2,4,6-trimethylbenzenesulfonyl chloride -Drug Synthesis Database

【结构式】

【分子编号】41158

【品名】2,4,6-trimethylbenzenesulfonyl chloride

【CA登记号】773-64-8

【分子式】C₉H₁₁ClO₂S

【分子量】218.70384

【元素组成】C 49.43% H 5.07% Cl 16.21% O 14.63% S 14.66%

与该中间体有关的原料药合成路线共 6 条

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1

该中间体在本合成路线中的序号：(XLV)

The reaction of (XXXVIII) with Li-TMP and LiBr in THF gives the lithium enolate (XLII), which is condensed with the chiral octadienoic aldehyde intermediate (XXV) in THF to yield the aldol adduct (XLIII). The reduction of the phenyl ester group of (XLIII) by means of LiAlH4 in THF affords the diol (XLIV), which is submitted to a regioselective esterification with mesitylenesulfonyl chloride (XLV) to provide the sulfonate (XLVI). The deoxygenation of (XLVI) by means of LiAlH4 gives the desired alcohol (XLVII), which is protected with Tbdms-OTf and TEA to yield the fully protected compound (XLVIII). The selective deprotection of (XLVIII) by means of DDQ in dichloromethane affords the diol (XLIX), which is selectively oxidated at the primary OH group with TEMPO and PhI(OAc)2 to provide the aldehyde (L). The condensation of (L) with phosphonate (LI) by means of K2CO3 and 18-C-6 in toluene furnishes the chiral octadecatetraenoic ester (LII).

参考文献中间体

合成目标

【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXV)	42632	(2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal		C₁₈H₂₄O₃	详情	详情
(XXXVIII)	42622	2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate		C₃₄H₅₂O₅Si	详情	详情
(XLII)	62849			C₃₄H₅₁LiO₅Si	详情	详情
(XLIII)	42641	2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate		C₅₂H₇₆O₈Si	详情	详情
(XLIV)	42642	(2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol		C₄₄H₇₀O₇Si	详情	详情
(XLV)	41158	2,4,6-trimethylbenzenesulfonyl chloride	773-64-8	C₉H₁₁ClO₂S	详情	详情
(XLVI)	62850	(2R,3R,4S,5S,6S,7Z)-2-{(Z,4S,5R,6S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl}-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienyl 2,4,6-trimethylbenzenesulfonate		C₅₃H₈₀O₉SSi	详情	详情
(XLVII)	42643	(3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol		C₄₄H₇₀O₆Si	详情	详情
(XLVIII)	42644	(5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether	n/a	C₅₀H₈₄O₆Si₂	详情	详情
(XLIX)	42645	(2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol	n/a	C₃₄H₆₈O₄Si₂	详情	详情
(L)	42646	(2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal	n/a	C₃₄H₆₆O₄Si₂	详情	详情
(LI)	27698	methyl 2-(diethoxyphosphoryl)acetate	1067-74-9	C₇H₁₅O₅P	详情	详情
(LII)	42647	methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate	n/a	C₃₇H₇₀O₅Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

1,3-Diaminopropane (VI) was protected as the bis-sulfonamide (VIII) by acylation with mesitylenesulfonyl chloride (VII). The sodium salt of sulfonamide (VIII) was then alkylated with mesylate (V) in cold DMF/toluene to provide the fully protected tetraamine (IX). The sulfonyl and carbamate protecting groups of (IX) were finally removed by treatment with HCl in the presence of phenol at 80 C.

参考文献中间体

合成目标

【1】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	59218	3-[[(benzyloxy)carbonyl](ethyl)amino]propyl methanesulfonate		C₁₄H₂₁NO₅S	详情	详情
(VI)	19331	3-aminopropylamine; 1,3-propanediamine	109-76-2	C₃H₁₀N₂	详情	详情
(VII)	41158	2,4,6-trimethylbenzenesulfonyl chloride	773-64-8	C₉H₁₁ClO₂S	详情	详情
(VIII)	59219	N-{3-[(mesitylsulfonyl)amino]propyl}-2,4,6-trimethylbenzenesulfonamide		C₂₁H₃₀N₂O₄S₂	详情	详情
(IX)	59220	benzyl ethyl[12-ethyl-4,8-bis(mesitylsulfonyl)-13-oxo-15-phenyl-14-oxa-4,8,12-triazapentadec-1-yl]carbamate		C₄₇H₆₄N₄O₈S₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The title tetraamino derivative was prepared by two related methods. Conversion of cis-butenediol (I) into the diamine (II) was effected by Mitsunobu condensation of (I) with HN3 with concomitant reduction of the azido group in the presence of PPh3. Acylation of (II) with mesitylenesulfonyl chloride (III) provided the bis-sulfonamide (IV), which was subsequently alkylated with the bromosulfonamide (V) in the presence of NaH to furnish the protected tetraamine (VI). The sulfonamido groups of (VI) were finally hydrolyzed by an HOAc solution of HBr in the presence of phenol.

