CN105622609B - A kind of Li Gelieting preparation method - Google Patents
A kind of Li Gelieting preparation method Download PDFInfo
- Publication number
- CN105622609B CN105622609B CN201610135936.4A CN201610135936A CN105622609B CN 105622609 B CN105622609 B CN 105622609B CN 201610135936 A CN201610135936 A CN 201610135936A CN 105622609 B CN105622609 B CN 105622609B
- Authority
- CN
- China
- Prior art keywords
- methyl
- gelieting
- preparation
- purine
- diketone
- 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.)
- Active
Links
- 0 CC[n]1c(N2C(*)[C@](C)CCC2)nc(N(C)C(N2CC3N=C(C)c(cccc4)c4N3)=O)c1C2=O Chemical compound CC[n]1c(N2C(*)[C@](C)CCC2)nc(N(C)C(N2CC3N=C(C)c(cccc4)c4N3)=O)c1C2=O 0.000 description 3
- BOGDYUNJEZMDSS-UHFFFAOYSA-N CC[n]1c(Br)nc(N(C)C(N2Cc3nc(C)c(cccc4)c4n3)=O)c1C2=O Chemical compound CC[n]1c(Br)nc(N(C)C(N2Cc3nc(C)c(cccc4)c4n3)=O)c1C2=O BOGDYUNJEZMDSS-UHFFFAOYSA-N 0.000 description 1
- QTEQVEJOXGBDGI-UHFFFAOYSA-N CN(c1c(C(N2)=O)[nH]c(Br)n1)C2=O Chemical compound CN(c1c(C(N2)=O)[nH]c(Br)n1)C2=O QTEQVEJOXGBDGI-UHFFFAOYSA-N 0.000 description 1
- UHCUBOJGMLASBY-UHFFFAOYSA-N Cc1nc(CCl)nc2c1cccc2 Chemical compound Cc1nc(CCl)nc2c1cccc2 UHCUBOJGMLASBY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to bulk drug preparing technical field, and in particular to Li Gelieting preparation method is improved.The invention provides a kind of Li Gelieting preparation method, particle diameter is controlled to be micron order the acid binding agent natrium carbonicum calcinatum used in the step condensation reactions of Li Gelieting two, reaction is without using iodide catalyst, equally reduce reaction temperature, reaction time shortens, and two-step reaction is changed into " one kettle way " prepares the key intermediate E compounds that purity is high, yield is high.The preparation method of the present invention is adapted to Li Gelieting industrialized production, and finally gives high-purity, the Li Gelieting of high yield pulp1.
Description
Technical field
The invention belongs to bulk drug preparing technical field, and in particular to Li Gelieting preparation method is improved.
Background technology
Li Gelieting (Linagliptin), 8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydros -
3- methyl isophthalic acids-[(4- methyl -2- quinazolyls) methyl] -1H- purine -2,6- diketone, CAS：668270-12-0, chemical constitution
Formula is as follows：
Li Gelieting is formed by the research and development of Boehringer Ingelheim-Li Lai diabetes alliance, and it is a kind of with new effect
Diabetes B (T2DM) medicine of mechanism, obtains U.S. FDA approval listing in May, 2011, in June, 2011, is approved in Europe
Listing.In January, 2012, U.S. FDA approval Li Gelieting/Metformin hydrochloride listing, for treating adult T 2DM patient.2010
In October in year, Europe approval Li Gelieting is as the therapeutic alliance medicinal application of insulin in T2DM patient.In April, 2013, Li Ge
Row spit of fland obtains the import drugs registration certificate that China national food and medicine supervision and management general bureau (SFDA) issues, and is approved in Discussion on Chinese Listed
Sale, the granted of the new drug will provide brand-new therapeutic choice for vast Chinese diabetic, meet the long-term wind of diabetes
The Treatment need of danger management.
Through retrieving domestic and international patent document and scientific and technical literature, Li Gelieting applicable industry synthesis technique is related generally to：
1st, Chinese patent application CN104496989A, discloses a kind of Li Gelieting industrial preparation process, and the technique is
Reactant B (2- chloromethyl -4- methylquinazolins), reactant A (8- bromo- 7- (the 2- butine of equimolar amounts are put into a kettle.
