CN105330706B - The preparation method of canagliflozin intermediate - Google Patents
The preparation method of canagliflozin intermediate Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of canagliflozin intermediate, it the described method comprises the following steps: by 2, 3, 4, tetra--O- of 6- (trimethyl silicane)-maltonic acid-delta-lactone and 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene are added in organic solvent A, alkaline reagent is added under cryogenic, acidity alcohol solution deprotection and acid processing are added after fully reacting, alkaline solution tune pH value is added to 7~8, standing separates organic layer, water layer is extracted with organic solvent B, merge organic layer, washing, it is dry, filtering, it is concentrated to give grease, grease crystallization, filtering, obtain canagliflozin intermediate.Operation of the present invention is simple, is suitble to industrialized production, and yield is high, and purity is good.
Description
Technical field
The present invention relates to the field of chemical synthesis more particularly to a kind of preparation methods of canagliflozin intermediate.
Background technique
Canagliflozin, chemical name: (1S) -1,5- dehydrogenation -1- [3- [[5- (4- fluorophenyl) -2- thienyl] methyl] -4- first
Base phenyl]-D-Glucose alcohol, CAS:842133-18-0, structure:
Canagliflozin belongs to SGLT2 inhibitor, and SGLT2 inhibitor can increase the discharge of diabetic's glucose in urine to reduce and suffer from
Person's blood glucose, reduces patient's weight, and part SGLT2 inhibitor can still improve the secreting function of beta Cell of islet.Diabetes B
It may be with the improvement of hypertension while patient is using SGLT2 inhibitor treatment hyperglycemia.Since therapy target is only limited to kidney
It is dirty, potentially to the adverse reaction very little other than target spot.Clinical research at present statistics indicate that SGLT2 inhibitor have it is good
Drug effect, safety and tolerance, the discharge for increasing glucose in urine become a kind of method of new treatment diabetes B.Card
Lattice column are existing only by Tanabe Seiyaku Co Ltd (holding by Mitsubishi Chemical (the side pharmacy of Mitsubishi field)) exploitation
Submitting application for quotation by Yang Sen company, (Janssen Research&Development submits NDA application, Janssen-Cilag
Submit MAA application).
Currently, the preparation method and similar approach of canagliflozin disclosed in document include following documents report:
WO2008069327A1；WO2011047113A1；It can be summarized as following route:
In the route, 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) is activated first usually using n-BuLi
Methyl] thiophene obtains reactive intermediate, then with 2, the condensation of 3,4,6- tetra--O- (trimethyl silicane)-maltonic acid-delta-lactones, then
It chromatographs to obtain intermediate (II) through deprotection, acid processing rear pillar:
The feed way of the step condensation reaction is also easy to produce impurity, and whole yield is low, at high cost, and post-processing is cumbersome, is not easy to put
Mass production.
Summary of the invention
It is an object of the invention to solve above-mentioned technical problem, provide it is a kind of purity is high, high income canagliflozin among
The preparation method of body, this method is easy to operate, is suitble to industrial production.
Preparation method of the invention the following steps are included:
By tetra--O- of 2,3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone and 2- (4- fluorophenyl) -5- [(the iodo- 2- of 5-
Aminomethyl phenyl) methyl] thiophene is added in organic solvent A, alkaline reagent is added under cryogenic, is added after fully reacting acid
Alkaline solution tune pH value is added to 7~8 in alcoholic solution deprotection and acid processing, and standing separates organic layer, water layer organic solvent B
It extracts, merges organic layer, wash, dry, filter, being concentrated to give grease, grease crystallization, filtering obtain among canagliflozin
Body (II):
[(5- is iodo- by -5- with 2- (4- fluorophenyl) for tetra--O- of 2,3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone
2- aminomethyl phenyl) methyl] thiophene molar ratio be 1:1~2:1, preferably 1.8:1.
Preferably, the organic solvent A is selected from tetrahydrofuran, benzene, one or more, the preferred tetrahydro furan of toluene or ether
The mixed solvent muttered with toluene；The organic solvent B is selected from ethyl acetate, and one of ether and methylene chloride or a variety of are excellent
Select ethyl acetate.
