CN113248464B - Synthesis method of C-glycoside derivatives - Google Patents
Synthesis method of C-glycoside derivatives Download PDFInfo
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- CN113248464B CN113248464B CN202110603308.5A CN202110603308A CN113248464B CN 113248464 B CN113248464 B CN 113248464B CN 202110603308 A CN202110603308 A CN 202110603308A CN 113248464 B CN113248464 B CN 113248464B
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- 229930182476 C-glycoside Natural products 0.000 title claims abstract description 6
- 150000000700 C-glycosides Chemical class 0.000 title claims abstract description 6
- 238000001308 synthesis method Methods 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 69
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 36
- 238000010791 quenching Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000000171 quenching effect Effects 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 13
- MEMUCXUKCBNISQ-UHFFFAOYSA-N acetonitrile;trifluoroborane Chemical compound CC#N.FB(F)F MEMUCXUKCBNISQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims abstract description 10
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 3
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicinal chemistry, and particularly discloses a method for synthesizing a C-glycoside derivative. Adding a compound shown in the formula (II) and triethylsilane into dichloromethane, carrying out nitrogen protection, cooling by a dry ice acetonitrile bath at-35 ℃ to-45 ℃, dropwise adding 20% boron trifluoride acetonitrile complex, and carrying out heat preservation at-35 ℃ to-45 ℃ to carry out the synthesis reaction of the C-glycoside derivative shown in the formula (I); after that, the reaction system was added dropwise to an aqueous sodium hydrogencarbonate solution to quench the reaction. The method improves the reaction quenching mode in the existing synthesis process, can rapidly quench the reaction, has short quenching time and easy operation, and can effectively avoid the problem of impurity III growth caused by the temperature rise of a reaction system.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for synthesizing C-glucoside derivatives.
Background
Hyperglycemia is considered to be a major risk factor for developing diabetic complications and may be directly associated with impaired insulin secretion in late stage type II diabetes. Normalization of insulin can therefore be expected to improve blood glucose in type II diabetic patients. Most of the existing diabetes drugs are insulinotropic drugs or insulin sensitizers, such as sulfonylureas, glinides, thiazolidinediones, metformin and the like, and have potential side effects, such as easy weight gain, hypoglycemia, lactic acidosis and the like, so that the development of antidiabetic drugs with novel, safe and effective action mechanisms is urgently needed.
In the kidney, glucose can freely filter from the glomerulus (about 180 g/day), but is almost actively transported in the proximal convoluted tubule and reabsorbed. Two of the sodium-glucose transporters play an important role in glucose reabsorption, namely SGLT-1 and SGLT-2, and SGLT-2 plays a particularly prominent role. Evidence has shown that an important clinical advantage of SGLT-2 inhibitors is that they are less likely to cause hypoglycemia. While inhibition of SGLT-1 causes sugar-galactose malabsorption syndrome, which may lead to dehydration, there is evidence that SGLT-1 inhibitors will delay carbohydrate absorption and cause gastrointestinal symptoms that are intolerable to individuals, while selection of high SGLT-2 inhibitors will not block the glucose absorption and transport action of SGLT-1 in the intestinal tract, and thus are not likely to cause gastrointestinal symptoms. In addition, SGLT-1 is also highly expressed in human myocardial tissue, and its blockade may cause cardiac functional or organic lesions. Therefore, the development of a compound having high selectivity for SGLT-2 is of great significance for the research of drugs for treating diabetes.
The compound shown in the formula (I) is a C-glucoside derivative, is an SGLT-2 (sodium-glucose cotransporter 2) inhibitor, and is a novel oral hypoglycemic medicament which is recommended internationally for treating type 2 diabetes at present. It selectively inhibits SGLT-2 receptors of kidney proximal convoluted tubule, reduces glucose reabsorption to promote urine glucose excretion, and lowers blood glucose concentration.
Patent ZL201410004395.2 discloses a compound shown in formula (I) and a synthesis process thereof, but boron trifluoride diethyl etherate is required in the process, and is flammable and explosive, difficult to store and has serious potential safety hazard. The reaction conditions related to the patent can cause the preparation process to generate isomer impurities and byproduct impurities which are difficult to remove, and additional steps are needed to further control the impurities, so that the process is complex, the cost is high, and the application of large-scale industrial production is not facilitated.
