N-(4-Oxocyclohexyl)acetamide -Drug Synthesis Database

【结构式】

【分子编号】11895

【品名】N-(4-Oxocyclohexyl)acetamide

【CA登记号】27514-08-5

【分子式】C₈H₁₃NO₂

【分子量】155.19676

【元素组成】C 61.91% H 8.44% N 9.03% O 20.62%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

This compound can be obtained in two related ways: 1) The cyclization of 4-acetamidocyclohexanone (I) with thiourea (II) by means of Br2 in hot acetic acid gives 6-acetamido-2-amino-4,5,6,7-tetrahydrobenzothiazole (III), which by hydrolysis with refluxing aqueous HBr yields racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole (racemic IV). Optical resolution with L-(+)-tartaric acid affords the (S)-(-)-isomer (IV), which is finally treated with propionaldehyde and LiBH4. 2) The reaction of 4-aminocyclohexanol (V) with phthalic anhydride (VI) in toluene gives the phthalimido derivative (VII), which is oxidized with potassium dichromate - H2SO4 to the corresponding cyclohexanone (VIII). The cyclization of (VIII) with thiourea (II) and Br2 as before affords 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzothiazole (IX), which is deprotected with hydrazine in refluxing ethanol yielding racemic (IV), already obtained.

参考文献中间体

合成目标

【1】 Griss, G. et al. (Dr. Karl Thomae GmbH); Tetrahydrobenzothiazoles, their preparation and their use as intermediates or as medicines. AU 8551544; DE 3447075; DE 3508947; EP 0186087; ES 8707513; ES 8707514; ES 8707515; JP 1986155377; US 4731374 .
【2】 Schneider, C.S.; Mierau, J.; J. Dopamine autoreceptor agonists: Resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine. J Med Chem 1987, 30, 3, 494.
【3】 De Angelis, L.; Pramipexole Hydrochloride. Drugs Fut 1992, 17, 4, 291.

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)	11895	N-(4-Oxocyclohexyl)acetamide	27514-08-5	C₈H₁₃NO₂	详情	详情
(II)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(III)	11897	N-(2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)acetamide	104617-51-8	C₉H₁₃N₃OS	详情	详情
(IV)	11898	(6S)-2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-ylamine; (6S)-4,5,6,7-Tetrahydro-1,3-benzothiazole-2,6-diamine		C₇H₁₁N₃S	详情	详情
(V)	11899	4-Aminocyclohexanol; trans-4-Aminocyclohexanol	27489-62-9	C₆H₁₃NO	详情	详情
(VI)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(VII)	11901	2-(4-Hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione	104618-31-7	C₁₄H₁₅NO₃	详情	详情
(VIII)	11902	2-(4-Hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione		C₁₄H₁₃NO₃	详情	详情
(IX)	11903	2-(2-Amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)-1H-isoindole-1,3(2H)-dione		C₁₅H₁₃N₃O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

Condensation of 4-acetamidocyclohexanone (XVII) with N-(cyclopropylmethyl)piperazine (VI) in refluxing toluene, optionally in the presence of MsOH , followed by reduction by means of NaBH4 or H2 over PtO2 in EtOH yields the trans-diaminocyclohexane derivative (XVIII) . Hydrolysis of acetamide (XVIII) using either boiling aqueous HCl or p-TsOH in H2O at 120 °C in a sealed reactor gives the corresponding cyclohexylamine trihydrochloride (XXa) or tritosylate salt (XXb) (1-3). Finally, compounds (XIXa) or (XIXb) are acylated with 3-methoxy-4-nitrobenzoyl chloride (II) in the presence of DIEA in THF or aqueous NaOH .

参考文献中间体

合成目标

【1】 Grauert, M., Linz, G., Schmid, R., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Trihydrochloride forms of a dihydropteridinone derivative and process for preparation. WO 2007090844.
【2】 Linz, G., Kraemer, G.F., Gutschera, L., Asche, G. (Boehringer Ingelheim International GmbH). Method for the production of dihydropteridinones. WO 2006018220.
【3】 Schnaubelt, J., Herter, R. (Boehringer Ingelheim International GmbH). Process for manufacturing dihydropteridinones and intermediates thereof. WO 2012049153.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIXa)	68543	4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexanamine trihydrochloride		C₁₄H₂₇N₃.3HCl	详情	详情
(XIXb)	68544	4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexanamine tris(4-methylbenzenesulfonate)		C₁₄H₂₇N₃.3C₇H₈O₃S	详情	详情
(II)	21086	3-methoxy-4-nitrobenzoyl chloride		C₈H₆ClNO₄	详情	详情
(VI)	68532	N-(cyclopropylmethyl)piperazine；1-(Cyclopropylmethyl)piperazine	57184-25-5	C₈H₁₆N₂	详情	详情
(VII)	68533	N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxy-4-nitrobenzamide		C₂₂H₃₂N₄O₄	详情	详情
(XVII)	11895	N-(4-Oxocyclohexyl)acetamide	27514-08-5	C₈H₁₃NO₂	详情	详情
(XVIII)	68542	N-(4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)acetamide		C₁₆H₂₉N₃O	详情	详情

Extended Information