Preparation method for fused ring compound, and intermediate of fused ring compound

Abstract

Disclosed are a preparation method for a fused ring compound, and an intermediate of the fused ring compound. Provided is a compound of formula 3 or a compound of formula 4. Also provided is a preparation method for a compound of formula 5. The preparation method has mild reaction conditions, achieves a high yield and a high purity, is simple to operate, achieves a low cost, and is beneficial to industrial production. Moreover, it is precisely due to a new intermediate, i.e., the compound of formula 4, that the preparation method for the compound of formula 5 has mild reaction conditions, achieves a high yield and a high purity, is simple to operate, achieves a low cost, and is beneficial to industrial production.

Description

Preparation method of cyclic compound and intermediate thereof

[0001] This application claims priority to Chinese patent application CN2024101136267, filed on January 26, 2024, and to Chinese patent application CN2025100201136, filed on January 6, 2025. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to a preparation method of a cyclic compound and an intermediate thereof. Background Art

[0003] Patent WO2020088659A1 discloses a series of JAK inhibitors. The compound disclosed in Example 1 It has good JAK inhibitory activity. However, the preparation method disclosed in the patent has the problems of low yield, low purity, and inconvenience for industrial production, especially the key intermediate 1f The preparation process has low yield and low purity, and is not convenient for industrial production. Summary of the Invention

[0004] The present invention aims to overcome the low purity defects of the prior art preparation methods of cyclopentadienyl compounds 1f. The present invention provides a preparation method of a cyclopentadienyl compound and an intermediate thereof. The preparation method of the present invention has mild reaction conditions, high yield, high purity, simple operation, low cost, and is conducive to industrial production. And it is precisely because of the new intermediate compound of formula 4 (such as compound IV) of the present invention that the preparation method of formula 5 compound (such as compound V) has mild reaction conditions, high purity, high yield, simple operation, low cost, and is conducive to industrial production.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a compound of the following formula 3 or formula 4:

[0007] Wherein, PG1 and PG2 are independently amino protecting groups.

[0008] In one embodiment, PG1 is independently wherein R is independently C substituted with 1, 2 or 3 R1 6-10 Aryl; R1 is independently methyl, ethyl, isopropyl, n-propyl, tert-butyl, nitro or halogen, for example PG1 is

[0009] In one embodiment, PG2 is independently Wherein R2 is independently methyl, ethyl, isopropyl, n-propyl or tert-butyl, for example, PG2 is

[0010] In one embodiment, the compound of formula 3 or the compound of formula 4 is respectively the following compound:

[0011] The present invention also provides a method for preparing a compound of formula 5, comprising the following steps: reacting a compound of formula 1, a compound of formula 4, and triethyl orthoformate in ethyl acetate in the presence of Bronst acid to obtain a compound of formula 5;

[0012] The PG1 and PG2 are as defined in any of the previous schemes.

[0013] In the preparation method of the compound of formula 5, the reaction can be

[0014] In the preparation method of the compound of formula 5, the mass ratio of ethyl acetate to the compound of formula 4 can be (3-20):1, for example, 5-10:1, and for example, 4.5:1 or 5:1.

[0015] In the preparation method of the compound of formula 5, the Bronst acid can be an organic acid or an inorganic acid. The organic acid is, for example, p-toluenesulfonic acid.

[0016] In the preparation method of the compound of formula 5, the p-toluenesulfonic acid may be p-toluenesulfonic acid monohydrate.

[0017] In the preparation method of the compound of formula 5, the molar ratio of the compound of formula 4 to the Bronst acid is conventional in the art, for example, 1:(0.05-0.5), and another example is 1:0.1.

[0018] In the preparation method of the compound of formula 5, the molar ratio of the compound of formula 4 to the triethyl orthoformate is conventional in the art, for example, 1:(1-5), and another example is 1:2.5.

[0019] In the preparation method of the compound of formula 5, the raw materials of the reaction may be composed of ethyl acetate, the p-toluenesulfonic acid, the compound of formula 4 and triethyl orthoformate.

[0020] In the method for preparing the compound of formula 5, the reaction can be carried out under the protection of an inert gas, for example, under the protection of nitrogen.

[0021] In the method for preparing the compound of formula 5, the reaction temperature can be 20-90°C, for example, 25-32°C, 25-30°C or 80°C.

[0022] In the method for preparing the compound of formula 5, the reaction time is conventional in the art, for example, 1-5 h, such as 1.5 h, 2 h or 3 h.

