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CN108794548B - Process for preparing enggliflozin and intermediates thereof - Google Patents

Process for preparing enggliflozin and intermediates thereof Download PDF

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CN108794548B
CN108794548B CN201710294478.3A CN201710294478A CN108794548B CN 108794548 B CN108794548 B CN 108794548B CN 201710294478 A CN201710294478 A CN 201710294478A CN 108794548 B CN108794548 B CN 108794548B
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CN108794548A (en
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李阳
高鹏
徐洋平
孟庆义
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present invention relates to a process for preparing englitjing and intermediates thereof. The invention also relates to a novel preparation intermediate of the engagliflozin. The method and the novel intermediate can effectively control the impurity of the reaction, wherein the control on the isomer impurity is particularly outstanding, and finally, the quality control on the production of the Engliflozin bulk drug is facilitated, and the invention also provides convenience for the research on subsequent preparations.

Description

Process for preparing enggliflozin and intermediates thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing englitazone and an intermediate thereof. The invention also relates to a novel preparation intermediate of the engagliflozin.
Background
Engliflozin (empagliflozin), developed cooperatively by Boringer John and Gift, is a sodium-glucose cotransporter (SGLT 2) inhibitor useful in the treatment of type 2 diabetes. Currently, the products are marketed in various countries such as the united states, europe, japan, etc.
Enagliflozin may also be used in combination with other antidiabetic agents, for example with linagliptin or with metformin.
The structure of enggliflozin is as follows:
Figure BDA0001282717810000011
SGLT-2 inhibitors have been shown to block glucose reabsorption in the kidney and excrete excess glucose to the body, thereby achieving a blood glucose level lowering effect that is independent of beta cell function and insulin resistance. Meanwhile, recent EMPA-REG outcom clinical trial study data indicate that in adult patients with type 2 diabetes with high risk Cardiovascular (CV) events, the garbiance (enggliflozin) + standard care significantly reduced the cardiovascular risk of the patients compared to placebo+standard care. Thus, garbiance is currently the only hypoglycemic agent demonstrated to reduce cardiovascular risk in cardiovascular endpoint trials. Currently, the FDA has accepted a new supplementary drug application (sNDA) for the hypoglycemic agent gardiince.
There are several documents reported about the synthesis of engagliflozin, including WO2006120208, WO2011039108, WO2013068850, WO2014206299, WO2015101916, WO2015155739, etc.
However, there is still a need to develop a method for preparing englitazone which is more suitable for industrialization and easier for quality control, so as to meet the production requirements of the continuous expansion of the raw material medicines and preparations of the englitazone. Particularly, the control of isomer impurities is more beneficial to the subsequent further achievement of the pharmaceutical standard of the englitazone.
Disclosure of Invention
In one aspect, the invention provides a compound of formula 1,
Figure BDA0001282717810000012
wherein R is a hydroxyl protecting group.
In some embodiments of the invention, R is acetyl.
The invention also provides a preparation method of the compound of the formula 1, which comprises the following steps:
step (1): reacting a compound of formula 2 with sec-butylmagnesium chloride lithium chloride;
step (2): reacting the product obtained in the step (1) with a compound shown in a formula 3;
Figure BDA0001282717810000021
wherein,,
x is halogen, preferably I or Br;
r is a hydroxyl protecting group.
In some embodiments of the invention, R is acetyl.
In some embodiments of the invention, the compound of formula 1 obtained by the above preparation method is not purified.
In some embodiments of the invention, in step (1), the reaction solvent is: one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether or cyclohexane.
In some embodiments of the invention, in step (1), the reaction temperature is from-20 to 0 ℃, preferably from-10 to-5 ℃.
In some embodiments of the invention, in step (1), the molar ratio of the compound of formula 2 to sec-butylmagnesium chloride lithium chloride is from 1:1 to 2, preferably from 1:1 to 1.5.
In some embodiments of the present invention, step (1) is preferably performed under nitrogen blanket.
In some embodiments of the invention, in step (2), the reaction solvent is: one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, diethyl ether, methyl tertiary butyl ether or cyclohexane.
