Method for producing adrenergic receptor agonist intermediates

Abstract

[Solution] A method for producing an adrenergic receptor agonist intermediate, comprising the following steps: cyclizing compound E1 or E2 with compound F0 to obtain compound C. Here, R1 is a methyl group, ethyl group, isopropyl group, propyl group, tert-butyl group, or butyl group. R3 is H, Cl, F, or Br. L1 and L2 are leaving groups individually. This method makes raw materials readily available and avoids the use of toxic and harmful reagents. The reaction conditions are mild and the operation is simple, the yield is significantly improved, and costs are reduced, making it more suitable for commercial production.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, specifically to a method for producing an adrenergic receptor agonist intermediate.

Background Art

[0002] Vibegron is a selective human β-3 adrenergic receptor agonist. Activation of the β-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle when the bladder is full, allowing more urine to be stored, thereby reducing overactive bladder (OAB) in adults. TIFF2026521163000002.tif48128

[0003] The compound (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylic acid (Compound D1) or sodium (S)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-6-carboxylate (Compound D2) is an important intermediate in the synthesis of vibegron, and can be obtained by hydrolyzing Compound C under acidic conditions or alkaline conditions, respectively. TIFF2026521163000003.tif61128

[0004] Currently, the only reported synthesis route for this intermediate is the one disclosed by the original researcher in Patent WO2013062881. That is, using RM1 as a raw material, reacting it with dimethyl sulfate to produce Compound A, and reacting RM2 with chlorosulfonyl isocyanate to produce Compound B. Then, using ethylbenzene as a solvent, reacting A and B at a high temperature of 128°C for 48 hours to obtain the target Compound C. The reaction formula is as follows: TIFF2026521163000004.tif52170

[0005] The main drawbacks of this process are as follows: 1. The high price of RM2 keeps product costs at a high level; 2. The corrosive nature of isocyanate chlorosulfonate poses a high safety risk during production operations; 3. In the step where A and B react to produce C, not only is cyclopentadiene produced as a by-product, but it also has undesirable effects on the environment and workers. Furthermore, due to the high reaction temperature, polymerization inevitably occurs, generating a large amount of tar-like polymer. This adheres to the stirring paddle, increasing stirring resistance, making it unsuitable for scale-up production and creating difficulties in separation and purification processes; 4. In step C, post-reaction treatment requires purification by column chromatography, making it unsuitable for commercial production and resulting in low yields. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] To address the limitations of existing technologies, the present invention provides a method for producing adrenergic receptor agonist intermediates. This method utilizes readily available raw materials, avoids the use of toxic and harmful reagents, and employs mild reaction conditions and simple operation. As a result, yields are significantly improved, costs are reduced, and the method is suitable for commercial production. [Means for solving the problem]

[0007] To achieve the above objectives, the present invention employs the following technical solutions:

[0008] A method for producing an adrenergic receptor agonist intermediate, comprising the following steps:

[0009] To obtain compound C by cyclizing compound E1 or compound E2 with compound F0, TIFF2026521163000005.tif35149

[0010] Here, R1 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group.

[0011] R3 consists of a hydrogen atom (H), a chlorine atom (Cl), a fluorine atom (F), and a bromine atom (Br);

[0012] L1 and L2 are leaving groups on their own.

[0013] Furthermore, compound F0 is as shown by compound F, TIFF2026521163000006.tif24128

[0014] Here, R2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group;

[0015] R3 consists of H, Cl, F, and Br;

[0016] X is F, Cl, Br.

[0017] Furthermore, compound F0 is represented as compound F-1: TIFF2026521163000007.tif24128

[0018] Here, R2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group;

[0019] R3 is H;

[0020] X is F, Cl, Br;

[0021] Furthermore, compound F-1 has the following structure: TIFF2026521163000008.tif54135

[0022] X is F, Cl, Br.

[0023] Furthermore, compound F0 can be represented as compound F-2: TIFF2026521163000009.tif25128

[0024] Here, R2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group.

[0025] R3 is Cl, F, or Br;

[0026] X is F, Cl, or Br;

[0027] Furthermore, the compound of formula F-2 includes the following structure: TIFF2026521163000010.tif26128

[0028] Here, R2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group;

[0029] X is F, Cl, or Br;

[0030] Furthermore, the compound of formula F-2-1 includes the following structure: TIFF2026521163000011.tif55137

[0031] X is F, Cl, or Br;

[0032] Furthermore, the compound of formula F-2-2 includes the following structure: TIFF2026521163000012.tif54136 <00001​​​​​​​​​​​​​​​​​TIFF2026521163000014.tif23128

[0037] Here, R4 and R5 are each one of the C1-C6 alkyl groups.

