Synthesis method of (S)-2-(2-isopropyl phenyl) pyrrolidine

Abstract

The invention relates to a synthesis method of (S)-2-(2-isopropyl phenyl) pyrrolidine. The method comprises the following steps: firstly, converting aryl halide into a Grignard reagent, and carrying out ring opening reaction on the Grignard reagent and an N-protected 4-6-membered ring lactam compound to obtain an intermediate; and then removing a protecting group, and carrying out asymmetric hydrogenation under the condition of a chiral catalytic system to finally obtain (S)-2-(2-isopropyl phenyl) pyrrolidine with high optical purity. The method has good stereoselectivity, simplicity and convenience in operation and industrial adaptability, and is suitable for efficient synthesis of chiral amine compounds, especially chiral drug intermediates.

Description

Technical Field

[0001] This invention relates to the field of chiral 2-aryl substituted pyrrolidine synthesis technology, and in particular to a method for synthesizing (S)-2-(2-isopropylphenyl)pyrrolidine. Background Technology

[0002] (S)-2-(2-isopropylphenyl)pyrrolidine is a class of chiral heterocyclic compounds with important application prospects. Patent WO2019210828 first disclosed a method for preparing this compound in 2019. The method uses aryl brominated pyrrolidine as a starting material. First, after amino protection, a propenyl group is introduced via a palladium-catalyzed Suzuki coupling reaction. Then, the double bond is hydrogenated and reduced under palladium-carbon conditions to generate an isopropyl group. Finally, deprotection is performed under acidic conditions to obtain the target racemic (S)-2-(2-isopropylphenyl)pyrrolidine.

[0003]

[0004] The method has the following drawbacks: First, it is difficult to obtain the starting materials; second, the synthesis process involves two palladium-catalyzed reactions, and the catalytic system is complex and costly; third, the final product is a racemic mixture, which still needs to be further purified by means of enantiomeric separation to obtain the desired chiral product, resulting in low overall efficiency.

[0005] In subsequent research, some technical solutions have attempted to construct the chiral skeleton of (S)-2-(2-isopropylphenyl)pyrrolidine de novo using a chiral induction strategy. For example, patent documents such as WO2022140224 and WO2021133817 disclose the construction of an imine intermediate 8 starting with a chiral sulfonamide compound 6, followed by the introduction of a hemiacetal group, and then obtaining optically pure compound 1 through deprotection and cyclization steps. Isopropyl groups are then introduced along a route similar to WO2019210828 to finally synthesize (S)-2-(2-isopropylphenyl)pyrrolidine.

[0006]

[0007] Although this type of route can yield chiral pure compounds, its overall synthetic process is complex, involving multiple steps with demanding reaction conditions, resulting in poor atom economy, low yield, and significant difficulty in industrial implementation.

[0008] To further improve the synthesis efficiency of chiral (S)-2-(2-isopropylphenyl)pyrrolidine, in 2021, Jacek Mlynarski's group reported a synthesis strategy based on asymmetric catalysis in the journal Advanced Synthesis & Catalysis (2021, 363(5), 1317-1321).

[0009]

[0010] This method uses 2-isopropylaryl compound 11 as a starting material. First, a carboxyl intermediate 12 is formed by inserting a Grignard reagent into the carbonyl group. This intermediate is then esterified to obtain compound 13, which reacts with N-vinyl-2-pyrrolidone to generate an imine intermediate 14. Finally, optically pure (S)-2-(2-isopropylphenyl)pyrrolidine is prepared by hydrosilylation under the action of a chiral organozinc catalyst. This method simplifies the synthetic steps and improves chiral selectivity to some extent, but it still requires a high dose (10 mol%) of chiral catalyst. Further optimization of catalytic efficiency and atom economy is possible, and industrial application still faces challenges. Summary of the Invention

[0011] To address the aforementioned problems, this invention provides a method for synthesizing (S)-2-(2-isopropylphenyl)pyrrolidine: the method comprises an asymmetric hydrogenation reaction of an amino intermediate 17 under the action of a catalyst, wherein the catalyst is formed by complexing a transition metal precursor and a chiral ligand. The specific reaction is as follows:

[0012]

[0013] In some preferred embodiments, the molar ratio of the transition metal precursor to the chiral ligand is 1:2.0 to 1:2.5.

[0014] In some preferred embodiments, the molar ratio of the transition metal precursor to the chiral ligand is 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, or 1:2.5.

[0015] In some preferred embodiments, the transition metal precursor is an iridium complex, a rhodium complex, or a ruthenium complex.

[0016] In some preferred embodiments, the iridium complex is [Ir(COD)Cl]2 or [Ir(NBD)Cl]2.

