WO2020132819A1 - 一种(1r,3s)-3-氨基环戊醇盐酸盐的制备方法 - Google Patents

一种(1r,3s)-3-氨基环戊醇盐酸盐的制备方法 Download PDF

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WO2020132819A1
WO2020132819A1 PCT/CN2018/123142 CN2018123142W WO2020132819A1 WO 2020132819 A1 WO2020132819 A1 WO 2020132819A1 CN 2018123142 W CN2018123142 W CN 2018123142W WO 2020132819 A1 WO2020132819 A1 WO 2020132819A1
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preparing
reaction
chiral
carboxylic acid
aminocyclopentanol
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PCT/CN2018/123142
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French (fr)
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周章涛
叶伟平
费安杰
王杨
钱仲雯
周杏宝
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广东莱佛士制药技术有限公司
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    • 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
    • C07C213/02—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 involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/40—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the invention relates to the technical field of organic chemical synthesis, in particular to a method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride.
  • (1R,3S)-3-aminocyclopentanol hydrochloride is a very important pharmaceutical intermediate.
  • the global annual demand is more than 10 tons, and it basically depends on foreign manufacturers to manufacture. Production enterprises.
  • the main synthesis method for this key chiral intermediate (1R, 3S)-3-aminocyclopentanol is the chiral substrate method, and the process is to put optically pure (-)-Vince lactam in platinum and rhodium.
  • precious metal catalysts such as palladium or hydrogen
  • the double bond is reduced by hydrogenation, and then the nitrogen atom on the amide bond is protected, and then the ring is opened with a Grignard reagent.
  • the intermediate product after ring opening is then subjected to Baeyer-Villiger oxidation rearrangement reaction with oxidants such as hydrogen peroxide, t-butyl hydroperoxide or m-chloroperoxybenzoic acid.
  • the protective group on the amino group is removed to obtain the final product.
  • This method requires the use of expensive starting materials that are not supplied in large quantities. The steps are long and the cost is too high, which is not conducive to large-scale industrial production.
  • patent CN 102633657 reported that hydroxylamine was protected with benzyl chloroformate, and then mixed with cyclopentadiene. Under the action of sodium periodate oxidant, Diels-Alder reaction occurred to obtain cycloaddition. Intermediate. This intermediate can complete double bond reduction, ring opening, and deprotection to obtain the racemate in one step.
  • this patent only reports the synthesis method of racemate, and cannot obtain optically active products.
  • sodium periodate is expensive, making cost control difficult.
  • the present invention provides a method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride.
  • the method for preparation starts from simple and inexpensive materials and designs a Asymmetric synthesis route to obtain the target product (1R, 3S)-3-aminocyclopentanol hydrochloride.
  • the preparation method efficiently controls the generation of chiral centers, the cost is greatly reduced, and the optical purity is high.
  • a method for preparing (1R,3S)-3-aminocyclopentanol hydrochloride specifically includes the following steps:
  • the intermediate product II is deprotected under alkaline conditions to obtain the target configuration (1R,3S)-3-aminocyclopentanol; then acidified with hydrochloric acid-methanol solution to obtain the target product (1R,3S)-3 -Aminocyclopentanol hydrochloride.
  • the chiral carboxylic acid has the following structural formula:
  • R1 and R2 are different groups.
  • the chiral carboxylic acid includes R-mandelic acid, L-phenylalanine, L-proline, L-leucine, L-isoleucine or L- Valine.
  • the nitrogen-containing ligand includes pyridine, oxazoline or dimethylethylenediamine.
  • the molar ratio of chiral carboxylic acid to hydroxylamine hydrochloride is (1 to 1.5): (1.5 to 2.5).
  • the molar ratio of the chiral carboxylic acid-protected hydroxylamine, cyclopentadiene, cuprous chloride and nitrogen-containing ligand is (1 to 1.5): (2 ⁇ 2.5): (0.1 ⁇ 0.2): (0.05 ⁇ 0.1).
