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CN108794548A - Prepare that En Gelie is net and its method of intermediate - Google Patents

Prepare that En Gelie is net and its method of intermediate Download PDF

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Publication number
CN108794548A
CN108794548A CN201710294478.3A CN201710294478A CN108794548A CN 108794548 A CN108794548 A CN 108794548A CN 201710294478 A CN201710294478 A CN 201710294478A CN 108794548 A CN108794548 A CN 108794548A
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formula
compound
isomer
reaction
protecting group
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CN108794548B (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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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

The present invention relates to preparing, En Gelie is net and its method of intermediate.The invention further relates to the freshly prepared intermediates that En Gelie is net.Method used in the present invention and new intermediate can effectively control the impurity of reaction, wherein the control for isomer impurities is especially prominent, finally by convenient for the quality control of the net production of raw medicine of En Gelie, also be provided a convenient to the research of follow-up preparation.

Description

Process for the preparation of empagliflozin and intermediates thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing engelizin and an intermediate thereof. The invention also relates to a novel preparation intermediate of the empagliflozin.
Background
Empagliflozin (empagliflozin) was developed cooperatively by blinger hagghen and ritten, is a sodium-glucose cotransporter (SGLT2) inhibitor, and is useful in the treatment of type 2 diabetes. It is currently marketed in several countries such as the United states, Europe, Japan, etc.
Engagliflozin can also be used in combination with other antidiabetic drugs, for example with linagliptin or with metformin.
The structure of engagliflozin is as follows:
the recent clinical trial data of EMPA-REG OUTCOME show that Jardiance (Engelliflozin) + Standard Care significantly reduces the cardiovascular risk of patients in type 2 diabetes adult patients with high-risk Cardiovascular (CV) events compared to placebo + Standard Care.
For the synthesis of engliptin, there are several reports including WO2006120208, WO2011039108, WO2013068850, WO2014206299, WO2015101916, WO2015155739, and the like.
However, there is still a need to develop a preparation method of engagliflozin which is more suitable for industrialization and easier for quality control, so as to meet the expanding production requirements of raw material medicines and preparations of engagliflozin. Especially, the control of isomer impurities is more beneficial to the subsequent further reaching of the medical standard of the empagliflozin.
Disclosure of Invention
In one aspect, the invention provides a compound of formula 1,
wherein R is a hydroxyl protecting group.
In some embodiments of the invention, R is acetyl.
The present invention also provides a process for preparing the compound of formula 1 above, comprising the steps of:
step (1): reacting the compound of formula 2 with sec-butyl magnesium chloride lithium chloride;
step (2): reacting the product obtained in the step (1) with a compound shown in a formula 3 to obtain the compound;
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 present 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 than two of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether or cyclohexane.
In some embodiments of the present invention, in step (1), the reaction temperature is-20 to 0 ℃, preferably-10 to-5 ℃.
In some embodiments of the invention, in step (1), the molar ratio of the compound of formula 2 to the secondary butyl magnesium chloride lithium chloride is 1:1 to 2, preferably 1:1 to 1.5.
In some embodiments of the invention, step (1) is preferably carried out under nitrogen.
In some embodiments of the invention, in step (2), the reaction solvent is: one or more than two of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, diethyl ether, methyl tert-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 present invention, in step (2), the molar ratio of the compound of formula 2 to the compound of formula 3 is 1:1 to 3, preferably 1:1 to 2.
In some embodiments of the invention, step (2) is preferably carried out under nitrogen.
In some embodiments of the invention, the reaction of step (1) is carried out directly without work-up to the end of the reaction of step (2).
In some embodiments of the invention, step (1): under the protection of nitrogen, dropwise adding a sec-butyl magnesium chloride lithium chloride solution into the compound of the formula 2 in toluene, and reacting at-10 to-5 ℃ until the reaction is finished; step (2): and (3) under the protection of nitrogen, adding tetrahydrofuran into the toluene solution of the compound shown in the formula 3, cooling to-50 ℃, dropwise adding the reaction liquid obtained in the step (1), and reacting at-45 to-50 ℃ until the reaction is finished. In some embodiments of the present invention, after the two-step reaction is completed, the following post-treatment may be further performed: dropping mixed solution of acetic acid and water into the reaction solution at the temperature below minus 45 ℃, heating to room temperature after dropping, separating, washing the organic phase with water, drying, filtering and concentrating.
In another aspect, the present invention provides a compound of formula 4 having isomer-1 of no more than 3.5% and isomer-2 of no more than 0.1%,
wherein R is a hydroxyl protecting group, and the amounts of the isomer-1 and the isomer-2 are calculated by relative areas in a liquid phase map.
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 shown in the formula 4, which comprises the following steps that the compound shown in the formula 1 is obtained through reduction reaction:
wherein R is a hydroxyl protecting group.
In some embodiments of the invention, R is acetyl.
In some embodiments of the present invention, the compound of formula 4 obtained by the above preparation method contains isomer-1 in an amount of not more than 3.5%, the amount of said isomer-1 being calculated from the relative area in the liquid phase diagram.