Preferably, the alkaline reagent is selected from lithium methide, hexyllithium, n-BuLi or tert-butyl lithium, preferably normal-butyl
Lithium.
Preferably, 2,3,4,6- tetra--O- (trimethyl silicane)-maltonic acid-delta-lactone and 2- (4- is added in alkaline reagent
Fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene mixed organic solvents in, i.e., two kinds of reaction raw materials are organic molten
Alkaline reagent is added in agent after mixing.
Preferably, the acid is selected from methanesulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid, preferably methanesulfonic acid.
Preferably, mole of the n-BuLi and 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene
Than for 2:1~3:1, preferably 2.2:1.
Preferably, the reaction temperature of the cryogenic conditions is -65~-75 DEG C.
Preferably, the crystallization solvent is selected from toluene, tetrahydrofuran, ethyl acetate, methylene chloride, normal heptane, preferably first
Benzene/normal heptane.
Preferably, the toluene and normal heptane volume ratio are 1:2-1:10, preferably 1:5.
Particularly preferred reaction scheme is by tetra--O- of 2,3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone and 2-
(4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene is added to the in the mixed solvent of toluene and tetrahydrofuran, -
N-BuLi is added at 65 DEG C -75 DEG C, is reacted 1~3 hour at -65 DEG C -75 DEG C, methanesulfonic acid methanol solution is added, is stirred at room temperature
12~18 hours, saturated sodium bicarbonate solution tune pH value is added to 7~8, standing separates organic layer, and aqueous layer with ethyl acetate mentions
It takes, merges organic layer, water washing, anhydrous sodium sulfate dries, filters, is concentrated to give grease, after grease heats dissolved clarification with toluene
It is added drop-wise to crystallization in the n-heptane solution quickly stirred, filters, obtains canagliflozin intermediate (II).
Preparation method of the present invention not first activates raw material 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene
Pheno, but two kinds of raw materials are first mixed and add alkaline reagent afterwards, by the change of this reaction step, inventor sends out in surprise
Now final resulting intermediate purity is high, yield are good, moreover, further, this method does not need column chromatography procedure, method operation
Simply, it is suitble to industrial production.
Specific embodiment
The present invention is illustrated below with reference to embodiment, but the contents of the present invention are not limited to specific embodiment.
Embodiment 1:1- (1- methoxyl group glycopyranosyl) -4- methyl -3- [5- (4- fluorophenyl) -2- thienyl methyl] benzene
Preparation
By the iodo- 1- of 5- [- 5- (4- fluorophenyl) -2- thienyl methyl] -2- methylbenzene (100g, 0.245mol), tetrahydro furan
It mutters (600ml), reaction is added in toluene (1.1L), tetra--O- of 2,3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone (247g)
In bottle, stirring to dissolved clarification is opened frozen cooling to -65 DEG C -85 DEG C, is added dropwise n-butyllithium solution (200ml), process control is added dropwise
Temperature drips at -65 DEG C -85 DEG C and is stirred to react 2h for -65 DEG C -85 DEG C after finishing, TLC detects raw material fully reacting.
Methanesulfonic acid methanol solution (65g/800ml) is added drop-wise in reaction solution, reaction 16h is warmed to room temperature after finishing.It is added dropwise
The aqueous solution of saturated sodium bicarbonate is 7~8 to pH, and stratification, aqueous layer with ethyl acetate (1.5L × 2) extracts twice, is merged
Organic layer is washed twice time with aqueous solution (3L × 2), and organic layer anhydrous sodium sulfate dries, filters, and is concentrated to get yellow oily
Object.
Grease 500ml toluene is heated into dissolved clarification, is added drop-wise in 2.8L normal heptane, drop filters after finishing, and is dried in vacuo
Night obtains 90g white solid, molar yield 77.5%.