[0038] Furthermore, R4 and R5 in compound F1 are each one of the following: methyl group, ethyl group, propyl group, butyl group, isopropyl group, or tert-butyl group.

[0039] Furthermore, formula F includes the compound F2: TIFF2026521163000015.tif28128

[0040] Here, R4, R6, and R7 are each one of the C1-C6 alkyl groups.

[0041] Furthermore, in compound F2, R4, R6, and R7 are each one of the following: methyl group, ethyl group, propyl group, butyl group, isopropyl group, or tert-butyl group.

[0042] Furthermore, compound E1 or compound E2 reacts with compound F0 under alkaline reagent conditions.

[0043] Furthermore, alkaline reagents contain either organic or inorganic bases.

[0044] Furthermore, the organic base includes one of the following: triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine.

[0045] Furthermore, the alkaline reagent contains triethylamine or N,N-diisopropylethylamine.

[0046] The molar ratio of compound E1 or E2, compound F0, and alkaline reagent is 1.0:(0.5~3.0):(0.5~5.0), and further 1.0:(1.0~1.5):(1.0~3.0);

[0047] Furthermore, the molar ratio of compound E1, compound F-1, and alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and also 1.0:(1.0~1.5):(1.0~1.5).

[0048] Furthermore, the molar ratio of compound E1, compound F-2, and alkaline reagent is 1.0:(0.5~2.0):(1.5~4.0), and also 1.0:(1.0~1.5):(1.5~3.0).

[0049] Furthermore, the molar ratio of compound E1, compound F1, and alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and also 1.0:(1.0~1.5):(1.0~1.5).

[0050] The molar ratio of compound E2, compound F1, and alkaline reagent is 1.0:(0.5~2.0):(0.5~3.0), and further 1.0:(1.0~1.5):(1.5~2.0).

[0051] The molar ratio of compound E1, compound F2, and alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~1.5);

[0052] The molar ratio of compound E2, compound F2, and alkaline reagent is 1.0:(0.5~2.0):(0.5~3.0), and further 1.0:(1.0~1.5):(1.5~2.0).

[0053] Furthermore, the reaction temperature range is 25-120°C, and even further, 50-110°C.

[0054] Furthermore, the organic solvent includes one of the following: ethyl acetate, isopropyl acetate, toluene, or acetonitrile. [Effects of the Invention]

[0055] Beneficial effects of the present invention compared to conventional technology:

[0056] The process employed in this invention allows for gentle and direct setting of reaction conditions, is easy to operate, and is suitable for scale-up and commercial production. The materials used are highly safe, do not generate harmful by-products to the environment or human health, and meet the requirements for green and environmentally friendly development.

[0057] The raw materials used in the process of this invention are inexpensive and readily available, resulting in low product costs and clear price competitiveness.

[0058] The yield of products manufactured using the process of the present invention is higher than that of existing technologies. [Brief explanation of the drawing]

[0059] [Figure 1] This is the high-performance liquid chromatogram of Example 1; [Figure 2] This is the chiral purity high-performance liquid chromatogram of Example 1; [Figure 3] This is the hydrogen spectrum of Example 1. [Modes for carrying out the invention]

[0060] The present invention will be described in more detail below, and specific examples will be shown.

[0061] In some examples, compound E1 or compound E2 reacts with compound F0 as shown in Formula 1: TIFF2026521163000016.tif36144

[0062] The reaction conditions include reactions in an alkaline environment and include alkaline reagents, i.e., organic or inorganic bases. Inorganic bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide. Organic bases include triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some examples, the alkaline reagents include triethylamine and N,N-diisopropylethylamine.

[0063] The molar ratio of compound E1 or E2, compound F0, and alkaline reagent is 1.0:(0.5~3.0):(0.5~5.0), and further 1.0:(1.0~1.5):(1.0~4.0).

[0064] The reaction solvents include ethyl acetate, isopropyl acetate, toluene, and acetonitrile, with ethyl acetate or toluene being preferred.

[0065] The reaction temperature ranges from 25 to 120°C, and more specifically, from 50 to 110°C. Specifically, these ranges are 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, and 120°C.