In some embodiments of the invention, in step (2), the reaction temperature is from-60 to-30 ℃, preferably from-50 to-45 ℃.
In some embodiments of the invention, in step (2), the molar ratio of the compound of formula 2 to the compound of formula 3 is from 1:1 to 3, preferably from 1:1 to 2.
In some embodiments of the present invention, step (2) is preferably performed under nitrogen blanket.
In some embodiments of the invention, the end of the reaction of step (1) is carried out directly without post-treatment to the reaction of step (2).
In some embodiments of the invention, step (1): under the protection of nitrogen, dropwise adding sec-butyl magnesium chloride lithium chloride solution into toluene, and reacting at-10 to-5 ℃ until the completion; step (2): under the protection of nitrogen, tetrahydrofuran is added into toluene solution of the compound shown in the formula 3, the temperature is reduced to-50 ℃, the reaction liquid in the step (1) is dripped, and the reaction is finished at-45 to-50 ℃. In some embodiments of the invention, after the two-step reaction is completed, the following post-treatments may also be performed: dropwise adding a mixed solution of acetic acid and water into the reaction solution at the temperature below-45 ℃, heating to room temperature after the dropwise adding, separating liquid, washing an organic phase with water, drying, filtering and concentrating.
In another aspect, the invention provides a compound of formula 4 having no more than 3.5% isomer-1 and no more than 0.1% isomer-2,
Figure BDA0001282717810000031
wherein R is a hydroxyl protecting group, and the amounts of the isomer-1 and the isomer-2 are calculated from the relative areas in the liquid phase diagram.
In some embodiments of the invention, R is acetyl.
In some embodiments of the invention, isomer-2 is no more than 0.05%.
In some embodiments of the invention, the compound of formula 4 is not purified.
The invention provides a preparation method of the compound of the formula 4, which comprises the steps of obtaining the compound of the formula 1 through reduction reaction:
Figure BDA0001282717810000032
wherein R is a hydroxyl protecting group.
In some embodiments of the invention, R is acetyl.
In some embodiments of the invention, the compound of formula 4 obtained by the above-described preparation method contains not more than 3.5% of isomer-1, the amount of said isomer-1 being calculated from the relative areas in the liquid phase pattern.
In some embodiments of the invention, the compound of formula 4 obtained by the above-described preparation method contains not more than 0.1% or 0.05% of isomer-2, the amount of said isomer-2 being calculated from the relative areas in the liquid phase pattern.
In some embodiments of the invention, the compound of formula 4 obtained by the above preparation method is not purified.
In some embodiments of the invention, the reaction solvent in the reduction reaction is: one or more of acetonitrile, dichloromethane, chloroform and toluene.
In some embodiments of the invention, the reaction temperature in the reduction reaction is-20 to 0 ℃, preferably-10 to 0 ℃.
In some embodiments of the invention, the reduction reaction is preferably carried out under the action of a lewis acid and a silane reagent. The Lewis acid is boron trifluoride; the silane reagent is triethylsilane; the molar ratio of the lewis acid to the silane reagent is 1:1. The molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 10, preferably from 1:1 to 5, most preferably from 1:1 to 3.
In some embodiments of the invention, the reduction reaction is preferably carried out under nitrogen protection.
In some specific embodiments of the invention, the compound of formula 1 is added to acetonitrile under the protection of nitrogen, triethylsilane is added at-10 ℃, boron trifluoride acetonitrile solution is added dropwise, and the reaction is finished at-5-0 ℃. In some embodiments of the invention, the following post-treatments may also be performed after the reaction is complete: adding saturated sodium bicarbonate solution dropwise to adjust pH to 6.5-7.0, separating, extracting water phase with ethyl acetate, washing the extract with water and saturated saline water, drying, and concentrating to obtain compound of formula 4. In some embodiments of the invention, the compound of formula 4 may also be prepared by recrystallisation from methanol after concentration.
The invention also provides the use of a compound of formula 1 for the preparation of a compound of formula 4 wherein the amount of isomer-1 and isomer-2 calculated from the relative areas in the liquid phase pattern is not more than 3.5% and the amount of isomer-2 is not more than 0.1% of isomer-1, preferably not more than 0.05% of isomer-2.