Base) -3- methyl xanthines), acid binding agent, add appropriate solvent, reacted 3-8 hour in 0-140 DEG C, after TLC detection reactions are complete,
Reaction mother liquor is not handled is directly added into reactant C ' ((R) -3- phthaloyl imino piperidines tartaric acid), acid binding agent N, N- bis-
Wopropyl ethyl amine reacts 3-10 hours in 0-125 DEG C, after TLC detection reactions completely, reaction mother liquor addition monoethanolamine is not handled anti-
Should, react 2-10 hour, dropwise addition purified water after TLC detection reactions completely, suction filtration is got profit Ge Lieting crude products, re-refines lattice of getting profit
Arrange spit of fland fine work.Synthetic route is as follows：
Although the technique is often walked reacted after do not handle directly reaction go down, simplify operating procedure, its second step
Acid binding agent uses organic base DIPEA, and this undoubtedly adds production cost, and temperature during the deprotection of the 3rd step
Degree reaches 100 DEG C, and this certainly will cause the increase of accessory substance, and harsh to equipment requirement, and raw material (R) -3- O-phthalics
Acylimino piperidines tartaric acid has higher production cost, and domestic temporarily without large-scale production, therefore is unfavorable for industrialization
Big production.
2nd, Chinese patent application CN104387390A, discloses a kind of preparation method of purine derivative, and the technique is logical
Crossing compound A (the bromo- 7- of 8- (2- butynyls) -3- methyl xanthines) and compound B (2- chloromethyl -4- methylquinazolins) is having
In machine solvent, in the presence of alkali and phase transfer catalyst, in 50 DEG C of -70 DEG C of reactions to reacting complete, the first reaction mixing is obtained
Thing, then adds compound C ((R) -3- t-butoxycarbonyl aminos piperidines) into the first reactant mixture, anti-at 70 DEG C -90 DEG C
It should extremely react complete, then isolated compound E (1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- fourths
Alkynes -1- bases) -8- [(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine),
Compound E obtains Li Gelieting after deprotection.Synthetic route is as follows：
Although the technique compound E is prepared by the method for " one kettle way ", the first step has used phase transfer to urge
Agent, and the compound E prepared purity is not high, is that follow-up refine brings difficulty, meets medicinal it is difficult to prepare
The bulk drug of level.
3rd, Chinese patent application CN104844602A, discloses a kind of Li Gelieting preparation method, and the technique is in carbon
In the presence of acid potassium salt or sodium carbonate, using inorganic salts containing iodine as catalyst, with METHYLPYRROLIDONE or N, N- dimethyl methyl
Under the conditions of acid amides is solvent, 30-80 DEG C, compound A (the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,
6- diketone) to be reacted with compound C ((R) -3- amino piperidine compounds), reaction terminates to be directly added into compound B without isolation
(2- chloromethyl -4- methylquinazolins), generation compound E (1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2-
Butine -1- bases) -8- [(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysenes -1H- is fast
Purine), compound E is deprotected the Ge Lieting that gets profit.Synthetic route is as follows：
The technique makes yield be improved by changing the implementation of reaction sequence and " one kettle way ", but the technique is
Li Gelieting purity is improved, catalyst-inorganic salts of class containing iodine have been used, this undoubtedly adds production cost.
4th, PCT Patent Application WO2014/097314A1, the technique is, using 3- methyl xanthines as initiation material, to pass through bromine
Metaplasia reacts generation into the bromo- 3- methyl xanthines of 8-, then with the bromo- 2- butine of 1- in the presence of acid binding agent DIPEA
Compound A (the bromo- 7- of 8- (2- butynyls) -3- methyl xanthines), compound A and compound B (2- chloromethyl -4- methyl quinoline azoles
Quinoline) in DMSO solution, potassium carbonate makees acid binding agent, and TBAB cooks phase transfer catalyst, and reaction prepares intermediate D
(the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acids-[(4- methyl -2- quinazolyls) methyl] -1H- purine -2,6- bis-
Ketone), acid binding agent is then made with potassium carbonate, KI makees catalyst, and compound C ((R) -3- t-butoxycarbonyl aminos piperidines) is instead
Should prepare intermediate E (1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8- [(R) -
3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine), it is finally de- with trifluoroacetic acid
Protection is the Ge Lieting that gets profit.Synthetic route is as follows：
The technique is cumbersome, complex operation, and uses phase transfer catalyst TBAB and catalyst KI,
Production cost is added, industrialized production is limited.
5th, PCT Patent Application WO2015/004599A1, the technique is by compound A (the bromo- 7- of 8- (2- butynyls) -3-
Methyl xanthine) and compound B (2- chloromethyl -4- methylquinazolins) in N, N- diisopropyl acetamide solutions, with carbonic acid
Potassium makees acid binding agent, reaction prepare compound D (the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acids-[(4- methyl -
2- quinazolyls) methyl] -1H- purine -2,6- diketone), then exist with compound C ((R) -3- t-butoxycarbonyl aminos piperidines)
In N, N- diisopropyl acetamide solution, acid binding agent is made with potassium carbonate, reaction prepares compound E (1- [(4- methyl-quinoline azoles
Quinoline -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8- [(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,
6- diketone -2,3,6,7- tetrahydrochysene -1H- purine), finally deprotection prepares Li Gelieting.Synthetic route is as follows：
The technological reaction cycle is long, cumbersome, and it often walks intermediate all by purification and then input next step, causes production
Product yield is low, and solvent load is big and waste of the energy, is not suitable for industrialized production.
