CN104402946B - Canagliflozin intermediate and its unbodied preparation method - Google Patents
Canagliflozin intermediate and its unbodied preparation method Download PDFInfo
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- CN104402946B CN104402946B CN201410653240.1A CN201410653240A CN104402946B CN 104402946 B CN104402946 B CN 104402946B CN 201410653240 A CN201410653240 A CN 201410653240A CN 104402946 B CN104402946 B CN 104402946B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention provides canagliflozin intermediate and its unbodied preparation method, wherein canagliflozin unbodied preparation method the step of include passing through by (1S) 1,5 dehydrogenation 1 [3 [[5 (4 fluorophenyl) 2 thienyls] methyl] 4 aminomethyl phenyls] D glucitols heat dissolved clarification in good solvent, then it is added drop-wise in the poor solvent quickly stirred, the solid separated out is filtered, obtains amorphous canagliflozin.The preparation method of the present invention can reduce solvent load, and products obtained therefrom is easily separated, moreover, products obtained therefrom yield is good, purity is high, method is simple to operate.
Description
Technical field
The present invention relates to the field of chemical synthesis, more particularly to the preparation of a kind of canagliflozin intermediate and its amorphous form
Method.
Background technology
Canagliflozin, chemical name：(1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -4-
Aminomethyl phenyl]-D-Glucose alcohol, CAS:842133-18-0, structure：
Canagliflozin belongs to SGLT2 inhibitor, and the discharge that SGLT2 inhibitor can increase diabetic's glucose in urine is suffered from reducing
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
May be with the improvement of hypertension while patient is using SGLT2 inhibitor treatment hyperglycaemia.Because therapy target is only limited to kidney
It is dirty, potentially to the adverse reaction very little beyond target spot.The as shown by data SGLT2 inhibitor of clinical research at present has good
Drug effect, security and tolerance, increasing the discharge of glucose in urine turns into a kind of method of new treatment diabetes B.
Canagliflozin is by Tanabe Seiyaku Co Ltd (holding by Mitsubishi Chemical (the side pharmacy of Mitsubishi field)) exploitation.
At present, the preparation method of canagliflozin disclosed in document and similar approach are reported including following documents：WO
2008069327A1；WO 2011047113A1；Following route can be summarized as：
In the route, canagliflozin hemihydrate form is obtained usually using acetone/water or ethanol/water.
The content of the invention
It is an object of the invention to provide one kind to prepare canagliflozin intermediate and its unbodied method.
It is an object of the invention to provide a kind of preparation method of canagliflozin intermediate, comprise the following steps：
By-the O- of 2,3,4,6- tetra- (trimethyl silicane)-maltonic acid-delta-lactone and 2- (4- fluorophenyls) -5- [(the iodo- 2- of 5-
Aminomethyl phenyl) methyl] thiophene adds in organic solvent A, adds alkaline reagent under cryogenic, added after reacting completely acid
Alcoholic solution deprotection and acid treatment, add alkaline solution and adjust pH value to stand to 7~8 and separate organic layer, water layer organic solvent B
Extraction, merge organic layer, wash, dry, filter, being concentrated to give grease, grease crystallization, filtering, obtaining among canagliflozin
Body (II).
[(5- is iodo- by -5- with 2- (4- fluorophenyls) for-O- of 2,3,4,6- tetra- (trimethyl silicane)-maltonic acid-delta-lactone
2- aminomethyl phenyls) methyl] thiophene mol ratio be 1:1~2:1, preferably 1.8:1.
Preferably, the organic solvent A is selected from tetrahydrofuran, benzene, the one or more of toluene or ether, preferably tetrahydrochysene furan
The mixed solvent muttered with toluene；The organic solvent B is selected from ethyl acetate, the one or more in ether and dichloromethane, 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, alkaline reagent is added into 2,3,4,6- tetra--O- (trimethyl silicane)-maltonic acid-delta-lactone and 2-
In the mixed organic solvents of (4- fluorophenyls) -5- [(the iodo- 2- aminomethyl phenyls of 5-) methyl] thiophene, i.e., two kinds of reaction raw materials are organic
In solvent alkaline reagent is added after mixing.
Preferably, the acid is selected from methanesulfonic acid, trifluoroacetic acid or p-methyl benzenesulfonic acid, preferably methanesulfonic acid.
Preferably, the n-BuLi rubs with 2- (4- fluorophenyls) -5- [(the iodo- 2- aminomethyl phenyls of 5-) methyl] thiophene
You are than being 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, dichloromethane, preferably normal heptane, first
Benzene/normal heptane.
Preferably, toluene and the normal heptane volume ratio is 1:2-1:10, preferably 1:5.
Particularly preferred reaction scheme is by-the O- of 2,3,4,6- tetra- (trimethyl silicane)-maltonic acid-delta-lactone and 2-
(4- fluorophenyls) -5- [(the iodo- 2- aminomethyl phenyls 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, add saturated sodium bicarbonate solution and adjust pH value to stand to 7~8 and separate organic layer, aqueous layer with ethyl acetate carries
Take, merge organic layer, water washing, anhydrous sodium sulfate drying, filter, be concentrated to give grease, after grease heats dissolved clarification with toluene
Crystallization in the n-heptane solution quickly stirred is added drop-wise to, filters, obtains canagliflozin intermediate (II).
