A method for racemizing a pharmaceutical intermediate

Abstract

This invention discloses a racemization method for a pharmaceutical intermediate. The invention provides a racemization method for a substrate as shown in Formula I, comprising the following steps: in an organic solvent, at a reaction temperature of 80-165°C and under the action of a base, substrate I undergoes the reaction shown below to obtain compound II; wherein substrate I is a racemic mixture, an R-configuration, an S-configuration, a R-predominantly-configured racemic compound, or an S-predominantly-configured racemic compound; the carbons indicated by * are S-configured and / or R-configured chiral carbons; the base is one or more of an alkali metal hydroxide, an alkali metal hydride, and an alkali metal alkoxide. The method of this invention has a high yield, can be readily used for drug synthesis, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for racemizing pharmaceutical intermediates. Background Technology

[0002] Aticaprant, chemically named (S)-4-(4-((2-(3,5-dimethylphenyl)pyrrolidone-1-yl)methyl)phenoxy)-3-fluorobenzamide, with the structural formula shown below, is a potent, centrally penetrating KOR antagonist developed by Eli Lilly and Company. Clinically, it is used to treat smoking cessation, alcohol cessation, anxiety, and depression. (Journal of Medicinal Chemistry, 2011, 54, 8000-8012.)

[0003]

[0004] In the preparation of aticaprant, the construction of the (S)-2-(3,5-dimethylphenyl)pyrrolidine (S-type-I) fragment is the key to the synthetic route. The main methods for preparing the (S)-2-(3,5-dimethylphenyl)pyrrolidine (S-type-I) fragment are as follows:

[0005] Method 1: (ACS Omega, 2020, 5, 26938-26945.)

[0006]

[0007] Although this method directly prepares the desired S-type I, it involves a long process with an overall yield of 26.1%. The multi-step reaction requires purification by column chromatography, and the reduction of imine requires ultra-low temperature (-78°C), making the conditions quite harsh and unsuitable for large-scale industrial production.

[0008] Method 2: (Advanced Synthesis&Catalysis, 2021, 363, 1317-1321.)

[0009]

[0010] The drawbacks of this route are that it requires ultra-low temperature (-78℃), the ee value of the product obtained by chiral catalysis is not high (94% ee), and the feed amount is only in the milligram level (82 mg). The multi-step reaction requires column chromatography purification.

[0011] Method 3: (Organic Letters, 2017, 19, 4215-4218.)

[0012]

[0013] The drawback of this route is that it requires the use of expensive metal catalysts and the product has a low ee value (93% ee).

[0014] In summary, the currently reported chemical synthesis methods for (S)-2-(3,5-dimethylphenyl)pyrrolidine mainly belong to or are similar to the methods mentioned above. However, they usually have one or more drawbacks, such as expensive metal reagents, lengthy steps, and numerous side reactions. By comparing the various methods mentioned above, we adopted a series of reactions, similar to Method 3, including the Grignard reaction, to obtain the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine. Then, we resolved this racemic compound to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine. This method is simple to operate and has low cost, but it suffers from low yield and significant waste in the resolution reaction. Therefore, achieving the racemization of the other configuration (R)-2-(3,5-dimethylphenyl)pyrrolidine in the mother liquor is key to realizing the industrial production of this route.

[0015] To date, no literature has reported on the racemization and resolution of 2-(3,5-dimethylphenyl)pyrrolidine compounds, and this invention has a positive impact on the production of aticaprant. Summary of the Invention

[0016] The technical problem to be solved by this invention is that the existing methods for preparing (S)-2-(3,5-dimethylphenyl)pyrrolidine are costly, have many side reactions, or have low yields, making them unsuitable for industrial production. This invention provides a racemization method for pharmaceutical intermediates. The method of this invention avoids the use of expensive metal catalysts or chiral reagents in the preparation process, has low cost, fewer reaction steps, high yield, reduces waste emissions, and makes up for the low yield of the resolution route, making it more suitable for industrial production.

[0017] This invention provides a method for racemizing a substrate as shown in Formula I, comprising the following steps: in an organic solvent, at a reaction temperature of 80-165°C and under the action of a base, substrate I undergoes the reaction shown below to obtain compound II; wherein substrate I is a racemic mixture, an R-configuration, an S-configuration, a R-predominantly-configured racemic compound, or an S-predominantly-configured racemic compound; * indicates a carbon with an S-configuration and / or an R-configuration chiral carbon; wherein the base is one or more of an alkali metal hydroxide, an alkali metal hydride, and an alkali metal alkoxide;

[0018]

[0019] In some embodiments, the organic solvent is one or more of amide solvents (e.g., N,N-dimethylformamide and / or N,N-dimethylacetamide), sulfoxide solvents (e.g., dimethyl sulfoxide), alcohol solvents (e.g., ethylene glycol), and ether solvents (e.g., ethylene glycol monomethyl ether), preferably dimethyl sulfoxide.

