CN108033955A - A kind of preparation method of antidiabetic drug canagliflozin - Google Patents
A kind of preparation method of antidiabetic drug canagliflozin Download PDFInfo
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- CN108033955A CN108033955A CN201711350872.0A CN201711350872A CN108033955A CN 108033955 A CN108033955 A CN 108033955A CN 201711350872 A CN201711350872 A CN 201711350872A CN 108033955 A CN108033955 A CN 108033955A
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- C07—ORGANIC CHEMISTRY
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- 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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Abstract
The present invention discloses a kind of preparation method of antidiabetic drug canagliflozin, includes the following steps：Using 4 toluene bromides as raw material, 5 bromine, 2 methyl benzyl chloride is prepared through Blanc chloromethylations；2 (2 methyl, 5 bromobenzyl) 5 (4 fluorophenyl) thiophene are made through paying a gram alkylated reaction under the catalysis of zinc chloride with 2 (4 fluorophenyl) thiophene in 5 bromine, 2 methyl benzyl chloride；2 (2 methyl, 5 bromobenzyl) 5 (4 fluorophenyl) thiophene and 2,3,4,6 4 O trimethyls silicon substrate D glucolactones are through being condensed, being etherified, demethoxylation reaction antidiabetic drug canagliflozin.The process route of the present invention it is raw materials used it is cheap be easy to get, technique industrialization easy to implement, gained final products purity is high；And the process route of the present invention is novel, synthetic route is short, and without dangerous complicated technology in reaction, equipment is simple, easy to operate, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of process for preparing medicine, more particularly to a kind of antidiabetic drug canagliflozin for diabetes B
Preparation method.
Background technology
Canagliflozin (canagliflozin, 1), entitled (1S) -1,5- dehydrogenations -1-C- [3- [[5- (the 4- fluorobenzene of chemistry
Base) -2- thienyls] methyl] -4- aminomethyl phenyls]-D-Glucose alcohol hydrate (2: 1) is by Mitsubishi Tanabe
A kind of oral 2 type of C- glycosides sodium dependent glucose that Pharma companies original is ground cotransports body inhibitor.Can be near by blocking
Distal convoluted tubule makes the glucose of filtration be discharged from urine the re-absorption of glucose, so as to reach hypoglycemic purpose.In March, 2013 head
It is secondary to ratify to list through U.S. FDA, it is clinically used for treatment diabetes B, trade name Invokana.
The synthetic method of canagliflozin is mainly the following：
The first synthetic schemes is using the bromo- 2- methyl benzoic acids of 5- as starting material, through chloride, with 2- (4- fluorophenyls)
Thiophene, which is paid, gram to be acylated, and is then reduced, then with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyras saccharic acids 1, in 5-
Canagliflozin is made in ester condensation, methyl-etherified, reduction de-methoxy.Its process route is as follows：
Program route is shorter, but starting material synthesis difficulty is big, of high cost, expensive.Such as document：PCT
Int.Appl.,2016098016；PCT Int.Appl.,2016016852.
Second of synthetic schemes is equally using 5- nitro -2- methyl benzoyl chlorides as starting material, with the bromo- 5- thiophene boron of 2-
Sour coupled reaction, then pays with 2- p-fluorophenyls thiophene and gram is acylated, nitro reduction, diazotising bromo, then with 2,3,4,6-
Canagliflozin is made in four-O- trimethylsilyl-D- glucopyras saccharic acids 1, ester condensation in 5-, methyl-etherified, reduction de-methoxy.
Its process route is as follows：
The synthetic schemes route is grown, and yield is low.Such as patent：CN104311532.
The third scheme is equally using 2- methyl -5- bromobenzaldehydes as starting material, passes through fourth with 2- p-fluorophenyl thiophene
Base lithium reacts, reduction, then with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyras saccharic acids 1, ester condensation in 5-, first
Etherificate, reduces de-methoxy, is made.Concrete technology route is as follows：
The raw materials technology is expensive, twice using butyl lithium, process dangerous higher.Such as patent：CN104987320.
4th kind of scheme is using 2 thiophene carboxaldehyde as starting material, reacts, then aoxidizes, chloride with 4- bromofluorobenzenes, with
4- toluene bromides react, reduction, then with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyras saccharic acids 1, the contracting of 5- lactones
Close, methyl-etherified, reduction de-methoxy is made.Concrete technology route is as follows：
The synthetic schemes reaction scheme is longer, and yield is relatively low.Such as patent：Eur.Pat.Appl.,20152918579.
5th kind of synthetic schemes be using o-toluic acid as starting material, through bromo, then with 2- p-fluorophenyl thiophene
Generation friedel-crafts reaction, reduction, then with 2,3,4,6- tetra--O- trimethylsilyl-D- glucopyras saccharic acids 1, the contracting of 5- lactones
Close, methyl-etherified, canagliflozin is made in reduction de-methoxy.
