A method for preparing 4-aminobutanol, a key intermediate of Celexa and ALC-0315
Through a new preparation method, the esterification and reduction reaction is carried out using 4-aminobutyric acid and catalyst system, which successfully improves the yield of 4-aminobutanol and the safety and feasibility of the process, and solves the problems of high preparation costs and poor total yield in the prior art. It is suitable for the industrial production of Cialisipa and ALC-0315.
Patent Information
- Application Number
- CN202411942249.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-27
- Publication Date
- 2025-04-04
AI Technical Summary
The methods for preparing key intermediate 4-aminobutanol in the prior art have problems such as high production costs, poor overall yield, dangerous reaction and cumbersome post-reaction processing, which are difficult to meet the process requirements of large-scale preparation.
Using 4-aminobutyric acid as the raw material, the intermediate ester was formed through the esterification reaction, and then the pretreated catalysts bisoctadecyldimethylammonium chloride, aluminum trichloride and sodium borohydride were reduced in one pot method to obtain 4-aminobutanol.
The method is simple to operate and has high yields, avoiding the use of expensive reducing reagents and dangerous reactions, is suitable for industrial production, reduces product preparation costs, and increases the total yield.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical organic synthesis, and specifically relates to a method for preparing 4-aminobutanol, a key intermediate of Celexa and ALC-0315. Background Art
[0002] Selexipa is an oral, highly selective, long-acting prostacyclin (IP) receptor agonist prodrug. It is a potential drug for the treatment of various vascular diseases such as pulmonary hypertension and occlusive arteriosclerosis. On December 21, 2015, the U.S. FDA approved the marketing of Selexipa Chemicalbook, a new drug developed by Actelion, for the treatment of adult patients with pulmonary hypertension. Pulmonary hypertension is a chronic progressive lung disease with a poor prognosis. Patients may die prematurely or require lung transplantation. Selexipa can relax the smooth muscle of the blood vessel wall, dilate blood vessels, and reduce pulmonary artery pressure. It has been recognized as an orphan drug by the U.S. FDA. 4-Aminobutanol is a key intermediate of Selexipa.
[0003] The structure of Celexa is as follows:
[0004]
[0005] ALC-0315 (2036272-55-4) is an ionizable amino lipid that has been used in combination with other lipids to form lipid nanoparticles. Lipid nanoparticles have been used in the study of mRNA (COVID-19) vaccines. 4-Aminobutanol is a key intermediate of ALC-0315.
[0006] The structure of ALC-0315 is as follows:
[0007]
[0008] There are many methods for preparing 4-amino-1-butanol reported in the literature, most of which start from different nitrogen-containing raw materials, such as 4-hydroxyazide reduction (azide will explode and is not suitable for industrial production); 4-halogenated butyronitrile reduction (reaction raw materials are not easy to obtain, and it involves cyanide hydrogenation reduction, and the reaction conditions are relatively harsh); 2-butene-1,4-diol reductive amination to prepare 4-amino-1-butanol, using expensive rhodium acetate as a catalyst, the cost is relatively high; using 4-aminobutyric acid as a raw material, first protecting the amino group with Boc, then activating the carboxyl group with methyl chloroformate, then reducing the carboxyl group with sodium borohydride, and finally removing the Boc protecting group to obtain 4-amino-1-butanol, the total yield is only 68%, and in the second step of reducing the carboxylic acid, the amount of sodium borohydride used is too large (7 equivalents), the cost is high, and silica gel column chromatography is used for separation, because This is not suitable for industrial application; 2,3-dihydrofuran is used as raw material, first acidified, the intermediate and hydroxylamine hydrochloride are heated to react to obtain 4-hydroxybutyl oxime, and then reduced under the catalysis of Raney nickel to obtain 4-amino-1-butanol. The raw material 2,3-dihydrofuran of this method is relatively expensive, and it involves dangerous catalytic hydrogenation reactions; the latest patent uses 2-pyrrolidone as the main raw material, synthesizes N-protected pyrrolidone intermediates under the catalysis of alkaline catalysts; then borohydride reduction is used to obtain N-protected 4-amino-1-butanol derivative crude products, distillation purification, N-protected 4-amino-1-butanol derivatives are hydrogenated to remove the protecting group, generate 4-amino-1-butanol crude products, and then distill and purify to obtain 4-amino-1-butanol pure products. This method undergoes two-step distillation purification, high reaction energy consumption, and the total yield is only 60-76%. There are also methods of using nitrogen-containing reagents to introduce nitrogen sources for synthesis, such as the Gabriel amine synthesis method (yield is only 15%).