Another object of the present invention is to provide a kind of preparation method of amorphous canagliflozin to comprise the following steps：
By (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -4- aminomethyl phenyls]-D- grapes
Sugar alcohol heats dissolved clarification in good solvent, is added drop-wise in the poor solvent quickly stirred, and solid separates out, and drop filters after finishing, and obtains
Amorphous canagliflozin.
The good solvent refers to the solvent good to canagliflozin dissolubility, and the poor solvent refers to canagliflozin dissolubility
The solvent of difference.
Preferably, the good solvent is selected from acetone, ethanol, methyl tertiary butyl ether(MTBE) or ethyl acetate, more preferably methyl- tert
Butyl ether.
Preferably, the methyl tertiary butyl ether(MTBE) and (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls]
Methyl] -4- aminomethyl phenyls]-D-Glucose alcohol volume mass ratio be 5:1~15:1, preferably 10:1.
Preferably, the poor solvent is selected from normal heptane, n-hexane, hexamethylene or isopropyl ether, more preferably normal heptane.
Preferably, the normal heptane and (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -
4- aminomethyl phenyls]-D-Glucose alcohol volume mass ratio be 30:1~100:1, preferably 50:1.
Described volume mass than unit magnitude can be ml/g, L/kg or other reciprocity magnitudes unit.
Dry temperature is 30-40 DEG C, and preferably 30 DEG C, drying mode is forced air drying.
The preparation method of the present invention can reduce quantity of solvent, and products obtained therefrom is easily separated, moreover, present invention gained canagliflozin
Amorphous products yield is good, purity is high and method is simple to operate.
Brief description of the drawings
Fig. 1 is the X- powder diagrams of the gained solid of embodiment 1.
Fig. 2 is that the HPLC of the products obtained therefrom of embodiment 1 analyzes collection of illustrative plates.
Embodiment
The present invention is illustrated below with reference to embodiment, but present disclosure is not limited to specific embodiment.
Embodiment 1：Unbodied preparation
By methyl tertiary butyl ether(MTBE) (300ml), (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] first
Base] -4- aminomethyl phenyls]-D-Glucose alcohol (30g) add reaction bulb in, heat dissolved clarification, reaction solution is added drop-wise to what is quickly stirred
In normal heptane (1500ml), solid separates out, and drop filters after finishing, and 30 DEG C of forced air drying 4h of solid, obtains 27.2g white solids, pure
Degree reaches 99.82%, and related collection of illustrative plates is shown in Fig. 2, and the X- powder diffraction spectrums of products obtained therefrom are shown in Fig. 1, as seen from the figure the solid forms
To be amorphous.
1H NMR(500MHz,DMSO-d6)：δ 2.27 (s, 3H), 3.17-3.26 (m, 3H), 3.27-3.31 (m, 1H),
3.45-3.49 (m, 1H), 3.70-3.74 (m, 1H), 3.98-4.00 (d, J=9.4Hz, 1H), 4.08-4.16 (m, 2H),
4.40 (t, J=5.8Hz, 1H), 4.69-4.70 (d, 1H), 4.88-4.90 (m, 2H), 6.79-6.80 (d, J=3.6Hz,
1H), 7.12-7.15 (m, 2H), 7.17-7.21 (m, 2H), 7.24 (s, 1H), 7.26-7.27 (m, 2H), 4.88-4.90 (d, J
=3.6Hz, 1H), 7.57-7.60 (m, 2H)；13C NMR(500MHz)：δ 18.7,33.4,61.4,70.44,74.7,78.5,
81.1,81.3,115.7,123.3,126.2,126.3,126.9,130.5,134.9,137.3,140.2,143.6,160.4；
MS(m/z)：462.17[M+NH4]+
Embodiment 2：Unbodied preparation
By ethyl acetate (300ml), (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -
4- aminomethyl phenyls]-D-Glucose alcohol (30g) add reaction bulb in, heat dissolved clarification, reaction solution is added drop-wise to the isopropyl quickly stirred
In ether (1500ml), solid separates out, and drop filters after finishing, and 30 DEG C of forced air drying 4h of solid, obtains 25.6g white solids, purity reaches
To 98.77%.
Analyzed through structural identification, gained white solid XRPD collection of illustrative plates is consistent with Fig. 1, and products obtained therefrom is same as Example 1.
Embodiment 3：Unbodied preparation
By ethyl acetate (300ml), (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -
4- aminomethyl phenyls]-D-Glucose alcohol (30g) add reaction bulb in, heat dissolved clarification, reaction solution is added drop-wise to the positive heptan quickly stirred
In alkane (1500ml), solid separates out, and drop filters after finishing, and 30 DEG C of forced air drying 4h of solid, obtains 24.7g white solids, purity reaches
To 98.82%.
Analyzed through structural identification, gained white solid XRPD collection of illustrative plates is consistent with Fig. 1, and products obtained therefrom is same as Example 1.
