine ester (XII). The acylation of (XII) with pentanoyl chloride (XIII) by means of DIEA in toluene yields the N-disubstituted valine ester (XIV), which is finally deprotected by hydrogenation with H2 over Pd/C in EtOH.

1 Moenius, T.; et al.; Carbon-14 labelling of Diovan(TM) in its valine-moiety. J Label Compd Radiopharm 2000, 43, 13, 1245.
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) 41945 (1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(I) 45269 (1S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C12H18BrNO3S 详情 详情
(II) 32024 diphenylmethanimine 1013-88-3 C13H11N 详情 详情
(III) 41946 (1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C25H28N2O3S 详情 详情
(III) 45270 (1S)-4-[2-[(dibenzylene)amino]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C25H28N2O3S 详情 详情
(IV) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(V) 41940 (1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C28H34N2O3S 详情 详情
(V) 45271 (1S)-4-[(2S)-2-[(dibenzylene)amino]-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione C28H34N2O3S 详情 详情
(VI) 41941 tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C20H34N2O5S 详情 详情
(VI) 45272 (1R)-4-[(2S)-2-amino-3-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thiatricyclo[5.2.1.0(1,5)]decane-3,3-dione C16H27NO3S 详情 详情
(VII) 41947 tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C20H34N2O5S 详情 详情
(VII) 45273 tert-butyl (1S)-1-[[(1S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]carbonyl]-2-methylpropylcarbamate C20H34N2O5S 详情 详情
(VIII) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VIII) 45274 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(IX) 41942 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate C17H25NO4 详情 详情
(IX) 45275 benzyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate C17H25NO4 详情 详情
(X) 41936 benzyl (2S)-2-amino-3-methylbutanoate C12H17NO2 详情 详情
(X) 45276 benzyl (2S)-2-amino-3-methylbutanoate C12H17NO2 详情 详情
(XI) 15538 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole 124750-51-2 C33H25BrN4 详情 详情
(XII) 41943 benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C45H41N5O2 详情 详情
(XII) 45277 benzyl (2S)-3-methyl-2-([[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C45H41N5O2 详情 详情
(XIII) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(XIV) 41944 benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C50H49N5O3 详情 详情
(XIV) 45278 benzyl (2S)-3-methyl-2-(pentanoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)butanoate C50H49N5O3 详情 详情

合成路线6

该中间体在本合成路线中的序号:(III)

Treatment of 2-hydroxy-5-nitrobenzyl bromide (I) with triphenylphosphine in refluxing chloroform provides phosphonium bromide derivative (II), which is converted into 2-butyl-5-nitro benzofuran (IV) by first reaction with pentanoyl chloride (III) in refluxing chloroform in the presence of pyridine, followed by treatment with Et3N in refluxing toluene. Acylation of (IV) with anisoyl chloride (V) by means of tin tetrachloride in dichloroethane furnishes 2-butyl-3-(4-methoxy benzoyl)-5-nitro benzofuran (VI), whose methoxy group is then converted into an hydroxy group by treatment with aluminum chloride in refluxing dichloroethane, yielding hydroxy benzoyl derivative (VII). Condensation of (VII) with N,N-dibutyl-N-(3-chloropropyl)amine (VIII) by means of K2CO3 in refluxing butanone affords compound (IX), which is then hydrogenated over PtO2 in EtOH to give amino derivative (X). Finally, the target product is obtained by reaction of (X) with methanesulfonyl chloride and Et3N in dichloroethane and hydrochloride salt formation with HCl in AcOEt/ethyl ether.