[0009] Therefore, the current method for preparing 4-aminobutanol, the key intermediate of Celecoxib and ALC-0315, has various defects such as high production cost, poor overall yield, dangerous reaction, and complicated post-reaction treatment, and cannot meet the process requirements for large-scale preparation. Summary of the invention
[0010] The present invention aims to provide a large-scale industrial synthesis method of 4-aminobutanol, a key intermediate of Celexa and ALC-0315.
[0011] The invention uses 4-aminobutyric acid as a raw material for esterification, and then reduces the intermediate ester under the action of a pretreated catalyst dioctadecyl dimethyl ammonium chloride and a mixture of aluminum chloride and sodium borohydride, so as to obtain the product 4-aminobutanol in a one-pot process. The operation is simple, the yield is high, the use of expensive reducing agents and dangerous reactions is avoided, and industrial production is facilitated.
[0012] In order to solve the above technical problems, the technical solution of the present invention is:
[0013] A method for preparing 4-aminobutanol, a key intermediate of Celexa and ALC-0315, comprises the following steps:
[0014] S1: 4-aminobutyric acid is used as a raw material, thionyl chloride is added dropwise, and then the reaction mixture is refluxed in ethanol to obtain an intermediate ester;
[0015] S2: The intermediate ester obtained in step S1 is reacted with sodium borohydride under a catalyst condition at room temperature to obtain the target product 4-aminobutanol.
[0016] Preferably, in step S1, the molar ratio of thionyl chloride to 4-aminobutyric acid is (1.2-2.5):1.
[0017] Preferably, in step S1, a base is added to the reaction system to adjust the pH of the reaction system, and the molar ratio of the base to thionyl chloride is: (1-2.5):1, and the base here can be one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate.
[0018] By adopting the above technical scheme, the alkali can be one or more of the carbonates, the post-treatment is simple, the reaction process is easy to observe, and basically no new impurities that are difficult to remove are introduced.
[0019] Preferably, in step S1, the reaction conditions are: reaction temperature is 80-90° C., and reaction time is 2-4 h.
[0020] Preferably, in step S2, the catalyst is a pretreated mixture of dioctadecyl dimethyl ammonium chloride and aluminum chloride, and the molar ratio of dioctadecyl dimethyl ammonium chloride to aluminum chloride is (1-2):(1-2).
[0021] Preferably, S2 further comprises a pretreatment in which the catalyst is a mixture of dioctadecyl dimethyl ammonium chloride and aluminum chloride, and the specific steps are as follows:
[0022] At room temperature, 120-180 mL of toluene was added with dioctadecyl dimethyl ammonium chloride (10 mmol) and aluminum chloride (10 mol), and the reaction solution was stirred at 90-100° C. for 5-6 h, and then spin-dried and dried to obtain a pretreated product.
[0023] Preferably, in step S2, the catalyst added to the reaction system is a mixture of dioctadecyl dimethyl ammonium chloride and aluminum chloride in a ratio of (0.1-0.25):1 to the intermediate ester; the ratio of sodium borohydride added to the reaction system is (0.5-1.5):1 to the intermediate ester;.
[0024] Preferably, in step S2, the reaction conditions are: reaction temperature is 10-30° C., and reaction time is 2-4 h.
