Preparation method of adrenergic receptor agonist intermediate

Abstract

A preparation method of an adrenergic receptor agonist intermediate comprises the following steps: cyclizing a compound of formula E1 or a compound of formula E2 and a compound of formula F0 to obtain a compound of formula C, in which R1 is methyl, ethyl, isopropyl, propyl, tertiary butyl or butyl; r3 is H, Cl, F or Br; and L1 and L2 are independently leaving groups. According to the method, raw materials are easy to obtain, toxic and harmful reagents are avoided, the reaction condition is mild, the operation is simple, the yield is greatly improved, the cost is reduced, and commercial production is more facilitated.

Description

A method for preparing an adrenergic receptor agonist intermediate Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a method for preparing an adrenergic receptor agonist intermediate. Background Art

[0002] Vibergron is a selective human beta-3 adrenergic receptor agonist. Activation of the beta-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling, allowing the bladder to hold more urine and thereby alleviating overactive bladder (OAB) in adults.

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

[0004] Currently, the only reported synthesis of this intermediate found is the original synthesis route disclosed in patent WO2013062881. RM1 is reacted with dimethyl sulfate to produce compound A; RM2 reacts with chlorosulfonic acid isocyanate to produce compound B. Compounds A and B are then reacted at 128°C for 48 hours in ethylbenzene to yield the target compound C. The reaction formula is as follows:

[0005] The main disadvantages of this process are: 1. RM2 is expensive, which keeps product costs high; 2. Chlorosulfonic acid isocyanate is highly corrosive, posing a high safety risk in production operations; 3. The reaction between A and B to produce C not only decomposes and produces cyclopentadiene as a byproduct, which is environmentally and operator-unfriendly, but also, due to the high reaction temperature, inevitably undergoes polymerization, generating a large amount of tar-like polymer that adheres to the stirring paddle, increasing stirring resistance and hindering scale-up production while also complicating separation and purification. 4. Post-reaction treatment in step C requires column chromatography purification, making it unsuitable for commercial production and resulting in low yields.

[0006] Summary of the Invention

[0007] In response to the shortcomings of the prior art, the present invention provides a method for preparing an adrenergic receptor agonist intermediate. This method makes raw materials easily available, avoids the use of toxic and hazardous reagents, has mild reaction conditions, is simple to operate, greatly improves yield, reduces costs, and is more conducive to commercial production.

[0008] To achieve the above object, the present invention adopts the following technical solutions:

[0009] A method for preparing an adrenergic receptor agonist intermediate comprises the following steps:

[0010] The compound of formula E1 or the compound of formula E2 is cyclized with the compound of formula F0 to obtain a compound of formula C,

[0011] Wherein R1 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0012] R3 is H, Cl, F, Br;

[0013] L1 and L2 are independently leaving groups.

[0014] Further, the compound of formula F0 includes the compound of formula F shown as:

[0015] Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0016] R3 is H, Cl, F, Br;

[0017] X is F, Cl, or Br.

[0018] Further, the compound of formula FO is shown as the compound of formula F-1:

[0019] Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0020] R3 is H;

[0021] X is F, Cl, or Br;

[0022] Further, the compound of formula F-1 includes the following structure:

[0023] X is F, Cl, or Br.

[0024] Further, the compound of formula FO is shown as the compound of formula F-2:

[0025] Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0026] R3 is Cl, F, or Br;

[0027] X is F, Cl, or Br;

[0028] Further, the compound of formula F-2 includes the following structure:

[0029] Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0030] X is F, Cl, or Br;

[0031] Further, the compound of formula F-2-1 includes the following structure:

[0032] X is F, Cl, or Br;

[0033] Further, the compound of formula F-2-2 includes the following structure:

[0034] X is F, Cl, or Br;

[0035] Furthermore, the F-2-3 compound includes the following structure:

[0036] X is F, Cl, or Br.

[0037] Further, Formula F includes compounds of Formula F1:

[0038] Wherein, R4 and R5 are respectively one of C1-C6 alkyl groups.

[0039] Furthermore, R4 and R5 in the compound of formula F1 are each one of methyl, ethyl, propyl, butyl, isopropyl and tert-butyl.

[0040] Further, Formula F includes compounds of Formula F2:

[0041] Wherein, R4, R6, and R7 are each one of C1-C6 alkyl groups.

