CN108610316A - The preparation method of Dapagliflozin - Google Patents
The preparation method of Dapagliflozin Download PDFInfo
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- CN108610316A CN108610316A CN201611126934.5A CN201611126934A CN108610316A CN 108610316 A CN108610316 A CN 108610316A CN 201611126934 A CN201611126934 A CN 201611126934A CN 108610316 A CN108610316 A CN 108610316A
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- 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
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Abstract
The present invention relates to the preparation method of Dapagliflozin, this method using II compound of formula and III compound of formula as starting material, through condensation, ether, restore and etc. obtain Dapagliflozin, can be used for treating type II diabetes.Present invention process reasonable design, reaction yield is high, and the Dapagliflozin purity of preparation is high, is highly suitable for the industrialized production of Dapagliflozin.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, are specifically related to the preparation method of compound Dapagliflozin.
Background technology
Dapagliflozin, chemical name：(2S, 3R, 4R, 5S, 6R) -2- (the chloro- 3- of 4- (4- ethoxybenzyls) phenyl) -6- (hydroxyl first
Base) tetrahydrochysene -2H- pyrans -3,4,5- triols, structure：
Type II diabetes [Non-Insulin Dependent Diabetes Mellitus (NIDDM)] it is characterized in that because of excessive Hepatic glucose production and
Periphery insulin resistance induced hyperglycemia.It is believed that hyperglycemia is that the Major Risk Factors of diabetic complication occur, it is likely that
It is reduced directly by closing with the insulin secretion for late NIDDM occur.It is expected that Na-dependent glucose transporter (SGLT2) presses down
Preparation can help plasma glucose levels to restore normal in kidney by promoting glucose to drain, while may help weight recovery
Normally.
Persistently the plasma glucose levels of control diabetic can offset the diabetic complication for appearing in terminal illness
Occur and β Cells Depletions.It is reported that pancreas islet can be improved with long-term (6 months) treatment Zucker diabetes rats of SGLT2 inhibitor
Reaction of the element to glucemia, improves the sensibility of insulin, delays these animal nephrosis and neuropathic breaking-out, does not find kidney trouble
Become and plasma electrolyte is lacked of proper care.It is contemplated by glucose in promotion urine to drain, the selective depression of diabetic SGLT2 can make
Plasma glucose levels restore normal, because improving insulin sensitivity, delaying complications of diabetes occurs.
Chemical compounds I is a kind of SGLT2 inhibitor, can be used for treating or delay breaking-out or the progress of diabetes, including glycosuria
Sick complication such as retinopathy, neuropathy, nephrosis and retardance wound healing and relevant disease such as insulin resistance and Portugal
Grape sugar homeostasis is damaged (IGH), hyperglycemia, hyperinsulinemia, hyperlipidemia fat acid or glycerine level, fat, hyperlipemia
Disease includes hypertriglyceridemia, hypertension, atherosclerosis and relevant disease, and for improving high density lipid water
It is flat.
Currently, the preparation method of chemical compounds I disclosed in international literature is mainly：US7932379, US6515117 and
US7919598 can be summarized as following route：
The route steps are longer, are unfavorable for industrial amplification, it is therefore desirable to provide the operation for shortening step, make it in preparationization
The intermediate generated during object I is closed at least to improve yield and purity.This method is needed further exist for using three-dimensional selective
It operates to prepare substantially enantiomer-pure compound.
Invention content
It is an object of the invention to solve above-mentioned technical problem, provide that a kind of purity is high, type I compound of high income reaches lattice
Net preparation method is arranged, is included the following steps：
A, IV compound of formula is obtained by the reaction with III compound of formula in II compound of formula,
Wherein, R1 is hydroxy-protecting agent, and X is selected from bromine or iodine；Preferably, R1 is silylation, and X is bromine；It is furthermore preferred that R1 is
Trimethyl silicon substrate；
III compound of formula is added in organic solvent, cool down simultaneously nitrogen protection, is slowly added to butyl lithium, III compound of formula is anti-
After answering completely, it is slowly added to II compound of formula.After completion of the reaction, it is slowly added to the aqueous solution of acid one, controls temperature, after finishing certainly
It is so warming up to 0~40 DEG C, is reacted 2~3 hours, post-processing obtains IV compound of formula.Acid one is selected from hydrochloric acid, sulfuric acid, nitric acid, methylsulphur
Acid or trifluoroacetic acid, preferably trifluoroacetic acid.
Butyl lithium is selected from n-BuLi or tert-butyl lithium, preferably n-BuLi, III compound of formula：II chemical combination of formula
Object：The molar ratio of butyl lithium is about 1:1.0-2.0:1.0-2.0 preferably 1:1.5:1.3.
