CN116041259A - Hydroxychloroquine derivative and preparation method thereof - Google Patents

Abstract

The invention discloses a hydroxychloroquine derivative and a preparation method thereof. The raw materials are commercially available, the cost is low, the reaction conditions of each unit in the reaction process are mild and controllable, the yield is high, and the obtained hydroxychloroquine valine ester salt has high purity, good water solubility and strong stability, and is suitable for large-scale production and application of hydroxychloroquine amino acid ester salt.

Description

Hydroxychloroquine derivative and preparation method thereof

Technical Field

The invention relates to the field of biological medicine, in particular to a hydroxychloroquine derivative and a preparation method thereof.

Background

Hydroxychloroquine (HCQ) belongs to the 4-aminoquinoline phospholipase A2 inhibitor, and was synthesized in the earliest 1944. Since weakly basic hydroxychloroquine enters cells and accumulates in lysosomal acid vesicles, release of haemolytic enzymes is inhibited by an increase in lysosomal pH, thereby affecting haemolytic levels, interfering with plasmodium growth, and originally used for malaria treatment. In the subsequent researches, hydroxychloroquine is found to have anti-inflammatory effect, particularly has good treatment effect on systemic lupus erythematosus, is the first medicament for treating lupus erythematosus in China at present, has good treatment effect on oral discoid lupus erythematosus, and has obvious improvement on various signs of patients compared with the prior treatment, and adverse reaction is slight; the Chinese medicinal composition has definite curative effect on treating the rheumatoid arthritis, can improve the symptoms of the rheumatoid arthritis, and has extremely low incidence of adverse reaction. Meanwhile, hydroxychloroquine also has pharmacological effects of reducing blood sugar, reducing blood fat, resisting infection and the like. In recent studies, hydroxychloroquine has been found to have a therapeutic effect on cardiovascular diseases, renal diseases and tumors.

Hydroxychloroquine was found to have some anti-covd-19 activity in the early stages of 2019's new coronaries. The results of 36 new coronavirus patients diagnosed in france, using a treatment regimen of hydroxychloroquine in combination with azithromycin from an early stage, showed that hydroxychloroquine treatment was effective and resulted in a significant correlation with the reduction/disappearance of the new coronavirus load. Although hydroxychloroquine was ultimately demonstrated to have no therapeutic effect on new coronaries, this has led to a greater understanding of hydroxychloroquine studies.

However, hydroxychloroquine is oily liquid and has poor light stability, so that the hydroxychloroquine preparation is very difficult to succeed, and has poor water solubility and poor oral bioavailability. Thus Sanofi Aventis US LLC developed hydroxychloroquine sulfate-hydroxychloroquine sulfate. Hydroxychloroquine sulfate is white solid powder and is easy to dissolve in water, and is approved by the United states FDA to be marketed in the 4 th month of 1955 and the trade name of Plaquenil, the oral bioavailability of the hydroxychloroquine sulfate is up to 99 percent, and the hydroxychloroquine sulfate is clinically used for treating acute attack and control of malaria, discoid lupus erythematosus, systemic lupus erythematosus, acute and chronic rheumatic arthritis and the like.

But at present, the product is marketed in various countries worldwide such as europe and japan. However, similarly, hydroxychloroquine sulfate is poor in photostability, so that it is quite practical to find a novel water-soluble derivative of hydroxychloroquine with good stability.

The present invention is directed to a hydroxychloroquine derivative and a method for preparing the same, wherein hydroxychloroquine and valine are used for reaction, so as to improve the water solubility and stability of hydroxychloroquine.

Disclosure of Invention

The invention aims to overcome the defects of the technology and provide a hydroxychloroquine derivative and a preparation method thereof.

In order to solve the technical problems, the technical scheme provided by the invention is that the hydroxychloroquine derivative has a structure shown in a formula I:

the invention also provides a preparation method of the hydroxychloroquine derivative, which comprises the following steps:

step 1) adding hydroxychloroquine sulfate into a three-mouth bottle, adding pure water, adding NaOH, stirring in an ice bath, and extracting with ethyl acetate to obtain hydroxychloroquine;

step 2) adding hydroxychloroquine into DMF, adding CBZ-L-valine, adding DCC and DMAP, and stirring at normal temperature for reaction to obtain CBZ-L-hydroxychloroquine valine ester.