Therefore, research and development of a synthetic process capable of effectively controlling and reducing the generation of impurities are needed, the subsequent treatment difficulty of the synthetic product is reduced, and the product quality of the compound of the formula (I) and the derivative thereof is ensured.
Disclosure of Invention
In the process of researching the industrial production of the compound shown in the formula (I), the inventor of the application finds that a new impurity is generated in the production process, the structure of the impurity is shown in the formula (X), and the impurity is not easy to remove by a subsequent crystallization means.
Through intensive studies, the applicant found that the cause of the above impurities is: in the industrial production process, because the reaction system is far larger than the reaction quenching reagent, the quenching mode of adding the quenching reagent to the reaction system is adopted; in the synthesis process of the compound shown in the formula (I), after the synthesis reaction is finished, the temperature of a reaction system is increased to room temperature from-78 ℃, and sodium bicarbonate aqueous solution is added dropwise for quenching, and in the temperature increasing process, the bicyclo [3.1.0] hexane bridge ring fragment in the structure of the synthesized compound shown in the formula (I) is easy to open under the catalysis of boron trifluoride existing in the reaction system, so that impurities shown in the formula (X) are generated, and the reaction is as follows:
（I）（X）
in contrast, the applicant attempted to carry out quenching directly at the reaction temperature, but the aqueous sodium bicarbonate solution added dropwise to the reaction system rapidly freezes at a low temperature, and could not quench the reaction efficiently and had safety problems.
In order to solve the problems in the prior art, the invention provides a synthesis method of a C-glycoside derivative shown as a formula (I), which comprises the following steps:
（Ⅱ）（Ⅰ）
adding a compound shown as a formula (II) and triethylsilane into dichloromethane, cooling to-35 to-45 ℃ under the protection of nitrogen, dropwise adding boron trifluoride acetonitrile complex at a controlled temperature, and carrying out heat preservation at-35 to-45 ℃ to carry out a synthesis reaction of the compound shown as the formula (I); after the reaction is finished, directly dripping the reaction solution at the temperature of minus 35 ℃ to minus 45 ℃ into a sodium bicarbonate water solution for quenching reaction.
In order to realize the invention, the boron trifluoride acetonitrile complex is preferably used for replacing boron trifluoride diethyl etherate in the original process, and the reaction temperature is increased from-78 ℃ to-35 ℃ to-45 ℃; the temperature of the reaction system is increased, so that the reaction system can be directly dripped to the quenching reagent at a certain speed without a temperature rise program.
Further, the boron trifluoride acetonitrile complex is 20% of boron trifluoride acetonitrile complex (20% refers to the mass ratio of the complex to acetonitrile, and is a standard specification on the market), and the mass fraction of sodium bicarbonate in the sodium bicarbonate aqueous solution is 5wt% to 9wt%, preferably 5 wt%.
Preferably, the volume usage ratio of the reaction solution to the sodium bicarbonate aqueous solution is 100: 10-100: 15.
further preferably, the dropping rate of the reaction solution into the aqueous sodium bicarbonate solution is controlled to be 5kg/min to 12 kg/min.
Further, the temperature of the sodium bicarbonate water solution is 5-30 ℃, and preferably 20-30 ℃.
