Synthesis method of Pinefibrate intermediate

Abstract

The invention discloses a synthetic method of a Pinefibrate intermediate, which belongs to the technical field of drug intermediate synthesis, and is characterized in that 3-(4-methoxyphenoxy) propylamine reacts with m-chlorophenol and homologues thereof and 2-chlorobenzoxazole and homologues thereof, and the Pinefibrate intermediate is prepared by adopting a one-pot method. The method has the beneficial effects that the acid-binding agent is creatively utilized, 3-(4-methoxyphenoxy) propylamine reacts with m-chlorophenol and homologues thereof and 2-chlorobenzoxazole and homologues thereof, and the one-pot method is adopted to prepare the palmacate intermediate, so that the reaction period is greatly shortened, and the problems that the process route is relatively long and the cost is high in the prior art are solved. And the problems of low production efficiency, low yield, difficulty in industrial production and the like of palmacate are invisibly caused.

Description

Technical field:

[0001] The present invention belongs to the technical field of pharmaceutical intermediate synthesis, and more specifically relates to a method for synthesizing a Pemabet intermediate. Background technology:

[0002] Pemafibrate is a novel, highly selective PPARα modulator that has been shown to be more effective than fenofibrate in regulating lipid metabolism. It reduces plasma triglyceride (TG) levels and increases high-density lipoprotein cholesterol (HDL-C) levels by binding to PPARα and regulating the expression of genes involved in lipid metabolism. On October 19, 2023, the China National Drug Administration accepted the marketing application for pemafibrate tablets. Previously, pemafibrate had been approved in Japan for the treatment of hyperlipidemia (including familial hyperlipidemia).

[0003] The only method for synthesizing Pemabet is the process route published by its original manufacturer, Japan Kowa Co., Ltd. The synthesis method of patent WO2006090768A is as follows:

[0004]

[0005] (S)-2-hydroxybutyric acid n-butyl ester (Compound B-1) and trifluoromethanesulfonic anhydride synthesize compound B, 3-hydroxybenzaldehyde (Compound A) and Compound B react under the action of alkaline substances to generate Compound C, Compound C and Compound D undergo condensation reaction to generate Compound E, Compound E and Compound F react to generate Compound G, and Compound G is deprotected to obtain the Pemabet product (Compound 1). The entire process route is a five-step reaction, and the process route is relatively long, which invisibly causes problems such as low production efficiency and low yield of Pemabet and difficulty in industrial production.

[0006] In the process route described in CN 116462638 A, compound 9 is first subjected to dehydration condensation with compound 10 to generate aldolamine, and then a reducing agent is added to complete the alkylation reaction of the amine through a reduction reaction to obtain compound 11, and then a substitution reaction is carried out with compound 12 to obtain compound 13. The synthesis method is as follows:

[0007]

[0008] This method adopts a step-by-step synthesis method with a long process route, which inevitably causes problems such as low production efficiency and yield of Pemabet and difficulty in industrial production. Summary of the invention:

[0009] In order to solve the above problems and overcome the shortcomings of the prior art, the present invention provides a method for synthesizing a Pemabet intermediate, which can effectively solve the problems of the step-by-step synthesis method, the long process route, and the invisibly low production efficiency and yield of Pemabet, as well as the difficulty in industrial production.

[0010] The specific technical solution of the present invention to solve the above technical problems is: a method for synthesizing a Pemabet intermediate, characterized by comprising the following steps:

[0011] Step 1: Under nitrogen protection, add 3-(4-methoxyphenoxy)propylamine to organic solvent I, stir evenly, add acid binding agent to the reaction system, and heat the system to reflux; add reactant I and reactant II dropwise to the reaction system, and control the temperature to react until the reaction is complete;

[0012] Step 2: distill under reduced pressure to remove the organic solvent I in the system;

[0013] Step 3: Add organic solvent II and purified water, stir evenly and let stand, collect the organic phase and aqueous phase after the first extraction,

[0014] Adding organic solvent II to the aqueous phase at least once for extraction, stirring evenly and letting it stand, and combining the organic phases after extraction;

[0015] Add hydrochloric acid aqueous solution to the combined organic phase, stir, then add saturated sodium chloride solution, stir evenly and let stand, then separate the liquids and retain the organic phase;

[0016] Step 4: Slowly add organic solvent III to the organic phase, control the temperature at 45°C and stir for 2 hours. After the addition is completed, cool to 10°C and stir for 3 hours, filter, and vacuum dry the filter cake to obtain the Pemabet intermediate;

[0017] The structural formula of the reactant I is:

[0018] The structural formula of the reactant II is:

[0019] R of the reactant I and the reactant II is F or Cl or Br or I.

