Preparation method of baricitinib
By using benzyl-protected 4-chloropyrrolopyrimidine and performing bromo, Michael addition and Grignard reactions, the problems of low yield and low purity in the existing Barrektinib synthesis methods are solved, and an efficient and economical synthesis process is achieved.
Patent Information
- Application Number
- CN202510183333.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-19
- Publication Date
- 2025-05-23
AI Technical Summary
In the existing barictinib synthesis method, expensive raw materials and complex reaction conditions are used, resulting in low yield, low purity, and high process cost.
Benzyl-protected 4-chloropyrrolopyrimidine, and through bromine, Michael addition and Grignard reaction, the expensive raw materials 1H-pyrazole-4-boronic acid pinenol ester and tetratriphenylphosphate palladium are avoided, thereby improving the yield and purity of the coupling reaction.
It improves the yield and purity of baricinib, reduces process costs, is suitable for industrial production, and simplifies reaction conditions.
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Figure CN120025337A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a method for preparing baricitinib. Background Art
[0002] Baricitinib, a white to off-white solid, is called Baricitinib in English. It has a CAS number of 1187594-09-7, a molecular formula of C16H17N7O2S, and a relative molecular mass of 371.42. Baricitinib is an oral JAK inhibitor discovered by Incyte and licensed to Eli Lilly. Baricitinib is a tyrosine protein kinase (JAK) 1 / 2 inhibitor, which is taken orally once a day. It is suitable for adult patients with moderate to severe active RA who have poor efficacy or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). It can be used in combination with methotrexate or other non-biological disease-modifying antirheumatic drugs.
[0003] There are four types of JAK enzymes, namely JAK1, JAK2, JAK3 and TYK2. JAK-dependent cytokines are involved in the pathogenesis of a variety of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be widely used to treat various inflammatory diseases. In kinase detection experiments, the inhibitory intensity of baricitinib against JAK1 and JAK2 is 100 times higher than that of JAK3.
[0004] Baricitinib has been approved and marketed in more than 75 countries (including the United States, China, and Japan) for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA). In addition, baricitinib has been approved in more than 50 countries for the treatment of adult patients with moderate to severe atopic dermatitis (AD). At the same time, baricitinib has also been approved in multiple countries for the treatment of COVID-19-related infections in hospitalized adult patients.
[0005] There are three existing methods for synthesizing baricitinib:
[0006] 1. The target product is obtained by Michael addition and Suzuki reaction of the raw materials. However, this method requires the use of relatively expensive raw materials 1H-pyrazole-4-boronic acid pinacol ester and tetrakistriphenylphosphine palladium, which is costly and has a low reaction yield. In the last step of the Suzuki reaction, the hydrogen on the nitrogen of the raw material is relatively active and is prone to side reactions, which reduces the purity and yield of the product.
[0007] 2. The raw material 4-chloropyrrolopyrimidine is first protected with BOC anhydride, and then subjected to Michael addition and Suzuki coupling reaction to obtain compound 13, which is then hydrolyzed with hydrochloric acid to obtain the target product. However, this route also uses relatively expensive 1H-pyrazole-4-boronic acid pinacol ester and tetrakistriphenylphosphine palladium. In the Suzuki coupling reaction, the BOC protecting group in compound 11 is easily removed under high temperature conditions, making the active hydrogen on the nitrogen susceptible to attack and producing side reactions, resulting in more impurities and lower yields;
[0008] 3. The difference from the first two methods is that chloromethyl trimethylsilyl ethyl ether is used to protect the nitrogen atom on the pyrrole ring of 4-chloropyrrolopyrimidine. However, in the above protection reaction, the reaction needs to be carried out at -10°C, the reaction conditions are relatively harsh, the reaction yield is also low, and expensive raw materials 1H-pyrazole-4-boronic acid pinacol ester and tetrakistriphenylphosphine palladium are also used in the reaction. In addition, the hydroxymethyl intermediate produced during the deprotection process is not easy to react completely, resulting in a reduced yield.
