CN114478454A - SGLT2 inhibitor key intermediate and preparation method thereof - Google Patents

SGLT2 inhibitor key intermediate and preparation method thereof Download PDF

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CN114478454A
CN114478454A CN202011305941.8A CN202011305941A CN114478454A CN 114478454 A CN114478454 A CN 114478454A CN 202011305941 A CN202011305941 A CN 202011305941A CN 114478454 A CN114478454 A CN 114478454A
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compound
reaction
independently selected
concentrated
ethyl acetate
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陈剑
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Nanjing Huaguan Biotechnology Co ltd
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    • 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
    • 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
    • C07D407/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages

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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention discloses a key intermediate of an SGLT2 inhibitor and a preparation method thereof. Specifically, the invention relates to a derivative shown in a general formula (I) and a preparation method thereof. Wherein various substituents in the general formula (I) are the same as the definitions in the specification. The compound has obvious process and cost advantages for the synthesis of a series of SGLT2 inhibitors.

Description

SGLT2 inhibitor key intermediate and preparation method thereof
Technical Field
The present invention relates to intermediates useful in the preparation of SGLT2 inhibitors and to processes for their preparation.
Background
Diabetes belongs to chronic metabolic diseases, and is increased year by year in China, and the diabetes patients who are the first to live in the world at present. In the current main treatment mode, the purpose of controlling blood sugar is achieved by inhibiting the cotransporter 2 (SGLT2) of the proximal tubule to lower the blood sugar. Currently, a number of SGLT2 inhibitors are marketed globally as follows.
Figure BSA0000225300630000011
As can be seen from the above formula, the SGLT2 inhibitor is currently divided into three major portions from a structural point of view, a leftmost sugar ring portion, a middle aromatic heterocyclic portion, and a rightmost aromatic ring portion. The formula is shown as follows.
Figure BSA0000225300630000012
From literature research, it is known that the main synthetic process route of the above drugs is to construct an aromatic ring first and then to dock the aromatic ring with a sugar ring fragment to obtain a main structure, and the typical route is as follows.
Figure BSA0000225300630000021
The main problem of the current route is the high cost of the heterocyclic moiety in the partial structure, and the cost of the route is increased by introducing the expensive fragment earlier, based on which we developed the corresponding route and finally introduced the right aromatic ring fragment to try to reduce the cost of the process route, typical route is as follows.
Figure BSA0000225300630000022
From the above routes, the new route designed by the patent preferentially constructs a sugar ring and a middle aromatic ring system, and then completes the construction of the rightmost aromatic ring with higher cost through the Barluenga reaction, thereby reducing the material cost to the maximum extent.
Meanwhile, the method finds that a series of molecules in the SGLT2 inhibitor can be synthesized in a convergent manner through the route, and multiple APIs share one intermediate (a compound 13 in the formula), so that the cost after subsequent industrial amplification is further reduced, and the synthesis efficiency is improved.
Disclosure of Invention
Based on the problem of higher cost in the current process of SGLT2 inhibitors, we developed a less costly and more convergent and efficient process route. Among them, the key intermediate (formula I) is not reported in the literature. Therefore, we have studied the preparation process thereof and the process for synthesizing API.
That is, the present invention is the invention described below.
1. Compounds according to formula (I) and possible salts thereof.
Figure BSA0000225300630000031
Wherein:
r1 is independently selected from trimethylsilyl, acetyl, benzoyl, benzyl, and hydrogen atoms.
R2 is independently selected from halogen fluorine, chlorine, methyl and hydrogen atoms.
R3 is independently selected from methyl, ethyl, isopropyl, trifluoromethyl and hydrogen atom
2. The compounds in the general formula (I) are used for synthesizing a series of SGLT2 inhibitors. The chemical formula is as follows:
Figure BSA0000225300630000032
wherein:
r4 is independently selected from the group consisting of p-ethoxy benzene ring, benzothiophene ring and p-3-tetrahydrofuryloxy benzene ring.
