CN111704636A - A kind of preparation method of aminoglycoside drug intermediate - Google Patents

Abstract

The invention discloses a preparation method of an aminoglycoside drug intermediate, wherein the intermediate is 1,3,2 ', 6', 3 '' -penta-N-tosylkanamycin B, and the preparation method comprises the following steps: adding kanamycin B, an acid-binding agent and a mixed solvent into a reaction kettle, adding paratoluensulfonyl chloride at the temperature of 0-30 ℃, and stirring and reacting for 8-18 hours at the temperature of 0-30 ℃; adding an inert solvent, stirring for 1-24 hours, crystallizing, filtering, and drying to obtain the 1,3,2 ', 6', 3 '' -penta-N-p-toluenesulfonylkanamycin B. The invention uses Ts as a protecting group, and adopts three or more solvents as reaction solvents, so that the reaction conditions are milder, the safety coefficient is high, the yield of the obtained product can reach more than 90 percent, and the purity can reach more than 95 percent.

Description

A kind of preparation method of aminoglycoside drug intermediate

technical field

The invention relates to a preparation method of an aminoglycoside drug intermediate.

Background technique

3′,4′-dideoxy-kanamycin B, or debekacin, is a semi-synthetic aminoglycoside antibiotic that has been marketed. It is a new broad-spectrum antibiotic with unique chemical structure and antibacterial properties. The mechanism of action is not only small cross-resistance with other antibiotics and antibacterials, but also mostly synergistic.

1,3,2',6',3''-penta-N-p-toluenesulfonylkanamycin B is a key intermediate in the synthesis of 3',4'-dideoxy-kanamycin B.

3′,4′-dideoxy-kanamycin B structural formula:

Key Intermediate A (1,3,2',6',3''-penta-N-p-toluenesulfonylkanamycin B) structural formula:

Master's thesis "Research on the Synthesis Process of Rebekacin Intermediates" (Wu Fangyuan, 2010, Zhengzhou University) discloses a 1,3,2',6',3''-penta-N-p-toluenesulfonyl card The preparation method of namycin B:

Add 20g kanamycin B and 24g sodium carbonate to a 500mL round-bottomed flask, add 110mL water to the flask, stir, add 220mL dioxane after it is completely dissolved, cool the system in an ice bath, and stir to separate 40g of p-toluenesulfonyl chloride was added in batches, and the temperature of the system was controlled to be below 10°C. After the addition, the stirring was continued. After 8 hours of reaction, the reaction was monitored by TLC to the end point. TLC showed a product with Rr=0.15, chloroform:ethanol=10: 1 Development, rotary evaporation at 50°C to remove most of the solvent, after concentration, the system was poured into water to precipitate a large amount of white solids, filtered under reduced pressure, and the filter cake was washed with water until the filtrate became neutral, and the filter cake was dried to obtain 44.6 g of white solids with a yield of 44.6 g. 83.5% (72% of literature value).

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide an aminoglycoside drug intermediate 1,3,2',6',3''-penta-N-p-toluenesulfonyl kanamycin with high yield and high purity Method for the preparation of B.

The technical solution to achieve the object of the present invention is a preparation method of an aminoglycoside drug intermediate, wherein the intermediate is 1,3,2',6',3''-penta-N-p-toluenesulfonyl kanamycin Element B, the preparation method is as follows:

Add kanamycin B, acid binding agent and mixed solvent into the reaction kettle, add p-toluenesulfonyl chloride at 0～30°C, and stir and react at 0～30°C for 8～18 hours; after the reaction, add an inert solvent and stir to separate out. crystal, suction filtration, and drying to obtain 1,3,2',6',3''-penta-N-p-toluenesulfonylkanamycin B;

The mixed solvent is a solvent system composed of three or more solvents, including water, alcohol, and one or more of -dichloromethane, ethyl acetate, and chloroform.

The acid binding agent is one or more combinations of sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide and potassium hydroxide.

The inert solvent is one or more combinations of hexane, heptane, diethyl ether and methyl tert-butyl ether.

