CN108276396A - A method of synthesis ipragliflozin - Google Patents
A method of synthesis ipragliflozin Download PDFInfo
- Publication number
- CN108276396A CN108276396A CN201810143774.8A CN201810143774A CN108276396A CN 108276396 A CN108276396 A CN 108276396A CN 201810143774 A CN201810143774 A CN 201810143774A CN 108276396 A CN108276396 A CN 108276396A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- reaction
- ipragliflozin
- synthesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XLFAUMVSMQPABZ-UHFFFAOYSA-N CCCc1ccc(cc(C(c2cc(Br)ccc2F)O)[s]2)c2c1 Chemical compound CCCc1ccc(cc(C(c2cc(Br)ccc2F)O)[s]2)c2c1 XLFAUMVSMQPABZ-UHFFFAOYSA-N 0.000 description 1
- IKGTVOQAJKYBGO-UHFFFAOYSA-N Fc(c(Cc1cc2ccccc2[s]1)c1)ccc1Br Chemical compound Fc(c(Cc1cc2ccccc2[s]1)c1)ccc1Br IKGTVOQAJKYBGO-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods of synthesis ipragliflozin, include the following steps：(1) 6 compound of alkylated reaction production is occurred into for 4 compound of formula and 5 compound of formula；(2) 6 compound of formula is deprotected 7 compound of production, i.e. ipragliflozin.Compared with the existing technology, the starting material used is cheap and easy to get, and synthetic route is shorter for preparation method disclosed by the invention, and easy to operate, cost is relatively low, and overall yield is higher, meets the theory of Green Chemistry, is suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a method of synthesis ipragliflozin.
Background technology
Ipragliflozin L-PROLINE salt is by Astellas (Astellas), Japanese longevity drugmaker (Kotobuki
Pharma) and Mo Shadong (Merck Sharp＆Dohme, MSD) develop jointly a kind of sodium glucose co-transporter 2 white 2
(SGLT2) inhibitor, for treating type-2 diabetes mellitus.The medicine obtains Japanese pharmaceutical product medical instrument synthesis on January 17th, 2014
Mechanism (PMDA) approval listing, by above-mentioned three company in Japanese list marketing, trade nameChina is adult's glycosuria
The highest country of patient, diabetic are up to 1.1 hundred million.SGLT-2 inhibitor causes that researcher's is wide as novel antidiabetic drug
General concern, ipragliflozin L-PROLINE salt represent drug as it and have broad prospects.
Entitled (1S) -1,5- dehydrogenations -1-C- { 3- [(1- benzothiophene -2- bases) first of chemistry of ipragliflozin L-PROLINE salt
Base] -4- fluorophenyls }-D-Glucose alcohol-(2S)-pyrrolidines -2- carboxylic acids (1: 1), concrete structure is as follows：
Currently, for the research of ipragliflozin L-PROLINE salt synthesis, people have done many work：
Patent WO2004080990A1 and US2006122126A1 disclose a kind of synthesis ipragliflozin L-PROLINE salt
Method, this method are starting material using the bromo- 2- fluorobenzaldehydes of 5- and benzothiophene, and 3 compound of formula is obtained by addition reaction,
Hydroxyl is protected by tert-butyl chloro-silicane again, is then coupled 14 compound of production with 13 compound of formula, so
After be deprotected and eliminate two molecules hydroxyl groups productions, 6 compound, be finally deprotected 7 compound of production, i.e. ipragliflozin, see road
Line one.This route reaction condition is more harsh, complicated for operation, and total recovery is not high, is unfavorable for industrialized production.
Route one
Patent WO2008075736A1 and US8198464B2 disclose a kind of side of synthesis ipragliflozin L-PROLINE salt
Method, this method are starting material using the bromo- 2- fluorobenzaldehydes of 5- and benzothiophene, and 3 compound of formula is obtained by addition reaction, then
Replaced to obtain 17 compound of formula with thionyl chloride, then 17 compound of formula obtains the change of formula 4 in the effect dehalogenation of sodium borohydride
Object is closed, 4 compound of formula is coupled and is hydrolyzed 19 compound of production with 18 compound of formula, then passes through acylation, demethylation, water
Solution obtains 7 compound of formula, and 9 compound of formula, i.e. ipragliflozin L-PROLINE salt is obtained by the reaction with 8 compound of formula again in 7 compound of formula,
See route two.Such method and step is more, severe reaction conditions, and purification process is complicated, is unfavorable for industrialized production.