6th, Canadian patent application CA2586938A1, the technique is by compound A (the bromo- 7- of 8- (2- butynyls) -3-
Methyl xanthine) and compound B (2- chloromethyl -4- methylquinazolins) in METHYLPYRROLIDONE, sodium carbonate ties up acid
Agent, reaction prepares intermediate D (the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acids-[(4- methyl -2- quinazolines
Base) methyl] -1H- purine -2,6- diketone), then under DIPEA alkalescence condition and compound C ' ((R) -3-
Phthaloyl imino piperidines) reaction prepare intermediate E ' (1- [(4- methylquinazolin -2- bases) methyl] -3- methyl -
7- (2- butine -1- bases) -8- (3- (R)-phenyl-diformyl imido piperidin-1-yl)-xanthine), neighbour is finally sloughed in monoethanolamine
Phenyl-diformyl base is the Ge Lieting that gets profit.Synthetic route is as follows：
This process route is similar with the process route of foregoing 1, CN104496989A, and simply reaction temperature is different, and first and second
Step reaction is all pyroreaction, harsher to equipment requirement, and raw material (R) -3- phthaloyl imino piperidines has
Higher production cost, and it is domestic temporarily without large-scale production, therefore it is unfavorable for industrialized production.
7th, Matthias Eckhardt et al., 8- (3- (R)-Aminopiperidin-1-yl) -7-but-2-
ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione
(BI 1356),a Highly Potent,Selective,Long-Acting,and Orally Bioavailable DPP-
4Inhibitor for the reatment of Type 2Diabetes, J.Med.Chem.2007,50,6450-6453 should
The technique of document description is compound A (the bromo- 7- of 8- (2- butynyls) -3- methyl xanthines) and compound B (2- chloromethyls -4-
Methylquinazolin) in DMF solvent, potassium carbonate makees acid binding agent, prepares the intermediate D (bromo- 7- (2- of 8-
Butynyl) -3,7- dihydro -3- methyl isophthalic acids-[(4- methyl -2- quinazolyls) methyl] -1H- purine -2,6- diketone), then exist
Reacted under the conditions of potassium alkaline with compound C ((R) -3- t-butoxycarbonyl aminos piperidines), Li Ge is prepared after deprotection
Arrange spit of fland.Synthetic route is as follows：
Column chromatography purifying is used in the finally purification of this route, is unfavorable for industrialized production.
In summary, Li Gelieting applicable industry synthesis technique, mainly passes through compound A (8- bromo- 7- (2- butine
Base) -3- methyl xanthines) and compound B (2- chloromethyl -4- methylquinazolins) reaction generation intermediate D (8- bromo- 7- (2- fourths
Alkynyl) -3,7- dihydro -3- methyl isophthalic acids-[(4- methyl -2- quinazolyls) methyl] -1H- purine -2,6- diketone), Ran Houhe
(R) -3- amino piperidine compounds (compound C, C '), which react, obtains corresponding intermediate E class compound, and intermediate E class
Compound is usually paste compound, and one is purification difficult, and two be to bring difficulty for subsequent reactions charge ratio, is unfavorable for industrialization
Big production.In addition, phase transfer catalyst TBAB, the inorganic salt catalyst of class containing iodine are also used in most of technique,
Production cost is also increased, industrialized production is limited.
Therefore the process for finding a suitable Li Gelieting industrialized production is imperative.
The content of the invention
It is an object of the invention to provide a kind of method for improving key intermediate E compounds yield and purity, finally make
Li Gelie statin response cycle times, it is easy to operate, it is adapted to the method for industrialized production.
To improve intermediate E compound (1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- butine -1-
Base) -8- [(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine) yield
And purity, the present invention in the step condensation reactions of Li Gelieting two by the acid binding agent natrium carbonicum calcinatum used control particle diameter 50~
200 μm-i.e. micron order, and reaction temperature is 55~60 DEG C, and two-step reaction is prepared using the method for " one kettle way "
Intermediate E compound；After intermediate E compound is refined by dichloromethane and n-hexane, it is deprotected with trifluoroacetic acid, anhydrous second
Alcohol and methyl tertiary butyl ether(MTBE) are refining to obtain target product Li Gelieting.
