[1(S),3[4R,5S,6S(R)]]-1-[[[[2-(4-nitrophenyl)methoxy]carbonyl]amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[6-(1-hydroxyethyl)-4-methyl-2-[[(4-nitrophenyl)methoxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol | 246519-28-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [1(S),3[4R,5S,6S(R)]]-1-[[[[2-(4-nitrophenyl)methoxy]carbonyl]amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[6-(1-hydroxyethyl)-4-methyl-2-[[(4-nitrophenyl)methoxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol
• 英文别名: (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-2-[[(2R,3R)-2-[[[(S)-2-(4-nitrobenzyloxycarbonyl)amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester；4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)-butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate；4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)butanoyl]amino}methyl)-tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate；4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}-amino)butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate；(4-nitrophenyl)methyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2R,3R)-2-[[[(2S)-3-methyl-2-[(4-nitrophenyl)methoxycarbonylamino]butanoyl]amino]methyl]oxolan-3-yl]sulfanyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate
• CAS: 246519-28-8
• 化学式: C₃₅H₄₁N₅O₁₂S
• 分子量: 755.803
• InChiKey: YYIZIIQVGLDWHB-WGAZCQSNSA-N

物化性质

• 沸点：
  976.9±65.0 °C(Predicted)
• 密度：
  1.44±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  53
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  260
• 氢给体数：
  3
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  [1(S),3[4R,5S,6S(R)]]-1-[[[[2-(4-nitrophenyl)methoxy]carbonyl]amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[6-(1-hydroxyethyl)-4-methyl-2-[[(4-nitrophenyl)methoxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol 在 palladium on activated charcoal 氢气 作用下， 以 1,4-二氧六环 、 phosphate buffer 为溶剂， 反应 5.5h， 以65%的产率得到OCA 983
  参考文献：
  名称：

  口服THF1β-甲基卡巴培南的聚合合成。

  摘要：

  从M2-磷酸酯1开始开发了口服THF1β-甲基卡巴培南4（OCA-983）和5的聚合合成方法。M2-磷酸酯1与含有必需的前药侧链9和10的THF硫醇反应，分别以46％和42％的总收率得到所需的口服THF1β-甲基咔ap烯4和5。

  DOI：

  10.7164/antibiotics.52.643
• 作为产物：
  描述：

  S-[(2R,3R)-tetrahydro-2-[[[(S)-3-methyl-2-[[[(4-nitrophenyl)methoxy]carbonyl]amino]-1-oxobutyl]amino]methyl]-3-furanyl](α,2S,3S)-3-[(R)-1-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-α-methyl-4-oxo-2-azetidinemethanethiolate 在 ammonium bifluoride 、 三乙胺 、 亚磷酸三乙酯 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 N,N-二甲基甲酰胺 为溶剂， 反应 64.0h， 生成 [1(S),3[4R,5S,6S(R)]]-1-[[[[2-(4-nitrophenyl)methoxy]carbonyl]amino-3-methyl-1-oxobutyl]amino]-2,5-anhydro-3-S-[6-(1-hydroxyethyl)-4-methyl-2-[[(4-nitrophenyl)methoxy]carbonyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-1,4-dideoxy-3-thio-D-threo-pentitol
  参考文献：
  名称：

  EFFICIENT SYNTHESIS OF ORAL THF 1β-METHYLCARBAPENEM (OCA-983) VIA THE WITTIG PROCESS

  摘要：

  An efficient and reproducible synthesis of orally active 2-tetrahydrofuranylthio-1 beta -methylcarbapenem 16 (OCA-983) via the Wittig process was developed. The intramolecular reductive cyclization of the thioester-oxalimide 13 with triethyl phosphite to the 2-tetrahydrofuranylthio-1 beta -methylcarbapenem 14 was carried out in two steps in order to obtain a reproducible yield.

  DOI：

  10.1081/scc-100000586

文献信息

• Process improvement in the preparation of (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  申请人：American Home Products Corporation

  公开号：US20020128283A1

  公开（公告）日：2002-09-12

  The invention is a process improvement for producing the carbapenem antibacterial agent (4R, 5S, 6S)-3-[[(2R, 3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid by hydrogenation of 4-nitrobenzyl (4R, 5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R, 3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}amino)butanoyl]amino}methyl)-tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in a biphasic solvent mixture comprising a water portion and an organic solvent portion, not containing an acid acceptor. Separating the water portion from the organic portion and isolating (4R, 5S, 6S)-3-[[(2R, 3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid from the separated water portion by lyophilization or reverse osmosis.