Route two
Patent WO2015177083A1 discloses a kind of method of synthesis ipragliflozin L-PROLINE salt, and this method uses 2-
(the bromo- 2- luorobenzyls of 5-) benzothiophene and 3,4,6- tri--O- benzyl-D- glucose epoxides are starting material, in Grignard Reagent
Under the action of be alkylated 7 compound of production, i.e. ipragliflozin is shown in route three.The method expensive starting materials are not easy to be made, in reaction
High poison reagent need to be used, industrialized production is unfavorable for.
Route three
Invention content
Goal of the invention：In order to overcome product yield in the method for preparing ipragliflozin at present low, complex synthetic route and life
The defects of of high cost is produced, there is industrialization potential the present invention provides one kind and high income, purity are high, simply synthesize ipragliflozin
Method.
Technical solution：The method of synthesis ipragliflozin of the present invention, includes the following steps：
(1) 6 compound of alkylated reaction production is occurred into for 4 compound of formula and 5 compound of formula；
(2) 6 compound of formula is deprotected 7 compound of production, i.e. ipragliflozin；
Step (1) reaction carries out in the system including n-BuLi and zinc bromide-lithium-bromide solution, step (1) reaction
Specific method be：4 compound of formula is first mixed with n-BuLi, is stirred to react in reaction dissolvent at -50~-30 DEG C, then
Continue to be stirred to react at 85-95 DEG C with zinc bromide-lithium-bromide solution, 5 compound of formula again to obtain the final product.Preferably, step (1) is reacted
Specific method be：Under argon gas or nitrogen protection, 4 compound of formula is first mixed with n-BuLi, at -40 DEG C in reaction dissolvent
It is stirred to react, then continues to be stirred to react at 90 DEG C with zinc bromide-lithium-bromide solution, 5 compound of formula again to obtain the final product.Wherein, formula 4
Compound, 5 compound of formula, n-BuLi, zinc bromide-lithium-bromide solution molar ratio be 1: (4.5-5.5): (1-1.1):
(0.5-0.6), preferably 1: 5: 1.05: 0.57.Zinc bromide-the lithium-bromide solution is the butyl oxide of zinc bromide-lithium bromide
Solution (34%w/w), the wherein molar ratio of zinc bromide and lithium bromide are 1: 1.Reaction dissolvent is butyl oxide, acetone, toluene, heptane
One or more of, preferably butyl oxide and acetone.
Step (2) reaction carries out in the system including boron chloride and pentamethylbenzene, wherein 6 compound of formula, pentamethyl
Benzene, boron chloride molar ratio be 1: (14-16): (4.5-5.5), preferably 1: 15: 5.04.Reaction dissolvent be dichloromethane,
One or more of acetone, toluene, heptane, preferably dichloromethane.Reaction temperature is -70~-82 DEG C, preferably -78 DEG C.
Reaction time is 3-5h.
In step (1), 5 compound of formula is prepared by following methods：
10 compound of formula is successively carried out two-step reaction and obtains 11 compound of formula by (1-1) with sodium acetate, hydrobromic acid；
11 compound of formula is reacted 5 compound of production with cylite by (1-2)；
The specific method of step (1-1) is：10 compound of formula is successively carried out two-step reaction with sodium acetate, hydrobromic acid to obtain
11 compound of formula；In first step reaction, the molar ratio of the sodium acetate and 10 compound of formula is (1-1.2): 1, preferably
1.1∶1.Reaction condition is 135-145 DEG C and is heated to reflux that preferably 140 DEG C are heated to reflux.In second step reaction, the hydrogen
The molar ratio of bromic acid and 10 compound of formula is (10-12): 1, preferably 11: 1.The hydrobromic acid is preferably a concentration of 33%
(w/w) acetum of hydrobromic acid.Reaction dissolvent is dichloromethane, acetone, toluene, one or more of heptane, preferably
For dichloromethane.Reaction condition, which moves to after being 0 DEG C stirred below at 20-30 DEG C, to be continued to stir, and reaction condition is preferably to be stirred at 0 DEG C
It is moved to after mixing 30 minutes and continues stirring at room temperature until the reaction is complete.
Step (1-2) reaction carries out in the system including catalyst, and the catalyst is iron sulfite, 11 chemical combination of formula
Object, cylite, catalyst molar ratio be 1: (9-13)：(9-13), preferably 1: 12: 12.Reaction dissolvent be methanol, ethyl alcohol,
One or more of isopropanol, preferably methanol.Reaction condition is to be heated to reflux 10-14 hours.