[0025] Preferably, in step S2, the post-reaction treatment conditions are: the temperature is 0-5°C, and isopropanol is added.
[0026] By adopting the above technical solution, isopropanol is added to quench the excess sodium borohydride, the reaction is mild, the introduced impurities can be effectively reduced, and almost no side reactions will be produced with substances in the system.
[0027] As a preference: in step S2, the crude product is distilled to further improve the purity.
[0028] The reaction formula involved in the present invention is as follows:
[0029]
[0030] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:
[0031] (1) The present invention uses 4-aminobutyric acid as a raw material, adds thionyl chloride dropwise, and then refluxes the reaction solution in ethanol to obtain an intermediate ester. The reaction conversion rate is high, the raw materials used are cheap and easy to obtain, the intermediate does not need to be separated, the one-pot preparation method is simple to handle.
[0032] The obtained intermediate ester reacts with sodium borohydride at room temperature under catalyst conditions, and the conversion rate reaches 89%, which greatly improves the reaction yield. The invention selects the optimal conditions from the perspectives of catalyst, reaction time and reaction temperature.
[0033] In summary, the method provided by the present invention has short steps, simple operation, safety and reliability, good process stability, low energy consumption, cheap and readily available reaction raw materials, and high product yield.
[0034] By adopting the above technical scheme, an industrial preparation method of 4-aminobutanol, a key intermediate of Celecoxib and ALC-0315, is provided, which reduces the preparation cost of the product with low raw material prices, and improves the yield by optimizing the selection and dosage of catalysts, avoids the use of expensive reducing reagents and dangerous reactions, and is conducive to industrial production. DETAILED DESCRIPTION
[0035] The present invention will be further described below in conjunction with the examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.
[0036] Unless otherwise specified, the raw materials in the following examples and comparative examples are all commercially available products.
[0037] The yield calculation method of the product in the following examples and comparative examples is as follows:
[0038] Yield (%) = (actual product output / theoretical output mass) × 100%.
[0039] Example 1
[0040] S1, 4-aminobutyric acid (50mmol) was added to a reaction flask, 60ml of ethanol was added, thionyl chloride (75mmol) was added dropwise to the reaction flask under stirring at room temperature, and the addition was completed, the reaction solution was heated to 80-90°C, refluxed at this temperature for 2-4 hours, and the solvent was spin-dried. 150ml of ethanol was added to the residue at room temperature, and alkali was added to the ethanol solution at this temperature, under nitrogen protection, and stirring until no gas was released, and stirring was continued for half an hour.
[0041] S2, under nitrogen protection, add pretreated catalyst dioctadecyl dimethyl ammonium chloride and aluminum chloride (7.5mmol) to the reaction bottle, add sodium borohydride (50mmol) in portions under ice-salt bath, remove ice-salt bath after addition, stir the reaction system at room temperature for 2 hours, track by TLC, complete the reaction, cool the reaction solution to zero degrees, control the temperature at this temperature, add 25ml of isopropanol to the reaction bottle under stirring, continue stirring for 2 hours, filter and centrifuge. The mother liquor is spin-dried to obtain a crude product, which is distilled under reduced pressure to obtain a product 4-aminobutanol light yellow liquid, 3.96g, yield 89%, content: 99.62% (see Figure 2 ), refractive index: 1.4617, NMR results: see Figure 1 .
[0042] Comparative Example 1
[0043] Compared with Example 1, in this example, no catalyst was added to S2, and other conditions were the same as in Example 1, and no target product 4-aminobutanol was produced.
[0044] Comparative Example 2
[0045] Compared with Example 1, in this example, no catalyst was added to S2, the reaction temperature was raised to 60-85°C, and the other conditions were the same as those in Example 1. The target product 4-aminobutanol was dried to obtain a total of 0.45 g, with a yield of 10%.
