(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol -Drug Synthesis Database

【结构式】

【分子编号】13488

【品名】(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol

【CA登记号】2914-69-4

【分子式】C₄H₆O

【分子量】70.09104

【元素组成】C 68.55% H 8.63% O 22.83%

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：(XI)

YM-796 can be obtained by two different ways: 1) The Wittig condensation of 1-methylpiperidin-4-one (I) with 2-(diethoxyphosphoryl)acetic acid ethyl ester (II) by means of NaH in dimethoxyethane gives 2-(1-methylpiperidin-4-ylidene) acetic acid ethyl ester (III), which is cyclized with ethyl lactate (IV) by means of NaH in DMSO yielding 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylic acid ethyl ester (V). The decarboxylation of (V) with refluxing aqueous 1N HCl affords 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one (VI), which is submitted to a new Wittig condensation with methyltriphenylphosphonium iodide (or bromide) (VII) by means of NaH in DMSO to give racemic 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (VIII). Finally, this compound is submitted to optical resolution with L-tartaric acid or with di-p-toluoyl-D-tartaric acid. 2) The Wittig condensation of 4-oxopiperidine-1-carboxylic acid ethyl ester (IX) with phosphorane (VII) as before gives the corresponding methylene derivative (X), which is submitted to alkoxybromination with N-bromosuccinimide (NBS) and (S)-3-butyn-2-ol (XI) yielding (S)-4-(bromomethyl)-4-(1-methyl-2-propynyloxy)piperidine-1-carboxylic acid ethyl ester (XII). The radical cyclization of (XII) with NaBH4 catalyzed by bis(dimethylglyoximato)(pyridine)cobalt(III) chloride [chlorocobaloxime(III)] affords (S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (XIII), which is finally reduced with sodium bis(2-methoxyethoxy)aluminum hydride (vitride) in toluene and treated with fumaric acid to obtain the sesquifumarate salt.

参考文献中间体

合成目标

【1】 Ngo, J.; Martel, A.M.; Castaner, J.; YM-796. Drugs Fut 1997, 22, 2, 144.
【2】 Tsukamoto, S.; Kondo, Y.; Igarashi, S.; An efficient synthesis of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane by cobaloxime(I)-mediated radical cyclization. Heterocycles 1995, 41, 8, 1771-1778.
【3】 Tsukamoto, S.; Fujii, M.; Yasunaga, T.; Matsuda, K.; Wanibuchi, F.; Hidaka, K.; Furuya, T.; Tamura, T.; Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists. Chem Pharm Bull 1995, 43, 5, 842-852.
【4】 Tsukamoto, S.-I.; Nagaoka, H.; Usuda, S.; Harada, M.; Tamura, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic spiro cpds. and their preparation. AU 8823449; EP 0311313; JP 1990036183; US 4996210 .
【5】 Tsukamoto, S.; Kohinata, T.; Fujii, M.; Tomisawa, S. (Yamanouchi Pharmaceutical Co., Ltd.); (-)-(S)-2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4,5]decane L-tartrate. EP 0590150; JP 1993508699; WO 9220683 .

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)	10919	1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one	1445-73-4	C₆H₁₁NO	详情	详情
(II)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(III)	13480	ethyl 2-(1-methyl-4-piperidinylidene)acetate		C₁₀H₁₇NO₂	详情	详情
(IV)	13481	ethyl lactate; ethyl 2-hydroxypropanoate	97-64-3	C₅H₁₀O₃	详情	详情
(V)	13482	ethyl 2,8-dimethyl-3-oxo-1-oxa-8-azaspiro[4.5]decane-4-carboxylate		C₁₃H₂₁NO₄	详情	详情
(VI)	13483	2,8-Dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one		C₁₀H₁₇NO₂	详情	详情
(VII)	13484	Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide	2065-66-9	C₁₉H₁₈IP	详情	详情
(VIII)	13485	2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane		C₁₁H₁₉NO	详情	详情
(IX)	13486	Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone	29976-53-2	C₈H₁₃NO₃	详情	详情
(X)	13487	ethyl 4-methylene-1-piperidinecarboxylate		C₉H₁₅NO₂	详情	详情
(XI)	13488	(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol	2914-69-4	C₄H₆O	详情	详情
(XII)	13489	ethyl 4-(bromomethyl)-4-[[(1S)-1-methyl-2-propynyl]oxy]-1-piperidinecarboxylate		C₁₃H₂₀BrNO₃	详情	详情
(XIII)	13490	ethyl (2S)-2-methyl-3-methylene-1-oxa-8-azaspiro[4.5]decane-8-carboxylate		C₁₃H₂₁NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Acylation of 1-acetyl-1,2,3,4-tetrahydroquinoline (I) with 2-chloropropionyl chloride (II) by means of AlCl3 provides the quinoline derivative (III), which is deacetylated by treatment with HCl to give 1,2,3,4-tetrahydro-6-(2-chloropropionyl)quinoline (IV). Condensation of compound (IV) with O-ethyl hydrazinethioformate (V) in refluxing acetonitrile yields the thiadiazinone (VI), which is then N-acylated at the quinoline ring with 3,4-dimethoxybenzoyl chloride (VII) by means of Et3N in methylene chloride to give the racemate EMD-53998 [rac-(VIII)]. Optical resolution of EMD-53998 can be performed by two different ways: a) enantioseparation via chromatography with Chiralpak AD in 100% EtOH as eluent and b) acylation of EMD-53998 with (S)-camphanoyl chloride (IX) by means of Et3N in methylene chloride followed by treatment with morpholine in the same solvent to afford a mixture of ()-EMD-53998 (EMD-57439) and the camphanoyl amide (X), which are separated by chromatography. Finally, the (+)-enantiomer, EMD-57033, is isolated by further treatment of amide (X) with morpholine in methylene chloride.