In step (1), effect of 4 formula of formula, 3 compound in triethylsilane and boron trifluoride ether
Under slough hydroxyl and be prepared,
3 compound of formula, triethylsilane, boron trifluoride ether molar ratio be 1: (2-3): (1-2), preferably 1: 2.19
: 1.14, the reaction dissolvent of decarboxylation reaction is one or more of dichloromethane, acetone, toluene, heptane, preferably dichloro
Methane.The reaction temperature of decarboxylation reaction is -15~-25 DEG C, preferably -20 DEG C.Reaction time is 0.5-1.5h.
3 formula of formula, 1 compound occurs addition reaction with 2 compound of formula and is prepared,
The specific method of the addition reaction is：In the case where tetrahydrofuran is as solvent condition, 2 compound of formula elder generation and positive fourth
Base lithium mixes, and is stirred to react, is then mixed again with 1 compound of formula, is continued to be stirred to react to obtain the final product, wherein 1 compound of formula, formula 2 are changed
Close object, n-BuLi molar ratio be 1: (1-2): (7-8.5), the preferably reaction temperature of 1: 1.05: 7.94 addition reaction for-
70~-82 DEG C, preferably -78 DEG C.
In more detail, the specific method of the addition reaction is：In the case where tetrahydrofuran is as solvent condition, 2 chemical combination of formula
Object is first mixed with n-BuLi, and 1-2h is stirred to react at -70~-82 DEG C, is then mixed again with 1 compound of formula, and continuation -70~-
1.5-2.5h is stirred to react at 82 DEG C to obtain the final product.
A method of synthesis ipragliflozin L-PROLINE salt includes the steps that above-mentioned synthesis ipragliflozin, further includes
The ipragliflozin is carried out with 8 compound of formula to react 9 compound of production, i.e. ipragliflozin L-PROLINE salt,
The molar ratio of 7 compound of formula and 8 compound of formula is 1: (1-1.1) is preferably 1: 1.The step salt-forming reaction is
The common reaction in this field, those skilled in the art can determine optimal reaction temperature, reaction by conventional experimental implementation
Time, raw material rate of charge.
The synthetic route of the ipragliflozin L-PROLINE salt of the present invention is as follows：
Advantageous effect：The present invention synthesizes the method for ipragliflozin L-PROLINE salt compared with the existing technology, and raw material is inexpensively easy
, it avoids using noble metal catalyst, reaction condition is mild, and good reaction selectivity, overall yield is higher, greatly reduces production
Cost is more suitable for industrialized production.
Specific implementation mode
Embodiment 1
(1) preparation of 11 compound of formula.
65.2g (1.1eq) sodium acetate is added in 700mL acetic anhydride, 140 DEG C are heated to reflux, a small amount of into reaction system
130.46g (724.20mmol, 1eq) D- galactolipins (10 compound of formula) are repeatedly added, after addition, reaction solution becomes clarification,
Continue return stirring 10 minutes.Hot solution is poured into the beaker containing 4000mL ice water, until ice water melts.By 1200mL bis-
Chloromethanes is added in mixed solution, then removes water phase.Organic phase uses ice water (3*4000mL), saturated aqueous sodium carbonate respectively
(4000mL) and brine (4000mL) wash.Organic phase is dried with sodium sulphate, is filtered, is concentrated under reduced pressure to give yellow oily and slightly produces
Object.Crude product is dissolved in a small amount of ether (about 250mL), petroleum ether (500mL) is added by priority and ethyl alcohol (2000mL) is precipitated
Precipitation.The suspension preserves 2-3 hours at 24 DEG C, is then stored 16 hours at -20 DEG C.Then filter white solid simultaneously
With petroleum ether, the solid is recrystallized in a small amount of hot ethanol, and store 16 hours at room temperature.Last filtering crystals are used in combination
Cold ethyl alcohol and petroleum ether obtain five-O- acetyl group β-D- galactopyranoses, under the conditions of 0 DEG C, by five-O- acetyl group β-
D- galactopyranoses are dissolved in dichloromethane, and the acetum (33%w/w, 11eq) of hydrobromic acid is added dropwise, is dripped in 10 minutes
Finish.Reaction mixture stirs 30 minutes at 0 DEG C, is then stirred at room temperature (about 3 hours) until the reaction is complete.Mixture
It is diluted, is washed twice with 30mL saturated sodium carbonate solutions, 200mL deionized waters washed once with 10mL dichloromethane.It will be organic
It is mutually dried and concentrated with sodium sulphate, obtains 2,3,4,6- tetra--O- acetyl group-α-D- galactopyranose bromides.2 will obtained, 3,
4,6- tetra--O- acetyl group-α-D- galactopyranose bromides hydrolyze in acid condition, obtain 11 compound 124.97g of formula；Purity
99.2%；Yield 71%；Mass spectrum (ESI)：M/z=241.9790 (M++H)。
(2) preparation of 5 compound of formula.