[0020] Furthermore, the acid binding agent is 4-dimethylaminopyridine or N,N-diisopropylethylamine or triethylamine.

[0021] Furthermore, the molar ratio of the 3-(4-methoxyphenoxy)propylamine to the acid binding agent is 1:(1.2-1.5).

[0022] Furthermore, the organic solvent I is acetone, acetonitrile or tetrahydrofuran.

[0023] Furthermore, the molar ratio of the 3-(4-methoxyphenoxy)propylamine, reactant I and reactant II is 1:(1.0-1.5):(1.0-1.2):10.

[0024] Furthermore, the organic solvent II is ethyl acetate, dichloromethane or chloroform.

[0025] Furthermore, the organic solvent III is a C5-C8 alkane or n-butyl ether or methyl tert-butyl ether.

[0026] Furthermore, the mass percentage of the hydrochloric acid aqueous solution in step 3 is 3-5%.

[0027] The beneficial effects of the present invention are:

[0028] The present invention creatively utilizes an acid-binding agent to react 3-(4-methoxyphenoxy)propylamine with m-chlorophenol and its homologues and 2-chlorobenzoxazole and its homologues, and adopts a one-pot method to prepare a pemabet intermediate, thereby greatly shortening the reaction cycle and solving the problems in the prior art of a long process route, which invisibly causes low pemabet production efficiency, low yield and difficulty in industrial production. Description of the drawings:

[0029] Attached Figure 1 It is a photo of the intermediate of the product of the present invention, Pemabet; Specific implementation method:

[0030] In the description of the present invention, specific details are only for a full understanding of the embodiments of the present invention, but those skilled in the art should know that the implementation of the present invention is not limited to these details. In addition, well-known structures and functions are not described or shown in detail to avoid blurring the key points of the embodiments of the present invention. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0031] Specific implementation of the present invention:

[0032] In order to better understand the present invention, a specific embodiment is used for illustration. It is worth emphasizing that the effect of this embodiment is not substantially different from the various embodiments within the protection scope of the present invention, including the respective reagents and the content ratio of the reagents, and all of them can achieve the effects described in the present invention and solve the above-mentioned problems. Other combinations are not described here.

[0033] Embodiment 1:

[0034] Synthesis of Pemabet intermediates

[0035] Step 1: Under nitrogen protection, weigh 90.5g (0.5mol) of 3-(4-methoxyphenoxy)propylamine, add it to 290ml acetone solution, stir evenly, add 96.8g of N,N-diisopropylethylamine, heat to 50℃ and reflux. Weigh 66g of m-chlorophenol and 78g of 2-chlorobenzoxazole, slowly drip into the reaction system, control the temperature not to exceed 65℃, set the temperature to 50℃ after the addition is complete, stir the reaction for 10h, monitor the reaction process by TLC, and wait until the reaction is complete;

[0036] Step 2: At 35-40°C, P≤-0.085MPa, the system solution is subjected to reduced pressure distillation to remove acetone.

[0037] Step 3: 236 ml of ethyl acetate solution and 472 ml of purified water were added to the system, stirred for 10 min and then allowed to stand for 30 min. After the first extraction, the organic phase and the aqueous phase were collected separately. 236 ml of ethyl acetate was added to the aqueous phase, stirred for 10 min and then allowed to stand for 30 min. After the second extraction, the organic phase and the aqueous phase were collected separately. 236 ml of ethyl acetate was added to the aqueous phase for the third extraction. After the extraction, the organic phases were combined;

[0038] Add 159 ml of 3% hydrochloric acid aqueous solution to the combined organic phase, stir for 15 minutes, then add 159 ml of saturated sodium chloride solution for the fourth extraction, continue stirring for 15 minutes, let stand for 30 minutes, then separate the liquids and retain the organic phase;

[0039] Step 4: Slowly drop organic solvent III into the organic phase. Organic solvent III is a C5-C8 alkane. After multiple experiments, it has been verified that C5-C8 alkanes have no difference in the final effect of the present invention. As a preferred solution, n-heptane is used in this embodiment.

[0040] After the addition of 708 ml of n-heptane, the mixture was stirred at 45°C for 2 hours, then cooled to 10°C and stirred for 3 hours. The filter cake was vacuum dried at 60°C for 6 hours to obtain 150.9 g of Pemabet intermediate with a yield of 74.7%.

