CN118834169A - Etazomib hydrobromide preparation method of octyl intermediate - Google Patents

Abstract

The present invention provides a method for preparing an eptazocine hydrobromide intermediate, and the reaction steps include: reacting compound I or its salt and formaldehyde reagent in the presence of acid 1 and organic solvent 1, concentrating to dryness after the reaction, dispersing the concentrate with water, adjusting the pH to alkaline, then extracting with organic solvent 2, and finally concentrating to obtain a crude compound II; and salifying the crude compound II with acid 2 to obtain a salt of compound II. The present invention adopts a salt type control method to obtain a salt of the eptazocine hydrobromide intermediate shown in formula II with high yield and high purity for the first time. The salt-type compound can convert the compound of formula II from an oily free base into a white solid powder, which is convenient for transportation and storage; in addition, the free base shown in formula II can be further obtained with high yield and high purity through the salt-type compound, which is superior to the existing synthesis process and has good industrial production application prospects.

Description

A preparation method of eptazocine hydrobromide intermediate

Technical Field

The invention relates to the field of drug synthesis, and in particular to a method for preparing an eptazocine hydrobromide intermediate.

Background Art

Eptazocine hydrobromide was originally developed by Nihon Lyakuhin Kogyo Co., Ltd. and was launched in Japan in 1987. It is a central analgesic that can inhibit pain transmission by binding to κ opioid receptors and effectively relieve various pains, such as cancer pain and postoperative pain. In terms of analgesia, the analgesic efficacy of Eptazocine Hydrobromide is 1-2 times that of Pentazocine. Its structural formula is:

US4008219A discloses a method for synthesizing eptazocine hydrobromide. After the starting compound is cyclized by Mannich reaction, it is subjected to sodium borohydride reduction reaction, hydrogenation reduction reaction, and demethylation and salt formation with hydrobromic acid to obtain eptazocine hydrobromide. The reaction route is:

Among them, the compound It is a key intermediate in the synthesis of eptazocine hydrobromide, mainly composed of the compound It is obtained by the Mannich reaction, but the reaction also causes intermolecular reactions, resulting in the generation of a large number of impurities. US4008219A uses distillation purification to purify the compound. However, due to impurities and compounds The properties of the products are similar, and it is difficult to effectively remove impurities by distillation purification, resulting in low product purity. In addition, the distillation consumes a lot of energy and results in large product losses.

Since the existing technology has problems such as low yield and low purity, it is urgent to develop a method for preparing eptazocine hydrobromide intermediate suitable for industrial production.

Summary of the invention

The object of the present invention is to provide a method for preparing an eptazocine hydrobromide intermediate to solve the problems of low yield, low purity and the like in the prior art.

In order to solve the above technical problems, the present invention provides the following technical solutions:

In one aspect, the present invention provides a method for preparing a salt of an eptazocine hydrobromide intermediate shown in formula II, comprising the following steps:

Step 1: Compound I or its salt and formaldehyde reagent react in the presence of acid 1 and organic solvent 1, and after the reaction is completed, concentrate to dryness, disperse the concentrate with water, adjust the pH to alkaline, then extract with organic solvent 2, and finally concentrate to obtain a crude compound II;

Step 2: The crude compound II is reacted with acid 2 to obtain a salt of the compound II;

Wherein, the structure of compound I is:

The structure of compound II is:

In some embodiments, in step 1, the salt of Compound I is a hydrochloride, hydrobromide, sulfate, tartrate, mandelate, maleate, fumarate, oxalate or citrate of Compound I;

In some embodiments, in step 1, the formaldehyde reagent is aqueous formaldehyde solution, triformaldehyde or polyformaldehyde;

In some embodiments, in step 1, the organic solvent 1 is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate, methanol, ethanol, isopropanol and n-butanol;

In some embodiments, in step 1, the acid 1 is an organic acid or an inorganic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, mandelic acid or citric acid.

In some embodiments, in step 1, the organic solvent 2 is selected from one or more of dichloromethane, toluene, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.