11 compound of 124.97g (514.18mmol) formula is dissolved in a small amount of methanol, and 1.05Kg (6.16mol) bromine is added
Change benzyl and 1.71Kg (6.16mol) ferrous sulfate, be heated to reflux, reacts 12 hours.After the reaction was complete, cooling reaction solution to room
Temperature is filtered to remove iron sulfite, is spin-dried for solvent, and crude by column chromatography purifying obtains 5 compound 285.25g of formula；Purity
99.5%；Yield 92%；Mass spectrum (ESI)：M/z=602.1668 (M++H)。
(3) benzo [b] thiophene -2-methanol, the preparation of α-(the bromo- 2- fluorophenyls of 5-) (3 compound of formula).
At -78 DEG C, 16.6g (124mmol) benzothiophene (2 compound of formula) is dissolved in 200mL tetrahydrofurans, is added
78.5mL (937mmol) n-BuLi, mixture stir 1.5 hours at -78 DEG C.By the bromo- 2- fluorine of 23.95g (118mmol) 5-
Benzaldehyde (1 compound of formula) is dissolved in 300mL tetrahydrofurans, and it is mixed with above-mentioned benzothiophene solution, at -78 DEG C after
Continuous stirring 2 hours.Water and ether are added into reaction mixture, detaches organic phase, magnesium sulfate is used in combination to dry, then filters and true
Sky is dry.Gained crude by column chromatography (ethylacetate-hexane) purifies, and obtains benzo [b] thiophene -2-methanol, (5- is bromo- by α-
2- fluorophenyls) (3 compound of formula) 35.4g；Purity 99.5%；Yield 89%；Mass spectrum (ESI)：M/z=335.9620 (M++H)。
(4) benzo [b] thiophene, the preparation of 2- [(the bromo- 2- fluorophenyls of 5-) methyl] (4 compound of formula).
By 35.4g (105mmol) benzo [b] thiophene -2-methanol, α-(the bromo- 2- fluorophenyls of 5-) (3 compound of formula) is dissolved in
In 800mL dichloromethane, and -20 DEG C are cooled to, 36.5mL (230mmol) triethylsilanes and 15.2mL are added into the solution
(120mmol) boron trifluoride ether, mixture continue stirring 30 minutes at -20 DEG C.Unsaturated carbonate is added into reaction mixture
Hydrogen sodium water solution detaches organic phase, is used in combination magnesium sulfate to dry, then filters and be dried in vacuo.Gained crude by column chromatography (second
Acetoacetic ester-hexane) purifying, obtain benzo [b] thiophene, 2- [(the bromo- 2- fluorophenyls of 5-) methyl] (4 compound of formula) 30.4g；Purity
99.5%；Yield 90.1%；Mass spectrum (ESI)：M/z=319.9671 (M++H)。
(5) (1S) -1,5- dehydrations -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls] -2,3,4,6- tetra--O- benzyls
The preparation of base-D-Glucose alcohol (6 compound of formula).
Under protection of argon gas, by 30.4g (94.61mmol) benzo [b] thiophene, 2- [(the bromo- 2- fluorophenyls of 5-) methyl] (formula
4 compounds) it is dissolved in the in the mixed solvent of butyl oxide (30mL) and toluene (50mL), after being cooled to -40 DEG C, into reaction mixture
The n-heptane solution (1.05eq, 99.34mmol, 36.71mL) of n-BuLi is added dropwise.After being reacted 2 hours under the conditions of -40 DEG C, to anti-
Answer in mixture be added dropwise zinc bromide-lithium bromide butyl oxide solution (34%w/w, 0.55eq, 52.04mmol, 47.67g, wherein
The molar ratio of zinc bromide and lithium bromide is 1: 1), after being added dropwise, reaction is warming up to room temperature.Then, by 285.25g
5 compound of (473.05mmol) formula is added in reaction system, is warming up to 90 DEG C and is stirred 2 hours.After reaction, it is cooled to
Room temperature, mixture are quenched with HCl/water solution, and separation organic phase is dry and is spin-dried for solvent, by crude by column chromatography (heptane-second
Acetoacetic ester) purifying, obtain (1S) -1,5- dehydrations -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls] -2,3,4,6-
Four-O- benzyls-D-Glucose alcohol (6 compound of formula) 62.2g；Purity 99.6%；Yield 86%；Mass spectrum (ESI)：M/z=
764.2972(M++H)。
(6) preparation of ipragliflozin (7 compound of formula).