[0020] In some embodiments, the alkali metal hydroxide is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide, preferably potassium hydroxide.

[0021] In some embodiments, the alkali metal hydride is sodium hydride.

[0022] In some embodiments, the alkali metal alkoxide is sodium methoxide and / or sodium ethoxide.

[0023] In some embodiments, the reaction temperature is 100-140°C.

[0024] In some embodiments, the molar ratio of the base to the substrate I is (1:1) to (4:1).

[0025] In some embodiments, the racemization method further includes one or more of the following post-processing steps, such as quenching, extraction, washing, drying, concentration, and recrystallization.

[0026] The present invention also provides a method for resolving compound II, comprising the following steps: in an organic solvent, compound II reacts with a resolving agent as shown below to obtain compound S-type-I and compound R-type-I; the solvent is ethanol and / or methanol; the resolving agent is D-tartaric acid;

[0027]

[0028] In some embodiments, the organic solvent is ethanol, preferably 95% ethanol, 83% ethanol or 90% ethanol.

[0029] In some embodiments, the molar ratio of the resolving agent to compound II is (1:1) to (2:1).

[0030] In some embodiments, the separation method further includes the following post-processing step: recrystallization, preferably recrystallization using the organic solvent.

[0031] This invention also provides a method for preparing the compound S-type-I, which includes the following steps:

[0032] (1) Compound R-type-I was racemized as shown above to obtain compound II;

[0033] (2) Compound II is separated into compound S-type-I by the separation method shown above;

[0034]

[0035] In the racemization method of the present invention, the "organic solvent" is a commonly used solvent in this type of reaction in the art, and its boiling point should be higher than the reaction temperature when it is used as a solvent.

[0036] In the racemization method of the present invention, the "R-configuration-dominant racemate" refers to the racemate in which the R configuration accounts for more than 50%.

[0037] In the racemization method of the present invention, the "S-configuration-dominant racemic compound" refers to the racemic compound in which the S-configuration accounts for more than 50%.

[0038] In the racemization method of the present invention, the other reaction conditions are conventional conditions for such reactions in the art.

[0039] In the separation method of the present invention, the other reaction conditions are conventional conditions for such reactions in the art.

[0040] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0041] The reagents and raw materials used in this invention are all commercially available.

[0042] The positive and progressive effects of this invention are as follows: the reagents used in the racemization method of this invention are economical and environmentally friendly, the preparation cost is low, the post-processing is simple, the product yield is high, the purity is high, and it can be successfully used for the synthesis of aticaprant, making it suitable for industrial production. Detailed Implementation

[0043] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0044] In the following examples, the HPLC conditions were: ChiralPak OD-H (4.6 mm × L 250 mm), n-hexane (containing 0.1% diethylamine): ethanol (containing 0.1% diethylamine) = 95:5, flow rate: 0.6 mL / min, column temperature: 35 °C, and detection wavelength: 268 nm.

[0045] Example 1

[0046] 100 g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration: R configuration = 25:75) was taken, and dimethyl sulfoxide (400 ml) and potassium hydroxide (64 g, 2 eq) were added. The mixture was heated to 120 °C and stirred for 3 hours. Heating was stopped, and the reaction solution was poured into water (2 L). Dichloromethane was added for extraction, and the organic layer was separated. The aqueous phase was extracted three times with dichloromethane (500 ml × 3 times). The organic layers were combined, washed with saturated sodium chloride until neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 88.7 g of racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, with a yield of 88.7% and a purity of 98.88%.

[0047] 40 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine was added to 95% ethanol, followed by D-tartaric acid (35.9 g, 1.05 eq) for resolution and crystallization. The product was recrystallized from 95% ethanol to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine-tartrate, with a yield of 37.33%. The salt was detected by chiral HPLC. Referring to the literature ACS Omega, 2020, 5, 26938-26945, the peak of (S)-2-(3,5-dimethylphenyl)pyrrolidine with a retention time of 9.391 min, a peak area of ​​73.5143, and a peak height of 287.84 was found; the peak of (R)-2-(3,5-dimethylphenyl)pyrrolidine with a retention time of 8.124 min, a peak area of ​​0.3604, and a peak height of 1.84 was found. Therefore, (S)-2-(3,5-dimethylphenyl)pyrrolidine:(R)-2-(3,5-dimethylphenyl)pyrrolidine = 99.51:0.49.