[0023] In the method for preparing the compound of formula 5, the reaction may further include post-treatment, which may include filtration and washing. The temperature is preferably lowered to 0-5°C before filtration, and the washing solvent is preferably ethyl acetate.

[0024] The method for preparing the compound of formula 5 may further comprise the following steps: subjecting the compound of formula 3 to a reduction reaction to obtain a compound of formula 4; the reduction reaction is scheme 1 or scheme 2:

[0025] Scheme 1: Under a hydrogen atmosphere, in an organic solvent, the compound of formula 3 undergoes a reduction reaction under the catalysis of Pd / C to obtain a compound of formula 4;

[0026] Scheme 2: In a solvent, in the presence of iron powder and ammonium chloride, the compound of formula 3 undergoes a reduction reaction to obtain a compound of formula 4; the solvent is a mixed solvent of an alcohol solvent and water;

[0027] The reaction can be

[0028] In the reduction reaction, in Scheme 1, the organic solvent may be a mixed solvent of an alcohol solvent and an ester solvent. The alcohol solvent may be, for example, methanol. The ester solvent may be, for example, ethyl acetate. The volume ratio of the alcohol solvent to the ester solvent may be, for example, 1:(1-5), or, for example, 1:3.

[0029] In the reduction reaction, in Scheme 1, the volume mass ratio of the organic solvent to the compound of Formula 3 can be 5-20 mL / g, for example, 10 mL / g.

[0030] In the reduction reaction, in Scheme 1, the mass ratio of the compound of Formula 3 to the Pd / C can be 1:(0.05-0.5); for example, 1:0.1.

[0031] In the reduction reaction, in Scheme 1, the reaction temperature is conventional in the art, such as 15-90°C, for example 25°C or 71°C.

[0032] In the reduction reaction, in Scheme 2, the alcohol solvent may be methanol.

[0033] In the reduction reaction, in Scheme 2, the mass ratio of the alcohol solvent to the compound of Formula 3 is conventional in the art, for example, (5-12):1, and another example is 8:1.

[0034] In the reduction reaction, in Scheme 2, the mass ratio of water to the compound of Formula 3 is conventional in the art, for example, (1-5):1, and another example is 2.91:1.

[0035] In the reduction reaction, in Scheme 2, the molar ratio of the compound of Formula 3 to the iron powder is conventional in the art, for example, (2-8):1, and another example is 4:1.

[0036] In the reduction reaction, in Scheme 2, the molar ratio of the compound of Formula 3 to ammonium chloride is conventional in the art, for example, (2-8):1, and another example is 5:1.

[0037] In the reduction reaction, Scheme 2 can be carried out under the protection of an inert gas, for example, under the protection of nitrogen.

[0038] In the reduction reaction, in scheme 2, iron powder can be added in batches.

[0039] In the reduction reaction, Scheme 2 may include the following steps: reacting an alcohol solvent, water, iron powder, ammonium chloride and the compound of Formula 3, and adding iron powder during the reaction to continue the reaction.

[0040] The method for preparing the compound of formula 5 may further comprise the following steps: in n-butanol, in the presence of a base, a substitution reaction is carried out between the compound of formula 1 and the compound of formula 2 to prepare a compound of formula 3;

[0041] The substitution reaction can be

[0042] In the substitution reaction, the mass ratio of n-butanol to the compound of formula 2 may be (6-50):1, for example (10-20):1, and for example 9.34:1.

[0043] In the substitution reaction, the base is conventional in the art, for example, an organic base, and another example is N,N-diisopropylethylamine.

[0044] In the substitution reaction, the molar ratio of the base to the compound of formula 2 is conventional in the art, for example, (1-5):1, and another example is 3:1.

[0045] In the substitution reaction, the molar ratio of the compound of formula 1 to the compound of formula 2 is conventional in the art, for example, (0.7-3):1, and another example is 1.05:1.

[0046] The temperature of the substitution reaction is conventional in the art, for example, 80 to 140°C, for example, 120 to 125°C.

[0047] The substitution reaction may further include post-treatment, which may include concentration, filtration and washing. The washing solvent may be, for example, n-butanol.

