Synthesis method of (1R, 2S)-2, 6-dimethyl-2, 3-dihydro-1H-indene-1-amine

Abstract

The invention provides a synthesis method of (1R, 2S)-2, 6-dimethyl-2, 3-dihydro-1H-indene-1-amine, which comprises the following steps: reacting xylene with S-2-bromo-methyl propionate to generate a chiral ester intermediate, carrying out ring closing reaction to generate (2s)-2, 6-dimethyl-1-indanone, and directly generating (1R, 2S)-2, 6-dimethyl-2, 3-dihydro-1H-indene-1-amine through chiral induced reduction by utilizing the steric hindrance of chiral methyl, thereby obtaining the (1R, 2S)-2, 6-dimethyl-2, 3-dihydro-1H-indene-1-amine. According to the present invention, the 2, 3-dihydro-1H-indene-1-amine is synthesized through the method, the method is the chiral intermediate preparation process with characteristics of high selectivity and high directionality starting from the initial raw material, the use of the expensive heavy metal chiral catalyst is avoided, the reaction is simplified, and the method is the synthesis method with characteristics of economy, safety and easy expanded production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for synthesizing the chiral intermediate (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine. Background Technology

[0002] (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine, as an important chiral intermediate, is widely used in the synthesis of active ingredients in indeneamine-based fine chemicals, neuropharmaceuticals, and agrochemicals. Its (1R,2S) configuration product exhibits good activity; however, (S,R)2,6-dimethyl-1-aminoindene, (R,R)2,6-dimethyl-1-aminoindene, and (S,S)2,6-dimethyl-1-aminoindene are interfering. To obtain high-purity chiral isomers, the synthetic methods reported in the literature include: 1) The literature Tetrahedron 2007, 63(29), 6755-6763 reported that 2,6-dimethyl-1-indanone was used as a raw material and asymmetric hydrogenation was carried out in the presence of a rhodium or ruthenium-based chiral catalyst to obtain (1S,2S)-2,6-dimethyl-1-hydroxyindanone. Then, the Mitsunobu reaction was used to replace the hydroxyl group with azide in DPPA and then reduced with LiAlH4 to obtain (1R,2S)-2,6-dimethyl-1-aminoindanone. Although this scheme does not interfere with isomers, it uses a special chiral catalyst, requires relatively harsh conditions, and uses racemic 2,6-dimethyl-1-indanone as a starting material for asymmetric hydrogenation. The reaction is complex, and the chiral catalysts used in the asymmetric hydrogenation, as well as the reagents used in the Mitsunobu and reduction reactions (such as rhodium or ruthenium-based chiral catalysts), are very expensive. It can only be prepared in the laboratory and is not suitable for large-scale production. 2) WO2024 / 201469 A1 discloses a synthetic route, which also uses racemic 2,6-dimethyl-1-indanone as a starting material. The preparation process is as follows: The route is very lengthy. To obtain a product with chiral purity, each step is cumbersome and requires some expensive metal reagents (Ni(OAc)2) or Cu(OAc)2, and the yield is only 40%; 3) Bayer's patent CN106414420A and the literature Chemistry A European Journal. 2014, 20(35), 11084-90 disclose the following synthetic scheme, This method involves cyclizing phthaloyl-protected starting material A under Pd(PPh3)4 catalysis to obtain intermediate B. The protecting group in intermediate B is then removed with hydrazine hydrate to yield the racemic trans isomer C. However, neither of the two Bayer publications mentioned above addresses how to obtain the single isomer (1R,2S)-2,6-dimethyl-1-aminoindenhydride from intermediate C. Furthermore, starting material A is difficult to obtain, making the synthesis inconvenient. Secondly, it requires an expensive palladium catalyst, and the yield is not high (CN106414420A reports a cyclization yield of only 55%), and the dr value of the product is also not very high (according to Chemistry A European Journal. 2014, 20). (35), 11084-90 reported that the best dr value of the analogue without methyl on the benzene ring can only be 98:2). Since no method for preparing the single isomer (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine from the racemic intermediate C is provided, it poses a great difficulty and unpredictability for those skilled in the art. 4) Patent CN108794339A discloses a method for resolving racemates to obtain optically pure (r,s)2,6-dimethyl-1-aminoindene. It uses 2,6-dimethylindene as raw material, converts it into indoxime, and then reduces it to obtain the racemic 2,6-dimethyl-1-aminoindene. Then, through cis-trans separation and chiral resolution, (r,s)2,6-dimethyl-1-aminoindene is obtained. This synthesis process not only requires cis-trans separation but also reduction and racemate resolution, etc. The steps are complicated, the cost is high, the yield is low, and there are many by-products.

