Ogleron raw material intermediate and synthesis method and Ogleron raw material synthesis method

Abstract

The present invention provides an oglerone raw material intermediate and a synthesis method, and a method for synthesizing an oglerone raw material, relating to the technical field of pharmaceutical synthesis. The synthesis method provided by the present invention does not require the use of complex catalytic systems and expensive and hazardous reagents. The synthesis route is rational and safe, the reaction raw materials used are inexpensive and readily available, the atom economy is high, the reaction conditions are mild, the byproducts are controllable, and the reaction is environmentally friendly. It does not require the use of complex mechanical equipment and expensive catalysts. It can efficiently synthesize the oglerone raw material intermediate (methyl 5-bromo-2-indolecarboxylate) and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to an oglerone raw material intermediate and a synthesis method thereof, and an oglerone raw material synthesis method. Background Art

[0002] Orforglipron (CAS: 2212020-52-3) is a glucagon-1 receptor agonist that mimics intestinal hormones, stimulating insulin secretion and inhibiting glucagon release, thereby effectively lowering blood sugar levels. It also acts on receptors in the brain to reduce hunger, suppress appetite, and slow the passage of food through the digestive tract and its digestion and absorption capacity. Patent publication number CN109790161A provides a pyrazolopyridine derivative with GLO-1 receptor agonist activity and specifically provides a synthetic route for orforglipron, using methyl 5-bromo-2-indolecarboxylate (CAS: 16732-70-0) as a raw material to synthesize orforglipron through a multi-step reaction:

[0003] .

[0004] Among them, 5-bromo-2-indolecarboxylic acid methyl ester is a key raw material for the synthesis of oglerone and is also an important pharmaceutical and pesticide intermediate. The prior art provides a method for synthesizing 5-bromo-2-indolecarboxylic acid methyl ester by condensing ethyl azidoacetate and m-bromobenzaldehyde, followed by heating and ring closing under the action of rhodium catalyst. The synthetic route is:

[0005] ;

[0006] Also provided is a method for synthesizing methyl 5-bromo-2-indolecarboxylate by diazotization using 4-bromoaniline as a raw material to generate phenylhydrazine hydrochloride, which is then subjected to an aldehyde-amine condensation reaction with ethyl pyruvate to generate a hydrazone, and then subjected to an intramolecular Borsche-Drechsel cyclization reaction. The synthetic route is:

[0007] .

[0008] However, the high price of azide and rhodium catalysts and the poor stability of azide during the reaction process pose a major safety hazard, making it difficult to carry out large-scale industrial production. The diazotization reaction requires the use of sodium nitrite, which is genotoxic and carcinogenic, and is prone to introducing high-risk impurities such as nitrosamines. They are prone to decomposition and even explosion under high temperature, light or mechanical impact, posing a huge threat to production safety. In addition, the Borsche-Drechsel cyclization reaction relies on a large amount of polyphosphoric acid as a catalyst, resulting in extremely high viscosity of the reaction system, increased side reactions and cumbersome post-processing. Production efficiency and reaction purity are difficult to meet expectations. Therefore, there is an urgent need to provide a solution to improve the above problems. Summary of the Invention

[0009] The purpose of the present invention is to provide an oglerone raw material intermediate and a synthesis method and an oglerone raw material synthesis method. The synthesis route is reasonable, the raw materials are cheap and easily available, the atom economy is high and it is environmentally friendly. It does not require the use of complex mechanical equipment and expensive catalysts, and can efficiently synthesize the oglerone raw material intermediate (5-bromo-2-indolecarboxylic acid methyl ester), which is suitable for industrial large-scale production.

[0010] In the first aspect, the present invention provides an oglerone raw material intermediate and tautomers as shown in Formula I:

[0011] .

[0012] In a second aspect, the present invention also provides a method for synthesizing an oglerone raw material intermediate, comprising: condensing ethyl 3-bromopyruvate and 4-bromoaniline in a first solvent under the action of a water scavenger to produce an intermediate shown in formula I;

[0013] .

[0014] Optionally, the dehydrating agent includes at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride.

[0015] Optionally, the molar ratio of the water scavenger to the ethyl 3-bromopyruvate is (3-6):1.

[0016] Optionally, the first solvent includes one of toluene, xylene, ethyl acetate, dichloromethane, chloroform, and 1,2-dichloroethane.

[0017] Optionally, the molar ratio of the ethyl 3-bromopyruvate to the 4-bromoaniline is (0.5-1.5):1.

[0018] Alternatively, the condensation reaction is carried out at 25°C-40°C.

[0019] Optionally, the condensation reaction is carried out for 6 h to 8 h.