Reaction dissolvent is selected from tetrahydrofuran, benzene,toluene,xylene or ether, and the mixing of preferably tetrahydrofuran and toluene is molten
Agent；
B, V compound of formula is obtained by the reaction in IV compound of formula,
Ethyl alcohol dissolving is added in V compound of formula, acidity alcohol solution, insulation reaction 5 are slowly added to after being cooled to 0~40 DEG C
~8 hours, post-processing obtained V compound of formula.Wherein acidity alcohol solution is selected from hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid or trifluoro second
The ethanol solution of acid, preferably ethanol solution hydrochloride.
V compound of formula can also use organic solvent recrystallization purifying.V compound good solvent of formula is dissolved, is added not
Good solvent crystallization, wherein good solvent are selected from methanol, ethyl alcohol, normal propyl alcohol or isopropanol, preferably normal propyl alcohol；Poor solvent is selected from just
Heptane, n-hexane or hexamethylene, preferably normal heptane.
C, V compound reduction reaction of formula obtains type I compound,
Reducing agent is silane and boron trifluoride ether mixture, and wherein silane is selected from triethylsilane, trimethyl silane, different
Propyl silane or phenyl silane, preferably triethylsilane.
Reduction reaction temperature in step c is -20~-10 DEG C；
Preparation method provided by the invention being capable of high yield, V compound of formula of high-purity.With the formula V of high-purity
Type I compound prepared by compound has higher purity, without being further purified.
Specific implementation mode
Below in conjunction with specific embodiment, embodiment of the present invention is described in detail.Under
Face embodiment is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment 1
The preparation of compound 4a
Compound 3a (180g, 0.55mol), tetrahydrofuran (360ml), toluene (720ml) are added in 5L there-necked flasks, stirred
Mix to dissolved clarification, nitrogen protection, dry ice-propanone bath is cooled to -80~-70 DEG C, be added dropwise n-butyllithium solution (287ml,
0.715mol, 1.3eq), process control temp is added dropwise at -80~-70 DEG C, drips and is stirred to react 0.5h for -80~-70 DEG C after finishing.Drop
Add the solution for being dissolved in toluene (360ml) of compound 2a (400g, 0.86mol), process control temp be added dropwise at -80~-70 DEG C,
It is stirred to react 1 hour for -80~-70 DEG C after drop finishes.
The solution that trifluoroacetic acid (126g, 1.10mol) is dissolved in water (600mL) is added drop-wise in reaction solution, and control temperature is small
In -20 DEG C, drop warms naturally to 10~20 DEG C after finishing, and reacts 2~3 hours.
Reaction finishes, and water (180ml), ethyl acetate (180ml) are added into reaction solution, is layered after stirring 30min, water layer
Ethyl acetate (540ml) extracts, and merges organic layer.It is washed successively with saturated sodium bicarbonate aqueous solution (720ml) and water (720ml)
It washs, anhydrous sodium sulfate (400g) is 2 hours dry, and after filtering, 42 DEG C are concentrated to dryness to obtain compound 4a (230g), yield
98.4%.
Embodiment 2
The preparation of compound 4a
Compound 3a (180g, 0.55mol), tetrahydrofuran (360ml), toluene (720ml) are added in 5L there-necked flasks, stirred
Mix to dissolved clarification, nitrogen protection, dry ice-propanone bath is cooled to -80~-70 DEG C, be added dropwise n-butyllithium solution (287ml,
0.715mol, 1.3eq), process control temp is added dropwise at -80~-70 DEG C, drips and is stirred to react 0.5h for -80~-70 DEG C after finishing.Drop
Add the solution for being dissolved in tetrahydrofuran (360ml) of compound 2a (385g, 0.825mol), be added dropwise process control temp -80~-
It 70 DEG C, drips and is stirred to react 1 hour for -80~-70 DEG C after finishing.
The solution that trifluoroacetic acid (126g, 1.10mol) is dissolved in water (600mL) is added drop-wise in reaction solution, and control temperature is small
In -20 DEG C, drop warms naturally to 10~20 DEG C after finishing, and reacts 2~3 hours.
Reaction finishes, and water (180ml), ethyl acetate (180ml) are added into reaction solution, is layered after stirring 30min, water layer
Ethyl acetate (540ml) extracts, and merges organic layer.It is washed successively with saturated sodium bicarbonate aqueous solution (720ml) and water (720ml)
It washs, anhydrous sodium sulfate (400g) is 2 hours dry, and after filtering, 42 DEG C are concentrated to dryness to obtain compound 4a (225g), yield
96.2%.
