CN1681769A - 胺衍生物 - Google Patents
胺衍生物 Download PDFInfo
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- CN1681769A CN1681769A CNA038215721A CN03821572A CN1681769A CN 1681769 A CN1681769 A CN 1681769A CN A038215721 A CNA038215721 A CN A038215721A CN 03821572 A CN03821572 A CN 03821572A CN 1681769 A CN1681769 A CN 1681769A
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- methyl
- methylbutylamine
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- isobutoxy
- leucinol
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- 150000001412 amines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- USDOSECTZYSNEF-JTQLQIEISA-N (2s)-4-methyl-1-(2-methylpropoxy)pentan-2-amine Chemical compound CC(C)COC[C@@H](N)CC(C)C USDOSECTZYSNEF-JTQLQIEISA-N 0.000 claims abstract description 9
- VPSSPAXIFBTOHY-LURJTMIESA-N (2s)-2-amino-4-methylpentan-1-ol Chemical compound CC(C)C[C@H](N)CO VPSSPAXIFBTOHY-LURJTMIESA-N 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 4
- UECKDTNJEKHBKF-JTQLQIEISA-N (2s)-4-methyl-1-(2-methylprop-2-enoxy)pentan-2-amine Chemical compound CC(C)C[C@H](N)COCC(C)=C UECKDTNJEKHBKF-JTQLQIEISA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- SGAKODIXAHVUKL-LFELFHSZSA-M sodium;(2s,3s)-3-[[(2s)-4-methyl-1-(2-methylpropoxy)pentan-2-yl]carbamoyl]oxirane-2-carboxylate Chemical compound [Na+].CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C([O-])=O SGAKODIXAHVUKL-LFELFHSZSA-M 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229940124530 sulfonamide Drugs 0.000 description 7
- 150000003456 sulfonamides Chemical class 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ZOFRRNUENOHELM-LURJTMIESA-N (2s)-2-amino-4-methylpentanal Chemical compound CC(C)C[C@H](N)C=O ZOFRRNUENOHELM-LURJTMIESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及可用作合成(2S，3S)－3－[[(1S)－1－异丁氧基甲基－3－甲基丁基]氨基甲酰基]环氧乙烷－2－甲酸钠的中间体的(1S)－1－异丁氧基甲基－3－甲基丁胺及其制备方法。该方法包括在碱存在下使L－亮氨醇与下式表示的化合物反应并还原得到的(1S)－1－(2－甲基－2－丙烯氧基甲基)－3－甲基丁胺：(其中X为离去基团)。
Description
技术领域
本发明涉及一种胺衍生物及其制备方法。
背景技术
