(R)-methylnaltrexone bromide | 916055-92-0

• 物质功能分类: 原料药 - 影响组织代谢的药物
• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: (R)-methylnaltrexone bromide
• 英文别名: (5α,17R)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-17-ium bromide；(5α,17R)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-17-methyl-6-oxomorphinanium bromide；methylnaltrexone bromide；naltrexone methyl bromide；morphinanium, 17R, 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-17-methyl-6-oxo-,salt, (5α)-(9Cl)；(R)-N-Methylnaltrexone bromide；(R)-N-methylnaltrexone；(3R,4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-ium-7-one;bromide
• CAS: 916055-92-0
• 化学式: Br*C₂₁H₂₆NO₄
• 分子量: 436.346
• InChiKey: IFGIYSGOEZJNBE-NQMNLMSRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.33
• 重原子数：
  27
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

溴甲纳曲酮是在欧盟范围内首个被批准用于治疗阿片类药物诱导便秘的药物。但该药禁用于已知或疑似存在机械性胃肠道阻塞的患者。

作为一种选择性μ阿片受体拮抗剂，溴甲纳曲酮属于季铵盐类化合物，这限制了其通过血脑屏障的能力，使其主要在周围组织如胃肠道中发挥作用。因此，它能够减少阿片类药物引起的便秘作用，而不影响其对中枢神经系统的镇痛效果。

溴甲纳曲酮是吗啡酮类衍生物的一种。通过对文献的调研发现，制备溴甲纳曲酮的主要原料为盐酸纳曲酮。首先，通过碱化步骤得到游离碱；然后进行甲基化反应，最终获得目标产物——溴甲纳曲酮。

反应信息

• 作为反应物：
  描述：

  (R)-methylnaltrexone bromide 在 氧气 、 sodium chloride 作用下， 以 水 为溶剂， 反应 264.0h， 生成 (3R,4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-5,7-dioxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-ium bromide
  参考文献：
  名称：

  [EN] PREPARATION AND USE OF (PRÉPARATION ET UTILISATION DE (20090813US2007099946A1DOSHAN HAROLD D [US], et al2007050312,23-34,1081AD36,45ADDATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1978, CONE E J ET AL: "THE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINE", XP002503485, Database accession no. PREV197866060535CONE E J ET ALTHE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINEBIOSISBIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US1978PREV197866060535AA36,45ARESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY, vol. 20, no. 3, 1978, pages 413 - 434, ISSN: 0034-5164RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY19782030034-5164413434OSINSKI J ET AL: "Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics study", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 780, no. 2, 25 November 2002 (2002-11-25), pages 251 - 259, XP004388356, ISSN: 1570-0232OSINSKI J ET ALDetermination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics studyJOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL2002112578021570-0232251259AA45AWO2008019115A2WYETH CORP [US], et al20080214361E1E
  [FR] PRÉPARATION ET UTILISATION DE (20090813US2007099946A1DOSHAN HAROLD D [US], et al2007050312,23-34,1081AD36,45ADDATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1978, CONE E J ET AL: "THE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINE", XP002503485, Database accession no. PREV197866060535CONE E J ET ALTHE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINEBIOSISBIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US1978PREV197866060535AA36,45ARESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY, vol. 20, no. 3, 1978, pages 413 - 434, ISSN: 0034-5164RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY19782030034-5164413434OSINSKI J ET AL: "Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics study", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 780, no. 2, 25 November 2002 (2002-11-25), pages 251 - 259, XP004388356, ISSN: 1570-0232OSINSKI J ET ALDetermination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics studyJOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL2002112578021570-0232251259AA45AWO2008019115A2WYETH CORP [US], et al20080214361E1E

  摘要：

  这项发明涉及(R)-8-酮-MNTX的合成，如公式(I)所示，以及相关方法和产品。

  公开号：

  WO2009099410A1
• 作为产物：
  描述：

  delta 7-methylnaltrexone bromide 在 甲酸 、 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 异丙醇 为溶剂， 反应 12.0h， 生成 (R)-methylnaltrexone bromide
  参考文献：
  名称：

  Synthesis of Naltrexone and (R)-Methylnaltrexone from Oripavine via Direct Oxidation of Its Quaternary Salts

  摘要：

  (R)-Methylnaltrexone and naltrexone were each prepared in four steps from oripavine in practical yields. The procedure involved quaternization of oripavine with cyclopropylmethyl halides, singlet oxygen oxidation of the quaternary salts, and the reduction of endo peroxides to 14-hydroxyketone functionalities. (R)-Methylnaltrexone was prepared from the corresponding R-diastereomer of the oripavine salt. All diastereomeric mixtures of the quaternary salts were subjected to N-demethylation with sodium thiolate to yield cyclopropyl methylnororipavine, which was converted into naltrexone by peracid oxidation and hydrogenation according to established procedures.

  DOI：

  10.1055/s-0034-1378808

文献信息

• [EN] PROCESSES FOR THE PREPARATION OF MORPHINANE AND MORPHINONE COMPOUNDS<br/>[FR] PROCÉDÉS POUR LA PRÉPARATION DE COMPOSÉS DE MORPHINANE ET DE MORPHINONE
  申请人：UNIV BROCK

  公开号：WO2010121369A1

  公开（公告）日：2010-10-28

  The present application describes processes for the synthesis of morphinane and morphinone compounds, useful as pharmaceutical agents. Also included are novel intermediates useful in the preparation of these compounds. The process comprises quaternization of oripavine to provide a mixture of the R- and S-isomeric (at the nitrogen) quaternary salts. The R-isomer is readily isolated and converted to various N-(R)-morphinane and N-(S)-morphinone compounds. The R-isomer, S-isomer or a mixture of R- and S-isomers may be demethylated and converted to various morphinane and morphinone compounds.