[0042] Furthermore, in the compound of formula F2, R4, R6, and R7 are each one of methyl, ethyl, propyl, butyl, isopropyl, and tert-butyl.

[0043] Further, the compound of formula E1 or the compound of formula E2 reacts with the compound of formula F0 under alkaline reagent conditions,

[0044] Furthermore, the alkaline agent includes an organic base or an inorganic base,

[0045] Furthermore, the organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine or 4-dimethylaminopyridine,

[0046] Furthermore, the alkaline agent includes triethylamine or N,N-diisopropylethylamine.

[0047] The molar ratio of the compound of formula E1 or E2, the compound of formula F0, and the alkaline agent is 1.0:(0.5-3.0):(0.5-5.0), further 1.0:(1.0-1.5):(1.0-3.0);

[0048] Furthermore, the molar ratio of the compound of formula E1, the compound of formula F-1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), and further 1.0:(1.0-1.5):(1.0-1.5).

[0049] Furthermore, the molar ratio of the compound of formula E1, the compound of formula F-2, and the alkaline agent is 1.0:(0.5-2.0):(1.5-4.0), and further 1.0:(1.0-1.5):(1.5-3.0).

[0050] Further, the molar ratio of the compound of formula E1, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-1.5);

[0051] The molar ratio of the compound of formula E2, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0), further 1.0:(1.0-1.5):(1.5-2.0);

[0052] The molar ratio of the compound of formula E1, the compound of formula F2, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-1.5);

[0053] The molar ratio of the compound of formula E2, the compound of formula F2, and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0), further 1.0:(1.0-1.5):(1.5-2.0).

[0054] Furthermore, the reaction temperature range is 25 to 120°C, and further 50 to 110°C.

[0055] Furthermore, the organic solvent includes one of ethyl acetate, isopropyl acetate, toluene and acetonitrile.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] The process line adopted by the present invention directly has mild reaction conditions and simple operation, which is conducive to scale-up and commercial production. The materials used are highly safe and do not produce by-products that are unfriendly to the environment and human body, meeting the development requirements of green environmental protection.

[0058] The raw materials used in the circuit of the present invention are cheap and easily available, the product cost is low, and there is an obvious price competitive advantage.

[0059] The yield of the product prepared by the circuit of the present invention is higher than that of the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 is a high performance liquid chromatogram of Example 1;

[0061] Figure 2 is a high performance liquid chromatogram of chiral purity of Example 1;

[0062] Figure 3 shows the hydrogen spectrum of Example 1. DETAILED DESCRIPTION

[0063] The present invention is further described in detail below, and specific implementation methods are given.

[0064] In some embodiments, the compound of formula E1 or E2 reacts with a compound of formula F0, as shown in Formula 1:

[0065] The reaction conditions include reacting in an alkaline environment, including an alkaline reagent, including an organic base or an inorganic base. The inorganic base includes one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some embodiments, the alkaline reagent includes triethylamine or N,N-diisopropylethylamine.

[0066] The molar ratio of the compound of formula E1 or E2, the compound of formula F0, and the alkaline agent is 1.0:(0.5-3.0):(0.5-5.0), further 1.0:(1.0-1.5):(1.0-4.0).

[0067] The solvent for the reaction includes ethyl acetate, isopropyl acetate, toluene, acetonitrile, preferably ethyl acetate or toluene.

[0068] The reaction temperature is 25 to 120°C, and further 50 to 110°C, and further 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.

[0069] The compounds of formula E1 include the following structures:

[0070] The compounds of formula E2 include the following structures:

[0071] Compound of formula F0 React with the compound of formula E1 or E2, and cyclize to obtain the compound of formula C. The compound of formula F0 is a saturated or unsaturated carbon chain, and the three carbon atoms on the carbon chain cyclize with the compound of formula E1 or E2 to form a dihydropyrrolopyrimidine ring derivative.

[0072] In some embodiments, F0 is substituted 2-butanone;

[0073] R0 is 3 halogens, including F, Cl, and Br.

[0074] In some embodiments, F0 is a substituted 1,1,1-trihalogen-2-butanone,

[0075] In some embodiments, F0 is 4-oxoalkyl 4-substituted-1,1,1-trihalogen-2-butanone,

[0076] L1 and L2 are leaving groups, where L1 is an oxyalkyl group L2 is 1,1,1-trihalomethyl. In some embodiments, the compound of formula F includes compounds of formula F-1:

[0077] R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, or butyl;

[0078] R3 is H;

[0079] X is F, Cl, or Br.

