A method for synthesizing a sparsentan intermediate
By reacting in ethanol with the compound of formula I as raw material under the presence of acid, combining chloromethylation and sodium ethyl esters, the production cost of the Spasentan intermediate was successfully reduced, and the problems of difficult reaction control and high cost in the existing synthesis route were solved, and efficient and low-cost intermediate synthesis was achieved.
Patent Information
- Application Number
- CN202411962353.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-30
- Publication Date
- 2025-04-08
AI Technical Summary
In the existing Sparsontin intermediate synthesis route, the second step reaction is a free radical reaction, which is difficult to control, and is easy to produce more dibromide products, is not easy to purify, and the main raw materials are expensive, resulting in high production costs.
Using the compound of formula I as a starting material, reacted in ethanol in the presence of an acid to obtain the intermediate of formula II, and then undergoes chloromethylation reaction and reaction with sodium ethylate to form the Sparsontin intermediate. Under mild reaction conditions, this method has simple post-processing and high production efficiency.
It realizes the low-cost synthesis of Spasentan intermediates, with mild reaction conditions, simple post-processing and high production efficiency, providing convenience for industrial production.
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Figure CN119775136A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biomedicine, and particularly relates to a method for synthesizing a sparsentan intermediate. Background Art
[0002] Sparsentan is a novel dual-acting receptor antagonist designed to treat rare chronic kidney diseases such as focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (Ig AN). These diseases often lead to chronic renal failure, which seriously affects the quality of life and life expectancy of patients. Sparsentan demonstrates significant clinical efficacy by simultaneously blocking endothelin A receptors and angiotensin II receptors.
[0003] At present, the intermediate synthesis route of Sparsentan is as follows:
[0004]
[0005] In this route, 3-methyl-4-bromobenzoic acid is used as a raw material, which is subjected to esterification, bromination, and finally ethoxy substitution to obtain the target product; in this route, the second step reaction is a free radical reaction, which is more difficult to control and tends to generate a large amount of dibromo products, which are not easy to purify; in addition, the main raw materials of this synthetic route are expensive, resulting in high production costs.
[0006] Therefore, it is necessary to develop other better synthetic methods to produce intermediates of sparsentan. Summary of the invention
[0007] In order to solve the above technical problems, the purpose of the present invention is to provide a method for synthesizing a sparsentan intermediate; the synthesis method has low cost, milder reaction conditions, simple and convenient post-treatment, high production efficiency, and provides great convenience for industrial production.
[0008] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:
[0009] A method for synthesizing a sparsentan intermediate, comprising: using a compound represented by formula I as a raw material, reacting in an ethanol solvent in the presence of an acid to obtain an intermediate compound represented by formula II; the intermediate compound represented by formula II is then subjected to a chloromethylation reaction to synthesize a compound represented by formula III; the compound represented by formula III is then reacted with sodium ethoxide to generate a sparsentan intermediate represented by formula IV;
[0010] The synthetic route is:
[0011]
[0012] The synthesis method of the sparsentan intermediate specifically comprises the following steps:
[0013] Step (1), using the compound of formula 1 as a raw material, adding ethanol and acid to the mixture, heating and refluxing for a period of time, then cooling, concentrating under reduced pressure, extracting, backwashing, and concentrating under reduced pressure again to obtain an intermediate compound of formula II;
[0014] Step (2), heating the intermediate compound represented by formula II with a chlorine-containing Lewis acid, hydrochloric acid and paraformaldehyde in a solvent for reaction, extracting, washing, drying and concentrating under reduced pressure after the reaction to obtain a compound represented by formula III;
[0015] Step (3), heating the compound represented by formula III and sodium ethoxide in ethanol for reaction, cooling and filtering after the reaction, and concentrating under reduced pressure to obtain the sparsentan intermediate represented by formula IV.
[0016] Furthermore, in step (1), the molar ratio of the compound represented by formula I to the acid is 1:(0.15-0.60), and the volume molar ratio of ethanol to the compound represented by formula I is (3-5) ml:1 g.