1 Gubin, J.; Lucchetti, J.; Inion, H.; Chatelain, P.; Rosseels, G.; Kilenyi, S. (Sanofi-Synthélabo); Benzofuran derivs., benzothiophenes, indoles or indolizines, process for production and compsns. containing them. EP 0471609; FR 2665444; JP 1992316554; US 5223510 .
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) 50821 alpha-Bromo-4-nitro-o-cresol; Koshland's reagent; 2-Hydroxy-5-nitrobenzyl bromide 772-33-8 C7H6BrNO3 详情 详情
(II) 50822 (2-hydroxy-5-nitrobenzyl)(triphenyl)phosphonium bromide C25H21BrNO3P 详情 详情
(III) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(IV) 50823 2-butyl-5-nitro-1-benzofuran C12H13NO3 详情 详情
(V) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VI) 50824 (2-butyl-5-nitro-1-benzofuran-3-yl)(4-methoxyphenyl)methanone C20H19NO5 详情 详情
(VII) 50825 (2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxyphenyl)methanone C19H17NO5 详情 详情
(VIII) 50826 N,N-dibutyl-N-(3-chloropropyl)amine; N-butyl-N-(3-chloropropyl)-1-butanamine 36421-15-5 C11H24ClN 详情 详情
(IX) 50827 (2-butyl-5-nitro-1-benzofuran-3-yl)[4-[3-(dibutylamino)propoxy]phenyl]methanone C30H40N2O5 详情 详情
(X) 50828 (5-amino-2-butyl-1-benzofuran-3-yl)[4-[3-(dibutylamino)propoxy]phenyl]methanone C30H42N2O3 详情 详情

合成路线7

该中间体在本合成路线中的序号:(II)

The intermediate (R)-formyl amide (IX) was synthesized as follows. Acylation of the lithium anion of (S)-4-benzyl-2-oxazolidinone (I) with valeryl chloride (II) provided acyl oxazolidinone (III). Subsequent diastereoselective benzyloxymethylation of (III) with chloride (IV) and TiCl4 gave benzyl ether (V). Hydrolysis of (V) with lithium peroxide, followed by coupling of the resulting carboxylic acid (VI) with diethylamine in the presence of TBTU yielded diethylamide (VII). Hydrogenolysis of the benzyl group of (VII) using Pearlman's catalyst afforded alcohol (VIII), which was oxidized to aldehyde (IX) by means of Dess-Martin periodinane or NaOCl in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) to give (IX).

1 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
2 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .
3 Plamondon, L.; Adams, J.; Elliot, P. (ProScript, Inc.); Proteasome inhibitors, ubiquitin pathway inhibitors or agents that interfere with the activation of NF-kappaB via the ubiquitin proteasome pathway to treat inflammatory and autoimmune diseases. WO 9915183 .
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(III) 29431 (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(IV) 14560 Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene 3587-60-8 C8H9ClO 详情 详情
(V) 37794 (4S)-4-benzyl-3-[(2R)-2-[(benzyloxy)methyl]pentanoyl]-1,3-oxazolidin-2-one C23H27NO4 详情 详情
(VI) 37795 (2R)-2-[(benzyloxy)methyl]pentanoic acid C13H18O3 详情 详情
(VII) 37796 (2R)-2-[(benzyloxy)methyl]-N,N-diethylpentanamide C17H27NO2 详情 详情
(VIII) 37797 (2R)-N,N-diethyl-2-(hydroxymethyl)pentanamide C10H21NO2 详情 详情
(IX) 37798 (2R)-N,N-diethyl-2-formylpentanamide C10H19NO2 详情 详情

合成路线8

该中间体在本合成路线中的序号:(VIII)

This compound can be obtained by several related ways: 1.- The cyclization of 3-aminothiophene-2-carboxamide (I) with pentanoyl anhydride (II) by means of DCC, DMAP and pyridine in DMF and NaOH gives 2-butylthieno[3,2-d]pyrimidin-4(3H)-one (III), which by reaction with POCl3 or SOCl2 affords 2-butyl-4-chlorothieno[3,2-d]pyrimidine (IV). Finally, this compound is condensed with cyclohexylamine (V) by means of triethylamine in in THF. 2.- The intermediate 2-butylthieno[3,2-d]pyrimidin-4-(3H)-one (III) can be obtained by other ways: a.- By cyclization of amide (I) with pentanoic acid (VI) by means of DCC, DMAP and pyridine in DMF and NaOH. b.- By cyclization of 3-aminothiophene-2-carboxylic acid methyl ester (VII) with pentanoic acid (VI) by means of DCC, DMAP and ammonia in dichloromethane. c.- By cyclization of 3-aminothiophene-2-carboxylic acid methyl ester (VII) with pentanoyl chloride (VIII) by means of pyridine and ammonia. d.- By cyclization of 3-aminothiophene-2-carboxylic acid (IX) with pentanoic anhydride (II) and ammonia.