[0080] Further, the compound of formula F-1 includes the following structure:

[0081] In some embodiments, the compound of formula F includes compounds of formula F-2:

[0082] Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0083] R3 is Cl, F, or Br;

[0084] X is F, Cl, or Br;

[0085] Further, the compound of formula F-2 includes the following structure:

[0086] Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl;

[0087] X is F, Cl, or Br;

[0088] Further, the compound of formula F-2-1 includes the following structure:

[0089] X is F, Cl, or Br;

[0090] Further, the compound of formula F-2-2 includes the following structure:

[0091] X is F, Cl, or Br;

[0092] Furthermore, the F-2-3 compound includes the following structure:

[0093] In certain embodiments, R3 of the compound of formula F0 is H, which is further substituted with acrylate.

[0094] When L1 and L2 are leaving groups, where L1 is an oxyalkyl group L2 is

[0095] Further, Formula F includes compounds of Formula F1:

[0096] Wherein, R4 and R5 are respectively one of C1-C6 alkyl groups.

[0097] Furthermore, R4 and R5 in the compound of formula F1 are each one of methyl, ethyl, propyl, butyl, isopropyl and tert-butyl.

[0098] Furthermore, the specific structure of the F1 compound is as follows:

[0099] When R3 of the compound of formula F0 is H, it is further substituted by acrylate.

[0100] L1 and L2 are leaving groups, where L1 is an oxyalkyl group L2 is Formula F includes compounds of formula F2:

[0101] Wherein, R4, R6, and R7 are each one of C1-C6 alkyl groups.

[0102] Furthermore, in the compound of formula F2, R4, R6, and R7 are each one of methyl, ethyl, propyl, butyl, isopropyl, and tert-butyl.

[0103] When R4 of the compound of formula F2 is one of methyl, ethyl, propyl, butyl, isopropyl and tert-butyl, R6 and R7 are respectively one of methyl, ethyl, propyl, butyl, isopropyl and tert-butyl.

[0104] The structure of F2 is preferably the following:

[0105] The compound of formula E1 or E2 reacts with the compound of formula F-1, as shown in Formula 2:

[0106] In some embodiments R3 is H.

[0107] The reaction conditions shown in Formula 2 include reacting in an alkaline environment, including an alkaline reagent, including an organic base or an inorganic base. The inorganic base includes one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some embodiments, the alkaline reagent includes triethylamine and N,N-diisopropylethylamine.

[0108] The molar ratio of the compound of formula E1 or E2, the compound of formula F-1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-2.0).

[0109] The molar ratio of the compound of formula E1, the compound of formula F-1, and the alkaline reagent is 1.0:(0.5~2.0):(0.5~2.0), further 1.0:(1.0~1.5):(1.0~1.5), and further: 1.0:1.0:1.0, 1.0:1.5:1.0, 1.0:1.0:2.0, 1.0:1.5:2.0, 1.0:1.2:1.5.

[0110] The molar ratio of the compound of formula E2, the compound of formula F-1, and the alkaline reagent is 1.0:(0.5~2.0):(0.5~3.0), further 1.0:(1.0~1.5):(1.5~2.0), and further: 1.0:1.0:1.0, 1.0:1.5:1.0, 1.0:1.0:2.0, 1.0:1.5:2.0, 1.0:1.2:1.5.

[0111] The solvent for the reaction includes ethyl acetate, isopropyl acetate, toluene, acetonitrile, preferably ethyl acetate or toluene.

[0112] The reaction temperature is 25 to 120°C, and further 50 to 110°C, and further 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.

[0113] The compound of formula E1 or E2 reacts with the compound of formula F-2, as shown in Formula 3:

[0114] In some embodiments R3 is F, Cl, or Br.

[0115] The reaction conditions shown in Formula 3 include reacting in an alkaline environment, including an alkaline reagent, including an organic base or an inorganic base. The inorganic base includes one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some embodiments, the alkaline reagent includes triethylamine or N,N-diisopropylethylamine.

[0116] The molar ratio of the compound of formula E1 or E2, the compound of formula F-2, and the alkaline agent is 1.0:(0.5-2.0):(1.5-5.0), further 1.0:(1.0-1.5):(1.5-4.0).

