Process method for synthesizing (S)-(+)-1-aminoindene
The ammonia reduction reaction of 1-indenone and ammonia-methanol solution, and the salt separation of (S)-(+)-α-methoxyphenylacetic acid was successfully solved, and the reaction conditions and yield of the existing (S)-(+)-1-aminoin preparation method were harsh, and the high yield of the high efficiency, safe and easy-to-operate process was achieved, which was suitable for industrial production.
Patent Information
- Application Number
- CN202411822566.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-12
- Publication Date
- 2025-03-28
AI Technical Summary
The existing preparation method of (S)-(+)-1-aminoinide has harsh reaction conditions, high equipment requirements, and problems of safety risks and low yield, making it difficult to be suitable for industrial production.
The ammonia reduction reaction was carried out by 1-indenone and ammonia-methanol solution to form 1-aminoindan, and then the salt was dissolved through (S)-(+)-α-methoxyphenylacetic acid to form (S)-(+)-1-aminoinden. This method uses titanium catalyst and borohydride as reducing agents, with mild reaction conditions and short steps, which are suitable for industrial production.
It realizes a process with good selectivity, short steps, high yield and easy operation, avoiding the use of high-temperature and high-pressure reactions and dangerous reagents, and the final product purity can reach 99.8%, which is suitable for industrial amplified production.
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Abstract
Description
Technical Field
[0001] The invention relates to a process for synthesizing (S)-(+)-1-aminoindene, belonging to the technical field of pharmaceutical intermediates. Background Art
[0002] (S)-(+)-1-Aminoindane is mainly used as an intermediate for physiologically active compounds in medicine or organic chemistry. It contains an aminoindane skeleton and is widely used in natural products and drug molecules.
[0003] At present, there are not many methods for preparing (S)-(+)-1-aminoindene reported in the literature: the usual route is to use 1-indanone amination reaction, followed by salt formation and resolution to obtain (S)-(+)-1-aminoindene.
[0004] (1) 1-Indanone reacts with hydroxylamine hydrochloride and sodium acetate, and then is post-treated to obtain 1E-indan-1-one oxime, which is then subjected to rhodium catalysis / cesium carbonate high-pressure hydrogenation to obtain (S)-(+)-1-aminoindene.
[0005]
[0006] (2) 1-Indanone reacts with hydroxylamine hydrochloride and sodium acetate, and then is post-treated to obtain 1E-indan-1-one oxime, which is then reacted with benzyl bromide to generate (E)-2,3-dihydro-1H-indan-1-one-benzyl oxime, which is then separated by (S)-valine and borane / THF salt formation to obtain (S)-(+)-1-aminoindane.
[0007]
[0008] (3) 1-Indanone is reacted with hydroxylamine hydrochloride and sodium acetate, and then post-treated to obtain 1E-indan-1-one oxime, which is then reacted with acetic anhydride and pyridine to generate (E)-2,3-dihydro-1H-indan-1-one-acetyl oxime, which is then catalyzed by rhodium and hydrogenated with cesium carbonate under high pressure to obtain (S)-(+)-1-aminoindene.
[0009]
[0010] (4) 1-Indanone reacts with ammonium formate and zinc powder to generate 1-aminoindan, which then undergoes an enzymatic reaction with reduced coenzyme II to obtain (S)-(+)-1-aminoindane.
[0011]
[0012] The above four methods have harsh reaction conditions and high requirements for equipment, which are not conducive to large-scale production. In addition, the first / third method requires high-pressure hydrogenation reaction, which is dangerous; the second / third method has complicated steps and is not easy to operate. The third method uses hazardous chemicals such as acetic anhydride, which poses safety risks; the fourth method has poor selectivity and harsh reaction conditions, and the yields of the above four methods are not high, which is not suitable for industrial production; the fourth method requires the use of zinc powder, which is not easy to operate, has certain dangers, and has high safety risks. Summary of the invention
[0013] In order to overcome the above defects, the present invention provides an improved process for synthesizing (S)-(+)-1-aminoindene. 1-indanone is used as a raw material, and an ammonia-methanol solution is subjected to an ammoniation reduction reaction to generate 1-aminoindan, and then (S)-(+)-α-methoxyphenylacetic acid is used to form a salt and split to generate (S)-(+)-1-aminoindene. The method has the advantages of good selectivity, short steps, high yield, and easy operation, has potential technical advantages, and is suitable for industrial scale-up production.