In the above synthesis method, the preparation method of the compound represented by the formula (II) comprises the following steps:
(1) suspending D- (+) -gluconic acid-1, 5-lactone in tetrahydrofuran, adding N-methylmorpholine, controlling the temperature to be 0-10 ℃, dropwise adding trimethylchlorosilane, and heating to 30-35 ℃ for reaction after dropwise adding; after the reaction is finished, cooling to 10-20 ℃, adding toluene for dilution, and dropwise adding water for quenching reaction; extracting, filtering, distilling under reduced pressure, and replacing toluene to obtain a toluene solution of a compound shown in a formula (III);
(2) suspending a compound shown as a formula (IV), a compound shown as a formula (V), benzyltriethylammonium chloride and Cs2CO3 in N-methylpyrrolidone, reacting at 60-70 ℃, cooling to 20-30 ℃ after the reaction is finished, adding methyl tert-butyl ether for extraction twice, carrying out reduced pressure distillation on an organic phase, replacing with absolute ethyl alcohol, supplementing N-methylpyrrolidone, cooling for crystallization, filtering, recrystallizing a filter cake with absolute ethyl alcohol, filtering, and drying to obtain a compound shown as an off-white formula (VI);
(3) adding a compound shown as a formula (VI), toluene and tetrahydrofuran into a reactor A, reducing the temperature to minus 80 ℃ to minus 70 ℃ under the protection of nitrogen, and dropwise adding n-butyllithium/n-hexane solution; after dripping, keeping the temperature and reacting for 2-5 hours; adding a compound shown as a formula (III) and methylbenzene into a reactor B, and cooling to minus 80 to minus 70 ℃ under the protection of nitrogen; dropwise adding the feed liquid in the reactor A into the reactor B, and controlling the temperature to be minus 80 ℃ to minus 70 ℃; after dripping, reacting for 1-4 hours at a constant temperature; dripping methanesulfonic acid/methanol solution at controlled temperature, and heating to 20-30 ℃ for reaction after dripping; adding sodium bicarbonate aqueous solution into the reaction system to quench the reaction, adding ethyl acetate to extract twice, and carrying out reduced pressure distillation and toluene replacement on an organic phase; and (3) dropwise adding the toluene solution into n-heptane for crystallization, centrifuging and drying to obtain a yellow powdery compound shown in the formula (II).
Preferably, after the compound represented by formula (I) is synthesized by the aforementioned synthesis method, it is further purified as follows:
(1) stirring the quenched compound solution shown in the formula (I), standing, and separating liquid; extracting the water phase twice with ethyl acetate, combining the organic phases, and washing with purified water; controlling the temperature of the organic phase to 35-50 ℃, carrying out reduced pressure distillation, and adding ethyl acetate to obtain an ethyl acetate solution of the compound shown in the formula (I);
(2) adding an ethyl acetate solution of a compound shown in a formula (I), N-methylmorpholine and DMAP into a reactor, cooling to 0-10 ℃, dropwise adding acetic anhydride, and reacting at 25-35 ℃ after dropwise adding; adding ethyl acetate and water for extraction after reaction, backwashing an organic phase with water, distilling under reduced pressure, replacing with absolute ethyl alcohol, crystallizing and filtering, recrystallizing a filter cake with an ethanol/acetonitrile system, filtering, and drying to obtain a compound shown in a formula (VII);
dissolving a compound shown as a formula (VII) and lithium hydroxide monohydrate in methanol, water and tetrahydrofuran, reacting at 30-40 ℃, spin-drying the solvent, adjusting the pH to 6.0-7.0 by using dilute hydrochloric acid, adding ethyl acetate for extraction, backwashing an organic phase by using water, carrying out reduced pressure distillation, and replacing by using absolute ethyl alcohol to obtain a free ethanol solution of the compound shown as the formula (I);
adding free ethanol solution of the compound shown in the formula (I) and water into a reaction bottle, adding L-proline, and crystallizing to prepare the cocrystal of the compound shown in the formula (I) and the L-proline.
The compound shown in the formula (I) synthesized by the invention has the impurity content less than 0.05 percent through detection, and compared with the prior art, the impurity content is effectively reduced, and the synthesis method has good repeatability.
The compound shown in the formula (I) synthesized by the invention can be used as a raw material for further preparing derivatives thereof, such as a eutectic compound with L-proline and the like.
The invention has the beneficial effects that:
in the industrial amplification research of the compound shown in the formula (I), repeated research shows that the generation of isomer impurities and byproduct impurities can be effectively removed by replacing reagents in key reaction steps and adjusting and optimizing key reaction conditions, so that the product quality is ensured, the subsequent treatment difficulty is reduced, and the production efficiency is improved. Particularly, the method improves the reaction quenching mode in the synthesis process, can rapidly quench the reaction, has short quenching time and easy operation, and can effectively avoid the problem of impurity growth caused by the temperature rise of a reaction system.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the invention and together with the description, serve to explain the principles of the invention.
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without inventive exercise.
Fig. 1 shows the results of measuring the content of impurity (X) in the L-proline eutectic compound of the compound of formula (I) prepared in example 1 by high performance liquid chromatography.