[0017] Furthermore, the reaction temperature of step (1) is 80-90°C, and the reaction time is 16-24h.
[0018] Furthermore, in step (2), the molar ratio of paraformaldehyde to the intermediate compound shown in formula II is (1.3-3.0) : 1, the molar ratio of the intermediate compound shown in formula II to the chlorine-containing Lewis acid is 1: (0.5-1.0), and the mass volume ratio of the intermediate compound shown in formula II to hydrochloric acid is 1g: (0.0-3.0) ml.
[0019] Preferably, the chlorine-containing Lewis acid is at least one of zinc chloride, aluminum chloride and chlorosulfonic acid.
[0020] Furthermore, the reaction temperature of step (2) is 50-80°C, and the reaction time is 3-8h.
[0021] Furthermore, in step (3), the molar ratio of the compound represented by formula III to sodium ethoxide is 1:(1.2-1.5).
[0022] Furthermore, the reaction temperature of step (3) is 50-80°C, and the reaction time is 3-10h.
[0023] The beneficial effects of the present invention are:
[0024] The invention provides a novel synthesis method of a sparsentan intermediate. The synthesis method has low raw material cost when preparing the sparsentan intermediate, milder reaction conditions, simple and convenient post-treatment, high production efficiency, and provides great convenience for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 This is the NMR spectrum of the sparsentan intermediate prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0026] The technical solutions in the present invention will be described clearly and completely below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0027] The present invention provides a method for synthesizing a sparsentan intermediate, wherein a compound represented by formula I is used as a raw material, reacted in an ethanol solvent in the presence of an acid to obtain an intermediate compound represented by formula II, the intermediate compound represented by formula II is then subjected to a chloromethylation reaction to synthesize a compound represented by formula III, and the compound represented by formula III is then reacted with sodium ethoxide to generate a sparsentan intermediate represented by formula IV;
[0028] The synthetic route is:
[0029]
[0030] The synthesis method of the sparsentan intermediate specifically comprises the following steps:
[0031] Step (1), using the compound of formula 1 as a raw material, adding ethanol and acid to the mixture, heating and refluxing for a period of time, then cooling, concentrating under reduced pressure, extracting, backwashing, and concentrating under reduced pressure again to obtain an intermediate compound of formula II;
[0032] Step (2), heating the intermediate compound represented by formula II with a chlorine-containing Lewis acid, hydrochloric acid and paraformaldehyde in a solvent for reaction, extracting, washing, drying and concentrating under reduced pressure after the reaction to obtain a compound represented by formula III;
[0033] Step (3), heating the compound represented by formula III and sodium ethoxide in ethanol for reaction, cooling and filtering after the reaction, and concentrating under reduced pressure to obtain the sparsentan intermediate represented by formula IV.
[0034] In step (1), the molar ratio of the compound represented by formula I to the acid is 1:(0.15-0.60), and the volume molar ratio of ethanol to the compound represented by formula I is (3-5) ml:1 g.
[0035] In step (1), the acid is selected from at least one of hydrochloric acid, sulfuric acid and thionyl chloride.
[0036] The reaction temperature of step (1) is 80-90°C and the reaction time is 16-24h.
[0037] The extraction solvent in step (1) is one or more of toluene, ethyl acetate, and 2-methyltetrahydrofuran. The volume molar ratio of the extraction solvent to the compound represented by formula I is (3-5) ml: 1 g.
[0038] In step (2), the molar ratio of the amount of paraformaldehyde to the intermediate compound shown in formula II is (1.3-3.0):1, and the molar ratio of the amount of the intermediate compound shown in formula II to the chlorine-containing Lewis acid is 1:(0.5-1.0). The chlorine-containing Lewis acid is at least one of zinc chloride, aluminum chloride, and chlorosulfonic acid. The mass volume ratio of the intermediate compound shown in formula II to hydrochloric acid is 1g:(0.0-3.0)ml.
