2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one -Drug Synthesis Database

【结构式】

【分子编号】48910

【品名】2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one

【CA登记号】

【分子式】C₉H₉NOS

【分子量】179.2426

【元素组成】C 60.31% H 5.06% N 7.81% O 8.93% S 17.89%

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：(III)

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：(V)

The monoamine intermediate (IV) has been obtained as follows: The condensation of 2(R)-(benzyloxycarbonylamino)-3-(2-naphthyl)propionic acid (I) with 3-(tert-butoxycarbonylamino)-2-hydroxypropylamine (II) gives the corresponding amide (III), which is regioselectively deprotected by hydrogenolysis to yield the desired monoamine (IV). The condensation of 2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (V) with 4-chlorobutyric acid ethyl ester (VI) gives the corresponding cyclic amide (VII), which is hydrolyzed to afford the carboxylic acid (VIII). The condensation of acid (VIII) with the intermediate amine (IV) provides the amide (IX), which is finally N-deprotected to furnish the target diamide.

参考文献中间体

合成目标

【1】 Huang, P.; Funamizu, H.; Loew, G.H.; et al.; Rational design, discovery, and synthesis of a novel series of potent growth hormone secretagogues. J Med Chem 2001, 44, 24, 4082.
【2】 Salmon, R.; Sunley, R.L.; Godfrey, C.R.A.; Urch, C.J.; Lewis, T.; Bishop, N.D. (AstraZeneca plc); Bicycle amine derivs.. US 5912254; US 6066646 .

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)	54458	(2R)-2-{[(benzyloxy)carbonyl]amino}-3-(2-naphthyl)propanoic acid		C₂₁H₁₉NO₄	详情	详情
(II)	54459	tert-butyl 3-amino-2-hydroxypropylcarbamate		C₈H₁₈N₂O₃	详情	详情
(III)	54460	benzyl (1R)-2-({3-[(tert-butoxycarbonyl)amino]-2-hydroxypropyl}amino)-1-(2-naphthylmethyl)-2-oxoethylcarbamate		C₂₉H₃₅N₃O₆	详情	详情
(IV)	54461	tert-butyl 3-{[(2R)-2-amino-3-(2-naphthyl)propanoyl]amino}-2-hydroxypropylcarbamate		C₂₁H₂₉N₃O₄	详情	详情
(V)	48910	2,3,4,5-Tetrahydro-1,5-benzothiazepin-4-one		C₉H₉NOS	详情	详情
(VI)	54462	4-Chlorobutyric acid ethyl ester; Ethyl 4-chlorobutyrate	3153-36-4	C₆H₁₁ClO₂	详情	详情
(VII)	54463	ethyl 4-[4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]butanoate		C₁₅H₁₉NO₃S	详情	详情
(VIII)	54464	4-[4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]butanoic acid		C₁₃H₁₅NO₃S	详情	详情
(IX)	54465	tert-butyl 2-hydroxy-3-{[(2R)-3-(2-naphthyl)-2-({4-[4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]butanoyl}amino)propanoyl]amino}propylcarbamate		C₃₄H₄₂N₄O₆S	详情	详情

Extended Information