  • the amount of palladium carbon is 2% to 6% of the mass of the intermediate product I.
  • the reaction temperature of the palladium carbon-hydrogen system is 50-60°C.
  • the intermediate product I is a chiral bridge ring compound.
  • the preparation method of (1R,3S)-3-aminocyclopentanol hydrochloride provided by the present invention uses an inexpensive chiral carboxylic acid as a chiral inducing group, with high efficiency and low cost.
  • the preparation method of (1R,3S)-3-aminocyclopentanol hydrochloride provided by the present invention adopts a copper-catalyzed oxidation reaction system by using an amide formed from a raw material chiral carboxylic acid and hydroxylamine as a chiral source
  • the chiral hetero Diels-Alder reaction product can be obtained quickly, followed by reduction and deprotection reactions, which can efficiently control the generation of chiral centers, greatly reduce the cost, and have high optical purity.
  • the single-pass conversion rate is effectively improved, and the operation and control are convenient, there are no special requirements for equipment, the reaction efficiency is high, and it is suitable for large-scale mass production promotion.
  • Step 1 Preparation of hydroxylamine protected by R-mandelic acid
  • Step 2 Preparation of intermediate product I obtained by Diels-Alder reaction
  • Step 4 Preparation of the target product (1R,3S)-3-amino-cyclopentanol hydrochloride
  • hydroxylamine hydrochloride (16g, 0.23mol) and anhydrous methanol (100mL) were added, and then a solution of potassium hydroxide (22g, 0.39mol) in methanol (80mL) was added dropwise to this mixture, resulting in a large amount of white solid ; Filter to remove the white solid, and then cool the filtrate in an ice bath for later use, and add the L-Boc-phenylalanine ethyl ester prepared above to the hydroxylamine methanol solution.
  • Step 2 Preparation of intermediate product I obtained by Diels-Alder reaction
  • Cuprous chloride (1.0g, 0.01mol, 0.2equiv.) and pyridine (0.2mL, 2.5mmol, 0.05equiv.) were added to the L-Boc-phenylalanine protected hydroxylamine (14g, 0.05mol, 1.0equiv) .) with cyclopentadiene (5.0 g, 0.075 mol, 1.5 equiv.) in methanol.
  • the whole mixed solution was stirred and reacted in air for three hours at room temperature.
  • the reaction solution was then quenched with adipic acid tetraethylamine solution (0.5M) and extracted three times with ethyl acetate.
  • the intermediate product I obtained in the previous step was dissolved in methanol (50 mL), and then acetic acid (0.5 mL) and 10% palladium carbon (0.5 g) were added in sequence. The whole system was reacted under a hydrogen atmosphere at 50°C for 2 hours; after the reaction was completed, the reaction solution was filtered through a small section of diatomaceous earth to remove insoluble inorganic substances, and the filtrate was removed under reduced pressure to remove all volatile components to obtain 12.7 g Racemate intermediate, intermediate product II, yield about 95%.
  • Step 4 Preparation of the target product (1R,3S)-3-amino-cyclopentanol hydrochloride
  • hydroxylamine hydrochloride (17g, 0.24mol) and anhydrous methanol (100mL) were added, and then a solution of potassium hydroxide (22g, 0.41mol) in methanol (80mL) was added dropwise to this mixture, resulting in a large amount of white solid ; Filter to remove the white solid, and then cool the filtrate in an ice bath for use, add the L-Boc-proline ethyl ester prepared above to the methanol solution of hydroxylamine.
  • Step 2 Preparation of intermediate product I obtained by Diels-Alder reaction
  • Cuprous chloride (1.0g, 0.01mol, 0.2equiv.) and pyridine (0.2mL, 2.5mmol, 0.05equiv.) were sequentially added to L-Boc-proline protected hydroxylamine (12g, 0.05mol, 1.0equiv. ) With cyclopentadiene (5.0 g, 0.075 mol, 1.5 equiv.) in methanol.
