Application of Mitsunobu reagent in synthesis of ipropam hydrochloride

Abstract

The invention belongs to the field of drug synthesis, and particularly relates to an application of a Mitsunobu reagent in the synthesis of ipropam hydrochloride, which is characterized in that an aldehyde group is reduced into benzyl alcohol by sodium borohydride in a protic solvent to obtain an intermediate 1; the intermediate 1 rapidly reacts in BEHT trifluoromethanesulfonate, a high-purity intermediate 2 can be obtained through simple extraction, water washing, recrystallization and filtration, and the BEHT trifluoromethanesulfonate has the characteristic of high conversion rate which is not possessed by other ordinary Mitsunobu reaction reagents in the reaction. The intermediate 2 is hydrolyzed by sodium hydroxide and deprotected by trifluoroacetic acid, and the purity reaches 99% or above under recrystallization. The method is high in reaction conversion rate, high in repeatability, simple in preparation method, low in equipment requirement and easy for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to the application of a photocatalytic reagent in the synthesis of iprocoprine hydrochloride. Background Technology

[0002] Ipoxopram hydrochloride is the first oral inhibitor of factor B targeting the alternative complement pathway, used to treat paroxysmal nocturnal hemoglobinuria (PNH) in adults.

[0003] Ipoxopram hydrochloride (represented as API) has the chemical name 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoate, and its structural formula is as follows:

[0004]

[0005] Patent CN112513025A discloses a method for synthesizing a key intermediate of iprocoprine hydrochloride, using Ir(CO)₂acac as a catalyst, and undergoing reduction and hydrogenation at a hydrogen pressure of 20 bar to obtain intermediate 2. This method requires a large amount of catalyst and has a conversion rate of only 62%-88%, resulting in excessively high costs. Furthermore, it uses special pressurized equipment (hydrogenation reactor), which carries certain risks. The reaction route is shown below:

[0006]

[0007] Patent CN114057692B discloses another synthetic method for a key intermediate of iprocoprine hydrochloride, which uses sodium borohydride acetate, which undergoes a reductive amination reaction to obtain intermediate 2. This method carries certain risks due to the use of sodium borohydride acetate, and the yield is too low (14%), resulting in excessively high costs. The reaction route is shown below:

[0008]

[0009] Based on this, the present invention is proposed. Summary of the Invention

[0010] The purpose of this invention is to provide an application of a photopolymerization reagent in the synthesis of iprocoprine hydrochloride, in order to solve the above-mentioned problems.

[0011] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies. This invention proposes an important application of a photopolymerization reagent (BEHT trifluoromethanesulfonate) in the synthesis of a key intermediate (intermediate 2) of iprodione hydrochloride, bypassing the low yield problems of heavy metal-catalyzed pressurized reactions and sodium borohydride reducing amination. This improves yield and purity while reducing cost.

[0012] The structural formula of BEHT trifluoromethanesulfonate is shown in Formula 1:

[0013]

[0014] Studies have shown that this reagent poses no risk of explosion and has good stability. HNMR Verify its chemical stability.

[0015] Reaction mechanism: BEHT trifluoromethanesulfonate activates alcohols via protonation of betaine intermediates to form phosphonium ions, which are then substituted by nucleophiles (such as amines) via an SN2 pathway, accompanied by configuration inversion.

[0016]

[0017] This invention uses 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as the starting material to synthesize intermediate 1, 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester. This intermediate further undergoes a photo-extending reaction with a chiral amine to obtain intermediate 2. Intermediate 2 is hydrolyzed under alkaline conditions and then undergoes a deprotection reaction under acidic conditions to obtain iprocoprine hydrochloride. The synthetic process of this invention is simple, with good yields and a purity exceeding 99%.

[0018] The application of a photo-extending reagent in the synthesis of iprocoprine hydrochloride, wherein the photo-extending reagent is one of diisopropyl azodicarbonate, diethyl azodicarbonate, tetramethylazodicarbonamide, and BEHT trifluoromethanesulfonate.

[0019] The structural formula of BEHT trifluoromethanesulfonate is shown in Formula 1:

[0020]

[0021] A further improvement is made to the method for synthesizing iprocoprine hydrochloride, which includes the following steps:

[0022] Step 1: Add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester to a protic solvent, then add a reducing agent in batches to carry out the reaction. After the reaction is completed, wash with water, separate the liquid and concentrate to obtain intermediate 1.

[0023] Step 2: Add the first solvent, intermediate 1, and chiral amine to the photo-extending reagent and react under inert gas protection. After the reaction is complete, wash with water and concentrate to obtain intermediate 2.