[0003] People have made great efforts in the research of chiral synthesis along with the development of science and technology. A good process route not only needs to have excellent yield and stereoselectivity, but reaction cost is also an important factor that needs to be considered in industrial production. Stereoselectivity can be obtained by controlling it with chiral catalysts, but it is unpredictable. The influence of various conditions and reagents in chiral reactions on optical purity is also unpredictable. How to optimize the process to reduce costs and by-products in large-scale reactions is a bottleneck and obstacle to the vigorous promotion of the process.

[0004] In summary, existing technologies have long synthetic routes, high step costs, complex requirements for equipment and catalysts, demanding conditions, low yields and purity, or lack further implementation guidance. Furthermore, chiral preparation itself is unpredictable. Therefore, there is an urgent technical need to develop a new process with a clear route, simple process, controllable cost, and readily available raw materials. Summary of the Invention

[0005] To address the aforementioned problems in the prior art, this invention innovatively introduces a chiral methyl group via methyl S-2-bromo-propionate, providing a novel synthetic route for (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine. Utilizing the steric hindrance of the chiral methyl group, a method for directly generating the R-configured amino product is unexpectedly obtained through chiral-induced reduction. The synthetic route of this invention is as follows: In step 1), p-xylene and methyl S-2-bromopropionate are used as raw materials and reacted in a solvent with added alkaline substances to obtain compound I; in step 2), compound I is reacted in a solvent with added acidic substances to obtain compound II; in step 3), compound II is reacted in a solvent with added acidic substances, and a reducing agent is added to continue the reaction to obtain the product of this invention (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine.

[0006] Preferably, the solvent in step 1) is selected from one or more of DMF (i.e., N,N-dimethylformamide), N-methylpyrrolidone, acetonitrile, and tetrahydrofuran, more preferably DMF and / or N-methylpyrrolidone, and even more preferably DMF; in another preferred embodiment, the alkaline substance in step 1) is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium tert-butoxide, and sodium tert-butoxide, more preferably potassium carbonate and potassium tert-butoxide.

[0007] Preferably, in step 1), the mass ratio of p-xylene to methyl S-2-bromo-propionate is 1-5:1-5, more preferably 1-2:1-2, and most preferably 1:1-2; the reaction system is heated to reflux and the reflux reaction time is ≥2h, preferably ≥5h, and more preferably ≥8h; in another preferred embodiment, the product is concentrated by filtration and then extracted, dried and concentrated to obtain compound I; preferably, ethyl acetate and water are used for extraction and separation, and ethyl acetate is added to the aqueous phase for extraction.

[0008] Preferably, the solvent in step 2) is selected from one or more of toluene, benzene, xylene, chloroform, and carbon tetrachloride, more preferably one or more of toluene, xylene, and chloroform, and more preferably toluene; in another preferred embodiment, the acidic substance in step 2) includes one or more of PPA (Polyphosphoric acid, CAS: 8017-16-1), trifluoroacetic acid, p-TsOH (p-toluenesulfonic acid), pentafluoropropionic acid, difluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and benzoic acid, more preferably one or more of PPA, trifluoromethanesulfonic acid, and methanesulfonic acid, and more preferably PPA.

[0009] Preferably, in step 2), the mass-to-volume ratio (g / ml) of compound I to solvent is 1:5-20, more preferably 1:10-15 (g / ml); the reaction system is heated to 50-150°C, preferably 60-100°C, more preferably 70-90°C; in another preferred embodiment, after the reaction stops, the temperature is lowered to below room temperature, the reaction is quenched with water, the organic phase is extracted, and the mixture is dried and concentrated to obtain compound II, preferably, the temperature is lowered to below 10°C, more preferably to 0-5°C; in another preferred embodiment, after the product in step 2 is quenched with water, the mixture is separated, the aqueous phase is extracted with toluene, and the mixture is dried and concentrated to obtain compound II.

