CN114591313A - Preparation method of canagliflozin - Google Patents
Preparation method of canagliflozin Download PDFInfo
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- CN114591313A CN114591313A CN202011404255.6A CN202011404255A CN114591313A CN 114591313 A CN114591313 A CN 114591313A CN 202011404255 A CN202011404255 A CN 202011404255A CN 114591313 A CN114591313 A CN 114591313A
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- canagliflozin
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- bromoglucose
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- 229960001713 canagliflozin Drugs 0.000 title claims abstract description 22
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 5
- -1 preferably Substances 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 150000003751 zinc Chemical class 0.000 claims 1
- 150000003752 zinc compounds Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 5
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000033679 diabetic kidney disease Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- MGXZKAYHSITHMW-UHFFFAOYSA-N 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene Chemical compound CC1=CC=C(I)C=C1CC1=CC=C(C=2C=CC(F)=CC=2)S1 MGXZKAYHSITHMW-UHFFFAOYSA-N 0.000 description 2
- VLRIERSBZHUCOW-UHFFFAOYSA-N 2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene Chemical compound CC1=CC=C(Br)C=C1CC1=CC=C(C=2C=CC(F)=CC=2)S1 VLRIERSBZHUCOW-UHFFFAOYSA-N 0.000 description 2
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000012209 glucono delta-lactone Nutrition 0.000 description 1
- 229960003681 gluconolactone Drugs 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention provides a preparation method of canagliflozin, which comprises the following steps: (1) reacting the compound of formula (III) with alpha-bromoglucose to convert the compound of formula (II) (2) and hydrolyzing the compound of formula (II) to obtain the compound of formula (I). The method for preparing the canagliflozin has the advantages of cheap and easily-obtained alpha-bromoglucose raw material, short steps, mild reaction conditions, easy purification, simple operation and high yield, greatly reduces the production cost, and is suitable for industrialization.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of canagliflozin.
Background
Canagliflozin (canagliflozin) is a selective sodium-glucose cotransporter (SGLT2) inhibitor that has been approved for improving glycemic control in adult patients with type 2 diabetes. The drug acts independently of insulin, selectively inhibits SGLT2 in the kidney, and helps the patient to excrete excess glucose from the urine. Canagliflozin, co-developed by mitsubishi corporation and qiangsheng corporation, was approved by FDA in us for marketing at 29 days 3 and 3 months 2013, and was the first FDA-approved sodium glucose co-transporter 2(SGLT2) inhibitor. The medicine is approved by European Committee (EC) in 2013 at 11/25, and can be used for treating adult type 2 diabetes. The canagliflozin can inhibit SGLT2, so that glucose in renal tubules cannot be successfully reabsorbed into blood and is discharged with urine, thereby reducing the blood glucose concentration. The us Food and Drug Administration (FDA) has approved the hypoglycemic drug canagliflozin in 2019 as a new indication: for adult patients with type 2 diabetes and diabetic nephropathy and urine containing a certain amount of protein, reducing the risk of end-stage renal disease, worsening renal function, cardiovascular death, heart failure hospitalization. Is currently the only drug suitable for helping type 2 diabetes reduce the risks associated with diabetic nephropathy, including the risk of hospitalization for heart failure. The net sales of vigorous canagliflozin in 2019 was $ 7.35 billion. The chemical name is (1S) -1, 5-dehydrogenation-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol hydrate (2: 1), and the structure is as follows:
the current preparation method of canagliflozin is reported at home and abroad: WO2005/012326 discloses a synthesis method, which comprises synthesizing side chain 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene or 2- (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene, and then condensing and coupling the side chain and protected gluconolactone to obtain canagliflozin, wherein the specific route is as follows:
the route has low overall yield and high production cost, and is not suitable for industrial production.