[0046] Comparative Example 3
[0047] Compared with Example 1, in this example, the catalyst in S2 is changed to aluminum chloride, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is obtained by drying, with a total of 2.14 g and a yield of 48%.
[0048] Comparative Example 4
[0049] Compared with Example 1, in this example, the catalyst in S2 is changed to ferric chloride, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is obtained by drying, with a total of 1.87 g and a yield of 42%.
[0050] Comparative Example 5
[0051] Compared with Example 1, in this example, the catalyst in S2 is changed to zinc chloride, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is obtained by drying, with a total of 1.91 g and a yield of 43%.
[0052] Comparative Example 6
[0053] Compared with Example 1, in this example, the catalyst in S2 is changed to tin chloride, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is obtained by drying, with a total of 1.82 g and a yield of 41%.
[0054] Comparative Example 7
[0055] Compared with Example 1, in this example, the catalyst in S2 is changed to titanium tetrachloride, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is obtained by drying, with a total of 1.34 g and a yield of 30%.
[0056] Comparative Example 8
[0057] Compared with Example 1, in this example, the catalyst in S2 is changed to aluminum chloride, the reaction temperature is raised to 60-85°C, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is dried to obtain a total of 2.00 g, with a yield of 45%.
[0058] Comparative Example 9
[0059] Compared with Example 1, in this example, the catalyst in S2 is changed to aluminum chloride, the reaction temperature is raised to 60-85°C, the reaction time is 8h, and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is dried to obtain a total of 1.82 g, with a yield of 41%.
[0060] Comparative Example 10
[0061] Compared with Example 1, in S2 of this example, the catalyst is changed to pretreated catalyst dioctadecyl dimethyl ammonium chloride and aluminum ferric chloride (the pretreatment method is the same as that of dioctadecyl dimethyl ammonium chloride and aluminum trichloride), and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is dried to obtain a total of 3.69 g, with a yield of 83%.
[0062] Comparative Example 11
[0063] Compared with Example 1, in S2 of this example, the catalyst is changed to pretreated catalyst dioctadecyl dimethyl ammonium chloride and zinc chloride (the pretreatment method is the same as that of dioctadecyl dimethyl ammonium chloride and aluminum chloride), and other conditions are the same as those in Example 1. The target product 4-aminobutanol is dried to obtain a total of 3.24 g, with a yield of 73%.
[0064] Comparative Example 12
[0065] Compared with Example 1, in S2 of this example, the catalyst is changed to pretreated catalyst dioctadecyl dimethyl ammonium chloride and tin chloride (the pretreatment method is the same as that of dioctadecyl dimethyl ammonium chloride and aluminum chloride), and the other conditions are the same as those in Example 1. The target product 4-aminobutanol is dried to obtain a total of 3.60 g, with a yield of 81%.
[0066] Comparative Example 13
[0067] Compared with Example 1, in S2 of this example, the catalyst is changed to pretreated catalyst dioctadecyl dimethyl ammonium chloride and titanium tetrachloride (the pretreatment method is the same as that of dioctadecyl dimethyl ammonium chloride and aluminum chloride), and other conditions are the same as those in Example 1. The target product 4-aminobutanol is dried to obtain a total of 3.20 g, with a yield of 72%.
[0068] Comparative Example 14
[0069] Compared with Example 1, in S2 of this example, the reaction temperature was raised to 60-85°C, and other conditions were the same as those in Example 1. The target product 4-aminobutanol was obtained by drying, with a total of 3.78 g and a yield of 85%.
[0070] Comparative Example 15
[0071] Compared with Example 1, in S2 of this example, the reaction time was 12 h, and other conditions were the same as those in Example 1. The target product 4-aminobutanol was obtained by drying, with a total of 3.96 g and a yield of 89%.
[0072] Comparative Example 16
[0073] Compared with Example 1, in this example, the amount of catalyst used in S2 is 0.5 eq, and other conditions are the same as those in Example 1. The target product 4-aminobutanol is obtained by drying, with a total of 3.92 g and a yield of 88%.