参考文献中间体

合成目标

【1】 Witiak, D.T.; Frydman, B.J.; Marton, L.J.; Reddy, V.K.; Valasinas, A.L. (Wisconsin Alumni Research Foundation); Conformationally restricted polyamines and their use as antineoplastic agents. JP 2002508739; WO 9817624 .
【2】 Witiak, D.T.; Frydman, B.J.; Marton, L.J.; Reddy, V.K.; Valasinas, A.L. (Wisconsin Alumni Research Foundation); Conformationally restricted polyamines. US 5889061 .

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)	36965	(Z)-2-butene-1,4-diol	6117-80-2	C₄H₈O₂	详情	详情
(II)	59440	(Z)-2-butene-1,4-diamine; (Z)-4-amino-2-butenylamine		C₄H₁₀N₂	详情	详情
(III)	41158	2,4,6-trimethylbenzenesulfonyl chloride	773-64-8	C₉H₁₁ClO₂S	详情	详情
(IV)	59441	N-{(Z)-4-[(mesitylsulfonyl)amino]-2-butenyl}-2,4,6-trimethylbenzenesulfonamide		C₂₂H₃₀N₂O₄S₂	详情	详情
(V)	59442	N-(3-bromopropyl)-N-ethyl-2,4,6-trimethylbenzenesulfonamide		C₁₄H₂₂BrNO₂S	详情	详情
(VI)	59443	N-{3-[ethyl(mesitylsulfonyl)amino]propyl}-N-{(Z)-4-[{3-[ethyl(mesitylsulfonyl)amino]propyl}(mesitylsulfonyl)amino]-2-butenyl}-2,4,6-trimethylbenzenesulfonamide		C₅₀H₇₂N₄O₈S₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

Alternatively, diol (I) was converted to the bis-sulfonate ester (VII) under phase-transfer conditions. Alkylation of the sodium salt of N-ethyl-1,3-propanediamine disulfonamide (VIII) with the bis-mesytilate (VII) produced (VI), which was then deprotected as above.

参考文献中间体

合成目标

【1】 Reddy, V.K.; Valasinas, A.; Sarkar, A.; Basu, H.S.; Marton, L.J.; Frydman, B.; Conformationally restricted analogues of 1N,12N-bisethylspermine: Synthesis and growth inhibitory effects on human tumor cell lines. J Med Chem 1998, 41, 24, 4723.
【2】 Witiak, D.T.; Frydman, B.J.; Marton, L.J.; Reddy, V.K.; Valasinas, A.L. (Wisconsin Alumni Research Foundation); Conformationally restricted polyamines and their use as antineoplastic agents. JP 2002508739; WO 9817624 .
【3】 Witiak, D.T.; Frydman, B.J.; Marton, L.J.; Reddy, V.K.; Valasinas, A.L. (Wisconsin Alumni Research Foundation); Conformationally restricted polyamines. US 5889061 .

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)	36965	(Z)-2-butene-1,4-diol	6117-80-2	C₄H₈O₂	详情	详情
(III)	41158	2,4,6-trimethylbenzenesulfonyl chloride	773-64-8	C₉H₁₁ClO₂S	详情	详情
(VI)	59443	N-{3-[ethyl(mesitylsulfonyl)amino]propyl}-N-{(Z)-4-[{3-[ethyl(mesitylsulfonyl)amino]propyl}(mesitylsulfonyl)amino]-2-butenyl}-2,4,6-trimethylbenzenesulfonamide		C₅₀H₇₂N₄O₈S₄	详情	详情
(VII)	59444	(Z)-4-[(mesitylsulfonyl)oxy]-2-butenyl 2,4,6-trimethylbenzenesulfonate		C₂₂H₂₈O₆S₂	详情	详情
(VIII)	59445	N-ethyl-N-{3-[(mesitylsulfonyl)amino]propyl}-2,4,6-trimethylbenzenesulfonamide		C₂₃H₃₄N₂O₄S₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

Cycloaddition of 5-hexen-1-ol (I) with (II) in presence of NaHCO3 yields isoxazoline (III). Alternatively (III) can be obtained by treatment of (I) with diethyl nitromalonate (A) in mesitylene. Isoxazoline (III) is then oxidized by means of Jones reagent to provide acid (IV) which is coupled in presence of BOP with the imidazole derivative (V) and hydrolyzed with LiOH affording derivative (VI). Acid (VI) is coupled with derivative (IX) (obtained by reaction of diaminopropionate (VII) with (VIII) in presence of DIEA) by means of BOP, and finally hydrolyzed to afford the desired product.

