Omariglitazone raw material intermediate and synthetic method thereof, and synthetic method of Omariglitazone raw material

Abstract

The invention provides an omarigliflozin raw material intermediate, a synthesis method and a synthesis method of an omarigliflozin raw material, and relates to the technical field of medicine synthesis. The synthesis method provided by the invention does not need to use a complex catalytic system and expensive and dangerous reagents, the synthesis route is reasonable and safe, the used reaction raw materials are cheap and easy to obtain, the atom economy is high, the reaction conditions are mild, byproducts are controllable and environment-friendly, complex mechanical equipment and expensive catalysts do not need to be used, and the method is suitable for industrial production. The method can be used for efficiently synthesizing an omariglone raw material intermediate (5-bromo-2-indolemethyl formate), and is suitable for industrial large-scale generation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly relates to an intermediate of an orforglipron raw material, a synthesis method thereof, and a synthesis method of an orforglipron raw material. Background Art

[0002] Orforglipron (CAS: 2212020-52-3) is a glucagon-like peptide-1 (GLP-1) receptor agonist. By mimicking human intestinal hormones, it stimulates insulin secretion and inhibits glucagon release, thereby effectively reducing blood glucose levels. At the same time, it can act on receptors in the brain to reduce hunger and inhibit appetite, and can delay the passage speed and digestion and absorption ability of food in the digestive tract. The patent with the publication number CN109790161A provides a pyrazolopyridine derivative with GLO-1 receptor agonist activity, and specifically provides a synthesis route of orforglipron. Using methyl 5-bromo-2-indolecarboxylate (CAS: 16732-70-0) as a raw material, orforglipron is synthesized through multiple steps: 。

[0003] Among them, methyl 5-bromo-2-indolecarboxylate is a key raw material for the synthesis of orforglipron and is also an important pharmaceutical and pesticide intermediate. In the prior art, a method for synthesizing methyl 5-bromo-2-indolecarboxylate by condensing ethyl azidoacetate with m-bromobenzaldehyde and then heating and ring-closing under the action of a rhodium catalyst is provided. The synthesis route is: ; A method for synthesizing methyl 5-bromo-2-indolecarboxylate by diazotizing 4-bromoaniline to generate phenylhydrazine hydrochloride, then performing an aldehyde-amine condensation reaction with ethyl pyruvate to form a hydrazone, and subsequently performing an intramolecular Borsche-Drechsel cyclization reaction is also provided. The synthesis route is: 。

[0004] However, the prices of azides and rhodium catalysts are expensive, and the stability of azides during the reaction process is poor, posing a large safety hazard and making it difficult to carry out large-scale industrial production. The diazotization reaction requires the use of sodium nitrite, which has genetic toxicity and carcinogenicity, and is prone to introducing high-risk impurities such as nitrosamines. It is easy to decompose or even explode under high temperature, light, or mechanical shock, posing a huge threat to production safety. Moreover, the Borsche-Drechsel cyclization reaction relies on a large amount of polyphosphoric acid as a catalyst, resulting in an extremely high viscosity of the reaction system, an increase in side reactions, and cumbersome post-treatment, making it difficult to achieve the expected production efficiency and reaction purity. Therefore, there is an urgent need to provide a solution to improve the above problems. Summary of the Invention

[0005] The object of the present invention is to provide an intermediate of ogliflozin raw material, a synthesis method thereof and a synthesis method of ogliflozin raw material. The synthesis route is reasonable, the raw materials are cheap and easily available, the atom economy is high and it is environmentally friendly. There is no need to use complex mechanical equipment and expensive catalysts, and the intermediate of ogliflozin raw material (methyl 5-bromo-2-indolecarboxylate) can be efficiently synthesized, which is suitable for large-scale industrial production.

[0006] In the first aspect, the present invention provides an intermediate of ogliflozin raw material shown in formula I and its tautomer: .

[0007] In the second aspect, the present invention also provides a synthesis method of an intermediate of ogliflozin raw material, including: condensing ethyl 3-bromopyruvate and 4-bromoaniline in a first solvent under the action of a water removing agent to form the intermediate shown in formula I; .

[0008] Optionally, the water removing agent includes at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate and anhydrous calcium chloride.