The process route uses bromine, and environmental pollution is serious.Such as patent：CN103980263.
The content of the invention
Goal of the invention：The present invention be directed to existing for the existing preparation method of canagliflozin starting material synthesis difficulty greatly, cost
A kind of the problems such as high, expensive, toxic contaminants, there is provided preparation method of new antidiabetic drug canagliflozin.
Technical solution：A kind of preparation method of antidiabetic drug canagliflozin of the present invention, includes the following steps：
(1) using 4- toluene bromides as raw material, the bromo- 2- methyl benzyl chlorides of 5- are prepared through Blanc chloromethylations；
(2) the bromo- 2- methyl benzyl chlorides of 5- pass through under the catalysis of zinc chloride with 2- (4- fluorophenyls) thiophene and pay a gram alkylated reaction
2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene is made；
(3) 2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene and tetra--O- trimethyl silicon substrate-D- Portugals of 2,3,4,6-
1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- are made through condensation, etherification reaction in grape saccharic acid lactone
(4- fluorophenyls) -2- thienyls] methyl] benzene；
(4) 1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thienyls]
Methyl] benzene reacts through demethoxylation, obtain antidiabetic drug canagliflozin.
Step (1)：Prepare the bromo- 2- methyl benzyl chlorides (I) of 5-
It is preferred that 4- toluene bromides and paraformaldehyde are prepared into 5- under the catalysis of chlorosulfonic acid and zinc chloride through chloromethylation
Bromo- 2- methyl benzyl chloride, selects acid reagent of the chlorosulfonic acid as chloromethylation, sour dosage is few, with traditional chloromethylation side
Method is compared, high income, easy to operate.Specific reaction is as follows：
Wherein, Blanc chloromethylations are preferred first carries out under ice bath, and then heating to 60~70 DEG C, the reaction was continued,
6~8h of reaction time.
Step (2)：Prepare 2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene (II)
Specific reaction is as follows：
The temperature that gram alkylated reaction is paid in this step is preferably 70~90 DEG C, and the reaction time is 7~8h.Reaction dissolvent can
Select ethyl acetate, carbon disulfide etc., ethyl acetate.
This step is used as catalyst using zinc chloride, avoids the accessory substance that brings using aluminium chloride more, with high income
Advantage.
Step (3)：Preparation 1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -
2- thienyls] methyl] benzene (III)
2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene can first with tetra--O- trimethyl silicon substrates-D- of 2,3,4,6-
Glucolactone reacts, and is condensed under the catalysis of butyl lithium, 1- (1-O- first is then made with methanol etherification in acid condition
Base-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thienyls] methyl] benzene；Specific reaction is such as
Under：
Wherein, the acid condition of etherification reaction is methanesulfonic acid.
The reaction dissolvent of this step can select ether, tetrahydrofuran, toluene etc., and preferably tetrahydrofuran/toluene mixing is molten
Agent.
Step (4)：Prepare canagliflozin (IV)
It is preferred that by 1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thiophene
Base] methyl] benzene is catalyzed triethyl group silicon hydrogen reduction demethoxylation by zinc chloride and is made, and specific reaction is as follows：
Beneficial effect：Compared with prior art, remarkable advantage of the invention is, used in the process route of (1) present invention
Cost of material is cheap and easily-available, technique industrialization easy to implement, and gained final products purity is high；(2) process route of the invention is new
Grain husk, synthetic route is short, and without dangerous complicated technology in reaction, equipment is simple, easy to operate, is adapted to industrialized production.
Brief description of the drawings
Fig. 1 is the hydrogen spectrum for the canagliflozin that embodiment measures；
Fig. 2 is the carbon spectrum for the canagliflozin that embodiment measures.
Embodiment
Technical scheme is described further below.
A kind of preparation method of antidiabetic drug canagliflozin of the present invention, this method is using 4- toluene bromides as starting material, warp
Blanc chloromethylations (i.e. Blanc chloromethylation), pass through under Louis acid catalysis with 2- (4- fluorophenyls) thiophene
Pay a gram alkylated reaction and 2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene is made, then with 2,3,4,6- tetra--O- three
Methylsilyl-D-Glucose acid lactone obtains antidiabetic drug canagliflozin through condensation, etherificate, demethoxylation.
