A process for the preparation of an anthracycline intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an anthracene ring medicine intermediate. The anthracene ring medicine intermediate is prepared by reacting SM with butanone glycol ketal, compared with the prior art, the preparation method can quantitatively obtain the related intermediate at room temperature, can significantly reduce the reaction temperature and the use of water separator, can simplify the reaction operation, can reduce the energy consumption, can significantly improve the yield and purity of the product, and is more suitable for industrial application.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a preparation method of an anthracycline drug intermediate. BACKGROUND

[0002] Anthracyclines or anthracycline antibiotics are a kind of chemotherapy drugs derived from Streptomyces peucetius var. caesius. Anthracyclines, including doxorubicin, epirubicin, daunorubicin and aclacinomycin, are widely used in the treatment of hematological malignancies and solid tumors, such as acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarcoma and ovarian cancer, etc. Anthracyclines can be combined with other chemotherapy drugs and molecular targeted drugs. The combination therapy based on anthracyclines is usually the standard first-line treatment, which has the advantages of wide anti-tumor spectrum, strong anti-tumor effect and definite efficacy.

[0003] The structural formula of a common anthracycline is as follows:

[0004]

[0005] In the synthesis of the above drugs, the protection reaction of the side chain ketone carbonyl group is usually involved, such as the synthesis route of amonofide hydrochloride reported in the literature J. Org. Chem., 1987, 52, 4477-4485: the intermediate 7 is reacted with ethylene glycol to protect the carbonyl group to generate a ketal derivative (R)-(-)-9-acetamido-9-[1,1-(ethylenedioxy)ethyl]-6,11-dihydroxy-7,8,9,10-tetrahydro-anthracene-5,12-dione (1), and the specific route is as follows:

[0006]

[0007] In the prior art, ethylene glycol, 1,3-propanediol or neopentyl glycol is usually used as a protection reagent for the protection of the side chain carbonyl group in the synthesis of the above anthracycline intermediate, and high-temperature reflux reaction is used, which not only easily leads to the occurrence of side reactions, but also has high requirements for the machine equipment, thereby increasing the energy consumption and production cost.

[0008] In view of the many problems existing in the synthesis of the above anthracycline side chain carbonyl protection intermediate, the present inventors have found, through continuous exploration and experiments, a process route which is simple in operation, short in production cycle, low in reaction energy consumption, high in yield and more suitable for industrial production. SUMMARY

[0009] In view of the technical problems existing in the preparation process of the side chain carbonyl protection intermediate (I) of anthracycline drugs, the application provides a new method for preparing the intermediate compound by protecting the ketone carbonyl group.

[0010] The specific technical scheme of the application is as follows:

[0011] A preparation method of an anthracycline drug intermediate (I) is provided, and the specific steps are as follows:

[0012] At room temperature, SM, butanone glycol ketal (MED), ethylene glycol and a catalyst are added into a dry reaction solvent, temperature control stirring reaction is carried out, and the target compound I is prepared, and the reaction route is as follows:

[0013]

[0014] wherein R 1 = H, R 2 = OH or NHCOCH3, R 3 = OH or H or;

[0015]

[0016] Preferably, the catalyst is selected from one or a combination of p-toluenesulfonic acid, camphorsulfonic acid, alpha-naphthalenesulfonic acid and beta-naphthalenesulfonic acid, preferably beta-naphthalenesulfonic acid; wherein the camphorsulfonic acid can be a single isomer or a mixture or racemate of 1R-(-)-10-camphorsulfonic acid and 1S-(+)-10-camphorsulfonic acid.

[0017] Preferably, the reaction solvent is selected from one or a combination of benzene, toluene, xylene, dichloromethane and chloroform, preferably dichloromethane.

[0018] Preferably, the molar ratio of SM to MED is 1:1.2-1.8, preferably 1:1.4.

[0019] Preferably, the molar ratio of SM to ethylene glycol is 1:0.02-0.15, preferably 1:0.06.

[0020] Preferably, the molar ratio of SM to catalyst is 1:0.01-0.05, preferably 1:0.03.

[0021] Preferably, the temperature control temperature is 10-50 DEG C, preferably 20-25 DEG C.