[0017] In some preferred embodiments, the chiral ligand is a spirobiphosphine ligand or a binaphthyldiamine ligand, preferably (R,R)-f-spiroPhos or (S,S)-f-Bianphane.

[0018] In some preferred embodiments, the conditions for the asymmetric hydrogenation reaction include a hydrogen pressure of 0.5 to 2.0 MPa, preferably 1.0 MPa.

[0019] In some preferred embodiments, the reaction temperature is 20–50°C, preferably 30°C.

[0020] In some preferred embodiments, the reaction time is 48 to 96 hours, preferably 72 hours.

[0021] In some preferred embodiments, the conditions for the asymmetric hydrogenation reaction include hydrogen pressures of 0.5 MPa, 1.0 MPa, 1.5 MPa, and 2.0 MPa.

[0022] In some preferred embodiments, the reaction temperature is 20°C, 30°C, 40°C, or 50°C.

[0023] In some preferred embodiments, the reaction time is 48 hours, 60 hours, 72 hours, 84 hours, or 96 hours.

[0024] In some preferred embodiments, the amino intermediate 17 is obtained by directly reacting 2-isopropylbromobenzene with 1-(tert-butoxycarbonyl)-2-pyrrolidone via Grignard reagent conversion for ring opening, and then subjecting the resulting intermediate to acid deprotection, as shown below:

[0025]

[0026] In some preferred embodiments, the deprotection reaction uses a mixture of hydrogen chloride and 1,4-dioxane solution, ethanol, or ethyl acetate as a solvent.

[0027] Beneficial effects:

[0028] The synthetic method provided by this invention has good process adaptability and industrial feasibility, and can effectively improve the preparation efficiency and optical purity of target chiral compounds. This method exhibits high stereoselectivity in the construction of chiral centers, and the products are easy to separate and purify, which helps simplify subsequent processing and reduce production costs. The overall route combines atom economy and ease of operation, making it suitable for the large-scale synthesis of chiral drug intermediates. Attached Figure Description Figure 1 The nuclear magnetic resonance spectrum (H NMR) of the main product in the fourth step of Example 1 is shown, with CDCl3 as the detection solvent. Figure 2 The chiral HPLC chromatogram of the crude intermediate 1 obtained in step 4 of Example 1 is shown. Figure 3 The chiral HPLC chromatogram of the hydrochloride salt of compound 5 obtained in step 4 of Example 1 is shown. Detailed Implementation

[0029] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0030] Terminology Explanation:

[0031] (1) Grignard reagents: organometallic compounds formed by the reaction of organic halogens with metallic magnesium in anhydrous ether solvents, with the general formula R–Mg–X (where R is an alkyl or aryl group and X is a halogen). These reagents have strong nucleophilicity and are often used in addition reactions with electrophilic substrates such as carbonyl groups, and are widely used in the construction of carbon-carbon bonds.

[0032] (2) Isopropyl magnesium chloride-lithium chloride complex (i-PrMgCl·LiCl): This complex system is formed by isopropyl magnesium chloride and lithium chloride, and tetrahydrofuran is usually used as the solvent. While maintaining the nucleophilic activity of Grignard reagents, this complex exhibits higher reaction selectivity and substrate adaptability due to the synergistic coordination effect of LiCl, and is suitable for addition reactions of substrates with large steric hindrance.

[0033] (3) 1-(tert-Butoxycarbonyl)-2-pyrrolidinone: 2-pyrrolidinone compounds whose nitrogen atom is protected by tert-Butoxycarbonyl (Boc). Their structure contains a protecting group that can be removed under acidic conditions. They are often used for selective protection of amine compounds in multi-step synthesis.

[0034] (4) Imine Intermediate: An intermediate with a C=N double bond structure formed by the condensation reaction of a carbonyl compound and an amine compound. This type of intermediate can be used in subsequent reduction or addition reactions and plays an important role in the synthesis of chiral amines such as reductive amination.

[0035] (5) Asymmetric Reductive Amination: A method that converts carbonyl compounds and amine substrates into chiral amine compounds through the synergistic effect of a reducing agent and a chiral catalyst. This reaction combines the in-situ formation of imines with stereoselective reduction and is suitable for the synthesis of chiral amine target compounds.

[0036] (6) [Ir(COD)Cl]2: Dichlorobis(1,5-cyclooctadiene)iridium complex, a transition metal catalyst precursor commonly used in asymmetric hydrogenation reactions. This complex can complex with chiral ligands to form an active catalytic system, enabling precise induction of chiral centers.