3. The reaction conditions of claim 2 are heating in an organic solvent under the condition of alkali to obtain the compound represented by the general formula (III).
Wherein:
the base is independently selected from potassium carbonate, potassium phosphate, sodium carbonate and potassium hydroxide, with potassium carbonate being preferred.
The organic solvent is independently selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran and toluene, wherein dioxane is preferred.
Detailed Description
The following examples and preparation examples illustrate the present invention, but the present invention is not limited thereto.
The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.
Typical route a:
Figure BSA0000225300630000041
example 1:
Figure BSA0000225300630000042
adding the compound 08 into a mixed solvent of tetrahydrofuran and toluene, and cooling the system to-78 ℃. Butyl lithium (2.5M) was then added dropwise, and the reaction was incubated for 30 minutes after the addition. And slowly dropwise adding the tetrahydrofuran solution of the compound 07 into the reaction system, and maintaining the reaction temperature not higher than-75 ℃ in the dropwise adding process. The system was stirred for 2 hours with heat preservation. The reaction was then quenched with saturated aqueous ammonium chloride, the aqueous phase extracted with ethyl acetate, the organic phases combined, dried over sodium sulfate and concentrated to give compound 09. Compound 09 was directly subjected to the subsequent reaction without purification.
Example 2:
Figure BSA0000225300630000051
compound 09 was dissolved in dichloromethane solvent and the system was then cooled to-78 ℃. And dropwise adding a mixed solution of boron trifluoride diethyl etherate and triethylsilylhydride into the system, and maintaining the temperature not higher than-70 ℃ in the dropwise adding process. Subsequently, the system was slowly warmed to 0 ℃ and stirred for 1 hour. The reaction was quenched by adding aqueous sodium hydroxide, the mixture was stirred at room temperature for 30 minutes, then concentrated hydrochloric acid was added to adjust the pH to acidity, the organic phase was extracted with ethyl acetate, and the residue was purified with silica gel column (elution system: DCM: MeOH 50: 1) to give compound 10.
Example 3:
Figure BSA0000225300630000052
compound 10 was dissolved in dichloromethane solution followed by addition of oxalyl chloride and catalytic amount of DMF. The system was stirred at room temperature for 3 hours. After subsequent concentration to remove excess oxalyl chloride, chloroform was added to redissolve. The system was cooled to 0 ℃ and triethylamine and N, O-dimethylhydroxylamine hydrochloride were added. The system was stirred at room temperature overnight and then quenched by addition of dilute hydrochloric acid. The organic phases were collected, concentrated and the residue was purified using a silica gel column (eluent: petroleum ether: ethyl acetate 2: 1) to give compound 11.
Example 4:
Figure BSA0000225300630000061
compound 11 was dissolved in tetrahydrofuran as a solvent, and then the system was cooled to-78 ℃ and then DABAL-H (1.0M toluene solution) was added dropwise to the reaction system, and the system was allowed to react for 3 hours while maintaining the temperature. Subsequently, the reaction was quenched by adding saturated ammonium chloride, the reaction system was extracted with ethyl acetate, the organic phase was collected and concentrated, and the residue was purified with a silica gel column (elution system: petroleum ether: ethyl acetate: 5: 1) to obtain compound 12.
Example 5:
Figure BSA0000225300630000062
adding the compound 12 into dioxane, then adding p-toluenesulfonyl hydrazide, adding the system to 80 ℃ to react for 3 hours, then cooling the system to room temperature, filtering, concentrating the filtrate, and purifying the residue by column chromatography (elution system: petroleum ether: ethyl acetate: 3: 1) to obtain a compound 13.
Example 6:
Figure BSA0000225300630000063
compound 13 was added to dioxane, followed by the addition of boronic acid fragments and potassium carbonate. The system was heated to 110 ℃ for 16 hours. Then the system was cooled, and dichloromethane and aqueous sodium bicarbonate solution were added for liquid separation. The organic phase was collected, concentrated and the residue was purified using column chromatography to give compound 14.