Step 3) adding CBZ-L-hydroxychloroquine valine ester into pure water, adding Pd/C, stirring at 15-20 ℃ for reaction, and slowly dropwise adding dilute hydrochloric acid while reacting to obtain hydroxychloroquine valine ester;

and 4) adding the hydroxychloroquine valine ester into an organic solvent, adding tetrahydrofuran as a catalyst, adding acid to form salt with the catalyst, and carrying out recrystallization refining to obtain the hydroxychloroquine valine ester salt.

Further, the molar ratio of hydroxychloroquine sulfate to NaOH in the step 1 is 1:1.1-1.3; the extraction solvent is any one of ethyl acetate, petroleum ether and toluene, and more preferably ethyl acetate.

Further, the molar ratio of hydroxychloroquine to CBZ-L-valine in the step 2 is 1:1.2-1.4; the molar ratio of DCC to hydroxychloroquine is 1:1.1-1.2; the amount of DMAP is 1 to 3 percent of the total mass of hydroxychloroquine and CBZ-L-valine.

Further, the molar ratio of CBZ-L-hydroxychloroquine valine ester to Pd/C in the step 3 is 1:1.3 to 1.4.

Further, the organic solvent in the step 4 is any one of ethyl acetate and DMF; the concentration of the dilute hydrochloric acid is 5-10%; the tetrahydrofuran content is 1-3% of hydroxychloroquine valine ester.

Further, the acid added in the step 4 is any one of dilute hydrochloric acid, hydrobromic acid and maleic acid; the solvent used for recrystallization is any one or a mixture of more of ethyl acetate, ethanol, acetone and dichloromethane, wherein the ethyl acetate is the best.

Compared with the prior art, the invention has the advantages that: the preparation method of the hydroxychloroquine derivative provided by the invention has reasonable step design, adopts hydroxychloroquine and valine as starting raw materials, and obtains water-soluble hydroxychloroquine valine ester salt through protection, acyl chlorination, esterification, deprotection and acidification salt formation reaction; the raw materials used in the invention are commercially available, the cost is low, the reaction conditions of each unit in the reaction process are mild and controllable, the yield is high, the purity of the obtained hydroxychloroquine valine ester salt is high, the water solubility is good, the stability is strong, and the method is suitable for large-scale production and application of hydroxychloroquine amino acid ester salt.

Drawings

FIG. 1 is a synthetic scheme of a hydroxychloroquine derivative and a preparation method thereof according to the invention.

Detailed Description

The following is a further detailed description of a hydroxychloroquine derivative and a method for preparing the same according to the present invention, with reference to examples.

EXAMPLE 1 preparation of hydroxychloroquine

In a dry 500mL three-necked flask, 21.7g hydroxychloroquine sulfate and 150mL pure water were added, and the mixture was stirred and dissolved, then 2.6g aqueous NaOH solution was added, 150mL ethyl acetate was slowly added while stirring to separate out an organic phase, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was further washed with saturated NaCl solution and pure water, and then dried over anhydrous sodium sulfate, filtered, concentrated and dried to give 16g of a colorless transparent oil, the yield was 95%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

4.16(s,1H),3.89(s,1H),8.36(d,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(d,1H),3.42(m,2H),2.63(m,1H),2.57(m,2H),2.43(m,2H),3.01(m,2H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H)

EXAMPLE 2 preparation of hydroxychloroquine

In a dry 500mL three-necked flask, 21.7g of hydroxychloroquine sulfate and 150mL of pure water were added, and the mixture was stirred and dissolved, then 2.2g of aqueous NaOH solution was added, 150mL of ethyl acetate was slowly added while stirring to separate out an organic phase, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, the organic phase was further washed with saturated NaCl solution and pure water, and then dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain 15.6g of a colorless transparent oil, the yield was 93%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