[0048] The present invention also provides a method for preparing a compound of formula 4, comprising the following steps: subjecting a compound of formula 3 to a reduction reaction to obtain a compound of formula 4; the reduction reaction is Scheme 1 or Scheme 2:

[0049] Scheme 1: Under a hydrogen atmosphere, in an organic solvent, the compound of formula 3 undergoes a reduction reaction under the catalysis of Pd / C to obtain a compound of formula 4;

[0050] Scheme 2: In a solvent, in the presence of iron powder and ammonium chloride, the compound of formula 3 undergoes a reduction reaction to obtain a compound of formula 4; the solvent is a mixed solvent of an alcohol solvent and water;

[0051] The reduction reaction can be as described in any of the previous schemes.

[0052] The reduction reaction may include a method for preparing the compound of formula 3, and the method for preparing the compound of formula 3 is as described in any of the previous schemes.

[0053] The present invention also provides a method for preparing a compound of formula 3, comprising the following steps: in n-butanol, in the presence of a base, allowing a compound of formula 1 to undergo a substitution reaction with a compound of formula 2 to prepare a compound of formula 3;

[0054] The substitution reaction can be as described in any of the previous schemes.

[0055] The present invention also provides a method for preparing the compound of formula 8, which comprises the following steps:

[0056] S1: In ethyl acetate, in the presence of p-toluenesulfonic acid, the compound of formula 4 reacts with triethyl orthoformate to obtain the compound of formula 5;

[0057] S2: preparing a compound of formula 6 by hydrolyzing the compound of formula 5;

[0058] S3: preparing a compound of formula 7 by deprotection reaction of the compound of formula 6;

[0059] S4: The compound of formula 7 is subjected to a substitution reaction to obtain a compound of formula 8;

[0060] Wherein, the preparation method of the compound of formula 5 is as described in any of the previous schemes;

[0061] In the method for preparing the compound of Formula 8, the hydrolysis reaction is conventional in the art, for example, the compound of Formula 5 is hydrolyzed in a solvent in the presence of a base. The base can be an inorganic base, such as NaOH. The solvent can be a mixed solvent of an alcohol and water.

[0062] In the method for preparing the compound of Formula 8, the deprotection reaction is conventional in the art, for example, the deprotection reaction of the compound of Formula 6 is carried out in an organic solvent in the presence of an acid. The acid can be an organic acid or an inorganic acid, such as HCl or TFA. The organic solvent can be a halogenated hydrocarbon solvent.

[0063] In the method for preparing the compound of Formula 8, the substitution reaction is conventional in the art, for example, a substitution reaction is carried out between the compound of Formula 7 and propylsulfonyl chloride in an organic solvent in the presence of a base. The organic solvent may be an amide solvent and / or a sulfoxide solvent. The base may be an organic base, such as TEA.

[0064] The preparation method of the compound of formula 8 can be:

[0065] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0066] The reagents and raw materials used in the present invention are commercially available.

[0067] The positive advantages of the present invention are that the preparation method of the present invention has mild reaction conditions, high yield, high purity, simple operation, low cost, and is conducive to industrial production. Moreover, it is precisely because of the new intermediate compound of formula 4 (e.g., compound IV) of the present invention that the preparation method of compound of formula 5 (e.g., compound V) also has mild reaction conditions, high purity, high yield, simple operation, low cost, and is conducive to industrial production.

[0068] For example, compared with the preparation method of the compound of formula 5 in the prior art, the preparation method of the present application improves the purity of the compound due to the use of the new intermediate compound of formula 4, greatly reduces the amount of solvent used, simplifies the operation, and optimizes the process. DETAILED DESCRIPTION

[0069] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0070] Example 1 Preparation of Compound V

[0071] Raw material ratio

[0072] Steps

[0073] Compound IV (301.7 g), triethyl orthoformate (230.6 g), TsOH·H2O (11.8 g) and ethyl acetate (1360 g) were added to a 3 L four-necked flask and stirred at 25°C to 30°C for 1.5 hours. TLC detected that the raw material reacted completely, and HPLC control detected that compound IV was ≤1%.

[0074] 1. Filter and cool to 0-5℃, keep warm and stir for 1 hour, filter, and rinse the filter cake with ethyl acetate (pre-cooled at 0-5℃, 406g).

[0075] 2. Drying: Dry in vacuo at 45°C for 20-40 hours to obtain 232.5 g of a yellow solid, which was identified as compound V.

[0076] Example 2 Preparation of Compound V

[0077] The following reaction steps refer to the reaction steps in Example 1.

[0078] Experimental conclusion: The reaction temperature can be lowered to 25-30°C and the reaction volume can be modified to 5V.