WO2009/035969 discloses a synthesis method, wherein after synthesizing side chain 2- [ (5-bromo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene or 2- (5-iodo-2-methylphenyl) methyl ] -5- (4-fluorophenyl) thiophene, the side chain reacts with 2,3,4, 6-O-tet-pivaloyl-alpha-D-bromoglucopyranose, and the deprotection group is hydrolyzed to obtain canagliflozin, and the specific synthetic route is as follows:
the price of the starting raw material 2,3,4, 6-O-tet-amyl-alpha-D-bromo glucopyranose in the route is higher, because in the prior art, the preparation method of the alpha-bromo-tetraacyl glucose generally leads the sugar to react with acylation in the presence of alkali so as to obtain the derivative protected by the tetraacyl group of the sugar, the yield is lower, the hydroxyl is difficult to be completely protected, the separation and the purification are difficult, the obtained derivative protected by the tetraacyl group of the sugar reacts with acetyl bromide so as to prepare the alpha-bromo-tetraacyl glucose, the used alkali and acyl halide have large amount, and more three wastes are generated. Therefore, the price of the 2,3,4, 6-O-tet-pivaloyl-alpha-D-bromo glucopyranose is higher, so that the production cost of the canagliflozin is higher and the canagliflozin is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a synthetic route, which has the advantages of easily available raw materials, short reaction steps, easy purification, simple operation, high yield and low production cost.
The invention can realize the purpose by the following technical scheme:
the invention also provides a preparation method of the canagliflozin, which comprises the following steps:
(1) converting a compound of formula (III) to formula (II) by reaction with alpha-bromoglucose:
wherein R1, R2 are selected from Piv or Bz groups, and R1 and R2 do not simultaneously represent Piv groups. When R1 is Piv, R2 cannot be Piv group, and when R2 is Piv, R1 cannot be Piv group;
(2) hydrolyzing the compound of formula (II) to provide a compound of formula (I):
alpha-bromoglucose, the structure of which is selected from the group consisting of formula (IVA), formula (IVB), formula (IVC) or a mixture of compounds of formula (IVA), (IVB), (IVC) or a mixture of compounds of formula (IVA), (IVB).
The alpha-bromoglucose mixture can be directly used as a medicine synthesis intermediate, does not need separation and purification, and can be directly used for synthesizing the diabetes drugs, so that the yield is improved, the production period is greatly shortened, and the production cost is reduced.
In order to achieve the purpose of the present invention, the present inventors have finally obtained the following technical solutions through a large number of experimental reaction studies:
Detailed Description
In order to more clearly understand the present invention, we further illustrate in connection with the reaction example:
1. synthesis of a compound of formula (ii):
10g of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene was placed in a three-necked flask and purged with nitrogen 3 times, and 20ml of anhydrous toluene/anhydrous n-butyl ether (5:3) degassed with nitrogen was added thereto, followed by cooling to-45- -35 ℃. 10.3ml of n-butyllithium (2.5Min n-hexane, 1.05 equivalent) is dropwise added, and the temperature is controlled to be between 45 ℃ below zero and 35 ℃ for more than 30 minutes in the dropwise adding process. After the dropwise addition, the reaction is carried out for 3h at the temperature of between 45 ℃ below zero and 35 ℃, and HPLC detection shows that the reaction of the raw materials is finished. Dropwise adding a solution (34w percent, 0.55 equivalent) of zinc bromide and lithium bromide butyl ether, and slowly heating to room temperature for reaction for 1 hour after the dropwise adding is finished. After the reaction was complete, 15g of a mixture of α -bromoglucose (a mixture of compounds of formulae (IVA), (IVB), (IVC)) was added (dissolved in anhydrous toluene to make a 1M solution). The temperature is increased to 90 ℃ for reaction for 3 h. After the reaction was completed, HPLC analysis was performed, and the temperature was lowered to 0 ℃ to quench the reaction with 200ml of 1N hydrochloric acid. The layers were separated, the aqueous layer was extracted with 200ml ethyl acetate and the organic phases were combined. The organic phase was washed with 200ml of saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to give a brown oil. The brown oil was dissolved in 200ml of ethanol and eluted by silica gel column chromatography (n-heptane: ethyl acetate: 15:1-5:1) to give a white solid. Purity: 98.5% and yield 78.6%.
