CN105906627A - Synthesis method of linagliptin intermediate - Google Patents
Synthesis method of linagliptin intermediate Download PDFInfo
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- CN105906627A CN105906627A CN201610189177.XA CN201610189177A CN105906627A CN 105906627 A CN105906627 A CN 105906627A CN 201610189177 A CN201610189177 A CN 201610189177A CN 105906627 A CN105906627 A CN 105906627A
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
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Abstract
The invention discloses a synthesis method of a linagliptin intermediate. The synthesis method comprises adding 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine (e), (R)-3-Boc-aminopiperidine (f), potassium carbonate and acetonitrile into a reactor, carrying out uniform mixing and carrying out a reaction process under the conditions of heating reflux, a reaction temperature of 80-85 DEG C and reaction time of 24-48h, wherein a mole ratio of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine (e), (R)-3-Boc-aminopiperidine (f) to potassium carbonate is 1: (1.2-1.6): (3-7) and a ratio of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine (e) to acetonitrile is 100: (400-1000)g/ml. The synthesis method of the linagliptin intermediate (g) prevents generation of debromination impurities (i), is simple and easy in a post-treatment step and solves the problem that the intermediate is not easily separated from a solvent and is difficultly purified and separated.
Description
Technical field
The present invention relates to the synthetic method of a kind of Li Gelieting intermediate.
Background technology
Have several DPP-4 inhibitor class medicines at present and be approved the treatment for T2DM patient.Li Gelieting
(linagliptin) it is a newcomer therein.Li Gelieting is by a 8-of Boehringer Ingelheim company design synthesis
(3-amino piperidine)-xanthine derivative (WO 2004018468/CN 1675212), for the DPP-4 inhibitor that activity is the strongest
(IC50=1nmol/L), there is high selectivity, long-acting and orally active feature, there is good security and tolerance simultaneously
Property.
Obtain U.S. FDA approval listing in May, 2011, in June, 2011, be approved listing in Europe.In October, 2010, Europe batch
Quasi-Li Gelieting as the therapeutic alliance medicinal application of insulin in T2DM patient.In April, 2013, Li Gelieting obtains state of China
The import drugs registration certificate that family's food and medicine supervision and management general bureau (CFDA) issues, is approved to sell in Discussion on Chinese Listed.
1-[(4-methyl-quinazoline-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-(3-(R)-amino-piperazine
Pyridine-1-base)-xanthine (Li Gelieting):
The synthesis route of existing Li Gelieting is broadly divided into two.Wherein a route is as follows:
During synthetic intermediate (g) (tertbutyloxycarbonyl-Li Gelieting), CN102127080 A is by 10.00kg
(33.66mol) 3-methyl-7-(2-butine-1-base)-8-bromine xanthine, 7.13kg (37.02mol) 2-chloromethyl-4-methyl
Quinazoline, 3.92kg (37.02mol) natrium carbonicum calcinatum and 30 liters of METHYLPYRROLIDONEs are initially charged with in reactor.Will reaction
Device content is heated to 140 DEG C and stirs 2 hours in 140 DEG C.This patent with METHYLPYRROLIDONE as solvent, required instead
Answer temperature high, it is necessary to just to carry out more than 110 DEG C, but owing to reaction temperature is high, the debrominate of a bigger intermediate (e) can be produced
Impurity (i), the extremely difficult removing of this impurity, removing this impurity needs extremely complex purge process.In patent, the method is not simultaneously
Also reside in post-processing step in place of foot and add a large amount of water and ethanol dilution, and add acetic acid to separate out solid product, finally use second
Alcohol and water washs, thus causes a large amount of waste water to produce, and is unfavorable for environmental protection.
In order to overcome the problems referred to above, patent CN 104387390 A discloses compound (c) and compound (d) at N, N-bis-
Methylacetamide, dimethyl sulfoxide (DMSO), in 1-METHYLPYRROLIDONE, or a combination thereof solvent, deposit at potassium carbonate and TBAB
Under, react 4 hours-8 hours at 50 DEG C-70 DEG C, obtain the first reactant mixture；Then add in the first reactant mixture
Compound (f), reacts 10 hours-14 hours at 70 DEG C-90 DEG C, is then peeled off obtaining compound (g).Such second reaction exists
Under potassium carbonate and TBAB co-catalysis effect, compound (c) can carried out at 70 DEG C-90 DEG C with compound (d)
Reaction.But owing to the second reaction has TBAB, other impurity can be produced, and the more difficult removing of TBAB,
Causing separation difficulty, purity is low, it is impossible to be directly used as medicine.