[0066] Compound E1 has the following structure: TIFF2026521163000017.tif55128

[0067] Compound E2 has the following structure: TIFF2026521163000018.tif55154

[0068] Formula F0 compound TIFF2026521163000019.tif18128 reacts with compound E1 or E2 to produce compound C via cyclization. Compound F0 is a saturated or unsaturated carbon chain, and three carbons on this carbon chain cyclize with compound E1 or E2 to form a dihydropyrrolopyrimidine ring derivative.

[0069] In some examples, F0 is substituted 2-butanone. TIFF2026521163000020.tif26128

[0070] R0 consists of three halogens (including F, Cl, and Br).

[0071] In some examples, F0 is a substituted 1,1,1-trihalogen-2-butanone. TIFF2026521163000021.tif27128

[0072] In some examples, F0 is 4-oxoalkyl 4-substituted-1,1,1-trihalogen-2-butanone, TIFF2026521163000022.tif27128

[0073] L1 and L2 are leaving groups, and L1 is an oxoalkyl group. In TIFF2026521163000023.tif14128, L2 is 1,1,1-trihalomethyl.

[0074] In some examples, compound F is as shown in compound F-1: TIFF2026521163000024.tif24128

[0075] R2 is a methyl group, ethyl group, isopropyl group, propyl group, tert-butyl group, or butyl group;

[0076] R3 is H;

[0077] X is F, Cl, Br.

[0078] Furthermore, compound F-1 has the following structure: TIFF2026521163000025.tif55159

[0079] In some examples, compound F is represented as compound F-2: TIFF2026521163000026.tif27128

[0080] Here, R2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group.

[0081] R3 consists of Cl, F, and Br;

[0082] X is F, Cl, Br;

[0083] Furthermore, compound F-2 has the following structure: TIFF2026521163000027.tif26128

[0084] Here, R2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group;

[0085] X is F, Cl, Br;

[0086] Furthermore, compound F-2-1 has the following structure: TIFF2026521163000028.tif54130

[0087] X is F, Cl, Br;

[0088] Furthermore, the compound of formula F-2-2 includes the following structure: TIFF2026521163000029.tif82128

[0089] X is F, Cl, Br;

[0090] Furthermore, compound F-2-3 includes the following structure: TIFF2026521163000030.tif83128

[0091] In some examples, R3 in the formula F0 compound is H, and furthermore, it is a substituent of the acrylic acid ester.

[0092] If L1 and L2 are leaving groups, L1 is an oxyalkyl group. The filename is TIFF2026521163000031.tif16128, and L2 is The filename is TIFF2026521163000032.tif13128.

[0093] Furthermore, formula F includes the compound of formula F1: TIFF2026521163000033.tif24128

[0094] Here, R4 and R5 are each one of the C1-C6 alkyl groups.

[0095] Furthermore, R4, R in compound F1 5は、 Each of these is either a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, or a tert-butyl group.

[0096] Furthermore, the specific structure of the F1 compound is as follows: TIFF2026521163000034.tif254162TIFF2026521163000035.tif89155

[0097] When R3 of compound F0 is H, it further becomes an acrylate ester substituted product.

[0098] L1 and L2 are leaving groups, and L1 is an oxoalkyl group. TIFF2026521163000036.tif17128, L2 is The formula is TIFF2026521163000037.tif15128. Formula F contains the compound F2: TIFF2026521163000038.tif30128

[0099] Here, R4, R6, and R7 are each one of the C1-C6 alkyl groups.

[0100] Furthermore, in compound F2, R4, R6, and R7 are each one of the following: methyl group, ethyl group, propyl group, butyl group, isopropyl group, or tert-butyl group.

[0101] If R4 of the compound of formula F2 is one of a methyl group, ethyl group, propyl group, butyl group, isopropyl group, or tert-butyl group, then R6 and R7 will be one of a methyl group, ethyl group, propyl group, butyl group, isopropyl group, or tert-butyl group, respectively.

[0102] The structure of F2 is preferably as follows: TIFF2026521163000039.tif186148

[0103] Compound E1 or E2 reacts with compound F-1 as shown in Formula 2: TIFF2026521163000040.tif40144

[0104] In some embodiments, R3 is H.

[0105] The reaction conditions shown in Formula 2 include a reaction in an alkaline environment and include an alkaline reagent, i.e., an organic base or an inorganic base. Inorganic bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide. Organic bases include triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some examples, the alkaline reagent includes triethylamine or N,N-diisopropylethylamine.

