TW201348244A - Synthesis method of saccharide drug contrast agent precursor - Google Patents

Abstract

This invention relates to a novel synthesis method of a saccharide drug contrast agent precursor. In this method, after completing synthesis of a main structure Z-Gly-ah, the galactosamine GalNAc(OAc)4 is used for coupling, and the product is directly precipitated by using the dichloromethane, so as to reduce the loss of galactosamine during liquid chromatography extraction. In addition, the benzyloxycarbonyl is used instead of the trifluoroacetic acid as the protection group to ensure the unity of the phase, thereby greatly reducing the synthesis time and costs.

Description

Method for synthesizing saccharide drug contrast agent precursor

The invention relates to a method for synthesizing a precursor of a saccharide drug contrast agent, in particular to a synthetic method capable of reducing the loss of galactosamine in the preparation process.

Since there are special receptors on human cells that can accept certain proteins or peptides, if this particularity is applied, that is, if specific proteins or peptides are radioactive, these proteins or peptides are used. After entering the human body, it can accumulate in specific organs or tissues, and can achieve the purpose of disease treatment or nuclear diagnostic imaging diagnosis.
There are about 200,000 aspiratecoprotein receptors (ASGPR) on the surface of mammalian hepatocytes, which have special affinity for galactose (Gal) and N-acetylgalactosamine (GalNAc). Especially when the matrix contains three galactose or N-acetyl galactosamine, it can exhibit a stronger affinity, almost 10 times that of a single sugar. Based on this characteristic, YEE (G-ah-GalNAc) ₃ has been applied as a carrier of genes and drugs, and successfully loaded genes and drugs into liver cells, and this property is also developed for the detection of hepatic fibrosis. Nuclear medicine contrast agents are quite helpful.
In the past, when synthesizing G-ah-GalNAc, please refer to the first figure for the synthesis method; as shown in the figure, it is prepared by reacting D-galactosamine under the conditions of containing pyridine and acetic anhydride. The less active compound GalNAc(OAc) ₄ . The compound GalNAc(OAc) _{4 is} then reacted with trimethyl-silyl trifluoromethane sulfonate (TMSOTf) to form a highly active Oxazoline derivative for about 24 hours. The oxazoline derivative and the 6-trifluoroacetic acid aminohexanol (TFA-ah) having an amine protecting group will be coupled to form 6-trifluoroacetic acid hexyl β-N-oxime under the catalysis of sulfuric acid. A galactosamine peracetate (TFA-ah-GalNAc(OAc) ₃ ). This compound TFA-ah-GalNAc(OAc) _{3 was} subjected to the first liquid chromatography for 48 hours with 90% ethanol.
Next, the compound TFA-ah-GalNAc(OAc) _{3 was} first protected with sodium methoxide under the action of sodium methoxide, and then added with a solution containing triethylamine in ethanol overnight. After concentration, it was purified with aqueous acetic acid, that is, the second liquid chromatography, and after chromatography, it was dried. Since acetic acid reacts with the hydroxyl group of the compound TFA-ah-GalNAc(OAc) ₃ to form esters, we must stir the hydrogen-oxygen anion exchange resin (DOWEX, OH ^- form) several times to reduce the "hydroxy esterification". phenomenon. After the nitrogen trifluoride protecting group at the nitrogen end is removed, the compound ah-GalNAc can be produced.
The compound ah-GalNAc is bonded to a glycine containing a carbobenzoxy (Cbz or Z) protecting group, and then 1,3-dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole are added. (N-Hydroxybenzotriazole, HOBt), stirred in a solution of anhydrous nitrogen and N, N-dimethylformamide (DMF) overnight at room temperature to give the compound ZG-ah-GalNAc. Finally, the benzyloxycarbonyl protecting group is removed by hydrogenation reduction to give the final product glycine aminohexyl β-N-decyl galactosamine (G-ah-GalNAc).
In this synthesis method, there are two liquid chromatography separation procedures, which allows only about 30% of GalNAc(OAc) ₄ to be converted into the final product G-ah-GalNAc, and the entire synthesis process takes about 30 days. , plus the GalN used in the process. HCl, also known as D-galactosamine, is very expensive, and when it is nearly 50% depleted in liquid chromatography separation, cost control is undoubtedly an obstacle.
In addition, if the hydroxyl group on GalNAc is removed too early, and acetic acid is used as the embankment, the hydroxyl group on the GalNAc and the acetic acid will act to esterify, so it needs to be removed by the hydroxide-type anion exchange resin. However, the protection efficiency of the esters of the esters is poor, and it needs to be stirred overnight, which is quite time consuming. And when the hydroxide-type anion exchange resin is added too much, the pH of the solution rises too high to cause the GalNAc to break. Moreover, HOBt is difficult to remove by recrystallization, which often causes troubles in the next process.
Therefore, in view of the shortcomings of the past synthesis methods which are not conducive to improving efficiency or reducing cost, the present invention discloses a novel synthesis method to overcome these problems.