参考文献中间体

合成目标

【1】 Withyak, J.; Pitts, W.J.; Smallheer, J.M.; et al.; Isoxazolines as potent antagonists of the integrin alphavbeta3. J Med Chem 2000, 43, 1, 27.
【2】 Voss, M.E.; Jadhav, P.K.; Smallheer, J.M.; Batt, D.G.; Pitts, W.J.; Wityak, J. (DuPont Pharmaceuticals Co.); Isoxazoline and isoxazole derivs. as integrin receptor antagonists. EP 0828737; JP 1999506436; US 5710159; WO 9637492 .
【3】 Jadhav, P.; Repta, A.J.; Pitts, W.J.; Hussain, M.A.; Batt, D.G. (DuPont Pharmaceuticals Co.); Heterocyclic integrin inhibitor prodrugs. WO 9843962 .

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)	41159	diethyl 2-nitromalonate		C₇H₁₁NO₆	详情	详情
(I)	41152	5-hexen-1-ol	821-41-0	C₆H₁₂O	详情	详情
(II)	30424	2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride	14337-43-0	C₄H₆ClNO₃	详情	详情
(III)	41153	ethyl 5-(4-hydroxybutyl)-4,5-dihydro-3-isoxazolecarboxylate		C₁₀H₁₇NO₄	详情	详情
(IV)	41154	4-[3-(ethoxycarbonyl)-4,5-dihydro-5-isoxazolyl]butyric acid		C₁₀H₁₅NO₅	详情	详情
(V)	41155	1H-imidazol-2-ylamine; 1H-imidazol-2-amine; 2-Aminoimidazole	7720-39-0	C₃H₅N₃	详情	详情
(VI)	41156	5-[4-(1H-imidazol-2-ylamino)-4-oxobutyl]-4,5-dihydro-3-isoxazolecarboxylic acid		C₁₁H₁₄N₄O₄	详情	详情
(VII)	41157	tert-butyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate		C₁₂H₂₄N₂O₄	详情	详情
(VIII)	41158	2,4,6-trimethylbenzenesulfonyl chloride	773-64-8	C₉H₁₁ClO₂S	详情	详情
(IX)	36588	tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate		C₁₆H₂₆N₂O₄S	详情	详情

合成路线6

该中间体在本合成路线中的序号：(V)

Alkylation of N-ethyl mesitylenesulfonamide (I) with 4-bromobutyronitrile (II) in the presence of NaH afforded the cyano sulfonamide (III). After catalytic hydrogenation of the cyano group of (III), the resulting amine (IV) was acylated with mesitylenesulfonyl chloride (V) to give the bis-sulfonamide (VI) (1). Subsequent condensation of (VI) with the bis-sulfonate (VII) produced the tetra-sulfonamide (VIII). Finally, cleavage of the mesitylenesulfonyl protecting groups of (VIII) using HBr in HOAc furnished the corresponding tetraamine, which was isolated as the hydrochloride salt.

参考文献中间体

合成目标

【2】 Marton, L.J.; Frydman, B. (SLIL Biomedical Corp.); Novel polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases. WO 0066175 .
【1】 Sarkar, A.; Basu, H.S.; Marton, L.J.; Valasinas, A.; Frydman, B.; Reddy, V.K.; Conformationally restricted analogues of 1N,14N-bisethylhomospermine (BE-4-4-4): Synthesis and growth inhibitory effects on human prostate cancer cells. J Med Chem 2001, 44, 3, 390.

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)	46925	N-ethyl-2,4,6-trimethylbenzenesulfonamide		C₁₁H₁₇NO₂S	详情	详情
(II)	34789	4-bromobutanenitrile	5332-06-9	C₄H₆BrN	详情	详情
(III)	46926	N-(3-cyanopropyl)-N-ethyl-2,4,6-trimethylbenzenesulfonamide		C₁₅H₂₂N₂O₂S	详情	详情
(IV)	46927	N-(4-aminobutyl)-N-ethyl-2,4,6-trimethylbenzenesulfonamide		C₁₅H₂₆N₂O₂S	详情	详情
(V)	41158	2,4,6-trimethylbenzenesulfonyl chloride	773-64-8	C₉H₁₁ClO₂S	详情	详情
(VI)	46928	N-ethyl-N-[4-[(mesitylsulfonyl)amino]butyl]-2,4,6-trimethylbenzenesulfonamide		C₂₄H₃₆N₂O₄S₂	详情	详情
(VII)	46929	((1R,2R)-2-[[(mesitylsulfonyl)oxy]methyl]cyclopropyl)methyl 2,4,6-trimethylbenzenesulfonate		C₂₃H₃₀O₆S₂	详情	详情
(VIII)	46930	N-ethyl-N-[4-[[((1R,2R)-2-[[[4-[ethyl(mesitylsulfonyl)amino]butyl](mesitylsulfonyl)amino]methyl]cyclopropyl)methyl](mesitylsulfonyl)amino]butyl]-2,4,6-trimethylbenzenesulfonamide		C₅₃H₇₈N₄O₈S₄	详情	详情

Extended Information