The alcohol constituting the mixed solvent is methanol, ethanol or isopropanol.

The substance ratio of kanamycin B to p-toluenesulfonyl chloride is 1:5-6.

In the mixed solvent, the mass ratio of water and organic solvent is 1:1-5, preferably 1:2-3.5.

Preferably, in the mixed solvent, the mass ratio of water and organic solvent is 1:2-4, preferably 1:2.5-3.

The mass ratio of kanamycin B to the acid binding agent is 1:0.4-2, preferably 1:0.8-1.1.

The mass ratio of kanamycin B to the mixed solvent is 1:10-30, preferably 1:14-16.

After the reaction is completed, an inert solvent is added, and the mixture is stirred for 1 to 24 hours and then crystallized.

The present invention has positive effects:

(1) The present invention uses Ts (p-toluenesulfonyl) as a protective group, and adopts three or more solvent systems as reaction solvents. The reaction conditions are milder, the safety factor is high, and the yield of the obtained product can reach more than 90%. , the purity can reach more than 95%.

(2) The post-processing is convenient, no concentration is needed, and an inert solvent can be directly added for stirring and crystallization. The precipitated solid has good properties, no adhesion and no agglomeration.

Description of drawings

Fig. 1 is the HPLC spectrum of the intermediate prepared in Example 1.

FIG. 2 is the hydrogen nuclear magnetic resonance spectrum of the intermediate prepared in Example 1. FIG.

Fig. 3 is the carbon nuclear magnetic resonance spectrum of the intermediate prepared in Example 1.

FIG. 4 is the mass spectrum of the intermediate prepared in Example 1. FIG.

Figure 5 is the HPLC spectrum of the intermediate prepared in Example 2.

FIG. 6 is the HPLC spectrum of the intermediate prepared in Example 3. FIG.

FIG. 7 is the HPLC spectrum of the intermediate prepared in Example 4. FIG.

FIG. 8 is the HPLC spectrum of the intermediate prepared in Example 5. FIG.

FIG. 9 is the HPLC spectrum of the intermediate prepared in Example 6. FIG.

FIG. 10 is the HPLC chart of the intermediate prepared in Comparative Example 1. FIG.

FIG. 11 is the HPLC chart of the intermediate prepared in Comparative Example 2. FIG.

Detailed ways

(Example 1)

The aminoglycoside drug intermediate prepared in this example is 1,3,2',6',3''-penta-N-p-toluenesulfonylkanamycin B, and the reaction formula is as follows:

where Ts is p-toluenesulfonyl.

The preparation method of the present embodiment is as follows:

Add 50 g of kanamycin B, 50 g of sodium carbonate, 200 g of water, 200 g of ethanol and 400 g of dichloromethane to the reaction kettle, stir evenly; add 120 g of p-toluenesulfonic acid at 0 to 30 °C (25 °C in this example) Acid chloride, in the three solvent systems of water-ethanol-dichloromethane, stirred and reacted at 25°C for 16 hours, and the reaction of the central control raw materials was completed.

400 g of hexane was added, and after stirring for 2 hours, suction filtration and drying were performed to obtain 120 g of an intermediate with a yield of 92.3% and a purity of 95.90% detected by HPLC (see Figure 1).

The structure of the obtained compound was confirmed, and the sample of the compound was detected by H NMR, C NMR and mass spectrometry.

The specific test results are as follows:

¹ H NMR (600 MHz, DMSO) δ 7.79 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 6.7 Hz, 1H), 7.46 (dd, J = 13.1, 8.1 Hz, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.28 (dd, J =8.2, 1.7 Hz, 2H), 4.83 (d, J = 4.1 Hz, 1H), 4.80 (d, J = 3.3 Hz, 1H), 3.91 –3.82 (m, 1H), 3.59 (dd, J = 9.9 , 5.0 Hz, 1H), 3.51 – 3.44 (m, 1H), 3.43 – 3.39 (m, 1H), 3.36 – 3.30 (m, 1H), 3.23 (dd, J = 16.0, 9.4 Hz, 1H), 3.13( ddd, J = 18.7, 9.2, 5.2 Hz, 2H), 3.05 – 2.93 (m, 2H), 2.78 (ddd, J = 13.4, 9.7, 4.3 Hz, 1H), 2.43 (t, J = 6.0 Hz, 3H) , 2.35 (t, J = 6.2 Hz, 3H), 2.32(s, 2H), 2.24 (s, 1H), 1.69 (dd, J = 9.6, 3.7 Hz, 1H), 1.00 (dd, J = 26.3,13.7 Hz, 1H).