[0020] In a third aspect, the present invention further provides a method for synthesizing an oglerone raw material, comprising: subjecting an intermediate represented by formula I to a Friedel-Crafts reaction in a second solvent under the catalysis of a Lewis acid to produce an oglerone raw material represented by formula II;

[0021] .

[0022] Optionally, the second solvent includes one of dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, toluene, and nitrobenzene;

[0023] Optionally, the Lewis acid includes aluminum trichloride, titanium tetrachloride, zinc chloride, ferric chloride, tin tetrachloride and indium trichloride.

[0024] Optionally, the Friedel-Crafts reaction is carried out at -10°C to 25°C.

[0025] Optionally, the Friedel-Crafts reaction is carried out for 6 h to 10 h.

[0026] Optionally, the molar ratio of the Lewis acid to the intermediate represented by formula I is (1-2.5):1. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The structural formula of an oglerone raw material intermediate provided by the present invention;

[0028] Figure 2 This is the H NMR spectrum of ethyl 3-bromopyruvate obtained in Preparation Example 1 of the present invention;

[0029] Figure 3 This is the H-NMR spectrum of the raw material intermediate of oglerone prepared in Example 1 of the present invention;

[0030] Figure 4 This is the H NMR spectrum of the oglerone raw material prepared in Application Example 1 of the present invention. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs.

[0032] See also Figure 1 The present invention provides a raw material intermediate of oglerone, the structure of which is shown in Formula I:

[0033] .

[0034] In fact, the intermediate represented by formula I is named by the systematic nomenclature: ethyl (Z)-3-bromo-2-((4-bromophenyl)amino)acrylate.

[0035] Specifically, the present invention also provides a method for synthesizing an oglerone raw material intermediate, comprising condensing ethyl 3-bromopyruvate and 4-bromoaniline in a first solvent in the presence of a dehydrating agent to produce the intermediate represented by Formula I. The dehydrating agent absorbs the water produced during the synthesis process, thereby promoting the forward reaction and improving the yield of the intermediate represented by Formula I.

[0036] Specifically, the reaction formula of the synthesis method provided by the present invention is:

[0037] .

[0038] In some embodiments, the ethyl 3-bromopyruvate and 4-bromoaniline used in the synthesis process can be commercially available conventional products, for example, the CAS number of ethyl 3-bromopyruvate is 70-23-5, and the CAS number of 4-bromoaniline is 106-40-1. Furthermore, conventional synthesis can also be performed in the laboratory, for example, by mixing bromine with ethyl pyruvate for substitution to produce ethyl 3-bromopyruvate.

[0039] Furthermore, when synthesizing ethyl 3-bromopyruvate, ethyl pyruvate can be preliminarily dissolved in an organic solvent to form an ethyl pyruvate solution, and then liquid bromine is added dropwise to carry out a substitution reaction, followed by separation and purification to obtain ethyl 3-bromopyruvate. Specifically, the organic solvent used can be one of diethyl ether, dichloromethane, chloroform, acetonitrile, 1,2-dichloroethane, methanol, and ethanol, and the molar ratio of the total amount of liquid bromine added dropwise to the ethyl pyruvate is (0.9-1.2):1.

[0040] In some embodiments, the dehydrating agent used in the synthesis process includes at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride. In practice, adding at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride to the reaction system for dehydration can form hydrated crystals and thus specifically remove water.

[0041] Specifically, 1 mol of ethyl 3-bromopyruvate reacts with 1 mol of 4-bromoaniline to produce 1 mol of the intermediate represented by Formula I and 1 mol of water. Absorbing this water with a desiccant effectively promotes the forward direction of the synthesis reaction. In practice, the desiccant is essential only for its ability to specifically absorb water in this reaction system and not react with the reactants or products.

[0042] In some embodiments, to improve the dispersibility of the dehydrating agent in the reaction system, the dehydrating agent can be pre-ground to uniformly disperse the powdered dehydrating agent in the first solvent, thereby effectively improving the dehydration efficiency of the dehydrating agent and thereby facilitating an increase in the reaction rate. Specifically, the dehydrating agent can be pre-screened through a 100-500 mesh sieve, and the molar ratio of the dehydrating agent to ethyl 3-bromopyruvate can be (3-6):1.

[0043] In some embodiments, the first solvent includes one of toluene, xylene, ethyl acetate, dichloromethane, chloroform, and 1,2-dichloroethane. Conducting the synthesis reaction in a solvent environment facilitates sufficient contact and reaction between the reactants. Specifically, the first solvent used can be an organic solvent commonly used in the art, and must be non-reactive with the reactants (ethyl 3-bromopyruvate, 4-bromoaniline) and the product (the intermediate shown in Formula I). Furthermore, the amount of the first solvent used must be sufficient to completely dissolve the reactants.