In still another aspect, the invention also provides a preparation method of the englitazone, which comprises the steps of obtaining a compound of formula 4 through a reduction reaction of the compound of formula 1, and obtaining the compound of formula 4 through a deprotection reaction.
Figure BDA0001282717810000041
Wherein R is a hydroxyl protecting group.
In some embodiments of the invention, R is acetyl.
In some embodiments of the invention, the reaction solvent in the reduction reaction is: one or more of acetonitrile, dichloromethane, chloroform and toluene.
In some embodiments of the invention, the reaction temperature in the reduction reaction is-20 to 0 ℃, preferably-10 to 0 ℃.
In some embodiments of the invention, the reduction reaction is preferably carried out under the action of a lewis acid and a silane reagent. The Lewis acid is boron trifluoride; the silane reagent is triethylsilane; the molar ratio of the lewis acid to the silane reagent is 1:1. The molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 10, preferably from 1:1 to 5, most preferably from 1:1 to 3.
In some embodiments of the invention, the reduction reaction is preferably carried out under nitrogen protection.
In some embodiments of the invention, the reduction reaction yields a compound of formula 4 having no more than 3.5% of isomer-1, no more than 0.1% or 0.05% of isomer-2, the amounts of isomer-1 and isomer-2 being calculated from the relative areas in the liquid phase pattern.
In some embodiments of the invention, after the reduction reaction, the compound of formula 4 may be recrystallized, for example, using an alcoholic solvent including methanol.
In some embodiments of the invention, the deprotection reaction, the reaction solvent is: tetrahydrofuran, methanol, ethanol, dichloromethane, acetonitrile or N, N-dimethylformamide.
In some embodiments of the invention, the deprotection reaction is performed in the presence of a base. The base is selected from sodium methoxide, sodium hydroxide, potassium hydroxide or sodium tert-butoxide.
In some embodiments of the invention, the reaction temperature in the deprotection reaction is 0 to 60 ℃, preferably 20 to 40 ℃.
In some embodiments of the present invention, the molar ratio of the compound of formula 4 to the base in the deprotection reaction is 1:2 to 0.01, preferably 1:1.5 to 0.1.
In some embodiments of the invention, the deprotection reaction is preferably conducted under a nitrogen blanket.
In some embodiments of the invention, the end of the reduction reaction may be followed by a deprotection reaction without post-treatment.
In the specific embodiment of the reduction reaction of the invention, the compound of the formula 1 is added into acetonitrile under the protection of nitrogen, triethylsilane is added at the temperature of minus 10 ℃, then boron trifluoride acetonitrile solution is added dropwise, and the reaction is finished at the temperature of minus 5 to 0 ℃. In a specific embodiment of the reduction reaction of the present invention, the following post-treatment may be further performed after the reaction is completed: adding saturated sodium bicarbonate solution dropwise to adjust pH to 6.5-7.0, separating, extracting water phase with ethyl acetate, washing the extractive solution with water and saturated saline water, drying, and concentrating to obtain compound of formula 4. In a specific embodiment of the reduction reaction of the present invention, the compound of formula 4 may also be prepared by recrystallisation from methanol after concentration.
In the specific embodiment of the deprotection reaction, the compound of the formula 4 is added into a mixed solvent of tetrahydrofuran-methanol (1:1), sodium methoxide is added at the temperature of-5 ℃, the reaction is finished at the temperature of 20-30 ℃, and the crude product of the englitazone is obtained by concentration. In the specific embodiment of the deprotection reaction of the invention, the crude product of the englitazone can be further recrystallized and purified. In a specific embodiment of the deprotection reaction of the present invention, the englitjing is slurried with isopropyl acetate-water.
The invention also provides the use of a compound of formula 1 for the preparation of englitjing.
The invention has the following advantages:
1. the preparation of the compound of formula 1 and the further preparation of the compound of formula 4, or the further use of the compound in the preparation of the enggliflozin, can effectively control the impurity of the reaction, wherein the control of the isomer impurity is particularly outstanding, the quality control of the production of the enggliflozin bulk drug is facilitated finally, and the research of the subsequent preparation is also facilitated.