In some embodiments, in step 1, the reaction temperature is 25 to 80°C, preferably 30 to 80°C; the reaction time is 2 to 30 hours, preferably 5 to 15 hours;

In some embodiments, in step 1, the molar ratio of compound I or its salt to the formaldehyde reagent is 1:(1-10), preferably 1:(1-5);

In some embodiments, in step 1, the molar ratio of compound I to acid 1 is 1:(1-5), preferably 1:(1-2); the molar ratio of the salt of compound I to acid 1 is 1:(0.3-5), preferably 1:(0.3-1).

In some embodiments, in step 2, the acid 2 is an organic acid or an inorganic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, tartaric acid, mandelic acid, maleic acid, fumaric acid, or citric acid.

In some embodiments, in step 2, the reaction temperature is 0 to 80°C, preferably 40 to 80°C; the reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.

In some embodiments, in step 2, the step of reacting the crude compound II with acid 2 to form a salt comprises:

The crude compound II is dissolved in an organic solvent 3 to obtain a solution of the compound II. After the solution is clear, an acid 2 is added to carry out a salt-forming reaction. After the reaction is completed, the solution is cooled, filtered and dried to obtain a salt of the compound II.

In some embodiments, the organic solvent 3 is selected from one or more of ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, n-butanol, acetone and toluene;

In some embodiments, the temperature is lowered to -20 to 30°C, preferably 10 to 30°C after the reaction is completed.

On the other hand, the present invention also provides a method for preparing an eptazocine hydrobromide intermediate represented by formula II, comprising the following steps:

Step 1: Prepare the salt of compound II by the above method;

Step 2: Disperse the salt of compound II with water, adjust the pH to alkaline, then extract with organic solvent 4, and finally concentrate to obtain compound II.

In some embodiments, the organic solvent 4 is selected from one or more of dichloromethane, toluene, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.

The present invention has achieved the following beneficial effects:

The present invention adopts a salt type control method to obtain the salt of the eptazocine hydrobromide intermediate shown in formula II with high yield and high purity for the first time. On the one hand, the salt type compound can convert the oily free base of the compound of formula II into a white solid powder, which is convenient for transportation and storage; on the other hand, the eptazocine hydrobromide intermediate shown in formula II can be further obtained by free separation with high yield and high purity through the salt type compound, which is superior to the existing synthesis process and has good industrial production application prospects.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and/or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

FIG1 is a HPLC chromatogram of the crude compound II in step 1 of Example 1.

FIG2 is a HPLC chromatogram of the oxalate of Compound II in Step 2 of Example 1.

FIG3 is the ¹ H NMR spectrum of the oxalate of Compound II in Step 2 of Example 1.

FIG. 4 is the ¹ H NMR spectrum of the citrate salt of Compound II of Example 2.

FIG5 is the ¹ H NMR spectrum of the mandelate salt of Compound II of Example 3.

FIG6 is the ¹ H NMR spectrum of the maleate salt of Compound II of Example 4.

FIG. 7 is the ¹ H NMR spectrum of the tartrate salt of Compound II in Example 5.

FIG8 is the ¹ H NMR spectrum of the hydrochloride salt of Compound II of Example 6.

FIG9 is a mass spectrum of Compound II of Example 7.

FIG. 10 is the ¹ H NMR spectrum of Compound II of Example 7.

FIG11 is a HPLC chromatogram of the vacuum distillation purified product of Comparative Example 1.

DETAILED DESCRIPTION

The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. 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.

Example 1

Step 1: Preparation of crude compound II

Ethanol (800 mL), 37% formaldehyde aqueous solution (83 g) and concentrated hydrochloric acid (33.6 g) were added to compound I (83 g) in sequence, and the mixture was heated to 60° C. and stirred for reaction for 10 hours. After the reaction, the reaction solution was concentrated and dispersed in water, the pH of the dispersion was adjusted to 9, and then extracted with dichloromethane, and finally the organic phase was concentrated to dryness to obtain 72.9 g of crude compound II, with an HPLC purity of 95.2% (see Figure 1 for the HPLC chromatogram).

Step 2: Preparation of Compound II Oxalate

The crude compound II (72.9 g) obtained in step 1 was dissolved in isopropanol (380 mL), and then oxalic acid (26 g) was added, and the mixture was stirred at 60°C for 1 hour. After the reaction, the reaction solution was cooled to 25°C and stirred for 3 hours, and then filtered and dried to obtain 84.79 g of compound II oxalate, with a total yield of 72.2% and a purity of 99.5% (see Figure 2 for the HPLC chromatogram).