In some embodiments of the present invention, the compound of formula 4 obtained by the above preparation method contains isomer-2 in an amount of not more than 0.1% or 0.05%, the amount of said isomer-2 being calculated from the relative area in the liquid phase diagram.
In some embodiments of the present 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 or toluene.
In some embodiments of the present invention, the reaction temperature in the reduction reaction is-20 to 0 ℃, preferably-10 to 0 ℃.
In some embodiments of the invention, the reduction is preferably carried out with 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 1: 1-10, preferably 1: 1-5, and most preferably 1: 1-3.
In some embodiments of the present invention, the reduction reaction is preferably performed under nitrogen protection.
In some embodiments of the invention, under the protection of nitrogen, the compound of formula 1 is added with triethylsilane at-10 ℃ in acetonitrile, then boron trifluoride acetonitrile solution is added dropwise, and the reaction is completed at-5-0 ℃ after the dropwise addition. In some embodiments of the present invention, the following post-treatment may also be performed after the reaction is completed: and dropwise adding a saturated sodium bicarbonate solution to adjust the pH value to 6.5-7.0, separating liquid, extracting a water phase by using ethyl acetate, washing an extract by using water and saturated saline solution, drying and concentrating to obtain the compound shown in the formula 4. In some embodiments of the present invention, the compound of formula 4 may also be prepared by recrystallization from methanol after concentration.
The present invention also provides the use of a compound of formula 1 for the preparation of a compound of formula 4, wherein in the compound of formula 4, isomer-1 is not more than 3.5% and isomer-2 is not more than 0.1%, and the amounts of isomer-1 and isomer-2 are calculated from the relative areas in the liquid phase diagram, preferably, isomer-2 is not more than 0.05%.
In another aspect, the invention also provides a preparation method of the empagliflozin, which comprises the steps that the compound shown in the formula 1 is subjected to reduction reaction to obtain a compound shown in the formula 4, and the compound shown in the formula 4 is subjected to deprotection reaction to obtain the empagliflozin.
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 or toluene.
In some embodiments of the present invention, the reaction temperature in the reduction reaction is-20 to 0 ℃, preferably-10 to 0 ℃.
In some embodiments of the invention, the reduction is preferably carried out with 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 1: 1-10, preferably 1: 1-5, and most preferably 1: 1-3.
In some embodiments of the present invention, the reduction reaction is preferably performed under nitrogen protection.
In some embodiments of the invention, the reduction reaction results in a compound of formula 4 in which isomer-1 is not more than 3.5%, isomer-2 is not more than 0.1%, or 0.05%, and the amounts of isomer-1 and isomer-2 are calculated from the relative areas in the liquid phase spectrum.
In some embodiments of the invention, after the reduction reaction, the compound of formula 4 may be recrystallized, for example, using alcoholic solvents including methanol.
In some embodiments of the present invention, in the deprotection reaction, the reaction solvent is: one or more than two of tetrahydrofuran, methanol, ethanol, dichloromethane, acetonitrile or N, N-dimethylformamide.
In some embodiments of the invention, the deprotection reaction is carried out 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 present invention, in the deprotection reaction, the reaction temperature 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 present invention, the deprotection reaction is preferably performed under nitrogen protection.
In some embodiments of the invention, the deprotection reaction may be performed directly without post-treatment at the end of the reduction reaction.
In the specific embodiment of the reduction reaction, under the protection of nitrogen, the compound of the formula 1 is added into acetonitrile, triethylsilane is added at the temperature of minus 10 ℃, then boron trifluoride acetonitrile solution is dropwise added, and the reaction is completed at the temperature of minus 5-0 ℃ after the dropwise addition. In the embodiment of the reduction reaction of the present invention, the following post-treatment may be further performed after the reaction is completed: and dropwise adding a saturated sodium bicarbonate solution to adjust the pH value to 6.5-7.0, separating liquid, extracting a water phase by using ethyl acetate, washing an extraction liquid by using water and saturated saline solution respectively, drying and concentrating to obtain the compound shown in the formula 4. In the reduction reaction embodiment of the present invention, the compound of formula 4 can be obtained by recrystallization from methanol after concentration.
In the specific embodiment of the deprotection reaction, the compound shown in 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 a crude product of empagliflozin is obtained by concentration. In the specific embodiment of the deprotection reaction of the invention, the crude empagliflozin can be further recrystallized and purified. In a particular embodiment of the deprotection reaction of the present invention, the empagliflozin is slurried with isopropyl acetate-water.
The invention also provides the use of a compound of formula 1 for the preparation of empagliflozin.
The invention has the following advantages:
1. when the compound of the formula 1 is prepared and the compound of the formula 4 is further prepared, or the compound is further used for preparing the engagliflozin, impurities of the reaction can be effectively controlled, wherein the control on isomer impurities is particularly prominent, the quality control of the production of the raw material drug of the engagliflozin is facilitated, and the research on subsequent preparations is also facilitated.