At -78 DEG C, 6 compound of 62.2g (81.36mmol) formula is dissolved in dichloromethane, and pentamethylbenzene is added
180.62g (1.22mol) and boron chloride 410mL (0.41mol), reaction mixture stir 4 hours at -78 DEG C, reaction knot
Methanol is added in Shu Houxiang reaction systems, reaction is quenched.Room temperature is then raised temperature to, mixture is spin-dried for, by crude by column chromatography
(methanol-chloroform) purifies, and obtains ipragliflozin (7 compound of formula) 24.65g；Purity 99.6%；Yield 75%；M/z=
404.1094(M++H)。
(7) preparation of ipragliflozin L-PROLINE salt.
In methylene chloride, 24.65g (61.02mmol) ipragliflozins and 7.02g (61.02mmol) L-PROLINE is added,
35 DEG C are heated to stir 3 hours.After reaction, cooling mixture, the solid crude product being obtained by filtration, recrystallizing methanol obtain
To ipragliflozin L-PROLINE salt 31.35g；Purity 99.8%；Yield 99%；Mass spectrum (ESI)：M/z=519.1727 (M++H)。
Embodiment 2
(1) preparation of 11 compound of formula
It is same as Example 1, it differs only in：In first step reaction, the molar ratio of sodium acetate and 10 compound of formula is 1
∶1.Reaction condition is 135 DEG C and is heated to reflux.In second step reaction, the molar ratio of hydrobromic acid and 10 compound of formula is 10: 1.Instead
It is acetone to answer solvent.11 compound purity 99.1% of gained formula；Yield 70.8%；Mass spectrum (ESI)：M/z=241.9790 (M++
H)。
(2) preparation of 5 compound of formula.
It is same as Example 1, it differs only in：11 compound of formula, cylite, ferrous sulfate molar ratio be 1: 9: 9.Instead
It is ethyl alcohol to answer solvent.5 compound purity 99.5% of gained formula；Yield 90.5%；Mass spectrum (ESI)：M/z=602.1668 (M++
H)。
(3) benzo [b] thiophene -2-methanol, the preparation of α-(the bromo- 2- fluorophenyls of 5-) (3 compound of formula).
It is same as Example 1, it differs only in：1 compound of formula, 2 compound of formula, the molar ratio of n-BuLi are 1: 1: 7.
Reaction temperature is -70 DEG C.Gained benzo [b] thiophene -2-methanol, α-(the bromo- 2- fluorophenyls of 5-) (3 compound of formula) purity
99.5%；Yield 87%；Mass spectrum (ESI)：M/z=335.9620 (M++H)。
(4) benzo [b] thiophene, the preparation of 2- [(the bromo- 2- fluorophenyls of 5-) methyl] (4 compound of formula).
It is same as Example 1, it differs only in：3 compound of formula, triethylsilane, boron trifluoride ether molar ratio be 1
: 2: 1, reaction dissolvent is acetone.Reaction temperature is -15 DEG C.Gained benzo [b] thiophene, 2- [(the bromo- 2- fluorophenyls of 5-) methyl]
(4 compound of formula) purity 99.4%；Yield 90%；Mass spectrum (ESI)：M/z=319.9671 (M++H)。
(5) (1S) -1,5- dehydrations -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls] -2,3,4,6- tetra--O- benzyls
The preparation of base-D-Glucose alcohol (6 compound of formula).
It is same as Example 1, it differs only in：4 compound of formula, formula 5 compound, n-BuLi, zinc bromide-lithium bromide
The molar ratio of butyl oxide solution is 1: 4.5: 1: 0.5.4 compound of formula is stirred to react with n-BuLi at -30 DEG C, then again with
Zinc bromide-lithium-bromide solution, 5 compound of formula continue to be stirred to react at 85 DEG C.Gained (1S) -1,5- dehydrations -1- [3- (1- benzene
Bithiophene -2- ylmethyls) -4- fluorophenyls] -2,3,4,6- tetra--O- benzyls-D-Glucose alcohol (6 compound of formula) purity 99.5%；
Yield 85%；Mass spectrum (ESI)：M/z=764.2972 (M++H)。
(6) preparation of ipragliflozin (7 compound of formula).