The main object of the present invention is to provide a method for synthesizing a saccharide drug contrast agent precursor, which simplifies and integrates the synthesis method of the galactose peptide derivative G-ah-GalNAc, thereby saving process cost and process time.
A secondary object of the present invention is to provide a method for synthesizing a precursor of a saccharide drug contrast agent, which, after completion of the synthesis of the main structure Z-Gly-ah, participates in the coupling of galactosamine GalNAc(OAc) ₄ instead of After the combination of galactosamine and ah, it is coupled with Z-Gly, so that the reduction of galactosamine in the synthesis process can be reduced by reducing the coupling of galactosamine.
Another object of the present invention is to provide a method for synthesizing a precursor of a saccharide drug contrast agent, which uses a benzyloxycarbonyl group as a protecting group in the synthesis process to improve structural steric hindrance to ensure unity of phase.
A further object of the present invention is to provide a method for synthesizing a precursor of a saccharide drug contrast agent, which utilizes the good solubility of GalNAc and ZG-ah in methylene chloride, thereby eliminating the purification step of liquid chromatography and directly depositing high The purity of the product improves the efficiency of the synthesis.
In order to achieve the above object, the present invention discloses a method for synthesizing a saccharide drug contrast agent precursor, the steps comprising: synthesizing a compound Z-Gly-ah; synthesizing a compound GalNAc(OAc) ₄ ; coupling the compound Z- Gly-ah and the compound GalNAc(OAc) ₄ in a solution containing one of dichloromethane and a plurality of solvents; extracting the solution; removing the water and concentrating the extracted solution; adding sodium methoxide to remove the compound GalNAc(OAc) ₄ acetyl group; adjust the pH of the solution to 6 using a hydrogen type cation exchange resin; filter and concentrate the solution; wash the solution with dichloromethane, and filter again to obtain a compound ZG-ah-GalNAc And hydrogenation of the compound ZG-ah-GalNAc to obtain a compound G-ah-GalNAc.

