1-Diazo-2-oxopropylphosphonic acid dimethyl ester -Drug Synthesis Database

【结构式】

【分子编号】32432

【品名】1-Diazo-2-oxopropylphosphonic acid dimethyl ester

【CA登记号】

【分子式】C₅H₉N₂O₄P

【分子量】192.111302

【元素组成】C 31.26% H 4.72% N 14.58% O 33.31% P 16.12%

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：(XX)

The hydrogenation of the double bond of (XVIII) with H2 and Lindlar catalyst affords the corresponding saturated aldehyde (XIX), which is condensed with the diazophosphonate (XX) giving the acetylenic derivative (XXI). The bromination of (XXI) with N-bromosuccinimide (NBS) and AgNO3 yields the bromoacetylenic compound (XXII), which is desilylated with HF and TBAF affording the dihydroxy derivative (XXIII). The resilylation of (XXIII) with CF3CO-N(Me)-Tms gives the bis(trimethylsilyl) derivative (XXIV), which is finally converted into the desired intermediate, the stannane (XXV) by reaction with tributyltin hydride, PPh3 and Pd dibenzylideneacetone complex.

参考文献中间体

合成目标

【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	21859	2,2,2-trifluoro-N-methyl-N-(trimethylsilyl)acetamide	C₆H₁₂F₃NOSi	详情	详情
(XVIII)	32430	(E,4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methyl-2-hexenal	C₃₃H₆₃NO₅Si₂	详情	详情
(XIX)	32431	(4S,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]-4-methylhexanal	C₃₃H₆₅NO₅Si₂	详情	详情
(XX)	32432	1-Diazo-2-oxopropylphosphonic acid dimethyl ester	C₅H₉N₂O₄P	详情	详情
(XXI)	32433	(2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₅NO₄Si₂	详情	详情
(XXII)	32434	(2S,3S,4S,5S,6R,9S,11S)-2-((2S,3S)-7-bromo-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-6-heptynyl)-9-ethyl-3,5,11-trimethyl-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₄H₆₄BrNO₄Si₂	详情	详情
(XXIII)	32435	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-2-hydroxy-3-methyl-6-heptynyl]-9-ethyl-4-hydroxy-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one	C₂₂H₃₆BrNO₄	详情	详情
(XXIV)	32436	(2S,3R,4S,5S,6R,9S,11S)-2-[(2S,3S)-7-bromo-3-methyl-2-[(trimethylsilyl)methyl]-6-heptynyl]-9-ethyl-3,5,11-trimethyl-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₃₀H₅₆BrNO₂Si₂	详情	详情
(XXV)	32437	(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-2-[(2S,3S,6E)-3-methyl-7-(tributylstannyl)-2-[(trimethylsilyl)methyl]-6-heptenyl]-4-[(trimethylsilyl)methyl]-1-oxa-7-azaspiro[5.5]undecan-8-one	C₄₂H₈₅NO₂Si₂Sn	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Formylation of methyl 4-hydroxyphenylacetate (I) by reaction with MgCl2 and formaldehyde in acetonitrile yields aldehyde (II), which is then brominated by means of NBS in DMF to provide bromo derivative (III). Treatment of (III) with methoxyethoxymethyl chloride and DIEA furnishes O-protected derivative (IV), which is then subjected to Suzuki reaction with boronic acid (V) catalyzed by Pd(PPh3)4 in refluxing toluene in the presence of Na2CO3 to afford biphenyl (VI). Treatment of (VI) with dimethyl-1-diazo-2-oxopropylphosphonate (VII) in MeOH in the presence of K2CO3 furnishes alkyne (VIII), which is then coupled with the iodo-benzonitrile (IX) by means of catalytic Pd(PPh3)2Cl2, CuI and Et3N in acetonitrile to provide indole (X). Saponification of the methyl ester group of (X) with NaOH in THF, followed by hydrolysis with HCl in EtOH, gives carboxylic acid (XI), which is finally converted into the desired product by transformation of the nitrile moiety into an amidine via standard Pinner/aminolysis conditions with NH3 in EtOH followed by treatment with refluxing HCl.

参考文献中间体

合成目标

【1】 Young, W.B.; Kolesnikov, A.; Rai, R.; et al.; Optimization of a screening lead for factor VIIa/TF. Bioorg Med Chem Lett 2001, 11, 17, 2253.
【2】 Young, W.B.; Kakimura, H.; Nakaike, S.; Taniguchi, K.; Kobayashi, Y.; Ishii, T.; Amada, H.; Miyata, N.; Kametani, S.; Optimization of a screening lead for factor VIIIA/TF. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 48.

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)	15822	Methyl 4-hydroxyphenylacetate; methyl 2-(4-hydroxyphenyl)acetate	14199-15-6	C₉H₁₀O₃	详情	详情
(II)	48883	methyl 2-(3-formyl-4-hydroxyphenyl)acetate		C₁₀H₁₀O₄	详情	详情
(III)	48884	methyl 2-(3-bromo-5-formyl-4-hydroxyphenyl)acetate		C₁₀H₉BrO₄	详情	详情
(IV)	48885	methyl 2-[3-bromo-5-formyl-4-[(2-methoxyethoxy)methoxy]phenyl]acetate		C₁₄H₁₇BrO₆	详情	详情
(V)	40934	3-nitrophenylboronic acid	13331-27-6	C₆H₆BNO₄	详情	详情
(VI)	48886	methyl 2-[5-formyl-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate		C₂₀H₂₁NO₈	详情	详情
(VII)	32432	1-Diazo-2-oxopropylphosphonic acid dimethyl ester		C₅H₉N₂O₄P	详情	详情
(VIII)	48887	methyl 2-[5-ethynyl-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate		C₂₁H₂₁NO₇	详情	详情
(IX)	48888	N-(4-cyano-2-iodophenyl)methanesulfonamide		C₈H₇IN₂O₂S	详情	详情
(X)	48889	methyl 2-[5-[5-cyano-1-(methylsulfonyl)-1H-indol-2-yl]-6-[(2-methoxyethoxy)methoxy]-3'-nitro[1,1'-biphenyl]-3-yl]acetate		C₂₉H₂₇N₃O₉S	详情	详情
(XI)	48890	2-[5-(5-cyano-1H-indol-2-yl)-6-hydroxy-3'-nitro[1,1'-biphenyl]-3-yl]acetic acid		C₂₃H₁₅N₃O₅	详情	详情

Extended Information