Embodiment 3
The preparation of compound 5a
Ethyl alcohol (1.3L) is added in compound 4a (230g, 054mol), stirs dissolved clarification, is cooled to 10~20 DEG C, first is added dropwise
The ethanol solution (105.7g is dissolved in 500ml) of sulfonic acid drips insulation reaction 5~8 hours after finishing.Reaction solution is poured into unsaturated carbonate hydrogen
In sodium water solution (1.8L), water (1.8L) and ethyl acetate (1.8L) is added, is layered after stirring 30min, aqueous layer with ethyl acetate
(1.8L) is extracted, and merges organic layer, and organic layer is washed with saturated sodium-chloride water solution (900ml), and anhydrous sodium sulfate (500g) is dry
Dry 2 hours, compound 5a (242.7g, grease), yield 99.0%, purity are concentrated to dryness to obtain for 42 DEG C after filtering
95.9%.
Embodiment 4
The preparation of compound 5a
Ethyl alcohol (13L) is added in compound 4a (230g, 054mol), stirs dissolved clarification, is cooled to 10~20 DEG C, is added dropwise
2mol/L ethanol solution hydrochlorides drip insulation reaction 5~8 hours after finishing.Reaction solution is poured into saturated sodium bicarbonate aqueous solution
In (1.8L), water (1.8L) and ethyl acetate (1.8L) is added, is layered after stirring 30min, aqueous layer with ethyl acetate (1.8L) extraction
It taking, merges organic layer, organic layer is washed with saturated sodium-chloride water solution (900ml), and anhydrous sodium sulfate (500g) is 2 hours dry,
It is concentrated to dryness to obtain compound 5a (242.7g, grease), yield 99.0%, purity 97.4% for 42 DEG C after filtering.
Embodiment 5
The purifying of compound 5a
Normal propyl alcohol (720ml) will be added in 3 gained compound 5a (240g) of embodiment, 40 DEG C of stirring dissolved clarifications are cooled to 10
~20 DEG C, normal heptane (3.6L), water (18ml) is added, a large amount of solids are precipitated, continues stirring 5 hours, filtering, filter cake normal heptane
(300ml x 2) is washed.40 DEG C of solid is dried in vacuo 3 hours, obtains compound 5a (206.6g, white solid), yield 86.1%,
Purity 99.4%.
Embodiment 6
The preparation of type I compound
5 gained compound 4a (10.0g, 22.1mmol, 1.0eq) of embodiment is dissolved in dichloromethane (50mL) and acetonitrile
In (50mL), the molecular sieve (30g) that activation is added is dried overnight.
Above-mentioned solution is added in reaction bulb, under nitrogen protection be added triethylsilane (7.7g, 66.2mmol,
3.0eq), -20 DEG C~-10 DEG C are cooled to, boron trifluoride ether (6.3g, 44.2mmol, 2.0eq) is added dropwise, after being added dropwise, is protected
Temperature stirring 4 hours, then it is warmed to room temperature stirring 1 hour.Saturated sodium bicarbonate solution (100mL) and acetic acid second are added into reaction solution
Ester (100mL), liquid separation, water phase use ethyl acetate (50mL) extraction primary, merge organic phase, washed once with water (50mL) again
Afterwards, anhydrous sodium sulfate is dried, and filtering is concentrated to dryness to obtain type I compound 8.8g, yield 97.3%, purity 99.8%, maximum single miscellaneous
0.03%.
Spectroscopic data：
1H NMR(400MHz,CDCl3)δ(ppm)1.75(s,3H),1.77(s,3H),1.85-1.87(d,3H),5.12
(br, 2H), 6.06-6.10 (q, J=6.4Hz, 1H), 6.99 (s, 1H), 7.04-7.07 (m, 1H), 7.28-7.31 (m, 1H),
7.40-7.43(m,1H),7.44-7.53(m,2H),7.85(s,1H)。
IR(KBr):3478,3268,3081,2982,1627,1514,1483,1551,1455,1427,1397,1189,
1274,1096,860,819,775cm-1.MS(m/z)：471.06031[M+H]+。
Comparative example 1
The preparation of type I compound
Compound 4a ' (10.0g, 22.1mmol, 1.0eq, purity 90.2%) is dissolved in dichloromethane (50mL) and acetonitrile
In (50mL), the molecular sieve (30g) that activation is added is dried overnight.
Above-mentioned solution is added in reaction bulb, under nitrogen protection be added triethylsilane (7.7g, 66.2mmol,
3.0eq), -20 DEG C~-10 DEG C are cooled to, boron trifluoride ether (6.3g, 44.2mmol, 2.0eq) is added dropwise, after being added dropwise, is protected
Temperature stirring 4 hours, then it is warmed to room temperature stirring 1 hour.Saturated sodium bicarbonate solution (100mL) and acetic acid second are added into reaction solution
Ester (100mL), liquid separation, water phase use ethyl acetate (50mL) extraction primary, merge organic phase, washed once with water (50mL) again
Afterwards, anhydrous sodium sulfate is dried, and filtering is concentrated to dryness to obtain type I compound 7.4g, yield 83.1%, purity 85.0%.