In order to provide a better understanding and understanding of the features of the present invention and the efficacies achieved, the preferred embodiments and detailed descriptions are provided as follows:
Based on many disadvantages in the past technology, the synthesis efficiency is not ideal, or the cost is too high to be popular, so the present invention proposes this synthesis method to overcome these problems.
First, please refer to the second figure, which is a flow chart of the steps for synthesizing the precursor of the saccharide drug contrast agent of the present invention; as shown in the figure, the steps include:
Step S1: synthesizing a compound Z-Gly-ah;
Step S2: synthesizing a compound GalNAc(OAc) ₄ ;
Step S3: coupling the compound Z-Gly-ah and the compound GalNAc(OAc) ₄ to a solution containing one of dichloromethane and a plurality of solvents;
Step S4: extracting the solution;
Step S5: removing water and concentrating the extracted solution;
Step S6: adding sodium methoxide to remove the ethyl thiol group of the compound GalNAc(OAc) _{4 in} the solution;
Step S7: using a hydrogen type cation exchange resin to adjust the pH of the solution to 6;
Step S8: filtering and concentrating the solution;
Step S9: washing the solution with dichloromethane, again filtering to obtain a compound ZG-ah-GalNAc; and step S10: hydrogenating the compound ZG-ah-GalNAc to obtain a compound G-ah-GalNAc.
In these steps, the key feature is to simplify and integrate the techniques for synthesizing G-ah-GalNAc in the past. In step S1, the compound Z-Gly-ah is synthesized separately without galactose ammonia GalNAc (OAc). ₄ ) Participate too early. For the synthesis of Z-Gly-ah, please refer to the third figure, which uses a compound Z-Gly-OH and uses N-hydroxybutylimine (NHS) to contain 1,3- The reaction is carried out in a solution of dicyclohexylcarbodiimide (DCC) and molecular sieve in tetrahydrofuran (THF), and after stirring overnight at room temperature, it is coupled with 6-aminohexanol (ah) to form The compound Z-Gly-ah.
After the preparation of the compound Z-Gly-ah, the compound GalNAc(OAc) _{4 is} synthesized in step S2, please refer to the fourth figure, which uses the compound GalN. HCl is the reactant, that is, D-(+)-Galactosamine hydrochloride is treated with a solution of pyridine in acetic anhydride to protect the hydroxyl group to form the compound GalNAc(OAc) ₄ .
After synthesizing the compound Z-Gly-ah and the compound GalNAc(OAc) ₄ , the next step is to couple the two in step S3. Please refer to the fifth figure, which is to treat the compound Z-Gly-ah and the compound GalNAc(OAc) ₄ in a plurality of solvents. The present invention selects 1, 2 at 50 ° C containing TMSOTf, a small amount of DMF and dichloromethane. The mixture was stirred overnight in a dichloroethane solution to carry out a coupling reaction.
Further, in steps S4 to S8, the coupled product is further processed. After the 1,2-dichloroethane solution is cooled, the TMSOTf derivative is neutralized with triethylamine, and then extracted four times with a saturated sodium hydrogencarbonate solution (take the organic layer), and then extracted once with an aqueous solution of sodium chloride. (take the organic layer). The organic layer was then dehydrated with anhydrous sodium sulfate and concentrated. The obtained concentrated residue was then subjected to the protection of the ethyl hydrazide group with 0.10 M sodium methoxide (NaOMe), and finally the pH was adjusted to 6 with a hydrogen-type cation exchange resin (DOWEX, H ⁺ form), that is, acidification treatment.
After the acidified product is filtered again and concentrated, the residue is washed with dichloromethane, and the solid is collected again to obtain a high purity 6-(Benzyloxycarbonylglycylamino)hexyl β-N-acetyl-galactosamine, that is, Compound ZG-ah-GalNAc.
Please refer to the sixth figure. In the final step S10, the compound ZG-ah-GalNAc is dissolved in methanol and added with an appropriate amount of 10% palladium carbon catalyst, and then shaken at room temperature in a 50 psi hydrogen atmosphere. Overnight, hydrogenation reduction, filtration and concentration gave the final product G-ah-GalNAc. This G-ah-GalNAc product does not have to be further separated and purified.
Through the steps of the present invention which are gradually disclosed above, the same products as in the prior art can be prepared, but the yield can be as high as 75%, and the cost and the synthesis time are greatly reduced because it is not necessary to face the highly active intermediate oxazoline. The problem of long synthesis time and deterioration also reduces the possible loss of galactose during the synthesis process, because the present invention first synthesizes Z-Gly-ah, and galactose ammonia is directly coupled with it instead of galactose. After the combination of ammonia and ah, Z-Gly is coupled; and Cbz is taken by discarding the TFA protecting group to avoid a phase change of at least 20% caused by the TFA protecting group, ensuring the quality of the product.
The compound G-ah-GalNAc provided by the invention has high yield and low cost, and based on its affinity with mammalian hepatocytes, it can be more commonly used in the preparation of contrast agents, or to further develop liver cancer-related Derivatives such as labeling or radiation therapy are undoubtedly a synthetic method for the precursor of glycoconjugates with significant medical value.
The following are the details of the actual embodiment and related parameters in the experimental operation of the present invention:

[synthetic ZG-ah]
[Benzyl(6-hydroxyhexylcarbamoyl)methylcarbamate]
4 g of 4A molecular sieve, Cbz-Glycine (Z-Gly-OH, 2.09g, 10mmol), N, N'-Dicyclohexylcarbodiimide (DCC, 3.09g, 15mmole) and N-hydroxysuccinimde (NHS) were weighed in a 100 ml round bottom flask. , 1.38 g, 12 mmole), and evacuated for 2 hours. After adding 30 ml of anhydrous THF, it was stirred at room temperature overnight. The filtrate was filtered with a ceramic funnel, and then 6-aminohexanol (ah, 1.17 g, 10 mmol) was added and stirred overnight at room temperature, concentrated under reduced pressure, and then evaporated overnight. The mixture was stirred with an aqueous solution of 300 ml of 50% ethanol in an ice bath for 30 minutes, and then the filtrate was filtered with a ceramic funnel, and concentrated under reduced pressure with methanol at 35 ° C, and then vacuumed overnight. After stirring in an ice bath, 150 ml of EtOAc was stirred for 30 minutes, and then the solid was filtered with a ceramic funnel, and finally vacuumed overnight. A white solid ZG-ah (1.4 g, 45%) was obtained.
Its analysis data:
IR (neat): n _NH = 3386 cm ^-1 , 3265 cm ^-1 , n _{C = O} = 1690 cm ^-1 , 1650 cm ^-1 .
¹ H-NMR (CDCl ₃ ): δ 7.38 (m, 5H, Ph- H ), 6.18 (br, 1H, C ₆ -N H ), 5.57 (br, 1H, C ₈ -N H ), 5.12 (s , 2H, C ₁₀ - H ₂ ), 3.83 (d, 2H, C ₈ - H ₂ ), 3.63 (t, 2H, C ₁ - H ₂ ), 3.24 (t, 2H, C ₆ - H ₂ ), 1.83 (br, 1H, O H ), 1.55 (m, 4 H, C ₂ - H ₂ & C ₅ - H ₂ ), and 1.35 (m, 4 H, C ₃ - H ₂ & C ₄ - H ₂ ).
¹³ C-NMR (CDCl ₃ ): d 169 ( C ₇ ), 158 ( C ₉ ), 137 ( C ₁₀ ), 128 ( C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ & C ₁₆ ), 67 ( C ₁₀ ), 62( C ₁ ), 44( C ₈ ), 39( C ₆ ), 32( C ₂ ), 29( C ₅ ), 27( C ₄ ), and 25( C ₃ ).
MS: m/z 331 [(M+Na)] ⁺ .

[Synthetic GalNAc(OAc) ₄ ]
[β-N-Acetylgalactosamine per-O-acetate]
In a 250 ml round bottom flask, D-(+)-Galactosamine hydrochloride [GalN.HCl] (15 g, 69.9 mmol) was suspended in anhydrous pyridine (60 ml) and 10.5 M acetic anhydride (90 ml) and stirred at room temperature. Overnight (about 16 hours). After filtering the suspension, the solid was washed alternately with glacial acetic acid and water and dried to give a white solid. After extraction with 15 ml of diethyl ether, a white solid product, GalNAc (OAc) ₄ (20.4 g, 75%).
Its analysis data:
IR (neat): n _NH = 3230 cm ^-1 , n _{C = O} = 1750 cm ^-1 , 1730 cm ^-1 .
¹ H-NMR (CDCl ₃ ): δ 5.68 (d, 1H, C ₁ - H ), 5.38 (s, 1H, N H ), 5.36 (dd, 1H, C ₄ - H ), 5.06 (dd, 1H, C ₃ - H ), 4.43 (dd, 1H, C ₂ - H ), 4.15 (dd, 1H, C ₆ - H _b ), 4.07 (dd, 1H, C ₆ - H _a ), 4.00 (td, 1H, C ₅ - H ), 2.15 (s, 3 H, C ₈ - H ₃ ), 2.11 (s, 3 H, C ₁₄ - H ₃ ), 2.05 (s, 3H, C ₁₂ - H ₃ ), 2.03 (s , 3H, C ₁₀ - H ₃ ) and 2.00 (s, 3 H, C ₁₆ - H ₃ ).
¹³ C-NMR (CDCl ₃ ): δ 170 ( C ₇ , C ₉ , C ₁₁ and C ₁₃ ), 169 ( C ₁₅ ), 93 ( C ₁ ), 71 ( C ₅ ), 70 ( C ₃ ), 66 ( C ₄ ), 61 ( C ₆ ), 49 ( C ₂ ), 23 ( C ₈ ) and 20 ( C ₁₀ , C ₁₂ , C ₁₄ and C ₁₆ ).

[Synthetic ZG-ah-GalNAc]
[6-(Benzyloxycarbonylglycylamino)hexyl β-N-acetyl-galactosamine]
In a 250 ml round bottom flask, GalNAc(OAc) ₄ (3, 1.2 g, 3.1 mmol) and ZG-ah (2, 1.14 g, 3.7 mmol) were added and vacuum was applied for 2 hours. Adding 1,2-dichloroethane (100 ml), dichloromethane (20 ml) and anhydrous dimethylformamide (DMF, 4 ml) followed by trimethylsilyl trifluoromethane sulfonate (TMSOTf, 0.7 ml) to form a reddish brown solution Connect the drying tube, heat to 50 ° C, and stir overnight. After cooling the reaction mixture to room temperature, triethylamine (1 ml) was added and stirred for 5 minutes, and then 5 g of NaHCO3 and 50 ml of deionized water were added and stirred for 5 minutes. Wash with saturated sodium bicarbonate solution (100 mL x 4) and iced 1N sodium chloride (100 mL). The residue was washed portionwise into a 500 ml round bottom flask with 300 ml of methanol, and then a mixture of 0.572 ml of 5.4 M NaOMe / MeOH was placed on a glass lid and stirred at room temperature for 2 hours. Add appropriate amount of DOWEX 50W X8 (H ⁺ form) to adjust the pH value to about 6 (measured by litmus paper), stir at room temperature for 30 min, concentrate at 25 ° C under reduced pressure, and then vacuum overnight. Under ice bath, 150 ml of dichloromethane was added and stirred for 30 minutes, and the solid was filtered off with a ceramic funnel. A light brown solid product, ZG-ah-GalNAc (1.18 g, 75%), was obtained by vacuuming overnight.
Its analysis data:
IR (KBr): n _NH = 3377 cm ^-1 , n _{C = O} = 1747 cm ^-1 , 1657 cm ^-1 . ¹ H-NMR (CD ₃ OD): d 7.35 (m, 5 H, Ph- H ) , 5.08 (s, 2 H, C ₁₈ - H ₂ ), 4.36 (d, 1 H, C ₁ - H ), 3.83 (m, 3 H, C ₂ - H , C ₃ - H , C ₄ - H ) , 3.71 (m, 4 H, C ₆ - H ₂ & C ₁₆ - H ₂ ), 3.55 (dd, 1 H, C ₅ - H ), 3.43 (t, 2 H, C ₉ - H ₂ ), 3.20 ( t, 2 H, C ₁₄ - H ₂ ), 1.94 (s, 3 H, C ₈ - H ₃ ), 1.51 (m, 4 H, C ₁₀ - H ₂ , and C ₁₃ - H ₂ ), and 1.34 ( m, 4 H, C ₁₁ - H ₂ , and C ₁₂ - H ₂ ).
¹³ C-NMR (CD ₃ OD): d 173 ( C ₇ ), 171 ( C ₁₅ ), 157 ( C ₁₇ ), 137 ( C ₁₉ ), 128 ( C ₂₀ , C ₂₂ , and C ₂₄ ), 127 ( C ₂₁ , and C ₂₂ ), 102 ( C ₁ ), 75 ( C ₅ ), 72 ( C ₄ ), 69 ( C ₃ ), 68 ( C ₉ ), 67 ( C ₁₈ ), 62 ( C ₆ ), 51 ( C ₂ ), 44 ( C ₁₆ ), 39 ( C ₁₄ ), 29 ( C ₁₀ ), 28 ( C ₁₃ ), 26 ( C ₁₁ ), 25 ( C ₁₂ ), and 23 ( C ₈ ).
MS: m/z 534 [(M+Na) ⁺ ].

[Synthesis G-ah-GalNAc]
[6-(glycylamino)hexyl β-N-acetyl-galactosamine]
ZG-ah-GalNAc (6, 1.18 g, 2.3 mmol) was dissolved in 50 ml of methanol, and after adding 180 mg of 10% Pd/C, it was shaken overnight in a 50 psi H ₂ atmosphere with a hydrogenation reduction apparatus. The filtrate was filtered through a Buchner funnel and concentrated under reduced pressure and dried in vacuo overnight. The white solid product G-ah-GalNAc (0.96 g, 80%) was obtained.
Its analysis data:
IR (KBr): n _NH = 3310 cm ^-1 , n _{C = O} = 1650 cm ^-1 .
¹ H-NMR (CD ₃ OD): d 4.36 (d, 1 H, C ₁ - H ), 3.83 (m, 3 H, C ₂ - H , C3-H, C ₄ - H ), 3.71 (m, 2 H, C ₆ - H ₂ ), 3.55 (dd, 1 H, C ₅ - H ), 3.43 (t, 2 H, C ₉ - H ₂ ), 3.30 (t, 2 H, C ₁₆ - H ₂ ) , 3.20 (t, 2 H, C ₁₄ - H ₂ ), 1.94 (s, 3 H, C ₈ - H ₃ ), 1.51 (m, 4 H, C ₁₀ - H ₂ , and C ₁₃ - H ₂ ), And 1.34 (m, 4 H, C ₁₁ - H ₂ , and C ₁₂ - H ₂ ).
¹³ C-NMR (CD ₃ OD): d 173 ( C ₇ & C ₁₅ ), 102 ( C ₁ ), 75 ( C ₅ ), 72 ( C ₄ ), 69 ( C ₃ ), 68 ( C ₉ ), 61 ( C ₆ ), 53 ( C ₂ ), 43 ( C ₁₆ ), 39 ( C ₁₄ ), 33 ( C ₁₀ ), 29 ( C ₁₃ ), 26 ( C ₁₁ ), 25 ( C ₁₂ ), and 23 ( C ₈ ).
MS: m/z 400 [(M+Na) ⁺ ], and 378 [(M+1) ⁺ ].

