4-chloro-1-butanol -Drug Synthesis Database

【结构式】

【分子编号】22336

【品名】4-chloro-1-butanol

【CA登记号】928-51-8

【分子式】C₄H₉ClO

【分子量】108.56756

【元素组成】C 44.25% H 8.36% Cl 32.65% O 14.74%

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：(II)

Monoalkylation of 1,3-propanediamine (I) with 4-chlorobutanol (II) in refluxing n-BuOH afforded diaminoalcohol (III), which was protected as the bis-carbamate (IV) upon treatment with Boc2O. Subsequent reaction of (IV) with methanesulfonyl chloride and Et3N provided mesylate (V), and this was further treated with ethanolic ammonia to yield primary amine (VI). Condensation of amine (VI) with (methoxycarbonylmethyl) phenyl carbonate (VII) in refluxing toluene gave carbamate (VIII). Saponification of the methyl ester function of (VIII) then furnished carboxylic acid (IX). 1,6-Hexanediamine (X) was condensed with N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (XI) to produce the (6-aminohexyl)guanidine derivative (XII). This was then coupled with carboxylic acid (IX) using DCC and HOBt. Finally, the N-Boc groups were deprotected with trifluoroacetic acid in CH2Cl2.

参考文献中间体

合成目标

【1】 Lebreton, L.; Annat, J.; Derrepas, P.; Dutartre, P.; Renaut, P.; Structure-immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety. J Med Chem 1999, 42, 2, 277.

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)	19331	3-aminopropylamine; 1,3-propanediamine	109-76-2	C₃H₁₀N₂	详情	详情
(II)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(III)	22337	4-[(3-aminopropyl)amino]-1-butanol		C₇H₁₈N₂O	详情	详情
(IV)	22338	tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(4-hydroxybutyl)carbamate		C₁₇H₃₄N₂O₅	详情	详情
(V)	22339	4-((tert-butoxycarbonyl)[3-[(tert-butoxycarbonyl)amino]propyl]amino)butyl methanesulfonate		C₁₈H₃₆N₂O₇S	详情	详情
(VI)	22340	tert-butyl 4-aminobutyl[3-[(tert-butoxycarbonyl)amino]propyl]carbamate		C₁₇H₃₅N₃O₄	详情	详情
(VII)	22341	methyl 2-[(phenoxycarbonyl)oxy]acetate		C₁₀H₁₀O₅	详情	详情
(VIII)	22342	methyl 9-(tert-butoxycarbonyl)-2,2-dimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oate		C₂₁H₃₉N₃O₈	详情	详情
(IX)	22343	9-(tert-butoxycarbonyl)-2,2-dimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oic acid		C₂₀H₃₇N₃O₈	详情	详情
(X)	22344	1,6-hexanediamine; 6-aminohexylamine	124-09-4	C₆H₁₆N₂	详情	详情
(XI)	22345	tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate		C₁₂H₂₂N₂O₄S	详情	详情
(XII)	22346	tert-butyl (Z)-[(6-aminohexyl)amino][(tert-butoxycarbonyl)amino]methylidenecarbamate		C₁₇H₃₄N₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Condensation of trimethylhydroquinone (I) with 4-chloro-1-butanol (II) in the presence of phosphomolybdic acid in refluxing toluene yielded the chlorobutyl ether (III). Benzhydrylpiperazine (VI), (prepared from chlorodiphenylmethane (IV) and piperazine (V)), was then condensed with chloride (III) to give the target compound, which was isolated as the dihydrochloride salt.

参考文献中间体

合成目标

【1】 Kawasaki, N.; Satoh, T.; Nagai, H.; Nishiki, M.; Matsumoto, H.; Inagaki, N.; Miyataka, H.; Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions. Chem Pharm Bull 1999, 47, 2, 177.

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)	26357	2,3,5-trimethyl-1,4-benzenediol	700-13-0	C₉H₁₂O₂	详情	详情
(II)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(III)	27973	4-(4-chlorobutoxy)-2,3,6-trimethylphenol		C₁₃H₁₉ClO₂	详情	详情
(IV)	27974	Benzhydrylchloride; 1,1-Diphenylchloromethane; Dibenzyl chloride; Alpha-Chlorodiphenylmethane; Chlorodiphenylmethane; Diphenylchloromethane; 1-[chloro(phenyl)methyl]benzene	90-99-3	C₁₃H₁₁Cl	详情	详情
(V)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(VI)	20796	N-(Benzhydryl)piperazine; 1-Benzhydrylpiperazine; 1-(dibenzyl)piperazine	841-77-0	C₁₇H₂₀N₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The reaction of 4-chloro-1-butanol (I) with allylamine (II) by means of K2CO3 in refluxing THF gives N-allyl-N-(4-hydroxybutyl)amine (III), which is condensed with the pyrrolo[2,3-d]pyrimidine derivative (IV) by heating at 130 C in DMSO to afford the tertiary amine (V). The reaction of (V) with TBAF and Ts-F in THF provides the 4-fluorobutyl derivative (VI). Finally, the hydrogenation of the allylic double bond of (VI) with H2 over Pd/C in ethanol gives the target LWH-154.

参考文献中间体

合成目标

【1】 Gold, P.W.; Contoreggi, C.; Webster, E.L.; Eckelman, W.C.; Rice, K.C.; Hsin, L.-W.; Chrousos, G.P.; Synthesis of [3H] (4-fluorobutyl)propyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine: A potent radioligand for corticotropin-releasing hormone type 1 receptor. J Label Compd Radiopharm 2000, 43, 9, 899.

