Synthesis method of upatinib intermediate
By reacting compound A1 and A2 under alkaline conditions, and using aprotic solvent and crystallization steps, the problems of low yield and complex operation of uppatinib intermediate A3 are solved, achieving an efficient and simple preparation method, which is suitable for industrial production.
Patent Information
- Application Number
- CN202311166040.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-11
- Publication Date
- 2025-03-11
AI Technical Summary
In the prior art, the yield of uppatinib intermediate A3 is low, the operation is complicated, and the purification steps are cumbersome, which is not conducive to commercial production.
Using a new synthesis method, by reacting compound A1 and A2 in the presence of alkaline substances, the reaction temperature is controlled at 0-25°C, an aprotic solvent such as N-N-dimethylacetamide is used as the reaction medium, and the purified compound A3 is obtained through the crystallization step.
It greatly improves the conversion rate of A3, reduces raw material residues, simplifies the operation process, improves the purity and yield of the product, and is suitable for industrial production.
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Figure CN119591603A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing an intermediate of a JAK inhibitor upadacitinib. Background Art
[0002] The specific causes of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are unknown. From medical practice, it is speculated that they are closely related to the partial defects of the patient's immune function. Rheumatoid arthritis has a long course and because it often has immune dysfunction, patients often die from complications such as cardiovascular, infection and renal impairment.
[0003] Currently, JAK inhibitors are one of the effective means of treating such immune system diseases. Among them, Upadacitinib, an experimental new drug developed by AbbVie for the treatment of rheumatoid arthritis and psoriatic arthritis, is a new type of JAK1 inhibitor.
[0004] JAK1 is a kinase that plays a key role in the pathophysiology of a variety of inflammatory diseases, including rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), psoriatic arthritis (PsA), etc. AbbVie is also evaluating the potential of upadacitinib to treat other immune diseases, including PsA, ankylosing spondylitis, AS and atopic dermatitis.
[0005] So far, there are few patent reports on upadacitinib at home and abroad. The main reported patent synthesis route is the synthesis route of the original AbbVie (W02017066775Al)
[0006]
[0007] In this route, when preparing the intermediate compound A3, due to the strong alkalinity of lithium tert-butoxide, benzyl (3R, 4S)-3-(N-(tert-butoxycarbonyl)-N-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl) glyceryl)-4-ethylpyrrolidine-1-carboxylate, i.e. A3, has two chiral centers and undergoes isomerization under strong alkaline conditions, resulting in diastereomers (A3').
[0008] At the same time, due to the large particle size of lithium tert-butoxide, the reaction system is not fully contacted, and there are more raw materials remaining, which results in a very low conversion rate of A3, and the operation is complicated and the purification steps are cumbersome, which is not conducive to commercial production. Therefore, it is of practical social significance and economic value to develop a method for preparing the intermediate I of the JAK1 inhibitor upadacitinib, which is simple to operate, low in cost and high in yield. Summary of the invention
[0009] The purpose of the present invention is to solve the technical problems in the prior art such as low yield of upadacitinib intermediate, complex operation, tedious purification, etc., and to provide a method for synthesizing upadacitinib intermediate.
[0010] To achieve the above object, the present invention provides the following technical solutions:
[0011] A method for preparing an upadacitinib intermediate compound represented by formula A3, comprising reacting compounds A1 and A2 in a reaction medium in the presence of an alkaline substance,
[0012] The compound A1 is benzyl (3R, 4S)-3-(2-bromoacetyl)-4-ethylpyrrolidine-1-carboxylate, and its structural formula is
[0013]
[0014] Compound A2 is ethyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl) carbamate, with the structural formula
[0015]
[0016] The structural formula of compound A3 is
[0017] Furthermore, the alkaline substance is selected from one or more of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, preferably selected from potassium carbonate, cesium carbonate, sodium methoxide or sodium ethoxide.
[0018] Furthermore, the molar ratio of the amount of the alkaline substance to compound A2 is 1.50:1.00 to 1.10:1.00.
[0019] Furthermore, the reaction temperature is 0-25°C, preferably 0-10°C or 10-18°C or 12-18°C.
[0020] Further, the reaction medium is an aprotic solvent; preferably, the aprotic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, NN-dimethylacetamide, NN-dimethylformamide, more preferably selected from NN-dimethylacetamide.
[0021] Furthermore, the molar ratio of compound A1 to compound A2 is (0.9-1.60):1.00.
[0022] Furthermore, the preparation method also includes a crystallization step to obtain purified compound A3.
[0023] In a particular embodiment, the crystallization step is to mix the product obtained in the previous step with a crystallization solvent in water, take the organic phase and heat it to dissolve it, then cool it down to crystallize, and recrystallize it.