[0079] Example 3 Preparation of Compound IV

[0080] Raw material ratio:

[0081] Steps

[0082] 1. Add Compound III (180.3 g), reduced iron powder (68.5 g), methanol (1441 g), NH4Cl (93.3 g), and water (524 g) to a 10 L reactor under nitrogen. Start stirring, raise the temperature to reflux (internal temperature 71°C), and stir at this temperature for 1 hour. Add reduced iron powder (9.79 g), continue stirring at this temperature for another 1 hour, and take a sample for control. TLC checks whether the reaction of the raw materials is complete, and HPLC tests for Compound III ≤1%.

[0083] 2. Filter and cool to an internal temperature of 60-65°C, add THF (3115 g) and diatomaceous earth (350 g), stir for 15 minutes, filter (pad 350 g of diatomaceous earth), wash the reactor with THF (1602 g), and then rinse the filter cake.

[0084] 3. Concentration and crystallization: The filtrate was concentrated under reduced pressure at 50°C to a remaining volume of about 1.8 L, cooled to ~38°C with stirring, and water (900 g) was added dropwise to the remaining filtrate. After the addition was complete, the mixture was kept warm and stirred (20-30°C).

[0085] 4. Filter and rinse the filter cake with a mixture of THF (267 g) and water (1200 g).

[0086] 5. Drying: vacuum drying at 45°C for 40 hours to obtain 140.2 g of solid, which was identified as compound IV.

[0087] 1H NMR (400MHz, DMSO-d6) δ7.86(d,J=8.8Hz,2H),7.62(s,1H),7.48(s,1H),7.47(s,1H),7.33(d,J=8 .8Hz,2H),6.67(d,J=4.0Hz,1H),5.53(s,1H),4.56(s,2H),2.29(s,3H),2.02(s,6H),1.32(s,9H).

[0088] Example 4 Preparation of Compound IV

[0089] The following reaction steps refer to the reaction steps in Example 3.

[0090] According to the calculation method of actual yield = actual mass * purity / theoretical mass, the actual yield of this embodiment is 94.3%.

[0091] Example 5: Preparation of Compound III

[0092] Raw material ratio:

[0093] Steps

[0094] Add Compound I (78.7 g), Compound II (132.9 g), N,N-diisopropylethylamine (146.6 g), and n-butanol (737 g) to a 2 L flask and stir. Raise the temperature to reflux (external temperature 120-125°C). Maintain the temperature and stir for 3-4 hours. HPLC analysis shows that the concentration of Compound II is ≤1%.

[0095] The temperature was reduced to 75-80°C by steaming, and the solvent (-200 g) was concentrated under reduced pressure. The temperature was naturally reduced to 0-5°C, and the mixture was stirred at this temperature for 0.5 hours.

[0096] Filter and rinse the filter cake with n-butanol (pre-cooled at 0-5℃, 121g) and then with water (225g).

[0097] The product was dried under vacuum at 50°C for 20 to 40 hours to obtain 183.1 g of a yellow solid, which was identified as compound III.

[0098] 1H NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.86(s,1H),8.02(d,J=8.8Hz,2H),7.84(d,J=4.0Hz,1H),7 .70(s,1H),7.45(d,J=8.8Hz,2H),7.13(d,J=4.0Hz,1H),2.37(s,6H),2.36(s,3H),1.39(s,9H).

[0099] Example 6: Synthesis of Compound VIII

[0100] Compound VIII was prepared by referring to the method of Example 1 in patent WO2020088659A1.

[0101] Comparative Example 1: Preparation of Compound V

[0102] Compound IV (23 g), triethyl orthoformate (9.2 g), and TsOH·H2O (0.47 g) were added to Toluene (250 mL) and stirred at 120°C overnight; cooled to room temperature; diluted with H2O (400 mL), extracted with EA (800 mL), and the organic phase was washed with saturated brine (300 mL*2) and dried over anhydrous sodium sulfate; and concentrated to obtain compound V (10.23 g) with HPLC purity of 86.02%.

[0103] Comparative Example 2: Preparation of Compound V

[0104] Based on Comparative Example 1, the following experiments were conducted, and the reaction conditions not explicitly stated were the same as those in Comparative Example 1:

Claims

1. A compound of Formula 3 or a compound of Formula 4 as follows: Among them, PG1 and PG2 are each independently an amino protecting group.

