Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【药物名称】Indiplon, NBI-34060

【化学名称】N-Methyl-N-[3-[3-(thien-2-ylcarbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]acetamide

【CA登记号】325715-02-4

【 分 子 式 】C20H16N4O2S

【 分 子 量 】376.44012

【开发单位】DOV Pharmaceutical (Originator), Neurocrine Biosciences (Licensee), Pfizer (Licensee)

【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sleep Disorders, Treatment of, GABA(A) Receptor Agonists

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

Condensation of 2-acetylthiophene (I) with dimethylformamide dimethylacetal produced enaminone (II), which was subsequently cyclized to the isoxazole (III) upon treatment with hydroxylamine. Further condensation of (III) with dimethylformamide dimethylacetal, with concomitant isoxazole ring opening, gave rise to the enamino nitrile (IV). This was then cyclized with aminoguanidine nitrate (V) under basic conditions to furnish the intermediate aminopyrazole (VI).

参考文献 中间体
【2】 Tomcufcik, A.S.; Dusza, J.P.; Albright, J.D.; Beer, B. (Wyeth); N-Methyl-N-(-[3-[-2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl]phenyl)acetamide and compsns. and methods related thereto. US 6399621 .
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
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) 24490 1-(2-Thienyl)-1-ethanone; 2-Acetylthiophene 88-15-3 C6H6OS 详情 详情
(II) 59943 (E)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-one C9H11NOS 详情 详情
(III) 59944 5-(2-thienyl)isoxazole C7H5NOS 详情 详情
(IV) 59945 (E)-3-(dimethylamino)-2-(2-thienylcarbonyl)-2-propenenitrile C10H10N2OS 详情 详情
(V) 10015 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide 79-17-4 CH6N4 详情 详情
(VI) 59946 (3-amino-1H-pyrazol-4-yl)(2-thienyl)methanone C8H7N3OS 详情 详情

合成路线2

3-(Acetamido)acetophenone (VII) was converted to enaminone (VIII) upon condensation with dimethylformamide dimethylacetal. The amide N of (VIII) was then alkylated by means of iodomethane and NaH or, alternatively, under phase-transfer conditions to give (IX). Finally, condensation between enaminone (IX) and aminopyrazole (VI) in refluxing AcOH provided the target pyrazolopyrimidine.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Dusza, J.P.; Tomcufcik, A.S.; Albright, J.D. (Wyeth); Aryl and heteroaryl 7-(aryl and heteroaryl)-pyrazolo[1,5-a]pyrimidin-3-ylmethanones. DE 3422844; EP 0129847; JP 1985019788 .
【3】 Tomcufcik, A.S.; Dusza, J.P.; Albright, J.D.; Beer, B. (Wyeth); N-Methyl-N-(-[3-[-2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl]phenyl)acetamide and compsns. and methods related thereto. US 6399621 .
【4】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 59946 (3-amino-1H-pyrazol-4-yl)(2-thienyl)methanone C8H7N3OS 详情 详情
(VII) 11983 3'-Acetamidoacetophane; m-Acetamidoacetophenone; N-(3-Acetylphenyl)acetamide 7463-31-2 C10H11NO2 详情 详情
(VIII) 11985 N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]acetamide C13H16N2O2 详情 详情
(IX) 59947 N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide C14H18N2O2 详情 详情

合成路线3

Bromination of 5-aminopyrazole (XI) with Br2 in AcOH gives 4-bromo-5-aminopyrazole (XII), which is cyclized with N-[3-[3-(dimethylamino)-2-propenoyl]phen-yl]-N-methylacetamide (X) in AcOH to yield the 3-bromo-pyrazolo[1,5-a]pyrimidine derivative (XIII). Finally, this compound can be condensed with either 2-thienylcarbonyl chloride (XIV) by means of Zn or Mg or with 2-thienylboronic acid (XV) and CO by means of a Pd(0) catalyst.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 59947 N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide C14H18N2O2 详情 详情
(XI) 56012 1H-pyrazol-5-amine; 1H-pyrazol-5-ylamine 916420-28-5 C3H5N3 详情 详情
(XII) 62961 4-bromo-1H-pyrazol-5-ylamine; 4-bromo-1H-pyrazol-5-amine C3H4BrN3 详情 详情
(XIII) 62962 N-[3-(3-bromopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide C15H13BrN4O 详情 详情
(XIV) 14103 2-Thiophenecarbonyl chloride 5271-67-0 C5H3ClOS 详情 详情
(XV) 62963 2-thiophenylboronic acid C4H5BO2S 详情 详情