The invention provides a kind of Li Gelieting preparation method, its synthetic route is as follows：
Its reactions steps is as follows：
With compound A (the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone), compound B
(2- chloromethyl -4- methylquinazolins), compound C ((R) -3- t-butoxycarbonyl aminos piperidines) are raw material, in micron order carbonic acid
Under the conditions of sodium (being used as acid binding agent), METHYLPYRROLIDONE (NMP), reaction temperature is 55~60 DEG C, prepares intermediate
Compound E (1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8- [(R) -3- (tertiary fourth oxygen
Carbonylamino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine)；
Midbody compound E (1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8-
[(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine) pass through dichloromethane
After alkane (DCM) and n-hexane are refined, then it is deprotected with trifluoroacetic acid (TFA), absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) are refining to obtain
Target product Li Gelieting.
It is preferred that, described micron order acid binding agent sodium carbonate, particle diameter is 50~200 μm.
Described micron order acid binding agent sodium carbonate, can be by the way that commercially available sodium carbonate be crushed with pulverizer after, then use corresponding mesh
Several screen cloth sievings.
In raw material, compound A, compound B, compound C rate of charges are mol ratio 1.0:1.0-1.5:1.0-1.5, preferably
For 1.0:1.20:1.20.
It is preferred that, during three kinds of raw material reactions, the 1st step is：Compound A and compound B is first in the N- first of micron order sodium carbonate
In base -2-Pyrrolidone solution, reacted 4 hours at 55~60 DEG C；2nd step is：Compound C, and micron order sodium carbonate are added,
Reacted 6 hours at 55~60 DEG C.
It is preferred that, described micron order acid binding agent sodium carbonate, first step reaction and compound A rate of charges are mol ratio 1.5:
1.0, second step reaction and compound A rate of charges are mol ratio 1.5:1.0.
After intermediate E compound is refined by dichloromethane and n-hexane, its character becomes powder solid by paste.
It is preferred that, process for purification is：Intermediate E dichloromethane is dissolved, and anhydrous sodium sulfate drying is used after washing, and filtering is concentrated under reduced pressure,
N-hexane is added, solid is separated out, filtered, is dried.
Midbody compound E after refined obtains target product Li Gelieting, and method preferably is：Intermediate E is used two
Chloromethanes dissolves, and is cooled to less than 10 DEG C, and trifluoroacetic acid is added dropwise, and reacts at room temperature 5 hours, and the carbon that mass percent is 20% is added dropwise
Sour aqueous solutions of potassium to pH=10~11, washing organic layer to pH=6~7, anhydrous sodium sulfate drying, filtering, organic layer is evaporated, and is used
Absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) crystallize the Ge Lieting that gets profit.
The beneficial effects of the invention are as follows：
The present invention preparation method, by by the size controlling of acid binding agent sodium carbonate at 50~200 μm, without using iodate
Thing catalyst, equally reduces reaction temperature, and the reaction time shortens, and the purity of intermediate E compound is improved；
Intermediate E compound is improved yield by the implementation of " one kettle way ", shortens reaction time, reduces production cost；
After intermediate E compound is refined by dichloromethane and n-hexane, pleasantly surprised discovery, its character becomes powder by paste and consolidated
Body, one side purity is improved, and on the other hand brings convenient for subsequent reactions charge ratio, is adapted to industrialized production, and its
Purity is also improved, and guarantee is provided to finally give high-purity Li Gelieting.
In the preparation process in accordance with the present invention, the yield of intermediate E compound is more than 90%, purity be 99.5% with
On.
In the preparation process in accordance with the present invention, Li Gelieting yield is more than 86%, and purity is more than 99.7%.
The method of the present invention is particularly suitable for Li Gelieting industrialized production.
Embodiment
For a better understanding of the present invention, with reference to the embodiment content that the present invention is furture elucidated.But the present invention's
Content is not limited only to the following examples.
Embodiment 1
By compound A (the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone) (10g,
33.7mmol) it is added to compound B (2- chloromethyl -4- methylquinazolins, 2- (chloromethyl) -4-
Methylquinazoline) (7.8g, 40.4mmol) and the N- methyl -2- pyrroles of 50 μm of sodium carbonate (5.4g, 50.55mmol)
In alkanone 30ml solution, reacted 4 hours at 55~60 DEG C, add 50 μm of sodium carbonate (5.4g, 50.55mmol), while plus
Enter compound C ((R) -3- t-butoxycarbonyl aminos piperidines) (8.1g, 40.4mol), 6h is reacted at 55~60 DEG C, reaction terminates
60ml pure water is added afterwards, solid is separated out, and filtering, wet cake dichloromethane 80ml is dissolved, and anhydrous sodium sulfate drying is used after washing,
Filtering, is concentrated under reduced pressure into 20ml, adds n-hexane 80ml, separates out solid, and filtering is drying to obtain Li Gelieting intermediate Es (1-
[(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- butine -1- bases) -8- [(R) -3- (t-butoxycarbonyl amino) -
Piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine) 17.7g, yield is 91.8%, and purity is 99.6%.