4.16(s,1H),3.89(s,1H),8.36(d,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(d,1H),3.42(m,2H),2.63(m,1H),2.57(m,2H),2.43(m,2H),3.01(m,2H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H)

EXAMPLE 3 preparation of hydroxychloroquine

In a dry 500mL three-necked flask, 21.7g hydroxychloroquine sulfate and 150mL pure water were added, and the mixture was stirred and dissolved, then 2.6g aqueous NaOH solution was added, 150mL toluene was slowly added while stirring to separate out an organic phase, the aqueous phase was extracted with toluene, the organic phases were combined, the organic phase was washed with saturated NaCl solution and pure water, dried over anhydrous sodium sulfate, filtered, concentrated and dried to give 15.1g of a colorless transparent oil, the yield was 90%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO)δ(ppm)；

4.16(s,1H),3.89(s,1H),8.36(d,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(d,1H),3.42(m,2H),2.63(m,1H),2.57(m,2H),2.43(m,2H),3.01(m,2H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H)

EXAMPLE 4 preparation of CBZ-L-hydroxychloroquine valine ester

In a dry 500mL single-neck flask, 16.8g of hydroxychloroquine and 17.57g of CBZ-L-valine are added, 250mL of DMF is added, the mixture is uniformly mixed, 12.36g of DCC and 1.03g of DMAP are added, and the mixture is stirred at normal temperature for reaction for 8 hours. The reaction solution was suction-filtered and the solvent was removed by rotary evaporation under vacuum to give 27.3g of CBZ-L-hydroxychloroquine valine ester as a white solid with a yield of 96%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),7.39(m,1H),8.36(d,1H),7.36(m,1H),7.73(m,1H),6.44(d,1H),8.23(d,1H),7.33(m,1H),7.33(m,1H),7.33(m,1H),7.32(m,1H),5.05(s,2H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.21(m,1H),1.44(m,1H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.98(m,3H),0.98(m,3H)

EXAMPLE 5 preparation of CBZ-L-hydroxychloroquine valine ester

In a dry 500mL single-neck flask, 16.8g of hydroxychloroquine and 15.06g of CBZ-L-valine are added, 250mL of DMF is added, the mixture is uniformly mixed, 12.36g of DCC and 0.96g of DMAP are added, and the mixture is stirred at normal temperature for reaction for 8 hours. The reaction solution was suction-filtered and the solvent was removed by rotary evaporation under vacuum to give 26.4g of CBZ-L-hydroxychloroquine valine ester as a white solid with a yield of 93%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),7.39(m,1H),8.36(d,1H),7.36(m,1H),7.73(m,1H),6.44(d,1H),8.23(d,1H),7.33(m,1H),7.33(m,1H),7.33(m,1H),7.32(m,1H),5.05(s,2H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.21(m,1H),1.44(m,1H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.98(m,3H),0.98(m,3H)

EXAMPLE 6 preparation of CBZ-L-hydroxychloroquine valine ester

In a dry 500mL single-neck flask, 16.8g of hydroxychloroquine and 17.57g of CBZ-L-valine are added, 250mL of DMF is added, the mixture is uniformly mixed, 11.33g of DCC and 1.03g of DMAP are added, and the mixture is stirred at normal temperature for reaction for 8 hours. The reaction solution was suction-filtered and the solvent was removed by rotary evaporation under vacuum to give 26g of CBZ-L-hydroxychloroquine valine ester as a white solid in 91.4% yield.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),7.39(m,1H),8.36(d,1H),7.36(m,1H),7.73(m,1H),6.44(d,1H),8.23(d,1H),7.33(m,1H),7.33(m,1H),7.33(m,1H),7.32(m,1H),5.05(s,2H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.21(m,1H),1.44(m,1H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.98(m,3H),0.98(m,3H)