[0041] Embodiment 2:

[0042] Step 1: Under nitrogen protection, weigh 90.5g (0.5mol) of 3-(4-methoxyphenoxy)propylamine, add it to 360ml tetrahydrofuran solution, stir evenly, add 51g of triethylamine, heat to 58℃ and reflux. Weigh 87g of m-bromophenol and 99g of 2-bromobenzoxazole, slowly drip into the reaction system, control the temperature not to exceed 65℃, set the temperature to 55℃ after the addition is complete, stir the reaction for 10h, monitor the reaction process by TLC, and wait until the reaction is complete;

[0043] Step 2: At 35-40°C, P≤-0.085MPa, the system solution is subjected to reduced pressure distillation to remove the system solvent tetrahydrofuran.

[0044] Step 3: Add 236 ml of dichloromethane solution and 472 ml of purified water to the system, stir for 10 min and let stand for 30 min, collect the organic phase and the aqueous phase separately after the first extraction, add 236 ml of dichloromethane to the aqueous phase, stir for 10 min and let stand for 30 min, perform the second extraction, collect the organic phase and the aqueous phase separately, add 236 ml of dichloromethane to the aqueous phase for the third extraction, combine the organic phases after extraction, and discard the aqueous phase.

[0045] To the combined organic phase, add 159 ml of 4% hydrochloric acid aqueous solution, stir for 15 minutes, then add 159 ml of saturated sodium chloride solution for the fourth extraction, continue stirring for 15 minutes, let stand for 30 minutes, then separate the liquids and retain the organic phase.

[0046] Step 4: 708 ml of n-butyl ether was added dropwise to the organic phase under stirring. After the addition was completed, the temperature was controlled at 45°C and stirred for 2 hours, then the temperature was lowered to 10°C and stirred for 3 hours. Filter, and the filter cake was vacuum dried at 60°C for 6 hours to obtain 148.6 g of Pemabet intermediate with a yield of 73.6%.

[0047] Embodiment 3:

[0048] Under nitrogen protection, weigh 90.5g (0.5mol) of 3-(4-methoxyphenoxy)propylamine, add it to 360ml acetonitrile solution, stir evenly, add 62g of 4-dimethylaminopyridine, heat to 58℃ and reflux. Weigh 89g of 3-fluorophenol and 99g of 2-bromobenzoxazole, slowly drip into the reaction system, control the temperature not to exceed 65℃, after the addition is completed, set the temperature to 55℃, stir the reaction for 10h, and monitor the reaction process by TLC. Monitor the reaction process by TLC until the reaction is complete;

[0049] Step 2: At 35-40°C, P≤-0.085MPa, the system solution is subjected to reduced pressure distillation to remove the system solvent acetonitrile.

[0050] Step 3: Add 236 ml of chloroform solution and 472 ml of purified water to the system, stir for 10 min and then let stand for 30 min. After the first extraction, collect the organic phase and the aqueous phase separately. Add 236 ml of chloroform to the aqueous phase, stir for 10 min and then let stand for 30 min. After the second extraction, collect the organic phase and the aqueous phase separately. Add 236 ml of chloroform to the aqueous phase for the third extraction. After the extraction, combine the organic phases and discard the aqueous phase.

[0051] To the combined organic phase, add 159 ml of 5% hydrochloric acid aqueous solution, stir for 15 minutes, then add 159 ml of saturated sodium chloride solution for the fourth extraction, continue stirring for 15 minutes, let stand for 30 minutes, then separate the liquids and retain the organic phase.

[0052] Step 4: Add 708 ml of methyl tert-butyl ether dropwise to the organic phase under stirring. After the addition is completed, stir at 45°C for 2 hours, then cool to 10°C and stir for 3 hours. Filter and vacuum dry the filter cake at 60°C for 6 hours to obtain 152.1 g of Pemabet intermediate with a yield of 75.2%.

[0053] In order to more intuitively demonstrate the process advantages of the present invention, the synthesis method of the present invention using the Pemabet intermediate is compared with the method using equivalent replacement in the same process.

[0054] Comparative Example 1:

[0055] The same as Example 1, except that no acid binding agent was used, resulting in an incomplete reaction with a yield of only 21%, which is much lower than the reaction yield when an acid binding agent was used.

[0056] Comparative Example 2:

[0057] The same as Example 1, except that the reactants described in patent CN116462638A are introduced by reference, and the Pemabet intermediate is prepared by a one-pot reaction method as in the present invention; specifically:

[0058] Comparative Example 3:

[0059] Same as Example, except that reactant I is replaced by compound 10 in the route described in CN 116462638 A, that is, the compound of formula I and the compound of formula III and compound 10 are reacted under the reaction conditions described herein, and the compound of formula IV cannot be obtained.