[0117] The molar ratio of the compound of formula E1, the compound of formula F-2, and the alkaline agent is 1.0:(0.5-2.0):(1.5-4.0), further 1.0:(1.0-1.5):(2.0-3.0), further 1.0:1.0:2.0, 1.0:1.0:3.0, 1.0:1.5:2.0, 1.0:1.0:2.5, 1.0:1.5:2.0;

[0118] The molar ratio of the compound of formula E2, the compound of formula F-2, and the alkaline reagent is 1.0:(0.5~2.0):(0.5~5.0), further 1.0:(1.0~1.5):(2.5~4.0), further 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, 1.0:1.5:4.0.

[0119] The solvent for the reaction includes ethyl acetate, isopropyl acetate, toluene, acetonitrile, preferably ethyl acetate or toluene.

[0120] The reaction temperature is 25 to 120°C, and further 50 to 110°C, and further 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.

[0121] The compound of formula E1 or E2 reacts with the compound of formula F1, as shown in formula 4:

[0122] The reaction conditions shown in Formula 4 include reacting in an alkaline environment, including an alkaline reagent, including an organic base or an inorganic base. The inorganic base includes one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some embodiments, the alkaline reagent includes triethylamine and N,N-diisopropylethylamine.

[0123] The molar ratio of the compound of formula E1 or E2, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-2.0).

[0124] The molar ratio of the compound of formula E1, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-1.5);

[0125] The molar ratio of the compound of formula E2, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0), further 1.0:(1.0-1.5):(1.5-2.0);

[0126] The solvent for the reaction includes ethyl acetate, isopropyl acetate, toluene, acetonitrile, preferably ethyl acetate or toluene.

[0127] The reaction temperature is 25 to 120°C, and further 50 to 110°C, and further 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.

[0128] The compound of formula E1 or E2 reacts with the compound of formula F2, as shown in Formula 5:

[0129] The reaction conditions shown in Formula 5 include reacting in an alkaline environment, including an alkaline reagent, including an organic base or an inorganic base. The inorganic base includes one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. The organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine, or 4-dimethylaminopyridine. In some embodiments, the alkaline reagent includes one of triethylamine and N,N-diisopropylethylamine.

[0130] The molar ratio of the compound of formula E1 or E2, the compound of formula F2, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-2.0).

[0131] The molar ratio of the compound of formula E1, the compound of formula F2, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), further 1.0:(1.0-1.5):(1.0-1.5);

[0132] The molar ratio of the compound of formula E2, the compound of formula F2, and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0), further 1.0:(1.0-1.5):(1.5-2.0).

[0133] The solvent for the reaction includes ethyl acetate, isopropyl acetate, toluene, acetonitrile, preferably ethyl acetate or toluene.

[0134] The reaction temperature is 25 to 120°C, and further 50 to 110°C, and further 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.

[0135] Example 1

[0136] Compound E1 (99.9 mmol), isopropyl acetate, compound F-1 (100.2 mmol, 1,1,1-trichloro-4-ethoxy-3-en-2-one), and triethylamine (100.8 mmol) were added sequentially to a reaction flask. The reaction was heated to approximately 90°C and allowed to react. After completion, the temperature was cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with isopropyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to yield 13.2 g of compound C, with a yield of 68.1%. The purity was 98.1% (see Figure 1), and the chiral purity was 99.8% (see Figure 2).

[0137] 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 = 9.8 4Hz, 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)

[0138] Example 2

[0139] Compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester 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 added sequentially to a reaction flask. The reaction was heated to 110°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 7.8 g of compound C (71.7% yield). Purity: 98.8%; chiral purity: 99.6%.

[0140] Example 3

[0141] At room temperature, 10.0 g (56.0 mmol) of compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester 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 added sequentially to a reaction flask. The reaction was heated to 50°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 8.0 g of compound C, with a yield of 73.6%. Purity: 99.2%; chiral purity: 99.7%.