  • the whole mixed solution was stirred and reacted in air for three hours at room temperature.
  • the reaction solution was then quenched with adipic acid tetraethylamine solution (0.5M) and extracted three times with ethyl acetate.
  • the intermediate product I obtained in the previous step was dissolved in methanol (50 mL), and then acetic acid (0.5 mL) and 10% palladium carbon (0.5 g) were added in sequence. The whole system was reacted under hydrogen atmosphere at 50°C for 2 hours. After the reaction is completed, the reaction solution is filtered through a small section of diatomaceous earth to remove insoluble inorganic substances. The filtrate was further removed all the volatile components under reduced pressure to obtain 11.5 g of racemic intermediate, namely intermediate product II, with a yield of about 93%.
  • Step 4 Preparation of the target product (1R,3S)-3-amino-cyclopentanol hydrochloride
  • the intermediate product II from the previous step was mixed with potassium hydroxide and methanol in reaction bottle A, stirred for 3 hours, then all solvents were removed under vacuum, and then extracted with water-ethyl acetate.
  • the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a brown oil, namely (1R, 3S)-3-aminocyclopentanol.
  • the aqueous phase was adjusted to pH 2-3 with dilute hydrochloric acid and extracted with ethyl acetate to recover L-Boc-proline (6.2g).

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Abstract

(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，该方法以手性羧酸与羟胺形成的酰胺作为手性源，在铜催化的氧化反应体系中快速得到手性的狄尔斯-阿尔德反应产物，然后经过还原反应、碱性脱保护反应和酸化反应后得到目标产物。

Description

一种(1R,3S)-3-氨基环戊醇盐酸盐的制备方法 技术领域