[0009] In recent years, there have been many reports on the technical improvements of the synthesis process of baricitinib, and related literature and patents have been published. The synthesis process is roughly the same. It is obtained by Suzuki coupling under zero-valent palladium catalysis. The reaction equation is as follows:
[0010]
[0011] This synthetic route requires the use of organic boron reagents and zero-valent palladium catalysts, which results in high costs for the synthetic route.
[0012] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention
[0013] The purpose of the present invention is to solve the problem of how to improve the yield and purity of baricitinib, and provides a method for preparing baricitinib.
[0014] In order to achieve the above object, the present invention discloses a method for preparing baricitinib, and the preparation reaction equation is as follows:
[0015]
[0016] Where X is bromine, R 1 It is benzyl.
[0017] The preparation route is as follows:
[0018]
[0019] The specific steps are as follows:
[0020] S1, Pyrazole bromination: After mixing pyrazole with a solvent, the brominating reagent is added in batches at low temperature. After the reaction is complete, water is added for washing. After layering, it is dried and concentrated to obtain 4-bromopyrazole;
[0021] S2, Michael addition of 4-bromopyrazole and 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile: After mixing 4-bromopyrazole, 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile with a solvent, a base is added in batches at low temperature, and then the temperature is raised to room temperature for reaction. After the reaction is complete, it is processed to obtain intermediate 1;
[0022] S3, Protection of the amino group of 4-chloropyrrolopyrimidine: After mixing 4-chloropyrrolopyrimidine with a solvent, a base is added, and then it reacts with an amino-protecting reagent to obtain intermediate 2;
[0023] S4, Cross-coupling of intermediate 1 and intermediate 2: After mixing intermediate 2, TMEDA, copper(I) iodide with a solvent, a solution of isopropylmagnesium chloride in tetrahydrofuran is added dropwise at low temperature, and then intermediate 1 is added. The temperature is raised to complete the reaction, and after post-treatment and recrystallization, intermediate 3 is obtained;
[0024] S5, Deprotection of intermediate 3 to obtain baricitinib: After mixing intermediate 3 with a solvent, 1-chloroethyl chloroformate is added dropwise at low temperature, and then methanol is added. The temperature is raised to complete the reaction, and after post-treatment and recrystallization, baricitinib is obtained.
[0025] In the step S1, the brominating reagent is one of liquid bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide; the solvent is one of dichloromethane, ethyl acetate, water, dioxane, tetrahydrofuran; the reaction temperature is 0 - 10 °C.
[0026] In the step S2, the base is one of potassium carbonate, DBU, sodium tert-butoxide, sodium hydroxide; the solvent is one of dichloromethane, ethyl acetate, water, dioxane, tetrahydrofuran, DMF;
[0027] In the step S3, the amino-protecting group is benzyl; the base is one of potassium carbonate, DBU, sodium tert-butoxide, sodium hydroxide; the solvent is one of dichloromethane, ethyl acetate, water, dioxane, tetrahydrofuran, DMF; the reaction temperature is 40 - 50 °C.
[0028] In the step S4, the solvent is one of dichloromethane, n-hexane, toluene, dioxane, tetrahydrofuran, DMF; the dosage of TMEDA is 0.5 - 2 eq; the dosage of copper(I) iodide is 0.05 - 0.5 eq; the dosage of the solution of isopropylmagnesium chloride in tetrahydrofuran is 1 - 2 eq; the recrystallization solvent is at least one of methanol, ethanol, isopropanol, acetonitrile, dichloromethane, ethyl acetate, n-hexane, tetrahydrofuran.
[0029] In the step S5, the solvent is one of dichloromethane, n-hexane, toluene, dioxane, tetrahydrofuran, and DMF; the amount of 1-chloroethyl chloroformate is 1-2eq; and the recrystallization solvent is at least one of methanol, ethanol, isopropanol, acetonitrile, dichloromethane, ethyl acetate, n-hexane, and tetrahydrofuran.
[0030] Compared with the prior art, the beneficial effects of the present invention are:
[0031] 1. The present invention uses benzyl to protect 4-chloropyrrolopyrimidine. The benzyl-protected 4-chloropyrrolopyrimidine is relatively stable during the reaction and is finally easy to remove. In addition, pyrazole is used as the initial raw material. The pyrazole intermediate obtained by bromination and addition is coupled with benzyl-protected 4-chloropyrrolopyrimidine through a Grignard reaction to obtain a product. In the Grignard reaction, a catalytic amount of TMEDA and CuI is added, which greatly improves the yield of the coupling reaction, avoids the use of expensive raw materials 1H-pyrazole-4-boric acid pinacol ester and tetrakistriphenylphosphine palladium, and has a high improvement in the yield and purity of the product. The process raw materials are easily available and cheap, and the operation is simple, which is suitable for industrial production.
[0032] 2. The present invention screens different protecting groups of 4-chloropyrrolopyrimidine. Under cross-coupling conditions, benzyl-protected 4-chloropyrrolopyrimidine can obtain a stable and high reaction yield. BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Figure 1 is the HNMR spectrum of compound 5 in Example 1;
[0034] Figure 2 is the HNMR spectrum of compound 2 in Example 1;
[0035] Figure 3 is the HNMR spectrum of compound 3 in Example 1;
[0036] Figure 4 is the HNMR spectrum of compound 6 in Example 1;
[0037] Figure 5 is the HNMR spectrum of baricitinib in Example 1;
[0038] Figure 6 This is the HPLC spectrum of baricitinib in Example 1. DETAILED DESCRIPTION
[0039] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings.
[0040] Example 1 1.
[0042]
[0043] Into a 500 mL three-necked flask, compound 4 (15.36 g, 0.1 mol, 1.0 eq), 153.6 mL of DMF, and potassium carbonate (16.56 g, 0.12 mol, 1.2 eq) were successively added. The temperature was raised to 40 - 50 °C and reacted for 1 h, then cooled to 10 - 20 °C, and benzyl bromide (18.81 g, 0.11 mol, 1.1 eq) was added dropwise. After the addition was complete, the reaction was kept at a constant temperature for 2 h. The reaction was complete as monitored by TLC. Water was added to the reaction system, and a large amount of solid precipitated. After filtration, 23.2 g of the product was obtained with a yield of 95.3%. The HNMR spectrum of compound 5 is as Figure 1 shown.
[0044] 1 H NMR (500 MHz, Chloroform-d): δ 8.49 (s, 1H), 7.34–7.24 (m, 4H), 7.12 (ddq, J = 5.9, 1.6, 0.9 Hz, 2H), 7.02 (d, J = 7.0 Hz, 1H), 5.50 (q, J = 0.9 Hz, 2H). 2.
[0046]
[0047] Into a 500 ml three-necked flask, compound 1 (13.62 g, 0.2 mol, 1.0 eq) and 150 ml of dichloromethane were successively added. Then the temperature of the system was cooled to 0 - 10 °C, and NBS (37.38 g, 0.21 mol, 1.05 eq) was added in batches. After the addition was complete, the reaction was kept at a constant temperature for 1 h. The reaction was complete as monitored by TLC. 100 ml of water was added to the reaction system, and the mixture was stirred and separated into layers. The organic layer was washed with water twice, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 28.4 g of the product with a yield of 96.5%. The HNMR spectrum of compound 2 is as Figure 2 shown.
[0048] 1 H NMR (500 MHz, Chloroform-d): δ 7.83 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H). 3.
[0050]
[0051] Compound 2 (28.4 g, 0.193 mol), 2-[1-(ethylsulfonyl) azetidine-3-ylidene] acetonitrile (37.2 g, 0.22 mol), and 250 ml of tetrahydrofuran were added to a 500 ml three-necked flask, and then the system was cooled to 0-10°C, and DBU (5.88 g, 0.0386 mol) was added dropwise. After the addition was completed, the temperature was raised to 20-25°C, and the reaction was kept warm for 1 hour. The reaction was completed on the plate, and the reaction system was transferred to a 1L three-necked flask. 500 ml of water was added to the reaction system, stirred for 0.5 hours, cooled to 5-10°C, and filtered to obtain 59.5 g of the product with a yield of 92.5%. The HNMR spectrum of compound 3 is shown as follows: Figure 3 shown.
[0052] 1 H NMR (500MHz, Chloroform-d): δ7.66(s,1H),7.62(s,1H),4.01(d,J=12.5Hz,2H),3.76(d,J=12.5Hz,2H),3.17–3.08(m,4H),1.37(t,J=9.5Hz,3H). 4.
[0054]
[0055] In a 500 ml three-necked flask, compound 5 (23.2 g, 0.095 mol, 1.0 eq), TMEDA (11.0 g, 0.095 mol, 1.0 eq), cuprous iodide (1.8 g, 0.0095 mol, 0.1 eq), and 200 ml of tetrahydrofuran were added successively, and then the system was cooled to 0-5 ° C, and a 2 mol / L tetrahydrofuran solution of isopropylmagnesium chloride (57 ml, 0.114 mol, 1.2 eq) was added dropwise. After the addition was completed, the temperature was kept for 1 h, and compound 3 (31.65 g, 0.095 mol, 1.0 eq) was added. After the addition was completed, , heat to 40-45℃, keep warm for 1h, the reaction is complete, the reaction system is cooled to 0-5℃, saturated ammonium chloride aqueous solution is added to the reaction system to quench the reaction, stirred for 0.5h, the reaction system is decompressed at 40-50℃ to remove most of the tetrahydrofuran, then 200ml of ethyl acetate and 100ml of water are added, the extraction is layered, the water layer is back-extracted once, the organic layer is combined, washed with water twice, and then anhydrous sodium sulfate is added to the organic layer to dry, the organic layer is then spin-dried and 200ml of methanol is added to the organic layer and the temperature is raised to reflux to dissolve, then the temperature is lowered to 0-5℃ for crystallization for 1h, and 39.8g of the product is obtained by suction filtration, with a yield of 90.7%. The HNMR spectrum of compound 6 is shown in Figure 4 shown.
[0056] 11H NMR (500 MHz, Chloroform-d) δ 8.13 (s, 0H), 7.34–7.20 (m, 2H), 7.12 (ddq, J = 5.9, 1.6, 0.9 Hz, 1H), 5.49 (q, J = 0.9 Hz, 1H), 4.01 (d, J = 12.6 Hz, 1H), 3.76 (d, J = 12.6 Hz, 1H), 3.17–3.08 (m, 2H). 5、
[0058]
[0059] To a 500 ml three-necked flask, compound 6 (39.8 g, 0.086 mol, 1.0 eq) and 300 ml of dichloromethane were added successively. The temperature of the system was lowered to 0 - 5 °C, and 1-chloroethyl chloroformate (13.56 g, 0.095 mol, 1.1 eq) was added dropwise. After the addition, the mixture was kept warm for 1 h, then 50 ml of methanol was added. After the addition, the temperature was raised to reflux for 1 h. The reaction was complete by TLC. Then the system was rotary evaporated under reduced pressure at 40 - 45 °C. 140 ml of ethanol and 140 ml of acetonitrile were added, and the mixture was heated to reflux until clear. The temperature was lowered to 0 - 10 °C, and the product was filtered to obtain 28.67 g with a yield of 89.5%. The 1H NMR spectrum of baricitinib is as shown in Figure 5 shown, and the HPLC spectrum is as shown in Figure 6 shown.
[0060] 1 1H NMR (500 MHz, Chloroform-d) δ 8.69 (s, 1H), 8.21 (s, 1H), 7.80 (s, 1H), 7.26 (s, 1H), 4.01 (d, J = 12.6 Hz, 2H), 3.76 (d, J = 12.6 Hz, 2H), 3.14 (d, J = 9.6 Hz, 1H), 3.10 (d, J = 9.0 Hz, 3H), 1.39 (s, 1H), 1.35 (s, 1H).
[0061] Example 2
[0062] When only the equivalents of benzyl bromide and potassium carbonate in step 1 of the example were changed, the reaction results are shown in Tables 1 and 2 below:
[0063] Table 1 Effects of different equivalents of benzyl bromide on the reaction
[0064]
[0065]
[0066] Table 2 Effects of different equivalents of potassium carbonate on the reaction
[0067] Serial number Potassium carbonate equivalent / eq Benzyl bromide equivalent / eq Reaction temperature / ℃ Reaction time / h Reaction results 1 1.1 1.1 10-20 2 Yield 76% 2 1.2 1.1 10-20 2 Yield 95% 3 1.5 1.1 10-20 2 Yield 87% 4 2.0 1.1 10-20 2 Yield 73%
[0068] It can be seen from Table 1 and Table 2 that when the benzyl bromide equivalent is 1.1 and the potassium carbonate equivalent is 1.2, the yield of the reaction is the highest.
[0069] Example 3
[0070] When only the reaction temperature or NBS equivalent in step 2 of Example is changed, the reaction results are shown in Table 3 and Table 4.
[0071] Table 3 Effect of different temperatures on the reaction
[0072] Serial number Reaction temperature / ℃ NBS equivalent / eq Reaction time / h Reaction results 1 -10℃--5℃ 1.05 1 Yield 68% 2 0-10℃ 1.05 1 Yield 96% 3 15-25℃ 1.05 1 Yield 80% 4 30-40℃ 1.05 1 Yield 65%
[0073] Table 4 Effect of NBS equivalent on reaction
[0074] Serial number NBS equivalent / eq Reaction temperature / ℃ Reaction time / h Reaction results 1 1 0-10℃ 1 Yield 72% 2 1.05 0-10℃ 1 Yield 96% 3 1.2 0-10℃ 1 Yield 76% 4 1.5 0-10℃ 1 Yield 68%
[0075] It can be seen from Tables 3 and 4 that the reaction yield is the highest when the reaction temperature is 0-10°C and the NBS equivalent is 1.05eq.
[0076] Example 4
[0077] When only the amount of 2-[1-(ethylsulfonyl)azetidine-3-ylidene]acetonitrile and DBU in step 3 of Example was changed, the reaction results are shown in Tables 5 and 6.
[0078] Table 5 Effect of different equivalents of 2-[1-(ethylsulfonyl) azetidine-3-ylidene] acetonitrile on the reaction
[0079]
[0080] Table 6 Effect of DBU equivalent on reaction
[0081]
[0082] As shown in Tables 5 and 6, when the 2-[1-(ethylsulfonyl)azetidine-3-ylidene]acetonitrile equivalent is 1.1 and the DBU equivalent is 0.2, the reaction yield is the highest.
[0083] Example 5
[0084] When only the equivalent of 2 mol / L isopropyl magnesium chloride in tetrahydrofuran solution, TMEDA, and cuprous iodide in step 4 of Example were changed, the reaction results are shown in Tables 7, 8, and 9.
[0085] Table 7 Effect of different equivalents of 2 mol / L isopropyl magnesium chloride tetrahydrofuran solution on the reaction
[0086]
[0087] Table 8 Effect of TMEDA equivalent on reaction
[0088]
[0089]
[0090] Table 9 Effect of cuprous iodide equivalent on reaction
[0091]
[0092] As shown in Tables 7, 8 and 9, the reaction yield is highest when the equivalent of 2 mol / L isopropyl magnesium chloride in tetrahydrofuran solution is 1.2, the equivalent of TMEDA is 1.0, and the equivalent of cuprous iodide is 0.1.
[0093] Example 6
[0094] The coupling reaction results of 4-chloropyrrolopyrimidine with different protecting groups are shown in Table 11.
[0095] Table 10 Effects of different protecting groups on the reaction
[0096]
[0097] Reaction conditions: 2 mol / L isopropyl magnesium chloride in tetrahydrofuran solution (equivalent to 1.2), TMEDA (equivalent to 1.0), and cuprous iodide (equivalent to 0.1)
[0098] As shown in Table 10, the benzyl protecting group has the highest reaction yield.
[0099] Example 7
[0100] When only the equivalent of 1-chloroethyl chloroformate in step 5 of Example was changed, the reaction results were shown in Table 10.
[0101] Table 11 Effect of different equivalents of 1-chloroethyl chloroformate on the reaction
[0102] Serial number 1-Chloroethyl chloroformate / eq Reaction results 1 1.0 Yield 72% 2 1.1 Yield 89% 3 1.5 Yield 75% 4 2.0 Yield 58%
[0103] As shown in Table 11, when the 1-chloroethyl chloroformate is 1.1, the reaction yield is the highest.
[0104] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.
Claims
1. A method for preparing baricitinib, characterized in that: The preparation reaction equation is as follows: Wherein, X is bromine and R1 is benzyl.
2. The method for preparing baricitinib according to claim 1, wherein: The preparation route is as follows:
3. The method for preparing baricitinib according to claim 1, wherein: The specific steps are as follows: S1, bromination of pyrazole: after mixing pyrazole with a solvent, add a bromination reagent in batches at low temperature, wash with water after the reaction is complete, dry and concentrate after layering to obtain 4-bromopyrazole; S2, Michael addition of 4-bromopyrazole and 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile: 4-bromopyrazole, 2-[1-(ethylsulfonyl)azetidin-3-ylidene]acetonitrile and solvent are mixed, and a base is added in batches at low temperature, and then the mixture is heated to room temperature for reaction. After the reaction is complete, the intermediate 1 is obtained by post-treatment; S3, amino protection of 4-chloropyrrolopyrimidine: 4-chloropyrrolopyrimidine is mixed with a solvent, a base is added, and then reacted with an amino protecting agent to obtain intermediate 2; S4, cross-coupling of intermediate 1 and intermediate 2: intermediate 2, TMEDA, cuprous iodide and solvent are mixed, and a tetrahydrofuran solution of isopropyl magnesium chloride is added dropwise at low temperature, and then intermediate 1 is added, and the temperature is raised to react until completion, and then post-treatment and recrystallization are performed to obtain intermediate 3; S5, deprotection of intermediate 3 to obtain baricitinib: intermediate 3 is mixed with a solvent, 1-chloroethyl chloroformate is added dropwise at low temperature, methanol is added, the temperature is raised to react until completion, and post-treatment and recrystallization are performed to obtain baricitinib.
4. The method for preparing baricitinib according to claim 3, characterized in that: In step S1, the bromination reagent is one of liquid bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and pyridinium tribromide; the solvent is one of dichloromethane, ethyl acetate, water, dioxane, and tetrahydrofuran; and the reaction temperature is 0-10°C.
5. The method for preparing baricitinib according to claim 3, characterized in that: In step S2, the base is one of potassium carbonate, DBU, sodium tert-butoxide, and sodium hydroxide; and the solvent is one of dichloromethane, ethyl acetate, water, dioxane, tetrahydrofuran, and DMF.
6. The method for preparing baricitinib according to claim 3, characterized in that: In step S3, the amino protecting group is benzyl; the base is one of potassium carbonate, DBU, sodium tert-butoxide, and sodium hydroxide; the solvent is one of dichloromethane, ethyl acetate, water, dioxane, tetrahydrofuran, and DMF; and the reaction temperature is 40-50°C.
7. The method for preparing baricitinib according to claim 3, characterized in that: In the step S4, the solvent is one of dichloromethane, n-hexane, toluene, dioxane, tetrahydrofuran, and DMF; the amount of TMEDA is 0.5-2eq; the amount of cuprous iodide is 0.05-0.5eq; the amount of isopropyl magnesium chloride in tetrahydrofuran solution is 1-2eq; and the recrystallization solvent is at least one of methanol, ethanol, isopropanol, acetonitrile, dichloromethane, ethyl acetate, n-hexane, and tetrahydrofuran.
8. The method for preparing baricitinib according to claim 3, characterized in that: In the step S5, the solvent is one of dichloromethane, n-hexane, toluene, dioxane, tetrahydrofuran, and DMF; the amount of 1-chloroethyl chloroformate is 1-2eq; and the recrystallization solvent is at least one of methanol, ethanol, isopropanol, acetonitrile, dichloromethane, ethyl acetate, n-hexane, and tetrahydrofuran.