¹³ C NMR (151 MHz, DMSO) δ 142.97 (s), 142.80 – 142.33 (m), 141.24 (s), 140.95 (s), 139.03 (s), 137.72 (s), 135.67 (s), 129.54 (t , J = 38.8 Hz), 129.22 (s), 128.78 (s), 127.28 (s), 126.62 (dd, J = 40.1, 32.8 Hz), 101.33(s), 98.54 (s), 85.62 (s), 81.06 (s), 74.56 (s), 73.69 (s), 70.52 – 69.74(m), 67.51 (s), 59.96 (s), 59.27 (s), 58.33 (s), 52.48 (s), 51.88 (s) , 43.29(s), 40.03 (s), 39.79 (t, J = 17.7 Hz), 39.57 (d, J = 21.0 Hz), 39.43 – 38.99(m), 38.99 – 38.85 (m), 31.83 (s), 21.22 – 20.70 (m).

MS (ESI, m/z): 1277.6 [M ⁺ Na ⁺ ].

It can be seen from the detection data detected by mass spectrometry, H NMR spectrum and C NMR spectrum that 1,3,2',6',3''-penta-N-p-toluenesulfonyl kanamycin was prepared according to the method in this example. prime B.

(Example 2)

The preparation method of the present embodiment is as follows:

Add 50g kanamycin B, 60g potassium carbonate, 200g water, 200g ethanol and 400g dichloromethane to the reaction kettle, stir evenly; add 130g p-toluenesulfonyl chloride at 20°C, mix in three kinds of water-ethanol-dichloromethane In the solvent system, the reaction was stirred at 20° C. for 15 hours, and the reaction of the central control raw materials was completed.

400 g of heptane was added, and after stirring for 2 hours, suction filtration and drying were performed to obtain 119 g of an intermediate with a yield of 91.5% and a purity of 94.95% detected by HPLC (see Figure 5).

(Example 3)

The preparation method of the present embodiment is as follows:

Add 50g kanamycin B, 50g sodium hydroxide, 200g water, 200g ethanol, and 400g chloroform into the reaction kettle, stir evenly; add 100g p-toluenesulfonyl chloride at 5°C, under three solvent systems of water-ethanol-chloroform , The reaction was stirred at 15°C for 13 hours, and the reaction of the central control material was completed.

400 g of hexane was added, and after stirring for 2 hours, suction filtration and drying were performed to obtain 114 g of intermediate with a yield of 87.7% and a purity of 69.53% detected by HPLC (see Figure 6).

(Example 4)

The preparation method of the present embodiment is as follows:

Add 50g of kanamycin B, 40g of triethylamine, 200g of water, 200g of isopropanol, and 300g of ethyl acetate into the reaction kettle, stir evenly; add 110g of p-toluenesulfonyl chloride at Under the three solvent systems of ethyl acetate, the reaction was stirred at 25° C. for 9 hours, and the reaction of the central control raw materials was completed.

400 g of methyl tert-butyl ether was added, stirred for 10 hours, filtered and dried with suction to obtain 121 g of an intermediate with a yield of 93.1% and a purity of 79.73% detected by HPLC (see Figure 7).

(Example 5)

The preparation method of the present embodiment is as follows:

Add 50g of kanamycin B, 50g of potassium hydroxide, 200g of water, 200g of isopropanol, 200g of dichloromethane and 200g of chloroform into the reaction kettle, stir evenly; Under the four solvent systems of propanol-dichloromethane-chloroform, the reaction was stirred at 24°C for 16h, and the reaction of the central control material was completed.