Fig. 2 is a result of measuring the content of impurity (X) in the L-proline eutectic compound of the compound of formula (I) prepared in comparative example 1 by high performance liquid chromatography.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Preferred embodiments of the present invention will be described in detail with reference to the following examples. It is to be understood that the following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1
This example serves to illustrate the synthesis and purification of the compound of formula (I) starting from the compound of formula (II) and the further synthesis of the L-proline co-crystal complex of the compound of formula (I).
1. Dichloromethane (364.1 kg) was added to a 500L cryogenic reactor under nitrogen, stirring was turned on, and triethylsilane (20.3 kg) and the compound of formula (II) (28.1 kg) were added. Cooling to-40 deg.C. 20% boron trifluoride acetonitrile complex (69.1 kg) was added dropwise at controlled temperature for about 2 hours. After dropping, the reaction is carried out for 3 hours under the condition of heat preservation, and the compound of the formula (I) is synthesized.
2. A5% aqueous sodium bicarbonate solution (313.73 kg) was charged into a 1000L cryogenic reactor. The feed liquid with the temperature of minus 40 ℃ kept in the 500L cryogenic reaction kettle is directly dripped into the 1000L cryogenic reaction kettle for quenching reaction (dripping for about 1 hour), and the temperature in the 1000L cryogenic reaction kettle is controlled to be 20 ℃. Controlling the temperature of the quenched system at 25-30 ℃, stirring, standing and separating.
3. The aqueous phase was extracted twice with ethyl acetate (123.1 kg. times.2), and the organic phases were combined and washed once with purified water (136.8 kg).
The organic phase is distilled under reduced pressure to 114L at the temperature of 35-50 ℃, and ethyl acetate (205.2 kg) is added. Sampling and qualified moisture detection. Collecting the materials to obtain 286.5 kg of the compound ethyl acetate solution of the formula (I).
4. Adding an ethyl acetate solution (286.5 kg) of a compound shown in the formula (I), N-methylmorpholine (34.96 kg) and DMAP (0.343 kg) into a reactor, cooling to 0-10 ℃, dropwise adding acetic anhydride (29.38 kg), and reacting at 25-35 ℃ after dropwise adding; adding ethyl acetate (231.66 kg) and water (214.5 kg) for extraction after the reaction, backwashing an organic phase with water, distilling under reduced pressure, replacing with absolute ethyl alcohol, crystallizing and filtering, recrystallizing a filter cake with an ethanol/acetonitrile system, filtering, and drying to obtain a compound (VII) (27.7 kg);
dissolving a compound (53.61 kg) shown in the formula (VII) and lithium hydroxide monohydrate (17.69 kg) in methanol (254.1 kg), water (107.2 kg) and tetrahydrofuran (190.8 kg), reacting at 30-40 ℃, spin-drying the solvent, adjusting the pH to 6.0-7.0 by using dilute hydrochloric acid, adding ethyl acetate (386 kg) for extraction, backwashing an organic phase by using water, distilling under reduced pressure, and replacing by using absolute ethyl alcohol to obtain an ethanol solution (74.05 kg, 37.62 kg) containing the compound shown in the formula I) free body of the compound shown in the formula (I).
5. Preparation of a Compound of formula (I) L-proline eutectic Complex
Adding 74.05kg of free ethanol solution of the compound shown in the formula (I), 46.7kg of ethanol and 13.2kg of water into a reaction bottle, adding 18.81kg of L-proline, and crystallizing to prepare 43.93kg of a cocrystal of the compound shown in the formula (I) and the L-proline.
Example 2
This example uses a high performance liquid to detect the content of impurity (X) in the L-proline eutectic compound of the compound of formula (I) prepared in example 1.
The detection method specifically comprises the following steps:
reagent solution: diammonium phosphate, phosphoric acid, methanol, acetonitrile and ultrapure water.
The instrument equipment comprises: electronic balance, high performance liquid chromatograph, pH meter, and centrifuge.