[0106] The molar ratio of compound E1 or E2, compound F-1, and the alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~2.0).

[0107] The molar ratios of compound E1, compound F-1, and alkaline reagent are 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~1.5). Specifically, these are 1.0:1.0:1.0, 1.0:1.5:1.0, 1.0:1.0:2.0, 1.0:1.5:2.0, and 1.0:1.2:1.5.

[0108] The molar ratios of compound E2, compound F-1, and alkaline reagent are 1.0:(0.5~2.0):(0.5~3.0), and further 1.0:(1.0~1.5):(1.5~2.0). Specifically, these are 1.0:1.0:1.0, 1.0:1.5:1.0, 1.0:1.0:2.0, 1.0:1.5:2.0, and 1.0:1.2:1.5.

[0109] The reaction solvents include ethyl acetate, isopropyl acetate, toluene, and acetonitrile, with ethyl acetate or toluene being preferred.

[0110] The reaction temperature ranges from 25 to 120°C, and more specifically, from 50 to 110°C. Specifically, these ranges are 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, and 120°C.

[0111] Compound E1 or E2 reacts with compound F-2 as shown in Formula 3: TIFF2026521163000041.tif44145

[0112] In some embodiments, R3 is F, Cl, or Br.

[0113] The reaction conditions shown in Formula 3 include a reaction in an alkaline environment, an alkaline reagent, and an organic or inorganic base. The inorganic base includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide. The organic base includes triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some examples, the alkaline reagent includes triethylamine or N,N-diisopropylethylamine.

[0114] The molar ratio of compound E1 or E2, compound F-2, and the alkaline reagent is 1.0:(0.5~2.0):(1.5~5.0), and further 1.0:(1.0~1.5):(1.5~4.0).

[0115] The molar ratios of compound E1, compound F-2, and alkaline reagent are 1.0:(0.5~2.0):(1.5~4.0), further 1.0:(1.0~1.5):(2.0~3.0), and also 1.0:1.0:2.0, 1.0:1.0:3.0, 1.0:1.5:2.0, 1.0:1.0:2.5, and 1.0:1.5:2.0.

[0116] The molar ratios of compound E2, compound F-2, and alkaline reagent are 1.0:(0.5~2.0):(0.5~5.0), further 1.0:(1.0~1.5):(2.5~4.0), and also 1.0:1.0:3.0, 1.0:1.5:3.0, 1.0:1.0:2.5, 1.0:1.0:4.0, 1.0:1.5:2.5, and 1.0:1.5:4.0.

[0117] The reaction solvents include ethyl acetate, isopropyl acetate, toluene, and acetonitrile, with ethyl acetate or toluene being preferred.

[0118] The reaction temperature ranges from 25 to 120°C, and more specifically, from 50 to 110°C. Specifically, these ranges are 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, and 120°C.

[0119] Compound E1 or compound E2 reacts with compound F1 as shown in formula 4: TIFF2026521163000042.tif39145

[0120] The reaction conditions shown in Equation 4 include a reaction in an alkaline environment and include an alkaline reagent, i.e., an organic base or an inorganic base. Inorganic bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide. Organic bases include triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some examples, the alkaline reagent includes triethylamine or N,N-diisopropylethylamine.

[0121] The molar ratio of compound E1 or E2, compound F1, and the alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~2.0).

[0122] The molar ratios of compound E1, compound F1, and alkaline reagent are 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~1.5).

[0123] The molar ratios of compound E2, compound F1, and alkaline reagent are 1.0:(0.5~2.0):(0.5~3.0), and further 1.0:(1.0~1.5):(1.5~2.0);

[0124] The reaction solvents include ethyl acetate, isopropyl acetate, toluene, and acetonitrile, with ethyl acetate or toluene being preferred.

[0125] The reaction temperature ranges from 25 to 120°C, and more specifically, from 50 to 110°C. Specifically, these ranges are 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, and 120°C.

[0126] Compound E1 or E2 reacts with compound F2 as shown in Formula 5: TIFF2026521163000043.tif40144

[0127] The reaction conditions shown in Equation 5 include a reaction in an alkaline environment and include an alkaline reagent, i.e., an organic base or an inorganic base. Inorganic bases include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide. Organic bases include triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some examples, the alkaline reagent includes either triethylamine or N,N-diisopropylethylamine.

[0128] The molar ratio of compound E1 or E2, compound F2, and the alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~2.0).

