CN108017612A - A kind of preparation method of canagliflozin intermediate - Google Patents
A kind of preparation method of canagliflozin intermediate Download PDFInfo
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- CN108017612A CN108017612A CN201711227452.3A CN201711227452A CN108017612A CN 108017612 A CN108017612 A CN 108017612A CN 201711227452 A CN201711227452 A CN 201711227452A CN 108017612 A CN108017612 A CN 108017612A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
The invention discloses a kind of preparation method of canagliflozin intermediate, using substituted phenyl-bromide as starting material, is prepared into boride with connection boric acid pinacol ester first, then be prepared through Suzuki coupling reactions, F-K reaction and reduction reaction.It is an advantage of the invention that：Intermediate product CZ 2 is prepared by Suzuki coupling reactions, mild condition, is easy to operate and control; product yield and purity are good, then introduce arylmethyl through F-K reaction, construct main chain; route high income, process conditions are easily controllable, are suitable for large-scale industrial production.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of preparation method of canagliflozin intermediate.
Background technology
Canagliflozin is ground by Mitsubishi Tanabe Pharma companies original, and Johson ＆ Johnson develops a kind of new
Antidiabetic medicine, listing is approved by the FDA in the United States on March 29th, 2013, is first and is approved listing for controlling by U.S. FDA
Treat the sodium glucose co-transporter 2 white 2 of diabetes B（SGLT2）Inhibitor；Canagliflozin intermediate is synthesis canagliflozin
Important intermediate, during canagliflozin intermediate is synthesized, generally use grignard is anti-when building 2- aryl thiophene fragments
It should be synthesized, be docked by substituting halogeno-benzene to be prepared into after Grignard Reagent with 2- bromothiophenes progress grignard, but since grignard is anti-
Carried out in requisition under the conditions of stringent anhydrous and oxygen-free, reaction need to can be smoothed out after initiation, and this greatly limits this
The application of method industrially.
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of preparation method of canagliflozin intermediate, to substitute bromine
Benzene is prepared for starting material, and mild condition, is easy to operate and control.
The technical solution adopted by the present invention is：
A kind of preparation method of canagliflozin intermediate, using substituted phenyl-bromide as starting material, first with connection boric acid pinacol ester system
It is standby to be prepared into boride, then through Suzuki coupling reactions, F-K reaction and reduction reaction.
Further, it is characterised in that comprise the following steps that：
A, the preparation of intermediate product CZ-1：Substituted phenyl-bromide under the action of metallic catalyst, reacts shape with connection boric acid pinacol ester
Into CZ-1；
B, the preparation of intermediate product CZ-2：CZ-1 carries out Suzuki couplings under the action of catalyst, with 2- bromothiophenes, obtains
CZ-2；
C, the preparation of intermediate product CZ-3：CZ-2 carries out friedel-crafts acylation under Louis acid catalysis, with substituted benzoic acid,
CZ-3 is prepared；
D, the preparation of purpose product CZ-M：CZ -3 is under the action of catalyst and reducing agent, and carbonyl is through reduction reaction to methylene
Base, is prepared CZ-M；
Wherein：The chemical formula of the CZ-1 is；
The chemical formula of the CZ-2 is；
The chemical formula of the CZ-3 is；
The chemical formula of the CZ-M is；
For、Or,
For、Or。
Further, the metallic catalyst described in step a is selected from palladium carbon, palladium chloride, tetra-triphenylphosphine palladium and double (two
Tert-butyl-phenyl phosphine) palladium chloride is preferably double (di-tert-butyl-phenyl phosphine) palladium chlorides, and the substituted phenyl-bromide is with joining boric acid
The molar ratio of pinacol ester is 1.0:1.5 ~ 2.0, the inventory of metallic catalyst is the 0. 5% of substituted phenyl-bromide quality.
Further, the catalyst described in step b is selected from palladium carbon, palladium chloride, tetra-triphenylphosphine palladium and double (two tertiary fourths
Base Phenylphosphine) palladium chloride is preferably tetra-triphenylphosphine palladium, and the molar ratio of the CZ-1 and 2- bromothiophenes is 1.0:
1.0 ~ 1.5, the dosage of catalyst is the 5% of CZ-1 mass.
Further, the lewis acid described in step c is selected from alchlor, zinc chloride and magnesium chloride, is preferably trichlorine
Change aluminium, and the molar ratio of CZ-2 and substituted benzoic acid is：1.0: 1.1~1.5.