本发明涉及有机化学合成的技术领域，尤其是涉及一种(1R,3S)-3-氨基环戊醇盐酸盐的制备方法。
背景技术
(1R,3S)-3-氨基环戊醇盐酸盐是一种非常重要的医药中间体，全球每年的需求量都在10吨以上，且基本依赖国外厂商制造，国内目前还未见大规模生产的企业。
在2018年2月，美国FDA正式批准了由吉利德科学公司开发的以商品名Biktary上市的一种治疗HIV病毒感染的新药。新药中的主要活性成分为Bictegravir，而(1R,3S)-3-氨基环戊醇恰巧是Bictegravir的重要手性中间体，是构成Bictegravir手性分子的唯一手性源。随着此新药的上市，市场上对于这一手性中间体的需求量必将进一步上升。
目前，对于该关键手性中间体(1R,3S)-3-氨基环戊醇的主要合成方法有手性底物法，其过程是将光学纯的(-)-Vince内酰胺在铂、铑或钯等贵金属催化剂作用下氢化还原双键，然后再保护酰胺键上氮原子，之后用格氏试剂开环。开环后的中间产物再用过氧化氢、叔丁基过氧化氢或间氯过氧苯甲酸等氧化剂进行Baeyer-Villiger氧化重排反应。重排后的产物再脱去氨基上的保护基团得到最终产物，该方法需要使用昂贵的、没有大量供应的起始物料，步骤冗长，成本过高，不利于大规模工业生产。
除了上述方法外，专利CN 102633657有报导将羟胺用氯甲酸苄酯保护，然后再与环戊二烯混合，在高碘酸钠氧化剂的作用下，发生狄尔斯-阿尔德反应得到环加成中间体。此中间体经一步反应即可完成双键还原、开环、去保护得到消旋体。然而该专利仅仅报导了消旋体的合成方法，不能得到光学活性的产品。而且高碘酸钠价格昂贵，使得成本控制较难。
此外，还有专利CN106470975报导了使用扁桃酸拆分或者脂肪酶拆分的方案，但该专利中消旋体的合成采用低效率的方法合成，而且拆分需要丢弃一半以上的产品，使得产品成本较高。
综上所述，尽管目前已公开了如上所述的一些制备(1R,3S)-3-氨基环戊醇盐酸盐的方法，但其生产成本都较高，工业化前景低，仍需开发新的工艺路线来进一步降低药物生产成本。
发明内容
针对现有技术的不足，本发明提供了一种(1R,3S)-3-氨基环戊醇盐酸盐的制备方法， 该制备方法从简单、廉价的物料出发，设计了一条采用手性诱导的不对称合成路线，得到目标产物(1R,3S)-3-氨基环戊醇盐酸盐。
本发明是通过以下技术方案进行实现的：
一种(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，以手性羧酸与羟胺形成的酰胺作为手性源，在铜催化的氧化反应体系中快速得到手性的狄尔斯-阿尔德反应产物，之后经过还原反应和脱保护反应，以及酸化反应后得到目标产物。该制备方法高效地控制了手性中心的产生，成本大大降低，光学纯度高。
作为本发明的技术方案的进一步描述，一种(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，具体包括以下步骤：
S1.手性羧酸与盐酸羟胺反应，制备得到手性羧酸保护的羟胺；
S2.将新制的环戊二烯与所述的手性羧酸保护的羟胺混合，并在氯化亚铜-含氮配体-空气的体系中，发生狄尔斯-阿尔德反应，得到中间产物Ⅰ；
S3.所述中间产物Ⅰ在钯碳-氢气体系中，一步完成双键还原与氮-氧键还原断裂反应，得到中间产物Ⅱ；
S4.所述中间产物Ⅱ在碱性条件下脱保护，得到目标构型(1R,3S)-3-氨基环戊醇；之后用盐酸-甲醇溶液酸化，得到目标产物(1R,3S)-3-氨基环戊醇盐酸盐。
在本发明中，(1R,3S)-3-氨基环戊醇盐酸盐的合成路线如下所示：
Figure PCTCN2018123142-appb-000001
作为本发明的技术方案的进一步描述，所述手性羧酸具有以下结构式：
Figure PCTCN2018123142-appb-000002
其中，R1和R2为不同的基团。