EXAMPLE 7 preparation of valine hydroxychloroquine ester

Into a dry 250mL single-neck flask, 11.38g of CBZ-L-hydroxychloroquine valine ester is added, 100mL of pure water is added, 2.97g of Pd/C is added, 10 drops of diluted hydrochloric acid are slowly added dropwise, and the reaction is stirred for 12 hours at 15-20 ℃. The reaction solution was filtered and rotary evaporated in vacuo to give 8.55g of valyl hydroxychloroquine as a pale yellow oily liquid with a yield of 98%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),8.90(s,2H),8.36(d,1H),7.36(d,1H),7.73(d,1H),6.44(d,1H),8.23(d,1H),4.18(m,2H),2.63(m,1H),4.25(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.39(m,1H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.96(d,3H),0.96(d,3H)

EXAMPLE 8 preparation of valine hydroxychloroquine ester

Into a dry 250mL single-neck flask, 11.38g of CBZ-L-hydroxychloroquine valine ester is added, 100mL of pure water is added, 2.76g of Pd/C is added, 10 drops of diluted hydrochloric acid are slowly added dropwise, and the reaction is stirred for 12 hours at 15-20 ℃. The reaction solution was filtered and rotary evaporated in vacuo to give 8.28g of valyl hydroxychloroquine as a pale yellow oily liquid in 95% yield.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),8.90(s,2H),8.36(d,1H),7.36(d,1H),7.73(d,1H),6.44(d,1H),8.23(d,1H),4.18(m,2H),2.63(m,1H),4.25(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.39(m,1H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.96(d,3H),0.96(d,3H)

EXAMPLE 9 preparation of hydroxychloroquine valine hydrochloride

Into a 100mL single-neck flask, 4.36g of valine hydroxychloroquine and 25mL of LDMF are added, and the mixture is stirred at 15-20 ℃ for reaction, and 7 drops of 5% diluted hydrochloric acid are slowly added while the reaction is carried out. After the TLC detection reaction is finished, suction filtration is carried out, and filter cakes are dried in vacuum. And adding the filter cake into a 100mL single-neck flask, adding 40mL ethyl acetate, heating and refluxing to dissolve, cooling to 0-5 ℃, naturally crystallizing, filtering, washing the filter cake with cold ethyl acetate, and vacuum drying to obtain 4.35g of white solid hydroxychloroquine valine hydrochloride with the yield of 92%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),8.31(m,3H),8.36(m,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(m,1H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.95(m,1H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.93(d,3H),0.93(d,3H)

EXAMPLE 10 preparation of hydroxychloroquine valine hydrochloride

Into a 100mL single-neck flask, 4.36g of valine hydroxychloroquine and 25mL of LDMF are added, and the mixture is stirred at 15-20 ℃ for reaction, and 7 drops of 5% diluted hydrochloric acid are slowly added while the reaction is carried out. After the TLC detection reaction is finished, suction filtration is carried out, and filter cakes are dried in vacuum. And adding the filter cake into a 100mL single-neck flask, adding 40mL of acetone, heating and refluxing until the solution is clear, cooling to 0-5 ℃, naturally crystallizing, filtering, washing the filter cake with cold acetone, and vacuum drying to obtain 3.83g of white solid hydroxychloroquine valine hydrochloride with the yield of 81%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),8.31(m,3H),8.36(m,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(m,1H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.95(m,1H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.93(d,3H),0.93(d,3H)

EXAMPLE 11 preparation of valyl hydroxychloroquine hydrobromide

Into a 100mL single-neck flask, 4.36g of valine hydroxychloroquine and 25mL of MF are added, and the mixture is stirred at 15-20 ℃ to react, and 4 drops of hydrobromic acid are slowly dropped while the reaction is carried out. After the TLC detection reaction is finished, suction filtration is carried out, and filter cakes are dried in vacuum. And adding the filter cake into a 100mL single-neck flask, adding 40mL ethyl acetate, heating and refluxing to dissolve, cooling to 0-5 ℃, naturally crystallizing, filtering, washing the filter cake with cold ethyl acetate, and drying in vacuum to obtain 4.34g of white solid hydroxychloroquine hydrobromide with a yield of 84%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),8.31(m,3H),8.36(m,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(m,1H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.95(m,1H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.93(d,3H),0.93(d,3H)

EXAMPLE 12 preparation of hydroxychloroquine valine maleate

Into a 100mL single-neck flask, 4.36g of valine hydroxychloroquine and 25mL of MF were added, and the mixture was stirred at 15-20℃to react, and 2 drops of maleic acid were slowly added dropwise while reacting. After the TLC detection reaction is finished, suction filtration is carried out, and filter cakes are dried in vacuum. And adding the filter cake into a 100mL single-neck flask, adding 40mL ethyl acetate, heating and refluxing to dissolve, cooling to 0-5 ℃, naturally crystallizing, filtering, washing the filter cake with cold ethyl acetate, and vacuum drying to obtain 4.4g of white solid hydroxychloroquine maleate with the yield of 80%.