下式所示的(2S，3S)-3-[[(1S)-1-异丁氧基甲基-3-甲基丁基]氨基甲酰基]环氧乙烷-2-甲酸钠(下文称作化合物A)显示出组织蛋白酶抑制作用，并且用作治疗风湿性关节炎和骨质疏松症的药物(专利文献1：WO99/11640小册子)：
专利文献1描述了根据以下反应方案制备化合物A的方法(见专利文献1的实施例48)：
需要提供可在工业上使用的制备化合物A的合成方法。
发明内容
本发明的目的是提供一种可用作合成化合物A的中间体化合物的胺衍生物。该胺衍生物是下式表示的(1S)-1-异丁氧基甲基-3-甲基丁胺：
本发明的另一个目的是提供制备该胺衍生物的方法。
(1S)-1-异丁氧基甲基-3-甲基丁胺可根据以下反应方案获得：
步骤1：L-亮氨醇(leucinal)(2)→化合物(3)
L-亮氨醇(2)与化合物(4)的反应可以在诸如THF或DMSO的不参与反应的溶剂中，于-30℃至回流温度的温度下，在碱存在下进行。
在化合物(4)中由X代表的离去基团的例子包括卤素，如氯、溴和碘；对甲苯磺酰氧基；和甲磺酰氧基。
碱的例子包括碱金属氢化物，如NaH、LiH和KH；碱土金属氢化物，如CaH2；碱金属醇盐，如t-BuOK；无机碱，如NaOH和KOH；及有机碱，如三乙胺。
起始化合物，即L-亮氨醇可通过还原L-亮氨酸获得(例如美国专利3,935,280)。
步骤2：化合物(3)→化合物(1 )
该反应可以在诸如乙醇或乙酸的不参与反应的溶剂中，于1-100atm的氢气压力下，使用0.1-20％诸如Pd/C或阮内镍的可用于催化双键还原的催化剂进行。
(1S)-1-异丁氧基甲基-3-甲基丁胺也可以根据以下反应方案制备：
(其中，X具有与上述相同的离去基团)。
上述化合物A可以由以上所获得的(1S)-1-异丁氧基甲基-3-甲基丁胺根据以下反应方案制备(见专利文献1的实施例48和18a)：
本发明方法能够以高产率得到胺衍生物，即(1S)-1-异丁氧基甲基-3-甲基丁胺。能够以高产率由该胺衍生物得到上述化合物A。
通过以下实施例进一步描述本发明。
实施例1：(1S)-1-(2-甲基-2-丙烯氧基甲基)-3-甲基丁胺向溶于无水THF(200mL)的L-亮氨醇(20.0g，0.17mol)溶液中分批加入60％的NaH(7.92g，0.198mol)。将所得混合物在室温搅拌30分钟，再在50℃搅拌2小时。然后将混合物冷却至室温。向所得悬浮液中滴加溶于无水THF(50mL)中的3-氯-2-甲基丙烯(15.45g，0.17mol)溶液。将所得混合物在室温下搅拌20小时。减压下蒸除THF。向残留物中连续加入冰水与乙醚的混合物。将该混合物在室温下搅拌5分钟，并分离有机相。用乙醚对水相进行提取。将提取物与有机相合并。用1mol/L盐酸水溶液(7mL)洗涤合并的有机相，并用1mol/L盐酸水溶液(153mL)进行提取。通过加入碳酸钾使所得盐酸提取物的pH为约10，并用乙醚进行提取。用水洗涤有机相，经硫酸钠干燥，减压下放置以蒸除溶剂。得到油状产物的目的化合物(20.22g，69.2％)。
1H-NMR(CDCl3)δ：0.90(3H，d，J＝7Hz)，0.93(3H，d，J＝7Hz)，1.1-1.3(2H，m)，1.74(3H，s)，1.7-1.8(1H，m)，2.62(2H，宽峰s)，3.0-3.1(1H，m)，3.15(1H，dd，J＝8Hz& 9Hz)，3.38(1H，dd，J＝3Hz & 9Hz)，3.88(1H，d，J＝13Hz)，3.92(1H，d，J＝13Hz)，4.89(1H，s)，4.96(1H，s).
实施例2：(1S)-1-异丁氧基甲基-3-甲基丁胺
将(1S)-1-(2-甲基-2-丙烯氧基甲基)-3-甲基丁胺(51.9g，0.3mol)和5％Pd/C(10.4g)在乙醇(520mL)中的悬浮液在室温于氢气气氛(1atm)下搅拌18小时。在冰浴冷却下向所得反应混合物中加入6mol/L盐酸水溶液(52mL)。使用C盐对含水混合物进行过滤以除去不溶物，然后减压下放置以蒸除溶剂。将残留物溶解在水中，通过加入碳酸钾使所得水溶液的pH为约10。用乙醚提取该溶液。有机相经硫酸钠干燥，减压下放置以蒸除溶剂。得到油状化合物的目的化合物(48.6g，92.6％)。
bp：66-67℃/5mmHg
1H-NMR(CDCl3)δ：0.90(3H，d，J＝6Hz)，0.90(3H，d，J＝6Hz)，0.91(3H，d，J＝6Hz)，0.93(3H，d，J＝6Hz)，1.1-1.2(2H，m)，1.50(2H，宽峰s)，1.6-1.8(1H，m)，1.8-1.9(1H，m)，3.0-3.1(1H，m)，3.11(1H，dd，J＝8Hz & 9Hz)，3.16(1H，dd，J＝7Hz & 9Hz)，3.23(1H，dd，J＝7Hz & 9Hz)，3.37(1H，dd，J＝3Hz & 9Hz).