作为本发明的技术方案的进一步描述，所述手性羧酸包括R-扁桃酸、L-苯丙氨酸、L-脯氨酸、L-亮氨酸、L-异亮氨酸或L-缬氨酸。
作为本发明的技术方案的进一步描述，所述含氮配体包括吡啶、噁唑啉或二甲基乙 二胺。
作为本发明的技术方案的进一步描述，在S1中，手性羧酸与盐酸羟胺的摩尔比为(1～1.5)：(1.5～2.5)。
作为本发明的技术方案的进一步描述，在S2中，所述手性羧酸保护的羟胺、环戊二烯、氯化亚铜和含氮配体的摩尔比为(1～1.5)：(2～2.5)：(0.1～0.2)：(0.05～0.1)。
作为本发明的技术方案的进一步描述，在S3中，钯碳的用量为中间产物Ⅰ质量的2％～6％。
作为本发明的技术方案的进一步描述，在S3中，钯碳-氢气体系的反应温度为50-60℃。
作为本发明的技术方案的进一步描述，所述中间产物Ⅰ为手性桥环化合物。
基于上述的技术方案，本发明具有的技术效果为：
(1)本发明提供的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，采用廉价的手性羧酸作为手性诱导基团，效率高、成本低。
(2)本发明的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，狄尔斯-阿尔德反应在氯化亚铜-含氮配体-空气的体系中进行，反应过程中氧化羟胺生产亚硝基，从而避免使用价格较高的高碘酸钠，成本优势明显。
(3)本发明提供的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，通过以原料手性羧酸与羟胺形成的酰胺作为手性源，采用铜催化的氧化反应体系快速得到手性的杂狄尔斯-阿尔德反应产物，随后进行还原、脱保护反应，可高效地控制了手性中心的产生，成本大大降低，光学纯度高。在反应过程中，有效地改善了单程转化率，而且操作控制方便，对设备无特殊要求，反应效率高，适合规模化大生产推广。
具体实施方式
为了便于理解本发明，下面将结合具体的实施例对本发明进行更全面的描述。本发明给出了的较佳实施方式。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本发明的公开内容理解的更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施方式的目的，不是旨在于限制本发明。
实施例1
以R-扁桃酸为起始物料制备(1R,3S)-3-氨基环戊醇盐酸盐
第一步：R-扁桃酸保护的羟胺的制备
将R-扁桃酸(21.0g，0.14mol)与无水乙醇(100mL)混合于250mL单口圆底烧瓶中，再加入浓硫酸催化剂(3.0mL)；然后整个体系回流反应4小时，减压旋蒸除去有机溶剂，然后将残留物溶于二氯甲烷(200mL)中，依次经过饱和NaHCO3洗涤、食盐水洗涤和无水硫酸钠干燥后，过滤、旋干得23g无色油状物：R-扁桃酸乙酯。
在另一反应瓶中，加入盐酸羟胺(19g，0.27mol)与无水甲醇(100mL)，然后向此混合液中滴加氢氧化钾(25g，0.45mol)的甲醇(80mL)溶液，产生大量白色固体；过滤，除去白色固体，然后将滤液冰浴冷却备用，将前面制备的R-扁桃酸乙酯加入到羟胺的甲醇溶液中；室温搅拌过夜，减压旋蒸除去溶剂，加入水(150mL)溶解，乙酸乙酯洗涤，水相再用稀盐酸酸化至弱酸性；再将溶液减压旋干得白色固体，此粗产品再经甲醇重结晶得19.0g产品：手性羧酸保护的羟胺，收率约88.0％。
第二步：经狄尔斯-阿尔德反应得到的中间产物Ⅰ的制备
将氯化亚铜(1.0g，0.01mol，0.2equiv.)和吡啶(0.2mL，2.5mmol，0.05equiv.)依次加入到R-扁桃酸保护的羟胺(8.4g，0.05mol，1.0equiv.)与环戊二烯(5.0g，0.075mol，1.5equiv.)混合在一起的甲醇溶液中；整个混合溶液在室温条件下进行，于空气中搅拌反应三小时；然后混合反应液用已二酸四乙胺溶液(0.5M)淬灭，再用乙酸乙酯萃取三次；合并后的有机相依次用饱和食盐水洗涤、无水硫酸钠干燥，过滤除去干燥剂之后再在减压条件下浓缩得到9.8g粗产品：中间产物Ⅰ，收率约85.0％。此粗产品中间产物Ⅰ可不经进一步纯化直接在下一步反应中使用。