Further, the catalyst in step d is aluminium chloride, and reducing agent is selected from sodium borohydride, potassium borohydride and boron
Lithium hydride, and the molar ratio of CZ-3 and catalyst is 1.0:The molar ratio of 2.0 ~ 3.0, CZ -3 and reducing agent is：
1.0: 2.0~3.0。
The beneficial effects of the invention are as follows：Intermediate product CZ-2 is prepared by Suzuki coupling reactions, mild condition, is easy to grasp
To make and control, product yield and purity are good, then introduce arylmethyl through F-K reaction, construct main chain, route high income,
Process conditions are easily controllable, are suitable for large-scale industrial production.
Embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, the embodiment
It is only used for explaining the present invention, does not restrict the protection scope of the present invention.
Embodiment 1
A, the preparation of intermediate product CZ-1：35g fluorobromobenzenes are added in reaction bulb（0.2mol, 1eq）, 76.3g connection boric acid frequencies
That alcohol ester（0.3mol, 1.5eq）, 56g potassium propionates（0.5mol, 2.5eq）, double (di-tert-butyl-phenyl phosphine) palladium chlorides of 0.18g
With 800mL isopropyl acetates, stirring and dissolving, then heats to reflux, insulation reaction, TLC monitoring reactions.Reaction finishes, cooling
To room temperature, it is concentrated under reduced pressure and removes isopropyl acetate, add 500mL dichloromethane and 300mL water, stir dissolved clarification, stands liquid separation, water
Layer dichloromethane（150mL×2）Extraction, merges organic phase, uses saturated sodium-chloride（300mL×1）Washing, anhydrous sodium sulfate are done
It is dry, filter, be concentrated under reduced pressure into dry, obtain crude product.Crude product is beaten with 200mL ethyl acetate and 100mL petroleum ether and stirrings, filtering, stone
Oily ether rinsing, it is dry, obtain 41.5g CZ-1 solid products, yield：93%；
B, the preparation of intermediate product CZ-2：41.5g CZ-1 are added in reaction bulb（0.19mol, 1eq）, 34.0g 2- bromothiophenes
（0.21mol, 1.1eq）, 52.4g potassium carbonate（0.38mol, 2.0eq）With 500mL dimethyl ether and 100mL water, stirring and dissolving, so
Tetra- triphenyl phosphorus palladiums of 2.1g are put into afterwards, and stirring, then heats to 70~75 DEG C, insulation reaction, TLC monitoring is reacted.Reaction finishes,
It is cooled to room temperature, adds 300mL isopropyl acetates and 200mL water, stirring, stands liquid separation, water layer isopropyl acetate（150mL
×2）Extraction, merges organic phase, uses saturated sodium-chloride（300mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure into
It is dry, obtain crude product.Crude product 250mL ether stirring to pulps, are filtered, dry, obtain 28.9g CZ-2 solid products, yield：87%；
C, the preparation of intermediate product CZ-3：The bromo- 2- methyl benzoic acids of 34.1g 5- are added in reaction bulb（0.16mol,
1.0eq）, 2.9g DMF and 300mL dichloromethane, stirring and dissolving, is cooled to 0~5 DEG C, and 38.1g thionyl chlorides are added dropwise
（0.32mol, 2.0eq）.Drop finishes, and is warming up to 30~35 DEG C of reactions, TLC monitoring reactions.Raw material reaction finishes, and is cooled to 0~5
DEG C, add 53.4g anhydrous Aluminum chlorides in three batches into reaction bulb（0.4mol, 2.5eq）.Finish, stir, the dichloro of CZ-2 is added dropwise
Dichloromethane（28.9g/150mL, 0.16mol, 1eq）.Drop finishes, and is warming up to 30~35 DEG C of reactions, TLC monitoring reactions.React
Finish, reaction solution is poured into frozen water and is quenched, stir, stand liquid separation, water mutually uses dichloromethane（200mL×2）Extraction, merges organic
Phase, uses saturated sodium-chloride（300mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains crude product.Crude product 300mL
Ethyl acetate, which dissolves by heating, to be refined, and obtains 54.1g CZ-3 solid products, yield 89%；
D, the preparation of purpose product CZ-M：54.1g CZ-3 are added in reaction bulb（0.14mol, 1eq）With 450mL tetrahydrochysene furans
Mutter, stirring and dissolving is cooled to 0~5 DEG C, and 46.7g anhydrous Aluminum chlorides are then added portionwise（0.35mol, 2.5eq）.Finish, stir
30min, then add 13.3g to enter sodium borohydride in three batches（0.35mol, 2.5eq）.After finishing, it is heated to flowing back, insulation reaction, TLC
Monitoring reaction.Reaction finishes, and is cooled to 0~5 DEG C, and reaction is quenched with the dilute hydrochloric acid of 300mL 5%, and stirring, removes tetrahydrochysene furan under reduced pressure
Mutter, then add 300mL ethyl acetate, stand liquid separation, organic phase ethyl acetate（150mL×2）Extraction, merges organic phase,
Use saturated sodium-chloride（200mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains crude product.Crude product 300mL first
Alcohol reflux is beaten, dry, obtains 47.9g CZ-M solid products, yield 92%.