2. The compound of formula 3 or the compound of formula 4 according to claim 1, wherein It satisfies one or both of the following conditions: (1)PG1 is independently wherein R is independently C substituted by one, two or three Rs 1 aryl; R 6-10 is independently methyl, ethyl, isopropyl, n-propyl, tert-butyl, nitro or halogen, for example PG1 is 1 (2)PG2 is independently wherein R2 is independently methyl, ethyl, isopropyl, n-propyl or tert-butyl, for example PG2 is 3. The compound of formula 3 or the compound of formula 4 according to claim 1, characterized in that, The compound of Formula 3 or the compound of Formula 4 is respectively the following compound:

4. A method for preparing a compound of formula 5, characterized in that, It comprises the following steps: in ethyl acetate, in the presence of a Bronst acid, the compound of formula 4 reacts with triethyl orthoformate to obtain the compound of formula 5; The PG1 and PG2 are as described in claim 1 or 2.

5. The preparation method of the compound of formula 5 according to claim 4, characterized in that, The reaction is 6. The preparation method of the compound of formula 5 according to claim 4, characterized in that, The method for preparing the compound 5 satisfies one or more of the following conditions: (1) The mass ratio of the ethyl acetate to the compound of formula 4 is (3 - 20):1, such as 5 - 10:1, and further such as 4.5:1 or 5:1; (2) The Bronst acid is an organic acid or an inorganic acid; the organic acid is, for example, p-toluenesulfonic acid; the p-toluenesulfonic acid may be p-toluenesulfonic acid monohydrate; (3) The molar ratio of the compound of formula 4 to the Bronst acid is 1:(0.05 - 0.5), such as 1:0.1; (4) The molar ratio of the compound of formula 4 to the triethyl orthoformate is 1:(1 - 5), such as 1:2.5; (5) The raw materials for the reaction consist of ethyl acetate, the p-toluenesulfonic acid, the compound of formula 4, and the triethyl orthoformate; (6) The reaction is carried out under the protection of an inert gas, such as under the protection of nitrogen; (7) The temperature of the reaction is 20 - 90 °C, such as 25 - 32 °C, 25 - 30 °C, or 80 °C; (8) The reaction time is 1 - 5 h, such as 1.5 h, 2 h, or 3 h; (9) The reaction further includes post-treatment, and the post-treatment steps may include: filtration and washing; it is preferred to cool down to 0 - 5 °C before filtration, and the washing solvent is preferably ethyl acetate.