The above is only the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and the variations, modifications, and modifications of the shapes, structures, features, and spirits described in the claims of the present invention. All should be included in the scope of the patent application of the present invention.
The invention is a novelty, progressive and available for industrial use, and should meet the requirements of the patent application stipulated in the Patent Law of China, and the invention patent application is filed according to law, and the prayer bureau will grant the patent as soon as possible. prayer.

no

First: it is a chemical synthesis flow chart of the prior art;
Second: it is a flow chart of a method for synthesizing a precursor of a saccharide drug contrast agent of the present invention;
Third: it is a flow chart of Z-Gly-ah chemical synthesis according to a preferred embodiment of the present invention;
Figure _{4 is} a flow chart of the chemical synthesis of GalNAc(OAc) _{4 according to a} preferred embodiment of the present invention;
Fig. 5 is a flow chart showing the chemical synthesis of ZG-ah-GalNAc according to a preferred embodiment of the present invention.
Figure 6 is a flow chart showing the chemical synthesis of G-ah-GalNAc according to a preferred embodiment of the present invention.

Claims (6)

A method for synthesizing a precursor of a saccharide drug contrast agent, the steps of which comprise:
Synthesis of a compound Z-Gly-ah, the structure of which is


;
A compound GalNAc(OAc) _{4 was} synthesized and its structure is:


;
Coupling the compound Z-Gly-ah and the compound GalNAc(OAc) ₄ in a solution containing dichloromethane and one of a plurality of solvents;
Extracting the solution;
Removing the water and concentrating the extracted solution;
Adding sodium methoxide to remove the ethylene group of the compound GalNAc(OAc) _{4 in} the solution;
Using a hydrogen type cation exchange resin to adjust the pH of the solution to 6;
Filtering and concentrating the solution;
The solution was washed with dichloromethane and filtered again to obtain a compound ZG-ah-GalNAc, the structure of which was:


And hydrogenation reduction of the compound ZG-ah-GalNAc to obtain a compound G-ah-GalNAc, the structure of which is:


. The preparation method of claim 1, wherein in the step of synthesizing the compound Z-Gly-ah, the method further comprises the steps of:
Using a compound Z-Gly-OH, treated with 1,3-dicyclohexylcarbodiimide (DCC) and N-hydroxybutylimine (NHS), coupled with 6-aminohexanol to form the compound Z-Gly-ah;
Wherein, the structure of the compound Z-Gly-OH is:


. The preparation method of claim 1, wherein in the step of synthesizing the compound GalNAc(OAc) ₄ , the method further comprises the steps of:
Use a compound GalN. HCl, treated with a solution of acetic anhydride containing pyridine to form the compound GalNAc(OAc) ₄ ;
Among them, the compound GalN. The structure of HCl is:


. The synthesis method of claim 1, wherein the solvent is selected from the group consisting of trimethylsulfonyl trifluoromethanesulfonate, dimethylformamide, and 1,2-dichloroethane. At least one of the groups. The preparation method of claim 1, wherein in the step of extracting the solution, the method further comprises the steps of:
The solution was extracted four times with a saturated sodium bicarbonate solution; and the solution was extracted once with a sodium chloride solution. The preparation method according to the first aspect of the invention, wherein in the step of removing the water and concentrating the extracted solution, the water is removed by anhydrous sodium sulfate.