Intermediate E (15g, 26.2mmol) 150ml dichloromethane is dissolved, less than 10 DEG C are cooled to, 37.5ml is added dropwise
Trifluoroacetic acid, drop finishes, and reacts at room temperature 5 hours, the wet chemical that dropwise addition mass percent is 20% to pH=10~11, water
Organic layer is washed to pH=6~7, anhydrous sodium sulfate drying is filtered, organic layer is evaporated, with absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) knot
Crystalline substance is get profit Ge Lieting 10.8g, yield 87.2%, purity 99.9%.
Embodiment 2
Compound A (10g, 33.7mmol) is added to compound B (7.8g, 40.4mmol) and 100 μm of sodium carbonate
In the METHYLPYRROLIDONE 30ml solution of (5.4g, 50.55mmol), reacted 4 hours at 55~60 DEG C, add 100
μm sodium carbonate (5.4g, 50.55mmol), while adding compound C (8.1g, 40.4mol), reacts 6h, instead at 55~60 DEG C
60ml pure water is added after should terminating, solid is separated out, filtering, wet cake dichloromethane 80ml is dissolved, and anhydrous slufuric acid is used after washing
Sodium is dried, filtering, is concentrated under reduced pressure into 20ml, adds n-hexane 80ml, separates out solid, and filtering is drying to obtain in the middle of Li Gelieting
Body E 17.6g, yield is 91.3%, and purity is 99.5%.
Intermediate E (15g, 26.2mmol) 150ml dichloromethane is dissolved, less than 10 DEG C are cooled to, 37.5ml is added dropwise
Trifluoroacetic acid, drop finishes, and reacts at room temperature 5 hours, the wet chemical that dropwise addition mass percent is 20% to pH=10~11, water
Organic layer is washed to pH=6~7, anhydrous sodium sulfate drying is filtered, organic layer is evaporated, with absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) knot
Crystalline substance is get profit Ge Lieting 10.6g, yield 86.1%, purity 99.8%.
Embodiment 3
Compound A (10g, 33.7mmol) is added to compound B (7.8g, 40.4mmol) and 200 μm of sodium carbonate
In the METHYLPYRROLIDONE 30ml solution of (5.4g, 50.55mmol), reacted 4 hours at 55~60 DEG C, add 200
μm sodium carbonate (5.4g, 50.55mmol), while adding compound C (8.1g, 40.4mol), reacts 6h, instead at 55~60 DEG C
60ml pure water is added after should terminating, solid is separated out, filtering, wet cake dichloromethane 80ml is dissolved, and anhydrous slufuric acid is used after washing
Sodium is dried, filtering, is concentrated under reduced pressure into 20ml, adds n-hexane 80ml, separates out solid, and filtering is drying to obtain in the middle of Li Gelieting
Body E 17.5g, yield is 90.8%, and purity is 99.5%.
Intermediate E (15g, 26.2mmol) 150ml dichloromethane is dissolved, less than 10 DEG C are cooled to, 37.5ml is added dropwise
Trifluoroacetic acid, drop finishes, and reacts at room temperature 5 hours, the wet chemical that dropwise addition mass percent is 20% to pH=10~11, water
Organic layer is washed to pH=6~7, anhydrous sodium sulfate drying is filtered, organic layer is evaporated, with absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) knot
Crystalline substance is get profit Ge Lieting 10.7g, yield 86.4%, purity 99.7%.
Embodiment 4
Compound A (10g, 33.7mmol) is added to compound B (7.8g, 40.4mmol) and 300 μm of sodium carbonate
In the METHYLPYRROLIDONE 30ml solution of (5.4g, 50.55mmol), reacted 7 hours at 55~60 DEG C, add 300
μm sodium carbonate (5.4g, 50.55mmol), while adding compound C (8.1g, 40.4mol), reacts 8h, instead at 55~60 DEG C
60ml pure water is added after should terminating, solid is separated out, filtering, wet cake dichloromethane 80ml is dissolved, and anhydrous slufuric acid is used after washing
Sodium is dried, filtering, is concentrated under reduced pressure into 20ml, adds n-hexane 80ml, separates out solid, and filtering is drying to obtain in the middle of Li Gelieting
Body E 17.4g, yield is 90.2%, and purity is 99.5%.
