Taltobulin, SPA-110(trifluoroacetate salt), HTI-286, -Drug Synthesis Database

【结构式】

【药物名称】Taltobulin, SPA-110(trifluoroacetate salt), HTI-286

【化学名称】N,3,3-Trimethyl-L-phenylalanyl-N1-[3-carboxy-1(S)-isopropyl-2-butenyl]-N1,3-dimethyl-L-valinamide

【CA登记号】228266-40-8, 228266-41-9 (monotrifluoroacetate)

【分子式】C₂₇H₄₃N₃O₄

【分子量】473.66146

【开发单位】University of British Columbia (Originator), Wyeth Pharmaceuticals (Originator)

【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1 合成路线2 合成路线3

合成路线1

The amino acid building block (XI) was prepared as follows. Friedel-Crafts condensation of dimethylacrylic acid (I) with benzene in the presence of AlCl3 afforded 3-methyl-3-phenylbutanoic acid (II). After activation of acid (II) as the mixed anhydride (IV) by treatment with pivaloyl chloride (III) and Et3N, coupling with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (V) furnished the chiral N-acyl oxazolidinone (VI). Diastereoselective introduction of an azido group into the lithium enolate of (VI) by means of 2,4,6-triisopropylbenzenesulfonyl azide led to the (S,S)-azido compound (VII). Catalytic hydrogenation of azide (VII) in the presence of Boc2O provided the Boc-protected amine (VIII). The chiral auxiliary of (VIII) was removed by hydrolysis with lithium hydroperoxide, and the resultant carboxylic acid was further converted to the methyl ester (IX) upon treatment with an ethereal solution of diazomethane. The N-methyl derivative (X) was then prepared by alkylation of the tert-butyl carbamate (IX) with iodomethane in the presence of NaH. Basic hydrolysis of ester (X) provided the target N-Boc amino acid (XI).

参考文献中间体

【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 .

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)	34677	3-methyl-2-butenoic acid	541-47-9	C₅H₈O₂	详情	详情
(II)	38637	3-methyl-3-phenylbutyric acid		C₁₁H₁₄O₂	详情	详情
(III)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(IV)	55112	1,1-dimethylpropanoic 2-methyl-2-phenylbutanoic anhydride		C₁₆H₂₂O₃	详情	详情
(V)	12867	(4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone	17016-83-0	C₆H₁₁NO₂	详情	详情
(VI)	55113	(4S)-4-isopropyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one		C₁₇H₂₃NO₃	详情	详情
(VII)	55114	(4S)-3-[(2S)-2-azido-3-methyl-3-phenylbutanoyl]-4-isopropyl-1,3-oxazolidin-2-one		C₁₇H₂₂N₄O₃	详情	详情
(VIII)	55115	tert-butyl (1S)-1-{[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2-methyl-2-phenylpropylcarbamate		C₂₂H₃₂N₂O₅	详情	详情
(IX)	55116	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-methyl-3-phenylbutanoate		C₁₇H₂₅NO₄	详情	详情
(X)	55117	methyl (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoate		C₁₈H₂₇NO₄	详情	详情
(XI)	55118	(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid		C₁₇H₂₅NO₄	详情	详情

合成路线2

N-Boc-N-Methyl-L-valine (XII) was condensed with N,O-dimethylhydroxylamine by means of PyBOP as the coupling reagent. The resultant Weinreb amide (XIII) was then reduced to aldehyde (XIV) using LiAlH4. Wittig condensation of the valinal derivative (XIV) with (carbethoxyethylidene)triphenylphosphorane provided the unsaturated amino ester (XV). The N-Boc protecting group of (XV) was subsequently removed by treatment with trifluoroacetic acid, giving (XVI). Coupling of amino ester (XVI) with N-Boc-tert-leucine (XVII) was carried out via formation of the mixed anhydride of (XVII) with pivaloyl chloride. The resultant N-Boc dipeptide (XVIII) was further deprotected with trifluoroacetic acid, yielding (XIX). Coupling of dipeptide (XIX) with the N-Boc amino acid (IX) provided tripeptide (XX). The title compound was then obtained by sequential deprotection of the ethyl ester and N-Boc groups of (XX) using LiOH and trifluoroacetic acid, respectively.