2. The compound of formula 4 is deprotected to obtain enggliflozin, and sodium methoxide is used to further reduce impurity generation and avoid water use.
3. The reaction conditions such as the reaction reagent and the reaction temperature are relatively mild, and the heating time can be greatly shortened, so that the method is very important for industrial production. Reducing the temperature rise time can further reduce the generation of impurities.
Detailed Description
The following examples illustrate the technical aspects of the invention in further non-limiting detail. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. The solvents, reagents, raw materials, and the like used in the present invention are all commercially available chemically pure or analytically pure products.
EXAMPLE 1 preparation of Compound of formula 1 (R is acetyl)
Step 1:
Figure BDA0001282717810000051
to a three-necked flask, 916g of acetic anhydride, 126g of trifluoroacetic acid was added and stirred well. 200g of gluconolactone was added, and after slowly heating to 80℃the reaction was carried out for 4 hours. TLC was monitored to the end of the reaction. The reaction solution was transferred to a 2L single-necked flask and distilled under reduced pressure at 80℃until no significant liquid was eluted. 250ml of toluene was added and the mixture was distilled under reduced pressure at 80℃until no significant liquid was eluted, and the above-mentioned operation was repeated 3 times. Steaming at 80deg.C under reduced pressure with oil pump until no obvious liquid flows out, adding 400ml toluene, stirring, and standing. To obtain the toluene solution of 2,3,4, 6-tetra-O-acetyl-beta-D-glucolactone.
Step 2:
26.73g of magnesium turnings, 42.39g of lithium chloride and 500ml of tetrahydrofuran were added to a three-necked flask, and the mixture was replaced with nitrogen three times. And dropwise adding a mixed solution of the sec-butyl chloride and 500ml of tetrahydrofuran at the temperature of 0-5 ℃, and adding 2ml of methyl iodide as an initiator after 50ml of the mixed solution is dropwise added. Then continuously dripping the mixed solution of the sec-butyl chloride and the tetrahydrofuran, and stirring for 4 hours at 20-25 ℃ after the dripping is finished. To obtain sec-butyl magnesium chloride lithium chloride tetrahydrofuran solution (1M) for later use.
Step 3:
1-chloro-4-iodo-2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene (80 g,192.9 mmol) and toluene (144 ml) were added to the reaction flask, dissolved with stirring, nitrogen-protected, and cooled to-10 ℃; sec-butyl magnesium chloride lithium chloride (289.4 mmol) is added dropwise at the temperature of-10 to-5 ℃; after dripping, controlling the temperature to be between minus 10 ℃ and minus 5 ℃ and reacting for more than 1 hour; the toluene solution (385.8 mmol) of the product obtained in step 1 and tetrahydrofuran (97 ml) were added into a reaction flask, and the mixture was cooled to-50 ℃ under nitrogen protection; dropwise adding the reaction solution obtained in the step 2 at the temperature below-45 ℃; after the dripping, controlling the temperature to be between minus 45 ℃ and minus 50 ℃ for reaction for 1 hour. After the reaction, dropwise adding a mixed solution of acetic acid and water at a temperature below-45 ℃, heating to room temperature after the dropwise adding, separating liquid, washing an upper organic phase with water for 2 times, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound of the formula 1 (R is acetyl).
The relative area of the compound of formula 1 was 74.36% by LC-MS analysis.
EXAMPLE 2 preparation of Engliflozin
Step 1: preparation of Compounds of formula 4 (R is acetyl)
The compound of formula 1 (R is acetyl) (184.5 mmol) obtained in example 1 and acetonitrile (500 ml) are placed in a reaction flask, and the mixture is cooled to-10℃under nitrogen; triethylsilane (64.39 g,553.7 mmol) was added and stirred for 10min or more; slowly dropwise adding boron trifluoride acetonitrile solution (18 percent, 204.48 g) at the temperature of-10 to-5 ℃ and reacting for about 1h at the temperature of-5 to-0 ℃ after dropwise adding; after the reaction is finished, saturated sodium bicarbonate solution is dripped to adjust the pH to 6.5-7.0; separating, extracting the water phase with ethyl acetate for 2 times; the organic phases are combined, washed for 1 time by water and saturated saline water respectively, and dried by anhydrous sodium sulfate; concentrating under reduced pressure to dryness to obtain a compound of formula 4 (R is acetyl).