Chromatographic conditions are as follows: measuring by high performance liquid chromatography (0512 of the four Ministry of China pharmacopoeia 2020 edition), using octadecyl silane bonded silica gel as filler (Agilent Eclipse XDB-C18, 150mm × 4.6mm, 5 μm); the mobile phase A is 0.01mol/L diammonium hydrogen phosphate solution (taking 1.32g diammonium hydrogen phosphate, adding 1000mL of water for ultrasonic dissolution, adjusting the pH value to 5.00 +/-0.05) acetonitrile (90: 10 by using phosphoric acid), and the mobile phase B is water-acetonitrile (10: 90); the flow rate is 1.0 mL/min; the detection wavelength is 225 nm; the sample introduction volume is 10 muL; the column temperature was 25 ℃; the linear gradient elution was performed as follows.
Test solution: about 5mg of the eutectic compound prepared in example 1 was taken, placed in a 10mL measuring flask, dissolved in methanol and quantitatively diluted to the scale, and shaken up.
The determination method comprises the following steps: precisely measuring 10 muL of sample solution, injecting the sample solution into a liquid chromatograph, wherein a chromatogram is shown in figure 1, and the content of impurities shown in the formula X is lower than the limit of 0.05% according to the calculation of an area normalization method.
Example 3
In this example, three batches of samples were prepared according to the synthesis method described in example 1, and the samples were subjected to high performance liquid chromatography, and the results are shown below:
experimental results prove that the synthetic method provided by the invention has good repeatability.
Comparative example 1
This comparative example differs from example 1 in that: replacing boron trifluoride acetonitrile complex with equimolar boron trifluoride diethyl etherate complex, changing the reaction temperature to-78 ℃, after the reaction is finished, heating the reaction system to 10 ℃, and quenching the reaction in a manner of dropwise adding 5% sodium bicarbonate water solution into the reaction system. The remaining steps and the amounts of the reagents were the same as in example 1.
The detection result of the high performance liquid chromatography is shown in fig. 2, and a high impurity peak exists, and the content of the impurity (X) is 0.38%.
Further, after separating the impurity component, the study of mass spectrometry, nuclear magnetic resonance spectroscopy, elemental analysis, and the like confirmed that the impurity has a structure represented by formula (X).
Therefore, compared with the conventional synthesis method in the prior art, the synthesis method provided by the invention can effectively control and compress the impurity amount, and improve the product yield and the product quality.
Comparative example 2
According to the method of comparative example 1, boron trifluoride acetonitrile complex is selected to replace boron trifluoride diethyl etherate with different starting material amounts, the reaction temperature is changed to-40 ℃, after the reaction is finished, the reaction system is heated to 10 ℃, and the reaction is quenched by dripping 5% sodium bicarbonate water solution into the reaction system. And the high performance liquid detection is carried out on the sample, and the result shows that the content of the impurity X is 0.3%.
The foregoing are merely exemplary embodiments of the present invention, which enable those skilled in the art to understand or practice the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (8)
1. A synthetic method of a C-glycoside derivative shown as a formula (I) is characterized by comprising the following steps:
adding a compound shown as a formula (II) and triethylsilane into dichloromethane, cooling to-35 to-45 ℃ under the protection of nitrogen, dropwise adding boron trifluoride acetonitrile complex at a controlled temperature, and carrying out heat preservation at-35 to-45 ℃ to carry out a synthesis reaction of the compound shown as the formula (I); then, the reaction solution at the synthesis reaction temperature was directly added dropwise to an aqueous sodium bicarbonate solution to quench the reaction.
2. The synthesis method according to claim 1, wherein the boron trifluoride acetonitrile complex is 20% of boron trifluoride acetonitrile complex, and the mass fraction of sodium bicarbonate in the sodium bicarbonate aqueous solution is 5wt% to 9 wt%.
3. The synthesis method according to claim 2, wherein the volume usage ratio of the reaction solution to the sodium bicarbonate aqueous solution is 100: 10-100: 15.
4. the synthesis method according to claim 3, wherein the dropping rate of the reaction solution into the aqueous sodium bicarbonate solution is 5kg/min to 12 kg/min.
5. The synthesis method according to claim 4, wherein the temperature of the aqueous sodium bicarbonate solution is 5-30 ℃.
6. The synthesis method according to claim 5, wherein the temperature of the aqueous sodium bicarbonate solution is 20-30 ℃.