第三步：中间产物Ⅱ的制备
将上一步所得产品中间产物Ⅰ溶解于甲醇(50mL)中，然后再依次加入醋酸(0.5mL)与10％钯碳(0.5g)；整个体系再在氢气氛围中于50℃条件下反应2小时；反应完毕后，将反应液经过小段硅藻土过滤以除去不溶无机物；滤液再在减压条件下除去所有的挥发组分得到9.4g的外消旋体中间体，即中间产物Ⅱ，收率约94.0％。
第四步：目标产物(1R,3S)-3-氨基-环戊醇盐酸盐的制备
将上一步的中间产物Ⅱ与氢氧化钾和甲醇混合于一干燥的反应瓶A中，搅拌3个小时；然后在真空条件下除去所有溶剂，再用水-乙酸乙酯萃取；有机相再经无水硫酸钠干燥、过滤与浓缩，得到棕色油状物，即(1R,3S)-3-氨基环戊醇；水相用稀盐酸调节pH值到2-3后用乙酸乙酯萃取回收R-扁桃酸(3.6g)；再于另一干燥的反应瓶B中加入无水甲醇(20mL)，然 后乙酰氯(3.5mL，50.0mmol)在冰浴冷却条件下滴加到反应瓶B中，原位生成氯化氢的甲醇溶液；制备好氯化氢的甲醇溶液之后，再将前面所述的棕色油状物(1R,3S)-3-氨基环戊醇，溶解于少量甲醇中并滴加到氯化氢的甲醇溶液中，最后在减压条件下除去所有挥发组分，得到最终产物(1R,3S)-3-氨基-环戊醇盐酸盐固体4.6g，收率约85％。
实施例2
以L-苯丙氨酸为起始物料制备(1R,3S)-3-氨基环戊醇盐酸盐
第一步：L-苯丙氨酸保护的羟胺的制备
将L-苯丙氨酸(37g，0.14mol)与无水乙醇(100mL)混合于250mL单口圆底烧瓶中，然后再将SOCl 2(25g，0.21mol)滴加到反应瓶中；然后整个体系回流反应5小时，减压旋蒸除去有机溶剂，得L-苯丙氨酸乙酯盐酸盐。然后再将L-苯丙氨酸乙酯盐酸盐与碳酸氢钠(35g，0.42mol)、甲醇150mL混合于反应瓶中，再缓慢滴加二碳酸二叔丁酯(35g,0.16mol)到此混合液中。室温搅拌反应过夜，乙酸乙酯萃取三次，合并有机相，再经干燥、过滤、减压蒸馏得L-Boc-苯丙氨酸乙酯35g，收率约86％。
在反应瓶中，加入盐酸羟胺(16g，0.23mol)与无水甲醇(100mL)，然后向此混合液中滴加氢氧化钾(22g，0.39mol)的甲醇(80mL)溶液，产生大量白色固体；过滤除去白色固体，然后将滤液冰浴冷却备用，将前面制备的L-Boc-苯丙氨酸乙酯加到羟胺的甲醇溶液中。室温搅拌过夜，减压旋蒸除去溶剂，加入水(150mL)溶解，乙酸乙酯洗涤，水相再用稀盐酸酸化至弱酸性。再将溶液减压旋干得白色固体，此粗产品再经甲醇重结晶得28g产品，即L-苯丙氨酸保护的羟胺，收率约85％。
第二步：经狄尔斯-阿尔德反应得到的中间产物Ⅰ的制备
氯化亚铜(1.0g，0.01mol，0.2equiv.)和吡啶(0.2mL，2.5mmol，0.05equiv.)依次加入到L-Boc-苯丙氨酸保护的羟胺(14g，0.05mol，1.0equiv.)与环戊二烯(5.0g，0.075mol，1.5equiv.)的甲醇溶液中。整个混合溶液在室温条件下，于空气中搅拌反应三小时。然后反应液用已二酸四乙胺溶液(0.5M)淬灭，再用乙酸乙酯萃取三次。合并后的有机相依次用饱和食盐水洗涤、无水硫酸钠干燥，过滤除去干燥剂之后再在减压条件下浓缩得到13g粗产品，即中间产物Ⅰ，收率约80％。此粗产品可不经进一步纯化直接在下一步反应中使用。
第三步：中间产物Ⅱ的制备
将上一步所得中间产物Ⅰ溶解于甲醇(50mL)中，然后再依次加入醋酸(0.5mL)与10％钯碳(0.5g)。整个体系再在氢气氛围中于50℃条件下反应2小时；反应完毕后，将反应液经过小段硅藻土过滤以除去不溶无机物，滤液再在减压条件下除去所有的挥发组分得到 12.7g外消旋体中间体，即中间产物Ⅱ，收率约95％。