[0060] Comparative Example 4:

[0061] The reactants described in the patent WO2006090768A are introduced in the cited manner, except that the Pemabet intermediate is prepared by a one-time feeding method, i.e., a "one-pot method" as in the present invention; specifically:

[0062] In route 1, compound C, compound D and compound F also cannot be reacted in one pot to obtain compound G. The reaction between compound C and compound D also belongs to an aldehyde-amine condensation reaction. One molecule of H2O is removed during the reaction, and then a reducing agent is added to complete the alkylation reaction of the amine through a reduction reaction, and then a substitution reaction is carried out to generate compound G. This reaction route is the same type of reaction as the route described in CN116462638 A.

[0063] Table 1: Comparative test data of different embodiments and comparative examples

[0064]

[0065] From the data analysis in Table 1, we can see that:

[0066] (1) It can be seen from Examples 1-3 that the present invention creatively utilizes an acid-binding agent to react 3-(4-methoxyphenoxy)propylamine with m-chlorophenol and its homologues and 2-chlorobenzoxazole and its homologues, and adopts a one-pot method to prepare the pemabet intermediate, which greatly shortens the reaction cycle and solves the problems in the prior art that the process route is long, which invisibly causes low pemabet production efficiency, low yield and difficulty in industrial production.

[0067] (2) In Comparative Example 1, since no acid binding agent was used, the reaction was not complete and the yield was only 21%, which was much lower than the reaction yield when an acid binding agent was used.

[0068] (3) In Comparative Example 2:

[0069] Compound 9 is first subjected to dehydration condensation with compound 10 to generate aldehyde amine, and then a reducing agent is added to complete the alkylation reaction of the amine through a reduction reaction to obtain compound 11, and then a substitution reaction is carried out with compound 12 to obtain compound 13. Compound 9, compound 10, and compound 12 are put into the reaction at the same time. Although an acid binding agent is used, a "one-pot" reaction cannot be carried out to obtain compound 13, because these belong to two different reaction types and different catalysts are used.

[0070] (4) In Comparative Example 3: Reactant I was replaced with compound 10 in the route described in CN 116462638 A, that is, the compound of formula I and the compound of formula III and compound 10 were reacted under the reaction conditions described herein, but the compound of formula IV could not be obtained.

[0071] (5) In Comparative Example 4, the Pemabet intermediate is prepared by a one-pot reaction as in the present invention; in Route 1, Compound C, Compound D and Compound F cannot be reacted in a one-pot reaction to obtain Compound G. The reaction between Compound C and Compound D also belongs to an aldehyde-amine condensation reaction, in which a molecule of H2O is removed, and then a reducing agent is added to complete the alkylation reaction of the amine through a reduction reaction, and then a substitution reaction is carried out to generate Compound G. This reaction route is the same type of reaction as the route described in CN116462638A.

[0072] As a preferred embodiment of the present invention, the present invention also examines the effect of the crystallization process on the preparation of the Pemabet intermediate;

[0073] Embodiment 4:

[0074] Same as Example 1, except that the crystallization process in step 4 is different, specifically:

[0075] Step 4: Slowly drop organic solvent III into the organic phase. Organic solvent 3 is a C5-C8 alkane. After multiple experiments, it has been verified that C5-C8 alkanes have no difference in the final effect of the present invention. As a preferred solution, n-heptane is used in this embodiment.

[0076] Slowly add 236 ml of n-heptane to the organic phase, and after the addition is completed, control the temperature at 45°C and stir for 2 hours, continue to add 472 ml of n-heptane, and after the addition is completed, cool to 10°C and stir for 3 hours. Filter until no liquid flows out, and vacuum dry the filter cake at 60°C for 6 hours to obtain 156.8 g of Pemabet intermediate with a yield of 77.6%.

[0077] Embodiment 5:

[0078] Same as Example 2, except that the crystallization process in step 4 is different, specifically:

[0079] Slowly add 236 ml of n-butyl ether to the organic phase, and after the addition is completed, control the temperature at 45°C and stir for 2 hours, continue to add 472 ml of n-butyl ether, and after the addition is completed, cool to 10°C and stir for 3 hours. Filter until no liquid flows out, and vacuum dry the filter cake at 60°C for 6 hours to obtain 157.4 g of Pemabet intermediate with a yield of 77.9%.