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)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(II)	13672	Allylamine; 2-Propen-1-amine	107-11-9	C₃H₇N	详情	详情
(III)	51571	4-(allylamino)-1-butanol		C₇H₁₅NO	详情	详情
(IV)	45880	4-chloro-7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine		C₁₈H₂₀ClN₃	详情	详情
(V)	51572	4-[allyl(7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1-butanol		C₂₅H₃₄N₄O	详情	详情
(VI)	51573	N-allyl-N-(4-fluorobutyl)-N-(7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine; N-allyl-N-(4-fluorobutyl)-7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine		C₂₅H₃₃FN₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Gold, P.W.; Contoreggi, C.; Webster, E.L.; Eckelman, W.C.; Rice, K.C.; Hsin, L.-W.; Chrousos, G.P.; Synthesis of [3H] (4-fluorobutyl)propyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine: A potent radioligand for corticotropin-releasing hormone type 1 receptor. J Label Compd Radiopharm 2000, 43, 9, 899.

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)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(II)	13672	Allylamine; 2-Propen-1-amine	107-11-9	C₃H₇N	详情	详情
(III)	51571	4-(allylamino)-1-butanol		C₇H₁₅NO	详情	详情
(IV)	45880	4-chloro-7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine		C₁₈H₂₀ClN₃	详情	详情
(V)	51572	4-[allyl(7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1-butanol		C₂₅H₃₄N₄O	详情	详情
(VI)	51573	N-allyl-N-(4-fluorobutyl)-N-(7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine; N-allyl-N-(4-fluorobutyl)-7-mesityl-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine		C₂₅H₃₃FN₄	详情	详情

合成路线5

该中间体在本合成路线中的序号：(I)

4-Chloro-1-butanol (I) is protected as the tetrahydropyranyl ether (III) by treatment with dihydropyran (II) in the presence of pyridinium p-toluenesulfonate (PPTS). Alkylation of the sodium derivative of phenothiazine (IV) with chloride (III) yields adduct (V), which is subsequently deprotected to alcohol (VI) with PPTS in MeOH-THF. The free alcohol (VI) is then chlorinated to (VII) by using SOCl2 in benzene. Finally, condensation of chloride (VII) with pyrrolidine (VIII) in THF at 100 C in a sealed tube provides the title compound.

参考文献中间体

合成目标

【1】 Guan, J.; et al.; Design, synthesis, and evaluation of new chemosensitizers in multi-drug-resistant Plasmodium falciparum. J Med Chem 2002, 45, 13, 2741.

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)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(II)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(III)	57750	2-(4-Chlorobutoxy)tetrahydropyran		C₉H₁₇ClO₂	详情	详情
(IV)	57751	10H-Phenothiazine; 2,3,5,6-Dibenzo-1,4-thiazine; Dibenzo-1.4-thiazine; Dibenzothiazine; Phenothiazine; Thiodiphenylamine	92-84-2	C₁₂H₉NS	详情	详情
(V)	57752	4-(10H-phenothiazin-10-yl)butyl tetrahydro-2H-pyran-2-yl ether; 10-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-10H-phenothiazine		C₂₁H₂₅NO₂S	详情	详情
(VI)	57753	4-(10H-phenothiazin-10-yl)-1-butanol		C₁₆H₁₇NOS	详情	详情
(VII)	57754	10-(4-chlorobutyl)-10H-phenothiazine		C₁₆H₁₆ClNS	详情	详情
(VIII)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情

合成路线6

该中间体在本合成路线中的序号：(XVI)

Intramolecular cyclization of (XIII) in the presence of potassium tert-butoxide affords a racemic mixture of syn adducts, which can be resolved by chiral chromatography to provide the target (R,R)-isomer (XIV). Methyl ether cleavage in (XIV) employing methanesulfonic acid affords phenol (XV). This is then alkylated with 4-chlorobutanol (XVI) yielding ether (XVII). After conversion of the primary hydroxyl group of (XVII) into mesylate (XVIII), condensation with diazabicyclo[2.2.2]octane produces the title ammonium salt

参考文献中间体

合成目标

【1】 Manning, R.E.; Tremont, S.J.; Glenn, K.C.; Keller, B.T. (Pharmacia Corp.); Combination therapy for the prophylaxis and treatment of hyperlipidemic conditions and disorders. WO 0168096 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	59715	2-butyl-2-({[4-(dimethylamino)-2-(4-methoxybenzyl)phenyl]sulfonyl}methyl)hexanal		C₂₇H₃₉NO₄S	详情	详情
(XIV)	59717	(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione		C₂₇H₃₉NO₄S	详情	详情
(XV)	59718	(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione		C₂₆H₃₇NO₄S	详情	详情
(XVI)	22336	4-chloro-1-butanol	928-51-8	C₄H₉ClO	详情	详情
(XVII)	59719	(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-5-[4-(4-hydroxybutoxy)phenyl]-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepine-1,1-dione		C₃₀H₄₅NO₅S	详情	详情
(XVIII)	59720	4-{4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1lambda~6~-benzothiepin-5-yl]phenoxy}butyl methanesulfonate		C₃₁H₄₇NO₇S₂	详情	详情
(XIX)	28358	1,4-diazabicyclo[2.2.2]octane	280-57-9	C₆H₁₂N₂	详情	详情

Extended Information