合成路线4

Cyclization of 2-aminopyrazole (XI) with the acetamide (X) in AcOH gives the pyrazolo[1,5-a]pyrimidine derivative (XVI), which is finally acylated with 2-thienylcarbonyl chloride (XIV) by means of AlCl3.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 59947 N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide C14H18N2O2 详情 详情
(XI) 56012 1H-pyrazol-5-amine; 1H-pyrazol-5-ylamine 916420-28-5 C3H5N3 详情 详情
(XIV) 14103 2-Thiophenecarbonyl chloride 5271-67-0 C5H3ClOS 详情 详情
(XVI) 62964 N-methyl-N-(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)acetamide C15H14N4O 详情 详情

合成路线5

Cyclization of ethoxymethylenemalonodinitrile (XVII) with hydrazine gives 5-aminopyrazole-4-carbonitrile (XVIII), which is further cyclized with acetamide (X) in refluxing AcOH to yield the 3-cyanopyrazolo[1,5-a]pyrimidine derivative (XIX). Finally, this compound is condensed with 2-bromothiophene (XX) by means of Mg.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 59947 N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide C14H18N2O2 详情 详情
(XVII) 13017 Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile 123-06-8 C6H6N2O 详情 详情
(XVIII) 57051 5-Amino-4-pyrazolecarbonitrile C4H4N4 详情 详情
(XIX) 62965 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide C16H13N5O 详情 详情
(XX) 13681 2-Bromothiophene 1003-09-4 C4H3BrS 详情 详情

合成路线6

Cyclization of 5-aminopyrazole-4-carboxylic acid ethyl ester (XXI) with either, 3,3-diethoxypropionic acid ethyl ester (XXII) or 3-oxopropionic acid ethyl ester (XXIII) in refluxing AcOH gives 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (XXIV), which is treated with POCl3 to yield the corresponding chloro derivative (XXV). Condensation of compound (XXV) with 3-(N-methylacetamido)phenylboronic acid (XXVI) by means of Pd(PPh3)4 and Na2CO3 in ethanol affords the pyrazolo-[1,5-a]pyrimidine-carboxylic acid ethyl ester (XXVII), which is finally condensed with 2-bromothiophene (XX) and Mg.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 13681 2-Bromothiophene 1003-09-4 C4H3BrS 详情 详情
(XXI) 51140 3-Amino-4-pyrazolecarboxylic acid ethyl ester; Ethyl 3-aminopyrazole-4-carboxylate; 3-Amino-4-carbethoxypyrazole 6994-25-8 C6H9N3O2 详情 详情
(XXII) 17901 Ethyl 3,3-diethoxypropanoate 10601-80-6 C9H18O4 详情 详情
(XXIII) 62966 ethyl 3-oxopropanoate C5H8O3 详情 详情
(XXIV) 62967 ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate C9H9N3O3 详情 详情
(XXV) 62968 ethyl 7-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate C9H8ClN3O2 详情 详情
(XXVI) 62969 3-[acetyl(methyl)amino]phenylboronic acid C9H12BNO3 详情 详情
(XXVII) 62970 ethyl 7-{3-[acetyl(methyl)amino]phenyl}pyrazolo[1,5-a]pyrimidine-3-carboxylate C18H18N4O3 详情 详情

合成路线7

Reaction of 3-(acetamido)acetophenone (VIII) with iodomethane and NaH gives 3-(N-methylacetamido)acetophenone (XXVIII), which is mixed with 3-oxo-3-(2-thienyl)propionitrile (VII) and treated with dimethylformamide dimethylacetal to yield a mixture of the dimethylaminomethylene derivatives (IV) and (X). This mixture, without isolation, is cyclized with aminoguanidine (V) by treatment first with NaOH in ethanol and then with refluxing AcOH.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 59945 (E)-3-(dimethylamino)-2-(2-thienylcarbonyl)-2-propenenitrile C10H10N2OS 详情 详情
(V) 10015 1-Hydrazinecarboximidamide; Hydrazinecarboximidamide 79-17-4 CH6N4 详情 详情
(VII) 62972 3-oxo-3-(2-thienyl)propanenitrile C7H5NOS 详情 详情
(VIII) 11983 3'-Acetamidoacetophane; m-Acetamidoacetophenone; N-(3-Acetylphenyl)acetamide 7463-31-2 C10H11NO2 详情 详情
(X) 59947 N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide C14H18N2O2 详情 详情
(XXVIII) 62971 N-(3-acetylphenyl)-N-methylacetamide C11H13NO2 详情 详情

合成路线8

The enamino nitrile (IV) can be obtained by condensation of 3-oxo-3-(2-thienyl)propionitrile (VII) with dimethylformamide dimethylacetal in chloroform.

参考文献 中间体
【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Tomcufcik, A.S.; Dusza, J.P. (Wyeth); (3-Amino-1H-pyrazol-4-yl)(aryl)methanones. EP 0129846; JP 1985013764; US 4900836 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 59945 (E)-3-(dimethylamino)-2-(2-thienylcarbonyl)-2-propenenitrile C10H10N2OS 详情 详情
(VII) 62972 3-oxo-3-(2-thienyl)propanenitrile C7H5NOS 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)