  本申请描述了合成吗啡烷和吗啡酮化合物的过程，这些化合物可用作药物。还包括在制备这些化合物过程中有用的新型中间体。该过程包括对奥利帕定进行季铵化，以提供R-和S-异构体（在氮上）季铵盐的混合物。R-异构体容易被分离并转化为各种N-(R)-吗啡烷和N-(S)-吗啡酮化合物。R-异构体、S-异构体或R-和S-异构体的混合物可以被去甲基化并转化为各种吗啡烷和吗啡酮化合物。
• 一种溴甲纳曲酮及其中间体新的制备方法
  申请人：重庆朗天制药有限公司

  公开号：CN107021978B

  公开（公告）日：2019-10-11

  本发明涉及溴甲纳曲酮及其中间体的一种制备方法。所述方法包括以下步骤：氯硅烷保护起始物料Ⅲ的3位酚羟基得到中间体Ⅳ，然后与溴甲基环丙烷缩合得到中间体Ⅴ，再甲基化得到中间体Ⅵ，中间体Ⅵ脱保护得到中间体Ⅶ，最后通过离子交换得到溴甲纳曲酮。本发明制备方法路线短，副产物少，产品纯度高，所用原料易得，价格较低，产品成本低，适合工业化生产。
• WO2006/127899
  申请人：——

  公开号：——

  公开（公告）日：——
• Synthesis of Naltrexone and (R)-Methylnaltrexone from Oripavine via Direct Oxidation of Its Quaternary Salts
  作者：Tomas Hudlicky、Ales Machara、Lukas Werner、Hannes Leisch、Robert Carroll、David Adams、D. Haque、D. Cox

  DOI：10.1055/s-0034-1378808

  日期：——

  (R)-Methylnaltrexone and naltrexone were each prepared in four steps from oripavine in practical yields. The procedure involved quaternization of oripavine with cyclopropylmethyl halides, singlet oxygen oxidation of the quaternary salts, and the reduction of endo peroxides to 14-hydroxyketone functionalities. (R)-Methylnaltrexone was prepared from the corresponding R-diastereomer of the oripavine salt. All diastereomeric mixtures of the quaternary salts were subjected to N-demethylation with sodium thiolate to yield cyclopropyl methylnororipavine, which was converted into naltrexone by peracid oxidation and hydrogenation according to established procedures.
• [EN] PREPARATION AND USE OF (PRÉPARATION ET UTILISATION DE (20090813US2007099946A1DOSHAN HAROLD D [US], et al2007050312,23-34,1081AD36,45ADDATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1978, CONE E J ET AL: "THE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINE", XP002503485, Database accession no. PREV197866060535CONE E J ET ALTHE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINEBIOSISBIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US1978PREV197866060535AA36,45ARESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY, vol. 20, no. 3, 1978, pages 413 - 434, ISSN: 0034-5164RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY19782030034-5164413434OSINSKI J ET AL: "Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics study", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 780, no. 2, 25 November 2002 (2002-11-25), pages 251 - 259, XP004388356, ISSN: 1570-0232OSINSKI J ET ALDetermination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics studyJOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL2002112578021570-0232251259AA45AWO2008019115A2WYETH CORP [US], et al20080214361E1E<br/>[FR] PRÉPARATION ET UTILISATION DE (20090813US2007099946A1DOSHAN HAROLD D [US], et al2007050312,23-34,1081AD36,45ADDATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1978, CONE E J ET AL: "THE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINE", XP002503485, Database accession no. PREV197866060535CONE E J ET ALTHE IDENTIFICATION AND MEASUREMENT OF 2 NEW METABOLITES OF NALTREXONE IN HUMAN URINEBIOSISBIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US1978PREV197866060535AA36,45ARESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY, vol. 20, no. 3, 1978, pages 413 - 434, ISSN: 0034-5164RESEARCH COMMUNICATIONS IN CHEMICAL PATHOLOGY AND PHARMACOLOGY19782030034-5164413434OSINSKI J ET AL: "Determination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics study", JOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL, vol. 780, no. 2, 25 November 2002 (2002-11-25), pages 251 - 259, XP004388356, ISSN: 1570-0232OSINSKI J ET ALDetermination of methylnaltrexone in clinical samples by solid-phase extraction and high-performance liquid chromatography for a pharmacokinetics studyJOURNAL OF CHROMATOGRAPHY B: BIOMEDICAL SCIENCES & APPLICATIONS, ELSEVIER, AMSTERDAM, NL2002112578021570-0232251259AA45AWO2008019115A2WYETH CORP [US], et al20080214361E1E
  申请人：PROGENICS PHARM INC

  公开号：WO2009099410A1

  公开（公告）日：2009-08-13

  This invention relates to synthesis of (R)-8-keto-MNTX, as shown in Formula (I), and related methods and products.

  这项发明涉及(R)-8-酮-MNTX的合成，如公式(I)所示，以及相关方法和产品。