[0024] Step 3: Intermediate 2 reacts with the hydrolysis reagent and the second solvent to obtain intermediate 3;

[0025] Step 4: Intermediate 3 is reacted in a third solvent and a deprotecting agent to obtain iprocoprine hydrochloride.

[0026] In a further improvement, the reaction temperature in step 1 is 0°C, and after the reaction is completed, it is cooled to 0°C and hydrochloric acid is added dropwise to quench the reaction.

[0027] In a further improvement, the reducing agent in step 1 is selected from sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and hydrogen, and the proton solvent is selected from methanol, ethanol, isopropanol, and tetrahydrofuran.

[0028] In a further improvement, the hydrolysis reagent in step 3 is one of lithium hydroxide solution, sodium hydroxide solution, or potassium hydroxide solution.

[0029] In a further improvement, the deprotection reagent in step 4 is selected from one of hydrochloric acid, trifluoroacetic acid, and sulfuric acid.

[0030] A further improvement is made to the preparation method of the BEHT trifluoromethanesulfonate, which includes the following steps:

[0031] Dichloromethane and triphenylphosphine were cooled to 0-5°C, and under nitrogen protection, diethyl azodicarbonate and trifluoromethanesulfonic acid were added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred until a solid precipitated. The mixture was concentrated, crystallized, and filtered to obtain BEHT trifluoromethanesulfonate.

[0032] In a further improvement, the first solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, n-heptane, and n-hexane.

[0033] In a further improvement, the third solvent is one or more of water, methanol, ethanol, tetrahydrofuran, and isopropanol.

[0034] In a further improvement, the second solvent is one or more of methanol, ethanol, tetrahydrofuran, and isopropanol.

[0035] Compared with the prior art, the beneficial effects of this invention are as follows:

[0036] The preparation method of this invention involves reducing an aldehyde group to benzyl alcohol in a protic solvent using sodium borohydride. After the reaction is complete, only liquid-liquid separation, concentration, and crystallization are required to obtain high-purity intermediate 1. Intermediate 1 reacts rapidly in a readily available photo-extending reagent (BEHT trifluoromethanesulfonate). After simple extraction, washing with water, recrystallization, and filtration, high-purity intermediate 2 is obtained. The special photo-extending reagent (BEHT trifluoromethanesulfonate) exhibits a high conversion rate in this step that is not found in other common photo-extending reagents. This reaction avoids the use of high-cost catalysts and low yields in the original literature, enabling this route to achieve production at a lower cost. After hydrolysis with sodium hydroxide and deprotection with trifluoroacetic acid, the final product obtained by recrystallization of intermediate 2 achieves a purity of over 99%. Furthermore, the preparation method of this invention has a high reaction conversion rate, strong reproducibility, simple preparation method, low equipment requirements, and is easy to industrialize. Attached Figure Description

[0037] Figure 1 This is the liquid phase spectrum of intermediate 1 obtained in Example 1;

[0038] Figure 2 This is the liquid phase spectrum of intermediate 2 obtained in Example 3;

[0039] Figure 3 This is the liquid phase spectrum of intermediate 3 obtained in Example 4;

[0040] Figure 4 This is the liquid phase spectrum of iprocoprine hydrochloride obtained in Example 5;

[0041] Figure 5 This is the 1H NMR spectrum of intermediate 1 obtained in Example 1;

[0042] Figure 6 This is the 1H NMR spectrum of BEHT trifluoromethanesulfonate obtained in Example 2;

[0043] Figure 7 This is the 1H NMR spectrum of intermediate 2 obtained in Example 3;

[0044] Figure 8 This is the 1H NMR spectrum of iprocoprine hydrochloride obtained in Example 5. Detailed Implementation

[0045] The present invention will now be described in further detail with reference to specific embodiments and accompanying drawings.

[0046] Example 1: Synthesis of Intermediate 1:

[0047] At 0°C, 50 mL of methanol was added sequentially to a 100 mL three-necked flask, followed by 5.0 g (17.3 mmol) of 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester. Then, 1.38 g (36 mmol) of sodium borohydride was added in portions. The mixture was stirred for 4–6 h, and TLC showed no significant residue of the starting material. The mixture was quenched dropwise with 20 mL of 2 mol / L hydrochloric acid, and then 50 mL of water and 50 mL of ethyl acetate were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.9 g (yield: 96%) of an off-white intermediate 1. MS m / z (ESI): 292.12 [M+1].