[0048] 40 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine was added to 90% ethanol, followed by D-tartaric acid (35.9 g, 1.05 eq) for resolution and crystallization. The product was recrystallized from 90% ethanol to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine-tartrate, with a yield of 32.33%. Chiral HPLC analysis showed that the ratio of (S)-2-(3,5-dimethylphenyl)pyrrolidine to (R)-2-(3,5-dimethylphenyl)pyrrolidine was 99.27:0.73.

[0049] Example 2

[0050] 120 g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 30:70) was taken, and dimethyl sulfoxide (480 ml) and sodium hydroxide (82.3 g, 3 eq) were added. The mixture was heated to 130 °C and stirred for 6.5 hours. Heating was stopped, and the reaction solution was poured into water (2.2 L). Dichloromethane was added for extraction, and the organic layer was separated. The aqueous phase was extracted three times with dichloromethane (500 ml × 3 times). The organic layers were combined, washed with saturated sodium chloride until neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 101.2 g of racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, with a yield of 84.3% and a purity of 98.34%.

[0051] Take 40g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, add 95% ethanol, and add D-tartaric acid (35.9g, 1.05eq) for resolution and crystallization. The product is recrystallized from 95% ethanol to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine-tartrate, with a yield of 36.8%. Chiral HPLC analysis of the salt showed that (S)-2-(3,5-dimethylphenyl)pyrrolidine:(R)-2-(3,5-dimethylphenyl)pyrrolidine = 99.15:0.85.

[0052] Take 40g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, add 83% ethanol, and add D-tartaric acid (35.9g, 1.05eq) for resolution and crystallization. The product is recrystallized from 83% ethanol to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine-tartrate, with a yield of 31.8%. Chiral HPLC analysis of the salt showed that (S)-2-(3,5-dimethylphenyl)pyrrolidine:(R)-2-(3,5-dimethylphenyl)pyrrolidine = 99.35:0.65.

[0053] Example 3

[0054] Take 80g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 25:75), add dimethyl sulfoxide (320ml) and cesium hydroxide (143.9g, 2.1eq), heat to 115℃, stir for 4.5 hours, stop heating, pour the reaction solution into water (2L), add dichloromethane for extraction, separate the organic layer, extract the aqueous phase three more times with dichloromethane, combine the organic layers, wash with saturated sodium chloride until neutral, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain 69.4g of racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, yield 86.7%, purity 97.13%.

[0055] Take 40g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, add 95% ethanol, and add D-tartaric acid (35.9g, 1.05eq) for resolution crystallization. The product is recrystallized from 95% ethanol to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine-tartrate, with a yield of 36.5%. The results of chiral HPLC analysis of the salt showed that (S)-2-(3,5-dimethylphenyl)pyrrolidine:(R)-2-(3,5-dimethylphenyl)pyrrolidine = 99.13:0.87.

[0056] Example 4

[0057] 80 g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 25:75) was taken, and dimethyl sulfoxide (320 ml) and sodium ethoxide (87 g, 2.8 eq) were added. The mixture was heated to 135 °C and stirred for 8 hours. Heating was stopped, and the reaction solution was poured into water (2 L). Dichloromethane was added for extraction, and the organic layer was separated. The aqueous phase was extracted three more times with dichloromethane. The organic layers were combined, washed with saturated sodium chloride until neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 67.4 g of racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, with a yield of 84.3% and a purity of 96.33%.

[0058] Take 40g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, add 95% ethanol, and add D-tartaric acid (35.9g, 1.05eq) for resolution crystallization. The product is recrystallized from 95% ethanol to obtain (S)-2-(3,5-dimethylphenyl)pyrrolidine-tartrate, with a yield of 34.3%. Chiral HPLC analysis of the salt showed that (S)-2-(3,5-dimethylphenyl)pyrrolidine:(R)-2-(3,5-dimethylphenyl)pyrrolidine = 99.07:0.93.

[0059] Structural confirmation of 2-(3,5-dimethylphenyl)pyrrolidine: 1 H NMR(400MHz, CDCl3+D2O)δ6.97(s,2H),6.87(s,1H),4.00-4.04(m,1H),3.16-3.21(m,1H),2. 94-3.01(m,1H),2.30(s,6H),2.11-2.20(m,1H),1.79-1.96(m,2H),1.61-1.71(m,1H).MS(ESI positive):m / z 176[M+H] + .

[0060] Example 5

[0061] Take 10g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 25:75), add DMF (50ml), add sodium hydroxide (4.6g, 2eq), heat to 110℃, react for 4 hours, and detect by chiral HPLC (S configuration:R configuration = 40:60). Then, use a mixed solvent of DMSO:DMF (2:1), but the reaction time needs to be extended to 12 hours to successfully racemate.

