3-甲基-4-(四氢-2H-吡喃-2-基氧基)-1-丁胺 | 183551-55-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧烷类
• 中文名称: 3-甲基-4-(四氢-2H-吡喃-2-基氧基)-1-丁胺
• 英文名称: (R)-4-amino-2-methyl-1-butanol tetrahydropyranyl ether
• 英文别名: (R)-3-methyl-4-[(tetrahydro-2H-pyran-2-yl)oxy]-1-butanamine；(R)-3-Methyl-4-tetrahydropyranyloxybutylamine；(3R)-3-methyl-4-(oxan-2-yloxy)butan-1-amine
• CAS: 183551-55-5
• 化学式: C₁₀H₂₁NO₂
• 分子量: 187.282
• InChiKey: ZCZPRAUWWCCPQT-YHMJZVADSA-N

物化性质

• 沸点：
  95℃
• 密度：
  0.97±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  13
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  44.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-甲基-4-(四氢-2H-吡喃-2-基氧基)-1-丁胺 在 对甲苯磺酸 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 18.0h， 生成 Methanesulfonic acid (R)-4-[6-(3,5-bis-trifluoromethyl-benzylcarbamoyl)-8-oxo-5-p-tolyl-8H-[1,7]naphthyridin-7-yl]-2-methyl-butyl ester
  参考文献：
  名称：

  Axially Chiral 1,7-Naphthyridine-6-carboxamide Derivatives as Orally Active Tachykinin NK₁ Receptor Antagonists:  Synthesis, Antagonistic Activity, and Effects on Bladder Functions

  摘要：

  Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C-(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-one [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C-(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition of [I-125]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

  DOI：

  10.1021/jm990220r
• 作为产物：
  描述：

  (3R)-3-甲基-4-[(四氢-2H-吡喃-2-基)氧基]-丁腈 在 lithium aluminium tetrahydride 作用下， 以 乙醚 为溶剂， 反应 1.0h， 以94%的产率得到3-甲基-4-(四氢-2H-吡喃-2-基氧基)-1-丁胺
  参考文献：
  名称：

  Axially Chiral 1,7-Naphthyridine-6-carboxamide Derivatives as Orally Active Tachykinin NK₁ Receptor Antagonists:  Synthesis, Antagonistic Activity, and Effects on Bladder Functions

  摘要：

  Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C-(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-one [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C-(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition of [I-125]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

  DOI：

  10.1021/jm990220r

文献信息

• Enantioselective synthesis of an axially chiral 1,7-naphthyridine-6-carboxamide derivative having potent antagonist activity at the NK1 receptor
  作者：Yoshinori Ikeura、Takayuki Doi、Akira Fujishima、Hideaki Natsugari

  DOI：10.1039/a805333b

  日期：——

  A new and highly potent NK1 antagonist, (aR,9R)-3 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione], was atropdiastereoselectively synthesized in good yield by cyclization of the chiral intermediate 6b.

  一种新的高效 NK1 拮抗剂 (aR,9R)-3 [(aR,9R)-7-[3,5-双(三氟甲基)苄基]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1、6,13-二酮]，通过手性中间体 6b 的环化反应，以良好的收率合成了异丙二astereoselectively。
• Process for preparation of tetrahydropyranyoxyamines
  申请人：——

  公开号：US20040030160A1

  公开（公告）日：2004-02-12

  Tetrahydropyranyloxyamines are extremely useful as intermediates in the production of pharmaceuticals and agricultural chemicals, and as raw materials, additives or precursors in the production of perfumes, resins and adhesives. The present invention provides a process for producing a tetrahydropyranyloxyamine from an aminoalcohol which is both simple and produces a high yield. According to the present invention, an aminoalcohol represented by a general formula (1) shown below is reacted with an acid, the obtained aminoalcohol salt is reacted with 3,4-dihydro-2H-pyran, and the obtained tetrahydropyranyloxyamine salt is subsequently reacted with an alkali to form a tetrahydropyranyloxyamine represented by the general formula (2) shown below. H 2 N—X—OH  (1) 1 (wherein in said formula (1) and said formula (2), X represents a methylene group, an ethylene group or a straight chain polymethylene group having 3 to 20 carbon atoms)

  四氢吡喃氧胺作为中间体在药品和农药生产中极为有用，作为原料、添加剂或 前体在香水、树脂和粘合剂生产中也极为有用。本发明提供了一种从氨基醇生产四氢吡喃氧胺的工艺，该工艺既简单又产率高。根据本发明，下图所示通式（1）代表的氨基醇与酸反应，得到的氨基醇盐与 3,4-二氢-2H-吡喃反应，得到的四氢吡喃氧基胺盐随后与碱反应，形成下图所示通式（2）代表的四氢吡喃氧基胺。 H 2 N-X-OH (1) 1 (其中，在所述式（1）和所述式（2）中，X 代表亚甲基、乙烯基或具有 3 至 20 个碳原子的直链聚亚甲基）。
• PROCESS FOR PREPARATION OF TETRAHYDROPYRANYLOXYAMINES
  申请人：Mitsubishi Rayon Co., Ltd.

  公开号：EP1241164B1

  公开（公告）日：2004-05-06
• Axially Chiral 1,7-Naphthyridine-6-carboxamide Derivatives as Orally Active Tachykinin NK₁ Receptor Antagonists:  Synthesis, Antagonistic Activity, and Effects on Bladder Functions
  作者：Hideaki Natsugari、Yoshinori Ikeura、Izumi Kamo、Takenori Ishimaru、Yuji Ishichi、Akira Fujishima、Toshimasa Tanaka、Fumiko Kasahara、Mitsuru Kawada、Takayuki Doi

  DOI：10.1021/jm990220r

  日期：1999.9.1

  Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK1 antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C-(9)-position, (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,-11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-di-one [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C-(9)-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl3). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC50 (inhibition of [I-125]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR,9R)-8b was ca. 750-fold higher than that of its enantiomer (aS,9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C-(6)(=O)-N-(7)-CH2Ar moiety is important for NK1 receptor recognition. The NK1 antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK1 antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.