Intermediate E (15g, 26.2mmol) 150ml dichloromethane is dissolved, less than 10 DEG C are cooled to, 37.5ml is added dropwise
Trifluoroacetic acid, drop finishes, and reacts at room temperature 5 hours, the wet chemical that dropwise addition mass percent is 20% to PH=10~11, water
Organic layer is washed to PH=6~7, anhydrous sodium sulfate drying is filtered, organic layer is evaporated, with absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) knot
Crystalline substance is get profit Ge Lieting 10.6g, yield 86.1%, purity 99.7%.
Comparative example 1 (patent CN104496989A)
By compound A (297g, 1mol), compound B (192g, 1mol), potassium carbonate (276g, 1mol) and 1000ml diformazans
Base sulfoxide hybrid reaction, be heated to 80 DEG C react 4 hours, reaction is finished, directly in reaction solution add compound C (R)-
3- BIDA piperidines tartaric acid (230g, 1mol), DIPEA (202g, 2mol), is heated to 85
DEG C reaction 4 hours, reaction is complete, and monoethanolamine (240g, 4mol) is added directly into reaction solution, is heated to 100 DEG C, reaction
10 hours, reaction was finished, and purified water is added dropwise into reaction solution, filtering, is dried to obtain 430g Li Gelieting crude products, is used anhydrous second
Alcohol and the refined Ge Lieting 342g, yield 72.4%, purity 98.7% of getting profit of methyl tertiary butyl ether(MTBE).
Comparative example 2 (patent CN104844602A)
By compound A (54g, 0.182mol), compound C (40g, 0.2mol), potassium carbonate (50g, 0.364mol), iodate
Potassium 0.6g (0.04mol) and the mixing of 270ml METHYLPYRROLIDONEs, stirring are warming up to 50 DEG C, react 4 hours, reacted
Finish, add compound B (36.5g, 0.192mol), continue to react 4 hours, reaction is finished, stop heating, be cooled to room temperature.Instead
Addition dichloromethane 500ml, water 1000ml in liquid is answered, static layering is stirred, water layer is extracted 2 times with dichloromethane 250ml, is merged
It is that 1% aqueous acetic acid 500ml is washed 1 time that mass percent is added in organic phase, organic phase, saturated sodium-chloride water solution washing
1 time, then anhydrous sodium sulfate drying, filtering, the faint yellow solid of evaporated under reduced pressure adds absolute ethyl alcohol 300ml, is heated to backflow
Dissolving, is slowly added dropwise water 300ml, is cooled to 20~30 DEG C, stirs 2 hours, filtering, dry intermediate E 90.4g, yield
86.8%, purity 98.9%.
Intermediate E (90g, 0.157mol) 900ml dichloromethane is dissolved, less than 10 DEG C are cooled to, 225ml tri- is added dropwise
Fluoroacetic acid, drop finishes, and reacts at room temperature 12 hours, the ammoniacal liquor that dropwise addition mass percent is 25~28% to PH=8, and washing organic layer is extremely
PH=6~7, anhydrous sodium sulfate drying, filtering, organic layer is evaporated, and is beaten 2 hours with absolute ethyl alcohol and stirring, get profit Ge Lieting
62.5g, yield 84.1%, purity 98.5%.
Table 1：Embodiment 1~4, comparative example 1, the key reaction condition of comparative example 2, the contrast of product content and yield
(note：The total recovery of Li Gelieting in form, in addition to comparative example 1, remaining is intermediate E yield × Li Ge
Arrange spit of fland yield.)
It can be seen that by above-described embodiment contrast：
1st, by 50~200 μm, reducing reaction temperature, improving intermediate the size controlling of acid binding agent sodium carbonate
The purity of E compounds, the purity for the Ge Lieting that finally makes to get profit is improved.
2nd, after by the way that intermediate E compound dichloromethane and n-hexane are refined, the character of intermediate E is become by paste
Into powdered, one is to improve purity, and two be to be adapted to industrialized production.
3rd, operated by the way that two step condensation reactions are carried out into " one kettle way ", shorten reaction time, simplify operation, reduce
Production cost, is easy to industrialized production.
4th, the temperature of comparative example 1 is high, and the cycle is long, and uses (R) -3- phthaloyl imino piperidines tartaric acid, should
Cost of material is high and without industrialized production, and uses organic acid binding agent DIPEA, adds and is produced into
This.