[0062] Comparative Example 1

[0063] 10 g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 25:75) was added to dimethyl sulfoxide (40 ml) along with 26 g (3 eq) of DBU (1,8-diazabicycloundec-7-ene). The mixture was heated to 120 °C and reacted for 6 hours. Chiral HPLC analysis showed no racemization. The results indicate that the racemization reaction could not proceed smoothly when DBU was used as a base.

[0064] Comparative Example 2

[0065] 10 g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 25:75), dimethyl sulfoxide (40 ml), and potassium hydroxide (6.4 g, 2 eq) were added. The mixture was heated to 75 °C and reacted for 4 hours. Chiral HPLC analysis showed that almost no racemization occurred. The results indicate that the racemization reaction cannot proceed smoothly at a temperature of 75 °C.

[0066] Comparative Example 3

[0067] Take 10g of compound (R)-2-(3,5-dimethylphenyl)pyrrolidine (S configuration:R configuration = 25:75), add N,N-dimethylacetamide, add 60% sodium hydride (4.6g, 2eq), heat to 50℃, react for 6 hours. Chiral HPLC detection showed no racemization. Then, use a mixed solvent of DMSO:N,N-dimethylacetamide (2:1), heat to 70℃, and it can be racemized successfully within 7 hours. However, HPLC detection showed that more impurities were generated.

[0068] Comparative Example 4

[0069] 10 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine was added to 95% ethanol, followed by the addition of D-dibenzoyl tartaric acid (21.5 g, 1.05 eq) for resolution and crystallization. The product was recrystallized from 95% ethanol with a yield of 74.3%. Chiral HPLC analysis confirmed that the product was a racemic mixture. The results indicate that using D-dibenzoyl tartaric acid as a resolving agent resulted in a racemic product.

[0070] Comparative Example 5

[0071] 10 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine was added to acetone, followed by the addition of D-tartaric acid (8.9 g, 1.05 eq) for resolution crystallization. The product was recrystallized from acetone with a yield of 44.3%. The product was confirmed to be a racemic mixture by chiral HPLC analysis. The results show that using acetone as the resolution solvent resulted in a racemic mixture.

[0072] Comparative Example 6

[0073] 10 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine was added to isopropanol, followed by D-tartaric acid (8.9 g, 1.05 eq) for resolution and crystallization. The product was recrystallized from isopropanol with a yield of 46.3%. The product was confirmed to be a racemic mixture by chiral HPLC. The results show that using isopropanol as the resolution solvent resulted in a racemic mixture.

[0074] Comparative Example 7

[0075] Take 5.0 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, add 95% ethanol, add L-malic acid (4.02 g, 1.05 eq) for resolution crystallization, and no solid precipitation is observed.

[0076] Comparative Example 8

[0077] Take 5.0 g of the racemic compound 2-(3,5-dimethylphenyl)pyrrolidine, add 95% ethanol, add D-malic acid (4.02 g, 1.05 eq) for resolution crystallization, and no solid precipitation is observed.

Claims

1. A method for resolving compound II, comprising the following steps: Step 1: In an organic solvent, at a reaction temperature of 100-140℃ and under the action of a base, substrate I undergoes the reaction shown below to obtain compound II; substrate I is an R-configuration or a predominantly R-configuration racemic compound; the base is one or both of alkali metal hydroxides and alkali metal alkoxides; the organic solvent is dimethyl sulfoxide; the molar ratio of the base to substrate I is (1:1)-(4:1); ； Step 2: Compound II is reacted with a resolving agent in an organic solvent as shown below to obtain compound S-type-I; the organic solvent is 95% ethanol; the resolving agent is... D -tartaric acid; 。 2. The splitting method as described in claim 1, characterized in that, It meets one or two of the following conditions: (1) The alkali metal hydroxide is one or more of sodium hydroxide, potassium hydroxide, cesium hydroxide and lithium hydroxide; (2) The alkali metal alkoxide is sodium methoxide and / or sodium ethoxide.

3. The splitting method as described in claim 2, characterized in that, The alkali metal hydroxide is potassium hydroxide.

4. The splitting method as described in claim 1, characterized in that, In the separation method, step 1 further includes one or more of the following post-processing steps: quenching, extraction, washing, drying, concentration, and recrystallization.

5. The splitting method as described in claim 1, characterized in that, It meets one or two of the following conditions: (1) The molar ratio of the resolving agent to compound II is (1:1)-(2:1); (2) In the splitting method, step 2 further includes the following post-processing step: recrystallization.

6. The splitting method as described in claim 1, characterized in that, In the separation method, step 2 further includes the following post-processing step: recrystallization using the organic solvent.

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