CN105481922A - Preparation method of cangrelor intermediate - Google Patents

Abstract

The object of the present invention is to provide a new preparation method of cangrelor intermediate (formula I), to solve the defects in the prior art. The preparation process includes the sealing reaction of formula II and ammonia, and ammoniation to obtain formula III; the amino compound III is coupled with tetraacetyl ribose IV under the action of a catalyst to obtain formula V; the nitro compound V is reduced to Obtain formula VI; Amino compound VI and orthoformate obtain formula VII through cyclization reaction; Formula VII obtains formula IX with 2-methylthioethylamine (formula VIII) coupling under the presence of alkali; Compound IX In the presence of , deprotection gives cangrelor intermediate formula I. The technical route adopted in the invention has the advantages of mild reaction conditions, high yield, wide source of raw materials, environmental friendliness and the like.

Description

A kind of preparation method of cangrelor intermediate

Technical field:

The invention relates to a chemical preparation method of a cangrelor intermediate (formula I), which has the advantages of mild reaction conditions, high yield, wide source of raw materials, and environmental friendliness.

Background technique:

Cangrelor is a reversible P2Y ₁₂ receptor antagonist developed by AstraZeneca and authorized by TheMedicinesCompany. It has the characteristics of fast onset and short half-life. It is an ideal intravenous antiplatelet drug to prevent harmful coronary artery disease. Blood clot formation for the potential prevention of acute thrombosis such as percutaneous coronary intervention and acute coronary syndrome. On June 22, 2015, Cangrelor was approved for marketing by the FDA. The formulation specification is 50 mg freeze-dried powder injection, and the trade name is Kengreal.

The structural formula of cangrelor is as follows:

The current preparation method of cangrelor reported in the literature only has the following process route disclosed by AstraZeneca in the patent CN1042430:

The compound formula I involved in the route is a key intermediate in the preparation process of cangrelor, and its stable source and low synthesis cost are the key to the production of cangrelor bulk drug.

Development company TheMedicinesCompany discloses a kind of process preparation method of formula I in document (J.Med.Chem.1999,42,213-220):

Wherein, the preparation of formula 1 can refer to the preparation method of the document Chem.Pharm.Bull.25 (8) 1959-1969 (1977), and the route is as follows:

The synthetic process route uses dangerous reagents such as sodium hydride, and iodine raw materials are expensive and have scarce sources, making it difficult to scale up production. At the same time, the overall synthesis yield is low, and the yield of the rearrangement and cyclization reaction for constructing the pyrimidine ring is only 50-75%, and there is no production cost advantage. The market supply of raw material 2-mercaptoadenosine is scarce, and highly toxic carbon disulfide is required for self-synthesis, and highly toxic hydrogen sulfide is produced, which will cause harm to production personnel and the environment, and is not conducive to industrial production.

Patent CN105061431 discloses another preparation method of formula I:

In this synthetic route, raw materials come from a wide range of sources. However, the construction process of the adenosine ring needs to use more than one equivalent of SBA for amino protection, and more than one equivalent of the catalyst TMSOTF, which increases the production cost and makes separation and purification difficult, which is not conducive to the requirements of environmental protection.

Invention content:

The purpose of the present invention is to provide a new preparation method of cangrelor intermediate (formula I), to solve the defects in the prior art. The technical route adopted in the invention has the advantages of mild reaction conditions, high yield, wide source of raw materials, environmental friendliness and the like.

The technical scheme adopted in the present invention is:

In step one, the reaction solvent is a protic solvent, including water, methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, tert-butanol;

In step 1, the reaction temperature is 30 to 120°C;

In step 2, the catalyst is methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid or sulfuric acid;

In step 2, the temperature of reaction is 40～140 ℃;

In step 3, the reducing agent can be carried out using a conventional reducing system in the field, preferably the following reducing system: hydrogen/palladium, hydrogen/nickel, zinc powder/acetic acid, iron powder/acetic acid, formic acid/nickel, hydrazine hydrate/nickel;

In step 3, the temperature of the reduction reaction is -20 to 140°C;

In step 4, the orthoformate is triethyl orthoformate or trimethyl orthoformate;

In step five, the alkali is potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine Or N-methylmorpholine, preferably triethylamine or potassium carbonate.

In step five, the reaction temperature is 40-150°C.