[0039] The reaction temperature of step (2) is 50-80°C and the reaction time is 3-8h.
[0040] In step (2), the mass volume ratio of the intermediate compound represented by formula II to the solvent is 1 g: (3.0-5.0) ml; the mass volume ratio of the intermediate compound represented by formula II to the extraction solvent is 1 g: (3.0-5.0) ml.
[0041] In step (3), the molar ratio of the compound represented by formula III to sodium ethoxide is 1:(1.2-1.5); and the mass volume ratio of the compound represented by formula III to ethanol is 1g:(4.0-6.0)ml.
[0042] The reaction temperature of step (3) is 50-80°C and the reaction time is 3-10h.
[0043] The synthesis method of the present invention is further described below by means of specific examples.
[0044] Example 1
[0045] Add 8 kg of the compound shown in formula I to a 50 L kettle, then add 32 L of ethanol, stir, add 1.2 L of concentrated sulfuric acid, heat to reflux (external temperature 90 ° C), and keep the reaction under reflux for 16 hours. Natural cooling, liquid phase detection, reduced pressure concentration (50 ° C), remove most of the ethanol, add 8 L of ice water at room temperature to quench the residue, add 1.5 kg of sodium carbonate, pH test paper to measure the solution is alkaline, stir for 15 minutes, separate, extract the water layer with 12 L of ethyl acetate twice, combine the organic layers, wash with saturated brine (5 L), dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain 9.6 kg of the product shown in formula II.
[0046] 1 kg of the product of formula II, dichloroethane (3 liters), hydrochloric acid (2 liters), and zinc chloride (560 g) were added to a 20-liter reactor, and finally paraformaldehyde (185 g) was added, and then heated to 60°C for reaction for 4 hours, and then cooled to room temperature, ice water (4 liters) was added to quench the reaction, and the liquids were separated. The aqueous phase was extracted with dichloroethane (1.5 L*2), and the organic phases were combined, washed with saturated brine (1 liter), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 889 g of a crude compound of formula III. This crude product was slurried with petroleum ether to obtain 860 g of a pure product.
[0047] In a 10L reactor, add 4.4L anhydrous ethanol and 860g of the compound shown in formula III, nitrogen protection, temperature control below 30°C, add sodium ethoxide (218g) in batches, the temperature rise is not obvious, the temperature is controlled below 30°C, after addition, heat to 60°C for 4 hours, liquid phase monitoring, there is still raw material, add 36g of sodium ethoxide, heat to 60°C for reflux reaction for 4 hours, liquid phase monitoring, the reaction is complete, vacuum concentration (50°C) to dryness, add 2L ethyl acetate and 3L ice water to the residue, stir evenly, and filter. The filtrate is separated, the water layer is extracted once with 1L ethyl acetate, the organic layer is combined, washed once with 1L saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 600g of the target product shown in formula IV.
[0048] The NMR spectrum of the sparsentan intermediate prepared in Example 1 is as follows: Figure 1 As shown, the data is as follows:
[0049] 1 H NMR (400 MHz, CDCl 3 )δ8.15(s,1H),7.81(dd,1H,J=4.0Hz),7.62(dd,1H,J=4.0Hz),4.59(s,2H,),4.39,( q,2H,J=8.0Hz), 3.66(qd,2H,J=8.0Hz), 1.41(t,3H,J=4.0Hz), 1.32(t,3H,J=4.0Hz).
[0050] Example 2
[0051] Add 8 kg of the compound shown in formula I to a 50 L kettle, then add 32 L of ethanol, stir, add 1.2 L of concentrated sulfuric acid, heat to reflux (external temperature 90 ° C), and keep the reaction under reflux for 16 hours. Natural cooling, liquid phase detection, reduced pressure concentration (50 ° C), remove most of the ethanol, add 8 L of ice water at room temperature to quench the residue, add 1.5 kg of sodium carbonate, pH test paper to measure the solution is alkaline, stir for 15 minutes, separate, extract the water layer with 12 L of ethyl acetate twice, combine the organic layers, wash with saturated brine (5 L), dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain 9.6 kg of the product shown in formula II.