[0129] The molar ratio of compound E1, compound F2, and alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), and further 1.0:(1.0~1.5):(1.0~1.5).

[0130] The molar ratios of compound E2, compound F2, and alkaline reagent are 1.0:(0.5~2.0):(0.5~3.0), and further 1.0:(1.0~1.5):(1.5~2.0).

[0131] The reaction solvents include ethyl acetate, isopropyl acetate, toluene, and acetonitrile, with ethyl acetate or toluene being preferred.

[0132] The reaction temperature ranges from 25 to 120°C, and more specifically, from 50 to 110°C. Specifically, these ranges are 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, and 120°C. [Examples]

[0133] TIFF2026521163000044.tif35128

[0134] Compound E1 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl ester] 14.2 g (99.9 mmol), isopropyl acetate, compound F-1 (1,1,1-trichloro-4-ethoxy-3-en-2-one) 21.8 g (100.2 mmol), and triethylamine 10.2 g (100.8 mmol) were sequentially added to a reaction bottle. The mixture was heated to approximately 90°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with isopropylacetic acid. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 13.2 g of compound C (yield 68.1%). Purity: 98.1% (see Figure 1), chiral purity: 99.8% (see Figure 2).

[0135] 1 H NMR (DMSO-d6,400MHz):δ7.92(1H,d,J=6.64Hz);δ6.27(1H,d,J=6.64Hz);δ5.05(1H,dd,J=9.84 Hz,3.56Hz); δ3.70(3H,s); δ3.16-3.01(2H,m); δ2.60-2.52(1H,m); δ2.21-2.13(1H,m) (see Figure 3). [Examples]

[0136] TIFF2026521163000045.tif35128

[0137] Compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride] 10.0 g (56.0 mmol), toluene, compound F-1(1,1,1-trichloro-4-ethoxy-3-en-2-one) 18.2 g (83.7 mmol), and N,N-diisopropylethylamine 14.5 g (112.2 mmol) were sequentially added to a reaction bottle. The mixture was heated to 110°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 7.8 g of compound C (yield 71.7%). Purity: 98.8%, Chiral purity: 99.6%. [Examples]

[0138] TIFF2026521163000046.tif35128

[0139] At room temperature, 10.0 g (56.0 mmol) of compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride], ethyl acetate, 14.6 g (67.1 mmol) of compound F-1(1,1,1-trichloro-4-ethoxy-3-en-2-one), and 8.5 g (84.0 mmol) of triethylamine were sequentially added to a reaction bottle. The mixture was heated to 50°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the solution was separated. The aqueous phase was extracted again with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 8.0 g of compound C (yield 73.6%). Purity: 99.2%, chiral purity: 99.7%. [Examples]

[0140] TIFF2026521163000047.tif35128

[0141] Under an inert gas atmosphere, 34 mL (0.3 mol) of trichloroacetyl chloride and 58 mL (0.6 mol) of vinyl ether were sequentially added to a reaction bottle. The mixture was stirred at room temperature for 24 hours, then concentrated under reduced pressure to remove unreacted trichloroacetic acid chloride and vinyl ether. The concentrated residue was compound F-2-2-2 (X is Cl). Toluene was added to the reaction bottle and stirred to dissolve, yielding a toluene solution of F-2-2-2 (X is Cl). Further, 71 g (0.50 mol) of compound E1[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl ester] was added, and 132 g (1.2 mol) of triethylamine was added dropwise. The mixture was heated to 60°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, liquid-liquid separation was performed, and the aqueous phase was extracted with toluene. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 58.7 g of compound C (yield 60.5%). Purity: 97.2%, chiral purity: 99.0%. [Examples]

[0142] TIFF2026521163000048.tif30128

[0143] Compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride]18.0g (101.1 mmol), toluene, compound G-1(3-methyl methoxyacrylate)15.2g (130.9 mmol), and triethylamine17.3g (171.0 mmol) were sequentially added to the reaction flask. The mixture was heated to 90°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was combined. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 12.3g of compound C (yield 62.9%). Purity: 98.7%, Chiral purity: 99.1%. [Examples]

[0144] TIFF2026521163000049.tif31128

[0145] At room temperature, 15.0 g (84.0 mmol) of compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride], ethyl acetate, 18.0 g (125.7 mmol) of compound G-2 (N,N-dimethylaminoacrylate ethyl), and 15.3 g (151.2 mmol) of triethylamine were sequentially added to a reaction bottle. The mixture was heated to 80°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the solution was separated. The aqueous phase was extracted again with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 7.5 g of compound C (yield 46.0%). Purity: 97.6%, chiral purity: 99.3%. [Examples]