[0142] Example 4

[0143] Under inert gas, 34 mL (0.3 mol) of trichloroacetyl chloride and 58 mL (0.6 mol) of ethyl vinyl ether were added sequentially to a reaction flask. The mixture was stirred at room temperature for 24 hours and then concentrated under reduced pressure to remove unreacted trichloroacetyl chloride and ethyl vinyl ether. The resulting residue was compound F-2-2-2 (X is Cl). Toluene was added to the reaction flask and stirred to dissolve the resulting toluene solution of F-2-2-2 (X is Cl). Compound E1 [methyl (S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate] (71 g (0.50 mol)] was then added, followed by the dropwise addition of 132 g (1.2 mol) of triethylamine. The reaction was heated to 60°C for reaction. After completion, the mixture was cooled to room temperature. Water was added to quench the reaction, the phases separated, and the aqueous phase was extracted with toluene. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to yield 58.7 g of compound C (60.5% yield). Purity: 97.2%; Chiral purity: 99.0%.

[0144] Example 5

[0145] Compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride] 18.0 g (101.1 mmol), toluene, compound G-1 (methyl 3-methoxyacrylate) 15.2 g (130.9 mmol), and triethylamine 17.3 g (171.0 mmol) were added sequentially to a reaction flask. The reaction was heated to 90°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 12.3 g of compound C (62.9% yield). Purity: 98.7%; chiral purity: 99.1%.

[0146] Example 6

[0147] At room temperature, 15.0 g (84.0 mmol) of compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride], ethyl acetate, 18.0 g (125.7 mmol) of compound G-2 (ethyl N,N-dimethylaminoacrylate), and 15.3 g (151.2 mmol) of triethylamine were added sequentially to a reaction flask. The reaction was heated to 80°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and oven-dried to obtain 7.5 g of compound C, with a yield of 46.0%. Purity: 97.6%; chiral purity: 99.3%.

[0148] Example 7

[0149] Compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester 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 added sequentially to a reaction flask. The reaction was heated to 110°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 7.5 g of compound C (70.8% yield). Purity: 97.9%; chiral purity: 99.7%.

[0150] Example 8

[0151] Compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride] 10.0 g (56.0 mmol), toluene, compound F-1 (1,1,1-trifluoro-4-propoxy-3-en-2-one) 14.3 g (78.6 mmol), and triethylamine 10.8 g (106.7 mmol) were added sequentially to a reaction flask. The reaction was heated to 90°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 7.5 g of compound C (70.6% yield). Purity: 97.5%; chiral purity: 99.5%.

[0152] Example 9

[0153] Compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride] 10.0 g (56.0 mmol), toluene, compound F-1 (1,1,1-tribromo-4-isopropoxy-but-3-en-2-one) 26.4 g (73.0 mmol), and triethylamine 10.2 g (101.1 mmol) were added sequentially to a reaction flask. The reaction was heated to 80°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 7.2 g of compound C (68.9% yield). Purity: 95.7%; chiral purity: 99.4%.

[0154] Example 10

[0155] Under inert gas, toluene was added to a reaction flask, along with 310.1 g (0.75 mol) of 1,1,1,4-tetrabromo-4-methoxybutan-2-one, 71 g (0.50 mol) of compound E1 [methyl (S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate], and 151.7 g (1.5 mol) of triethylamine. The reaction was heated to 70°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers separated, and the aqueous phase was extracted with toluene. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and oven-dried to yield 54.4 g of compound C, a 58.3% yield. Purity: 96.2%; chiral purity: 97.5%.

[0156] Example 11

[0157] Compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride] 10.0 g (56.1 mmol), toluene, compound G-1 (ethyl 3-methoxyacrylate) 12.1 g (84.2 mmol), and triethylamine 11.4 g (112.3 mmol) were added sequentially to a reaction flask. The reaction was heated to 50°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 6.98 g of compound C (65.3% yield). Purity: 98.1%; chiral purity: 99.2%.

[0158] Example 12

[0159] Compound E1 (methyl (S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylate) (71 g (0.5 mol), toluene, compound G-1 (isopropyl 3-ethoxyacrylate) (119 g (0.75 mol), and triethylamine (76 g (0.75 mol)) were added sequentially to a reaction flask. The reaction was heated to 90°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, recrystallized, filtered, and dried to yield 49.7 g of compound C (52.3% yield). Purity: 97.9%; chiral purity: 98.9%.

