Acetyl formyl mixed anhydride -Drug Synthesis Database

【结构式】

【分子编号】29135

【品名】Acetyl formyl mixed anhydride

【CA登记号】

【分子式】C₃H₄O₃

【分子量】88.06296

【元素组成】C 40.92% H 4.58% O 54.5%

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：(III)

The alkylation of ethyl benzoylacetate (A) with beta-ethoxyethyl bromide (B) using potassium carbonate in dimethyl formamide at 80 C gives the beta-3-keto ester (I). Condensation of (I) with guanidine hydrochloride (C) using sodium methoxide in tert-butanol at 80 C gives the pyrimidine (II). Protection of the amino group is achieved by tormylation at room temperature with the mixed anhydride (III) from formic and acetic acids. Chlorination with an excess of phosphorus oxychloride at 100 C gives a mixture of (V) and (VIII). The mixture of chloropyrimidines (V, VIII) is stirred at room temperature with excess hydrazi-ne hydrate to give the aminohydrazinopyrimidine (VI). This is heated with ethyl orthoformate in triglyme at 135 C to give the bicyclic compound (VII). This triglyme solution is then heated to 20 C to effect a Dimroth type rearrangement to give SC-33643.

参考文献中间体

合成目标

【1】 Rorig, K.L.; Heilman, R.D.; SC-33643. Drugs Fut 1985, 10, 4, 298.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	10004	Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester	94-02-0	C₁₁H₁₂O₃	详情	详情
(D)	21304	Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether	122-51-0	C₇H₁₆O₃	详情	详情
(B)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(I)	29133	diethyl 2-benzoylpentanedioate		C₁₆H₂₀O₅	详情	详情
(II)	29134	2-amino-5-(2-ethoxyethyl)-6-phenyl-4-pyrimidinol		C₁₄H₁₇N₃O₂	详情	详情
(III)	29135	Acetyl formyl mixed anhydride		C₃H₄O₃	详情	详情
(IV)	29136	5-(2-ethoxyethyl)-4-hydroxy-6-phenyl-2-pyrimidinylformamide		C₁₅H₁₇N₃O₃	详情	详情
(V)	29137	4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylformamide		C₁₅H₁₆ClN₃O₂	详情	详情
(VI)	29138	5-(2-ethoxyethyl)-4-hydrazino-6-phenyl-2-pyrimidinamine		C₁₄H₁₉N₅O	详情	详情
(VII)	29139	8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-5-amine		C₁₅H₁₇N₅O	详情	详情
(VIII)	29140	4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylamine		C₁₄H₁₆ClN₃O	详情	详情
(C)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The hydrolysis of methyl (2E, 4E)-hexadecadienoate (I) with KOH in THF gives the corresponding free acid (II), which is treated with (COCl)2 in dichloromethane to yield the acid chloride (III). The esterification of (III) with trichloroethanol (IV), TEA and DMAP affords the trichloroethyl ester (V), which is stereospecifically dihydroxylated by means of AD-mix-alpha, methanesulfonamide and NaHCO3 in t-butanol/water to provide the dihydroxyester (VI). The reaction of (VI) with SOCl2 in refluxing CCl4 gives the cyclic sulfite (VII), which is alkylated by means of CuCN, Li-C6H13 and BF3/Et2O in THF to give 5(S)-hydroxy-2(S)-hexyl-3(E)-hexadecanoic acid trichloroethyl ester (VIII). The cleavage of the ester group of (VIII) by means of Zn/AcOH yields the corresponding free acid (IX), which is submitted to cyclization by reaction with Br2 in CCl4/MeOH in the presence of NaHCO3 to afford the brominated beta lactone (X). Radical debromination of (X) by means of di-tert-butyl peroxide (DBPO), Ph2Se2, and Bu3SnH in toluene provides the beta lactone (XI), which is condensed with N-(benzyloxycarbonyl)-L-leucine (XII) by means of DCC and DMAP in dichloromethane to furnish the ester (XIII). The cleavage of the Boc group of (XIII) by means of H2 over Pd/C in THF gives the free amino acid ester (XIV), which is finally N-formylated by means of acetic formic anhydride (XV) in ethyl ether to yield the target tetrahydrolipstatin.