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.91 (d, J = 8.5Hz, 1H), 7.00 (s, 2H), 3.87 (s, 3H), 3.62 (m, 1H), 3.25 (d, J＝13.1Hz,1H),3.06–2.90(m,2H),2.70(s,3H),2.47(d,J＝13.3Hz,1H),2.34–2.28(m,1H),2.28–2.12(m ,2H),1.78(m,1H),1.45(s,3H).

Example 2

Step 1: Preparation of crude compound II

Methanol (100 mL), trioxymethylene (3.09 g) and oxalic acid (4.5 g) were added to compound I (8.4 g) in sequence, and the mixture was heated to 55° C. and stirred for reaction for 8 hours. After the reaction, the reaction solution was concentrated and dispersed in water, the pH of the dispersion was adjusted to 10, and then extracted with dichloromethane, and finally the organic phase was concentrated to dryness to obtain 7.83 g of crude compound II with an HPLC purity of 94.09%.

Step 2: Preparation of Compound II Citrate

The crude compound II (7.83 g) obtained in step 1 was dissolved in methanol (40 mL), and then citric acid (5.76 g) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, the reaction solution was cooled to 25° C. and stirred for 3 hours, and then filtered and dried to obtain 11.49 g of compound II citrate, with a total yield of 75.0% and a purity of 99.3%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.98–7.75(m,1H),7.11–6.86(m,2H),3.86(s,3H),3.43(m,1H),3.11(m,1H ),2.87(m,2H),2.65(d,J＝15.2Hz,2H),2.57(d,J＝15.2Hz,5H),2.41–

2.30(m,1H),2.29–2.13(m,2H),2.04(m,1H),1.77(m,1H),1.44(s,3H).

Example 3

Step 1: Preparation of crude compound II

Methanol (100 mL), paraformaldehyde (3.15 g) and oxalic acid (1.54 g) were added to the hydrochloride of compound I (10 g) in sequence, and the mixture was heated to 55° C. and stirred for reaction for 8 hours. After the reaction, the reaction solution was concentrated and dispersed in water, the pH of the dispersion was adjusted to 10, and then extracted with dichloromethane, and finally the organic phase was concentrated to dryness to obtain 7.33 g of crude compound II with an HPLC purity of 94.47%.

Step 2: Preparation of Compound II Mandelate Salt

The crude compound II (7.33 g) obtained in step 1 was dissolved in toluene (40 mL), and mandelic acid (4.56 g) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, the reaction solution was cooled to 25° C. and stirred for 3 hours, and then filtered and dried to obtain 10.83 g of compound II mandelate, with a total yield of 71.4% and a purity of 99.0%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.89–7.83(m,1H),7.44–7.38(m,2H),7.36–7.29(m,2H),7.29–7.22(m,1H),4.94 (s,1H),3.85(s,3H),3.10(m,1H),2.80–2.72(m,2H),2.30(s,3H),2.21(m,1H),2.13–2.00(m,2H ),1.90(m,1H),1.69(m,1H),1.38(s,3H).

Example 4

Step 1: Preparation of crude compound II

Methanol (100 mL), 37% formaldehyde aqueous solution (8.51 g) and oxalic acid (1.54 g) were added to the hydrochloride of compound I (10 g) in sequence, and the mixture was heated to 55° C. and stirred for reaction for 8 hours. After the reaction, the reaction solution was concentrated and dispersed in water, the pH of the dispersion was adjusted to 10, and then extracted with dichloromethane, and finally the organic phase was concentrated to dryness to obtain 7.11 g of crude compound II with an HPLC purity of 94.22%.

Step 2: Preparation of Compound II Maleate

The crude compound II (7.11 g) obtained in step 1 was dissolved in ethanol (40 mL), maleic acid (3.48 g) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, the reaction solution was cooled to 25° C. and stirred for 3 hours, then filtered and dried to obtain 9.26 g of the maleate salt of compound II, with a total yield of 70.3% and a purity of 99.0%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.6 Hz, 1H), 7.19–6.91 (m, 2H), 6.06 (s, 2H), 3.88 (s, 3H), 3.72 ( s,1H),3.40(s,1H),3.14(s,1H),3.02(t,J＝8.0Hz,1H),2.84(s,3H),2.62(s,1H),2.36–2.20(m ,2H),2.13(m,1H),1.84(m,1H),1.47(s,3H).