[0048] 1HNMR(400MHz,DMSO-d6)ppm7.60-7.61(d,1H),6.84(s,1H),6.79-6.80(d,,1H) ,4.77-4.80(m,1H),4.67-4.68(d,2H),3.82(s,3H),2..54(s,3H),1.60(s,9H).

[0049] The liquid phase spectrum of intermediate 1 is shown below. Figure 1 The proton NMR spectrum of intermediate 1 is shown below. Figure 5 .

[0050] Example 2: Synthesis of the photoelectrophoresis reagent BEHT trifluoromethanesulfonate:

[0051] At room temperature, 80 mL of dichloromethane and 20 g (896 mmol) of triphenylphosphine were added sequentially to a 250 mL three-necked flask. The temperature was lowered to 0-5 °C, and under nitrogen protection, 13.3 g (896 mmol) of DEAD (diethyl azodicarbonate) and 11.5 g (896 mmol) of trifluoromethanesulfonic acid were added dropwise. After the addition was completed, the temperature was restored to room temperature, and stirring was continued for 4-6 hours. A solid precipitated out. Half of the 40 mL of dichloromethane was concentrated, and then another 300 mL of dichloromethane was added. Crystallization occurred, and the product was filtered to obtain a pale yellow powder, BEHT trifluoromethanesulfonate (37.27 g, yield 83.5%). The product may contain a small amount of triphenylphosphine.

[0052] 1H NMR (400MHz, DMSO) δ10.56 (s, 0H), 7.99 (t, J = 7.1Hz, 1H), 7.96–7.81 (m, 4H), 4.0 8–4.03(m,1H),4.00–3.95(m,1H),1.19(t,J=7.2Hz,3H),0.97(t,J=7.0Hz,3H).

[0053] The 1H NMR spectrum of BEHT trifluoromethanesulfonate is shown below. Figure 6 .

[0054] Example 3: Synthesis of Intermediate 2:

[0055] At room temperature, 50 mL of dichloromethane, 5 g (17.2 mmol) of intermediate 1, 4.5 g (17.2 mmol) of chiral amine, and 2.22 g (17.2 mmol) of DIPEA (N,N-diisopropylethylamine) were added sequentially to a 250 mL three-necked flask. The mixture was cooled to 0-5 °C, and 12 g (21 mmol) of BEHT trifluoromethanesulfonate was added in portions under nitrogen protection. The mixture was stirred for 2 h, and TLC showed no obvious residue of raw material. 30 mL of water was added dropwise, and the mixture was separated. The organic phase was washed once with water and once with saturated brine. The solution was dried over anhydrous sodium sulfate and concentrated to obtain 10.2 g of brown solid. 20 mL of ethanol was added, and the mixture was recrystallized by reflux. The solution was cooled to 10-15 °C and filtered to obtain a white powder intermediate 2 (8.4 g, yield: 91.3%). 1 H NMR (400MHz, CDCl3) δ = 8.07 (d, J = 8.2, 2H), 7.67 (d, J = 7.7, 2H), 7.50 (d, J = 3.8, 1H),6.70(s,2H),3.95(s,3H),3.82(s,3H),3.64(t,J=14.5,3H),3.53(q,J=7. 1,2H),3.33(d,J=12.1,1H),2.63(d,J=15.7,4H),2.45(t,J=12.0,1H),1.98(d ,J=14.2,1H),1.79(t,J=11.2,2H),1.67(d,J=19.5,10H),1.29(t,J=7.0,3H).

[0056] The liquid phase spectrum of intermediate 2 is shown below. Figure 2 The proton NMR spectrum of intermediate 2 is shown below. Figure 7 .

[0057] Example 4: Synthesis of intermediate 3:

[0058] At room temperature, 40 mL of methanol, 10 mL of water, 8.0 g (14.6 mmol) of intermediate 2, and 30 mL (29.7 mmol) of 1 mol / L sodium hydroxide solution were added sequentially to a 250 mL three-necked flask. The mixture was heated to 50 °C and stirred for 2 h. TLC showed no obvious residue of raw material. The methanol was concentrated to dryness, 30 mL of water was added, and 2 mol / L hydrochloric acid was added dropwise to adjust the pH to 4-5. A solid precipitated out, which was filtered and dried to obtain a pale yellow solid intermediate 3 (7.3 g, yield: 93.6%).

[0059] The liquid phase spectrum of intermediate 3 is shown below. Figure 3 .