It is same as Example 1, it differs only in：6 compound of formula, pentamethylbenzene, boron chloride molar ratio be 1: 14:
4.5, reaction dissolvent is acetone, and reaction temperature is -70 DEG C.Gained ipragliflozin (7 compound of formula) 24.65g；Purity 99.5%；
Yield 73%；M/z=404.1094 (M++H)。
(7) preparation of ipragliflozin L-PROLINE salt.
It is same as Example 1, it differs only in：The molar ratio of 7 compound of formula and 8 compound of formula is 1: 1.1.Her lattice of gained
Arrange net L-PROLINE purity salt 99.5%；Yield 98.1%；Mass spectrum (ESI)：M/z=519.1727 (M++H)。
Embodiment 3
(1) preparation of 11 compound of formula
It is same as Example 1, it differs only in：In first step reaction, sodium acetate and the molar ratio of 10 compound of formula are
1.2∶1.Reaction condition is 145 DEG C and is heated to reflux.In second step reaction, hydrobromic acid and the molar ratio of 10 compound of formula are 12:
1.Reaction dissolvent is toluene.11 compound purity 99.2% of gained formula；Yield 70%；Mass spectrum (ESI)：M/z=241.9790 (M+
+H)。
(2) preparation of 5 compound of formula.
It is same as Example 1, it differs only in：11 compound of formula, cylite, ferrous sulfate molar ratio be 1: 13: 13.
Reaction dissolvent is isopropanol.5 compound purity 99.5% of gained formula；Yield 91%；Mass spectrum (ESI)：M/z=602.1668 (M++
H)。
(3) benzo [b] thiophene -2-methanol, the preparation of α-(the bromo- 2- fluorophenyls of 5-) (3 compound of formula).
It is same as Example 1, it differs only in：1 compound of formula, 2 compound of formula, the molar ratio of n-BuLi are 1: 2:
8.5.Reaction temperature is -82 DEG C.Gained benzo [b] thiophene -2-methanol, α-(the bromo- 2- fluorophenyls of 5-) (3 compound of formula) purity
99.5%；Yield 88%；Mass spectrum (ESI)：M/z=335.9620 (M++H)。
(4) benzo [b] thiophene, the preparation of 2- [(the bromo- 2- fluorophenyls of 5-) methyl] (4 compound of formula).
It is same as Example 1, it differs only in：3 compound of formula, triethylsilane, boron trifluoride ether molar ratio be 1
: 3: 2, reaction dissolvent is heptane.Reaction temperature is -25 DEG C.Gained benzo [b] thiophene, 2- [(the bromo- 2- fluorophenyls of 5-) methyl]
(4 compound of formula) purity 99.5%；Yield 89.5%；Mass spectrum (ESI)：M/z=319.9671 (M++H)。
(5) (1S) -1,5- dehydrations -1- [3- (1- benzothiophene -2- ylmethyls) -4- fluorophenyls] -2,3,4,6- tetra--O- benzyls
The preparation of base-D-Glucose alcohol (6 compound of formula).
It is same as Example 1, it differs only in：4 compound of formula, formula 5 compound, n-BuLi, zinc bromide-lithium bromide
The molar ratio of butyl oxide solution is 1: 5.5: 1.1: 0.6.4 compound of formula is stirred to react with n-BuLi at -50 DEG C, then again
Continue to be stirred to react at 95 DEG C with zinc bromide-lithium-bromide solution, 5 compound of formula.Gained (1S) -1,5- dehydrations -1- [3- (1-
Benzothiophene -2- ylmethyls) -4- fluorophenyls] -2,3,4,6- tetra--O- benzyls-D-Glucose alcohol (6 compound of formula) purity
99.48%；Yield 84%；Mass spectrum (ESI)：M/z=764.2972 (M++H)。
(6) preparation of ipragliflozin (7 compound of formula).
It is same as Example 1, it differs only in：6 compound of formula, pentamethylbenzene, boron chloride molar ratio be 1: 16:
5.5.Reaction dissolvent is heptane.Reaction temperature is -82 DEG C.Gained ipragliflozin (7 compound of formula) purity 99.5%；Yield
74%；M/z=404.1094 (M++H)。
(7) preparation of ipragliflozin L-PROLINE salt.