Its concrete technology route is as follows：
Embodiment
The preparation (I) of the bromo- 2- methyl benzyl chloride of the first step, 5-
4- toluene bromide 17g are taken, paraformaldehyde 3.9g, zinc chloride 1g, is dissolved in 100ml ethyl acetate, is sufficiently stirred, ice bath
Lower dropwise addition chlorosulfonic acid 11.6g, 2h is added dropwise, and after being added dropwise, system is warming up to 60 DEG C of reaction 5h, after reaction, reaction
Liquid is cooled to room temperature, slowly imports in 100g frozen water, and is stirred continuously, liquid separation, have it is several layers of be washed to neutrality, anhydrous sodium sulfate is done
Dry, filtering, filtrate decompression recycling design, residue is evaporated under reduced pressure to light yellow liquid 17.7g, yield 81%.
The hydrogen spectrum and carbon spectrum of this step products therefrom are as follows：
1HNMR(CDCl3, 300MHz):δ7.46(m),7.35(m),7.06(m),4.53(s,2H),2.36(s,3H).
13CNMR(CDCl3,75MHz):δ137.35,136.23,132.37,132.28,131.73,119.54,43.78,
18.32.
The preparation (II) of second step, 2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene
Bromo- 2- methyl benzyl chloride 50g, 2- (4- fluorophenyls) the thiophene 48g of 5- are taken, are dissolved in 200ml ethyl acetate, add zinc chloride
15g, is then to slowly warm up to 75 DEG C of reaction 7h, after reaction, is cooled to room temperature, and reaction solution is poured into 200ml water, liquid separation,
Organic layer adds 100ml washings, and the drying of organic layer anhydrous sodium sulfate, filters, 5g activated carbon decolorizings are added in filtrate, and flow back 3h,
Filter while hot, filtrate decompression recycling design, residue obtains white solid 78.3g, yield 87% with 70% alcohol crystal.
The hydrogen spectrum and carbon spectrum of this step products therefrom are as follows：
1HNMR (DMSO-d6,500MHz) δ 2.25 (3H, s), 4.15 (2H, s), 6.85 (1H, d, J=3.5Hz), 7.17
(1H, d, J=8.0Hz), 7.21 (2H, m), 7.31 (1H, d, J=3.5Hz), 7.36 (1H, dd, J=8.0,1.9Hz), 7.44
(1H, d, J=1.9Hz), 7.60 (2H, m)
13CNMR(DMSO-d6,125MHz):18.52,32.84,115.83,116.00,118.81,123.52,126.86,
126.99,127.05,129.50,130.41,131.60,132.37,135.54,140.63,141.16,142.46,162.42
3rd step, 1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thiophenes
Fen base] methyl] benzene preparation (III)
Take 2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene 134g, anhydrous THF/ toluene 300g (1：4) mix
Solvent adds to the 500ml reaction ax dried through nitrogen, and liquid nitrogen is cooled to -78 DEG C, 1.6molL is slowly added dropwise-1Hexyllithium oneself
Alkane solution 70ml, maintains stirring reaction 1h at a temperature of this.- 78 DEG C of tetra--O- trimethyl silicon substrate-D- grapes of 2,3,4,6- will be cooled to
The toluene solution 500g of saccharic acid lactone (200g) is slowly added dropwise into above-mentioned reaction solution, and -78 DEG C of the reaction was continued 3h, reaction finishes
Afterwards, the methanol solution (methanesulfonic acid 200g+ methanol 250g) of 450g Loprazolams is added at such a temperature.0 DEG C is warming up to continue to stir
Reaction 4h is mixed, then heats to 40 DEG C of stirring reaction 6h.After reaction, 5molL is used-1Sodium hydrate aqueous solution adjust it is anti-
Answer the pH to 7~8 of liquid.30min is stirred, is extracted with ethyl acetate (500ml × 2), organic phase is washed with saturated salt solution aqueous solution
To wash to neutrality, then add anhydrous sodium sulfate drying, filtering, filtrate decompression recycling design, obtains faint yellow sticky oil thing 137g,
Yield 76%.
The hydrogen spectrum of this step products therefrom is as follows：
1H NMR(DMSO-d6,500MHz)δ2.26(3H,s),2.91(1H,m),2.95(3H,s),3.21(1H,m),
3.37 (1H, m), 3.51-3.61 (2H, m), 3.75 (1H, m), 4.09~4.18 (1H, m), 4.51 (1H, m), 4.65~4.69
(2H, m), 4.94 (1H, d, J=5.5Hz), 6.77 (1H, d, J=3.5Hz), 7.14 (1H, d, J=8.0Hz), 7.20 (2H,
M), 7.26 (1H, d, J=3.5Hz), 7.32 (1H, m), 7.42 (1H, d, J=1.5Hz), 7.57 (2H, m)
The preparation (IV) of 4th step, canagliflozin
Take 1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thienyls]
Methyl] benzene 90g, dichloromethane 150ml and acetonitrile 250ml add 1L reaction bulbs in, stir evenly.Reaction solution is cooled to -5 DEG C,
5g zinc chloride are added, stir 30min, keep the temperature that 140g Et are added dropwise3SiH, drop finish, and system is to slowly warm up to 10 DEG C, reaction
2h.Reaction finishes, and system is cooled to -5 DEG C, and saturated sodium bicarbonate solution is added dropwise and adjusts pH to 6~7.With ethyl acetate (400g ×
2) extract, organic phase with saturated nacl aqueous solution, water washing to neutrality, then adds anhydrous sodium sulfate drying, filter successively, filter
Liquid, which is concentrated under reduced pressure, recycles ethyl acetate, adds 400g methanol and acetone (1:1) mixed solution, stirring, a large amount of solids separate out, cold
But 30min is stirred.Filtering, cold ethanol wash solid, and 50 DEG C are dried in vacuum overnight, and obtain white solid 125g, yield 74%, purity
99.32%.
