tributyl[(E)-3-chloro-1-propenyl]stannane -Drug Synthesis Database

【结构式】

【分子编号】50995

【品名】tributyl[(E)-3-chloro-1-propenyl]stannane

【CA登记号】

【分子式】C₁₅H₃₁ClSn

【分子量】365.57384

【元素组成】C 49.28% H 8.55% Cl 9.7% Sn 32.47%

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：(IV)

Addition of tributyltin hydride to the triple bond of propargyl alcohol (I) in the presence of AIBN provided a mixture of (Z)-(II) and (E)-3-(tributylstannyl)-2-propen-1-ol (III), which were separated by column chromatography. The desired (E)-allyl alcohol (III) was further converted to the corresponding chloride (IV) by treatment with PPh3 in refluxing CCl4. Alkylation of the nortropane derivative (V) with chloride (IV) in the presence of celite-supported KF furnished the N-(tributylstannyl)propenyl nortropane (VI). The target iodinated compound was then prepared by treatment of (VI) with N-iodosuccinimide.

参考文献中间体

合成目标

【2】 Elmaleh, D.R.; Madras, B.K.; Meltzer, P.; Hanson, R.N. (General Hospital Corporation; Harvard College; Northeastern University); Substd. 2-carboxyalkyl-3-(fluorophenyl)-8-(3-haloprofen-2-yl) nortropanes and their use as imaging agents for neurodegenerative disorders. EP 0734385; EP 1081147; WO 9511901 .
【1】 Elmaleh, D.R.; et al.; Preparation and biological evaluation of iodine-125-IACFT: A selective SPECT agent for imaging dopamine transporter sites. J Nucl Med 1996, 37, 7, 1197.

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)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(II)	52939	(Z)-3-(tributylstannyl)-2-propen-1-ol		C₁₅H₃₂OSn	详情	详情
(III)	52942	(E)-3-(tributylstannyl)-2-propen-1-ol	n/a	C₁₅H₃₂OSn	详情	详情
(IV)	50995	tributyl[(E)-3-chloro-1-propenyl]stannane		C₁₅H₃₁ClSn	详情	详情
(V)	52940	methyl (1R,2S,3S,5S)-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate	n/a	C₁₅H₁₈FNO₂	详情	详情
(VI)	52941	methyl (1R,2S,3S,5S)-3-(4-fluorophenyl)-8-[(E)-3-(tributylstannyl)-2-propenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate	n/a	C₃₀H₄₈FNO₂Sn	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Conjugate addition of tolylmagnesium bromide (II) to ecgonidine methyl ester (I) provided the 3-beta-tolyl tropane derivative (III). N-Dealkylation of (III) to produce the nortropane analogue (V) was carried out via acylation with trichloroethyl chloroformate, followed by reductive cleavage of the resultant trichloroethyl carbamate (IV) with Zn and HOAc. Alkylation of the secondary amine (V) with propargyl bromide (VI) afforded the corresponding propargyl amine (VII). Subsequent hydrostannylation of the propargyl group furnished the desired (E)-stannylpropenyl compound (VIII) along with the corresponding (Z)-isomer. In an improved procedure, amine (V) was alkylated with (E)-3-chloro-1-(tributylstannyl)-1-propene (IX) to yield pure (VIII). Finally, the title vinyl iodide was obtained by iododestannylation of (VIII) employing iodine in cold CHCl3.

参考文献中间体

合成目标

【1】 Emond, P.; et al.; Synthesis and ligand bindin of nortropane derivatives: N-substituted 2beta-carbomethoxy-3beta-(4'-iodophenyl)nortropane and N-(3-iodotrop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-disubstituted phenyl)nortropane. New high-affinity and selective compounds. J Med Chem 1997, 40, 9, 1366.
【2】 Mauclaire, L.; Edmond, P.; Guilloteau, D.; Besnard, J.-C.; Frangin, Y. (CIS Bio International); Tropane derivs. useable in particular for in vivo detection of dopamine transporters. EP 0901491; JP 2000510141; US 6180083; WO 9743285 .