It is same as Example 1, it differs only in：The molar ratio of 7 compound of formula and 8 compound of formula is 1: 1.1.Her lattice of gained
Arrange net L-PROLINE purity salt 99.6%；Yield 98%；Mass spectrum (ESI)：M/z=519.1727 (M++H)。
Claims (10)
1. a method of synthesis ipragliflozin, which is characterized in that include the following steps：
(1) 6 compound of alkylated reaction production is occurred into for 4 compound of formula and 5 compound of formula；
(2) 6 compound of formula is deprotected 7 compound of production, i.e. ipragliflozin；
2. the method for synthesis ipragliflozin according to claim 1, which is characterized in that step (1) is reacted including positive fourth
It is carried out in the system of base lithium and zinc bromide-lithium-bromide solution, the specific method of step (1) reaction is：4 compound of formula elder generation and positive fourth
Base lithium mix, be stirred to react in reaction dissolvent at -50~-30 DEG C, then again with zinc bromide-lithium-bromide solution, 5 compound of formula
Continue to be stirred to react at 85-95 DEG C to obtain the final product, wherein 4 compound of formula, 5 compound of formula, n-BuLi, zinc bromide-lithium bromide are molten
The molar ratio of liquid is 1: (4.5-5.5): (1-1.1): (0.5-0.6), reaction dissolvent are in butyl oxide, acetone, toluene, heptane
It is one or more of.
3. the method for synthesis ipragliflozin according to claim 1, which is characterized in that step (2) is reacted including trichlorine
Change and carried out in the system of boron and pentamethylbenzene, wherein 6 compound of formula, pentamethylbenzene, boron chloride molar ratio be 1: (14-
16): (4.5-5.5), reaction dissolvent are one or more of dichloromethane, acetone, toluene, heptane, and reaction temperature is -70
~-82 DEG C.
4. the method for synthesis ipragliflozin according to claim 1, which is characterized in that in step (1), the formula 5 is changed
Object is closed to be prepared by following methods：
10 compound of formula is successively carried out two-step reaction and obtains 11 compound of formula by (1-1) with sodium acetate, hydrobromic acid；
11 compound of formula is reacted 5 compound of production with cylite by (1-2)；
5. the method for synthesis ipragliflozin according to claim 4, which is characterized in that the specific method of step (1-1) is：
10 compound of formula is successively subjected to two-step reaction with sodium acetate, hydrobromic acid and obtains 11 compound of formula；It is described in first step reaction
The molar ratio of sodium acetate and 10 compound of formula be (1-1.2): 1, reaction condition is 135-145 DEG C and is heated to reflux；In second step
In reaction, the molar ratio of the hydrobromic acid and 10 compound of formula is (10-12): 1, reaction dissolvent is dichloromethane, acetone, first
One or more of benzene, heptane, reaction condition, which moves to after being 0 DEG C stirred below at 20-30 DEG C, to be continued to stir.
6. the method for synthesis ipragliflozin according to claim 4, which is characterized in that step (1-2) is reacted including urging
Carried out in the system of agent, the catalyst be ferrous sulfate, 11 compound of formula, cylite, catalyst molar ratio be 1:
(9-13): (9-13), reaction dissolvent are one or more of methanol, ethyl alcohol, isopropanol, and reaction condition is to be heated to reflux 10-
14 hours.
7. the method for synthesis ipragliflozin according to claim 1, which is characterized in that in step (1), the formula 4 is changed
Conjunction object is sloughed hydroxyl under the action of triethylsilane and boron trifluoride ether by 3 compound of formula and is prepared,
8. it is according to claim 7 synthesis ipragliflozin method, which is characterized in that 3 compound of formula, triethylsilane,
The molar ratio 1 of boron trifluoride ether: (2-3): the reaction dissolvent of (1-2), decarboxylation reaction are dichloromethane, acetone, toluene, heptan
The reaction temperature of one or more of alkane, decarboxylation reaction is -15~-25 DEG C.