Nuclear magnetic resonance hydrogen spectrum data: ¹ H NMR(300MHz,DMSO),δ(ppm)：

3.89(s,1H),8.31(m,3H),8.36(m,1H),7.36(d,1H),7.73(s,1H),6.44(d,1H),8.23(m,1H),4.18(m,2H),2.63(m,1H),4.21(m,1H),2.97(m,2H),2.43(m,2H),3.01(m,2H),2.95(m,1H),1.44(m,2H),1.37(m,2H),1.17(m,3H),1.15(m,3H),0.93(d,3H),0.93(d,3H)。

the invention and its embodiments have been described above with no limitation, but the examples shown are only one of the embodiments of the invention, and the actual structure is not limited thereto. In summary, if one of ordinary skill in the art is informed by this disclosure, a structural manner and an embodiment similar to the technical solution should not be creatively devised without departing from the gist of the present invention.

Claims (7)

1. A hydroxychloroquine derivative, which is characterized in that the structure of the hydroxychloroquine derivative is shown as a formula I:

2. a process for the preparation of hydroxychloroquine derivatives, comprising the steps of:

step 1) adding hydroxychloroquine sulfate into a three-mouth bottle, adding pure water, adding NaOH, stirring in an ice bath, and extracting with ethyl acetate to obtain hydroxychloroquine;

step 2) adding hydroxychloroquine into DMF, adding CBZ-L-valine, adding DCC and DMAP, and stirring at normal temperature for reaction to obtain CBZ-L-hydroxychloroquine valine ester.

Step 3) adding CBZ-L-hydroxychloroquine valine ester into pure water, adding Pd/C, stirring at 15-20 ℃ for reaction, and slowly dropwise adding dilute hydrochloric acid while reacting to obtain hydroxychloroquine valine ester;

and 4) adding the hydroxychloroquine valine ester into an organic solvent, adding tetrahydrofuran as a catalyst, adding acid to form salt with the catalyst, and carrying out recrystallization refining to obtain the hydroxychloroquine valine ester salt.

3. The method for preparing hydroxychloroquine derivative according to claim 2, wherein: the mol ratio of hydroxychloroquine sulfate to NaOH in the step 1 is 1:1.1-1.3; the extraction solvent is any one of ethyl acetate, petroleum ether and toluene, and more preferably ethyl acetate.

4. The method for preparing hydroxychloroquine derivative according to claim 2, wherein: the mol ratio of hydroxychloroquine to CBZ-L-valine in the step 2 is 1:1.2-1.4; the molar ratio of DCC to hydroxychloroquine is 1:1.1-1.2; the amount of DMAP is 1 to 3 percent of the total mass of hydroxychloroquine and CBZ-L-valine.

5. The method for preparing hydroxychloroquine derivative according to claim 2, wherein: the molar ratio of CBZ-L-hydroxychloroquine valine ester to Pd/C in the step 3 is 1:1.3 to 1.4.

6. The method for preparing hydroxychloroquine derivative according to claim 2, wherein: the organic solvent in the step 4 is any one of ethyl acetate and DMF; the concentration of the dilute hydrochloric acid is 5-10%; the tetrahydrofuran content is 1-3% of hydroxychloroquine valine ester.

7. The method for preparing hydroxychloroquine derivative according to claim 2, wherein: the acid added in the step 4 is any one of dilute hydrochloric acid, hydrobromic acid and maleic acid; the solvent used for recrystallization is any one or a mixture of more of ethyl acetate, ethanol, acetone and dichloromethane, wherein the ethyl acetate is the best.

Images