参考文献中间体

【1】 Roberge, M.; Andersen, R.; Piers, E.; Nieman, J.; Coleman, J. (University of British Columbia); Hemiasterlin analogs. WO 9932509 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	55118	(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenylbutanoic acid		C₁₇H₂₅NO₄	详情	详情
(XII)	27154	(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methylbutyric acid	45170-31-8	C₁₁H₂₁NO₄	详情	详情
(XIII)	55119	tert-butyl (1S)-1-{[methoxy(methyl)amino]carbonyl}-2-methylpropyl(methyl)carbamate		C₁₃H₂₆N₂O₄	详情	详情
(XIV)	55120	tert-butyl (1S)-1-formyl-2-methylpropyl(methyl)carbamate		C₁₁H₂₁NO₃	详情	详情
(XV)	55121	ethyl (E,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-2,5-dimethyl-2-hexenoate		C₁₆H₂₉NO₄	详情	详情
(XVI)	55122	ethyl (E,4S)-2,5-dimethyl-4-(methylamino)-2-hexenoate		C₁₁H₂₁NO₂	详情	详情
(XVII)	22251	(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine	62965-35-9	C₁₁H₂₁NO₄	详情	详情
(XVIII)	55123	ethyl (E,4S)-4-[{(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutanoyl}(methyl)amino]-2,5-dimethyl-2-hexenoate		C₂₂H₄₀N₂O₅	详情	详情
(XIX)	55124	ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate		C₁₇H₃₂N₂O₃	详情	详情
(XX)	55125	ethyl (6S,9S,12S,13E)-9-(tert-butyl)-12-isopropyl-2,2,5,11,14-pentamethyl-6-(1-methyl-1-phenylethyl)-4,7,10-trioxo-3-oxa-5,8,11-triaza-13-pentadecen-15-oate		C₃₄H₅₅N₃O₆	详情	详情

合成路线3

An alternative synthetic method employed the racemic amino acid (XXIX). The phenylpyruvic acid precursor (XXVII) was prepared from benzaldehyde (XXI) by several procedures. Condensation of benzaldehyde (XXI) with hydantoin (XXII) yielded the benzylidene hydantoin (XXIV), which was converted to (XXVII) by basic hydrolysis. Alternatively, aldehyde (XXI) was condensed with N-acetyl glycine or with the phosphonoacetate reagent (XXIII) to produce (XXV) or (XXVI), respectively. Basic hydrolysis of either (XXV) or (XXVI) led to the desired phenylpyruvic acid (XXVII). Dialkylation of keto acid (XXVII) with iodomethane and NaOH furnished the dimethyl derivative (XXVIII). Then, reductive amination of (XXVIII) with methylamine yielded the racemic amino acid (XXIX). Coupling of amino acid (XXIX) with the intermediate dipeptide (XIX) gave rise to tripeptide (XXX) as an epimeric mixture. After chromatographic isolation of the desired isomer, basic hydrolysis of the ethyl ester provided the title compound.

参考文献中间体

【1】 Zask, A.; Cheung, K.; Birnberg, G.; et al.; Synthesis and biological activity of analogs of the antimicrotubule agent HTI-286. Proc Am Assoc Cancer Res 2002, 43, Abst 3653.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIX)	55124	ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate		C₁₇H₃₂N₂O₃	详情	详情
(XXI)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(XXII)	32482	2,4-imidazolidinedione	461-72-3	C₃H₄N₂O₂	详情	详情
(XXIII)	55126	methyl 2-(acetyloxy)-2-(diethoxyphosphoryl)acetate		C₉H₁₇O₇P	详情	详情
(XXIV)	55127	5-[(Z)-phenylmethylidene]-2,4-imidazolidinedione		C₁₀H₈N₂O₂	详情	详情
(XXV)	55128	2-methyl-4-[(Z)-phenylmethylidene]-1,3-oxazol-5-one		C₁₁H₉NO₂	详情	详情
(XXVI)	55129	methyl (Z)-2-(acetyloxy)-3-phenyl-2-propenoate		C₁₂H₁₂O₄	详情	详情
(XXVII)	55130	2-Oxophenylpropionic acid; Alpha-keto-DL-phenylalanine; Benzylglyoxylic acid; Phenylpyruvic acid	156-06-9	C₉H₈O₃	详情	详情
(XXVIII)	55131	3-methyl-2-oxo-3-phenylbutanoic acid		C₁₁H₁₂O₃	详情	详情
(XXIX)	55132	N-methyl-3-phenylvaline		C₁₂H₁₇NO₂	详情	详情
(XXX)	55133	ethyl (E,4S)-4-[((2S)-3,3-dimethyl-2-{[3-methyl-2-(methylamino)-3-phenylbutanoyl]amino}butanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate		C₂₉H₄₇N₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)