[0009] Optionally, the molar ratio of the water removing agent to the ethyl 3-bromopyruvate is (3 - 6):1.

[0010] Optionally, the first solvent includes one of toluene, xylene, ethyl acetate, dichloromethane, chloroform and 1,2-dichloroethane.

[0011] Optionally, the molar ratio of the ethyl 3-bromopyruvate to the 4-bromoaniline is (0.5 - 1.5):1.

[0012] Optionally, the condensation reaction is carried out at 25°C - 40°C.

[0013] Optionally, the condensation reaction lasts for 6h - 8h.

[0014] In the third aspect, the present invention also provides a synthesis method of an ogliflozin raw material, including: carrying out a Friedel-Crafts reaction on the intermediate shown in formula I in a second solvent under the catalysis of a Lewis acid to form the ogliflozin raw material shown in formula II; .

[0015] Optionally, the second solvent includes one of dichloromethane, chloroform, 1,2-dichloroethane, nitromethane, toluene and nitrobenzene; Optionally, the Lewis acid includes aluminum trichloride, titanium tetrachloride, zinc chloride, ferric trichloride, tin tetrachloride and indium trichloride.

[0016] Optionally, the Friedel-Crafts reaction is carried out at -10°C to 25°C.

[0017] Optionally, the Friedel-Crafts reaction is carried out for 6 h - 10 h.

[0018] Optionally, the molar ratio of the Lewis acid to the intermediate shown in Formula I is (1 - 2.5):1. Description of the Drawings

[0019] Figure 1 It is the structural formula of an intermediate of the raw material of oregrelone provided by the present invention; Figure 2 It is the 1H NMR spectrum of ethyl 3-bromopyruvate prepared in Preparation Example 1 of the present invention; Figure 3 It is the 1H NMR spectrum of the intermediate of the raw material of oregrelone prepared in Example 1 of the present invention; Figure 4 It is the 1H NMR spectrum of the raw material of oregrelone prepared in Application Example 1 of the present invention. Detailed Description of the Invention

[0020] To make the objectives, 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. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without any creative effort shall fall within the protection scope of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein shall have the ordinary meanings as understood by those of ordinary skill in the art to which the present invention belongs.

[0021] See Figure 1 , the present invention provides an intermediate of the raw material of oregrelone, and its structure is as shown in Formula I: .

[0022] Actually, the intermediate shown in Formula I is named by the systematic nomenclature as: ethyl (Z)-3-bromo-2-((4-bromophenyl)amino)acrylate.

[0023] Specifically, the present invention also provides a synthesis method of an intermediate of the raw material of oregrelone, including: in a first solvent and under the action of a water scavenger, ethyl 3-bromopyruvate and 4-bromoaniline are condensed to form the intermediate shown in Formula I. Actually, in the synthesis process, the water scavenger can absorb the water generated by the reaction, thereby promoting the forward reaction and being beneficial to improving the yield of the intermediate shown in Formula I.

[0024] Specifically, the reaction formula of the synthesis method provided by the present invention is: .

[0025] In some embodiments, both ethyl 3-bromopyruvate and 4-bromoaniline used in the synthesis process can be commercially available conventional products. For example, the CAS of ethyl 3-bromopyruvate is 70-23-5, and the CAS of 4-bromoaniline is 106-40-1. Further, conventional synthesis can also be carried out in the laboratory. For example, bromine is mixed with ethyl pyruvate for substitution to generate ethyl 3-bromopyruvate.

[0026] Furthermore, when synthesizing ethyl 3-bromopyruvate, ethyl pyruvate can be pre-dissolved in an organic solvent to form an ethyl pyruvate solution, and then liquid bromine is added dropwise for substitution reaction, followed by separation and purification to obtain ethyl 3-bromopyruvate. Specifically, the organic solvent used can be one of ether, dichloromethane, chloroform, acetonitrile, 1,2-dichloroethane, methanol, and ethanol. The molar ratio of the total amount of liquid bromine added dropwise to ethyl pyruvate is (0.9-1.2):1.

[0027] In some embodiments, the water remover used in the synthesis process includes at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride. In fact, adding at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride to the reaction system for water removal can form hydrated crystals to specifically remove water.