1H-NMR:(400MHz, DMSO): δ=2.27 (s, 3H), 2.97 (s, 3H), 3.24-3.27 (m, 1H), 3.40-
3.42 (m, 1H), 3.54-3.63 (m, 2H), 3.75-3.78 (m, 2H), 4.08-4.21 (m, 2H), 4.51 (t, 1H, J=
6.0Hz), 4.64 (d, 1H, J=7.6Hz), 4.71 (d, 1H, J=5.2Hz), 4.94 (d, 1H, J=5.6Hz), 6.78 (d, 1H,
), J=3.6Hz 7.12-7.20 (m, 3H), 7.27 (d, 1H, J=3.6Hz), 7.37 (dd, 1H, J=8.0Hz), 7.49 (d, 1H,
), J=1.2Hz 7.56-7.61 (m, 2H)
MS (m/z): 497.3 [M+Na]+
Embodiment 2:
By the iodo- 1- of 5- [- 5- (4- fluorophenyl) -2- thienyl methyl] -2- methylbenzene (100g, 0.245mol), tetrahydro furan
It mutters (600ml), reaction is added in toluene (1.1L), tetra--O- of 2,3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone (247g)
In bottle, stirring to dissolved clarification is opened frozen cooling to -65 DEG C -85 DEG C, is added dropwise n-butyllithium solution (200ml), process control is added dropwise
Temperature drips at -65 DEG C -85 DEG C and is stirred to react 2h for -65 DEG C -85 DEG C after finishing, TLC detects raw material fully reacting.
P-methyl benzenesulfonic acid methanol solution (116g/800ml) is added drop-wise in reaction solution, reaction 16h is warmed to room temperature after finishing.
The aqueous solution of dropwise addition saturated sodium bicarbonate is 7~8 to pH, and stratification, aqueous layer with ethyl acetate (1.5L × 2) extracts twice,
Merge organic layer, is washed twice time with aqueous solution (3L × 2), organic layer anhydrous sodium sulfate dries, filters, and is concentrated to get yellow oil
Shape object.
Grease 500ml toluene is heated into dissolved clarification, is added drop-wise in 2.8L normal heptane, drop filters after finishing, and is dried in vacuo
Night obtains 84g white solid, molar yield 72.4%.
It is identical as 1 product of embodiment that gained white solid is confirmed through structure elucidation.
Embodiment 3:
By the iodo- 1- of 5- [- 5- (4- fluorophenyl) -2- thienyl methyl] -2- methylbenzene (100g, 0.245mol), tetrahydro furan
It mutters (600mL), in toluene (600ml) addition reaction flask, opens frozen cooling to -65 DEG C -85 DEG C, n-butyllithium solution is added dropwise
Process control temp is added dropwise at -65 DEG C -85 DEG C in (200ml), drips and is stirred to react 0.5h for -65 DEG C -85 DEG C after finishing, is added dropwise 2,3,4,
Process control temp is added dropwise in tetra--O- of 6- (trimethyl silicane)-maltonic acid-delta-lactone (247g) toluene (500ml) solution
At -65 DEG C -85 DEG C, drips and be stirred to react 2h for -65 DEG C -85 DEG C after finishing, TLC detects raw material fully reacting.
Methanesulfonic acid methanol solution (65g/800ml) is added drop-wise in reaction solution, reaction 16h is warmed to room temperature after finishing.It is added dropwise
The aqueous solution of saturated sodium bicarbonate is 7~8 to pH, and stratification, aqueous layer with ethyl acetate (1.5L × 2) extracts twice, is merged
Organic layer is washed twice time with aqueous solution (3L × 2), and organic layer anhydrous sodium sulfate dries, filters, and is concentrated to get yellow oily
Object.
Grease 500ml toluene is heated into dissolved clarification, is added drop-wise in 2.8L normal heptane, drop filters after finishing, and is dried in vacuo
Night obtains 61.1g white solid, molar yield 52.6%.
It is identical as 1 product of embodiment that gained white solid is confirmed through structure elucidation.