5th, comparative example 2, employ KI as catalyst, although shorten the reaction time, reduce reaction temperature, but
The Li Gelieting purity finally prepared is less than 99%, it is difficult to prepare the pharmaceutical grade bulk drug of high-purity.
The preferred embodiment to the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make a variety of equivalent changes on the premise of without prejudice to the invention spirit
Type or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (8)
1. a kind of Li Gelieting preparation method, described preparation method comprises the following steps：
With the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone, 2- chloromethyl -4- methyl quinoline azoles
Quinoline, (R) -3- t-butoxycarbonyl aminos piperidines are raw material, and acid binding agent, METHYLPYRROLIDONE are used as in micron order sodium carbonate
Under conditions of, reaction temperature be 55~60 DEG C, prepare midbody compound 1- [(4- methyl-quinazoline -2- bases) methyl] -
3- methyl -7- (2- butine -1- bases) -8- [(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7-
Tetrahydrochysene -1H- purine；
Midbody compound by dichloromethane and n-hexane it is refined after, then be deprotected with trifluoroacetic acid, absolute ethyl alcohol and methyl
Tertbutyl ether is refining to obtain Li Gelieting；
The particle diameter of described micron order sodium carbonate is 50~200 μm；
In raw material, the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone, 2- chloromethyl -4- methyl
The rate of charge of quinazoline and (R) -3- t-butoxycarbonyl amino piperidines is mol ratio 1.0:1.0-1.5:1.0-1.5.
2. a kind of Li Gelieting according to claim 1 preparation method, it is characterised in that in raw material, the bromo- 7- (2- of 8-
Butynyl) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone, 2- chloromethyl -4- methylquinazolins and the tertiary fourth oxygen of (R) -3-
The rate of charge of carbonylamino piperidines is that mol ratio is 1.0:1.2:1.2.
3. a kind of Li Gelieting according to claim 1 or 2 preparation method, it is characterised in that during three kinds of raw material reactions,
The first step is first by the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone and 2- chloromethyl -4- methyl
Quinazoline reacts in the METHYLPYRROLIDONE solution of micron order sodium carbonate；Second step adds (R) -3- tertiary butyloxycarbonyls
Base amino piperidine and the reaction of micron order sodium carbonate.
4. a kind of Li Gelieting according to claim 3 preparation method, it is characterised in that described micron order carbonic acid
The rate of charge of sodium, first step reaction and the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone is to rub
You compare 1.5:1.0.
5. a kind of Li Gelieting according to claim 3 preparation method, it is characterised in that described micron order carbonic acid
The rate of charge of sodium, second step reaction and the bromo- 7- of 8- (2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone is to rub
You compare 1.5:1.0.
6. a kind of Li Gelieting according to claim 1 or 2 preparation method, it is characterised in that midbody compound leads to
Cross dichloromethane and n-hexane it is refined after, powder solid is become by paste；Described process for purification is：Midbody compound
Dissolved with dichloromethane, anhydrous sodium sulfate drying used after washing, filtering is concentrated under reduced pressure, and adds n-hexane, separates out solid, filters,
Dry.
7. a kind of Li Gelieting according to claim 1 or 2 preparation method, it is characterised in that the intermediate after refined
Compound dichloromethane dissolves, and is cooled to less than 10 DEG C, and trifluoroacetic acid is added dropwise, and reacts at room temperature 5 hours, and mass percent is added dropwise
For 20% wet chemical to pH=10~11, washing organic layer to pH=6~7, anhydrous sodium sulfate drying, filtering has
Machine layer is evaporated, and Li Gelieting is obtained with absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) crystallization.