[0022] Preferably, the SM is an amrubicin synthesis intermediate, and the structure is as follows:

[0023]

[0024] Preferably, the SM is one of the following synthetic intermediates of epirubicin, doxorubicin, pirarubicin, valrubicin:

[0025]

[0026] Preferably, the SM is a synthetic intermediate of idarubicin or other synthetic intermediate of anthracycline with the following structure, and the specific structure is as follows:

[0027]

[0028] In a preferred embodiment, a post-treatment operation is performed, and the specific steps are as follows: after the reaction is completed, saturated sodium bicarbonate solution is added to the reaction solution, the organic layer is separated, and the organic phase is washed with purified water and saturated brine in sequence, and then the organic phase is combined, concentrated under reduced pressure, dried, and the target compound is obtained.

[0029] The dried reaction solvent in the present application is obtained by a conventional drying method in the art, such as molecular sieve water removal, rectification, and the like.

[0030] The drying in the post-treatment is a conventional drying method in the art.

[0031] The present application has the following beneficial effects:

[0032] The present application provides a new method for preparing an anthracycline intermediate (I), which uses butanone glycol ketal instead of the glycol commonly used in the prior art as a raw material for reaction, and can obtain the related intermediate almost quantitatively at room temperature, and can significantly reduce the reaction temperature and the use of a water separator, simplify the reaction operation, and reduce energy consumption. At the same time, the hydrolysis of the cyano group can be effectively inhibited during the preparation of the related intermediate containing a cyano group, and the product yield and purity are improved. Compared with the prior art, the preparation process of the present application has higher product yield and purity, and is more suitable for industrial production. DETAILED DESCRIPTION

[0033] The present application will be further described by the following examples, and it should be understood that: the examples of the present application are only used to illustrate the present application, and are not a limitation of the present application, so that the simple improvement of the present application under the premise of the method of the present application belongs to the scope of the present application.

[0034] Example 1

[0035] SM-1 (39.31 g, 0.10 mol), butanone glycol ketal (12.78 g, 0.11 mol), ethylene glycol (0.37 g, 0.02 mol), 1 S-(+)-10-camphorsulfonic acid (0.70 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 30-35 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product 39.65 g in a yield of 90.7% and a purity of 98.23%.

[0036] Example 2

[0037] SM-1 (39.31 g, 0.10 mol), butanone glycol ketal (12.78 g, 0.11 mol), ethylene glycol (0.37 g, 0.02 mol), 1 S-(+)-10-camphorsulfonic acid (0.70 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 30-35 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product 39.65 g in a yield of 90.7% and a purity of 98.23%.

[0038] Example 3

[0039] SM-1 (39.31 g, 0.10 mol), butanone glycol ketal (12.78 g, 0.11 mol), ethylene glycol (0.37 g, 0.02 mol), 1 S-(+)-10-camphorsulfonic acid (0.70 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 30-35 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product 39.65 g in a yield of 90.7% and a purity of 98.23%.

[0040] Example 4

[0041] SM-1 (39.30 g, 0.10 mol), butanone glycol ketal (20.91 g, 0.18 mol), ethylene glycol (0.37 g, 0.02 mol), 1R-(-)-10-camphorsulfonic acid (0.70 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 15-20 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product 42.40 g in 97.0% yield with a purity of 99.04%.

[0042] Example 5

[0043] SM-1 (39.30 g, 0.10 mol), butanone glycol ketal (22.07 g, 0.19 mol), ethylene glycol (0.37 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry chloroform (300 ml) at room temperature, and the mixture was stirred at 10-15 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product 40.26 g in 92.1% yield with a purity of 98.04%.

[0044] Example 6

[0045] SM-1 (39.30 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.12 g, 0.01 mol), α-naphthalenesulfonic acid (0.63 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 35-40 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product 41.88 g in 95.8% yield with a purity of 99.22%.

[0046] Example 7

[0047] SM-1 (39.30 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.93 g, 0.04 mol), p-toluenesulfonic acid (0.52 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 40-45 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with chloroform (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (42.49 g, 97.2% yield, 99.14% purity).

[0048] Example 8

[0049] SM-1 (39.32 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.36 g, 0.02 mol), β-naphthalenesulfonic acid (0.21 g, 0.001 mol) were added into dry benzene (300 ml) at room temperature, and the mixture was stirred at 45-50 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (42.05 g, 96.2% yield, 98.94% purity).

[0050] Example 9

[0051] SM-1 (39.30 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (1.24 g, 0.02 mol), β-naphthalenesulfonic acid (1.04 g, 0.005 mol) were added into dry toluene (300 ml) at room temperature, and the mixture was stirred at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product (42.35 g, 96.9% yield, 99.10% purity).

[0052] Example 10

[0053] SM-2 (40.90 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.37 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the reaction was carried out at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, stirred for 10-15 min, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 ml x 2), and the combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product 44.05 g, with a yield of 97.2% and a purity of 99.31%. ESI-HRMS (m / z): 454.1514 [M+H] + ; 1 H-NMR (600 MHz, DMSO-d6) δ: 9.02 (s, 2H), 8.06-8.12 (m, 4H), 5.80 (s, 1H), 4.92 (t, J = 7.9 Hz, 1H), 3.95-4.02 (m, 6H), 3.10 (s, 1H), 2.30-2.33 (m, 1H), 1.95-1.98 (m, 1H), 1.92 (s, 3H), 1.33 (s, 3H); 13 C-NMR (151 MHz, DMSO-d6) δ: 186.38, 186.22, 170.48, 154.26, 153.48, 146.37, 139.84, 134.46, 133.57, 125.69, 114.35, 110.58, 105.74, 66.31, 65.78, 42.59, 41.36, 23.18, 21.26.

[0054] Example 11

[0055] SM-3 (38.20 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.37 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the reaction was carried out at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, stirred for 10-15 min, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (50 ml x 2), and the combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the target product 41.55 g, with a yield of 97.5% and a purity of 99.16%.

[0056] Example 12

[0057] SM-4 (39.81 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.37 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product 42.89 g in a yield of 97.0% and a purity of 99.35%.

[0058] Example 15

[0059] SM-5 (52.82 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.36 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product 55.29 g in a yield of 96.8% and a purity of 99.02%.

[0060] Example 18

[0061] SM-6 (35.20 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.37 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product 37.33 g in a yield of 98.2% and a purity of 99.10%.

[0062] Example 19

[0063] SM-7 (36.80 g, 0.10 mol), butanone glycol ketal (16.26 g, 0.14 mol), ethylene glycol (0.37 g, 0.02 mol), β-naphthalenesulfonic acid (0.62 g, 0.003 mol) were added into dry dichloromethane (300 ml) at room temperature, and the mixture was stirred at 20-25 °C for about 1 h. Then saturated sodium bicarbonate solution (150 ml) was added, and the mixture was stirred for 10-15 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 ml x 2). The combined organic phase was washed with water (140 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The target product was obtained in a yield of 38.58 g (97.4%), with a purity of 99.41%.

Claims

1. A method for preparing an anthracycline drug intermediate, characterized in that, The specific steps are as follows: At room temperature, SM, butanone glycol ketal, ethylene glycol, and catalyst were added to a dry reaction solvent, and the reaction was carried out under controlled temperature and stirring to obtain target compound I. The reaction route is as follows: in or The catalyst is selected from one or a combination of p-toluenesulfonic acid, camphorsulfonic acid, α-naphthalenesulfonic acid, and β-naphthalenesulfonic acid; the temperature control temperature is 10~50℃; the molar ratio of SM to butanone ethylene glycol ketal is 1:1.2~1.8; the molar ratio of SM to ethylene glycol is 1:0.02~0.15; and the molar ratio of SM to catalyst is 1:0.01~0.

05.

2. The preparation method according to claim 1, characterized in that, The reaction solvent is selected from one or a combination of benzene, toluene, xylene, dichloromethane, and chloroform.

3. The method according to claim 1, characterized in that, The SM is a synthetic intermediate for amrubicin, and its structure is as follows: 。 4. The method according to claim 1, characterized in that, The SM is one of the synthetic intermediates of epirubicin, doxorubicin, pirarubicin, and pentyrubicin, and its structure is as follows: 。 5. The method according to claim 1, characterized in that, SM is described as an intermediate in the synthesis of Epibeca, and its structure is as follows: 。

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