[0160] Example 13

[0161] At room temperature, 10.0 g (56.1 mmol) of compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride], ethyl acetate, 10.9 g (84.2 mmol) of compound G-2 (methyl N,N-dimethylaminoacrylate), and 8.52 g (84.2 mmol) of triethylamine were added sequentially to a reaction flask. The reaction was heated to 80°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 6.8 g of the product in a 63.4% yield. Purity: 98.2%; chiral purity: 99.3%.

[0162] Example 14

[0163] At room temperature, 10.0 g (56.1 mmol) of compound E2 [(S)-5-amino-3,4-dihydro-2H-pyrrole-2-carboxylic acid methyl ester hydrochloride], ethyl acetate, 9.61 g (56.1 mmol) of compound G-2 (ethyl 3-(diethylamino)acrylate), and 11.4 g (112.3 mmol) of triethylamine were added sequentially to a reaction flask. The reaction was heated to 90°C and, after completion, cooled to room temperature. Water was added to quench the reaction, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was collected. The filtrate was concentrated, recrystallized, filtered, and dried to obtain 5.62 g of compound C, with a yield of 52.4%. Purity: 98.5%; chiral purity: 99.0%.

[0164] Comparative Example 1 (WO2013062881E1):

[0165] In a 50-L reactor, 6.60 kg (72.3 wt%) of compound A, 4.19 kg of compound B, and 9.54 L of ethylbenzene were added and stirred at 128°C for 48 hours. The temperature was then lowered to 35°C, and 14.3 L of toluene and 1.43 kg of activated carbon were added. The mixture was then stirred at 35°C for 1 hour. The mixture was filtered, and the filter cake was rinsed with 19.1 L of toluene. The combined filtrates were concentrated. Purification was then performed by column chromatography using 22.5 kg of silica gel and an acetone / heptane mixture as the eluent. The product solution was collected, concentrated, and crystallized using a 1:4 ratio of ethyl acetate to methyl tert-butyl ether. After stirring at 5-10°C for 1 hour, the mixture was centrifuged and the solid was vacuum-dried to yield 2.57 kg of product C. Yield: 44%; purity >99%.

[0166] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing an adrenergic receptor agonist intermediate, characterized in that: The following steps are involved: The compound of formula E1 or the compound of formula E2 is cyclized with the compound of formula F0 to obtain a compound of formula C, Wherein R1 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl; R3 is H, Cl, F, Br; L1 and L2 are independently leaving groups.

2. The method for preparing an adrenergic receptor agonist intermediate according to claim 1, characterized in that: The compounds of formula F0 include compounds of formula F as shown: Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl; R3 is H, Cl, F, Br; X is F, Cl, or Br.

3. The method for preparing an adrenergic receptor agonist intermediate according to claim 2, characterized in that: The compound of formula FO is shown as the compound of formula F-1: Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl; R3 is H; X is F, Cl, or Br.

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

5. The method for preparing an adrenergic receptor agonist intermediate according to claim 2, characterized in that: The compound of formula F0 is shown in the compound of formula F-2: Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl; R3 is Cl, F, Br; X is F, Cl, or Br.

6. The method for preparing an adrenergic receptor agonist intermediate according to claim 5, characterized in that: The compound of formula F-2 includes the following structure: Wherein R2 is methyl, ethyl, isopropyl, propyl, tert-butyl, butyl; X is F, Cl, Br; 7. The method for preparing an adrenergic receptor agonist intermediate according to claim 6, characterized in that: The compound of formula F-2-1 includes the following structure: X is F, Cl, Br; 8. The method for preparing an adrenergic receptor agonist intermediate according to claim 6, characterized in that: The compound of formula F-2-2 includes the following structure: X is F, Cl, Br; 9. The method for preparing an adrenergic receptor agonist intermediate according to claim 6, characterized in that: The compound of formula F-2-3 includes the following structure: X is F, Cl, or Br.

10. The method for preparing an adrenergic receptor agonist intermediate according to claim 1, characterized in that: Formula F includes compounds of formula F1: Wherein, R4 and R5 are respectively one of C1-C6 alkyl groups.

11. The method for preparing an adrenergic receptor agonist intermediate according to claim 10, characterized in that: R4 and R5 in the compound of formula F1 are respectively one of methyl, ethyl, propyl, butyl, isopropyl and tert-butyl.

12. The method for preparing an adrenergic receptor agonist intermediate according to claim 1, characterized in that: Formula F includes compounds of formula F2: Wherein, R4, R6, and R7 are each one of C1-C6 alkyl groups.