[0010] Preferably, the solvent in step 3) is selected from one or more of ammonia methanol, ammonia ethanol, and ammonia isopropanol, more preferably ammonia methanol and / or ammonia ethanol, and most preferably ammonia methanol; in another preferred embodiment, the acidic substance in step 3) is a Lewis acid, preferably including one or more of tetraisopropyl titanate, triisopropyl borate, trimethylchlorosilane, boron trifluoromethanesulfonate, and aluminum triisopropoxy, more preferably one or more of tetraisopropyl titanate and triisopropyl borate, and most preferably tetraisopropyl titanate; in another preferred embodiment, the reducing agent in step 3) includes one or more of sodium borohydride, lithium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium triisobutylborohydride, more preferably sodium borohydride and / or sodium cyanoborohydride, and most preferably sodium borohydride. In another preferred embodiment, the mass-volume ratio (g / ml) of compound II to solvent in step 3) is 1:5-20, more preferably 1:10-15 (g / ml); in another preferred embodiment, the molar ratio of compound II to acidic substance to reducing agent in step 3) is 1-3:1-3:1-3, more preferably 1-2:1-2:1-2; in another preferred embodiment, the reaction temperature before adding the reducing agent in step 3) is 10-60℃, preferably 15-50℃, more preferably 20-40℃; further, the reducing agent is added after cooling to below 10℃ in step 3), preferably 0-5℃; in another preferred embodiment, the reaction is quenched by adding saturated ammonium chloride solution in step 3), followed by extraction with an aqueous organic phase, concentration, and drying to obtain a crude product; in another preferred embodiment, the crude product is purified by washing and filtration.

[0011] All raw materials and reagents used in this invention were either commercially available or prepared experimentally. Methyl S-2-bromo-propionate was custom-made from Anhui Leyong Biotechnology Co., Ltd., listed on the Chemicalbook website. All other reagents and equipment were purchased from Sigma.

[0012] The beneficial effects of this invention are: 1) The intermediate products obtained by this invention have high yield and purity, which is beneficial for storage and process scale-up production.

[0013] 2) Existing synthetic methods require multiple complex steps or the use of expensive chiral catalysts, resulting in lengthy and tortuous reaction routes. In contrast, this invention, through a unique reaction strategy, unexpectedly and directly yields chiral intermediate products; compared to existing technologies, it significantly shortens the reaction route, reduces costs, simplifies operation, and allows for milder reaction conditions.

[0014] 3) The basicity of the benzylic methyl group of xylene and the strong electrophilicity of the α-position of the carbonyl group of methyl S-2-bromopropionate generate a chiral ester intermediate before ring closure. Then, the ring closure is completed in the next step under the action of acids such as PPA, which greatly improves the reaction efficiency and significantly increases the single-step ring closure yield.

[0015] 4) This invention innovatively utilizes the steric hindrance of chiral methyl groups to directly induce reduction to generate R-configured amino groups. During the chiral induced reduction reaction, the steric characteristics of the compound itself strictly limit and guide the direction and manner of attack of the reagents, enabling the reaction to proceed precisely in the direction of generating R-configured amino groups. This high degree of selectivity and directionality is difficult to achieve in traditional synthetic methods.

[0016] 5) The R-configuration amino product of this invention produces drugs with significantly higher efficacy than those prepared from the S-configuration amino product during the preparation and application of pesticides and corresponding new drugs. Attached Figure Description

[0017] Appendix Figure 1 The reverse phase liquid chromatography spectrum of chiral compound I in an embodiment of the present invention (reverse phase purity 98.3%) is shown. Appendix Figure 2 This is the normal phase liquid phase spectrum of chiral compound I according to an embodiment of the present invention (normal phase ee% is 100%). Appendix Figure 3 The NMR spectrum of chiral compound I in this embodiment of the invention; Appendix Figure 4 The reverse phase liquid chromatography spectrum of chiral compound II in an embodiment of the present invention (reverse phase liquid phase purity 97.8%) is shown. Appendix Figure 5 This is the normal phase liquid phase spectrum of chiral compound II in an embodiment of the present invention (normal phase ee% is 100%). Appendix Figure 6 The NMR spectrum of chiral compound II in an embodiment of the present invention is shown. Appendix Figure 7 The reverse liquid phase spectrum of the product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine in an embodiment of the present invention (reverse liquid phase purity 99.82%). Appendix Figure 8 The liquid phase normal phase spectrum of the product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine in an embodiment of the present invention (normal phase ee% is 100%, de% is 99.14%). Appendix Figure 9 The NMR spectrum of the product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine from an embodiment of the present invention is shown. Detailed Implementation