Embodiment 2
A, the preparation of intermediate product CZ-1：The fluoro- 4- methyl bromobenzenes of 37g 2- are added in reaction bulb（0.2mol, 1eq）, 101.7g
Connection boric acid pinacol ester（0.4mol, 2.0eq）, 56g potassium propionates（0.5mol, 2.5eq）, 0.19g pairs (di-tert-butyl-phenyl phosphine)
Palladium chloride and 1000mL ethyl acetate, stirring and dissolving, then heat to reflux, insulation reaction, TLC monitoring reactions.React
Finish, be cooled to room temperature, be concentrated under reduced pressure and remove ethyl acetate, add 600mL dichloromethane and 300mL water, stir dissolved clarification, standing point
Liquid, water layer dichloromethane（200mL×2）Extraction, merges organic phase, uses saturated sodium-chloride（300mL×1）Washing, anhydrous sulphur
The drying of sour sodium, filters, and is concentrated under reduced pressure into dry, obtains crude product.Crude product 300mL ethyl acetate and 150mL n-hexane stirring to pulps, mistake
Filter, n-hexane rinsing is dry, obtains 41.8g CZ-1 solid products, yield：90%；
B, the preparation of intermediate product CZ-2：41.8g CZ-1 are added in reaction bulb（0.18mol, 1eq）, 43.7g 2- bromothiophenes
（0.27mol, 1.5eq）, 62.1g potassium carbonate（0.38mol, 2.5eq）With 800mL dimethyl ether and 200mL water, stirring and dissolving, so
Tetra- triphenyl phosphorus palladiums of 2.1g are put into afterwards, and stirring, then heats to 70~75 DEG C, insulation reaction, TLC monitoring is reacted.Reaction finishes,
It is cooled to room temperature, adds 500mL ethyl acetate and 300mL water, stirring, stands liquid separation, aqueous layer with ethyl acetate（200mL×2）
Extraction, merges organic phase, uses saturated sodium-chloride（500mL×1）Washing, anhydrous sodium sulfate drying, filtering, be concentrated under reduced pressure into it is dry,
Obtain crude product.Crude product 250mL methyl tertiary butyl ether(MTBE) stirring to pulps, are filtered, dry, obtain 29.9g CZ-2 solid products, yield：
88%；
C, the preparation of intermediate product CZ-3：39.2g 4- trifluoromethyl -3- methyl benzoic acids are added in reaction bulb（0.19mol,
1.2eq）, 3.0g DMF and 500mL toluene, stirring and dissolving, is cooled to 0~5 DEG C, and 47.6g thionyl chlorides are added dropwise（0.4mol,
2.5eq）.Drop finishes, and is warming up to 30~35 DEG C of reactions, TLC monitoring reactions.Raw material reaction finishes, and 0~5 DEG C is cooled to, to reaction bulb
In add 64.1g anhydrous Aluminum chlorides in three batches（0.48mol, 3.0eq）.Finish, stir, the toluene solution of CZ-2 is added dropwise
（29.9g/200mL, 0.16mol, 1eq）.Drop finishes, and is warming up to 30~35 DEG C of reactions, TLC monitoring reactions.Reaction finishes, and will react
Liquid is poured into frozen water and is quenched, stirring, stands liquid separation, and water mutually uses toluene（300mL×2）Extraction, merges organic phase, with saturation chlorination
Sodium（300mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains crude product.Crude product is heated with 300mL ethyl acetate
Dissolving is refined, obtains 50.6g CZ-3 solid products, yield 86%；
D, the preparation of purpose product CZ-M：50.6g CZ-3 are added in reaction bulb（0.13mol, 1eq）With 500mL tetrahydrochysene furans
Mutter, stirring and dissolving is cooled to 0~5 DEG C, and 52.8g anhydrous Aluminum chlorides are then added portionwise（0.39mol, 3.0eq）.Finish, stir
30min, then add 21.1g to enter potassium borohydride in three batches（0.39mol, 3.0eq）.After finishing, it is heated to flowing back, insulation reaction, TLC
Monitoring reaction.Reaction finishes, and is cooled to 0~5 DEG C, and reaction is quenched with the dilute hydrochloric acid of 300mL 5%, and stirring, removes tetrahydrochysene furan under reduced pressure
Mutter, then add 500mL ethyl acetate, stand liquid separation, organic phase ethyl acetate（200mL×2）Extraction, merges organic phase,
Use saturated sodium-chloride（200mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains crude product.Crude product 300mL first
Alcohol reflux is beaten, dry, obtains 45.3g CZ-M solid products, yield 93%.