[0146] TIFF2026521163000050.tif43128

[0147] Compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride] 10.0 g (56.0 mmol), toluene, compound F-1(1,1,1-trichloro-4-methoxy-3-en-2-one) 17.0 g (84.0 mmol), and N,N-diisopropylethylamine 14.5 g (112.2 mmol) were sequentially added to a reaction bottle. The mixture was heated to 110°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 7.5 g of compound C (yield 70.8%). Purity: 97.9%, Chiral purity: 99.7%. [Examples]

[0148] TIFF2026521163000051.tif42128

[0149] Compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride]10.0g (56.0 mmol), toluene, compound F-1(1,1,1-trifluoro-4-propoxy-3-en-2-one)14.3g (78.6 mmol), and triethylamine10.8g (106.7 mmol) were sequentially added to a reaction bottle. The mixture was heated to 90°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 7.5g of compound C (yield 70.6%). Purity: 97.5%, Chiral purity: 99.5%. [Examples]

[0150] TIFF2026521163000052.tif35128

[0151] Compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride] 10.0 g (56.0 mmol), toluene, compound F-1(1,1,1-tribromo-4-isopropoxy-buto-3-en-2-one) 26.4 g (73.0 mmol), and triethylamine 10.2 g (101.1 mmol) were sequentially added to a reaction bottle. The mixture was heated to 80°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 7.2 g of compound C (yield 68.9%). Purity: 95.7%, chiral purity: 99.4%. [Examples]

[0152] TIFF2026521163000053.tif36128

[0153] Under an inert gas atmosphere, toluene was added to a reaction bottle, followed by the addition of 310.1 g (0.75 mol) of 1,1,1,4-tetrabromo-4-methoxybutan-2-one, then 71 g (0.50 mol) of compound E1[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl ester], and finally 151.7 g (1.5 mol) of triethylamine. The mixture was heated to 70°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with toluene. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 54.4 g of compound C (yield 58.3%). Purity: 96.2%, Chiral purity: 97.5%. [Examples]

[0154] TIFF2026521163000054.tif31128

[0155] Compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride]10.0g (56.1 mmol), toluene, compound G-1(3-methoxyacrylate ethyl)12.1g (84.2 mmol), and triethylamine11.4g (112.3 mmol) were sequentially added to the reaction flask. The mixture was heated to 50°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, liquid-liquid separation was performed, the aqueous phase was further extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 6.98g of compound C (yield 65.3%). Purity: 98.1%, chiral purity: 99.2%. [Examples]

[0156] TIFF2026521163000055.tif33128

[0157] Compound E1 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl ester] 71 g (0.5 mol), toluene, compound G-1 (3-ethoxypropenoic acid isopropyl ester) 119 g (0.75 mol), and triethylamine 76 g (0.75 mol) were sequentially added to the reaction flask. The mixture was heated to 90°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phase was combined. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to obtain 49.7 g of compound C (yield 52.3%). Purity: 97.9%, Chiral purity: 98.9%. [Examples]

[0158] TIFF2026521163000056.tif33128

[0159] At room temperature, 10.0 g (56.1 mmol) of compound E2[(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride], ethyl acetate, 10.9 g (84.2 mmol) of compound G-2(N,N-dimethylaminoacrylate methyl), and 8.52 g (84.2 mmol) of triethylamine were sequentially added to a reaction bottle. The mixture was heated to 80°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the solution was separated. The aqueous phase was extracted again with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 6.8 g of product (yield 63.4%). Purity: 98.2%, chiral purity: 99.3%. [Examples]

[0160] TIFF2026521163000057.tif32128

[0161] At room temperature, 10.0 g (56.1 mmol) of compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate methyl hydrochloride], ethyl acetate, 9.61 g (56.1 mmol) of compound G-2 (3-(diethylamino)acrylate ethyl), and 11.4 g (112.3 mmol) of triethylamine were sequentially added to a reaction bottle. The mixture was heated to 90°C to allow the reaction to proceed, and after the reaction was complete, it was cooled to room temperature. Water was added to stop the reaction, and the reaction was separated. The aqueous phase was extracted again with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 5.62 g of compound C (yield 52.4%). Purity: 98.5%, Chiral purity: 99.0%.