The preparation steps of cangrelor intermediate (formula I) comprise:

Formula II is reacted with ammonia and ammonified to obtain formula III; amino compound III is coupled with tetraacetylribose IV under the action of a catalyst to obtain formula V; nitro compound V is reduced to obtain formula VI through reduction system ; Amino compound VI and orthoformate undergo a cyclization reaction to obtain formula VII; formula VII is coupled with 2-methylthioethylamine (formula VIII) in the presence of a base to obtain formula IX; compound IX is obtained in the presence of a base , remove the protecting group to obtain cangrelor intermediate formula I.

In the present invention, formula II can be prepared by referring to the method of patent CN102718749.

The method of the invention has the advantages of mild reaction conditions, readily available raw materials, convenient post-reaction treatment, environmental friendliness, high product yield and the like, and is suitable for industrialized production.

detailed description:

The following examples further illustrate the present invention, but do not constitute any limitation to the present invention.

Example 1: Preparation of 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (III):

At room temperature, the compound II 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (32.2g, 100mmol) was dissolved in 80ml of absolute ethanol, and the system Add 150ml of ammonia water. The system was transferred to a closed high-pressure valve, and the system was reacted at an external temperature of 80°C for 3 hours, cooled to room temperature and stirred for 1 hour, filtered, washed with 50% ethanol, and dried to obtain 24.8 g of the light yellow title compound, with a yield of 82% . ESI-MS: [M+H] ⁺ = 303.61.

Example 2: Preparation of 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (III):

At room temperature, dissolve compound II 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (32.2g, 100mmol) in 80ml tert-butanol, and Add 150ml of ammonia water. The system was transferred to a closed high-pressure valve, and the system was reacted at an external temperature of 30°C for 6 hours, cooled to room temperature and stirred for 1 hour, filtered, washed with 50% tert-butanol, and dried to obtain 25.7 g of the light yellow title compound, yield 85%. ESI-MS: [M+H] ⁺ = 303.61.

Example 3: Preparation of 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (III):

At room temperature, compound II 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidine (32.2g, 100mmol) was suspended in 80ml of water, and 150ml was added to the system ammonia. The system was transferred to a closed high-pressure valve, and the system was reacted at an external temperature of 120°C for 2 hours, cooled to room temperature and stirred for 1 hour, filtered, washed with 50% ethanol, and dried to obtain 24.2 g of the light yellow title compound, with a yield of 80% . ESI-MS: [M+H] ⁺ = 303.61.

Example 4: (2R, 3R, 4S, 5R)-2-(6-chloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5 - Preparation of acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (V):

Under nitrogen protection, the compound III 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (30.3g, 100mmol) was suspended in 100ml xylene, and trifluoro methanesulfonic acid (0.45 g, 3 mmol), and the temperature of the reaction system was raised to 140°C. A solution of compound IV tetraacetylribose (63.6 g, 200 mmol) dissolved in 100 ml xylene was slowly added dropwise at a rate of 8 ml/min, and refluxed for 1 hour after the addition was completed. Stop the reaction, cool down to room temperature, add 100ml of water, adjust PH=8-9 with sodium bicarbonate solution, let stand to separate the liquids, dry the organic phase and concentrate under reduced pressure to obtain 51.6g of the title compound in oily form, with a yield of 92%. ESI-MS: [M+H] ⁺ = 561.9.

Example 5: (2R, 3R, 4S, 5R)-2-(6-chloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5 - Preparation of acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (V):

Under nitrogen protection, compound III 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (30.3g, 100mmol) was suspended in 100ml of toluene, and sulfuric acid (0.30 g, 3 mmol), the temperature of the reaction system was raised to 110°C. A solution of compound IV tetraacetyl ribose (63.6 g, 200 mmol) dissolved in 100 ml of toluene was slowly added dropwise at a rate of 8 ml/min, and refluxed for 1 hour after the addition was completed. Stop the reaction, cool down to room temperature, add 100ml of water, adjust the pH to 8-9 with sodium bicarbonate solution, let stand to separate the liquids, dry the organic phase and then concentrate to dryness under reduced pressure to obtain 49.9 g of the title compound as an oil, with a yield of 89%. The product was directly used in the next reaction. ESI-MS: [M+H] ⁺ = 561.9.

Example 6: (2R, 3R, 4S, 5R)-2-(6-chloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5 - Preparation of acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (V):

Under nitrogen protection, compound III 6-chloro-5-nitro-4-amino-2-(3,3,3-trifluoropropylthio)pyrimidine (30.3g, 100mmol) was dissolved in 100ml of acetonitrile, and p-toluenesulfonate was added acid (0.52g, 3mmol), and the reaction system was heated to 40°C. A solution of compound IV tetraacetyl ribose (63.6 g, 200 mmol) dissolved in 100 ml of toluene was slowly added dropwise at a rate of 8 ml/min, and refluxed for 1 hour after the addition was completed. Stop the reaction, cool down to room temperature, concentrate under reduced pressure to a volume of 60ml, add 100ml of water and 100ml of toluene, adjust the pH to 8-9 with sodium bicarbonate solution, let stand to separate the liquids, dry the organic phase and concentrate to dryness under reduced pressure to obtain an oil The title compound was 52.7g, the yield was 94%, and the product was directly used in the next reaction. ESI-MS: [M+H] ⁺ = 561.9.

Example 7: (2R, 3R, 4S, 5R)-2-(6-chloro-5-amino-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5- Preparation of acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (VI):

Under 40psi pressure, compound V (2R, 3R, 4S, 5R)-2-(6-chloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino )-5-acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (56.1g, 100mmol) and 2% (w/w) 5% Pt/C suspended in tetrahydrofuran mixture, at 25-30 ℃ hydrogenation for 5 hours. The mixture was filtered through celite and washed with tetrahydrofuran. The filtrates were combined, concentrated under reduced pressure to a volume of 150 ml, and the solid was precipitated by adding water, filtered, washed, and dried to obtain 50.4 g of the title compound with a yield of 95%. ESI-MS: [M+H] ⁺ =531.9, ¹ HNMR-δ(CDCl ₃ )/300MHz): 6.15(d, 1H, J=5.2), 5.91(t, 1H), 5.63(t, 1H), 4.40-4.36(m, 2H), 4.33(m, 1H), 3.19(m, 2H), 2.79(m, 2H), 2.13(s, 3H), 2.12(s, 3H), 2.11(s, 3H ).

Example 8: (2R, 3R, 4S, 5R)-2-(6-chloro-5-amino-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5- Preparation of acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (VI):

Under nitrogen protection, compound V (2R, 3R, 4S, 5R)-2-(6-chloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino) -5-Acetoxymethyl-3,4-di(acetoxy)tetrahydrofuran (56.1g, 100mmol) and zinc powder (32.5g, 500mmol) were suspended in xylene, kept warm at 140°C, and slowly added acetic acid (12.0g, 200mmol), kept stirring for half an hour, filtered and washed twice with hot xylene. The filtrates were combined, concentrated under reduced pressure to a volume of 20 ml, and the solid was precipitated by adding water, filtered, washed, and dried to obtain 48.8 g of the title compound with a yield of 92%. ESI-MS: [M+H] ⁺ =531.9, ¹ HNMR-δ(CDCl ₃ )/300MHz): 6.15(d, 1H, J=5.2), 5.91(t, 1H), 5.63(t, 1H), 4.40-4.36(m, 2H), 4.33(m, 1H), 3.19(m, 2H), 2.79(m, 2H), 2.13(s, 3H), 2.12(s, 3H), 2.11(s, 3H ).

Example 9: (2R, 3R, 4S, 5R)-2-(6-chloro-5-amino-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5- Preparation of acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (VI):

Under nitrogen protection, compound V (2R, 3R, 4S, 5R)-2-(6-chloro-5-nitro-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino) -5-Acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (56.1g, 100mmol) and Raney nickel (2.5g) were suspended in ethanol, kept at -20°C, and slowly added 80% Hydrazine hydrate (7.5g, 120mmol), kept stirring for 2 hours, filtered and washed twice with hot ethanol. The combined filtrates were concentrated under reduced pressure to a volume of 40 ml, and the solid was precipitated by adding water, filtered, washed, and dried to obtain 51.0 g of the title compound with a yield of 96%. ESI-MS: [M+H] ⁺ =531.9, ¹ HNMR-δ(CDCl ₃ )/300MHz): 6.15(d, 1H, J=5.2), 5.91(t, 1H), 5.63(t, 1H), 4.40-4.36(m, 2H), 4.33(m, 1H), 3.19(m, 2H), 2.79(m, 2H), 2.13(s, 3H), 2.12(s, 3H), 2.11(s, 3H ).

Example 10: (2R, 3R, 4S, 5R)-2-(6-chloro-2-(3,3,3-trifluoropropylthio)pyrimidin-9H-purin-9-yl)-5-acetyl Preparation of oxymethyl-3,4-bis(acetoxy)tetrahydrofuran (VII):

Under nitrogen protection, the compound (2R, 3R, 4S, 5R)-2-(6-chloro-5-amino-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5 -Acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (53.1 g, 100 mmol) was added to 260 ml of triethyl orthoformate to form a suspension. At room temperature, concentrated hydrochloric acid (30.0 g, 300 mmol) was slowly added dropwise, the reaction system changed from turbid to clear, and then became turbid again. After the dropwise addition was completed, the mixture was stirred at room temperature for half an hour to stop the reaction. The reaction solution was filtered, washed with petroleum ether, and dried to obtain 49.2 g of the title compound, with a yield of 91%. ESI-MS: [M+H] ⁺ =541.9, ¹ HNMR-δ(CDCl ₃ )/300MHz): 8.10(s, 1H), 6.14(d, 1H, J=5.3), 5.92(t, 1H), 5.62(t, 1H), 4.44-4.37(m, 2H,), 4.34(m, 1H), 3.18(m, 2H), 2.78(m, 2H), 2.12(s, 3H), 2.11(s, 3H ), 2.10(s, 3H).

Example 11: (2R, 3R, 4S, 5R)-2-(6-chloro-2-(3,3,3-trifluoropropylthio)pyrimidin-9H-purin-9-yl)-5-acetyl Preparation of oxymethyl-3,4-bis(acetoxy)tetrahydrofuran (VII):

Under nitrogen protection, the compound (2R, 3R, 4S, 5R)-2-(6-chloro-5-amino-2-(3,3,3-trifluoropropylthio)pyrimidin-4-ylamino)-5 -Acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (53.1 g, 100 mmol) was added to 250 ml of trimethyl orthoformate to form a suspension. At room temperature, concentrated hydrochloric acid (30.0 g, 300 mmol) was slowly added dropwise, the reaction system changed from turbid to clear, and then became turbid again. After the dropwise addition was completed, the mixture was stirred at room temperature for half an hour to stop the reaction. The reaction solution was filtered, washed with petroleum ether, and dried to obtain 48.7 g of the title compound, with a yield of 90%. ESI-MS: [M+H] ⁺ =541.9, ¹ HNMR-δ(CDCl ₃ )/300MHz): 8.10(s, 1H), 6.14(d, 1H, J=5.3), 5.92(t, 1H), 5.62(t, 1H), 4.44-4.37(m, 2H,), 4.34(m, 1H), 3.18(m, 2H), 2.78(m, 2H), 2.12(s, 3H), 2.11(s, 3H ), 2.10(s, 3H).

Example 12: Preparation of O, O, O-triacetyl-6-N-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)adenosine (IX) :

Under nitrogen protection, compound VII(2R, 3R, 4S, 5R)-2-(6-chloro-2-(3,3,3-trifluoropropylthio)pyrimidin-9H-purin-9-yl)-5 -Acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (54.1g, 100mmol) and compound VIII 2-(methylthio)ethylamine (9.1g, 100mmol) were suspended in 200ml tetrahydrofuran, and triethylamine was added (30.3g, 300mmol), stirred and reacted at 65°C for 2 hours. Cool the reaction solution to room temperature, concentrate the reaction solution under reduced pressure, add toluene and water, adjust the pH to 8-9 with dilute hydrochloric acid, and separate the layers. After the organic phase was dried, it was concentrated to dryness under reduced pressure to obtain 55.3 g of the title compound as an oil, with a yield of 93%, and the product was directly used in the next reaction. ESI-MS: [M+H] ⁺ = 596.6.

Example 13: Preparation of O, O, O-triacetyl-6-N-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)adenosine (IX) :

Under nitrogen protection, compound VII(2R, 3R, 4S, 5R)-2-(6-chloro-2-(3,3,3-trifluoropropylthio)pyrimidin-9H-purin-9-yl)-5 -Acetoxymethyl-3,4-bis(acetoxy)tetrahydrofuran (54.1g, 100mmol) and compound VIII2-(methylthio)ethylamine (9.1g, 100mmol) were suspended in 200ml of DMF, and potassium carbonate (41.4 g, 300mmol), stirred and reacted at 150°C for 1 hour. Cool to room temperature, concentrate the reaction solution under reduced pressure, add toluene and water, adjust the pH to 8-9 with dilute hydrochloric acid, and separate the layers. After the organic phase was dried, it was concentrated to dryness under reduced pressure to obtain 52.4 g of the title compound as an oil, with a yield of 88%, and the product was directly used in the next reaction. ESI-MS: [M+H] ⁺ = 596.6.

Example 14: Preparation of O, O, O-triacetyl-6-N-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)adenosine (IX) :

Under nitrogen protection, compound VII(2R, 3R, 4S, 5R)-2-(6-chloro-2-(3,3,3-trifluoropropylthio)pyrimidin-9H-purin-9-yl)-5 -Acetoxymethyl-3,4-di(acetoxy)tetrahydrofuran (54.1g, 100mmol) and compound VIII2-(methylthio)ethylamine (9.1g, 100mmol) were suspended in 200ml of acetonitrile, and pyridine (23.7 g, 300mmol), stirred and reacted at 40°C for 6 hours. The reaction solution was concentrated under reduced pressure, toluene and water were added, the pH was adjusted to 8-9 with dilute hydrochloric acid, and the layers were separated. After the organic phase was dried, it was concentrated to dryness under reduced pressure to obtain 54.1 g of the title compound as an oil, with a yield of 91%, and the product was directly used in the next reaction. ESI-MS: [M+H] ⁺ = 596.6.

Example 15: Preparation of 6-N-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)adenosine (I):

Under nitrogen protection, compound IXO, O, O-triacetyl-6-N-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)adenosine (59.6g, 100mmol) was suspended in 0.15mol/l sodium hydroxide-ethanol (667ml, 100mmol), and stirred at room temperature for 1 hour. Acetic acid (12.0 g, 200 mmol) was added dropwise, and stirred for half an hour after the drop was completed. The reaction solution was concentrated under reduced pressure to the remaining 80ml, and water was added to precipitate a solid, which was filtered, washed, and dried to obtain 41.7g of the title compound, with an HPLC purity of 99.75% and a yield of 89%. ESI-MS: [M+H] ⁺ =470.5, ¹ HNMR-δ(DMSO-d6)/300MHz): 8.28(s, 1H,), 8.15(s, 1H), 5.82(d, 1H, J=6.2 ), 5.45(d, 1H, J=6.2), 5.21(d, 1H, J=4.9), 5.09(t, 1H), 4.56(m, 1H), 4.12(m, 1H), 3.90(m, 1H ), 3.57 (m, 4H), 3.28 (m, 2H), 2.71 (m, 4H), 2.09 (s, 3H).

Claims (10)

1. a preparation method for new cangrelor intermediate (formula I), comprises the steps:

(1) formula II and ammonia carry out tube sealing reaction, and ammonification obtains formula III;

(2) aminocompound III is under the effect of catalyzer, obtains formula V with tetra-acetylated ribose IV coupling;

(3) nitro-compound V is through the effect of reduction system, and reduction obtains formula VI;

(4) aminocompound VI and ortho-formiate obtain formula VII through ring-closure reaction;

(5) formula VII in the presence of base, obtains formula IX with 2-methylthio group ethamine (formula VIII) coupling;

(6) Compound I X in the presence of base, and deprotection base obtains cangrelor intermediate formula I.

。

2. preparation method according to claim 1, is characterized in that, in step one, reaction solvent is protonic solvent, comprises water, methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols, the trimethyl carbinol.

3. preparation method according to claim 1, is characterized in that, in step one, temperature of reaction is 30 ~ 120 DEG C.

4. preparation method according to claim 1, is characterized in that, in step 2, catalyzer is methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, tosic acid, Phenylsulfonic acid or sulfuric acid.

5. preparation method according to claim 1, is characterized in that, in step 2, the temperature of reaction is 40 ~ 140 DEG C.

6. preparation method according to claim 1, it is characterized in that, in step 3, reductive agent can adopt the reduction system of this area routine to carry out, preferred following reduction system: hydrogen/palladium, hydrogen/nickel, zinc powder/acetic acid, iron powder/acetic acid, formic acid/nickel, hydrazine hydrate/nickel.

7. preparation method according to claim 1, is characterized in that, in step 3, the temperature of reduction reaction is-20 ~ 140 DEG C.

8. preparation method according to claim 1, is characterized in that, in step 4, described ortho-formiate is triethyl orthoformate or trimethyl orthoformate.

9. preparation method according to claim 1, it is characterized in that, in step 5, described alkali is salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, N-methyl piperidine or N-methylmorpholine, preferred triethylamine or salt of wormwood.

10. preparation method according to claim 1, is characterized in that, in step 5, temperature of reaction is 40 ~ 150 DEG C.