8. a kind of Li Gelieting according to claim 1 preparation method, it is characterised in that by the bromo- 7- of 33.7mmol8-
(2- butynyls) -3,7- dihydro -3- methyl isophthalic acid H- purine -2,6- diketone is added to 40.4mmol 2- chloromethyl -4- methyl quinoline azoles
In the METHYLPYRROLIDONE solution of quinoline and 50 μm of 50.55mmol sodium carbonate, react 4 hours, then add at 55~60 DEG C
Enter 50 μm of 50.55mmol sodium carbonate, while 40.4mol (R) -3- t-butoxycarbonyl amino piperidines is added, it is anti-at 55~60 DEG C
Answer 6 hours, prepare midbody compound 1- [(4- methyl-quinazoline -2- bases) methyl] -3- methyl -7- (2- butine -1-
Base) -8- [(R) -3- (t-butoxycarbonyl amino)-piperidin-1-yl] -2,6- diketone -2,3,6,7- tetrahydrochysene -1H- purine；
Midbody compound by dichloromethane and n-hexane it is refined after, then be deprotected with trifluoroacetic acid, absolute ethyl alcohol and methyl
Tertbutyl ether is refining to obtain Li Gelieting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610135936.4A CN105622609B (en) | 2016-03-10 | 2016-03-10 | A kind of Li Gelieting preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610135936.4A CN105622609B (en) | 2016-03-10 | 2016-03-10 | A kind of Li Gelieting preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105622609A CN105622609A (en) | 2016-06-01 |
| CN105622609B true CN105622609B (en) | 2017-08-25 |
Family
ID=56037991
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610135936.4A Active CN105622609B (en) | 2016-03-10 | 2016-03-10 | A kind of Li Gelieting preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105622609B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017638A (en) * | 2016-10-31 | 2018-05-11 | 江苏艾立康药业股份有限公司 | A kind of preparation method of Li Gelieting crystal forms |
| CN110964013B (en) * | 2018-09-29 | 2023-04-07 | 甘李药业股份有限公司 | Preparation method of linagliptin and intermediate thereof |
| CN109705121B (en) * | 2019-02-11 | 2022-04-01 | 深圳市第二人民医院 | Preparation method of linagliptin intermediate |
| CN109761983B (en) * | 2019-02-11 | 2022-03-04 | 深圳市第二人民医院 | Preparation method of linagliptin |
| CN110615790A (en) * | 2019-10-24 | 2019-12-27 | 北京融英医药科技有限公司 | Improved method of preparation process of linagliptin |
| CN112724140A (en) * | 2020-12-22 | 2021-04-30 | 山东永丞制药有限公司 | Novel preparation process of linagliptin |
| CN112552299B (en) * | 2020-12-25 | 2023-02-17 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of linagliptin for treating type II diabetes |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503781A (en) * | 2011-09-28 | 2012-06-20 | 河北工业大学 | Method for preparing phenol ether through reaction of phenolic compound and halogenated hydrocarbon |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
-
2016
- 2016-03-10 CN CN201610135936.4A patent/CN105622609B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102503781A (en) * | 2011-09-28 | 2012-06-20 | 河北工业大学 | Method for preparing phenol ether through reaction of phenolic compound and halogenated hydrocarbon |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105622609A (en) | 2016-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105622609B (en) | A kind of Li Gelieting preparation method | |
| CN103319483B (en) | A kind of preparation method of important intermediate of linagliptin | |
| CN106966947B (en) | A kind of preparation method of vildagliptin | |
| CN104945299B (en) | A kind of high-efficiency synthesis method of vildagliptin | |
| CN104672238B (en) | A kind of Li Gelieting preparation method | |
| CN105936634A (en) | Synthetic method of linagliptin | |
| CN110483415A (en) | A kind of method for preparing purified for disliking La Geli intermediate | |
| CN105906627A (en) | Synthesis method of linagliptin intermediate | |
| CN104844602B (en) | A kind of preparation method of Li Gelieting | |
| CN105906628A (en) | Preparation method of linagliptin | |
| CN109336892A (en) | A kind of support method replaces the preparation method of cloth impurity | |
| CN104628679B (en) | Bitopertin synthetic method and its intermediate | |
| CN105481856B (en) | A kind of preparation method of 9-hydroxy-risperidone | |
| CN105440034B (en) | A kind of Li Gelieting and its intermediate preparation method | |
| CN107056720A (en) | A kind of preparation and purification method of Valsartan | |
| CN105524042B (en) | A method of preparing bent Ge Lieting | |
| CN101880270A (en) | Method for preparing 1,1-cyclopropanedimethyl cyclicsulfite | |
| CN106554354B (en) | The preparation method of the intermediate of Li Gelieting or its analog and Li Gelieting or its analog | |
| CN103450201B (en) | Preparation method of chiral 8-(3-aminopiperidine-1-yl)-xanthine | |
| CN102532128A (en) | Synthetic method of tropisetron and prepare method of hydrochloric acid tropisetron | |
| CN105358529A (en) | Novel method for synthesizing key intermediate of apixaban | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN101492430B (en) | Method for preparing high-purity cetirizine hydrochloride | |
| CN103130700B (en) | Preparation method of azelnidipine intermediate | |
| CN103980134B (en) | A kind of preparation method of succsinic acid S-metoprolol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20161222 Address after: 200540 Shanghai city Jinshan District China Road No. 298 Applicant after: Shanghai Wanxiang Pharmaceutical Co., Ltd. Address before: 201518 Jinshan District Jin Zhang Road, Shanghai, No. 2068 Applicant before: Shanghai Wandai Pharmaceutical Co., Ltd. Applicant before: Shanghai Wanxiang Pharmaceutical Co., Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |