(4aR,7aS)-6-(2,2-Diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole synthesis method

Abstract

The invention discloses a method for synthesizing (4aR,7aS)-6-(2,2-diethoxyethyl) hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole. The method comprises mixing a compound of formula (I) or an acid addition salt of the compound of formula (I), water, potassium hydroxide and a phase transfer agent, then adding a compound of formula (II) and reacting at 80-100 °C, and performing post-treatment to obtain an intermediate of an aminoquinazoline tyrosine kinase inhibitor. The method can greatly improve the yield of the intermediate, and has high purity and high raw material conversion efficiency; at the same time, when the synthesis method is scaled up, it can also maintain excellent yield and purity, avoid the generation of by-products, be more environmentally friendly, and is conducive to industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more specifically, to a method for synthesizing (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole. Background Art

[0002] Human epidermal growth factor receptor (HER, EGFR) is a member of the protein tyrosine kinase family, which is widely distributed on the cell membranes of various tissues in the human body and can regulate cell proliferation, growth, metastasis and apoptosis. Its structure consists of three parts: an extracellular ligand-binding region, a transmembrane region and an intracellular tyrosine kinase region. According to the structural differences of the receptors, HER can be divided into four subtypes, namely HER1 (EGFR, ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). It has been found that HER is overexpressed or abnormally activated in a variety of tumor cells such as breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, malignant glioma and prostate cancer.

[0003] In addition, studies have shown that the overexpression or abnormal activation of HER is closely related to the degree of tumor differentiation, malignancy and prognosis (Baselga.J., Oncologist 2002, 7, 2-8). Therefore, inhibiting HER has become a hot topic in the research of anti-tumor drugs.

[0004] Patent CN201410175636.X discloses a class of aminoquinazoline tyrosine kinase inhibitors with irreversible Pan-HER inhibitory effects. These compounds have excellent anti-tumor effects and good tolerance while reducing drug resistance. Among them, step 2 of Example 9 of this patent discloses one of the intermediates for synthesizing aminoquinazoline tyrosine kinase inhibitors: (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (the compound of formula (III) below). The synthesis process of this intermediate is as follows: (4aR,7aS)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (10.0 g, 77.36 mmol), 2-bromo-1,1-diethoxyethane (18.0 mL, 116.0 mmol) and diisopropylethylamine (27.1 mL, 154.7 mmol) are dissolved in DMF (100 mL), heated to 80 °C and reacted for 8.0 h to obtain the compound of formula (III), that is, the intermediate of the aminoquinazoline tyrosine kinase inhibitor.

[0005]

[0006] However, the yield of the compound of formula (III) obtained in this synthesis process is only 37.1%, which is very low and not suitable for industrial scale-up. Moreover, the organic solvents used are prone to cause environmental pollution, severely restricting the preparation of subsequent aminoquinazoline tyrosine kinase inhibitors and their preparation costs. Therefore, how to improve the yield of this type of intermediate compound and explore a synthetic process that can be scaled up has become a technical problem that urgently needs to be solved. Summary of the Invention

[0007] Aiming at the above-mentioned problems in the prior art, the primary object of the present invention is to provide a method for synthesizing (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole. The method can greatly improve the yield of the product, with high purity and high raw material conversion efficiency. At the same time, when the synthesis method is scaled up, it can also maintain excellent yield and purity, avoid the generation of by-products, be more environmentally friendly, and facilitate industrial production.

[0008] The above object of the present invention is achieved by the following scheme:

[0009] The present invention provides a method for synthesizing (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole: A compound of formula (I) or an acid addition salt of the compound of formula (I), water, a basic auxiliary agent, and a phase transfer agent are mixed, and then a compound of formula (II) is added, and the reaction is carried out under heating conditions, and after-treatment is carried out to obtain the compound of formula (III) (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole; wherein, the basic auxiliary agent is potassium hydroxide or sodium hydroxide, and the structures of the compound of formula (I), the compound of formula (II), and the compound of formula (III) are respectively shown as follows:

[0010]

[0011] The inventors found through screening that in a reaction system with potassium hydroxide (KOH) or sodium hydroxide (NaOH) as the basic auxiliary agent, water as the reaction solvent, and a phase transfer agent, the product (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole has a high yield, high product purity, and high raw material conversion efficiency. Its yield can reach more than 80%, and the purity can reach more than 96%. In addition, when the reaction system is scaled up, it can also maintain excellent yield and purity, avoid the generation of by-products, facilitate industrial production, and greatly reduce the preparation cost of subsequent aminoquinazoline tyrosine kinase inhibitors. The present invention uses water as the reaction solvent, which is green and environmentally friendly and more friendly to the environment.

[0012] In some embodiments, the phase transfer agent is selected from one or more of tetrabutylammonium bromide, potassium iodide, and 18-crown-6. In some more preferred embodiments, the phase transfer agent is 18-crown-6. Under this preferred phase transfer agent, the synthesis method can achieve higher yield and product purity.

[0013] In some embodiments, the acid addition salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I), or the hydrobromide salt of the compound of formula (I), or the phosphate salt of the compound of formula (I), or the acetate salt of the compound of formula (I); in some preferred embodiments, the acid addition salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I). The acid addition salt of the compound of formula (I) is more conducive to preservation than the compound of formula (I).

[0014] In some embodiments, the heating temperature of the heating condition is 60-100 °C; in some preferred embodiments, the heating temperature of the heating condition is 80-100 °C; in some more preferred embodiments, the heating temperature of the heating condition is 90-100 °C.

[0015] In some embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(0.9-1.5); in some preferred embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(1.2-1.5); in some more preferred embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:1.3. Within this preferred equivalent ratio range, the compound of formula (III) has higher product purity.

[0016] In some embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the basic auxiliary agent is 1.0:(2.3-3.0); in some preferred embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the basic auxiliary agent is 1.0:(2.3-2.6); in some more preferred embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the basic auxiliary agent is 1.0:2.5.

[0017] In some embodiments, the equivalent ratio of the compound of formula (I) to the phase transfer agent is 1.0:(0.01-0.05). In some preferred embodiments, the equivalent ratio of the compound of formula (I) to the phase transfer agent is 1.0:(0.01-0.03); in some more preferred embodiments, the equivalent ratio of the compound of formula (I) to the phase transfer agent is 1.0:0.02.

[0018] In some embodiments, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I), the compound of formula (II), the basic auxiliary agent and the phase transfer agent is 1.0:1.3:2.5:0.02.

[0019] In some embodiments, the dosage ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to water is 1 g:(3 - 6) mL. In some preferred embodiments, the dosage ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to water is 1 g:(4 - 6) mL; in some more preferred embodiments, the dosage ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to water is 1 g:4 mL.

[0020] In some embodiments, the post-treatment is to add sodium chloride to the reaction solution until saturation, stir and then let it stand for layering. The upper organic phase is taken and dissolved in water, extracted with an organic solvent, dried, and concentrated to obtain the compound of formula (III) (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole.

[0021] In some embodiments, the extraction with an organic solvent is as follows: First, extract the organic phase dissolved in water with n-hexane to remove impurities; then discard the n-hexane layer, and continue to extract the aqueous layer with dichloromethane.

[0022] In some embodiments, after adding the compound of formula (II), the reaction is carried out at 100 °C.

[0023] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a method for synthesizing (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole. Under the reaction system with potassium hydroxide (KOH) or sodium hydroxide (NaOH) as the basic auxiliary agent, water as the reaction solvent and a phase transfer agent, the prepared product has a high yield, high purity, and high raw material conversion efficiency. The yield can reach more than 80%, and the purity can reach more than 96%. In addition, when the reaction system is scaled up for production, it can also maintain excellent yield and purity, avoid the generation of by-products, and is conducive to industrial production. The present invention uses water as the reaction solvent, which is green and environmentally friendly and more friendly to the environment. Detailed implementation manners

[0024] The present invention will be further elaborated in detail below in conjunction with specific embodiments. The embodiments are only used to explain the present invention and are not intended to limit the scope of the present invention. The test methods used in the following embodiments are all conventional methods unless otherwise specified; the materials, reagents, etc. used are all reagents and materials that can be obtained from commercial channels unless otherwise specified.

[0025] The equivalent ratio in the present invention is the molar equivalent ratio, and the equivalent unit is eq. For example, the equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(0.9 - 1.5), which means that when the amount of the compound of formula (I) or the acid addition salt of the compound of formula (I) is 1.0 mol, the amount of the compound of formula (II) is 0.9 - 1.5 mol. That is, when expressing the relative amounts of the two in equivalents, the compound of formula (I) or the acid addition salt of the compound of formula (I) is 1.0 eq, and the amount of the compound of formula (II) is 0.9 - 1.5 eq.

[0026] The "volume - mass ratio of water to the compound of formula (I) is (3 - 6) mL / g" or "the dosage ratio of the compound of formula (I) to water is 1 g:(3 - 6) mL" mentioned in the present invention both mean that when the amount of the compound of formula (I) is 1 g, the amount of the solvent water used is 3 - 6 mL. For example, when describing the dosage ratio of the compound of formula (I) to water as 1 g:4 mL or the volume - mass ratio of water to the compound of formula (I) as 4 mL / g, it both means that when the amount of the compound of formula (I) is 1 g, the amount of the solvent water used is 4 mL.

[0027] In the present invention, 18 - crown - 6 represents 18 - crown - ether - 6, TBAB represents tetrabutylammonium bromide, KI represents potassium iodide, DMSO represents dimethyl sulfoxide, DME represents dimethyl ether, MeCN represents acetonitrile, NMP represents N - methylpyrrolidone, EtOH represents ethanol, THF represents tetrahydrofuran, DMF represents N,N - dimethylformamide, t - BuOH represents tert - butanol, t - BuOK represents potassium tert - butoxide, CsF represents cesium fluoride, DIPEA represents N,N - diisopropylethylamine, Cs2CO3 represents cesium carbonate, 1,4 - Dioxane represents 1,4 - dioxane, 1,2 - ethanediol represents 1,2 - ethylene glycol, and Acetone represents acetone.

[0028] The low - resolution mass spectrometry (MS) data was determined by a spectrometer of Agilent 6320 series LC - MS equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C). The G1329A autosampler and G1315B DAD detector were used for analysis, and the ESI source was used for the LC - MS spectrometer.

[0029] Low-resolution mass spectrometry (MS) data was determined using a spectrometer of Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315D DAD detector applied for analysis, and an ESI source applied to the LC-MS spectrometer.

[0030] Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a specification of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peaks were recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase was a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure water solution (phase B).

[0031] Nuclear magnetic resonance spectroscopy data was determined using a Bruker Avance 400 nuclear magnetic resonance spectrometer or a Bruker Avance III HD600 nuclear magnetic resonance spectrometer, with CDC13, DMSO-d6, CD3OD or Acetone-d6 as solvents (reported in ppm), and using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When there are multiple peaks, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (double of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets). The coupling constant is expressed in hertz (Hz).

[0032] The compound purity was evaluated using an Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection was at 210 nm and 254 nm, with a Zorbax SB-C18 column with a specification of 2.1×30 mm, 4 μm, for 10 minutes, a flow rate of 0.6 mL / min, 5 - 95% of (0.1% formic acid acetonitrile solution) of (0.1% formic acid aqueous solution), and the column temperature maintained at 40 °C.

[0033] Example 1 Preparation of (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole

[0034] At 25 °C, the hydrochloride of the compound of formula (I) (chemical name: (4aR,7aS)-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole hydrochloride, 1.07 g, 1.0 eq) was dissolved in the solvent water (the volume-mass ratio of water to the hydrochloride compound of formula (I) was 6 mL / g), put into a reaction kettle, and an aqueous potassium hydroxide solution was slowly dropped in (the equivalent ratio of the hydrochloride of the compound of formula (I) to potassium hydroxide was 1 eq:2.5 eq). After completion, a phase transfer catalyst tetrabutylammonium bromide (TBAB, the equivalent ratio of the hydrochloride of the compound of formula (I) to TBAB was 1 eq:0.05 eq) was added, and bromoacetaldehyde diethyl acetal of formula (II) was dropped (the equivalent ratio of the hydrochloride of the compound of formula (I) to the compound of formula (II) was 1 eq:1.5 eq). After dropping, the temperature was raised to 100 °C, and the reaction started to be monitored by GC (gas chromatography) after 5.0 h. Thereafter, samples were taken for detection every 1.0 h until the hydrochloride of compound (I) ≤ 1.0%. Heating was stopped, sodium chloride was added until saturation, stirred and left to stand for stratification. The upper organic phase was taken, the organic phase was dissolved in water, and the aqueous layer was extracted with n-hexane three times (to remove impurities), the n-hexane layer was discarded, and the aqueous layer was continuously extracted with dichloromethane (to extract the product compound (III)). The dichloromethane layer was dried. The compound of formula (III) (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole had a purity of 75.5% and a yield of 89%. The spectral data of the product are as follows: MS(ESI,pos.ion) m / z: 246.2 [M+1] + ; 1 H NMR(400 MHz, CDCl3): δ 4.54 (t, 1H), 4.05 (s, 2H), 3.75 (m, 2H), 3.68 (m, 2H), 3.54 (m, 4H), 2.88 (m, 2H), 2.80 (m, 2H), 2.65 (d, 2H), 1.21 (t, 6H). The specific reaction formula of the preparation process is as follows:

[0035]

[0036] Examples 2 - 13 Preparation of (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole

[0037] Examples 2 - 13 refer to the preparation process of Example 1, the difference lies in the different reaction conditions. The reaction conditions and reaction results are shown in Table 1 below.

[0038] Table 1

[0039]

[0040]

[0041] As can be seen from Table 1 above, when potassium hydroxide (KOH) is used as the basic auxiliary agent, water is used as the reaction solvent, and the phase transfer agents are TBAB, KI or 18-crown-6, the product has a high yield, high purity, and high raw material conversion efficiency. And it can be seen from Examples 10 to 13 that the above reaction system can also maintain excellent yield and purity during scale-up production, avoid the generation of by-products, and is conducive to industrial production.

[0042] Example 14 Process Comparison of (4aR,7aS)-6-(2,2-Diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole

[0043] The specific situation of optimizing the process of Example 14 by using different basic auxiliary agents, solvents, and reaction temperatures, without adding a phase transfer catalyst, and monitoring the reaction progress by HPLC in-process control is shown in Table 2 below. Among them, the types of basic auxiliary agents used include inorganic bases CsF, DIPEA, Cs2CO3, and t-BuOK. The types of solvents used include DMSO, NMP, THF, DMF, MeCN, 1,4-Dioxane, 1,2-ethanediol, EtOH, DME, and Acetone.

[0044] Table 2

[0045]

[0046]

[0047] Note: "N / A" in the table means that since the HPLC purity of compound (III) in the reaction solution after the reaction is too low or the HPLC of the reaction solution shows many impurities (the HPLC purity is far lower than 40%), the yield is not further calculated; "producing many impurities" means that the HPLC purity is far lower than 40%.

[0048] As can be seen from Table 1 above, in Processes 1 to 6, CsF is used as the basic auxiliary agent. When the solvent is DMSO, the yields of the products in Processes 1 and 2 are 50% and 48% respectively, and the purities are 70% and 67% respectively. When other solvents are selected, the product purity is too low and the yield is negligible.

[0049] In Processes 7, 8 to 12, DIPEA and Cs2CO3 are used as the basic auxiliary agents respectively. From the data, it can be seen that when different solvents are selected, the product purity is too low and the product yield is negligible.

[0050] Processes 13 - 18 are examples using 0.1 g of the hydrochloride salt of compound (I) and t-BuOK as the basic auxiliary agent. As can be seen from the table, when the solvent is THF, MeCN, or DMF, the product purity is too low. When DMSO, 1,2-ethylene glycol, or t-BuOH is used as the solvent and the reaction is carried out at 80 °C, the product yield is between 50% and 62%, and the purity is between 40% and 80%.

[0051] However, the inventors continued the experiment and found that when using the t-BuOK / t-BuOH system for further scale-up research, the content of by-products gradually increased during the scale-up experiment. For example, in Processes 19 - 23, as the feeding amount of the hydrochloride salt of compound (I) increased step by step, by-product (1-((4aR,7aS)-hexahydro-5H-cyclopenta[b][1,4]dioxin-6-yl)ethan-1-one) would be produced when bromoacetaldehyde diethyl acetal of compound (II) was in an organic solvent in the presence of a base. When the feeding amount of compound (I) was 50 g, the content of the finally formed by-product was as high as 54.61%, while the content of the product was only 42.86%, and the product yield also decreased from 62% to 54%.

[0052] From the above situation of process optimization, it can be seen that the synthesis method of (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole (compound of formula (III)) provided by the present invention, under the reaction system using potassium hydroxide (KOH) or sodium hydroxide (NaOH) as the basic auxiliary agent, water as the reaction solvent, and a phase transfer agent, the product (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole has a relatively high yield, high purity, and high raw material conversion efficiency. Its yield can reach more than 80%, and the purity can reach more than 96%. In addition, when the said reaction system is used for large-scale production, it can also maintain excellent yield and purity, avoid the generation of by-products, and is conducive to industrial production. The present invention uses water as the reaction solvent, which is green and environmentally friendly and more friendly to the environment.

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description and ideas. It is not necessary and impossible to list all the implementation manners here. Any modifications, equivalent substitutions, and improvements made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing (4aR,7aS)-6-(2,2-diethoxyethyl)hexahydro-5H-[1,4]dioxino[2,3-c]pyrrole, characterized in that, The compound of formula (I) or an acid addition salt of the compound of formula (I), water, a basic auxiliary agent, and a phase transfer agent are mixed, and then the compound of formula (II) is added, and the reaction is carried out under heating conditions, and aftertreatment is carried out to obtain the compound of formula (III) (4aR,7aS)-6-(2,2 - diethoxyethyl)hexahydro - 5H - [1,4]dioxino[2,3 - c]pyrrole; wherein, the basic auxiliary agent is potassium hydroxide or sodium hydroxide; the structures of the compound of formula (I), the compound of formula (II), and the compound of formula (III) are respectively shown as follows:

2. The synthesis method according to claim 1, wherein The phase transfer agent is selected from one or more of tetrabutylammonium bromide, potassium iodide, and 18 - crown - 6.

3. The synthesis method according to claim 1, wherein The phase transfer agent is 18 - crown - 6.

4. The synthesis method according to claim 1, characterized in that, The acid addition salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I), or the hydrobromide salt of the compound of formula (I), or the phosphate salt of the compound of formula (I), or the acetate salt of the compound of formula (I).

5. The synthesis method according to claim 1, characterized in that, The acid addition salt of the compound of formula (I) is the hydrochloride salt of the compound of formula (I).

6. The synthesis method according to claim 1, wherein The heating temperature under the heating conditions is 60 - 100 °C.

7. The synthesis method according to claim 1, characterized in that, The heating temperature under the heating conditions is 80 - 100 °C.

8. The synthesis method according to claim 1, characterized in that The heating temperature under the heating conditions is 90 - 100 °C.

9. The synthesis method according to claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(0.9 - 1.5).

10. According to the synthesis method described in claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:(1.2 - 1.5).

11. According to the synthesis method described in claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the compound of formula (II) is 1.0:1.

3.

12. The synthesis method according to claim 1, wherein, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the basic auxiliary agent is 1.0:(2.3 - 3.0).

13. The synthesis method according to claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the basic auxiliary agent is 1.0:2.

5.

14. The synthesis method according to claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the phase transfer agent is 1.0:(0.01 - 0.05).

15. The synthesis method according to claim 1, characterized in that, The equivalent ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to the phase transfer agent is 1.0:0.

02.

16. The synthesis method according to claim 1, characterized in that, The dosage ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to water is 1 g:(3 - 6) mL.

17. The synthesis method according to claim 1, characterized in that, The dosage ratio of the compound of formula (I) or the acid addition salt of the compound of formula (I) to water is 1 g:4 mL.

18. The synthesis method according to claim 1, characterized in that, The aftertreatment is to add sodium chloride to the reaction solution until saturation, stir and then let it stand for layering, take the upper organic phase and dissolve it in water, extract with an organic solvent, dry, and concentrate to obtain the compound of formula (III).

19. The synthesis method according to claim 18, characterized in that, The extraction with an organic solvent is as follows: first, extract the organic phase dissolved in water with n - hexane to remove impurities; then discard the n - hexane layer, and continue to extract the water layer with dichloromethane.

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