6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride -Drug Synthesis Database

【结构式】

【分子编号】43006

【品名】6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride

【CA登记号】

【分子式】C₁₁H₁₃Cl₂NO₂S

【分子量】294.20116

【元素组成】C 44.91% H 4.45% Cl 24.1% N 4.76% O 10.88% S 10.9%

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：(VIII)

Synthesis of Intermediate (VII): Acylation of p-chloroaniline (I) with dimethylmalonic acid (A) and SOCl2 gives (II), which is then cyclized to quinolinedione (III) by means of P2O5 in CH3SO3H. Reduction of the carbonyl groups of (III) with LiAlH4 in THF/Et2O in presence of AlCl3 provides tetrahydroquinoline (IV), which is further sulfonated with pyridine/SO3, yielding derivative (V). Removal of the chloro substituent of (V) by hydrogenation in basic conditions (in the presence of either NaHCO3/H2O or Et3N in MeOH) affords sulfonic acid (VI), which is converted to the sulfonyl chloride (VII) by means of ultrasound in acetonitrile or 1,3-dimethylimidazolidin-2-one (DMID) followed by treatment with POCl3 in pyridine. This conversion can also be achieved by treatment with PPh3 in dichloromethane and sulfuryl chloride. Alternatively, (V) can be converted into (VII) by a first sulfonation to yield (VIII) followed by removal of the chloro substituent in the same conditions described above. Intermediate (VI) can also be obtained as follows: Bromination of quinolinone (IX) with Br2 in CHCl3 yields derivative (X), which is then reduced with LiAlH4/AlCl3 in THF/Et2O to give tetrahydroquinoline (XI). (XI) is then converted into (XII) by sulfonation with DMF/sulfur trioxide complex. Finally, hydrogenation of (XII) over Pd/C in the presence of NaHCO3 allows removal of the bromo substituent, providing (VI).

参考文献中间体

合成目标

【1】 Donovan, V.; Brundish, D.; Bull, A.; et al.; Design and synthesis of thrombin inhibitors: Analogues of MD-805 with reduced stereogenicity and improved potency. J Med Chem 1999, 42, 22, 4584.
【2】 Hoyle, W.; Howarth, G.A.; Brundish, D.E.; Kane, P.D.; Walker, C.V.; Hayler, J.; Fullerton, J.D.; Smith, G.P.; Wathey, W.B.; Le Grand, D.M.; Allen, M.C.; Herold, P. (Novartis AG); Trypsin and thrombin inhibitors. EP 0815103; JP 1999502219; WO 9629327 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	42999	2,2-dimethylmalonic acid	595-46-0	C₅H₈O₄	详情	详情
(I)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情
(II)	43000	3-(4-chloroanilino)-2,2-dimethyl-3-oxopropionic acid		C₁₁H₁₂ClNO₃	详情	详情
(III)	43001	6-chloro-3,3-dimethyl-2,4(1H,3H)-quinolinedione		C₁₁H₁₀ClNO₂	详情	详情
(IV)	43002	3,3,6-trimethyl-1,2,3,4-tetrahydroquinoline		C₁₂H₁₇N	详情	详情
(V)	43003	6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonic acid		C₁₁H₁₄ClNO₃S	详情	详情
(VI)	43004	3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonic acid		C₁₁H₁₅NO₃S	详情	详情
(VII)	43005	3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride		C₁₁H₁₄ClNO₂S	详情	详情
(VIII)	43006	6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride		C₁₁H₁₃Cl₂NO₂S	详情	详情
(IX)	43007	3,3-dimethyl-3,4-dihydro-2(1H)-quinolinone		C₁₁H₁₃NO	详情	详情
(X)	43008	6-bromo-3,3-dimethyl-3,4-dihydro-2(1H)-quinolinone		C₁₁H₁₂BrNO	详情	详情
(XI)	43009	6-bromo-3,3-dimethyl-1,2,3,4-tetrahydroquinoline		C₁₁H₁₄BrN	详情	详情
(XII)	43010	6-bromo-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonic acid		C₁₁H₁₄BrNO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Coupling Method 1. Treatment of L-Arginine (XIII) with K2CO3 and assembling to intermediate (VII) affords derivative (XIV). After protection of the piperidine derivative (XV) as its tert-butyl ether (XVI) by means of isobutylene (B) in acidic media, (XVI) is condensed with (XIV) in the presence of Et3N to yield (XVII). Finally, elimination of the protecting groups with TFA, HBr gas or HCl in AcOH affords the desired product. 2. Alternatively, the coupling can be performed by reaction of nitro-protected L-arginine (XVIII) with isobutyl chloroformate in DMF in the presence of NMM, followed by reaction with protected piperidine derivative (XVI) to yield (XIX). Removal of the Boc group with HCl in AcOH or in dichloromethane/AcOH (2:1) and assembling to sulfonyl chloride intermediate (VII) with DIEA in DMF yields protected derivative (XX). Reductive cleavage of the nitro protecting group of (XX) with Pd/C, H2 in MeOH/AcOH/H2O (15:0.1:1), followed by elimination of the t-Bu protecting group in the conditions described above, yields the desired product.

参考文献中间体

合成目标

【1】 Donovan, V.; Brundish, D.; Bull, A.; et al.; Design and synthesis of thrombin inhibitors: Analogues of MD-805 with reduced stereogenicity and improved potency. J Med Chem 1999, 42, 22, 4584.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(VII)	43006	6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride		C₁₁H₁₃Cl₂NO₂S	详情	详情
(XIII)	22853	Arginine; 2-Amino-5-guanidinopentanoic acid		C₆H₁₄N₄O₂	详情	详情
(XIV)	43011	N(5)-[amino(imino)methyl]-N(2)-[(3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]ornithine		C₁₇H₂₇N₅O₄S	详情	详情
(XV)	43012	2-(4-piperidinyl)-1-ethanol	622-26-4	C₇H₁₅NO	详情	详情
(XVI)	43013	4-[2-(tert-butoxy)ethyl]piperidine; tert-butyl 2-(4-piperidinyl)ethyl ether		C₁₁H₂₃NO	详情	详情
(XVII)	43014	N-[4-[[amino(imino)methyl]amino]-1-([4-[2-(tert-butoxy)ethyl]-1-piperidinyl]carbonyl)butyl]-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonamide		C₂₈H₄₈N₆O₄S	详情	详情
(XVIII)	43017			C₁₁H₂₁N₅O₆	详情	详情
(XIX)	43015			C₂₂H₄₂N₆O₆	详情	详情
(XX)	43016			C₂₈H₄₇N₇O₆S	详情	详情

Extended Information