第四步：目标产物(1R,3S)-3-氨基-环戊醇盐酸盐的制备
将上一步的中间产物Ⅱ与氢氧化钾和甲醇混合于反应瓶A中，搅拌3个小时，然后真空条件下除去所有溶剂，再用水-乙酸乙酯萃取；有机相再经无水硫酸钠干燥、过滤与浓缩得到棕色油状物，即(1R,3S)-3-氨基环戊醇。水相用稀盐酸调节pH值到2-3后用乙酸乙酯萃取回收L-Boc-苯丙氨酸(7.5g)。再于另一干燥的反应瓶B中加入无水甲醇(20mL)，乙酰氯(3.5mL，50mmol)在冰浴冷却条件下滴加到反应瓶B中，原位生成氯化氢的甲醇溶液。制备好氯化氢的甲醇溶液之后，再将前面所述棕色油状物即(1R,3S)-3-氨基环戊醇溶解于少量甲醇中并滴加到氯化氢的甲醇溶液中，最后在减压条件下除去所有挥发组分得到最终产物(1R,3S)-3-氨基-环戊醇盐酸盐固体4.2g，收率约81％。
实施例3
以L-脯氨酸为起始物料制备(1R,3S)-3-氨基环戊醇盐酸盐
第一步：L-脯氨酸保护的羟胺的制备
将L-脯氨酸(16g，0.14mol)与无水乙醇(100mL)混合于250mL单口圆底烧瓶中，然后再将SOCl 2(25g，0.21mol)滴加到反应瓶中；然后整个体系回流反应5小时，减压旋蒸除去有机溶剂，得L-脯氨酸乙酯盐酸盐。然后再将L-脯氨酸乙酯盐酸盐与碳酸氢钠(35g，0.42mol)、甲醇150mL混合于反应瓶中，再缓慢滴加二碳酸二叔丁酯(35g，0.16mol)到此混合液中。室温搅拌反应过夜，乙酸乙酯萃取三次，合并有机相，再经干燥、过滤、减压蒸馏得L-Boc-脯氨酸乙酯27g，收率约90％。
在反应瓶中，加入盐酸羟胺(17g，0.24mol)与无水甲醇(100mL)，然后向此混合液中滴加氢氧化钾(22g，0.41mol)的甲醇(80mL)溶液，产生大量白色固体；过滤除去白色固体，然后将滤液冰浴冷却备用，将前面制备的L-Boc-脯氨酸乙酯加到羟胺的甲醇溶液中。室温搅拌过夜，减压旋蒸除去溶剂，加入水(150mL)溶解，乙酸乙酯洗涤，水相再用稀盐酸酸化至弱酸性。再将溶液减压旋干得白色固体，此粗产品再经甲醇重结晶得25g产品，即L-脯氨酸保护的羟胺，收率约86％。
第二步：经狄尔斯-阿尔德反应得到的中间产物Ⅰ的制备
氯化亚铜(1.0g，0.01mol，0.2equiv.)和吡啶(0.2mL，2.5mmol，0.05equiv.)依次加入到L-Boc-脯氨酸保护的羟胺(12g，0.05mol，1.0equiv.)与环戊二烯(5.0g，0.075mol，1.5equiv.)的甲醇溶液中。整个混合溶液在室温条件下，于空气中搅拌反应三小时。然后反应液用已二酸四乙胺溶液(0.5M)淬灭，再用乙酸乙酯萃取三次。合并后的有机相依次用饱 和食盐水洗涤、无水硫酸钠干燥，过滤除去干燥剂之后再在减压条件下浓缩得到粗产品12g，即中间产物Ⅰ，收率约83％。此粗产品可不经进一步纯化直接在下一步反应中使用。
第三步：中间产物Ⅱ的制备
将上一步所得中间产物Ⅰ溶解于甲醇(50mL)中，然后再依次加入醋酸(0.5mL)与10％钯碳(0.5g)。整个体系再在氢气氛围中于50℃条件下反应2小时。反应完毕后，将反应液经过小段硅藻土过滤以除去不溶无机物。滤液再在减压条件下除去所有的挥发组分得到外消旋体中间体11.5g，即中间产物Ⅱ，收率约93％。
第四步：目标产物(1R,3S)-3-氨基-环戊醇盐酸盐的制备
将上一步的即中间产物Ⅱ与氢氧化钾和甲醇混合于反应瓶A中，搅拌3个小时，然后真空条件下除去所有溶剂，再用水-乙酸乙酯萃取。有机相再经无水硫酸钠干燥、过滤与浓缩得到棕色油状物，即(1R,3S)-3-氨基环戊醇。水相用稀盐酸调节pH值到2-3后用乙酸乙酯萃取回收L-Boc-脯氨酸(6.2g)。再于另一干燥的反应瓶B中加入无水甲醇(20mL)，乙酰氯(3.5mL，50mmol)在冰浴冷却条件下滴加到反应瓶B中，原位生成氯化氢的甲醇溶液。制备好氯化氢的甲醇溶液之后，再将前面所述棕色油状物溶解于少量甲醇中并滴加到氯化氢的甲醇溶液中。然后再在减压条件下除去所有挥发组分得到最终产物(1R,3S)-3-氨基-环戊醇盐酸盐固体4.2g，收率约79％。