2. Deprotection of the compound of formula 4 to give engletin, use of sodium methoxide, may further reduce the generation of impurities and may also avoid the use of water.
3. The reaction conditions such as the reaction reagents and the reaction temperature are relatively mild, and the temperature rise time can be greatly shortened, which is very important for industrial production. Shortening the temperature rise time can further reduce the generation of impurities.
Detailed Description
The following examples further illustrate the technical solution of the present invention in non-limiting detail. They should not be considered as limiting the scope of the invention but merely as being exemplary illustrations and representative of the invention. 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 a Compound of formula 1(R is acetyl)
Step 1:
adding 916g of acetic anhydride and 126g of trifluoroacetic acid into a three-neck flask, uniformly stirring, adding 200g of gluconolactone, slowly heating to 80 ℃, reacting for 4h, monitoring by TLC until the reaction is finished, transferring the reaction liquid into a 2L single-neck flask, performing reduced pressure evaporation at 80 ℃ until no obvious liquid flows out, adding 250ml of toluene, performing reduced pressure evaporation at 80 ℃ until no obvious liquid flows out, repeating the operation for 3 times, performing reduced pressure evaporation at 80 ℃ by an oil pump until no obvious liquid flows out, adding 400ml of toluene, uniformly stirring, and standing for later use to obtain a toluene solution of 2,3,4, 6-tetra-O-acetyl- β -D-gluconolactone.
Step 2:
to a three-necked flask, 26.73g of magnesium chips, 42.39g of lithium chloride and 500ml of tetrahydrofuran were charged, and nitrogen gas was replaced three times. Controlling the temperature to be 0-5 ℃, dropwise adding a mixed solution of chlorosec-butyl alkane and 500ml of tetrahydrofuran, and adding 2ml of iodomethane as an initiator after 50ml of the mixed solution is dropwise added. And then continuing to dropwise add the mixed solution of chlorosec-butyl alkane and tetrahydrofuran, and stirring for 4 hours at 20-25 ℃ after the dropwise addition is finished. Obtaining a sec-butyl magnesium chloride lithium chloride tetrahydrofuran solution (1M) for later use.
And step 3:
adding 1-chloro-4-iodo-2- [4- ((S) -tetrahydrofuran-3-yloxy) -benzyl ] -benzene (80g, 192.9mmol) and toluene (144ml) to a reaction flask, stirring to dissolve, and cooling to-10 ℃ under nitrogen protection; controlling the temperature to be minus 10 to minus 5 ℃, and dropwise adding secondary butyl magnesium chloride and lithium chloride (289.4 mmol); after finishing dropping, controlling the temperature to be minus 10 to minus 5 ℃ and reacting for more than 1 hour; adding a toluene solution (385.8mmol) of the product obtained in the step 1 and tetrahydrofuran (97ml) into a reaction bottle, and reducing the temperature to-50 ℃ under the protection of nitrogen; controlling the temperature to be below 45 ℃ below zero, and dropwise adding the reaction solution in the step 2; after the dripping is finished, the temperature is controlled to be minus 45 ℃ to minus 50 ℃ for reaction for 1 hour. And after the reaction is finished, controlling the temperature to be below 45 ℃ below zero, dropwise adding a mixed solution of acetic acid and water, raising the temperature to room temperature after dropwise adding, separating, washing an upper organic phase for 2 times by using water, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound (R is acetyl) of the formula 1.
The relative area of the compound of formula 1 was 74.36% by LC/MS analysis.
EXAMPLE 2 preparation of Empagliflozin
Step 1: preparation of the Compound of formula 4 (R is acetyl)
Adding the compound of the formula 1(R is acetyl) (184.5mmol) prepared in example 1 and acetonitrile (500ml) into a reaction bottle, and reducing to-10 ℃ under the protection of nitrogen; adding triethylsilane (64.39g, 553.7mmol), and stirring for more than 10 min; slowly dripping boron trifluoride acetonitrile solution (18 percent, 204.48g) at the temperature of minus 10 to minus 5 ℃, and reacting for about 1 hour at the temperature of minus 5 to 0 ℃ after dripping; after the reaction is finished, dropwise adding a saturated sodium bicarbonate solution to adjust the pH value to 6.5-7.0; separating, extracting the water phase with ethyl acetate for 2 times; the combined organic phases are washed by water and saturated saline solution for 1 time respectively, and dried by anhydrous sodium sulfate; concentrating under reduced pressure to dryness to obtain the compound of formula 4 (R is acetyl).
According to LC-MS analysis, the relative area of the compound in the formula 4 is 69.7%, and the relative area of the isomer-1 is 3.46%; the relative area of isomer-2 was 0.04%.
The detection conditions were as follows:
a chromatographic column: waters CORTECS C18 (4.6X 100mm, 2.7 μm)
Flow rate: 1.0ml/min, wavelength: 225nm, column temperature: 45 ℃, injection volume: 10 μ l
Mobile phase A: 0.1% formic acid solution
Mobile phase B: acetonitrile
Gradient elution was performed as follows:
when the hydroxyl group in the compound of formula 1(R is hydrogen, relative area is 85%) is replaced with a methoxy group, the reduction is carried out using the same method as described above to give a compound of formula 4 in which the isomer-1 (R is hydrogen) is produced with a relative area of 8%.
Step 2:
and (3) under the protection of nitrogen, recrystallizing the compound of the formula 4 (R is acetyl) obtained in the step 1 twice by using methanol. Wherein the relative area of the compound of formula 4 is 97.54%.
Mixing the purified compound of formula 4 (R is acetyl) (10g, 161mmol) and THF-methanol (1:1) to reduce the temperature to-5 deg.C; sodium methoxide (16.1mmol) was added portionwise; and (3) adding sodium methoxide completely, raising the temperature to 20-30 ℃, stirring and reacting for more than 1h, and evaporating the organic solvent under reduced pressure to obtain the crude product of the engelizin (the relative area is 98.3%).
The pure engelet is obtained by pulping the crude engelet product through isopropyl acetate-water, and the relative area of the engelet is 99.55 percent by LC-MS analysis.