[0052] 1 kg of the product of formula II, dichloromethane (4 liters), hydrochloric acid (1 liter), and zinc chloride (324 g) were added to a 20-liter reactor, and finally paraformaldehyde (185 g) was added, and then heated to 60°C for 4 hours, and then cooled to room temperature, ice water (4 liters) was added to quench the reaction, and the liquids were separated. The aqueous phase was extracted with dichloroethane (1.5 L*2), and the organic phases were combined, washed with saturated brine (1 liter), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 760 g of a crude compound of formula III. This crude product was slurried with petroleum ether to obtain 700 g of a pure product.
[0053] In a 10L reactor, add 4.4L of anhydrous ethanol and 700g of the compound shown in Formula III, protect with nitrogen, control the temperature below 30°C, add sodium ethoxide (198g) in batches, the temperature rise is not obvious, control the temperature below 30°C, and after the addition, heat to 60°C for 4 hours, monitor the liquid phase, the reaction is completed, vacuum concentrate (50°C) to dryness, add 2L of ethyl acetate and 3L of ice water to the residue, stir evenly, and filter. The filtrate is separated, the water layer is extracted once with 1L of ethyl acetate, the organic layers are combined, washed once with 1L of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 450g of the target product shown in Formula IV.
[0054] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.
[0055] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.
Claims
1. A method for synthesizing a sparsentan intermediate, characterized in that: The compound represented by formula I is used as a raw material to react in the presence of an acid in an ethanol solvent to obtain an intermediate compound represented by formula II. The intermediate compound represented by formula II is then subjected to a chloromethylation reaction to synthesize a compound represented by formula III. The compound represented by formula III is then reacted with sodium ethoxide to produce a spassentan intermediate represented by formula IV. The synthetic route is:
2. The method for synthesizing a sparsentan intermediate according to claim 1, characterized in that: The steps include: Step (1), using the compound of formula 1 as a raw material, adding ethanol and acid to the mixture, heating and refluxing for a period of time, then cooling, concentrating under reduced pressure, extracting, backwashing, and concentrating under reduced pressure again to obtain an intermediate compound of formula II; Step (2), heating the intermediate compound represented by formula II with a chlorine-containing Lewis acid, hydrochloric acid and paraformaldehyde in a solvent for reaction, extracting, washing, drying and concentrating under reduced pressure after the reaction to obtain a compound represented by formula III; Step (3), heating the compound represented by formula III and sodium ethoxide in ethanol for reaction, cooling and filtering after the reaction, and concentrating under reduced pressure to obtain the sparsentan intermediate represented by formula IV.
3. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: In step (1), the molar ratio of the compound represented by formula I to the acid is 1:(0.15-0.60), and the volume molar ratio of ethanol to the compound represented by formula I is (3-5) ml:1 g.
4. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: The reaction temperature of step (1) is 80-90°C and the reaction time is 16-24h.
5. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: In step (2), the molar ratio of paraformaldehyde to the intermediate compound shown in formula II is (1.3-3.0):1, the molar ratio of the intermediate compound shown in formula II to the chlorine-containing Lewis acid is 1:(0.5-1.0), and the mass volume ratio of the intermediate compound shown in formula II to hydrochloric acid is 1g:(0.0-3.0)ml.
6. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: The chlorine-containing Lewis acid is at least one of zinc chloride, aluminum chloride and chlorosulfonic acid.
7. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: The reaction temperature of step (2) is 50-80°C and the reaction time is 3-8h.
8. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: In step (3), the molar ratio of the compound represented by formula III to sodium ethoxide is 1:(1.2-1.5).
9. The method for synthesizing a sparsentan intermediate according to claim 2, characterized in that: The reaction temperature of step (3) is 50-80°C and the reaction time is 3-10h.