[0162] Comparison Example 1 (WO2013062881A1) TIFF2026521163000058.tif36128

[0163] 6.60 kg (72.3 wt%) of compound A, 4.19 kg of compound B, and 9.54 L of ethylbenzene were added to a 50 L reaction vessel and reacted at 128°C for 48 hours with stirring. The mixture was then cooled to 35°C, 14.3 L of toluene and 1.43 kg of activated carbon were added, and the mixture was kept warm with stirring at 35°C for 1 hour. After filtration, the filtrate was washed with 19.1 L of toluene, and the filtrates were combined and concentrated. Purification was then performed by column chromatography using 22.5 kg of silica gel and an acetone / heptane mixed solvent as eluents. The product solution was recovered and concentrated, then crystallized in an ethyl acetate / methyl tert-butyl ether = 1 vol:4 vol system. After stirring at 5-10°C for 1 hour, the mixture was centrifuged, and the centrifuged solid was vacuum-dried to obtain 2.57 kg of product C (yield: 44%). Purity >99%.

[0164] Finally, the above embodiments are for illustrating, and not limiting, the technical problems of the present invention. Although the present invention has been described in detail with reference to the best embodiments, those skilled in the art should understand that it is possible to modify or make equivalent substitutions to the technical problems of the present invention, none of which should depart from the spirit and scope of the technical problems of the present invention and should be included within the claims of the present invention.

Claims

1. A method for producing an adrenergic receptor agonist intermediate, characterized by comprising the following steps: To obtain compound C by cyclizing compound E1 or E2 with compound F0. Here, R 1 These are methyl, ethyl, isopropyl, propyl, tert-butyl, and butyl groups; R 3 These are H, Cl, F, and Br; L 1 , L 2 Each of these is a leaving group on its own.

2. In the method for producing an adrenergic receptor agonist intermediate according to claim 1, the compound of formula F0 represents the compound of formula F, Here, R 2 These are methyl, ethyl, isopropyl, propyl, tert-butyl, and butyl groups; R 3 These are H, Cl, F, and Br; X is F, Cl, Br.

3. In the method for producing an adrenergic receptor agonist intermediate according to claim 2, the compound of formula F0 is represented by the compound of formula F-1, Here, R 2 These are methyl, ethyl, isopropyl, propyl, tert-butyl, and butyl groups; R 3 H is; X is F, Cl, Br.

4. The method for producing an adrenergic receptor agonist intermediate according to claim 3 is further characterized in that the compound of formula F-1 comprises the following structure: X is F, Cl, Br.

5. In the method for producing an adrenergic receptor agonist intermediate according to claim 2, the compound of formula F0 is represented as the compound of formula F-2. R 2 is a methyl group, an ethyl group, an isopropyl group, a propyl group, a tert-butyl group, or a butyl group. R 3 These are Cl, F, and Br; X is F, Cl, Br.

6. The method for producing an adrenergic receptor agonist intermediate according to claim 5 is characterized in that the compound of formula F-2 comprises the following structure: Here, R 2 These are methyl, ethyl, isopropyl, propyl, tert-butyl, and butyl groups; X is F, Cl, Br.

7. The method for producing an adrenergic receptor agonist intermediate according to claim 6 is characterized in that the compound of formula F-2-1 comprises the following structure: X is F, Cl, Br.

8. The method for producing an adrenergic receptor agonist intermediate according to claim 6 is characterized in that the compound of formula F-2-2 comprises the following structure: X is F, Cl, Br.

9. The method for producing an adrenergic receptor agonist intermediate according to claim 6 is characterized in that the compound of formula F-2-3 comprises the following structure: X is F, Cl, Br.

10. In the method for producing an adrenergic receptor agonist intermediate according to claim 1, formula F is formula F 1 It is characterized by containing a compound. Here, R 4 , R 5 Each of these is one of the C1-C6 alkyl groups.

11. In the method for producing an adrenergic receptor agonist intermediate according to claim 10, formula F 1 R in compounds 4 and R 5 teeth 、 Each of these groups is characterized by being one of the following: a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, or a tert-butyl group.

12. In the method for producing an adrenergic receptor agonist intermediate according to claim 1, formula F is formula F 2 It is characterized by containing a compound. Here, R 4 , R 6 , R 7 Each of these is one of the C1-C6 alkyl groups.

13. In the method for producing an adrenergic receptor agonist intermediate according to claim 12, formula F 2 In compounds, R 4 , R 6 , R 7 Each of these is one of the following: methyl group, ethyl group, propyl group, butyl group, isopropyl group, or tert-butyl group.