[0060] Example 5: Synthesis of iprocopran hydrochloride:

[0061] At room temperature, 30 mL of isopropanol, 7.0 g (13.4 mmol) of intermediate 3, and 20 mL (40 mmol) of 2 mol / L methanol hydrochloride were added sequentially to a 250 mL three-necked flask. The mixture was heated to 50-60 °C and stirred for 2 h. TLC showed no obvious residue of raw material. The solvent was concentrated to dryness, 22.5 mL of water was added dropwise, and the mixture was cooled to 10 °C and stirred for 1 h before filtration to obtain a white powder of iprocoplasma hydrochloride (API) (5.1 g, yield: 92.7%). MS m / z (ESI): 423.1 [M+1].

[0062] 1HNMR (400MHz, DMSO-d6δ) 12.89 (s, 1H), 10.85 (s, 1H), 8.13 (s, 0.9H), 7.99 (d, J = 8.0Hz, 2H), 7.69 (d, J=8.0Hz,2H),7.26(t,J=2.6Hz,1H),6.66(s,1H),6.42(t,J=2.6Hz,,1H),3.71(s,3H),3.53(d,J=11. 6Hz,1H),3.21(d,J=11.6Hz,1H),2.84(d,J=12.0Hz,1H),2.70-2.65(m,0.5H),2.54(s,1H),2.42(s,3 H),2.35-2.30(m,0.5H),2.12-2.02(m,1H),1.86-1.70(m,2H),1.59-1.48(m,1H),1.38-1.29(m,1H).

[0063] The liquid chromatography spectrum of iprocopran hydrochloride is shown below. Figure 4 The proton NMR spectrum of iprocoprine hydrochloride is shown below. Figure 8 .

[0064] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The application of a photoelectrophoresis reagent in the synthesis of iprocoprine hydrochloride, characterized in that: The photopolymerization reagent is one of diisopropyl azodicarbonate, diethyl azodicarbonate, tetramethylazodicarbonamide, and BEHT trifluoromethanesulfonate. The structural formula of BEHT trifluoromethanesulfonate is shown in Formula 1:

2. The application of the photopolymerization reagent according to claim 1 in the synthesis of iprocoprine hydrochloride, characterized in that: The method for synthesizing iprocoprine hydrochloride includes the following steps: Step 1: Add 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester to a protic solvent, then add a reducing agent in batches to carry out the reaction. After the reaction is completed, wash with water, separate the liquid and concentrate to obtain intermediate 1. Step 2: Add the first solvent, intermediate 1, and chiral amine to the photo-extending reagent and react under inert gas protection. After the reaction is complete, wash with water and concentrate to obtain intermediate 2. Step 3: Intermediate 2 reacts with the hydrolysis reagent and the second solvent to obtain intermediate 3; Step 4: Intermediate 3 is reacted in a third solvent and a deprotecting agent to obtain iprocoprine hydrochloride.

3. The application of the photopolymerization reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The reaction temperature in step 1 is 0℃. After the reaction is completed, the temperature is cooled to 0℃, and hydrochloric acid is added dropwise to quench the reaction.

4. The application of the photopolymerization reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The reducing agent in step 1 is selected from sodium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and hydrogen, and the protic solvent is selected from methanol, ethanol, isopropanol, and tetrahydrofuran.

5. The application of the photopolymerization reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The hydrolysis reagent in step 3 is one of lithium hydroxide solution, sodium hydroxide solution, or potassium hydroxide solution.

6. The application of the photoelectrophoresis reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The deprotection reagent in step 4 is selected from hydrochloric acid, trifluoroacetic acid, and sulfuric acid.

7. The application of the photopolymerization reagent according to claim 1 in the synthesis of iprocoprine hydrochloride, characterized in that: The preparation method of the BEHT trifluoromethanesulfonate includes the following steps: Dichloromethane and triphenylphosphine were cooled to 0-5°C, and under nitrogen protection, diethyl azodicarbonate and trifluoromethanesulfonic acid were added dropwise. After the addition was complete, the mixture was brought back to room temperature and stirred until a solid precipitated. The mixture was concentrated, crystallized, and filtered to obtain BEHT trifluoromethanesulfonate.

8. The application of the photoelectrophoresis reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The first solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, n-heptane, and n-hexane.

9. The application of the photopolymerization reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The third solvent is one or more of water, methanol, ethanol, tetrahydrofuran, and isopropanol.

10. The application of the photoelectrophoresis reagent according to claim 2 in the synthesis of iprocoprine hydrochloride, characterized in that: The second solvent is one or more of methanol, ethanol, tetrahydrofuran, and isopropanol.

Images