[0014] The process for synthesizing (S)-(+)-1-aminoindene of the present invention comprises the following steps:
[0015]
[0016] Step A: dissolving 1-indanone in an ammonia-methanol solution, adding a titanium catalyst in batches under cooling, and then adding a reducing agent to react. After the reaction is completed, adding an alkaline aqueous solution, and performing vacuum distillation to obtain 1-aminoindan;
[0017] Step B: 1-aminoindane and ethanol are mixed, (S)-(+)-α-methoxyphenylacetic acid is added to the mixture for reflux reaction, the mixture is cooled and filtered, and the solid is freed by adding a base to obtain (S)-(+)-1-aminoindane.
[0018] Furthermore, in step A, the titanium catalyst is selected from tetraethyl titanate, tetraisopropyl titanate or tetrabutyl titanate. When a titanium catalyst is used alone, at least 4 equivalents are required for the complete reaction. When a titanium catalyst is used together with triphenylboron, the amount can be reduced to 1-1.5 equivalents.
[0019] Furthermore, in step A, the reducing agent is selected from sodium borohydride, potassium borohydride or sodium cyanoborohydride.
[0020] Furthermore, in step A, the molar ratio of 1-indanone, ammonia-methanol, titanium catalyst and reducing agent is 1:2-8:1-1.5:1-1.5.
[0021] Furthermore, in step A, the alkaline aqueous solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution.
[0022] Furthermore, in step B, the molar ratio of 1-aminoindan to (S)-(+)-α-methoxyphenylacetic acid is 1:0.95-1.05.
[0023] Furthermore, in step B, the alkaline aqueous solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution.
[0024] Furthermore, in step B, the mother liquor obtained by filtration is freed by adding alkali and used for the salt separation of (R)-(-)-1-aminoindene.
[0025] Advantageous Effects of the Invention
[0026] 1. The process steps of the present invention are short, the selectivity is good, the reaction time is short, and the total yield can reach more than 47% (the highest yield is 50%); the raw materials in the route are easily available, no toxic intermediates are produced, the operation is simple, there is no high temperature and high pressure harsh reaction, and there is no heavy metal pollutant; the raw materials are easily available and the price is low. The method has potential technical advantages and is suitable for industrial scale-up production.
[0027] 2. The process of the present invention avoids the use of dangerous reagents such as acetic anhydride in other literature methods, and uses ammonia methanol solution to generate 1-aminoindane through ammonia reaction, and then (S)-(+)-α-methoxyphenylacetic acid salt separation to generate (S)-(+)-1-aminoindane, which greatly improves the yield of the target configuration product. It has good selectivity, mild and continuous reaction conditions, short reaction time, easy operation, and the purity of the final product can reach 99.8%. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Figure 1 This is the HNMR spectrum of the (S)-(+)-1-aminoindene product in Example 1. Specific embodiments
[0029] Example 1
[0030] Step A: Under nitrogen protection, 1-indanone (50g, 0.379mol) was dissolved in ammonia-methanol (20%, 260g), cooled to -10°C, triphenylboron (5.9g) was added, and then tetraethyl titanate (86.45g, 0.379mol) was added in five batches, and the reaction was continued to stir for 3h. The solution was poured into a 3L reaction bottle, sodium borohydride (14.34g, 0.379mol) was added at one time, and the gas was released. Stir for 30min. Pour into 1N sodium hydroxide aqueous solution (600mL), filter the solid, and wash the solid with methanol (640mL). The organic phase was concentrated, extracted with dichloromethane, and concentrated. The 110°C±10°C fraction was collected by reduced pressure distillation to obtain 47.87g of oily liquid, GC99.0%. The yield was 94.8%.
[0031] Step B: Add 1-aminoindane (47.87 g, 0.36 mol), ethanol (300 mL) and water (120 mL) into a reaction flask, start stirring, and add (S)-(+)-α-methoxyphenylacetic acid (59.82 g, 0.36 mol) at room temperature. Then heat and reflux for 3 h, cool to room temperature and filter. Add 150 mL of dichloromethane to the obtained solid, adjust the pH to 10-12 with sodium hydroxide (20%) solution, and extract with dichloromethane 3 times, 180 mL each time. After concentration, a light yellow oily substance is obtained, which is (S)-(+)-1-aminoindane (23.84 g, yield 49.8%), GC 99.8%, 99.1% ee.