The relative area of the compound of formula 4 was 69.7% and the relative area of isomer-1 was 3.46% by LC-MS analysis; the relative area of isomer-2 was 0.04%.
Figure BDA0001282717810000061
The detection conditions were as follows:
chromatographic column: waters CORTECS C18 (4.6X100 mm,2.7 μm)
Flow rate: 1.0ml/min, wavelength: 225nm, column temperature: 45 ℃, sample injection volume: 10 μl of
Mobile phase a:0.1% formic acid solution
Mobile phase B: acetonitrile
Gradient elution was performed as follows:
Figure BDA0001282717810000062
Figure BDA0001282717810000071
when the hydroxyl group in the compound of formula 1 (R is hydrogen and the relative area is 85%) is replaced with methoxy group, reduction is performed using the same method as described above to obtain the compound of formula 4, wherein the relative area of the produced isomer-1 (R is hydrogen) is 8%.
Step 2:
the compound of formula 4 (R is acetyl) obtained in step 1 is recrystallized twice from methanol under nitrogen protection. Wherein the relative area of the compound of formula 4 is 97.54%.
Mixing the purified compound of formula 4 (R is acetyl) (10 g,161 mmol) and a mixed solvent of THF-methanol (1:1), and reducing the temperature to-5 ℃; sodium methoxide (16.1 mmol) was added in portions; after the sodium methoxide is added, the temperature is raised to 20-30 ℃ and the mixture is stirred for more than 1 hour, the organic solvent is distilled off under reduced pressure, and the crude product of the englitazone (the relative area is 98.3%) is obtained.
The crude product of the englitazone is pulped by isopropyl acetate-water to obtain the pure product of the englitazone, and the relative area of the englitazone is 99.55 percent through liquid chromatography-mass spectrometry analysis.

Claims (65)

1. The compound of formula 1 is a compound of formula 1,
Figure FDA0004064871720000011
wherein R is acetyl.
2. A process for the preparation of a compound of formula 1 according to claim 1, comprising the steps of:
step (1): reacting a compound of formula 2 with sec-butylmagnesium chloride lithium chloride;
step (2): reacting the product obtained in the step (1) with a compound shown in a formula 3;
Figure FDA0004064871720000012
wherein,,
x is halogen;
r is acetyl.
3. The process of claim 2 wherein X is I or Br.
4. The process of claim 2, wherein the compound of formula 1 is not purified.
5. The process according to claim 2, wherein in the step (1), the reaction solvent is: one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether or cyclohexane.
6. The process according to claim 2, wherein in the step (1), the reaction temperature is-20 to 0 ℃.
7. The process according to claim 6, wherein in the step (1), the reaction temperature is-10 to-5 ℃.
8. The process according to claim 2, wherein in step (1), the molar ratio of the compound of formula 2 to sec-butylmagnesium chloride lithium chloride is from 1:1 to 2.
9. The process according to claim 8, wherein in step (1), the molar ratio of the compound of formula 2 to sec-butylmagnesium chloride lithium chloride is from 1:1 to 1.5.
10. The process of claim 2, wherein step (1) is performed under nitrogen.
11. The process according to claim 2, wherein in the step (2), the reaction solvent is: one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, diethyl ether, methyl tertiary butyl ether or cyclohexane.
12. The process according to claim 2, wherein in the step (2), the reaction temperature is-60 to-30 ℃.
13. The process according to claim 12, wherein in the step (2), the reaction temperature is-50 to-45 ℃.
14. The process according to claim 2, wherein in step (2), the molar ratio of the compound of formula 2 to the compound of formula 3 is from 1:1 to 3.
15. The process according to claim 14, wherein in step (2), the molar ratio of the compound of formula 2 to the compound of formula 3 is from 1:1 to 2.
16. The process of claim 2, wherein step (2) is performed under nitrogen.
17. The process according to claim 2, wherein the reaction in step (2) is carried out directly without any post-treatment after the completion of the reaction in step (1).