Example 7:
Figure BSA0000225300630000071
compound 12 was added to the dioxane solution followed by p-toluenesulfonyl hydrazide. The system was heated to 80 ℃ for 2 hours. Subsequently, a boronic acid fragment and potassium carbonate were added, and the reaction was continued to warm to 110 ℃ for 16 hours. After the reaction, the system was cooled to room temperature, and dichloromethane and aqueous sodium bicarbonate solution were added for liquid separation. The organic phase was collected, concentrated and the residue was purified using column chromatography to give compound 14.
Example 8:
Figure BSA0000225300630000072
compound 14 was added to the ethanol solution, followed by Pd/C (10%), and the system was purged three times with nitrogen, followed by purging three times with hydrogen. The system was then reacted at room temperature for 20 hours under a hydrogen atmosphere of 2 atmospheres. Subsequently, the system was filtered to remove the catalyst and concentrated to give compound 15.
Typical route B:
Figure BSA0000225300630000073
example 9:
Figure BSA0000225300630000081
adding the compound 16 into a mixed solvent of tetrahydrofuran and toluene, and cooling the system to-80 ℃. Butyl lithium (2.5M) was then added dropwise, and the reaction was incubated for 30 minutes after the addition. And slowly dropwise adding the tetrahydrofuran solution of the compound 07 into the reaction system, and maintaining the reaction temperature not higher than-78 ℃ in the dropwise adding process. The system was stirred for 2 hours with heat preservation. Then, the reaction was quenched with saturated aqueous ammonium chloride solution, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over sodium sulfate, and concentrated to give compound 17. Compound 17 was directly subjected to the subsequent reaction without purification.
Example 10:
Figure BSA0000225300630000082
compound 17 was dissolved in dichloromethane solvent and the system was then cooled to-78 ℃. And dropwise adding a mixed solution of boron trifluoride diethyl etherate and triethylsilylhydride into the system, and maintaining the temperature not higher than-70 ℃ in the dropwise adding process. Subsequently, the system was slowly warmed to 0 ℃ and stirred for 1 hour. The reaction was quenched by adding an aqueous solution of sodium hydroxide, the mixture was stirred at room temperature for 30 minutes, then concentrated hydrochloric acid was added to adjust the pH to acidity, ethyl acetate was extracted, the organic phase was collected and concentrated, and the residue was purified with a silica gel column (elution system: petroleum ether: ethyl acetate: 5: 1) to obtain compound 18.
Example 11:
Figure BSA0000225300630000091
dissolving the compound 18 in a solvent dichloromethane, then cooling the system to 0 ℃, adding a Dess-Martin reagent into the system, and then slowly warming the system to room temperature. The system was stirred at room temperature for 2 hours, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified with a silica gel column (elution system: petroleum ether: ethyl acetate 5: 1) to give compound 12.
Example 12:
Figure BSA0000225300630000092
adding the compound 12 into dioxane, then adding p-toluenesulfonylhydrazide, adding the system to 80 ℃ to react for 3 hours, then cooling the system to room temperature, filtering, concentrating the filtrate, and purifying the residue by column chromatography (elution system: petroleum ether: ethyl acetate: 3: 1) to obtain a compound 13.
Typical route C:
Figure BSA0000225300630000093
example 13:
Figure BSA0000225300630000101
adding the compound 19 into a mixed solvent of tetrahydrofuran and toluene, and cooling the system to-80 ℃. Butyl lithium (2.5M) was then added dropwise and the reaction incubated for 30 minutes after the addition. And slowly dropwise adding the tetrahydrofuran solution of the compound 07 into the reaction system, and maintaining the reaction temperature not higher than-78 ℃ in the dropwise adding process. The system was stirred for 2 hours with heat preservation. The reaction was then quenched with saturated aqueous ammonium chloride, the aqueous phase extracted with ethyl acetate, the organic phases combined, dried over sodium sulfate and concentrated to give compound 20. Compound 20 was directly subjected to the subsequent reaction without purification.