参考文献中间体

合成目标

【1】 Bodkin, J.A.; Humphries, E.J.; McLeod, M.D.; The total synthesis of (-)-tetrahydrolipstatin. Tetrahedron Lett 2003, 44, 14, 2869.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	64250	methyl (2E,4E)-2,4-hexadecadienoate	C₁₇H₃₀O₂	详情	详情
(II)	64251	(2E,4E)-2,4-hexadecadienoic acid	C₁₆H₂₈O₂	详情	详情
(III)	64252	(2E,4E)-2,4-hexadecadienoyl chloride	C₁₆H₂₇ClO	详情	详情
(IV)	50779	2,2,2-trichloro-1-ethanol	C₂H₃Cl₃O	详情	详情
(V)	64255	2,2,2-trichloroethyl (2E,4E)-2,4-hexadecadienoate	C₁₈H₂₉Cl₃O₂	详情	详情
(VI)	64254	2,2,2-trichloroethyl (E,4S,5S)-4,5-dihydroxy-2-hexadecenoate	C₁₈H₃₁Cl₃O₄	详情	详情
(VII)	64253	2,2,2-trichloroethyl (E)-3-[(4S,5S)-2-oxo-5-undecyl-1,3,2lambda~4~-dioxathiolan-4-yl]-2-propenoate	C₁₈H₂₉Cl₃O₅S	详情	详情
(VIII)	64256	2,2,2-trichloroethyl (2S,3E,5S)-2-hexyl-5-hydroxy-3-hexadecenoate	C₂₄H₄₃Cl₃O₃	详情	详情
(IX)	64257	(2S,3E,5S)-2-hexyl-5-hydroxy-3-hexadecenoic acid	C₂₂H₄₂O₃	详情	详情
(X)	64258	(3S,4R)-4-[(1S,2S)-1-bromo-2-hydroxytridecyl]-3-hexyl-2-oxetanone	C₂₂H₄₁BrO₃	详情	详情
(XI)	49605	(3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone	C₂₂H₄₂O₃	详情	详情
(XII)	22838	(2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid	C₁₄H₁₉NO₄	详情	详情
(XIII)	49606	(1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoate	C₃₆H₅₉NO₆	详情	详情
(XIV)	49607	(1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-amino-4-methylpentanoate	C₂₈H₅₃NO₄	详情	详情
(XV)	29135	Acetyl formyl mixed anhydride	C₃H₄O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

The reaction of L-tert-leucine (I) with Boc2O and TEA in methanol gives N-Boc-L-tert-leucine (II), which is condensed with N,O-dimethylhydroxylamine (III) by means of CDI in dichloromethane to yield the corresponding amide (IV) (1). The reaction of (IV) with methyl lithium in THF affords the chiral methylketone (V), which is deprotected by means of TFA in dichloromethane to provide the aminoketone (VI). The condensation of (VI) with 2(R)-(benzyloxyaminomethyl)hexanoic acid (VII) by means of EDC and HOBt in DMF leads to the amide (VIII), which is formylated by means of formylacetic anhydride (IX) in dichloromethane to give the precursor (X). Finally this compound is deprotected by hydrogenation with H2 over Pd/C in ethyl acetate to afford the target compound. Alternatively, the intermediate chiral ketone (V) can also be obtained by reaction of N-Boc-L-tert-leucine pentafluorophenyl ester (XI) with methyl lithium of methylmagnesium bromide

参考文献中间体

合成目标

【2】 Todd, R.S.; Beckett, R.P.; Brookings, D.C.; Smith, H.K.; Thompson, A.J. (British Biotech Pharmaceuticals Ltd.); Antimicrobial agents. EP 1169031; JP 2002541197; WO 0061134 .
【1】 Ayscough, A.; Beckett, R.P.; Brookings, D.C.; Clements, J.M.; East, S.P.; Keavey, K.; Smith, K.H.; Thomas, W.; Thompson, A.J.; Todd, R.S.; A new series of potent PDF inhibitors displaying broad-spectrum antibacterial activity against respiratory tract infections. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1677.

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)	28445	(2S)-2-amino-3,3-dimethylbutyric acid		C₆H₁₃NO₂	详情	详情
(II)	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
(III)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(IV)	60279	1,1-dimethylethyl 2,2-dimethyl-1-{[methyl(methyloxy)amino]carbonyl}propylcarbamate		C₁₃H₂₆N₂O₄	详情	详情
(V)	60280	1,1-dimethylethyl 1-acetyl-2,2-dimethylpropylcarbamate		C₁₂H₂₃NO₃	详情	详情
(VI)	60281	3-amino-4,4-dimethyl-2-pentanone		C₇H₁₅NO	详情	详情
(VII)	51563	(2R)-2-[[(benzyloxy)amino]methyl]hexanoic acid		C₁₄H₂₁NO₃	详情	详情
(VIII)	60282	N-(1-acetyl-2,2-dimethylpropyl)-2-({[(phenylmethyl)oxy]amino}methyl)hexanamide		C₂₁H₃₄N₂O₃	详情	详情
(IX)	29135	Acetyl formyl mixed anhydride		C₃H₄O₃	详情	详情
(X)	60283	N-(1-acetyl-2,2-dimethylpropyl)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanamide		C₂₂H₃₄N₂O₄	详情	详情
(XI)	60284	2,3,4,5,6-pentafluorophenyl 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3,3-dimethylbutanoate		C₁₇H₂₀F₅NO₄	详情	详情

Extended Information