[0044] In some embodiments, ethyl 3-bromopyruvate and 4-bromoaniline can be condensed and reacted at 25°C-40°C for 6-8 hours, and the precipitated hydrated crystals can be separated by filtration, and the organic phase can be separated and purified to obtain the intermediate represented by Formula I. In practice, the intermediate represented by Formula I can be synthesized at room temperature. Furthermore, to improve reaction efficiency, mixing methods commonly used in the art, such as stirring, sonication, shaking, and vortexing, can be used.

[0045] The present invention also provides a method for synthesizing an oglerone raw material, comprising: in a second solvent, under the catalysis of a Lewis acid, subjecting the intermediate represented by Formula I to a Friedel-Crafts reaction to produce the oglerone raw material represented by Formula II. In practice, the reaction formula during the reaction is:

[0046] .

[0047] In some embodiments, the second solvent used includes one of dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, toluene, and nitrobenzene. In addition, the Lewis acid used includes aluminum trichloride, titanium tetrachloride, zinc chloride, ferric chloride, tin tetrachloride, and indium trichloride. In a further embodiment, the molar ratio of the Lewis acid used to the intermediate represented by Formula I is (1-2.5):1. In addition, the intermediate represented by Formula I can be reacted in an environment of -10°C to 25°C for 6h-10h.

[0048] Preparation Example 1

[0049] This Preparation Example 1 provides a method for synthesizing ethyl 3-bromopyruvate, comprising: adding 180 g of ethyl pyruvate (CAS: 617-35-6) and 1000 mL of chloroform into a reactor, stirring and mixing, cooling the mixture to a constant temperature in an ice-water bath, and then adding 80 mL (1 eq) of liquid bromine dropwise, maintaining the temperature in the reactor at 25°C±1°C during the addition; heating the mixture to 62°C after the addition is complete, and reflux reacting for 4 hours. After the reaction is complete, washing the mixture twice with 400 mL of a saturated aqueous sodium chloride solution, and then washing the mixture with 400 mL of a saturated aqueous sodium bicarbonate solution until the pH reaches ≈ 7, separating the organic phase, and concentrating the mixture under reduced pressure to remove the solvent, thereby obtaining 272.7 g of ethyl 3-bromopyruvate as a yellow oily liquid, with a calculated yield of 90.2% and a detected purity of 98.0%.

[0050] The 3-bromopyruvic acid ethyl ester prepared in Preparation Example 1 was characterized by H NMR spectroscopy. Figure 2 As shown, its nuclear magnetic hydrogen spectrum data is: 1 H NMR (400 MHz, DMSO-d6) δ4.34 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H).

[0051] Preparation Example 2

[0052] Preparation Example 2 provides a method for synthesizing ethyl 3-bromopyruvate, comprising: adding 180 g of ethyl pyruvate (CAS: 617-35-6) and 1000 mL of ether into a reactor, stirring and mixing, cooling the mixture to a constant temperature in an ice-water bath, and then dropwise adding 80 mL (1 eq) of liquid bromine, maintaining the temperature in the reactor at 17°C±1°C during the dropwise addition; heating the mixture to 35°C after the dropwise addition is completed, and reflux reacting for 8 hours. After the reaction is completed, washing the mixture twice with 400 mL of a saturated aqueous sodium chloride solution, and then washing the mixture with 400 mL of a saturated aqueous sodium bicarbonate solution until the pH reaches ≈ 7, separating the organic phase, and concentrating the mixture under reduced pressure to remove the solvent, thereby obtaining 279.6 g of ethyl 3-bromopyruvate as a yellow oily liquid, with a calculated yield of 92.5% and a detected purity of 99.1%.

[0053] Example 1

[0054] This Example 1 provides a method for synthesizing an oglerone raw material intermediate, comprising: adding 200 g of ethyl 3-bromopyruvate, 176.4 g (1 eq) of 4-bromoaniline, 611.8 g (4.2 eq) of anhydrous sodium sulfate, and 1000 mL of toluene into a reactor, and stirring the mixture at room temperature for 6 h; after the reaction is completed, filtering the mixture, and concentrating the filtrate under reduced pressure to remove the solvent, thereby obtaining 352.9 g of the oglerone raw material intermediate represented by Formula I as a golden solid, with a calculated yield of 98.6% and a detected purity of 99.2%.

[0055] The raw material intermediate of oglerone prepared in Example 1 was characterized by nuclear magnetic hydrogen spectrum. Figure 3 As shown, its nuclear magnetic hydrogen spectrum data is: 1 H NMR (400 MHz, DMSO-d6) δ9.70 (s, 1H), 7.35-7.26 (m, 2H), 6.76-6.69 (m, 2H), 6.67 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz,3H).