[0074] It can be seen from the test results of Example 1 and Comparative Examples 1 and 2 that the reduction reaction using only sodium borohydride does not react at room temperature. Under heating conditions, the yield is very low, only 10%. In the absence of a catalyst, increasing the reaction temperature and increasing the reaction conditions have almost no effect on improving the reaction conversion rate.
[0075] It can be seen from the test results of Example 1 and Comparative Examples 3-9 that the reaction yield is increased by adding conventional Lewis acids: aluminum chloride, ferric chloride, zinc chloride, tin chloride, and titanium tetrachloride to the reduction reaction, but the overall result is not ideal, only about 45%. Increasing the reaction temperature and extending the reaction time have little effect on the yield.
[0076] It can be seen from the test results of Example 1 and Comparative Examples 10-13 that the reduction reaction plus the pretreated catalyst greatly improves the reaction yield, and the pretreated catalyst dioctadecyl dimethyl ammonium chloride and aluminum chloride and the pretreated catalyst dioctadecyl dimethyl ammonium chloride and ferric chloride have better effects. However, the catalyst dioctadecyl dimethyl ammonium chloride and ferric chloride themselves have colors and the subsequent processing process is not easy to observe. Therefore, pretreated dioctadecyl dimethyl ammonium chloride and aluminum chloride are preferably used as catalysts.
[0077] It can be seen from the test results of Example 1 and Comparative Examples 14-16 that the reduction reaction with pretreated dioctadecyldimethylammonium chloride and aluminum chloride catalyst increases the reaction temperature, but the yield decreases a little. This should be because the reaction temperature increases and the reaction by-products increase (which can also be observed from the reaction TCL tracking). Prolonging the reaction time and increasing the amount of catalyst have little effect on the reaction yield. Considering the production cost, the reaction conditions of the preferred example are.
[0078] After reading the contents taught in the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application. BRIEF DESCRIPTION OF THE DRAWINGS
[0079] Figure 1 This is the H NMR spectrum of the target product 4-aminobutanol;
[0080] Figure 2 It is the liquid chromatogram of the target product 4-aminobutanol.
Claims
1. A method for preparing 4-aminobutanol, a key intermediate of Celexa and ALC-0315, characterized in that: The following steps are involved: S1: 4-aminobutyric acid is used as a raw material, thionyl chloride is added dropwise, and then the reaction solution is refluxed in ethanol to obtain an intermediate ester; S2: The intermediate ester obtained in step S1 is reacted with sodium borohydride at room temperature under a catalyst condition to obtain the target product 4-aminobutanol.
2. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S1, the molar ratio of thionyl chloride to 4-aminobutyric acid is (1.2-2.5):
1.
3. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S1, the reaction conditions are: reaction temperature is 80-90° C., and reaction time is 2-4 h.
4. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S1, a base is added to the reaction system to adjust the pH of the reaction system, and the molar ratio of the base to thionyl chloride is (1-2.5):
1. The base here can be one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate.
5. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S2, the catalyst is a pre-prepared mixture of dioctadecyl dimethyl ammonium chloride and aluminum chloride, and the molar ratio of dioctadecyl dimethyl ammonium chloride to aluminum chloride is (1-2):(1-2).
6. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S2, the ratio of the catalyst (pre-prepared mixture of dioctadecyl dimethyl ammonium chloride and aluminum chloride) to the intermediate ester added to the reaction system is (0.1-0.25):1; the ratio of sodium borohydride to the intermediate ester added to the reaction system is (0.5-1.5):
1.
7. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S2, the reaction conditions are: reaction temperature is 10-30° C., and reaction time is 2-4 h.
8. A method for preparing 4-aminobutanol according to claim 1, characterized in that: In step S2, the post-reaction treatment conditions are: the temperature is 0-5°C, and isopropanol is added.