[0037] (7) (R,R)-spiroPhos: A spirocyclic bisphosphine chiral ligand with a C2 symmetric structure, which can complex with transition metal catalysts to form a catalytic system with high enantioselectivity, and is suitable for chiral construction reactions such as asymmetric hydrogenation.

[0038] (8) Amino Boc protection and deprotection:

[0039] This refers to the process of reversibly protecting amino groups through a Boc group. This protection method is introduced under basic conditions and can be removed under acidic conditions, and is widely used for the temporary shielding of amino groups in multi-step reactions.

[0040] (9) Amine Hydrochloride Salt: A salt compound formed by amino compounds and hydrochloric acid. It has good stability and crystallinity, making it easy to separate, store and use. It is often used as a purified form of amino products.

[0041] (10) Enantiomeric Excess (ee): The excess content of the major enantiomer in a chiral compound relative to the other enantiomer. It is often used to characterize the enantioselectivity of chiral reaction products.

[0042] (11) Crystallization Purification: A purification method that separates substances through crystallization based on the difference in solubility between the target product and impurities in the solvent. It is suitable for the separation and purification of organic compounds with good thermal stability and excellent crystallinity.

[0043] (12) Recovery rate (Isolated Yield): The percentage between the actual target product obtained from the reaction system and the theoretical yield, used to evaluate the material conversion efficiency of the synthesis process.

[0044] Example 1

[0045] Step 1 Grignard reagent exchange

[0046]

[0047] 10.0 g (1.0 eq.) of 2-isopropylbromobenzene 11 was mixed with 100 mL of dry tetrahydrofuran in a 250 mL three-necked flask. The system was purged three times with nitrogen, maintaining a nitrogen atmosphere. The mixture was cooled to -5 °C with ice-salt water, and then a tetrahydrofuran solution of isopropyl magnesium chloride and lithium chloride (1.3 M, 46.0 mL, 1.2 eq.) was added dropwise to the reaction flask. After the addition was complete, the reaction system was stirred at room temperature for 30 minutes. No further treatment was required, and the mixture could be used directly for the next reaction.

[0048] The second step is the ring-opening reaction of pyrrolidone.

[0049]

[0050] 1-(tert-butoxycarbonyl)-2-pyrrolidone (8.3 g, 1.0 eq.) was mixed with dry tetrahydrofuran (100 mL) in a 500 mL three-necked flask. The system was purged three times with nitrogen while maintaining a nitrogen atmosphere. The mixture was cooled to -60 °C under dry ice-acetone bath conditions, and then the Grignard reagent solution (1.1 eq.) obtained in the first step was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was stirred at this temperature for 30 minutes. After the reaction was confirmed by TLC, a saturated ammonium chloride solution (110 mL) was added to quench the reaction. The mixture was then stirred at room temperature for another hour, allowed to stand, and separated. The aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (200 mL) and concentrated to obtain crude intermediate 17, which could be used directly in the next reaction without further purification.

[0051] Step 3: Amin deBoc protection

[0052]

[0053] The crude product 16 was dissolved in 1,4-dioxane (40 mL) in a 250 mL three-necked flask. Then, a 4 M solution of 1,4-dioxane in hydrogen chloride (67 mL) was added to the reaction flask. The mixture was stirred at room temperature for 1 hour. After the reaction was completed by TLC monitoring, the solution was concentrated under reduced pressure to a final volume of about 30 mL. Then, methyl tert-butyl ether (50 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered to obtain amino hydrochloride 17 (7.6 g). The total yield of the first three steps was 70%.

[0054] Step 4: Asymmetric Reductive Amination

[0055]

[0056] Intermediate 17 (7.6 g) was added to a 250 mL autoclave, followed by 100 mL of dried tetrahydrofuran. Under a nitrogen atmosphere, a pre-prepared catalyst solution ([Ir(COD)Cl]2 / (R,R)-spiroPhos = 1 / 2.2, 0.031 mmol, 0.1 mol%) was added. The entire system was then purged three times with hydrogen, maintaining a hydrogen pressure of 1.0 MPa after purging. The autoclave was then stirred and reacted at 30 °C for 72 hours. After the reaction was complete, the mixture was concentrated to remove the organic phase. The residue was dissolved in 80 mL of 0.2 M dilute hydrochloric acid and then washed with 50 mL of methyl tert-butyl ether. The washed aqueous phase was then adjusted to pH 10 with 0.2M sodium hydroxide solution (90 mL), and then extracted twice with ethyl acetate (100 mL * 2). The combined organic phase was then washed once with saturated brine (70 mL), and then concentrated under reduced pressure to obtain crude intermediate 1 (4.7 g) with an optical purity of 90.3%. 1HNMR (600MHz, CDCl3) δ7.48-7.49(3H),7.25-7.26(1H),7.16-7.22(2H),4.45-4.47(1H),3.22-3.32(2H),3. 00-3.03(1H),2.86(1H),2.15-2.21(1H),1.91-1.97(1H),1.84-1.90(1H),1.62-1.68(1H),1.22-1.24(6H).