The hydrogen spectrum and carbon spectrum of this step products therefrom are as follows：
1HNMR(DMSO,400MHz):δ 7.62-7.58 (m, 2H), 7.29-7.12 (m, 6H), 6.81 (d, J=3.6Hz,
1H), 4.94 (d, J=4.8Hz, 2H), 4.74 (d, J=5.6Hz, 1H), 4.46 (m, 1H), 4.18-4.08 (m, 2H)；3.98
(d, J=9.2Hz, 1H), 3.72-3.69 (m, 1H), 3.47 (m, 1H), 3.30-3.14 (m, 4H)；2.27(s,3H).
13CNMR(100MHz,DMSO):δ162.60,160.17,143.65,140.24,138.25,137.38,134.96,
130.56,130.53,129.67,129.08,127.01,126.93,126.37,126.26,123.41,116.01,115.79,
81.34,81.22,78.50,74.70,70.44,61.45,33.46,18.83.
Claims (8)
1. a kind of preparation method of antidiabetic drug canagliflozin, it is characterised in that include the following steps：
(1) using 4- toluene bromides as raw material, the bromo- 2- methyl benzyl chlorides of 5- are prepared through Blanc chloromethylations；
(2) the bromo- 2- methyl benzyl chlorides of 5- are made with 2- (4- fluorophenyls) thiophene under the catalysis of zinc chloride through paying a gram alkylated reaction
2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene；
(3) 2- (2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene and tetra--O- trimethyls silicon substrates of 2,3,4,6--D-Glucose
1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorine is made through condensation, etherification reaction in acid lactone
Phenyl) -2- thienyls] methyl] benzene；
(4) 1- (1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thienyls] first
Base] benzene reacts through demethoxylation, obtain antidiabetic drug canagliflozin.
2. the preparation method of antidiabetic drug canagliflozin according to claim 1, it is characterised in that in step (1), by 4- bromines
Toluene prepares the bromo- 2- methyl benzyl chlorides of 5- under the catalysis of chlorosulfonic acid and zinc chloride with paraformaldehyde through chloromethylation.
3. the preparation method of antidiabetic drug canagliflozin according to claim 1, it is characterised in that described in step (1)
Blanc chloromethylations first carry out under ice bath, and then heating to 60~70 DEG C, the reaction was continued, 6~8h of reaction time.
4. the preparation method of antidiabetic drug canagliflozin according to claim 1, it is characterised in that in step (2), described pair
The temperature of gram alkylated reaction is 70~90 DEG C, and the reaction time is 7~8h.
5. the preparation method of antidiabetic drug canagliflozin according to claim 1, it is characterised in that in step (2), described pair
The solvent of gram alkylated reaction is ethyl acetate or carbon disulfide.
6. the preparation method of antidiabetic drug canagliflozin according to claim 1, it is characterised in that in step (3), the 2-
(2- methyl -5- bromobenzyls) -5- (4- fluorophenyls) thiophene elder generation and tetra--O- trimethyls silicon substrates of 2,3,4,6--D-Glucose acid lactone
Reaction, is condensed under the catalysis of butyl lithium, 1- (1-O- methyl-β-D- pyrans is then made with methanol etherification in acid condition
Glucose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thienyls] methyl] benzene.
7. the preparation method of antidiabetic drug canagliflozin according to claim 6, it is characterised in that reaction is molten in step (3)
Agent is ether, tetrahydrofuran or toluene.
8. the preparation method of antidiabetic drug canagliflozin according to claim 1, it is characterised in that in step (4), the 1-
(1-O- methyl-β-D- glucopyranose -1- bases) -4- methyl -3- [[5- (4- fluorophenyls) -2- thienyls] methyl] benzene passes through chlorine
Change zinc catalysis triethyl group silicon hydrogen reduction demethoxylation and canagliflozin is made.
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| CN108658929A (en) * | 2018-06-26 | 2018-10-16 | 宁波人健化学制药有限公司 | A kind of high-purity 2-（4- fluorophenyls）The preparation method of thiophene |
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