Example 5

Step 1: Preparation of crude compound II

Methanol (100 mL), 37% formaldehyde aqueous solution (9.7 g) and oxalic acid (5.4 g) were added to compound I (10 g) in sequence, and the mixture was heated to 55° C. and stirred for reaction for 8 hours. After the reaction, the reaction solution was concentrated and dispersed in water, the pH of the dispersion was adjusted to 10, and then extracted with dichloromethane, and finally the organic phase was concentrated to dryness to obtain 9.32 g of crude compound II with an HPLC purity of 94.52%.

Step 2: Preparation of Compound II Tartrate

The crude compound II (9.32 g) obtained in step 1 was dissolved in acetone (50 mL), and then tartaric acid (6 g) was added, and the mixture was stirred at 60° C. for 1 hour. After the reaction, the reaction solution was cooled to 25° C. and stirred for 3 hours, and then filtered and dried to obtain 12.4 g of compound II tartrate, with a total yield of 75% and a purity of 99.4%.

¹ HNMR (500MHz, DMSO) δ7.87 (d, J＝9.2Hz, 1H), 7.01–6.93 (m, 2H), 4.17 (s, 2H), 3.85 (s, 3H), 3.20 (dd, J＝ 12.5,8.3Hz,1H),2.86(dd,J＝12.6,2.0Hz,1H),2.80(dd,J＝10.6,4.6Hz,1H),2.66–2.57(m,1H),2.39(s,3H ), 2.24(dd,J＝14.1,1.0Hz,1H),2.19–2.08(m,2H),1.96(m,1H),1.76–1.67(m,1H),1.41(s,3H).

Example 6

Step 1: Preparation of crude compound II

Methanol (50 mL), 37% formaldehyde aqueous solution (4.9 g) and oxalic acid (2.7 g) were added to compound I (5 g) in sequence, and the mixture was heated to 55° C. and stirred for reaction for 8 hours. After the reaction, the reaction solution was concentrated and dispersed in water, the pH of the dispersion was adjusted to 10, and then extracted with dichloromethane, and finally the organic phase was concentrated to dryness to obtain 4.5 g of crude compound II with an HPLC purity of 95.41%.

Step 2: Preparation of Compound II Hydrochloride

The crude compound II (4.5 g) obtained in step 1 was dissolved in isopropanol (25 mL), and then hydrochloric acid isopropanol solution (3 g) was added, and the mixture was stirred at 60°C for 1 hour. After the reaction, the reaction solution was cooled to 25°C and stirred for 3 hours, and then filtered and dried to obtain 4.2 g of compound II hydrochloride, with a total yield of 71% and a purity of 99.2%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ10.93 (s, 1H), 7.94 (d, J = 8.6Hz, 1H), 7.15–6.90 (m, 2H), 3.88 (s, 3H), 3.72 ( s,1H),3.12(d,J＝14.9Hz,1H),3.01(t,J＝8.4Hz,1H),2.77(d,J＝4.1Hz,3H),2.64–2.53(m,2H), 2.46(d,J＝13.6Hz,1H), 2.27(ddd,J＝15.0,8.0,2.3Hz,1H), 1.77(dd,J＝15.1,3.4Hz,1H), 1.47(s,3H).

Example 7 Preparation of Compound II

Water (800 mL) was added to the oxalate of Compound II in Example 1 (84.79 g) to disperse the mixture, and the pH of the dispersion was adjusted to 9. The mixture was then extracted with dichloromethane (800 mL). The organic phase was concentrated and dried to obtain 62.8 g of pure Compound II as an oil with a free yield of 99.8% and a purity of 99.5%.

LC-MS(ESI):[M+H] ⁺ =260.1653

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.84 (d, J＝8.6Hz, 1H), 7.01–6.83 (m, 2H), 3.84 (s, 3H), 3.02–2.88 (m, 1H), 2.71(m,1H),2.62(m,1H),2.44–2.29(m,1H),2.19(m,4H),2.06(m,1H),1.88(m,2H),1.68(m,1H) ,1.39(s,3H).

Comparative Example 1

According to the preparation method of US4008219A:

Methanol (400 mL) and 37% formaldehyde aqueous solution (17.0 g) were added to the hydrochloride of compound I (0.101 mol) in sequence, and the mixture was heated to 40° C. and stirred for 48 hours. After the reaction, the reaction solution was concentrated to remove methanol, the pH of the concentrate was adjusted to 10, and then extracted with ether, and the organic phase was concentrated to dryness to obtain 21 g of crude compound II with a purity of 88.6%.

The crude compound II was subjected to vacuum distillation at 160-165°C and a vacuum degree below 0.8 mmHg to obtain 13 g of a yellow oil with a yield of 49.7% and a purity of 95.3% (see Figure 11 for the HPLC liquid chromatogram).

The above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims (10)

1. A method for preparing a salt of an intermediate of etazocine hydrobromide represented by formula II, comprising the steps of:

step 1: reacting the compound I or salt thereof with formaldehyde reagent in the presence of acid 1 and organic solvent 1, concentrating to dryness after the reaction is finished, dispersing concentrate with water, adjusting pH to alkalinity, extracting with organic solvent 2, and concentrating to obtain a crude product of the compound II;

step 2: salifying the crude product of the compound II with acid 2 to obtain salt of the compound II;

Wherein, the structure of the compound I is as follows:

the structure of compound II is:

2. The method of manufacturing according to claim 1, characterized in that:

In the step 1, the salt of the compound I is hydrochloride, hydrobromide, sulfate, tartrate, mandelate, maleate, fumarate, oxalate or citrate of the compound I;

In the step 1, the formaldehyde reagent is formaldehyde aqueous solution, trioxymethylene or paraformaldehyde;

In the step 1, the organic solvent 1 is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, toluene, ethyl acetate, methanol, ethanol, isopropanol and n-butanol;

in step 1, the acid 1 is an organic acid or an inorganic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, tartaric acid, maleic acid, fumaric acid, mandelic acid or citric acid.

3. The method of manufacturing according to claim 1, characterized in that:

In step 1, the organic solvent 2 is selected from one or more of dichloromethane, toluene, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.

4. The method of manufacturing according to claim 1, characterized in that:

in the step 1, the reaction temperature is 25-80 ℃ and the reaction time is 2-30 h;

In the step 1, the mol ratio of the compound I or the salt thereof to the formaldehyde reagent is 1 (1-10);

in the step 1, the mol ratio of the compound I to the acid 1 is 1 (1-5); the molar ratio of the salt of the compound I to the acid 1 is 1 (0.3-5).

5. The method of manufacturing according to claim 1, characterized in that:

In step 2, the acid 2 is an organic acid or an inorganic acid, preferably hydrochloric acid, sulfuric acid, hydrobromic acid, oxalic acid, tartaric acid, mandelic acid, maleic acid, fumaric acid, or citric acid.

6. The method of manufacturing according to claim 1, characterized in that:

In the step 2, the reaction temperature is 0-80 ℃ and the reaction time is 0.5-24 h.

7. The method of any one of claims 1-6, wherein:

In the step 2, the reaction step of salifying the crude product of the compound II with the acid 2 comprises the following steps:

Dissolving the crude product of the compound II in an organic solvent 3 to obtain a compound II solution, adding an acid 2 after dissolving, carrying out salt forming reaction, cooling after the reaction is finished, filtering and drying to obtain the salt of the compound II.

8. The method of manufacturing according to claim 7, wherein:

The organic solvent 3 is selected from one or more of ethyl acetate, isopropyl acetate, methylene dichloride, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol, n-butanol, acetone and toluene;

cooling to-20-30 deg.c after the reaction.

9. A preparation method of an eptazocine hydrobromide intermediate shown in a formula II, which comprises the following steps:

Step 1: a salt of compound II prepared by the method of any one of claims 1-8;

step 2: dispersing the salt of the compound II with water, adjusting the pH to be alkaline, extracting with an organic solvent 4, and concentrating to obtain the compound II.

10. The method of manufacturing according to claim 9, wherein:

The organic solvent 4 is selected from one or more of dichloromethane, toluene, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and isopropyl acetate.