18. The preparation method of claim 2, step (1): under the protection of nitrogen, dropwise adding sec-butyl magnesium chloride lithium chloride solution into toluene, and reacting at-10 to-5 ℃ until the completion; step (2): under the protection of nitrogen, tetrahydrofuran is added into toluene solution of the compound shown in the formula 3, the temperature is reduced to-50 ℃, the reaction liquid in the step (1) is dripped, and the reaction is finished at-45 to-50 ℃.
19. The process of claim 18, wherein after the reaction of step (1) and step (2), the following post-treatment is further performed: dropwise adding a mixed solution of acetic acid and water into the reaction solution at the temperature below-45 ℃, heating to room temperature after the dropwise adding, separating liquid, washing an organic phase with water, drying, filtering and concentrating.
20. A process for the preparation of a compound of formula 4 comprising the reduction of a compound of formula 1 according to claim 1:
Figure FDA0004064871720000021
wherein R is acetyl, the reduction reaction is carried out under the action of Lewis acid and silane reagent, and the Lewis acid is boron trifluoride;
the silane reagent is triethylsilane.
21. The process according to claim 20, wherein the compound of formula 4 contains not more than 3.5% of isomer-1, the amount of isomer-1 being calculated from the relative areas in the liquid phase pattern,
the structure of the isomer-1 is
Figure FDA0004064871720000022
Wherein R is acetyl.
22. The process of claim 21, wherein the compound of formula 4 contains not more than 0.1% or 0.05% of isomer-2, the amount of isomer-2 being calculated from the relative areas in the liquid phase pattern,
the structure of the isomer-2 is that
Figure FDA0004064871720000023
Wherein R is acetyl.
23. The process of claim 20, wherein the compound of formula 4 is not purified.
24. The production method according to claim 20, wherein in the reduction reaction, the reaction solvent is: one or more of acetonitrile, dichloromethane, chloroform and toluene.
25. The process according to claim 20, wherein the reaction temperature is-20 to 0 ℃.
26. The process according to claim 25, wherein the reaction temperature is-10 to 0 ℃.
27. The process of claim 20, wherein the lewis acid is boron trifluoride; the silane reagent is triethylsilane; the molar ratio of the lewis acid to the silane reagent is 1:1.
28. The process of claim 20, wherein the molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 10.
29. The process of claim 28, wherein the molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 5.
30. The process of claim 29, wherein the molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 3.
31. The method of claim 20, wherein the reduction is performed under nitrogen.
32. The process according to claim 31, wherein the compound of formula 1 is added in acetonitrile under nitrogen protection at-10 ℃ and boron trifluoride acetonitrile solution is added dropwise thereto, and the reaction is completed at-5 to 0 ℃.
33. The process of claim 32, wherein the reaction is further followed by the following post-treatment: adding saturated sodium bicarbonate solution dropwise to adjust pH to 6.5-7.0, separating, extracting water phase with ethyl acetate, washing the extract with water and saturated saline water, drying, and concentrating to obtain compound of formula 4.
34. The process of claim 33, wherein the compound of formula 4 is further recrystallized from methanol after concentration.
35. The use of a compound of formula 1 according to claim 1 for the preparation of a compound of formula 4,
Figure FDA0004064871720000031
wherein,,
r is an acetyl group, and the R is an acetyl group,
in the compound of formula 4, the isomer-1 is not more than 3.5%, the isomer-2 is not more than 0.1%, the amounts of the isomer-1 and the isomer-2 are calculated from the relative areas in the liquid phase pattern, and the structures of the isomer-1 and the isomer-2 are as follows:
Figure FDA0004064871720000032
wherein R is acetyl.
36. The use of claim 35, wherein isomer-2 is not more than 0.05%.
37. A preparation method of englitjing comprises the steps of carrying out reduction reaction on a compound of formula 1 in claim 1 to obtain a compound of formula 4, and carrying out deprotection reaction on the compound of formula 4 to obtain the compound of formula 4:
Figure FDA0004064871720000033
wherein,,
r is an acetyl group, and the R is an acetyl group,
in the compound of formula 4, the isomer-1 is not more than 3.5%, the isomer-2 is not more than 0.1%, the amounts of the isomer-1 and the isomer-2 are calculated from the relative areas in the liquid phase pattern, and the structures of the isomer-1 and the isomer-2 are as follows:
Figure FDA0004064871720000041
wherein R is acetyl; the reduction reaction is carried out under the action of Lewis acid and silane reagent, wherein the Lewis acid is boron trifluoride; the silane reagent is triethylsilane.