Embodiment 3
A, the preparation of intermediate product CZ-1：28g o-fluorobenzyl bromides are added in reaction bulb（0.16mol, 1eq）, 73.8g connection boric acid frequencies
That alcohol ester（0.29mol, 1.8eq）, 35.8g potassium propionates（0.32mol, 2.0eq）, double (di-tert-butyl-phenyl phosphine) dichloros of 0.14g
Change palladium and 600mL dichloromethane, stirring and dissolving, then heat to reflux, insulation reaction, TLC monitoring reactions.Reaction finishes, cold
But to room temperature, it is concentrated under reduced pressure and removes isopropyl acetate, add 300mL dichloromethane and 200mL water, stir dissolved clarification, stands liquid separation,
Water layer dichloromethane（100mL×2）Extraction, merges organic phase, uses saturated sodium-chloride（200mL×1）Washing, anhydrous sodium sulfate
It is dry, filter, be concentrated under reduced pressure into dry, obtain crude product.Crude product is beaten with 150mL ethyl acetate and 80mL petroleum ether and stirrings, filtering, stone
Oily ether rinsing, it is dry, obtain 32.8g CZ-1 solid products, yield：92%；
B, the preparation of intermediate product CZ-2：32.8g CZ-1 are added in reaction bulb（0.15mol, 1eq）, 28.8g 2- bromothiophenes
（0.18mol, 1.2eq）, 41.9g potassium carbonate（0.31mol, 2.0eq）With 400mL dimethyl ether and 100mL water, stirring and dissolving, so
Tetra- triphenyl phosphorus palladiums of 1.64g are put into afterwards, and stirring, then heats to 70~75 DEG C, insulation reaction, TLC monitoring is reacted.React
Finish, be cooled to room temperature, add 200mL isopropyl acetates and 150mL water, stirring, stands liquid separation, water layer isopropyl acetate
（100mL×2）Extraction, merges organic phase, uses saturated sodium-chloride（200mL×1）Washing, anhydrous sodium sulfate drying, is filtered, decompression
It is concentrated to dryness, obtains crude product.Crude product 250mL isopropyl ether stirring to pulps, are filtered, dry, obtain 23.4g CZ-2 solid products, are received
Rate：88%；
C, the preparation of intermediate product CZ-3：The chloro- 3- methyl benzoic acids of 32.3g 4- are added in reaction bulb（0.19mol,
1.5eq）, 2.3g DMF and 200mL dichloromethane, stirring and dissolving, is cooled to 0~5 DEG C, and 38.1g thionyl chlorides are added dropwise
（0.33mol, 2.5eq）.Drop finishes, and is warming up to 30~35 DEG C of reactions, TLC monitoring reactions.Raw material reaction finishes, and is cooled to 0~5
DEG C, add 52.0g anhydrous Aluminum chlorides in three batches into reaction bulb（0.39mol, 3.0eq）.Finish, stir, be added dropwise the two of CZ-2
Chloromethanes solution（23.4g/150mL, 0.13mol, 1eq）.Drop finishes, and is warming up to 30~35 DEG C of reactions, TLC monitoring reactions.Reaction
Finish, reaction solution is poured into frozen water and is quenched, stir, stand liquid separation, water mutually uses dichloromethane（150mL×2）Extraction, is associated with
Machine phase, uses saturated sodium-chloride（200mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains crude product.Crude product is used
300mL ethyl acetate, which dissolves by heating, to be refined, and obtains 38.2g CZ-3 solid products, yield 88%；
D, the preparation of purpose product CZ-M：38.2g CZ-3 are added in reaction bulb（0.12mol, 1eq）With 300mL tetrahydrochysene furans
Mutter, stirring and dissolving is cooled to 0~5 DEG C, and 32.0g anhydrous Aluminum chlorides are then added portionwise（0.24mol, 2.0eq）.Finish, stir
30min, then add 5.3g to enter lithium borohydride in three batches（0.24mol, 2.0eq）.After finishing, it is heated to flowing back, insulation reaction, TLC
Monitoring reaction.Reaction finishes, and is cooled to 0~5 DEG C, and reaction is quenched with the dilute hydrochloric acid of 200mL 5%, and stirring, removes tetrahydrochysene furan under reduced pressure
Mutter, then add 300mL ethyl acetate, stand liquid separation, organic phase ethyl acetate（100mL×2）Extraction, merges organic phase,
Use saturated sodium-chloride（200mL×1）Washing, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure, obtains crude product.Crude product 200mL first
Alcohol reflux is beaten, dry, obtains 32.9g CZ-M solid products, yield 90%.