[0057] The crude product was dissolved in anhydrous ethanol (15 mL), followed by the addition of an ethanol solution of hydrogen chloride (2 M, 2.5 mL). The mixture was stirred for 1 hour, then concentrated under reduced pressure to approximately 3 volumes of solution. The reaction flask was placed in a water bath at 5–10 °C and stirred to induce crystallization for 2 hours. Filtration yielded 4.7 g of the hydrochloride salt of compound 5, with a recovery rate of 85% and an optical purity of 97.7%.

[0058] Conclusion: This invention employs a direct addition reaction between Grignard reagents and cyclic lactam compounds. The first two steps can be completed sequentially in the same reaction system, and the resulting intermediate can be used in subsequent reactions without purification, significantly simplifying the process and reducing operational complexity and time costs. After removing the amino protecting group with the hydrogen chloride organic solution used, the target intermediate can be directly crystallized from the reaction system as a hydrochloride salt without additional purification steps, achieving simultaneous deprotection and purification. This simple operation is suitable for industrial scale-up. The fourth step uses metal-catalyzed asymmetric reductive amination to construct the chiral center of the target molecule, exhibiting good chiral selectivity. The optical purity of the crude product can reach approximately 90%, and after subsequent salt formation treatment, the optical purity of the final product is increased to over 97%, meeting the application requirements for high-purity chiral pharmaceutical intermediates.

[0059] Comparative Example 1

[0060] Intermediate 17 (1.5 g) was added to a 50 mL autoclave, followed by 20 mL of dried tetrahydrofuran. Under a nitrogen atmosphere, a pre-prepared catalyst solution ([Ir(COD)Cl]2 / (R)-BINAP = 1 / 2.2, 0.006 mmol, 0.1 mol%) was added. The entire system was then purged three times with hydrogen, maintaining a hydrogen pressure of 1.0 MPa after purging. The autoclave was then stirred and reacted at 30 °C for 72 hours. After the reaction was complete, the mixture was concentrated to remove the organic phase. The residue was dissolved in 20 mL of 0.2 M dilute hydrochloric acid and then washed with 20 mL of methyl tert-butyl ether. The washed aqueous phase was then adjusted to pH 10 with 0.2M sodium hydroxide solution (18 mL), and then extracted twice with ethyl acetate (30 mL * 2). The combined organic phase was then washed once with saturated brine (30 mL), and then concentrated under reduced pressure to obtain crude intermediate 1 (0.8 g) with an optical purity of 62.3%.

[0061] Comparative Example 2

[0062] Compound 17 has too low purity and yield, which in turn affects the purity and yield of compound 5.

[0063] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing (S)-2-(2-isopropylphenyl)pyrrolidine, characterized in that, The reaction involves the asymmetric hydrogenation of amino intermediate 17 under the action of a catalyst, wherein the catalyst is formed by complexing a transition metal precursor and a chiral ligand. The specific reaction is as follows:

2. The method according to claim 1, characterized in that, The molar ratio of the transition metal precursor to the chiral ligand is 1:2.0 to 1:2.5, preferably 1:2.

2.

3. The method according to claim 1 or 2, characterized in that, The transition metal precursor is an iridium complex, a rhodium complex, or a ruthenium complex; and / or, the iridium complex is [Ir(COD)Cl]2 or [Ir(NBD)Cl]2, preferably [Ir(COD)Cl]2.

4. The method according to claim 1 or 2, characterized in that, The chiral ligand is a spirobiphosphine ligand or a binaphthyldiamine ligand, preferably (R,R)-f-spiroPhos or (S,S)-f-Bianphane.

5. The method according to claim 1, characterized in that, The conditions for the asymmetric hydrogenation reaction include a hydrogen pressure of 0.5–2.0 MPa, preferably 1.0 MPa; a reaction temperature of 20–50°C, preferably 30°C; and a reaction time of 48–96 hours, preferably 72 hours.

6. The method according to claim 1, characterized in that, The amino intermediate 17 was obtained by directly reacting 2-isopropylbromobenzene with 1-(tert-butoxycarbonyl)-2-pyrrolidone after conversion with a Grignard reagent to open the ring. The resulting intermediate was then deprotected by acid, as shown in the figure.

7. The synthesis method according to claim 6, characterized in that, The deprotection reaction uses a mixture of hydrogen chloride and 1,4-dioxane solution, ethanol, or ethyl acetate as a solvent.

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