[0018] Example 1: The synthesis route is as follows: Step 1: Preparation of compound I In a 500ml three-necked flask, 100ml of DMF, 10.6g (0.1mol) of p-xylene, and 16.6g (0.12mol) of potassium carbonate were added. After stirring at room temperature for 30min, 18.37g (0.11mol) of methyl 2-bromopropionate was added dropwise. After the addition was complete, the mixture was stirred and heated to reflux, and the reaction was maintained at reflux for 10h. HPLC analysis showed that the p-xylene content of the starting material was less than 0.5%. The mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the layers were extracted with 500ml of ethyl acetate and 300ml of water. The aqueous phase was extracted twice with 100ml of ethyl acetate (100ml x 2). The combined organic phases were washed once with 300ml of saturated brine. After separation, the organic phase was dried over anhydrous sodium sulfate and concentrated to give 17.9g of compound I, with a yield of 93% and a purity of 98.3% as determined by HPLC. (See attached chromatogram) Figure 1 , 2 3) Step 2: Preparation of compound II Under nitrogen protection, 200 ml of toluene, 17.9 g (0.093 mol) of compound I, and 9 ml of PPA were added to a three-necked flask. The mixture was heated to 75-85 °C with stirring and maintained at this temperature for 5-8 hours. When the HPLC control showed that the concentration of intermediate 1 was less than 0.5%, the reaction was stopped. The mixture was cooled to 0-5 °C and quenched with 50 ml of water. The mixture was separated, and the aqueous phase was extracted once with 100 ml of toluene. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The concentrated intermediate II yielded 13.5 g, with a yield of 91% and an HPLC purity of 97.8%. (See attached compound chromatogram) Figure 4 , 5 6) Step 3: Synthesis of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine Add 150 ml of ammonia-methanol solution, 13.5 g (0.084 mol) of compound II, and 28.6 g (0.1 mol) of tetraisopropyl titanate to a three-necked flask. Stir and react at 20-35 °C for 8-10 h. Take a sample for TLC to ensure the reaction is complete. Cool to 0-5 °C and add 3.34 g (0.088 mol) of sodium borohydride. After the addition is complete, maintain the temperature at 0-5 °C for 1 h, then raise it to room temperature and maintain the reaction for 2-3 h. Take a sample for TLC to ensure the reaction is complete. Cool to 0-5 °C and add 20 ml of saturated ammonium chloride solution to quench the reaction. Then, remove methanol under reduced pressure, add 150 ml of ethyl acetate and 80 ml of water, stir to separate the layers, extract the aqueous phase twice with 100 ml of ethyl acetate, and combine the organic phases. The product was washed with 100 ml of saline solution and separated into layers. The organic phase was dried with anhydrous sodium sulfate and concentrated. The crude product obtained after concentration was dissolved in 50 ml of isopropanol and 25 ml of tetrahydrofuran by stirring and heating. The solution was kept at reflux and stirred for 1 hour. After cooling to room temperature by stirring, the mixture was filtered. The filter cake was dried to obtain 12.2 g of product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine, with a yield of 90%, HPLC purity of 99.82%, optical purity ee value of 100%, mp value of 89℃-91℃, and [α]20D of 3.5 (C=0.9, CHCl3). (See Appendix) Figure 7 , 8 9) Example 2: After replacing the solvent in step 1 with N-methylpyrrolidone instead of DMF, all other conditions were exactly the same as in Example 1; the detection data chromatogram of compound I was the same as in Example 1, with a yield of 91% and an HPLC purity of 97.5%; the final product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine had a yield of 91%, an HPLC purity of 99.62%, and a chiral purity ee value of 100%. The product chromatogram was the same as in Example 1.

[0019] Example 3: In step 1, the alkaline substance was replaced with potassium tert-butoxide, and the other conditions were the same as in Example 1, yielding compound I (identification chromatogram same as in Example 1), with a yield of 94.6% and a purity of 97.8%; the final product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine had a yield of 91.2%, an HPLC purity of 99.64%, and a chiral purity ee value of 100%. The product chromatogram was the same as in Example 1.

[0020] Example 4: After changing the solvent in step 2) from toluene to xylene and chloroform (1:1 molar ratio), the remaining operating conditions were exactly the same as in Example 1, yielding compound II (identification chromatogram same as in Example 1), with a yield of 89% and HPLC purity of 96.7%; the final product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine had a yield of 90.6%, HPLC purity of 99.71%, and optical purity ee value of 100%. The product chromatogram was the same as in Example 1.

[0021] Example 5: After replacing the acidic substance in step 2) with trifluoromethanesulfonic acid, the remaining operating conditions were exactly the same as in Example 1. The detection data of compound II were the same as in Example 1, with a yield of 88% and an HPLC purity of 97.2%. The final product (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine had a yield of 90.08%, an HPLC purity of 99.51%, and a chiral purity ee value of 100%. The product chromatogram was the same as in Example 1.