[0028] Specifically, 1 mol of ethyl 3-bromopyruvate reacts with 1 mol of 4-bromoaniline to generate 1 mol of the intermediate shown in Formula I and 1 mol of water. Absorbing water by the water remover can effectively promote the forward progress of the synthesis reaction. In fact, the use of the water remover is necessary to specifically absorb the water in this reaction system and does not react with the reactants and products.

[0029] In some embodiments, to improve the dispersibility of the water remover in the reaction system, the water remover can be pre-ground to uniformly disperse the powdery water remover in the first solvent, so as to effectively improve the water removal efficiency of the water remover and thus be conducive to increasing the reaction rate. Specifically, the water remover can be pre-screened through a 100-mesh to 500-mesh sieve, and the molar ratio of the water remover to ethyl 3-bromopyruvate can be (3-6):1.

[0030] In some embodiments, the first solvent includes one of toluene, xylene, ethyl acetate, dichloromethane, chloroform, and 1,2-dichloroethane. In fact, carrying out the synthesis reaction in a solvent environment is conducive to the reactants coming into full contact and reacting. Specifically, the first solvent used can be a commonly used organic solvent in the art, which is necessary not to react with the reactants (ethyl 3-bromopyruvate, 4-bromoaniline) and the product (the intermediate shown in Formula I). In addition, the amount of the first solvent used is necessary to completely dissolve the reactants.

[0031] In some embodiments, ethyl 3-bromopyruvate and 4-bromoaniline can be condensed at 25°C - 40°C for 6h - 8h, and then the precipitated hydrated crystal is removed by filtration and separation, and the organic phase is separated and purified to obtain the intermediate shown in Formula I. In fact, the intermediate shown in Formula I can be synthesized at room temperature. At the same time, in order to improve the reaction efficiency, common mixing methods in the art can also be used for mixing, such as stirring, ultrasonic treatment, oscillation, vortexing, etc.

[0032] The present invention also provides a method for synthesizing the raw material of oglitazone, comprising: in a second solvent and under the catalysis of a Lewis acid, the intermediate shown in Formula I undergoes a Friedel-Crafts reaction to generate the raw material of oglitazone shown in Formula II. In fact, the reaction formula during the reaction is: .

[0033] 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 trichloride, tin tetrachloride, and indium trichloride. In a further embodiment, the molar ratio of the Lewis acid to the intermediate shown in Formula I is (1 - 2.5):1. In addition, the intermediate shown in Formula I can be reacted in an environment of -10°C to 25°C for 6h - 10h.

[0034] Preparation Example 1

[0035] 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 reaction kettle, stirring and mixing, cooling to a constant temperature in an ice-water bath, and then dropwise adding 80 mL (1eq) of liquid bromine while maintaining the temperature in the reaction kettle at 25°C ± 1°C during the dropping process; after the dropping is completed, heating to 62°C and refluxing for 4h, after the reaction is completed, washing twice with 400 mL of saturated sodium chloride aqueous solution, and then washing with 400 mL of saturated sodium bicarbonate aqueous solution until pH≈7, separating the organic phase and concentrating under reduced pressure to remove the solvent, obtaining 272.7 g of ethyl 3-bromopyruvate as a yellow oily liquid, calculating the yield to be 90.2%, and detecting the purity to be 98.0%.

[0036] The nuclear magnetic resonance hydrogen spectrum of the ethyl 3-bromopyruvate prepared in Preparation Example 1 was characterized as Figure 2 shown, and its nuclear magnetic resonance hydrogen spectrum data are: 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).

[0037] Preparation Example 2

[0038] This Preparation Example 2 provides a method for synthesizing ethyl 3-bromopyruvate, including: adding 180 g of ethyl pyruvate (CAS: 617-35-6) and 1000 mL of diethyl ether into a reaction kettle, stirring and mixing them, cooling to a constant temperature in an ice-water bath, then dropwise adding 80 mL (1 eq) of liquid bromine, and maintaining the temperature in the reaction kettle at 17 °C ± 1 °C during the dropping process; after the dropping is completed, heating to 35 °C and refluxing for 8 h, after the reaction is completed, washing twice with 400 mL of saturated sodium chloride aqueous solution, and then washing with 400 mL of saturated sodium bicarbonate aqueous solution until the pH ≈ 7, separating the organic phase and concentrating under reduced pressure to remove the solvent, obtaining 279.6 g of ethyl 3-bromopyruvate as a yellow oily liquid, calculating the yield to be 92.5%, and detecting the purity to be 99.1%.