Claims (6)
1. a kind of preparation method of canagliflozin intermediate, it is characterised in that using substituted phenyl-bromide as starting material, first with joining boron
Sour pinacol ester is prepared into boride, then is prepared through Suzuki coupling reactions, F-K reaction and reduction reaction.
2. the preparation method of a kind of canagliflozin intermediate according to claim 1, it is characterised in that specific steps are such as
Under：
A, the preparation of intermediate product CZ-1：Substituted phenyl-bromide under the action of metallic catalyst, reacts shape with connection boric acid pinacol ester
Into CZ-1；
B, the preparation of intermediate product CZ-2：CZ-1 carries out Suzuki couplings under the action of catalyst, with 2- bromothiophenes, obtains
CZ-2；
C, the preparation of intermediate product CZ-3：CZ-2 carries out friedel-crafts acylation under Louis acid catalysis, with substituted benzoic acid,
CZ-3 is prepared；
D, the preparation of purpose product CZ-M：CZ -3 is under the action of catalyst and reducing agent, and carbonyl is through reduction reaction to methylene
Base, is prepared CZ-M；
Wherein：The chemical formula of the CZ-1 is；
The chemical formula of the CZ-2 is；
The chemical formula of the CZ-3 is；
The chemical formula of the CZ-M is；
For、Or,
For、Or。
3. the preparation method of a kind of canagliflozin intermediate according to claim 2, it is characterised in that described in step a
Metallic catalyst be selected from palladium carbon, palladium chloride, tetra-triphenylphosphine palladium and double (di-tert-butyl-phenyl phosphine) palladium chlorides, be preferably
Double (di-tert-butyl-phenyl phosphine) palladium chlorides, and the substituted phenyl-bromide and the molar ratio of connection boric acid pinacol ester are 1.0:
1.5 ~ 2.0, the inventory of metallic catalyst is the 0. 5% of substituted phenyl-bromide quality.
4. the preparation method of a kind of canagliflozin intermediate according to claim 2, it is characterised in that described in step b
Catalyst be selected from palladium carbon, palladium chloride, tetra-triphenylphosphine palladium and double (di-tert-butyl-phenyl phosphine) palladium chlorides, be preferably four or three
Phenylphosphine palladium, and the molar ratio of the CZ-1 and 2- bromothiophenes is 1.0:1.1 ~ 1.5, the dosage of catalyst is CZ-1 matter
The 5% of amount.
5. the preparation method of a kind of canagliflozin intermediate according to claim 2, it is characterised in that described in step c
Lewis acid be selected from alchlor, zinc chloride and magnesium chloride, be preferably alchlor, and CZ-2 and substituted benzoic acid feed intake
Molar ratio is：1.0: 1.0~1.5.
A kind of 6. preparation method of canagliflozin intermediate according to claim 2, it is characterised in that the institute in step d
It is aluminium chloride to state catalyst, and reducing agent is selected from sodium borohydride, potassium borohydride and lithium borohydride, and CZ -3 and catalyst feed intake
Molar ratio is 1.0:The molar ratio of 2.0 ~ 3.0, CZ -3 and reducing agent is：1.0: 2.0~3.0.
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| CN113683593A (en) * | 2021-09-07 | 2021-11-23 | 湖北石河医药科技有限公司 | Preparation method of canagliflozin intermediate and application of canagliflozin intermediate in preparation of canagliflozin |
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| CN103214471A (en) * | 2003-08-01 | 2013-07-24 | 田边三菱制药株式会社 | Novel compound |
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| CN113683593A (en) * | 2021-09-07 | 2021-11-23 | 湖北石河医药科技有限公司 | Preparation method of canagliflozin intermediate and application of canagliflozin intermediate in preparation of canagliflozin |
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