7. The method of any one of claims 1-6, wherein the compound of formula (II) is prepared by a method comprising the steps of:
(1) suspending D- (+) -gluconic acid-1, 5-lactone in tetrahydrofuran, adding N-methylmorpholine, controlling the temperature to be 0-10 ℃, dropwise adding trimethylchlorosilane, and heating to 30-35 ℃ for reaction after dropwise adding; after the reaction is finished, cooling to 10-20 ℃, adding toluene for dilution, and dropwise adding water for quenching reaction; extracting, filtering, distilling under reduced pressure, and replacing toluene to obtain a toluene solution of a compound shown in a formula (III);
(2) suspending a compound shown as a formula (IV), a compound shown as a formula (V), benzyltriethylammonium chloride and Cs2CO3 in N-methylpyrrolidone, reacting at 60-70 ℃, cooling to 20-30 ℃ after the reaction is finished, adding methyl tert-butyl ether for extraction twice, carrying out reduced pressure distillation on an organic phase, replacing with absolute ethyl alcohol, supplementing N-methylpyrrolidone, cooling for crystallization, filtering, recrystallizing a filter cake with absolute ethyl alcohol, filtering, and drying to obtain a compound shown as an off-white formula (VI);
(3) adding a compound shown as a formula (VI), toluene and tetrahydrofuran into a reactor A, reducing the temperature to minus 80 ℃ to minus 70 ℃ under the protection of nitrogen, and dropwise adding n-butyllithium/n-hexane solution; after dripping, keeping the temperature and reacting for 2-5 hours; adding a toluene solution of a compound shown as a formula (III) into a reactor B, and cooling to minus 80 to minus 70 ℃ under the protection of nitrogen; dropwise adding the feed liquid in the reactor A into the reactor B, and controlling the temperature to be minus 80 ℃ to minus 70 ℃; after dripping, reacting for 1-4 hours at a constant temperature; dripping methanesulfonic acid/methanol solution at controlled temperature, and heating to 20-30 ℃ for reaction after dripping; adding sodium bicarbonate aqueous solution into the reaction system to quench the reaction, adding ethyl acetate to extract twice, and carrying out reduced pressure distillation and toluene replacement on an organic phase; and (3) dropwise adding the toluene solution into n-heptane for crystallization, centrifuging and drying to obtain a yellow powdery compound shown in the formula (II).
8. A method for synthesizing a co-crystal of a compound shown as a formula (I) and L-proline is characterized by comprising the following steps:
adding a compound shown as a formula (II) and triethylsilane into dichloromethane, cooling to-35 to-45 ℃ under the protection of nitrogen, dropwise adding boron trifluoride acetonitrile complex at a controlled temperature, and carrying out heat preservation at-35 to-45 ℃ to carry out a synthesis reaction of the compound shown as the formula (I); then, directly dripping the reaction solution at the synthesis reaction temperature into a sodium bicarbonate aqueous solution to quench the reaction;
stirring the quenched compound solution shown in the formula (I), standing, and separating liquid; extracting the water phase twice with ethyl acetate, combining the organic phases, and washing with purified water; controlling the temperature of the organic phase to 35-50 ℃, carrying out reduced pressure distillation, and adding ethyl acetate to obtain an ethyl acetate solution of the compound shown in the formula (I);
adding an ethyl acetate solution of a compound shown in a formula (I), N-methylmorpholine and DMAP into a reactor, cooling to 0-10 ℃, dropwise adding acetic anhydride, and reacting at 25-35 ℃ after dropwise adding; adding ethyl acetate and water for extraction after reaction, backwashing an organic phase with water, distilling under reduced pressure, replacing with absolute ethyl alcohol, crystallizing and filtering, recrystallizing a filter cake with an ethanol/acetonitrile system, filtering, and drying to obtain a compound shown in a formula (VII);
dissolving a compound shown as a formula (VII) and lithium hydroxide monohydrate in methanol, water and tetrahydrofuran, reacting at 30-40 ℃, spin-drying the solvent, adjusting the pH to 6.0-7.0 by using dilute hydrochloric acid, adding ethyl acetate for extraction, backwashing an organic phase by using water, carrying out reduced pressure distillation, and replacing by using absolute ethyl alcohol to obtain a free ethanol solution of the compound shown as the formula (I);
adding free ethanol solution of the compound shown in the formula (I) and water into a reaction bottle, adding L-proline, and crystallizing to prepare the cocrystal of the compound shown in the formula (I) and the L-proline.
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