[0022] Example 6: After the solvent in step 3) was changed from ammonia-methanol to ammonia-ethanol, the remaining operation conditions were exactly the same as in Example 1. The yield of compound (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine was 89.8%, the HPLC purity was 99.5%, the chiral purity ee value was 100%, and the product chromatogram was the same as in Example 1.

[0023] Example 7: In step 3), the acidic substance was replaced with triisopropyl borate instead of tetraisopropyl titanate. The remaining operating conditions were exactly the same as in Example 1. The yield of compound (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine was 88%, the HPLC purity was 99.2%, the ee value was 100%, and the product chromatogram was the same as in Example 1.

[0024] Example 8: In step 3), the reducing agent was replaced with sodium cyanoborohydride. The remaining operating conditions were exactly the same as in Example 1. The yield of compound (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine was 89%, the HPLC purity was 99.1%, and the ee value was 99.8%. The product chromatogram was the same as in Example 1.

[0025] The above experimental results show that by optimizing the preparation process, a chiral product with high purity was obtained, avoiding the cumbersome steps and low yield caused by resolving agents, as well as the dangerous palladium-carbon catalytic reaction. The reaction route was significantly shortened, greatly improving the reaction efficiency and yield. This invention provides a more efficient, safe, and economical approach for the synthesis of related indanamine chiral drug molecules, and has broad application potential.

[0026] The specific embodiments described above do not constitute a limitation on the scope of protection of the present invention. Those skilled in the art can make various changes and applications to the present invention based on the above description.

Claims

1. A method for synthesizing (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine, characterized in that, The process route is as follows: in: Step 1) React p-xylene with methyl S-2-bromopropionate in a solvent containing an alkaline substance to prepare compound I; Step 2) Compound I reacts in a solvent containing an acidic substance to give compound II; Step 3) React compound II in a solvent containing an acidic substance and add a reducing agent to react and obtain the product of this invention (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine.

2. The method according to claim 1, characterized in that: The solvent in step 1) is selected from one or more of DMF, N-methylpyrrolidone, acetonitrile, and tetrahydrofuran; the alkaline substance in step 1) is selected from one or more of potassium phosphate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium tert-butoxide, and sodium tert-butoxide; the solvent in step 2) is selected from one or more of toluene, benzene, xylene, chloroform, and carbon tetrachloride; the acidic substance in step 2) includes one or more of PPA, trifluoroacetic acid, p-TsOH, pentafluoropropionic acid, difluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and benzoic acid; the solvent in step 3) is selected from one or more of ammoniam, ammoniaethanol, and ammoniaisopropanol; the acidic substance in step 3) is a Lewis acid; the reducing agent in step 3) includes one or more of sodium borohydride, lithium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and lithium triisobutylborohydride.

3. The method according to claim 2, characterized in that, The solvent in step 1) is DMF and / or N-methylpyrrolidone; the alkaline substance in step 1) is selected from potassium carbonate and / or potassium tert-butoxide; the solvent in step 2) is selected from one or more of toluene, xylene, and chloroform; the acidic substance in step 2) is selected from one or more of PPA, trifluoromethanesulfonic acid, and methanesulfonic acid; the solvent in step 3) is selected from ammonia methanol and / or ammonia ethanol; the acidic substance in step 3) includes one or more of tetraisopropyl titanate, triisopropyl borate, trimethylchlorosilane, boron trifluoromethanesulfonate, and aluminum triisopropoxy; the reducing agent in step 3) is sodium borohydride and / or sodium cyanoborohydride.

4. The method according to claim 3, characterized in that... The acidic substance in step 3) is tetraisopropyl titanate and / or triisopropyl borate; the reducing agent in step 3) is sodium borohydride.

5. The method according to claim 1, characterized in that, In step 1), the mass ratio of p-xylene and methyl S-2-bromopropionate is 1-5:1-5; in step 2), the mass-volume ratio (g / ml) of compound I to solvent is 1:5-20; in step 3), the mass-volume ratio (g / ml) of compound II to solvent is 1:5-20; and in step 3), the molar ratio of compound II to acidic substance to reducing agent is 1-3:1-3:1-3.

6. The method according to claim 5, characterized in that, In step 1), the mass ratio of p-xylene to methyl S-2-bromopropionate is 1-2:1-2; in step 2), the mass-volume ratio (g / ml) of compound I to solvent is 1:10-15; in step 3), the mass-volume ratio (g / ml) of compound II to solvent is 1:10-15; and in step 3), the molar ratio of compound II to acidic substance to reducing agent is 1-2:1-2:1-2.

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