Example 14:
Figure BSA0000225300630000102
compound 20 was dissolved in dichloromethane solvent and the system was then cooled to-78 ℃. And dropwise adding a mixed solution of boron trifluoride diethyl etherate and triethylsilylhydride into the system, and maintaining the temperature not higher than-70 ℃ in the dropwise adding process. Subsequently, the system was slowly warmed to 0 ℃ and stirred for 1 hour. The reaction was quenched by adding an aqueous solution of sodium hydroxide, the mixture was stirred at room temperature for 30 minutes, then concentrated hydrochloric acid was added to adjust the pH to acidity, ethyl acetate was extracted, the organic phase was collected and concentrated, and the residue was purified with a silica gel column (elution system: petroleum ether: ethyl acetate: 5: 1) to obtain compound 12.
Example 15:
Figure BSA0000225300630000103
adding the compound 12 into dioxane, then adding p-toluenesulfonyl hydrazide, adding the system to 80 ℃ to react for 3 hours, then cooling the system to room temperature, filtering, concentrating the filtrate, and purifying the residue by column chromatography (elution system: petroleum ether: ethyl acetate: 3: 1) to obtain a compound 13.
Typical route D:
Figure BSA0000225300630000111
example 16:
Figure BSA0000225300630000112
adding the compound 21 into a mixed solvent of tetrahydrofuran and toluene, and cooling the system to-80 ℃. Butyl lithium (2.5M) was then added dropwise, and the reaction was incubated for 30 minutes after the addition. And slowly dropwise adding the tetrahydrofuran solution of the compound 07 into the reaction system, and maintaining the reaction temperature not higher than-78 ℃ in the dropwise adding process. The system was stirred for 2 hours with heat preservation. The reaction was then quenched with saturated aqueous ammonium chloride, the aqueous phase extracted with ethyl acetate, the organic phases combined, dried over sodium sulfate, and concentrated to give compound 22. Compound 22 was directly subjected to the subsequent reaction without purification.
Example 17:
Figure BSA0000225300630000121
compound 22 was dissolved in tetrahydrofuran as a solvent, and then the system was cooled to-78 ℃ and then DABAL-H (1.0M in toluene) was added dropwise to the reaction system, and the system was allowed to react for 3 hours while maintaining the temperature. Subsequently, the reaction was quenched by adding saturated ammonium chloride, the reaction system was extracted with ethyl acetate, the organic phase was collected and concentrated, and the residue was purified with a silica gel column (elution system: petroleum ether: ethyl acetate: 5: 1) to obtain compound 12.
Example 18:
Figure BSA0000225300630000122
adding the compound 12 into dioxane, then adding p-toluenesulfonyl hydrazide, adding the system to 80 ℃ to react for 3 hours, then cooling the system to room temperature, filtering, concentrating the filtrate, and purifying the residue by column chromatography (elution system: petroleum ether: ethyl acetate: 3: 1) to obtain a compound 13.
Typical route E:
Figure BSA0000225300630000131
example 19:
Figure BSA0000225300630000132
dissolving the compound 01 in tetrahydrofuran solvent, adding N-methylmorpholine and cooling the reaction system to-5 ℃. Trimethylchlorosilane was added dropwise to the reaction system, and then the system was slowly warmed to room temperature, and stirring was continued for 16 hours. And then adding a toluene solution into the system, cooling to 5 ℃, slowly adding water for quenching, collecting an organic phase, and adding a sodium dihydrogen phosphate aqueous solution into the organic phase for washing. The organic phase was collected. The organic phase was concentrated to give crude compound 02. The crude product was used in the next step without purification.