38. The method of claim 37, wherein isomer-2 is not more than 0.05%.
39. The production method according to claim 37, wherein in the reduction reaction, the reaction solvent is: one or more of acetonitrile, dichloromethane, chloroform and toluene.
40. The production process according to claim 37, wherein the reaction temperature in the reduction reaction is-20 to 0 ℃.
41. The process according to claim 40, wherein the reaction temperature in the reduction reaction is-10 to 0 ℃.
42. The process of claim 37, wherein the lewis acid is boron trifluoride; the silane reagent is triethylsilane; the molar ratio of the lewis acid to the silane reagent is 1:1.
43. The process of claim 37, wherein the molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 10.
44. The process of claim 43, wherein the molar ratio of the compound of formula 1 to the silane reagent is 1:1-5.
45. The process of claim 44, wherein the molar ratio of the compound of formula 1 to the silane reagent is from 1:1 to 3.
46. The method of claim 37, wherein the reduction is performed under nitrogen.
47. The process of claim 37, wherein the compound of formula 4 is recrystallized after the reduction reaction.
48. The process of claim 47, wherein after the reduction reaction, the compound of formula 4 is recrystallized from methanol.
49. The process according to claim 37, wherein the deprotection reaction comprises the following reaction solvents: tetrahydrofuran, methanol, ethanol, dichloromethane, acetonitrile or N, N-dimethylformamide.
50. The process of claim 37, wherein the deprotecting is carried out in the presence of a base.
51. The process of claim 50, wherein the base is selected from sodium methoxide, sodium hydroxide, potassium hydroxide or sodium tert-butoxide.
52. The process according to claim 37, wherein the deprotection reaction is carried out at a reaction temperature of 0 to 60 ℃.
53. The process according to claim 52, wherein the deprotection reaction is carried out at a reaction temperature of 20 to 40 ℃.
54. The process according to claim 50, wherein the molar ratio of the compound of formula 4 to the base in the deprotection reaction is 1:2 to 0.01.
55. The process according to claim 54, wherein the molar ratio of the compound of formula 4 to the base in the deprotection reaction is 1:1.5-0.1.
56. The method of claim 37, wherein the deprotecting is carried out under nitrogen.
57. The process according to claim 37, wherein the deprotection reaction is carried out directly after completion of the reduction reaction without any post-treatment.
58. The preparation method of claim 37, wherein the reduction reaction is carried out by adding triethylsilane into acetonitrile under nitrogen protection, adding boron trifluoride acetonitrile solution at-10 deg.C, and reacting at-5-0 deg.C.
59. The process according to claim 58, wherein the reduction reaction is completed by further post-treatment as follows: adding saturated sodium bicarbonate solution dropwise to adjust pH to 6.5-7.0, separating, extracting water phase with ethyl acetate, washing the extractive solution with water and saturated saline water, drying, and concentrating to obtain compound of formula 4.
60. The process of claim 59, wherein the compound of formula 4 is further recrystallized from methanol after concentration.
61. The process for preparing the compound of claim 37, wherein the deprotection reaction comprises adding sodium methoxide into a mixed solvent of tetrahydrofuran-methanol at-5 ℃, reacting at 20-30 ℃ until the reaction is finished, and concentrating to obtain crude product of enggliflozin.
62. The process according to claim 61, wherein the volume ratio of tetrahydrofuran-methanol in the mixed solvent is 1:1.
63. The process of claim 61 wherein the crude englitant obtained in the deprotection reaction is further purified by recrystallization.
64. The process of claim 63 wherein in the deprotection reaction, the crude product of englitjing is slurried with isopropyl acetate-water.
65. The use of a compound of formula 1 according to claim 1 for the preparation of englitjing,
Figure FDA0004064871720000051
wherein R is acetyl.
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