400 g of hexane was added, and after stirring for 2 hours, suction filtration and drying were performed to obtain 117 g of intermediate with a yield of 90.0% and a purity of 82.37% detected by HPLC (see Figure 8).

(Example 6)

The preparation method of the present embodiment is as follows:

Add 50g of kanamycin B, 55g of sodium carbonate, 200g of water, 200g of ethanol, 300g of ethyl acetate and 100g of dichloromethane into the reaction kettle, stir evenly; add 105g of p-toluenesulfonyl chloride at Under the four solvent systems of ethyl acetate-dichloromethane, the reaction was stirred at 26 °C for 16 h, and the reaction of the central control raw materials was completed.

400 g of ether was added, and after stirring for 15 hours, suction filtration and drying were performed to obtain 122 g of an intermediate with a yield of 93.8% and a purity of 94.93% detected by HPLC (Figure 9).

(Comparative Example 1)

Add 50g of kanamycin B, 55g of sodium carbonate, 200g of water and 400g of dichloromethane to the reaction kettle, stir evenly; add 115g of p-toluenesulfonyl chloride at 13°C, stir and react at 23°C for 13h, the reaction of the central control raw materials is complete , added 400 g of heptane, stirred for 12 hours, filtered and dried with suction to obtain 97 g of intermediate with a yield of 74.6% and a purity of 59.5198% detected by HPLC (Figure 10).

(Comparative Example 2)

Add 50 g of kanamycin B, 50 g of sodium hydroxide, 200 g of water, and 400 g of chloroform into the reaction kettle, stir evenly, add 115 g of p-toluenesulfonyl chloride at 7 °C, and stir at 25 °C for 17 hours. 400 g of methyl tert-butyl ether was stirred for 15 hours, filtered and dried with suction to obtain 92 g of an intermediate with a yield of 70.8% and a purity of 57.0867% detected by HPLC (Figure 11).

The reaction solvent system composed of two solvents is adopted, and the yield after the reaction is low and the product purity is low.

Claims (10)

1. A preparation method of an aminoglycoside drug intermediate, wherein the intermediate is 1,3,2 ', 6', 3 '' -penta-N-p-toluenesulfonylkanamycin B, and is characterized by comprising the following steps:

adding kanamycin B, an acid-binding agent and a mixed solvent into a reaction kettle, adding paratoluensulfonyl chloride at the temperature of 0-30 ℃, and stirring and reacting for 8-18 hours at the temperature of 0-30 ℃; adding an inert solvent after the reaction is finished, stirring and crystallizing, filtering, and drying to obtain 1,3,2 ', 6', 3 '' -penta-N-p-toluenesulfonyl kanamycin B;

the mixed solvent is a solvent system consisting of three or more solvents, and comprises water and alcohol and one or more of dichloromethane, ethyl acetate and chloroform.

2. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: the acid-binding agent is one or more of sodium carbonate, potassium carbonate, triethylamine, sodium hydroxide and potassium hydroxide.

3. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: the inert solvent is one or more of hexane, heptane, diethyl ether and methyl tert-butyl ether.

4. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: the alcohol composing the mixed solvent is methanol, ethanol or isopropanol.

5. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: the mass ratio of kanamycin B to p-toluenesulfonyl chloride was 1: 5 to 6.

6. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: in the mixed solvent, the mass ratio of water to the organic solvent is 1: 1 to 5.

7. The method of claim 6, wherein the step of preparing the aminoglycoside intermediate comprises: in the mixed solvent, the mass ratio of water to the organic solvent is 1: 2 to 4.

8. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: the mass ratio of the kanamycin B to the acid-binding agent is 1: 0.4 to 2.

9. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: the mass ratio of kanamycin B to the mixed solvent is 1: 10 to 30.

10. The method of claim 1, wherein the step of preparing the aminoglycoside intermediate comprises: and after the reaction is finished, adding an inert solvent, stirring for 1-24 hours, and crystallizing.

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