[0039] Example 1

[0040] This Example 1 provides a method for synthesizing the raw material intermediate of oregrelone, including: 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 reaction kettle, stirring and reacting at room temperature for 6 h; after the reaction is completed, filtering, concentrating the filtrate under reduced pressure to remove the solvent, obtaining 352.9 g of the raw material intermediate of oregrelone shown in Formula I as a golden yellow solid, calculating the yield to be 98.6%, and detecting the purity to be 99.2%.

[0041] The nuclear magnetic resonance hydrogen spectrum of the raw material intermediate of oregrelone prepared in Example 1 was characterized as Figure 3 shown below, and its nuclear magnetic resonance hydrogen spectrum data are as follows 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).

[0042] Example 2

[0043] This Example 2 provides a method for synthesizing the raw material intermediate of oregrelone, including: 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 into a reaction kettle, stirring and reacting at room temperature for 8 h; after the reaction is completed, filtering, concentrating the filtrate under reduced pressure to remove the solvent, obtaining 350.1 g of the raw material intermediate of oregrelone shown in Formula I as a golden yellow solid, calculating the yield to be 97.8%, and detecting the purity to be 99.4%.

[0044] Application Example 1

[0045] This Application Example 1 provides a method for synthesizing the raw material of oregrelone, including: adding 200 g of the oregrelone raw material intermediate shown in Formula I and 1000 mL of dichloromethane into a reaction kettle, stirring in an ice-salt bath and slowly adding 167.3 g (1.8 eq) of anhydrous ferric chloride, then stirring and reacting at room temperature for 10 h; after the reaction is completed, 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 and then combining the organic phases, washing twice with 400 mL of saturated sodium chloride aqueous solution, and concentrating under reduced pressure to remove the solvent, obtaining 144.9 g of the oregrelone raw material as a grayish-white solid, calculating the yield to be 94.3%, and detecting the purity to be 98.5%.

[0046] The nuclear magnetic resonance hydrogen spectrum of the oregrelone raw material prepared in Application Example 1 was characterized as Figure 4 shown, and its nuclear magnetic resonance hydrogen spectrum data are as follows: 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).

[0047] Application Example 2

[0048] This Application Example 2 provides a method for synthesizing the raw material of oregrelone, including: adding 200 g of the oregrelone raw material intermediate shown in Formula I and 1000 mL of chloroform into a reaction kettle, stirring in an ice-salt bath and slowly adding 122.3 g (1.6 eq) of anhydrous aluminum chloride, then stirring and reacting at room temperature for 6 h; after the reaction is completed, 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 and then combining the organic phases, washing twice with 400 mL of saturated sodium chloride aqueous solution, and concentrating under reduced pressure to remove the solvent, obtaining 146.7 g of the oregrelone raw material as a grayish-white solid, calculating the yield to be 95.5%, and detecting the purity to be 98.9%.

[0049] Although the embodiments of the present invention have been described in detail above, it is obvious to those skilled in the art that various modifications and changes can be made to these embodiments. However, it should be understood that such modifications and changes are all within the scope and spirit of the present invention described in the claims. Moreover, the present invention described herein can have other embodiments and can be implemented or realized in various ways.

Claims

1. An intermediate and tautomer of oregrelon raw material represented by formula I: 。 2. A synthesis method of an oreglone raw material intermediate, characterized in that, Comprising: In the first solvent and under the action of a water scavenger, ethyl 3-bromopyruvate is condensed with 4-bromoaniline to form the intermediate shown in formula I; 。 3. The synthesis method according to claim 2, wherein The water scavenger 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 scavenger 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, wherein, 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, wherein The condensation reaction is carried out at 25°C - 40°C; and / or, the condensation reaction is carried out for 6h - 8h.

8. A method for synthesizing an oregrelon raw material, characterized in that, Comprising: In the second solvent and under the catalysis of a Lewis acid, the intermediate shown in formula I undergoes a Friedel-Crafts reaction to form the oregrelon raw material shown in 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 trichloride, 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 shown in formula I is (1 - 2.5):1.

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