[0032] Example 2
[0033] Step A: Under nitrogen protection, 1-indanone (50g, 0.379mol) was dissolved in ammonia-methanol (20%, 260g), cooled to -10°C, triphenylboron (5.9g) was added, and then tetraisopropyl titanate (107.72g, 0.379mol) was added in five batches, and the reaction was continued to stir for 3h. The solution was poured into a 3L reaction bottle, sodium borohydride (14.34g, 0.379mol) was added at one time, and the gas was released. Stir for 30min. Pour into 1N potassium hydroxide aqueous solution (600mL), filter the solid, and wash the solid with methanol (640mL). The organic phase was concentrated, extracted with dichloromethane, and concentrated. The 110°C±10°C fraction was collected by reduced pressure distillation to obtain 46.36g of oily liquid, GC 98.9%. The yield was 91.84%.
[0034] Step B: Add 1-aminoindane (46.36 g, 0.348 mol), ethanol (290 mL) and water (115 mL) into a reaction flask, start stirring, and add (S)-(+)-α-methoxyphenylacetic acid (54.94 g, 0.331 mol) at room temperature. Then heat and reflux for 3 h, cool to room temperature and filter. Add 145 mL of dichloromethane to the obtained solid, adjust the pH to 10-12 with sodium hydroxide (20%) solution, and extract with dichloromethane 3 times, 170 mL each time. After concentration, a light yellow oily substance is obtained, which is (S)-(+)-1-aminoindane (22.51 g, yield 48.55%), GC 99.43%, 99.3% ee.
[0035] Example 3
[0036] Step A: Under nitrogen protection, 1-indanone (50g, 0.379mol) was dissolved in ammonia-methanol (20%, 260g), cooled to -10°C, triphenylboron (5.9g) was added, tetraethyl titanate (86.45g, 0.379mol) was added in five batches, and the reaction was continued to stir for 3h. The solution was poured into a 3L reaction bottle, potassium borohydride (20.44g, 0.379mol) was added at one time, and the gas was released. Stir for 30min. Pour into 1N sodium hydroxide aqueous solution (600mL), filter the solid, and wash the solid with methanol (640mL). The organic phase was concentrated, extracted with dichloromethane, and concentrated. The 110°C±10°C fraction was collected by reduced pressure distillation to obtain 46.86g of oily liquid, GC99.2%. The yield was 92.83%.
[0037] Step B: Add 1-aminoindane (46.86 g, 0.352 mol), ethanol (300 mL) and water (120 mL) into a reaction flask, start stirring, and add (S)-(+)-α-methoxyphenylacetic acid (61.48 g, 0.37 mol) at room temperature. Then heat and reflux for 3 h, cool to room temperature and filter. Add 150 mL of dichloromethane to the obtained solid, adjust the pH to 10-12 with potassium hydroxide (20%) solution, and extract with dichloromethane 3 times, 180 mL each time. After concentration, a light yellow oily substance is obtained, which is (S)-(+)-1-aminoindane (23.01 g, yield 49.1%), GC 99.5%, 99.4% ee.
[0038] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.
Claims
1. A process for synthesizing (S)-(+)-1-aminoindene, characterized in that: The following steps are involved: Step A: dissolving 1-indanone in an ammonia-methanol solution, adding a titanium catalyst in batches under cooling, and then adding a reducing agent to react. After the reaction is completed, adding an alkaline aqueous solution, and performing vacuum distillation to obtain 1-aminoindan; Step B: 1-aminoindane and ethanol are mixed, (S)-(+)-α-methoxyphenylacetic acid is added to the mixture for reflux reaction, the mixture is cooled and filtered, and the solid is freed by adding a base to obtain (S)-(+)-1-aminoindane.
2. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: In step A, the titanium catalyst is selected from tetraethyl titanate, tetraisopropyl titanate or tetrabutyl titanate.
3. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: In step A, the reducing agent is selected from sodium borohydride, potassium borohydride or sodium cyanoborohydride.
4. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: The molar ratio of 1-indanone, ammonia-methanol, titanium catalyst and reducing agent is 1:2-8:1-1.5:1-1.
5.
5. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: In step A, the alkaline aqueous solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution.
6. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: In step B, the molar ratio of 1-aminoindan to (S)-(+)-α-methoxyphenylacetic acid is 1:0.95-1.
05.
7. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: In step B, the alkaline aqueous solution is selected from a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution.
8. The process for synthesizing (S)-(+)-1-aminoindene according to claim 1, characterized in that: In step B, the mother liquor obtained by filtration is freed by adding alkali and used for the salt separation of (R)-(-)-1-aminoindene.