Claims (3)
1.(1S)-1-异丁氧基甲基-3-甲基丁胺。
2.制备(1S)-1-异丁氧基甲基-3-甲基丁胺的方法，其包括将(1S)-1-(2-甲基-2-丙烯氧基甲基)-3-甲基丁胺还原。
3.制备(1S)-1-异丁氧基甲基-3-甲基丁胺的方法，其包括以下步骤：
在碱存在下使L-亮氨醇与具有下式的化合物反应：
其中X为离去基团，
得到(1S)-1-(2-甲基-2-丙烯氧基甲基)-3-甲基丁胺，和
还原(1S)-1-(2-甲基-2-丙烯氧基甲基)-3-甲基丁胺。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002265335 | 2002-09-11 | ||
| JP265335/2002 | 2002-09-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1681769A true CN1681769A (zh) | 2005-10-12 |
| CN100349855C CN100349855C (zh) | 2007-11-21 |
Family
ID=31986576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038215721A Expired - Fee Related CN100349855C (zh) | 2002-09-11 | 2003-09-09 | 胺衍生物 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US7132573B2 (zh) |
| EP (1) | EP1538142A4 (zh) |
| JP (1) | JP4376184B2 (zh) |
| KR (1) | KR20050042798A (zh) |
| CN (1) | CN100349855C (zh) |
| AU (1) | AU2003261875A1 (zh) |
| WO (1) | WO2004024672A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9169193B2 (en) * | 2005-12-22 | 2015-10-27 | Basf Se | Method for producing O-Alkylated aminoalcohols |
| KR20130114115A (ko) * | 2010-09-30 | 2013-10-16 | 머크 샤프 앤드 돔 코포레이션 | 올리고뉴클레오티드 전달을 위한 저분자량 양이온성 지질 |
| CN104803862A (zh) * | 2015-04-03 | 2015-07-29 | 广东省石油化工研究院 | 一种醚胺类浮选剂的合成方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3640855A (en) * | 1968-09-06 | 1972-02-08 | Chevron Res | C-alkyloxy substituted tert.-butyl amine as lubricating oil detergent |
| EP1022276B1 (en) | 1997-09-04 | 2003-05-28 | Nippon Chemiphar Co., Ltd. | Epoxysuccinamide derivatives |
-
2003
- 2003-09-09 KR KR1020057004010A patent/KR20050042798A/ko not_active Application Discontinuation
- 2003-09-09 US US10/527,153 patent/US7132573B2/en not_active Expired - Fee Related
- 2003-09-09 JP JP2004535909A patent/JP4376184B2/ja not_active Expired - Lifetime
- 2003-09-09 EP EP03795320A patent/EP1538142A4/en not_active Withdrawn
- 2003-09-09 WO PCT/JP2003/011468 patent/WO2004024672A1/ja active Application Filing
- 2003-09-09 CN CNB038215721A patent/CN100349855C/zh not_active Expired - Fee Related
- 2003-09-09 AU AU2003261875A patent/AU2003261875A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP1538142A1 (en) | 2005-06-08 |
| KR20050042798A (ko) | 2005-05-10 |
| JP4376184B2 (ja) | 2009-12-02 |
| US20050288530A1 (en) | 2005-12-29 |
| AU2003261875A1 (en) | 2004-04-30 |
| JPWO2004024672A1 (ja) | 2006-01-05 |
| EP1538142A4 (en) | 2006-07-26 |
| US7132573B2 (en) | 2006-11-07 |
| WO2004024672A1 (ja) | 2004-03-25 |
| CN100349855C (zh) | 2007-11-21 |
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