参考文献中间体

合成目标

【1】 Strube, J.; Jupke, A.; Schmidt-Traub, H.; Schulte, M.; Epping, A.; Devant, R.; Design, optimization, and operation of SMB chromatography in the production of enantiomerically pure pharmaceuticals. Chirality 1999, 11, 440.
【2】 Castaner, J.; Doggrell, S.A.; Brown, L.; EMD-57033. Drugs Fut 2002, 27, 1, 14.
【3】 Jonas, R.; Piulats, J.; Lues, I.; Klockow, M. (Merck Patent GmbH); Thiadiazinones. AU 8816646; DE 3719031; DE 3744149; EP 0294647; JP 1988310886; US 4916128 .
【4】 Klockow, M.; Lues, I.; Jonas, R.; Preparation of the enantiomers of the novel Ca-sensitizer EMD 53 998. Bioorg Med Chem Lett 1992, 2, 6, 589.

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)	51475	1-[3,4-dihydro-1(2H)-quinolinyl]-1-ethanone		C₁₁H₁₃NO	详情	详情
(II)	12926	2-Chloropropanoyl chloride; 2-Chloropropionyl chloride	7623-09-8	C₃H₄Cl₂O	详情	详情
(III)	51476	1-(1-acetyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-chloro-1-propanone		C₁₄H₁₆ClNO₂	详情	详情
(IV)	51477	2-chloro-1-(1,2,3,4-tetrahydro-6-quinolinyl)-1-propanone		C₁₂H₁₄ClNO	详情	详情
(V)	51478	O-ethyl 1-hydrazinecarbothioate		C₃H₈N₂OS	详情	详情
(VI)	51479	6-methyl-5-(1,2,3,4-tetrahydro-6-quinolinyl)-3,6-dihydro-2H-1,3,4-thiadiazin-2-one		C₁₃H₁₅N₃OS	详情	详情
(VII)	13488	(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol	2914-69-4	C₄H₆O	详情	详情
(VIII)	51480	5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one		C₂₂H₂₃N₃O₄S	详情	详情
(IX)	16583	(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride	39637-74-6	C₁₀H₁₃ClO₃	详情	详情
(X)	51481	5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolinyl]-6-methyl-3-[[(4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-yl]carbonyl]-3,6-dihydro-2H-1,3,4-thiadiazin-2-one		C₃₂H₃₅N₃O₇S	详情	详情
(XI)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Synthesis of the unsaturated acid precursor (V) is carried out as follows. Desilylation of 4-(trimethylsilyl)-3-butyn-2-ol (I) with tetrabutylammonium fluoride affords (II). The lithium acetylide generated from alkyne (II) is then carboxylated by CO2 to furnish the pentynoic acid derivative (III). Subsequent acetylation of the alcohol hydroxyl group of (III) leads to acetate ester (IV). Then, Lindlar hydrogenation of the triple bond gives rise to the cis alkene (V).

参考文献中间体

合成目标

【1】 Thompson, C.F.; Jamison, T.F; Jacobsen, E.N.; Total synthesis of FR901464. Convergent assembly of chiral componenents prepared by asymmetric catalysis. J Am Chem Soc 2000, 122, 45, 10482.

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)	62000	(2S)-4-(trimethylsilyl)-3-butyn-2-ol		C₇H₁₄OSi	详情	详情
(II)	13488	(2S)-3-Butyn-2-ol; (S)-(-)-3-Butyn-2-ol	2914-69-4	C₄H₆O	详情	详情
(III)	62111	(4S)-4-hydroxy-2-pentynoic acid		C₅H₆O₃	详情	详情
(IV)	62112	(4S)-4-(acetyloxy)-2-pentynoic acid		C₇H₈O₄	详情	详情
(V)	62113	(Z,4S)-4-(acetyloxy)-2-pentenoic acid		C₇H₁₀O₄	详情	详情

Extended Information