2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid -Drug Synthesis Database

【结构式】

【分子编号】48912

【品名】2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid

【CA登记号】68716-47-2

【分子式】C₆H₅BCl₂O₂

【分子量】190.8209

【元素组成】C 37.77% H 2.64% B 5.67% Cl 37.16% O 16.77%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XI)

Condensation of substituted aniline (I) with acrylic acid (II) in toluene affords bicyclic derivative (III), whose carbonyl is reduced by means of Red-Al in toluene to yield compound (IV). Conversion of (IV) into bicyclic hydrazine (V) is then performed by treatment with NaNO2 and HOAc followed by reduction of the resulting diazo derivative with LiAlH4 in THF. Derivative (V) is then subjected to a Fisher indole cyclization process by reaction with ketone (VI) and HCl in iPrOH to provide compound (VII), which is then regioselectively reduced with NaCNBH3 in TFA to give tetracyclic indoline (VIII). N-Protection of (VIII) with Boc2O and NaOH affords Boc protected derivative (IX), which is then selectively brominated by means of NBS in DMF to yield bromo derivative (X). Finally, the desired compound is obtained by a Suzuki cross-coupling reaction between (X) and boronic acid (XI) catalyzed by Pd(PPh3)4, followed by Boc removal with TFA in CH2Cl2.

参考文献中间体

合成目标

【1】 Robichaud, A.J.; Chen, W.; McClung, C.; et al.; Synthesis and biological evaluation of novel, selective 5-HT2C receptor agonists for the treatment of obesity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 105.

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)	25182	2-aminobenzenethiol	137-07-5	C₆H₇NS	详情	详情
(II)	19139	acrylic acid	79-10-7	C₃H₄O₂	详情	详情
(III)	48910	2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one		C₉H₉NOS	详情	详情
(IV)	22617	2,3,4,5-tetrahydro-1,5-benzothiazepine		C₉H₁₁NS	详情	详情
(V)	48146	3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine		C₉H₁₂N₂S	详情	详情
(VI)	27115	4-piperidinone	40064-34-4	C₅H₉NO	详情	详情
(VII)	48147	6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole		C₁₄H₁₆N₂S	详情	详情
(VIII)	48150	(8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole		C₁₄H₁₈N₂S	详情	详情
(IX)	48149	tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate		C₁₉H₂₆N₂O₂S	详情	详情
(X)	48911	tert-butyl (8aS,12aR)-2-bromo-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate		C₁₉H₂₅BrN₂O₂S	详情	详情
(XI)	48912	2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid	68716-47-2	C₆H₅BCl₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III). This is condensed with ethyl acetoacetate (IV) to produce enamine (V), which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI). Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII). Finally, displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound

参考文献中间体

合成目标

【1】 Nakazato, A.; et al.; Chemical modification of 4-carbamoyl-1,2,3,6-tetrahydropyridinopyrrolopyrimidine, CRA0316, for discovery CRH1 receptor antagonists. Drugs Fut 2002, 27, Suppl. A.
【2】 Kennis, L.; Kumagai, T.; Nakazato, A.; et al.; Synthesis, SAR and biological activities of CRH1 receptor: Novel 3- or 4-carbamoyl-1,2,5,6-tetrahydropyridinoquinoline derivative. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 258.
【3】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 .

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)	27739	2-bromoaniline	615-36-1	C₆H₆BrN	详情	详情
(II)	48912	2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid	68716-47-2	C₆H₅BCl₂O₂	详情	详情
(III)	60295	2',4'-dichloro[1,1'-biphenyl]-2-amine; 2',4'-dichloro[1,1'-biphenyl]-2-ylamine		C₁₂H₉Cl₂N	详情	详情
(IV)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(V)	60296	ethyl 3-[(2',4'-dichloro[1,1'-biphenyl]-2-yl)amino]-2-butenoate		C₁₈H₁₇Cl₂NO₂	详情	详情
(VI)	60297	8-(2,4-dichlorophenyl)-2-methyl-4-quinolinol		C₁₆H₁₁Cl₂NO	详情	详情
(VII)	60298	8-(2,4-dichlorophenyl)-2-methyl-4-quinolinyl trifluoromethanesulfonate		C₁₇H₁₀Cl₂F₃NO₃S	详情	详情
(VIII)	60299	1,2,3,6-tetrahydro-4-pyridinecarboxamide		C₆H₁₀N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

In a related synthetic strategy, 8-bromo-4-hydroxy-2-methylquinoline (I) is converted to aryl triflate (II) by using N-phenyl trifluoromethanesulfonimide and NaH. Displacement of the triflate group of (II) with 1,2,3,6-tetrahydropyridine-4-carboxamide (III) gives the tetrahydropyridyl quinoline (IV). The bromoquinoline (IV) is finally subjected to Suzuki coupling with 2,4-dichlorophenylboronic acid (V) to produce the title compound

参考文献中间体

合成目标

【1】 Kameo, K.; Kumagai, T.; Nakazato, A.; Okubo, T. (Taisho Pharmaceutical Co., Ltd.); Tetrahydropyridino or piperidino heterocyclic derivs.. EP 1299378; WO 0202549 .

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)	60306	8-bromo-2-methyl-4-quinolinol		C₁₀H₈BrNO	详情	详情
(II)	60307	8-bromo-2-methyl-4-quinolinyl trifluoromethanesulfonate		C₁₁H₇BrF₃NO₃S	详情	详情
(III)	60299	1,2,3,6-tetrahydro-4-pyridinecarboxamide		C₆H₁₀N₂O	详情	详情
(IV)	60308	1-(8-bromo-2-methyl-4-quinolinyl)-1,2,3,6-tetrahydro-4-pyridinecarboxamide		C₁₆H₁₆BrN₃O	详情	详情
(V)	48912	2,4-Dichlorophenylboronic acid; 2,4-Dichlorobenzeneboronic acid	68716-47-2	C₆H₅BCl₂O₂	详情	详情

Extended Information