14. A method for producing an adrenergic receptor agonist intermediate according to any one of claims 1 to 13, characterized in that a compound of formula E1 or a compound of formula E2 is reacted with a compound of formula F0 under alkaline reagent conditions.

15. The method for producing an adrenergic receptor agonist intermediate according to claim 14 is characterized in that the alkaline reagent includes an organic base or an inorganic base.

16. The method for producing an adrenergic receptor agonist intermediate according to claim 15 is characterized in that the organic base comprises any of triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine.

17. The method for producing an adrenergic receptor agonist intermediate according to claim 16 is characterized in that the alkaline reagent contains triethylamine or N,N-diisopropylethylamine.

18. The method for producing an adrenergic receptor agonist intermediate according to claim 17 is characterized in that the molar ratio of the compound of formula E1 or formula E2, the compound of formula F0, and the alkaline reagent is 1.0:(0.5-3.0):(0.5-5.0).

19. The method for producing an adrenergic receptor agonist intermediate according to claim 18 is characterized in that the molar ratio of the compound of formula E1 or formula E2, the compound of formula F0, and the alkaline reagent is 1.0:(1.0-1.5):(1.0-4.0).

20. In a method for producing an adrenergic receptor agonist intermediate according to claim 19, The molar ratio of compound E1, compound F-1, and alkaline reagent must be 1.0:(0.5–2.0):(0.5–2.0). The compound is characterized by having a molar ratio of formula E2 compound, formula F-1 compound, and alkaline reagent of 1.0:(0.5-2.0):(0.5-3.0).

21. In the method for producing an adrenergic receptor agonist intermediate according to claim 20, The molar ratio of compound E1, compound F-1, and alkaline reagent must be 1.0:(1.0–1.5):(1.0–1.5); The present invention is characterized by a molar ratio of compound E2, compound F-1, and alkaline reagent of 1.0:(1.0-1.5):(1.5-2.0).

22. In the method for producing an adrenergic receptor agonist intermediate according to claim 21, The molar ratio of compound E1, compound F-2, and alkaline reagent must be 1.0:(0.5–2.0):(1.5–4.0); The present invention is characterized by a molar ratio of compound E2, compound F-2, and alkaline reagent of 1.0:(0.5-2.0):(0.5-5.0).

23. In the method for producing an adrenergic receptor agonist intermediate according to claim 22, The molar ratio of compound E1, compound F-2, and alkaline reagent must be 1.0:(1.0–1.5):(2.0–3.0); The present invention is characterized in that the molar ratio of compound E2, compound F-2, and alkaline reagent is further 1.0:(1.0-1.5):(2.5-4.0).

24. In the method for producing an adrenergic receptor agonist intermediate according to claim 23, The molar ratio of compound E1, compound F1, and alkaline reagent must be 1.0:(0.5–2.0):(0.5–2.0); The molar ratio of compound E2, compound F1, and alkaline reagent must be 1.0:(0.5–2.0):(0.5–3.0); The molar ratio of compound E1, compound F2, and alkaline reagent must be 1.0:(0.5–2.0):(0.5–2.0); The compound is characterized by having a molar ratio of formula E2 compound, formula F2 compound, and alkaline reagent of 1.0:(0.5-2.0):(0.5-3.0).

25. In the method for producing an adrenergic receptor agonist intermediate according to claim 24, The molar ratio of compound E1, compound F1, and alkaline reagent must be 1.0:(1.0–1.5):(1.0–1.5); The molar ratio of compound E2, compound F1, and alkaline reagent must be 1.0:(1.0–1.5):(1.5–2.0); The molar ratio of compound E1, compound F2, and alkaline reagent must be 1.0:(1.0–1.5):(1.0–1.5); The present invention is characterized by a molar ratio of compound E2, compound F2, and alkaline reagent of 1.0:(1.0-1.5):(1.5-2.0).

26. The method for producing an adrenergic receptor agonist intermediate according to claim 25 is characterized in that the reaction temperature range is 25 to 120°C.

27. The method for producing an adrenergic receptor agonist intermediate according to claim 26 is characterized in that the reaction temperature range is 50 to 110°C.

28. The method for producing an adrenergic receptor agonist intermediate according to claim 27 is characterized in that the organic solvent comprises ethyl acetate, isopropyl acetate, toluene, and acetonitrile.

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