[0024] Alternatively, in a particular embodiment, the crystallization step is to precipitate a solid from the product obtained in the previous step in water, separate the solid, mix it with a crystallization solvent, and recrystallize it.
[0025] Furthermore, the solvent used in the crystallization step is selected from any one or a combination of two of EA (ethyl acetate), isopropyl acetate, 2-methyltetrahydrofuran, isopropyl ether, MTBE, methanol, toluene, n-heptane, acetonitrile, and tetrahydrofuran, preferably a combination of ethyl acetate and isopropyl ether.
[0026] Furthermore, the mass ratio of ethyl acetate to isopropyl ether is selected from 1:1 to 2;
[0027] Furthermore, the mass ratio of the crystallization solvent to the amount of A1 is (3-5):1, preferably 4:1.
[0028] Furthermore, the crystallization holding time in the crystallization step is 10 to 26 hours, preferably 18 hours; the crystallization holding temperature in the crystallization step is 10 to 20°C, preferably 15°C.
[0029] The meanings of the abbreviations in the present invention are:
[0030] Cs2CO3: Cesium carbonate
[0031] DMA: NN-dimethylacetamide
[0032] EA: Ethyl acetate
[0033] MTBE: Methyl tert-butyl ether
[0034] Cbz: benzyloxycarbonyl
[0035] Ts: p-Toluenesulfonyl
[0036] Boc: tert-butyloxycarbonyl
[0037] DIPEA: N,N-diisopropylethylamine
[0038] Compared with the prior art, the present invention has the following beneficial effects:
[0039] 1. Greatly improve the conversion rate of A3, the raw material residue is almost negligible, the yield is significantly improved, and the raw material cost is greatly saved.
[0040] 2. The reaction conditions are simple, the post-processing operation is convenient, and it is conducive to industrial production.
[0041] 3. The reaction selectivity is good, the reaction liquid has fewer monitored impurities, the crystallization solvent is appropriately selected, and the product purity is high.
[0042] 4. The selected crystallization solvent can remove non-enantiomer impurities simultaneously, without the need for a special chiral separation method.
[0043] Compared with the methods in the prior art, the method for synthesizing upadacitinib intermediates of the present application significantly reduces the cost while ensuring the yield, and can improve the quality of the final product. BRIEF DESCRIPTION OF THE DRAWINGS
[0044] Figure 1 This is the liquid phase spectrum of compound A3 obtained in Example 1, wherein the chromatographic peak with a retention time of 36.578 corresponds to the target product A3, and the chromatographic peak with a retention time of 37.152 corresponds to the diastereomer A3';
[0045] Figure 2 This is the liquid phase spectrum of compound A3 obtained in Example 2, wherein the chromatographic peak with a retention time of 36.467 corresponds to the target product A3, and the chromatographic peak with a retention time of 37.013 corresponds to the diastereomer A3'. DETAILED DESCRIPTION
[0046] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.
[0047] Example 1 Synthesis of Compound A3
[0048] To a 20L glass reactor, add 1.0kg of A2 (2.89mol), 5.0kg of DMA, and 0.2kg of sodium methoxide (3.7mol). After the addition is complete, add dropwise the prepared DMA solution of A1 (1.0kg A1 (2.82mol) dissolved in 2.0kg of DMA). Control the temperature at 15°C and react for 2h.
[0049] Crystallization: Add 4.5 kg of EA and purified water, take the organic phase, raise the temperature to 45-55°C, cool to 20°C for crystallization, and keep warm for 16 hours. Centrifuge and dry, and use a mixed solution of ethyl acetate-isopropyl ether (2.0 kg of ethyl acetate and 3.0 kg of isopropyl ether) for recrystallization to obtain upadacitinib intermediate A3.
[0050] The liquid phase spectrum of compound A3 is shown in Figure 1 As shown, the yield is 82.21%, the purity is 99.49%, and the isomer is 0.41%.
[0051] Example 2 Synthesis of Compound A3
[0052] To a 50L glass reactor, add 3.0kg of A2 (8.66mol), 16.0kg of DMA, and 3.3kg of cesium carbonate (10.13mol mol). After the addition is complete, add dropwise the prepared DMA solution of A1 (3.0kgA1 (8.47mol) dissolved in 6.3kg of DMA). Control the temperature at 12°C and react for 5h.
[0053] Crystallization: Add 12.5 kg EA and purified water, stir and separate the liquids, take the organic phase, heat to 45-60°C, dissolve, slowly cool to 10°C for crystallization, and keep warm for 18 hours. Centrifuge and dry, and use a mixed solution of ethyl acetate-isopropyl ether (6.0 kg ethyl acetate, 9.0 kg isopropyl ether) for recrystallization to obtain upadacitinib intermediate A3.