1 Crespo, M. I.; Pages, L.; Vega, A.; Segarra, V.; Lopez, M.; Domenech, T.; Miralpeix, M.; Beleta, J.; Ryder, H.; Palacios, J.M.; Design, synthesis, and biological activities of new thieno[3,2-d]pyrimidines as selective type 4 phosphodiesterase inhibitors. J Med Chem 1998, 41, 21, 4021.
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) 27682 3-amino-2-thiophenecarboxamide 147123-47-5 C5H6N2OS 详情 详情
(II) 27683 pentanoic anhydride 2082-59-9 C10H18O3 详情 详情
(III) 27684 2-butylthieno[3,2-d]pyrimidin-4(3H)-one C10H12N2OS 详情 详情
(IV) 27685 2-butyl-4-chlorothieno[3,2-d]pyrimidine C10H11ClN2S 详情 详情
(V) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(VI) 19682 pentanoic acid 109-52-4 C5H10O2 详情 详情
(VII) 27686 3-amino-2-thiophenecarboxylic acid methyl ester; methyl 3-amino-2-thiophenecarboxylate 22288-78-4 C6H7NO2S 详情 详情
(VIII) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(IX) 27687 3-amino-2-thiophenecarboxylic acid C5H5NO2S 详情 详情

合成路线9

该中间体在本合成路线中的序号:(I)

Condensation of pentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone (II) in the presence of n-butyllithium afforded the chiral N-acyl oxazolidinone (III). Subsequent asymetric alkylation of (III) with 1-bromo-2-butyne (IV) using LDA as the base produced the alkylated diastereoisomer (V). The chiral auxiliary oxazolidinone was finally removed by hydrolysis with lithium hydroperoxide to afford the required (R)-carboxylic acid.

1 Hauck, R.-S.; Elmazar, M.M.E.; Nau, H.; Bojic, U.; VPA-analogous antiepileptics. DE 4231085; US 5786380; WO 9406743 .
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) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 29431 (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(IV) 29428 1-bromo-2-butyne 3355-28-0 C4H5Br 详情 详情
(V) 29432 (4S)-4-benzyl-3-[(2R)-2-propyl-4-hexynoyl]-1,3-oxazolidin-2-one C19H23NO3 详情 详情

合成路线10

该中间体在本合成路线中的序号:(II)

Treatment of S-4-benzyl-2-oxazolidinone (II) with n-butyllithium, followed by acylation with valeroyl chloride (I) afforded the N-valeroyloxazolidinone (III). Subsequent alkylation of (III) with isopropyl triflate (V), prepared from isopropyl alcohol (IV) and trifluoromethanesulfonic anhydride, in the presence of LDA produced the (4S,2'R)-2-isopropylvaleroyl derivative (VI). Hydrolysis of (VI) using lithium peroxide yielded the chiral carboxylic acid (VII), which was converted to the corresponding acid chloride (VIII) by treatment with oxalyl chloride. Finally, reaction of (VIII) with ammonia furnished the title amide.

1 Yagen, B.; Bialer, M.; Spigelstein, O. (Yissum Research Development Co.); Propylisopropyl acetic acid and propylisopropyl acetamide stereoisomers, a method for their synthesis and pharmaceutical compsns. containing them. WO 9954282 .
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) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 15116 pentanoyl chloride; valeryl chloride 638-29-9 C5H9ClO 详情 详情
(III) 29431 (4S)-4-benzyl-3-pentanoyl-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(IV) 19250 2-propanol 67-63-0 C3H8O 详情 详情
(V) 35062 isopropyl trifluoromethanesulfonate C4H7F3O3S 详情 详情
(VI) 35063 (4S)-4-benzyl-3-[(2R)-2-isopropylpentanoyl]-1,3-oxazolidin-2-one C18H25NO3 详情 详情
(VII) 35064 (2R)-2-isopropylpentanoic acid C8H16O2 详情 详情
(VIII) 35065 (2R)-2-isopropylpentanoyl chloride C8H15ClO 详情 详情
Extended Information