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)	21118	methyl (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene-2-carboxylate		C₁₀H₁₅NO₂	详情	详情
(II)	35657	bromo(4-methylphenyl)magnesium	4294-57-9	C₇H₇BrMg	详情	详情
(III)	50267	methyl (1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₇H₂₃NO₂	详情	详情
(IV)	50993	2-methyl 8-(2,2,2-trichloroethyl) (1R,2S,3S,5S)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate		C₁₉H₂₂Cl₃NO₄	详情	详情
(V)	50994	methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₆H₂₁NO₂	详情	详情
(VI)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(VII)	50995	tributyl[(E)-3-chloro-1-propenyl]stannane		C₁₅H₃₁ClSn	详情	详情
(VIII)	50996	methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-(2-propynyl)-8-azabicyclo[3.2.1]octane-2-carboxylate		C₁₉H₂₃NO₂	详情	详情
(IX)	50997	methyl (1R,2S,3S,5S)-3-(4-methylphenyl)-8-[(E)-3-(tributylstannyl)-2-propenyl]-8-azabicyclo[3.2.1]octane-2-carboxylate		C₃₁H₅₁NO₂Sn	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

This compound has been obtained by two related ways: The demethylation of levorphanol (I) by the deGraw and Engstrom procedure (ethyl chloroformate and K2CO3 in refluxing chloroform and hydrolysis with NaOH) gives norlevorphanol (II), which is alkylated with propargyl bromide (III) and K2CO3 in hot DMF to yield the N-propargyl derivative (IV). The hydrostannylation of (IV) with HSnBu3 and Et3B in THF affords a mixture of the trans-(V) and cis-(VI) tributyltin precursors that are separated by column chromatography. Finally, the desired trans-isomer (V) is iodinated with I2 in CHCl3 to provide the target iodoallyl morphinan derivative. Alternatively, the hydrostannylation of propargyl alcohol (VI) by conventional methods gives the (E)-3-(tributylastannyl)allyl alcohol (VII), which is treated with CCl4 and PPh3 to yield the corresponding allyl bromide (VIII). Finally, the N-alkylation of norlevorphanol (II) with the allyl bromide (VIII) affords the already reported trans-(tributylstannyl)precursor (V).

参考文献中间体

合成目标

【1】 Neumeyer, J.L.; Negus, S.S.; Mello, N.K.; Cohen, D.J.; Gu, X.-H.; Rusovici, D.E.; DeNunzio, N.J.; van Vliet, L.A.; Bidlack, J.M.; Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: Synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan. Bioorg Med Chem Lett 2001, 11, 20, 2735.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(I)	43741	(1R,9R,10R)-17-methyl-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-4-ol		C₁₇H₂₃NO	详情	详情
(II)	43742	(1R,9R,10R)-17-azatetracyclo[7.5.3.0(1,10).0(2,7)]heptadeca-2,4,6-trien-4-ol		C₁₆H₂₁NO	详情	详情
(III)	54430	(1R,10R)-17-(2-propynyl)-17-azatetracyclo[7.5.3.0^1,10.0^2,7]heptadeca-2,4,6-trien-4-ol		C₁₉H₂₃NO	详情	详情
(IV)	54431	(1R,10R)-17-[(E)-3-(tributylstannyl)-2-propenyl]-17-azatetracyclo[7.5.3.0~1,10~.0~2,7~]heptadeca-2,4,6-trien-4-ol		C₃₁H₅₁NOSn	详情	详情
(V)	54432	(1R,10R)-17-[(Z)-3-(tributylstannyl)-2-propenyl]-17-azatetracyclo[7.5.3.0~1,10~.0~2,7~]heptadeca-2,4,6-trien-4-ol		C₃₁H₅₁NOSn	详情	详情
(VI)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(VII)	52942	(E)-3-(tributylstannyl)-2-propen-1-ol	n/a	C₁₅H₃₂OSn	详情	详情
(VIII)	50995	tributyl[(E)-3-chloro-1-propenyl]stannane		C₁₅H₃₁ClSn	详情	详情

Extended Information