[0054] The liquid phase spectrum of compound A3 is shown in Figure 2 As shown, the yield is 81.70%, the purity is 99.38%, and the isomer is 0.47%.
[0055] Example 3 Synthesis of Compound A3
[0056] To a 250 ml three-necked flask, add 10.0 g of A2 (0.03 mol), 50 ml of DMA, and 5.0 g of potassium carbonate (0.04 mol). Stir at room temperature for 1 h. Add dropwise the prepared DMA solution of A1 (12.0 g of A1 (0.03 mol) dissolved in 20 ml of DMA). After the addition is complete, control the temperature at 18 °C and react for 3 h.
[0057] Crystallization: Add 700 ml of purified water to the reaction solution to precipitate solids, filter and dry for 24 hours. Take the dried product, add EA (0.02 kg), stir at room temperature to dissolve, then add isopropyl ether (0.03 kg) dropwise, stir at room temperature, gradually precipitate solids, cool to 15 ° C for crystallization, and keep warm for 12 hours. Centrifuge and dry to obtain upadacitinib intermediate A3.
[0058] The yield of compound A3 is 65.73%, the purity is 99.60%, and the isomer content is 0.25%.
[0059] Comparative Example 1 Synthesis of Compound A3
[0060] To a 100ml three-necked flask, add 3.0g of A2 (0.009mol) and 15ml of DMA, stir until dissolved, add 2.0g of N-methylmorpholine, control the temperature at 0-10℃ and stir for 0.5h, add dropwise the prepared DMA solution of A1 (3.0g of A1 dissolved in 10ml of DMA), after the addition is complete, control the temperature at 0-10℃, react for 1h, take TLC sample, and it shows that no target product is generated. Raise the temperature to 25-30℃, continue the reaction for 1h, take TLC sample, and it shows that still no target product is generated, so abandon the reaction as N-methylmorpholine is not suitable as a base.
[0061] Comparative Example 2 Synthesis of Compound A3
[0062] Add 3.0 g of A2 (0.009 mol) and 15 ml of DMA to a 100 ml three-necked flask, stir to dissolve, add 2.0 g of DIPEA, control the temperature at 0-10°C and stir for 0.5 h, add dropwise the prepared DMA solution of A1 (3.0 g of A1 dissolved in 10 ml of DMA), after the addition is complete, control the temperature at 0-10°C, react for 1 h, take a TLC sample, and it shows that no target product is generated. Raise the temperature to 25-30°C, continue the reaction for 1 h, take a TLC sample, and it shows that still no target product is generated, so abandon the reaction as DIPEA is not suitable as a base.
[0063] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing an upadacitinib intermediate compound represented by formula A3, characterized in that: The method comprises reacting compounds A1 and A2 in the presence of a basic substance in a reaction medium. The structural formula of the compound A1 is The structural formula of compound A2 is The structural formula of compound A3 is 2. The preparation method according to claim 1, characterized in that: The alkaline substance is selected from one or more of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, preferably selected from potassium carbonate, cesium carbonate, sodium methoxide or sodium ethoxide.
3. The preparation method according to claim 1, characterized in that: The molar ratio of the amount of the alkaline substance to compound A2 is (1.50-1.10):1.
00.
4. The preparation method according to claim 1, characterized in that: The reaction temperature is 0-25°C, preferably 0-10°C or 10-18°C or 12-18°C.
5. The preparation method according to claim 1, characterized in that: The reaction medium is selected from aprotic solvents; preferably, the aprotic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, NN-dimethylacetamide, NN-dimethylformamide, more preferably selected from NN-dimethylacetamide.
6. The preparation method according to claim 1, characterized in that: The molar ratio of compound A1 to compound A2 is (0.9-1.60):1.
00.
7. The preparation method according to claim 1, characterized in that: The preparation method further comprises a crystallization step to obtain purified compound A3.
8. The preparation method according to claim 7, characterized in that: The solvent used in the crystallization step is selected from any one or a combination of two of EA (ethyl acetate), isopropyl acetate, 2-methyltetrahydrofuran, isopropyl ether, MTBE, methanol, toluene, n-heptane, acetonitrile, and tetrahydrofuran, preferably a combination of ethyl acetate and isopropyl ether.
9. The preparation method according to claim 7, characterized in that: The mass ratio of the crystallization solvent to the amount of A1 is (3-5):1, preferably 4:
1.
10. The preparation method according to claim 7, characterized in that: The crystallization holding time in the crystallization step is 10 to 26 hours, preferably 18 hours; the crystallization holding temperature in the crystallization step is 10 to 20°C, preferably 15°C.