[0080] Embodiment 6:

[0081] Same as Example 3, except that the crystallization process in step 4 is different, specifically:

[0082] Slowly add 236 ml of methyl tert-butyl ether to the organic phase, and after the addition is completed, control the temperature at 45°C and stir for 2 hours, continue to add 472 ml of methyl tert-butyl ether, and after the addition is completed, cool to 10°C and stir for 3 hours. Filter until no liquid flows out, and vacuum dry the filter cake at 60°C for 6 hours to obtain 158.2 g of Pemabet intermediate with a yield of 78.3%.

[0083] Table 2: Yields of Pemabet intermediates prepared in different examples

[0084] Reactant 2 Reactant 3 Acid Binding Agent Reaction Principle Crystallization Yield Example 1 m-Chlorophenol 2-Chlorobenzoxazole N,N-Diisopropylethylamine One Pot Method once 74.7％ Example 2 m-Bromophenol 2-Bromobenzoxazole Triethylamine One Pot Method once 73.6％ Example 3 3-Fluorophenol 2-Bromobenzoxazole 4-Dimethylaminopyridine One Pot Method once 75.2％ Example 4 m-Chlorophenol 2-Chlorobenzoxazole N,N-Diisopropylethylamine One Pot Method Two steps 77.6％ Example 5 m-Bromophenol 2-Bromobenzoxazole Triethylamine One Pot Method Two steps 77.9％ Example 6 3-Fluorophenol 2-Bromobenzoxazole 4-Dimethylaminopyridine One Pot Method Two steps 78.3％

[0085] From the analysis of Table 2, we can see that:

[0086] The yield of Example 4-6 is higher than that of Example 1-3, indicating that: compared with the single crystallization, although the same amount of crystallization solvent is used, the yield of the double crystallization is higher than that of the single crystallization.

[0087] However, two step crystallizations and one crystallization will not affect the overall reaction.

[0088] To sum up: the present invention creatively utilizes an acid binding agent to react 3-(4-methoxyphenoxy)propylamine with m-chlorophenol and its homologues and 2-chlorobenzoxazole and its homologues, and adopts a one-pot method to prepare the pemabet intermediate, which greatly shortens the reaction cycle and solves the problems in the prior art that the process route is long, which invisibly causes low pemabet production efficiency, low yield and difficulty in industrial production.

Claims

1. A method for synthesizing a Pemabet intermediate, characterized in that The steps include: Step 1: Under nitrogen protection, add 3-(4-methoxyphenoxy)propylamine to organic solvent I, stir evenly, add acid binding agent to the reaction system, and heat the system to reflux; add reactant I and reactant II dropwise to the reaction system, and control the temperature to react until the reaction is complete; Step 2: distill under reduced pressure to remove the organic solvent I in the system; Step 3: Add organic solvent II and purified water, stir evenly and let stand, collect the organic phase and aqueous phase after the first extraction, Adding organic solvent II to the aqueous phase at least once for extraction, stirring evenly and letting it stand, and combining the organic phases after extraction; Add hydrochloric acid aqueous solution to the combined organic phase, stir, then add saturated sodium chloride solution, stir evenly and let stand, then separate the liquids and retain the organic phase; Step 4: Slowly add organic solvent III to the organic phase, control the temperature at 45°C and stir for 2 hours. After the addition is completed, cool to 10°C and stir for 3 hours, filter, and vacuum dry the filter cake to obtain the Pemabet intermediate; The structural formula of the reactant I is: The structural formula of the reactant II is: R of the reactant I and the reactant II is F or Cl or Br or I.

2. The method for synthesizing the Pemabet intermediate according to claim 1, characterized in that The acid binding agent is 4-dimethylaminopyridine or N,N-diisopropylethylamine or triethylamine.

3. The method for synthesizing the Pemabet intermediate according to claim 2, characterized in that The molar ratio of the 3-(4-methoxyphenoxy)propylamine to the acid binding agent is 1:(1.2-1.5).

4. The method for synthesizing the Pemabet intermediate according to claim 1, characterized in that The organic solvent I is acetone, acetonitrile or tetrahydrofuran.

5. The method for synthesizing the Pemabet intermediate according to claim 1, characterized in that The molar ratio of the 3-(4-methoxyphenoxy)propylamine, reactant I and reactant II is 1:(1.0-1.5):(1.0-1.2):

10.

6. The method for synthesizing the Pemabet intermediate according to claim 1, characterized in that The organic solvent II is ethyl acetate, dichloromethane or chloroform.

7. The method for synthesizing the Pemabet intermediate according to claim 1, characterized in that The organic solvent III is C5-C8 alkane or n-butyl ether or methyl tert-butyl ether.

8. The method for synthesizing the Pemabet intermediate according to claim 1, characterized in that The mass percentage of the hydrochloric acid aqueous solution in step 3 is 3-5%.

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