Claims (8)

1. A compound of the formula 1,
wherein R is a hydroxyl protecting group, preferably acetyl.
2. A process for the preparation of a compound of formula 1 as claimed in claim 1, comprising the steps of:
step (1): reacting the compound of formula 2 with sec-butyl magnesium chloride lithium chloride;
step (2): reacting the product obtained in the step (1) with a compound shown in a formula 3 to obtain the compound;
wherein,
x is halogen, preferably I or Br;
r is a hydroxyl protecting group, preferably acetyl.
3. A compound of formula 4 having isomer-1 of not more than 3.5% and isomer-2 of not more than 0.1%,
wherein,
r is a hydroxyl protecting group, preferably acetyl,
the amounts of isomer-1 and isomer-2 were calculated from the relative areas in the liquid phase spectrum.
4. The compound of formula 4 according to claim 3, wherein isomer-2 is not more than 0.05%.
5. A process for preparing a compound of formula 4 according to claim 3 or 4, comprising reducing a compound of formula 1 to obtain:
wherein R is a hydroxyl protecting group, preferably acetyl.
6. Use of a compound of formula 1 according to claim 1 for the preparation of a compound of formula 4,
wherein,
r is a hydroxyl protecting group, preferably acetyl,
in the compound of the formula 4, the isomer-1 is not more than 3.5%, the isomer-2 is not more than 0.1%, and the amounts of the isomer-1 and the isomer-2 are calculated from the relative areas in the liquid phase diagram, and preferably, the isomer-2 is not more than 0.05%.
7. A preparation method of the empagliflozin comprises the steps that a compound shown in a formula 1 is subjected to reduction reaction to obtain a compound shown in a formula 4, and the compound shown in the formula 4 is subjected to deprotection reaction to obtain:
wherein,
r is a hydroxyl protecting group, preferably acetyl,
in the compound of the formula 4, the isomer-1 is not more than 3.5%, the isomer-2 is not more than 0.1%, and the amounts of the isomer-1 and the isomer-2 are calculated from the relative areas in the liquid phase diagram, and preferably, the isomer-2 is not more than 0.05%.
8. Use of a compound of formula 1 for the preparation of empagliflozin,
wherein R is a hydroxyl protecting group, preferably acetyl.
CN201710294478.3A 2017-04-28 2017-04-28 Process for preparing enggliflozin and intermediates thereof Active CN108794548B (en)

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Publication number Priority date Publication date Assignee Title
CN110698467A (en) * 2019-10-31 2020-01-17 黄冈鲁班药业股份有限公司 Synthetic method of engagliflozin
CN110698467B (en) * 2019-10-31 2023-05-23 黄冈鲁班药业股份有限公司 Synthesis method of englitjing
CN116063294A (en) * 2022-12-13 2023-05-05 山东能源集团新材料有限公司 A kind of preparation method and process system of empagliflozin bulk drug

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