7. The method for preparing the compound of formula 5 according to claim 6, characterized in that, The method for preparing the compound of formula 5 further includes the following step: the compound of formula 3 is prepared to obtain the compound of formula 4 through a reduction reaction; the reduction reaction is Scheme 1 or Scheme 2: Scheme 1: In a hydrogen atmosphere and in an organic solvent, the compound of formula 3 undergoes a reduction reaction under the catalysis of Pd / C to obtain the compound of formula 4; Scheme 2: In a solvent, in the presence of iron powder and ammonium chloride, the compound of Formula 3 undergoes a reduction reaction to obtain the compound of Formula 4; the solvent is a mixed solvent of an alcohol solvent and water; 8. The method for preparing the compound of formula 5 according to claim 7, characterized in that, The method for preparing the compound of formula 4 satisfies one or more of the following conditions: (1) In Scheme 1, the organic solvent is a mixed solvent of an alcohol solvent and an ester solvent; the alcohol solvent is, for example, methanol; the ester solvent is, for example, ethyl acetate; the volume ratio of the alcohol solvent to the ester solvent is, for example, 1:(1 - 5), and further such as 1:3; (2) In Scheme 1, the volume-mass ratio of the organic solvent to the compound of formula 3 is 5 - 20 mL / g, such as 10 mL / g; (3) In Scheme 1, the mass ratio of the compound of formula 3 to the Pd / C is 1:(0.05 - 0.5); such as 1:0.1; (4) In Scheme 1, the temperature of the reaction is 15 - 90 °C, such as 25 °C or 71 °C; (5) In Scheme 2, the alcohol solvent is methanol; (6) In Scheme 2, the mass ratio of the alcohol solvent to the compound of formula 3 is (5 - 12):1, such as 8:1; (7) In Scheme 2, the mass ratio of water to the compound of formula 3 is (1 - 5):1, such as 2.91:1; (8) In Scheme 2, the molar ratio of the compound of formula 3 to iron powder is (2 - 8):1, such as 4:1; (9) In Scheme 2, the molar ratio of the compound of formula 3 to ammonium chloride is (2 - 8):1, such as 5:1; (10) The second solution is carried out under the protection of an inert gas, for example, under the protection of nitrogen; (11) In the second solution, iron powder is added in batches; (12) The second solution includes the following steps: An alcohol solvent, water, iron powder, ammonium chloride and the compound of formula 3 react, and iron powder is added during the reaction to continue the reaction; (13) The reaction is 9. The method for preparing the compound of formula 5 as claimed in claim 7, wherein, The method for preparing the compound of formula 5 further comprises the following steps: in n-butanol and in the presence of a base, a substitution reaction occurs between the compound of formula 1 and the compound of formula 2 to prepare the compound of formula 3; 10. The method for preparing the compound of formula 5 according to claim 9, wherein The preparation method of the compound of formula 3 satisfies one or more of the following conditions: (1) The mass ratio of the n-butanol to the compound of formula 2 is (6 - 50):1, for example, (10 - 20):1, and further for example, 9.34:1; (2) The base is an organic base, for example, N,N-diisopropylethylamine; (3) The molar ratio of the base to the compound of formula 2 is (1 - 5):1, for example, 3:1; (4) The molar ratio of the compound of formula 1 to the compound of formula 2 is (0.7 - 3):1, and further for example, 1.05:1; (5) The temperature of the substitution reaction is 80 - 140 °C, for example, 120 - 125 °C; (6) The substitution reaction further includes post-treatment, and the post-treatment can be concentration, filtration and washing; the solvent for washing is, for example, n-butanol; (7) The substitution reaction is 11. A method for preparing a compound of formula 4, which comprises the following steps: The compound of formula 4 is prepared by the reduction reaction of the compound of formula 3; the reduction reaction is the first solution or the second solution: In the first solution, in a hydrogen atmosphere and in an organic solvent, the compound of formula 3 undergoes a reduction reaction under the catalysis of Pd / C to obtain the compound of formula 4; Scheme 2: In a solvent, in the presence of iron powder and ammonium chloride, the compound of Formula 3 undergoes a reduction reaction to obtain the compound of Formula 4; the solvent is a mixed solvent of an alcohol solvent and water; 12. The method for preparing the compound of formula 4 according to claim 11, characterized in that, The preparation method of the compound of formula 4 satisfies one or two of the following conditions (1) The conditions and operations of the reduction reaction are as described in claim 8; (2) The reduction reaction further includes the preparation method of the compound of formula 3, and the preparation method of the compound of formula 3 is as described in claim 9 or 10.

13. A method for preparing a compound of formula 3, characterized in that, It includes the following steps: In an organic solvent, in the presence of a base, a substitution reaction occurs between a compound of Formula 1 and a compound of Formula 2 to prepare a compound of Formula 3; 14. The method for preparing the compound of formula 3 according to claim 13, characterized in that, The substitution reaction is as described in claim 10.

15. A method for preparing a compound of formula 8, characterized in that, It includes the following steps: S1: In ethyl acetate, in the presence of p-toluenesulfonic acid, the compound of formula 4 reacts with triethyl orthoformate to obtain the compound of formula 5; S2: The compound of formula 5 is prepared into the compound of formula 6 by hydrolysis reaction; S3: The compound of formula 6 is prepared into the compound of formula 7 by deprotection reaction; S4: The compound of formula 7 is prepared into the compound of formula 8 by substitution reaction; Among them, the preparation method of the compound of formula 5 is as described in any one of claims 1-10; 16. The method for preparing the compound of formula 8 according to claim 15, wherein, The preparation method of the compound of formula 8 satisfies one or more of the following conditions: (1) The hydrolysis reaction is: in a solvent, the compound of formula 5 undergoes a hydrolysis reaction in the presence of a base; the base can be an inorganic base, for example, NaOH; the solvent can be a mixed solvent of an alcohol solvent and water; (2) The deprotection reaction is: in an organic solvent, the compound of formula 6 undergoes a deprotection reaction in the presence of an acid; the acid can be an organic acid or an inorganic acid, for example, HCl or TFA; the organic solvent can be a halogenated hydrocarbon solvent; (3) The substitution reaction is: in an organic solvent, in the presence of a base, the compound of formula 7 reacts with propylsulfonyl chloride to undergo a substitution reaction; the organic solvent can be an amide solvent and / or a sulfoxide solvent; the base can be an organic base, for example, TEA; (4) The preparation method of the compound of formula 8 is as follows:

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