  这项发明是一种用于生产碳青霉烯抗菌剂(4R, 5S, 6S)-3-[[[(2R, 3R)-2-[[[(S)-2-氨基-3-甲基-1-氧丁基]氨基]甲基]四氢-3-呋喃基]硫]-6-[(R)-1-羟乙基]-4-甲基-7-羟基-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸的工艺改进，通过在由含有水部分和有机溶剂部分组成的两相溶剂混合物中氢化4-硝基苄(4R, 5S, 6S)-6-[(1R)-1-羟乙基]-4-甲基-3-[(2R, 3R)-2-([(2S)-3-甲基-2-([4-硝基苄]氧}羰基)氨基]丁酰氨基}甲基)-四氢呋喃-3-基硫}-7-氧基-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸。将水部分与有机部分分离，并通过冻干或反渗透从分离的水部分中分离出(4R, 5S, 6S)-3-[[[(2R, 3R)-2-[[[(S)-2-氨基-3-甲基-1-氧丁基]氨基]甲基]四氢-3-呋喃基]硫]-6-[(R)-1-羟乙基]-4-甲基-7-羟基-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸。
• PROCESS IMPROVEMENT IN THE PREPARATION OF (4R, 5S, 6S)-3-[[(2R,3R)-2-[[[(S)-2-AMINO-3-METHYL-1-OXOBUTYL]AMINO]METHYL]TETRAHYDRO-3-FURANYL]THIO]-6-[(R)-1-HYDROXYETHYL]-4-METHYL-7-OXO-1-AZABICYCLO[3.2.0]HEPT-2-ENE-2-CARBOXYLIC ACID
  申请人：Wyeth, Five Giralda Farms

  公开号：US06649756B2

  公开（公告）日：2003-11-18

  The invention is a process improvement for producing the carbapenem antibacterial agent (4R, 5S, 6S)-3-[[2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid by hydrogenation of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[2R,3R)-2-({[(2S)-3-methyl-2-({[4-nitrobenzyl)oxy]carbonyl}amino)butanoyl]amino}methyl)-tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in a biphasic solvent mixture comprising a water portion and an organic solvent portion, not containing an acid acceptor. The water portion is separated from the organic solvent portion and (4R,5S,6S)-3-[[(2R,3R)-2-[[[(S)-2-amino-3-methyl-1-oxobutyl]amino]methyl]tetrahydro-3-furanyl]thio]-6-[R-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is isolated from the separated water portion by lyophilization or reverse osmosis.

  这项发明是一种生产碳青霉烯类抗菌剂(4R,5S,6S)-3-[[(2R,3R)-2-[(S)-2-氨基-3-甲基-1-氧丁基]氨基]-甲基]-四氢呋喃-3-基硫代-6-[(R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸的改进工艺，通过在不含酸受体的两相溶剂混合物中将4-硝基苄基(4R,5S,6S)-6-[(1R)-1-羟乙基]-4-甲基-3-[[[(2R,3R)-2-[[(2S)-3-甲基-2-[(4-硝基苄基)氧]羰基]氨基]丁酰]氨基]甲基]-四氢呋喃-3-基硫代-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸酯氢化而得。将水相与有机溶剂相分离，从分离出的水相中通过冻干或反渗透法分离出(4R,5S,6S)-3-[[(2R,3R)-2-[(S)-2-氨基-3-甲基-1-氧丁基]氨基]-甲基]-四氢呋喃-3-基硫代-6-[(R)-1-羟乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸。
• Convergent Syntheses of Oral THF 1.BETA.-Methylcarbapenems.
  作者：PANAYOTA BITHA、ZHONG LI、YANG-I LIN

  DOI：10.7164/antibiotics.52.643

  日期：——

  Convergent syntheses of oral THF 1beta-methylcarbapenems 4 (OCA-983) and 5 starting from M2-phosphate 1 were developed. Reaction of the M2-phosphate 1 with THF thiols containing a requisite prodrug side chain, 9 and 10, gave the desired oral THF 1beta-methylcarbapenems 4 and 5, respectively, in 46% and 42% overall yields.

  从M2-磷酸酯1开始开发了口服THF1β-甲基卡巴培南4（OCA-983）和5的聚合合成方法。M2-磷酸酯1与含有必需的前药侧链9和10的THF硫醇反应，分别以46％和42％的总收率得到所需的口服THF1β-甲基咔ap烯4和5。
• EFFICIENT SYNTHESIS OF ORAL THF 1β-METHYLCARBAPENEM (OCA-983) VIA THE WITTIG PROCESS
  作者：Panayota Bitha、Yang-I Lin

  DOI：10.1081/scc-100000586

  日期：2001.1

  An efficient and reproducible synthesis of orally active 2-tetrahydrofuranylthio-1 beta -methylcarbapenem 16 (OCA-983) via the Wittig process was developed. The intramolecular reductive cyclization of the thioester-oxalimide 13 with triethyl phosphite to the 2-tetrahydrofuranylthio-1 beta -methylcarbapenem 14 was carried out in two steps in order to obtain a reproducible yield.