Comparative example 2
Purifying formula 5a ' compounds：Methyl-1-C- (the chloro- 4 '-ethoxy diphenyl methylmethane 3- yls of 2-)-α-D- glucopyras
Sugar
Fully according to by patent CN200810088495.2 embodiments 17, formula 5a ' compounds, purity is prepared
89.1%.
Normal propyl alcohol (30ml) will be added in compound 5a ' (10g) obtained by upper step, 40 DEG C of stirring dissolved clarifications are cooled to 10~20
DEG C, normal heptane (150mlL) plus water (75 μ l) is added, a large amount of solids are precipitated, continues stirring 5 hours, filtering, filter cake normal heptane
(5ml) is washed.40 DEG C of solid is dried in vacuo 3 hours, obtains compound 5a ' (7.6g, white solid), yield 76.1%, purity
89.2%.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, without departing from the inventive concept of the premise, can also make several improvements and modifications, these improvements and modifications also should be regarded as
In protection scope of the present invention.
Claims (10)
1. a kind of preparation method of type I compound, which is characterized in that include the following steps：
A, IV compound of formula is obtained by the reaction with III compound of formula in II compound of formula,
B, V compound of formula is obtained by the reaction in IV compound of formula,
C, V compound reduction reaction of formula obtains type I compound,
Wherein, R1 is hydroxy-protecting agent, and X is selected from bromine or iodine.
2. preparation method according to claim 1, which is characterized in that R1 is silylation, preferably trimethyl silicon substrate；X is bromine.
3. preparation method according to claim 1 or 2, which is characterized in that in step a, described sour one selected from hydrochloric acid, sulphur
Acid, nitric acid, methanesulfonic acid or trifluoroacetic acid, preferably trifluoroacetic acid.
4. preparation method according to claim 1 or 2, which is characterized in that in step b, acidity alcohol solution is selected from hydrochloric acid, sulphur
The ethanol solution of acid, nitric acid, methanesulfonic acid or trifluoroacetic acid, preferably ethanol solution hydrochloride.
5. preparation method according to claim 1 or 2, which is characterized in that further include V compound of formula with having in step b
Solvent recrystallization purifying.
6. preparation method according to claim 5, which is characterized in that dissolve V compound of formula with good solvent, be added
Poor solvent crystallization.
7. preparation method according to claim 6, which is characterized in that the good solvent is selected from methanol, ethyl alcohol, normal propyl alcohol
Or isopropanol, preferred normal propyl alcohol.
8. preparation method according to claim 6, which is characterized in that the poor solvent be selected from normal heptane, n-hexane or
Hexamethylene, preferably normal heptane.
9. preparation method according to claim 1 or 2, which is characterized in that in step c, the reducing agent is silane and three
Boron fluoride ether mixtures.
10. preparation method according to claim 9, which is characterized in that the silane is selected from triethylsilane, trimethyl silicane
Alkane, isopropyl base silane or phenyl silane, preferably triethylsilane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400561A (en) * | 2018-12-21 | 2019-03-01 | 山东豪迈化工技术有限公司 | The synthetic method of Dapagliflozin |
| CN113880796A (en) * | 2021-10-14 | 2022-01-04 | 山东诚创蓝海医药科技有限公司 | Preparation method of dapagliflozin |
| CN114577944A (en) * | 2022-03-10 | 2022-06-03 | 山东鲁抗医药股份有限公司 | Method for detecting related substances in 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
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| CN104710486A (en) * | 2015-04-07 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Method for synthesizing SGLT2 inhibitor drugs |
| WO2015132803A2 (en) * | 2014-03-06 | 2015-09-11 | Msn Laboratories Private Limited | Process for the preparation of (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-d-glucitol and its solvate thereof |
| CN105481915A (en) * | 2014-09-19 | 2016-04-13 | 北京万生药业有限责任公司 | Preparation method of SGLT-2 inhibitor compound |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015132803A2 (en) * | 2014-03-06 | 2015-09-11 | Msn Laboratories Private Limited | Process for the preparation of (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-d-glucitol and its solvate thereof |
| CN105481915A (en) * | 2014-09-19 | 2016-04-13 | 北京万生药业有限责任公司 | Preparation method of SGLT-2 inhibitor compound |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400561A (en) * | 2018-12-21 | 2019-03-01 | 山东豪迈化工技术有限公司 | The synthetic method of Dapagliflozin |
| CN113880796A (en) * | 2021-10-14 | 2022-01-04 | 山东诚创蓝海医药科技有限公司 | Preparation method of dapagliflozin |
| CN114577944A (en) * | 2022-03-10 | 2022-06-03 | 山东鲁抗医药股份有限公司 | Method for detecting related substances in 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
| CN114577944B (en) * | 2022-03-10 | 2023-08-15 | 山东鲁抗医药股份有限公司 | Detection method for related substances in 5-bromo-2-chloro-4' -ethoxydiphenylmethane |
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