[0056] Example 2

[0057] This Example 2 provides a method for synthesizing an oglerone raw material intermediate, comprising: adding 200 g of ethyl 3-bromopyruvate, 176.4 g (1 eq) of 4-bromoaniline, 555.5 g (4.5 eq) of anhydrous magnesium sulfate, and 1000 mL of ethyl acetate to a reactor, and stirring the mixture at room temperature for 8 hours; after the reaction is completed, filtering the mixture, and concentrating the filtrate under reduced pressure to remove the solvent, thereby obtaining 350.1 g of the oglerone raw material intermediate represented by Formula I as a golden solid, with a calculated yield of 97.8% and a detected purity of 99.4%.

[0058] Application Example 1

[0059] This application example 1 provides a method for synthesizing an oglerone raw material, comprising: adding 200 g of an oglerone raw material intermediate represented by Formula I and 1000 mL of dichloromethane into a reactor, stirring in an ice-salt bath, slowly adding 167.3 g (1.8 eq) of anhydrous ferric chloride, and stirring at room temperature for reaction for 10 hours; after completion of the reaction, slowly adding the reaction solution into 800 mL of ice-cold dilute hydrochloric acid (0.1 mol / L) for quenching, extracting three times with 400 mL of ethyl acetate, combining the organic phases, washing twice with 400 mL of saturated sodium chloride aqueous solution, and concentrating under reduced pressure to remove the solvent, thereby obtaining 144.9 g of an off-white solid oglerone raw material, with a calculated yield of 94.3% and a detected purity of 98.5%.

[0060] The raw material of oglerone prepared according to Example 1 was characterized by nuclear magnetic hydrogen spectrum. Figure 4 As shown, its nuclear magnetic hydrogen spectrum data is: 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.62-7.25 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J= 7.1 Hz, 3H).

[0061] Application Example 2

[0062] This application example 2 provides a method for synthesizing an oglerone raw material, comprising: adding 200 g of an oglerone raw material intermediate represented by Formula I and 1000 mL of chloroform into a reactor, stirring in an ice-salt bath, slowly adding 122.3 g (1.6 eq) of anhydrous aluminum chloride, and stirring at room temperature for reaction for 6 hours; after completion of the reaction, slowly adding the reaction solution into 800 mL of ice-cold dilute hydrochloric acid (0.1 mol / L) for quenching, extracting three times with 400 mL of ethyl acetate, combining the organic phases, washing twice with 400 mL of saturated sodium chloride aqueous solution, and concentrating under reduced pressure to remove the solvent, thereby obtaining 146.7 g of an off-white solid oglerone raw material, with a calculated yield of 95.5% and a detected purity of 98.9%.

[0063] While the embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations of these embodiments are possible. However, it should be understood that such modifications and variations are within the scope and spirit of the present invention as set forth in the claims. Furthermore, the invention described herein is susceptible to other embodiments and may be practiced or implemented in a variety of ways.

Claims

1. An oglerone raw material intermediate and tautomers as shown in Formula I: 。 2. A method for synthesizing an oglerone raw material intermediate, characterized in that: include: In the first solvent and under the action of a water scavenger, ethyl 3-bromopyruvate and 4-bromoaniline are condensed to form an intermediate shown in formula I; 。 3. The synthesis method according to claim 2, characterized in that The dehydrating agent includes at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride.

4. The synthesis method according to claim 2, characterized in that The molar ratio of the water removal agent to the ethyl 3-bromopyruvate is (3-6):

1.

5. The synthesis method according to claim 2, characterized in that The first solvent includes one of toluene, xylene, ethyl acetate, dichloromethane, chloroform, and 1,2-dichloroethane.

6. The synthesis method according to claim 2, characterized in that The molar ratio of the ethyl 3-bromopyruvate to the 4-bromoaniline is (0.5-1.5):

1.

7. The synthesis method according to claim 2, characterized in that The condensation reaction is carried out at 25° C.-40° C.; and / or, the condensation reaction is carried out for 6 h-8 h.

8. A method for synthesizing an oglerone raw material, characterized in that: include: In a second solvent, under the catalysis of Lewis acid, the intermediate represented by formula I undergoes Friedel-Crafts reaction to produce the raw material of oglerone represented by formula II; 。 9. The synthesis method according to claim 8, characterized in that The second solvent includes one of dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, toluene, and nitrobenzene; and / or the Lewis acid includes aluminum trichloride, titanium tetrachloride, zinc chloride, ferric chloride, tin tetrachloride, and indium trichloride.

10. The synthesis method according to claim 8, characterized in that The Friedel-Crafts reaction is carried out at -10°C to 25°C; and / or the Friedel-Crafts reaction is carried out for 6h-10h; and / or the molar ratio of the Lewis acid to the intermediate represented by formula I is (1-2.5):1.

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