上述equiv.为当量的简写。
以上所述仅为本发明的优选实施例而己，不能被认为用于限定本发明的实施范围，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，以手性羧酸与羟胺形成的酰胺作为手性源，在铜催化的氧化反应体系中快速得到手性的狄尔斯-阿尔德反应产物，之后经过还原反应和脱保护反应，以及酸化反应后得到目标产物。
  2. 根据权利要求1所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，包括以下步骤：
    S1.手性羧酸与盐酸羟胺反应，制备得到手性羧酸保护的羟胺；
    S2.将新制的环戊二烯与所述的手性羧酸保护的羟胺混合，并在氯化亚铜-含氮配体-空气的体系中，发生狄尔斯-阿尔德反应，得到中间产物Ⅰ；
    S3.所述中间产物Ⅰ在钯碳-氢气体系中，一步完成双键还原与氮-氧键还原断裂反应，得到中间产物Ⅱ；
    S4.所述中间产物Ⅱ在碱性条件下脱保护，得到目标构型(1R,3S)-3-氨基环戊醇；之后用盐酸-甲醇溶液酸化，得到目标产物(1R,3S)-3-氨基环戊醇盐酸盐。
  3. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，所述手性羧酸具有以下结构式：
    Figure PCTCN2018123142-appb-100001
    其中，R1和R2为不同的基团。
  4. 根据权利要求3所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，所述手性羧酸包括R-扁桃酸、L-苯丙氨酸、L-脯氨酸、L-亮氨酸、L-异亮氨酸或L-缬氨酸。
  5. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，所述含氮配体包括吡啶、噁唑啉或二甲基乙二胺。
  6. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，在S1中，手性羧酸与盐酸羟胺的摩尔比为(1～1.5)：(1.5～2.5)。
  7. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，在S2中，所述手性羧酸保护的羟胺、环戊二烯、氯化亚铜和含氮配体的摩尔比为(1～1.5)：(2～2.5)：(0.1～0.2)：(0.05～0.1)。
  8. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，在S3中，钯碳的用量为中间产物Ⅰ质量的2％～6％。
  9. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，在S3中，钯碳-氢气体系的反应温度为50-60℃。
  10. 根据权利要求2所述的(1R,3S)-3-氨基环戊醇盐酸盐的制备方法，其特征在于，所述中间产物Ⅰ为手性桥环化合物。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111733195A (zh) * 2020-07-14 2020-10-02 宁波酶赛生物工程有限公司 制备(1r，3s)-3-氨基环戊醇的方法、整合酶抑制剂、应用
CN111733195B (zh) * 2020-07-14 2023-06-30 宁波酶赛生物工程有限公司 制备(1r，3s)-3-氨基环戊醇的方法、整合酶抑制剂、应用

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