3-amino-5-(trimethylsilyl)-4-pentynoic acid -Drug Synthesis Database

【结构式】

【分子编号】16301

【品名】3-amino-5-(trimethylsilyl)-4-pentynoic acid

【CA登记号】

【分子式】C₈H₁₅NO₂Si

【分子量】185.29814

【元素组成】C 51.86% H 8.16% N 7.56% O 17.27% Si 15.16%

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：(VII)

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 1) The reaction of 4-(benzoyloxy)-2-azetidinone (IV) with 2 equivalents of 1-lithio-2-(trimethylsilyl)acetylene (V) gives azetidinone (VI), which is opened with anhydrous HCl in ethanol, yielding racemic 3-amino-5-(trimethylsilyl)-4-pentynoic acid ethyl ester (VII). Resolution of (VII) by means of diastereomeric amide formation with (R)-O-methyl mandelic acid chloride (VIII) and chromatographic separation of the diastereoisomers (MPLC, ether/hexane) affords the amide (IX), which is then N-protected with Boc2O in acetonitrile to give (X). Treatment of (X) with tetramethylguanidine in methanol gives methyl ester (XI), which is finally treated first with TFA and then with HCl in ethanol to afford ethyl ester (III).

参考文献中间体

合成目标

【1】 Zablocki, J.A.; Rico, J.G.; Garland, R.B.; et al.; Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 1995, 38, 13, 2378-94.
【2】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17739	N,N,N',N'-tetramethylguanidine; 1,1,3,3-Tetramethylguanidine	80-70-6	C₅H₁₃N₃	详情	详情
(III)	16297	ethyl (3S)-3-amino-4-pentynoate		C₇H₁₁NO₂	详情	详情
(IV)	16298	4-oxo-2-azetanyl benzoate; 4-Benzoyloxy-2-azetidinone	28562-58-5	C₁₀H₉NO₃	详情	详情
(V)	16299	Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium	54655-07-1	C₅H₉LiSi	详情	详情
(VI)	16300	4-[2-(trimethylsilyl)ethynyl]-2-azetanone		C₈H₁₃NOSi	详情	详情
(VII)	16301	3-amino-5-(trimethylsilyl)-4-pentynoic acid		C₈H₁₅NO₂Si	详情	详情
(VIII)	16302	(2R)-2-methoxy-2-phenylethanoyl chloride		C₉H₉ClO₂	详情	详情
(IX)	16303	(3S)-3-[[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoic acid		C₁₇H₂₃NO₄Si	详情	详情
(X)	16304	ethyl (3S)-3-[(tert-butoxycarbonyl)[(2R)-2-methoxy-2-phenylethanoyl]amino]-5-(trimethylsilyl)-4-pentynoate		C₂₄H₃₅NO₆Si	详情	详情
(XI)	17740	ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-pentynoate		C₁₂H₁₉NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The ethyl ester (III), a chiral key intermediate of this synthesis, can be obtained as follows: 2) The treatment of (trimethylsilyl)acetylene (XII) with butyllithium and NMM in methyl tert-butyl ether (MTBE), followed by hydrolysis with aqueous HCl, gives 3-(trimethylsilyl)-2-propynal (XIII). Treatment of (XIII) with lithium bis(trimethylsilyl)amide (LiHMDS) and trimethylsilyl chloride at -20 C gives the imine (XIV), which is reacted in situ with lithium tert-butyl acetate followed by hydrolysis with aqueous NH4Cl to afford racemic tert-butyl ester (XV). Treatment of (XV) with refluxing ethanol in the presence of p-toluenesulfonic acid gives the corresponding ethyl ester (VII) (already obtained in the preceding scheme). Desilylation of (VII) with NaOEt/EtOH affords racemic 3-amino-4-pentynoic acid ethyl ester in situ, which is then resolved using R-(-)-mandelic acid in ethyl acetate/MTBE to give mandelic acid salt (XVI). Recrystallization of (XVI) from acetonitrile/MTBE and treatment with gaseous HCl in MTBE affords ethyl ester (III) as the hydrochloride.

参考文献中间体

合成目标

【1】 Graul, A.; Martel, A.M.; Castaner, J.; Xemilofiban. Drugs Fut 1997, 22, 5, 508.
【2】 Process for the preparation of ethyl 3S-[4[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate. US 5536869 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	33800	4-morpholinecarbaldehyde	4394-85-8	C₅H₉NO₂	详情	详情
(III)	16297	ethyl (3S)-3-amino-4-pentynoate		C₇H₁₁NO₂	详情	详情
(VII)	16301	3-amino-5-(trimethylsilyl)-4-pentynoic acid		C₈H₁₅NO₂Si	详情	详情
(XII)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(XIII)	20043	3-(trimethylsilyl)-2-propynal		C₆H₁₀OSi	详情	详情
(XIV)	16307	trimethyl-N-[(E)-3-(trimethylsilyl)-2-propynylidene]silanamine; N-(trimethylsilyl)-N-[(E)-3-(trimethylsilyl)-2-propynylidene]amine		C₉H₁₉NSi₂	详情	详情
(XV)	16308	tert-butyl 3-amino-5-(trimethylsilyl)-4-pentynoate		C₁₂H₂₃NO₂Si	详情	详情
(XVI)	16309	2(R)-Hydroxy-2-phenylacetic salt with acid 3(S)-amino-4-pentynoic acid ethyl ester		C₁₅H₁₉NO₅	详情	详情

Extended Information