13. The method for preparing an adrenergic receptor agonist intermediate according to claim 12, characterized in that: In the compound of formula F2, R4, R6, and R7 are respectively one of methyl, ethyl, propyl, butyl, isopropyl, and tert-butyl.

14. The method for preparing an adrenergic receptor agonist intermediate according to any one of claims 1 to 13, characterized in that: The compound of formula E1 or E2 reacts with the compound of formula F0 under alkaline reagent conditions.

15. The method for preparing an adrenergic receptor agonist intermediate according to claim 14, characterized in that: The alkaline agent includes an organic base or an inorganic base.

16. The method for preparing an adrenergic receptor agonist intermediate according to claim 15, characterized in that: The organic base includes one of triethylamine, pyridine, N,N-diisopropylethylamine or 4-dimethylaminopyridine.

17. The method for preparing an adrenergic receptor agonist intermediate according to claim 16, characterized in that: The alkaline reagent includes triethylamine or N,N-diisopropylethylamine.

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

19. The method for preparing an adrenergic receptor agonist intermediate according to claim 18, characterized in that: The molar ratio of the compound of formula E1 or E2, the compound of formula F0, and the alkaline agent is 1.0:(1.0-1.5):(1.0-4.0); 20. The method for preparing an adrenergic receptor agonist intermediate according to claim 19, characterized in that: The molar ratio of the compound of formula E1, the compound of formula F-1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0), The molar ratio of the compound of formula E2, the compound of formula F-1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0).

21. The method for preparing an adrenergic receptor agonist intermediate according to claim 20, characterized in that: The molar ratio of the compound of formula E1, the compound of formula F-1, and the alkaline agent is 1.0:(1.0-1.5):(1.0-1.5); The molar ratio of the compound of formula E2, the compound of formula F-1, and the alkaline agent is 1.0:(1.0-1.5):(1.5-2.0).

22. The method for preparing an adrenergic receptor agonist intermediate according to claim 21, characterized in that: The molar ratio of the compound of formula E1, the compound of formula F-2, and the alkaline agent is 1.0:(0.5-2.0):(1.5-4.0); The molar ratio of the compound of formula E2, the compound of formula F-2 and the alkaline agent is 1.0:(0.5-2.0):(0.5-5.0).

23. The method for preparing an adrenergic receptor agonist intermediate according to claim 22, characterized in that: The molar ratio of the compound of formula E1, the compound of formula F-2, and the alkaline agent is 1.0:(1.0-1.5):(2.0-3.0); The molar ratio of the compound of formula E2, the compound of formula F-2, and the alkaline agent is further 1.0:(1.0 to 1.5):(2.5 to 4.0).

24. The method for preparing an adrenergic receptor agonist intermediate according to claim 23, characterized in that: The molar ratio of the compound of formula E1, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0); The molar ratio of the compound of formula E2, the compound of formula F1, and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0); The molar ratio of the compound of formula E1, the compound of formula F2, and the alkaline agent is 1.0:(0.5-2.0):(0.5-2.0); The molar ratio of the compound of formula E2, the compound of formula F2 and the alkaline agent is 1.0:(0.5-2.0):(0.5-3.0).

25. The method for preparing an adrenergic receptor agonist intermediate according to claim 24, characterized in that: The molar ratio of the compound of formula E1, the compound of formula F1, and the alkaline agent is 1.0:(1.0-1.5):(1.0-1.5); The molar ratio of the compound of formula E2, the compound of formula F1, and the alkaline agent is 1.0:(1.0-1.5):(1.5-2.0); The molar ratio of the compound of formula E1, the compound of formula F2, and the alkaline agent is 1.0:(1.0-1.5):(1.0-1.5); The molar ratio of the compound of formula E2, the compound of formula F2 and the alkaline agent is 1.0:(1.0-1.5):(1.5-2.0).

26. The method for preparing an adrenergic receptor agonist intermediate according to claim 25, characterized in that: The reaction temperature range is 25~120℃.

27. The method for preparing an adrenergic receptor agonist intermediate according to claim 26, characterized in that the reaction temperature ranges from 50 to 110°C.

28. The method for preparing an adrenergic receptor agonist intermediate according to claim 27, characterized in that: The organic solvent includes one of ethyl acetate, isopropyl acetate, toluene and acetonitrile.

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