Example 20:
Figure BSA0000225300630000133
adding the compound 23 into a mixed solvent of tetrahydrofuran and toluene, and cooling the system to-80 ℃. Butyl lithium (2.5M) was then added dropwise, and the reaction was incubated for 30 minutes after the addition. And slowly dropwise adding the tetrahydrofuran solution of the compound 02 into the reaction system, and maintaining the reaction temperature not higher than-78 ℃ in the dropwise adding process. The system was stirred for 2 hours with heat preservation. The reaction was then quenched with purified aqueous solution, the aqueous phase extracted with isopropyl acetate, the organic phases combined, dried over sodium sulfate, and concentrated to give compound 24. Compound 24 was directly subjected to the subsequent reaction without purification.
Example 21:
Figure BSA0000225300630000141
compound 24 was dissolved in dichloromethane solvent and the system was then cooled to-78 ℃. And dropwise adding a mixed solution of boron trifluoride diethyl etherate and triethylsilylhydride into the system, and maintaining the temperature not higher than-70 ℃ in the dropwise adding process. Subsequently, the system was slowly warmed to 0 ℃ and stirred for 1 hour. The reaction was quenched by adding an aqueous solution of sodium hydroxide, the mixture was stirred at room temperature for 30 minutes, then concentrated hydrochloric acid was added to adjust the pH to acidity, ethyl acetate was extracted, the organic phase was collected and concentrated, and the residue was purified with a silica gel column (elution system: dichloromethane: methanol 5: 1) to obtain compound 25.
Example 22:
Figure BSA0000225300630000142
compound 25 is added to a solution of dichloromethane followed by the addition of activated manganese dioxide. The system was stirred at room temperature for 8 hours. The system was then filtered and the filtrate was collected and concentrated to give crude compound 26. The crude product was directly subjected to the subsequent reaction without purification.
Example 23:
Figure BSA0000225300630000151
compound 26 was added to dioxane, followed by p-toluenesulfonylhydrazide, the system was added to 80 ℃ to react for 3 hours, the system was then cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (elution system: dichloromethane: methanol ═ 10: 1) to give compound 27.

Claims (3)

1. Compounds according to formula (I) and possible salts thereof.
Figure FSA0000225300620000011
Wherein:
r1 is independently selected from trimethylsilyl, acetyl, benzoyl, benzyl and a hydrogen atom.
R2 is independently selected from halogen fluorine, chlorine, methyl and hydrogen atoms.
R3 is independently selected from methyl, ethyl, isopropyl, trifluoromethyl and hydrogen atoms.
2. The compounds in the general formula (I) are used for synthesizing a series of SGLT2 inhibitors. The chemical formula is as follows:
Figure FSA0000225300620000012
wherein:
r4 is independently selected from the group consisting of p-ethoxy benzene ring, benzothiophene ring and p-3-tetrahydrofuryloxy benzene ring.
3. The reaction conditions of claim 2 are heating in an organic solvent under the condition of alkali to obtain the compound represented by the general formula (III).
Wherein:
the base is independently selected from potassium carbonate, potassium phosphate, sodium carbonate and potassium hydroxide, with potassium carbonate being preferred.
The organic solvent is independently selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran and toluene, wherein dioxane is preferred.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101384576A (en) * 2006-02-15 2009-03-11 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
CN105541816A (en) * 2016-01-20 2016-05-04 大连理工大学 Synthetic method of Ipragliflozin
CN105828815A (en) * 2013-12-17 2016-08-03 勃林格殷格翰动物保健有限公司 Treatment of metabolic disorders in feline animals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101384576A (en) * 2006-02-15 2009-03-11 贝林格尔.英格海姆国际有限公司 Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture
CN105828815A (en) * 2013-12-17 2016-08-03 勃林格殷格翰动物保健有限公司 Treatment of metabolic disorders in feline animals
CN105541816A (en) * 2016-01-20 2016-05-04 大连理工大学 Synthetic method of Ipragliflozin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOSE BARLUENGA，等: "Metal-free carbon–carbon bond-forming reductive coupling between boronic acids and tosylhydrazones", 《NATURE CHEMISTRY》 *
张鑫: "艾格列净和达格列净的合成", 《上海应用技术学院专业学位硕士学位论文》 *

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