A method for synthesizing an entecavir intermediate

Abstract

The application discloses a synthesis method of an entecavir intermediate, which comprises the following steps: taking 4-hydroxy-2-cyclopentenone as raw material, and reacting with tert-butyldimethylsilylchloride in the presence of alkali to prepare compound (II); then, the compound (II) is reacted with imidazole and formaldehyde to obtain compound (III); then, the compound (III) is reacted with acetyl chloride in the presence of alkali to obtain compound (IV); then, a free radical initiator is added into the compound (IV), and then addition reaction occurs under the irradiation of ultraviolet light to obtain compound (V); finally, the compound (V) is reacted with tert-butyldimethylsilylchloride in the presence of alkali, and the entecavir intermediate is obtained. The entecavir intermediate prepared by the method is an important raw material for synthesizing the antiviral drug entecavir. Compared with the prior art, the method has the advantages of cheap and easily available raw material, simple process, short synthesis route, easy product purification, high total yield and easy industrialized production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing an entecavir intermediate. Background Art

[0002] Hepatitis type B (HBV) is one of the most threatening infectious diseases worldwide. Hepatitis B virus (HBV) is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (primary liver cancer). Currently, two main types of antiviral drugs are used clinically in my country: interferon-α and nucleoside or nucleotide analogs.

[0003] Entecavir (Formula 1), chemically known as 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, is a guanine nucleoside analog developed by Bristol-Myers Squibb in 1997. It was approved by the U.S. Food and Drug Administration (FDA) in March 2005 for the treatment of hepatitis B. Entecavir is phosphorylated in the body to form an active nucleoside analog that competes with nucleotides for incorporation into HBV DNA chains, terminating HBV DNA chain elongation and synthesis. It also inhibits the activity of the viral DNA polymerase and reverse transcriptase, thereby suppressing viral replication. Compared to other anti-HBV drugs, entecavir offers a strong antiviral effect, minimal side effects, and a low incidence of clinical drug resistance, making it one of the best treatments for chronic hepatitis B.

[0004]

[0005] The structure of entecavir contains a chiral five-membered carbon ring and a guanine core. The chiral five-membered carbon ring has three chiral centers and a methylene group outside the ring. The structure is relatively complex, and many synthesis methods have been reported.

[0006] US Patent No. 5,206,244, published in 1993, disclosed the preparation of entecavir and its use as an HBV inhibitor. The disclosed preparation method uses cyclopentadiene as the starting material and proceeds through a multi-step synthesis to obtain entecavir (Formula 2). This route, due to the gradual introduction of chiral centers, makes the control of optical impurities difficult and results in low yields.

[0007]

[0008] WO2004 / 052310 (Bristol-Myers Squibb) discloses a route using (+)-coreyl-actonediol as a starting material (Formula 3). The advantage of using (+)-coreylactonediol as a starting material is that it already contains all the chiral centers required for the product. The starting material itself has excellent optical purity and very low levels of optical isomers. Subsequent conversion of only a few functional groups is required to synthesize entecavir. The resulting product has excellent chiral purity.

[0009]

[0010] However, the problem with this route is that the yield of the coupling reaction between 2-amino-6-chloropurine and the five-membered ring core is very low, and the purity of the coupling product is poor, which affects the economic efficiency of the entire route.

[0011] WO2010 / 074534 discloses a method for preparing entecavir, which utilizes the following reaction to prepare entecavir (Formula 4). However, the reaction conditions are harsh and the reagents used are expensive, making it difficult to apply to industrial production.

[0012]

[0013] Patent CN103304375 discloses a route (Formula 5) for synthesizing entecavir using propargyl alcohol and allyl bromide as raw materials to prepare a five-membered carbon ring intermediate. This route has a high yield and low environmental pollution, but uses an expensive Grubbs second-generation catalyst to catalyze the metathesis of dienes to form the five-membered ring, which is costly.

[0014]

[0015] Zhou et al. disclosed a method for synthesizing entecavir, and the process route is shown in Formula 6:

[0016]

[0017] This process route starts from cheap and readily available 1,3-propylene glycol, uses the Sharpless epoxidation reaction to construct an asymmetric chiral center, and then undergoes multiple continuous transformations such as 1,3 dipolar cycloaddition and palladium / carbon reduction to obtain intermediate 17. Intermediate 17 is a key entecavir intermediate in this process route, but the steps for synthesizing intermediate 17 in this process are relatively cumbersome, requiring 13 steps and with low yield.

[0018] Liu et al. disclosed a method for synthesizing entecavir, and the process route is shown in Formula 7:

[0019]

[0020] In the process, the synthesis of intermediate 17 only needs 8 steps, but the synthesis uses expensive Nysted reagent, and highly toxic selenium dioxide, and the overall yield of the conversion of compound 103 to 104 is low, and the generated 104b cannot be further converted to entecavir. SUMMARY

[0021] The present application aims to provide a synthesis method of an entecavir intermediate to solve the problems existing in the synthesis method in the background art, such as harsh reaction conditions, safety hazards, high equipment requirements, complicated process, low yield, high cost, and other problems that are not conducive to industrial production.

[0022] The present application uses 4-hydroxy-2-cyclopentenone as a raw material, and through protection, MBH, and free radical addition reactions, the target product is obtained, and the reaction route is as shown below:

[0023]

[0024] The specific scheme is as follows:

[0025] A synthesis method of an entecavir intermediate comprises the following steps:

[0026] S1, 4-hydroxy-2-cyclopentenone reacts with tert-butyldimethylsilyl chloride in the presence of a base to prepare compound (II);

[0027] S2, compound (II) is reacted with imidazole and formaldehyde to obtain compound (III);

[0028] S3, compound (III) is reacted with acetyl chloride in the presence of a base to obtain compound (IV);

[0029] S4, a free radical initiator is added to compound (IV), and then an addition reaction occurs under the irradiation of ultraviolet light to obtain compound (V);

[0030] S5, compound (V) is reacted with tert-butyldimethylsilyl chloride in the presence of a base to prepare an entecavir intermediate.

[0031] Further, in steps S1, S3 and S5, dichloromethane is used as the solvent for the reaction, and the reaction temperature is controlled at 0-30°C, preferably 25°C.

[0032] Further, in steps S1 and S5, the base is one of triethylamine, imidazole, potassium carbonate or diisopropylethylamine, preferably imidazole.

[0033] Further, in step S1, the molar ratio of 4-hydroxy-2-cyclopentenone: base: tert-butyldimethylsilyl chloride is 1: (1-3): (1-3), more preferably 1: 1.5: 1.5.

[0034] Furthermore, in step S2, the molar ratio of the compound (II), imidazole and formaldehyde is 1:(1-3):(1-3), more preferably 1:2:1.5.

[0035] Furthermore, in step S2, the reaction uses a mixed solvent consisting of tetrahydrofuran and water in a volume ratio of 2:1 as a solvent, and the reaction temperature is controlled at 0°C to 30°C, preferably 25°C.

[0036] Furthermore, in step S3, the base is one of triethylamine, pyridine, potassium carbonate or diisopropylethylamine, preferably triethylamine.

[0037] Furthermore, in step S3, the molar ratio of the compound (III), the base and the acetyl chloride is 1:(1-3):(1-3), preferably 1:1.2:1.5.

[0038] Furthermore, in step S4, the free radical initiator is one of benzophenone, 4,4'-dimethoxybenzophenone or anthraquinone, preferably benzophenone.

[0039] Furthermore, in step S4, the reaction uses methanol as solvent, and the reaction temperature is -78°C to 0°C, preferably 0°C.

[0040] Furthermore, in step S4, the molar ratio of the compound (IV) to the free radical initiator is 1:(0.2-1), preferably 1:0.2.

[0041] Furthermore, in step S5, the molar ratio of the compound (V): base: tert-butyldimethylchlorosilane is 1:(1-3):(1-3), preferably 1:1.5:1.5.

[0042] The method for synthesizing entecavir using the entecavir intermediate synthesized by the above method comprises: firstly subjecting the above entecavir intermediate to a reduction reaction under the action of lithium triethylborohydride, then adding a purine derivative, triphenylphosphine and dimethyl azodicarboxylate to carry out a Mitsunobu reaction, and finally hydrolyzing and deprotecting the group to obtain entecavir.

[0043]

[0044] Compared with existing technologies, the present invention offers the following advantages: It provides a method for synthesizing an entecavir intermediate. This method features a simple process and utilizes readily available, inexpensive raw materials. Starting from the known compound 4-hydroxy-2-cyclopentenone, a five-step reaction process yields the key entecavir intermediate, which is then converted to entecavir via a further three-step conversion process. This represents the shortest entecavir synthesis route to date. Furthermore, the product is easily purified, exhibits a high overall yield, and is readily scalable for industrial production. DETAILED DESCRIPTION

[0045] The technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0046] Example 1

[0047] A method for synthesizing an entecavir intermediate comprises the following steps:

[0048] S1. Add 150 ml of dichloromethane to a 500 ml round-bottom flask, add 10 g of 4-hydroxy-2-cyclopentenone, add 10.4 g of imidazole and 22.9 g of tert-butyldimethylsilyl chloride at 0°C, and react at room temperature for 6 hours. The reaction is followed by thin layer chromatography (developing solvent: ethyl acetate: petroleum ether = 20:1). After the reaction is completed, add 200 ml of saturated brine, extract three times with 200 ml of dichloromethane, dry, concentrate, and separate on a silica gel column to obtain 20 g of compound (II) with a yield of 95%.

[0049]

[0050] The NMR data of compound (II) were measured as follows: 1 HNMR (CDCl3, 400MHz): δ7.43 (dd, J=2.4, 5.7Hz, 1H), 6.13 (dd, J=1.3, 5.7Hz, 1H), 4.95 (tdd, J=1.4, 2.4, 6.0H z,1H),2.68(dd,J=6.0,18.2Hz,1H),2.20(dd,J=2.4,18.2Hz,1H),0.88(s,9H),0.11(s,3H),and0.09(s,3H).

[0051] S2. In a 500 ml round-bottom flask, 100 ml of tetrahydrofuran and 50 ml of water were added as a mixed solvent, and 20 g of 4-[(tert-butyldimethylsilyloxysilyl)oxy]-2-cyclopentenone, 14.2 g of a commercially available 30% formaldehyde aqueous solution, and 12.8 g of imidazole were added. The reaction was maintained at 25°C. The reaction was followed by thin layer chromatography (developing solvent: ethyl acetate: petroleum ether = 5:1). After the reaction was completed, 200 ml of saturated brine was added, and the mixture was extracted three times with 300 ml of dichloromethane. The mixture was dried, concentrated, and purified by silica gel column to obtain 17 g of compound (III) with a yield of 75%.

[0052]

[0053] The NMR data of compound (III) are as follows: 1 HNMR (CDCl3, 400MHz): δ7.27-7.25(m,1H),4.93(dtt,1H),4.40(dtt,2H),2.81(dd,J=5.9,18.4 Hz,1H),2.35(brs,1H),2.34(dd,J=2.2,18.4Hz,1H),0.90(s,9H),0.12(s,3H),and0.11(s,3H).

[0054] S3. Add 150 ml of dichloromethane and 15 g of compound (III) to a 500 ml round-bottom flask, add 5.8 g of acetyl chloride and 12.8 g of triethylamine at 0°C, and react at room temperature for 4 hours. After the reaction is completed, add 100 ml of saturated sodium bicarbonate solution, extract three times with 300 ml of dichloromethane, dry, concentrate, and separate and purify on silica gel to obtain 15.8 g of compound (IV) with a yield of 90%.

[0055]

[0056] The NMR data of compound (IV) are as follows: 1 HNMR (CDCl3, 400MHz): δ7.27-7.25(m,1H),4.93(tdt,1H),4.75(dtt,2H),2.77(dd,J=5.9,18. 4Hz, 1H), 2.31 (dd, J = 2.2, 18.4Hz, 1H), 2.09 (s, 3H), 0.89 (s, 9H), 0.12 (s, 3H), and 0.10 (s, 3H).

[0057] S4. Add 100 ml of methanol to a 2500 ml round-bottom flask, add 1 g of compound (IV) and 128 mg of benzophenone, and react at 0°C under 365 nm ultraviolet light (LED, 15 W). The reaction is maintained at 0°C. The reaction is followed by thin layer chromatography (developing solvent: ethyl acetate: petroleum ether = 5:1). After the reaction is completed, the product is concentrated and purified by silica gel column to obtain 540 mg of entecavir intermediate (V) with a yield of 60%.

[0058]

[0059] The NMR data of compound (V) are as follows: 1HNMR (CDCl3, 400MHz): δ6.15(m,1H),5.41(m,1H),4.34(dt,J=6.0,6.2Hz,1H),3.84(d,J=5.7,Hz,2H),2.88( m,1H),2.67(dd,J=6.4,18.3Hz,1H),2.37(dd,J=6.1,18.1Hz,1H),0.88(s,9H),0.10(s,3H),and0.08(s,3H).

[0060] S5. Add 100 ml of dichloromethane to a 500 ml round-bottom flask, add 5 g of intermediate (V), add 2.0 g of imidazole and 4.4 g of tert-butyldimethylsilyl chloride at 0°C, react at room temperature for 12 hours, and follow the reaction by thin layer chromatography (developing solvent: ethyl acetate: petroleum ether = 20:1). After the reaction is completed, add 200 ml of saturated brine, extract three times with 100 ml of dichloromethane, dry, concentrate, and separate on a silica gel column to obtain 6.8 g of compound (VI) with a yield of 95%.

[0061]

[0062] The NMR data of compound (VI) are as follows: 1 HNMR (CDCl3, 400MHz): δ6.12 (dd, J=1.0, 2.5Hz, 1H), 5.41 (dd, J=1.0, 2.3Hz, 1H), 4.34 (dt, J=4.2, 6.2Hz, 1H), 3.72 (dq, J=5.7, 10.3Hz, 2H), 2.83 (m,1H),2.64(dd,J=6.1,18.3Hz,1H),2.32(ddd,J=1.0,4.5,18.1Hz,1H),0.87(s,18H),0.07(s,3H),0.06(s,3H),0.04(s,3H),and0.03(s,3H).

[0063] Entecavir was prepared using compound (VI) synthesized in Example 1:

[0064] (1) In a 500 ml round-bottom flask, 100 ml of tetrahydrofuran and 5 g of intermediate (VI) were added, and 16 ml of lithium triethylborohydride (1.0 MinTHF) was added at -78°C. The reaction was continued at -78°C for 1 hour. 50 ml of water was added to quench the reaction, and the mixture was extracted three times with 100 ml of ethyl acetate. The mixture was dried, concentrated, and separated on a silica gel column to obtain 4.5 g of compound (VII) with a yield of 90%.

[0065]

[0066] The NMR data of compound (VII) are as follows: 1 HNMR (CDCl3, 400MHz): δ6.12 (dd, J=1.0, 2.5Hz, 1H), 5.41 (dd, J=1.0, 2.3Hz, 1H), 4.34 (dt, J=4.2, 6.2Hz, 1H), 3.72 (dq, J=5.7, 10.3Hz, 2H), 2.83 (m,1H),2.64(dd,J=6.1,18.3Hz,1H),2.32(ddd,J=1.0,4.5,18.1Hz,1H),0.87(s,18H),0.07(s,3H),0.06(s,3H),0.04(s,3H),and0.03(s,3H).

[0067] (2) Add 50 ml of tetrahydrofuran, 5 g of compound (VII), 5 g of a purine derivative, and 5.3 g of triphenylphosphine to a 250 ml round-bottom flask. Add 3.5 g of dimethyl azodicarboxylate at 0°C. The reaction is maintained at 0°C. TLC is used to track the reaction (developing solvent: ethyl acetate: petroleum ether = 3:1). After the reaction is complete, add 100 ml of saturated brine, extract three times with 100 ml of dichloromethane, dry, concentrate, and separate and purify on a silica gel column to obtain 7.8 g of compound (VII). Yield: 80%.

[0068]

[0069] The NMR data of compound (VIII) are as follows: 1 HNMR (CDCl3, 400MHz): δ8.22(s,1H),5.69–5.67(m,1H),5.24(s,1H),4.84(s,1H),3.83–3.81( m,2H),2.70(s,1H),2.32–2.24(m,2H),1.43(s,18H),0.95–0.85(m,18H),0.10–0.07(m,12H).

[0070] (3) In a 100 ml round-bottom flask, 20 ml of tetrahydrofuran and 2 g of compound (VIII) were added. 9 ml of 3 M hydrochloric acid was slowly added dropwise at 0°C. The reaction was carried out at 60°C for 12 hours. After the reaction was completed, 50 ml of ethyl acetate was added and washed three times. The pH of the aqueous phase was adjusted to 7-7.5 with NaOH solution (6 mol / L). The solvent was dried and the product was separated and purified on a silica gel column to obtain 730 mg of the compound with a yield of 96%.

[0071]

[0072] The NMR data of the compound entecavir are as follows:1 HNMR (DMSO-D6, 400MHz): δ10.84(s,1H),7.65(s,1H),6.40(s,2H),5.36(dd,J=10.3,8.0Hz,1H),5.10(s,1H),4.85(d,J=3.1Hz,1H),4.8 1(t,J=5.3Hz,1H),4.56(s,1H),4.23(s,1H),3.54(t,J=6.1Hz,2H),2.55-2.50(m,1H),2.26-2.17(m,1H),2.04(dd,J=12.5,7.8Hz,1H).

[0073] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing an entecavir intermediate, characterized in that: The steps include: S1 and 4-hydroxy-2-cyclopentenone react with tert-butyldimethylsilyl chloride in the presence of a base to prepare compound (II); S2, reacting compound (II) with imidazole and formaldehyde to obtain compound (III); S3, reacting compound (III) with acetyl chloride in the presence of a base to obtain compound (IV); S4. Add a free radical initiator to compound (IV), and then react under ultraviolet light to obtain compound (V); S5. reacting compound (V) with tert-butyldimethylsilyl chloride in the presence of a base to obtain an entecavir intermediate; The structural formula of the compound (II) is: The structural formula of the compound (III) is: The structural formula of the compound (IV) is: The structural formula of the compound (V) is: The structural formula of the entecavir intermediate is: In steps S1 and S5, the base is imidazole; In step S4, the reaction uses methanol as a solvent, and the reaction temperature is -78°C to 0°C; the free radical initiator is one of benzophenone, 4,4'-dimethoxybenzophenone or anthraquinone.

2. The method for synthesizing the entecavir intermediate according to claim 1, wherein: In steps S1, S3 and S5, dichloromethane is used as the solvent, and the reaction temperature is controlled at 0°C to 30°C.

3. The method for synthesizing the entecavir intermediate according to claim 1, wherein: In step S1, the molar ratio of 4-hydroxy-2-cyclopentenone:base:tert-butyldimethylchlorosilane is 1:(1-3):(1-3).

4. The method for synthesizing an entecavir intermediate according to claim 1, wherein: In step S2, the molar ratio of the compound (II), imidazole and formaldehyde is 1:(1-3):(1-3).

5. The method for synthesizing the entecavir intermediate according to claim 1, wherein: In step S2, the reaction uses a mixed solvent consisting of tetrahydrofuran and water in a volume ratio of 2:1 as a solvent, and the reaction temperature is controlled at 0°C to 30°C.

6. The method for synthesizing an entecavir intermediate according to claim 1, wherein: In step S3, the base is one of triethylamine, pyridine, potassium carbonate or diisopropylethylamine.

7. The method for synthesizing an entecavir intermediate according to claim 1, wherein: In step S3, the molar ratio of the compound (III), the base and the acetyl chloride is 1:(1-3):(1-3).

8. The method for synthesizing the entecavir intermediate according to any one of claims 1 to 7, wherein: In step S5, the molar ratio of the compound (V): the base: tert-butyldimethylsilyl chloride is 1:(1-3):(1-3).

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