Comparative example 4：Unbodied preparation
By toluene (300ml), (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -4- methyl
Phenyl]-D-Glucose alcohol (30g) add reaction bulb in, heat dissolved clarification, normal heptane (3000ml) is slowly added dropwise into reaction solution,
Solid separates out, and drop filters after finishing, and 50 DEG C of forced air drying 4h of solid, obtains 18.8g white solids, purity reaches 87.55%.
Analyzed through structural identification, gained white solid XRPD collection of illustrative plates is consistent with Fig. 1, and products obtained therefrom is same as Example 1.
By comparing embodiment 1~3 and comparative example 4, the method for reverse charging sequence is (i.e.：By canagliflozin
Solution be added in poor solvent) solvent for use amount is smaller, product is readily isolated operation, the purity of product is high；Forward direction adds
The method of material order is (i.e.：Poor solvent is added in the solution of canagliflozin) solvent for use amount is larger, product is not easy to be separated
Operation.
Embodiment 5
The preparation of 1- (1- methoxyl groups glycopyranosyl) -4- methyl -3- [5- (4- fluorophenyls) -2- thienyl methyls] benzene
By the iodo- 1- of 5- [- 5- (4- fluorophenyls) -2- thienyl methyls] -2- methylbenzenes (100g, 0.245mol), tetrahydrochysene furan
Mutter (600ml), toluene (1.1L) ,-O- (the trimethyl silicane)-D- glucono-δ-lactones of 2,3,4,6- tetra- (247g) add reaction
In bottle, stir to dissolved clarification, open frozen cooling to -65 DEG C -85 DEG C, n-butyllithium solution (200ml) is added dropwise, process control is added dropwise
It is complete to drip -65 DEG C of -85 DEG C of stirring reaction 2h, TLC detection raw material reactions after finishing at -65 DEG C -85 DEG C for temperature.
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, merges
Organic layer, washed twice time with the aqueous solution (3L × 2), organic layer anhydrous sodium sulfate drying, filtering, be concentrated to give yellow oily
Thing.
Grease is heated into dissolved clarification with 500ml toluene, is added drop-wise in 2.8L normal heptanes, drop filters after finishing, and is dried in vacuo
At night, obtain 90g white solids, 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]+。
Claims (3)
1. a kind of unbodied preparation method of canagliflozin, comprises the following steps：
By (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -4- aminomethyl phenyls]-D-Glucose alcohol
Dissolved clarification is heated in good solvent, is then added drop-wise in the poor solvent quickly stirred, filters the solid of precipitation, in suitable temperature
The lower drying of degree, obtains amorphous canagliflozin, wherein the good solvent is methyl tertiary butyl ether(MTBE), the poor solvent is positive heptan
Alkane, the methyl tertiary butyl ether(MTBE) and (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorophenyls) -2- thienyls] methyl] -4- methyl
Phenyl]-D-Glucose alcohol volume mass ratio be 10:1, the normal heptane and (1S) -1,5- dehydrogenations -1- [3- [[5- (4- fluorobenzene
Base) -2- thienyls] methyl] -4- aminomethyl phenyls]-D-Glucose alcohol volume mass ratio be 50:1.
2. the unbodied preparation method of canagliflozin according to claim 1, it is characterised in that dry temperature is 30-
40 DEG C, drying mode is forced air drying.
3. the unbodied preparation method of canagliflozin according to claim 1, it is characterised in that dry temperature is 30
DEG C, drying mode is forced air drying.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11857559B2 (en) | 2018-09-10 | 2024-01-02 | Aurobindo Pharma Ltd. | Pharmaceutical composition comprising Canagliflozin, process of preparation and use thereof |
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| CN106146501A (en) * | 2015-03-26 | 2016-11-23 | 江苏豪森药业集团有限公司 | A kind of preparation method of unformed inhibitors of kinases |
| WO2017064679A1 (en) * | 2015-10-15 | 2017-04-20 | Lupin Limited | Process for the preparation of amorphous canagliflozin |
| CN105541817A (en) * | 2016-02-20 | 2016-05-04 | 浙江华海药业股份有限公司 | Method for preparing amorphous canagliflozin through heat treatment |
| WO2018020506A1 (en) * | 2016-07-25 | 2018-02-01 | Natco Pharma Ltd | Process for the preparation of amorphous form of canagliflozin |
| CN106588898A (en) | 2017-02-20 | 2017-04-26 | 浙江华海药业股份有限公司 | Preparation method for amorphous form of canagliflozin |
| CN107488156B (en) * | 2017-09-04 | 2020-05-26 | 上海现代制药股份有限公司 | Synthesis method of amorphous glucitol |
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| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant after: Lianyungang Hengyun Pharmaceutical Co. Ltd. Address before: 222200 Guanyun City, Jiangsu province Lingang Industrial Zone, the south side of the weft Road, eight Applicant before: Lianyungang Hengyun Pharmaceutical Co. Ltd. |
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| GR01 | Patent grant | ||
| GR01 | Patent grant |