9. the method for synthesis ipragliflozin according to claim 7, which is characterized in that 3 formula 1 of formula is changed
Object is closed to be prepared with the generation addition reaction of 2 compound of formula,
10. it is according to claim 9 synthesis ipragliflozin method, which is characterized in that the addition reaction it is specific
Method is：In the case where tetrahydrofuran is as solvent condition, formula 2 compound is first mixed with n-BuLi, is stirred to react, then again with formula
1 compound mixes, and continues to be stirred to react to obtain the final product, wherein 1 compound of formula, 2 compound of formula, the molar ratio of n-BuLi are 1: (1-
2): the reaction temperature of (7-8.5), addition reaction are -70~-82 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810143774.8A CN108276396A (en) | 2018-02-11 | 2018-02-11 | A method of synthesis ipragliflozin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810143774.8A CN108276396A (en) | 2018-02-11 | 2018-02-11 | A method of synthesis ipragliflozin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108276396A true CN108276396A (en) | 2018-07-13 |
Family
ID=62808404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810143774.8A Pending CN108276396A (en) | 2018-02-11 | 2018-02-11 | A method of synthesis ipragliflozin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108276396A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101568537A (en) * | 2006-12-21 | 2009-10-28 | 安斯泰来制药有限公司 | Method for producing C-glycoside derivative and synthetic intermediate thereof |
| JP2014070040A (en) * | 2012-09-28 | 2014-04-21 | Toyotama Koryo Kk | Manufacturing method of glucopyranosides, or manufacturing method of galactopyranosides and manufacturing method of intermediate of the same |
| CN106188022A (en) * | 2015-04-30 | 2016-12-07 | 上海医药工业研究院 | The preparation method that Yi Gelie is clean |
-
2018
- 2018-02-11 CN CN201810143774.8A patent/CN108276396A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101568537A (en) * | 2006-12-21 | 2009-10-28 | 安斯泰来制药有限公司 | Method for producing C-glycoside derivative and synthetic intermediate thereof |
| JP2014070040A (en) * | 2012-09-28 | 2014-04-21 | Toyotama Koryo Kk | Manufacturing method of glucopyranosides, or manufacturing method of galactopyranosides and manufacturing method of intermediate of the same |
| CN106188022A (en) * | 2015-04-30 | 2016-12-07 | 上海医药工业研究院 | The preparation method that Yi Gelie is clean |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| PT97746B (en) | PROCESS OF ENANTIO-SELECTIVE PREPARATION OF PHENYL-ISO-SERIN DERIVATIVES | |
| CN108675976A (en) | A kind of halogenated glucose carbon glycosides of 6- and its preparation method and application | |
| CN112142694A (en) | Polysubstituted tetrahydrofuran and tetrahydropyrane diene compound and preparation method thereof | |
| CN111995565B (en) | Preparation method of (S) -2-piperidinecarboxylic acid | |
| JPS58118571A (en) | Manufacture of octahydrobenzofuro(3,2-e) isoquinoline and intermediate therefor | |
| CN111057032B (en) | Preparation method of dapagliflozin | |
| CN112979402A (en) | Industrial production method of benzo [ a ] anthracene | |
| CN108276396A (en) | A method of synthesis ipragliflozin | |
| CN111410639A (en) | Preparation method of empagliflozin intermediate impurity | |
| CN101367780B (en) | Joint production method for (S)-3-hydroxyl-gamma-butyrolactone, (S)-3-hydroxyl tetrahydrofuran | |
| CN110128422B (en) | Synthesis method of 5-methoxy-7-azaindole | |
| CN109956948B (en) | Method for synthesizing natural product (-) -newboulidine | |
| CN110294708B (en) | Preparation method of trifluoroethylselenophenanthridine and 3, 4-dihydroisoquinoline derivatives | |
| CN1986548B (en) | Industrial continuous preparing process of N-tert-butoxy carbonyl-5-aza-2-oxa-3-one-dicyclo-[2,2,1] heptane | |
| CN112125788A (en) | Preparation method of liquid crystal monomer compound containing difluoromethyl ether bridge bond | |
| CN106432059A (en) | Preparation method of 3-hydroxypiperidine, preparation method of derivative of 3-hydroxypiperidine, and intermediate of 3-hydroxypiperidine | |
| CN108586340A (en) | A kind of synthetic method of 3- acyl groups hydrogenation azepines compound | |
| CN104610215A (en) | Preparation method of nebivolol intermediates and preparation method of nebivolol | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CN114890902B (en) | Preparation method of 2-methyl-3-trifluoromethyl aniline | |
| CN115197086B (en) | Preparation method of difluoromethoxy-containing m-diamide compound | |
| CN110746371B (en) | Intermediate for preparing aprepitant and preparation method and application thereof | |
| CN115246772B (en) | Preparation method of isobutyryl methyl acetate | |
| WO2024040754A1 (en) | Method for synthesizing cis-2-methyl-7-octadecene and cis-7,8-epoxy-2-methyloctadecane | |
| CN112794837B (en) | Synthesis method of heterochroman compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180713 |