2. Synthesis of Compounds of formula (II)
15.7g of zinc bromide was added to 90ml of anhydrous toluene, and the temperature was lowered to 20 ℃ and replaced with nitrogen 3 times. 51.4ml of n-butyllithium (2.5Min n-hexane, 1.05 equivalents) was added dropwise at 20 ℃ and, after completion of the addition, reacted at 20 ℃ for 2 hours. The temperature is reduced to-10 ℃. 50g of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophen in toluene (dissolved in 300ml of toluene) are added dropwise. After the dropwise addition, the reaction was carried out at-10 ℃ for 1 hour. 45ml of anhydrous n-butyl ether was added thereto, and the mixture was warmed to room temperature to react for 1.5 hours. 75g of a-bromoglucose mixture (mixture of compounds of the formulae (IVA), (IVB)) are then added to the mixture and the reaction is carried out for 3h while slowly increasing the temperature to 90 ℃. After the reaction was detected by HPLC, the temperature was lowered to 0 ℃ and the reaction was quenched with 250ml of 1N hydrochloric acid. The layers were separated, the aqueous layer was extracted with 250ml ethyl acetate and the organic phases were combined. The organic phase was washed with 250ml of saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation to give a brown oil. The brown oil was dissolved in 250ml of ethanol and eluted by silica gel column chromatography (n-heptane: ethyl acetate: 15:1-5:1) to give a white solid. Purity: 98.3%, yield: 79.2 percent.
3. Synthesis of canagliflozin
17.29g of the compound of formula (II) are weighed, 46ml of methanol and 0.84g (0.2 eq) of 30% sodium methoxide are added and reacted at 66 ℃ for 8-10h, and HPLC monitors the completion of the reaction of the starting materials. Acetic acid 0.2 equivalents was added and the pH was adjusted to neutral. The solvent was removed by rotary evaporation. 22ml of methanol was added to the residue, which was heated to 60 ℃. 22ml of water is slowly added dropwise, the temperature is reduced to room temperature, and 12ml of water is slowly added. Crystallization was carried out at 15 ℃ overnight. Filtering, and drying at 45 ℃ for 12 h. To obtain the white-like solid. Yield: 94.5%, purity: 99.98 percent.
The foregoing shows and describes embodiments of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (4)
1. A preparation method of canagliflozin is characterized by comprising the following steps:
(1) reacting a compound of formula (III) with α -bromoglucose to convert to formula (II):
wherein R1, R2 are selected from Piv or Bz groups, and R1 and R2 do not simultaneously represent Piv groups, when R1 is Piv, R2 cannot be a Piv group, and when R2 is Piv, R1 cannot be a Piv group;
(2) hydrolyzing the compound of the formula (II) to obtain the compound of the formula (I).
2. The method for preparing a canagliflozin hemihydrate according to claim 1, wherein: alpha-bromoglucose, the structure of which is selected from the group consisting of formula (IVA), formula (IVB), formula (IVC) or a mixture of compounds of formula (IVA), (IVB), (IVC) or a mixture of compounds of formula (IVA), (IVB).
3. The method for preparing a canagliflozin hemihydrate of claim 1, wherein: in the step (1), preparing an organic zinc compound by using butyl lithium and zinc salt, and then carrying out coupling reaction with alpha-bromoglucose, wherein the ratio of the compound (III) to the alpha-bromoglucose is as follows: 1:0-1:2, preferably 1.0 equivalent, and the reaction solvent is at least one selected from toluene/butyl ether and toluene/methyl cyclopentyl ether mixed solvent, preferably, the solvent is toluene/butyl ether combined solvent.
4. The method for preparing a canagliflozin hemihydrate according to claim 1, wherein: in the step (2), the reaction temperature is 60-66 ℃, the reaction time is about 6-10h, and the reaction solvent is at least one selected from methanol and ethanol, preferably, the solvent is methanol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202011404255.6A CN114591313A (en) | 2020-12-04 | 2020-12-04 | Preparation method of canagliflozin |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011404255.6A CN114591313A (en) | 2020-12-04 | 2020-12-04 | Preparation method of canagliflozin |
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| CN114716425A (en) * | 2022-04-11 | 2022-07-08 | 沧州那瑞化学科技有限公司 | Synthetic method of aromatic heterocyclic substituted methylene compound |
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| CN103596944A (en) * | 2011-04-13 | 2014-02-19 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of SGLT2 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114716425A (en) * | 2022-04-11 | 2022-07-08 | 沧州那瑞化学科技有限公司 | Synthetic method of aromatic heterocyclic substituted methylene compound |
| CN114716425B (en) * | 2022-04-11 | 2023-09-01 | 沧州那瑞化学科技有限公司 | Synthesis method of aromatic heterocyclic substituted methylene compound |
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