Claims (16)
1. a kind of preparation method of canagliflozin intermediate, comprising the following steps:
By tetra--O- of 2,3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone and 2- (4- fluorophenyl) -5- [(iodo- 2- methyl of 5-
Phenyl) methyl] thiophene is added in organic solvent A, alkaline reagent is added under cryogenic, it is molten that acid alcohol is added after fully reacting
Liquid deprotection simultaneously acid processing, addition alkaline solution tune pH value to 7~8, standing separate organic layer, and water layer is extracted with organic solvent B,
Merge organic layer, wash, dry, filter, being concentrated to give grease, grease crystallization, filtering obtain canagliflozin intermediate (I):
Wherein, organic solvent A is selected from tetrahydrofuran, and benzene, one of toluene and ether or a variety of, organic solvent B is selected from acetic acid
Ethyl ester, one of ether and methylene chloride or a variety of, cryogenic conditions are 0~-85 DEG C.
2. the preparation method of canagliflozin intermediate according to claim 1, it is characterised in that described 2,3,4,6- tetra--O-
(trimethyl silicane)-maltonic acid-delta-lactone rubs with 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene
You are than being 1.1:1~2.5:1.
3. the preparation method of canagliflozin intermediate according to claim 1, it is characterised in that described 2,3,4,6- tetra--O-
(trimethyl silicane)-maltonic acid-delta-lactone rubs with 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene
You are than being 1.8:1.
4. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the organic solvent A choosing
From the mixed solvent of tetrahydrofuran and toluene；The organic solvent B is selected from ethyl acetate.
5. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the alkaline reagent is selected from
Lithium methide, hexyllithium, n-BuLi or tert-butyl lithium.
6. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the alkaline reagent is selected from
N-BuLi.
7. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that alkaline reagent is added 2,
Tetra--O- of 3,4,6- (trimethyl silicane)-maltonic acid-delta-lactone and 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) first
Base] thiophene mixed organic solvents in.
8. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the acid is selected from methylsulphur
Acid, trifluoroacetic acid or p-methyl benzenesulfonic acid.
9. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the acid is selected from methylsulphur
Acid.
10. the preparation method of canagliflozin intermediate according to claim 6, which is characterized in that the n-BuLi with
The molar ratio of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene is 1.5:1~3:1.
11. the preparation method of canagliflozin intermediate according to claim 6, which is characterized in that the n-BuLi with
The molar ratio of 2- (4- fluorophenyl) -5- [(the iodo- 2- aminomethyl phenyl of 5-) methyl] thiophene is 2.2:1.
12. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the cryogenic conditions
Reaction temperature is -65~-75 DEG C.
13. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the solvent of Devitrification step
Selected from toluene, tetrahydrofuran, ethyl acetate, one of methylene chloride and normal heptane or a variety of.
14. the preparation method of canagliflozin intermediate according to claim 1, which is characterized in that the solvent of Devitrification step
Selected from toluene and normal heptane mixed solvent.
15. the preparation method of canagliflozin intermediate according to claim 14, which is characterized in that the toluene and positive heptan
The volume ratio of alkane is 1:2~1:10.
16. the preparation method of canagliflozin intermediate according to claim 14, which is characterized in that the toluene and positive heptan
The volume ratio of alkane is 1:5.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
| CN102648196A (en) * | 2009-10-14 | 2012-08-22 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| CN102985075A (en) * | 2010-05-11 | 2013-03-20 | 田边三菱制药株式会社 | Canagliflozin containing tablets |
-
2014
- 2014-06-05 CN CN201410247909.7A patent/CN105330706B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101573368A (en) * | 2006-12-04 | 2009-11-04 | 田边三菱制药株式会社 | Crystalline form of 1- (belta-D-glucopyranosyl) -4 -methyl- 3- [5- (4 -fluorophenyl) -2-thienylmethyl] benzene hemihydrate |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
| CN102648196A (en) * | 2009-10-14 | 2012-08-22 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| CN102985075A (en) * | 2010-05-11 | 2013-03-20 | 田边三菱制药株式会社 | Canagliflozin containing tablets |
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