In the presence of CN 104844602 A is disclosed in potash salt or sodium carbonate, with the inorganic salts containing iodine as catalyst, with
1-METHYLPYRROLIDONE or DMF are solvent, under the conditions of 30-80 DEG C, and the bromo-7-of 8-(2-butynyl)-3,7-bis-
Hydrogen-3-methyl isophthalic acid H-purine-2,6-diketone reacts with (R)-3-amino piperidine compounds, and reaction terminates the most directly to add
Entering 2-chloromethyl-4-methylquinazolin described in formula E, generate intermediate (g), intermediate (g) deprotection is got profit Ge Lieting.But this is special
Profit simply will contain iodine inorganic salts simply and substitute TBAB, and the second reaction is at potassium carbonate and the inorganic salts co-catalysis Han iodine
Under effect, compound (c) can react at 70 DEG C-90 DEG C with compound (d).But due to second reaction have containing iodine without
Machine salt, can produce other impurity, and the more difficult removing of the inorganic salts Han iodine, accordingly even when use complicated post processing method of purification,
But intermediate (g) purity obtained is low, and yield is low, and the product obtained with single step reaction also can contain corresponding impurity, causes
Final products are made to be directly used as medicine.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides the synthetic method of a kind of Li Gelieting intermediate, the method
Having simple to operate, more environmental protection, raw material is simple and easy to get, and impurity is few, yield high.
The invention provides the synthetic method of a kind of Li Gelieting intermediate, comprise the following steps:
By 1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e),
(R)-3-Boc-amino piperidine (f), potassium carbonate and acetonitrile addition reactor are interior and mix, and enter when being heated to reflux
Row reaction obtains tertbutyloxycarbonyl-Li Gelieting (g),
Wherein, reaction temperature is 80～85 DEG C, and the reaction time is 24～48h,
1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e), (R)-
3-Boc-amino piperidine (f), the mol ratio of potassium carbonate are 1:(1.2～1.6): (3～7),
1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e) and second
The ratio of nitrile is 100:(400～1000) g/ml.
Reaction temperature is 81～82 DEG C, and the reaction time is 28～35h.
1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e), (R)-
3-Boc-amino piperidine (f), the mol ratio of potassium carbonate are 1:(1.3～1.5): (4～5).
1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e) and second
The ratio of nitrile is 100:(500～700) g/ml.
Including also following steps: after the completion of reaction, be slowly added to 65～80 DEG C of hot water, under room temperature, stir slow cooling,
Separate out solid, be filtrated to get solid.
After being filtrated to get solid, in addition it is also necessary to carry out following steps: pulled an oar with 65～75 DEG C of hot water by solid, be slowly dropped to
Filter after room temperature.Filter cake washes with water, is dried, obtains tertbutyloxycarbonyl-Li Gelieting (g).
Compared with prior art, the present invention's has a beneficial effect:
(1) synthetic method of the intermediate (c) of the present invention, gained intermediate (c) purity is high, need not purify, can directly enter
Next step reaction of row, does not affect subsequent reactions product purity.And solve be diluted with water after the asking of solid filtration difficulty that separate out
Topic.
The synthetic method of the intermediate (e) of the present invention, solves the problem of product filtration difficulty after reaction.I.e. reacting
Cheng Hou, after the methanol dilution reactant liquor by 0.5 times of volume of addition, then filters, and prior art is provided without adding first
The method of alcohol dilute reaction solution, filtration difficulty, filtering velocity is slow, and water capacity is high, and when causing subsequent treatment, DMAC is difficult to remove.
(2) synthetic method of the intermediate (g) of the present invention has done significant improvement, uses excess relative to intermediate (f)
Intermediate (e), and the addition mole of potassium carbonate is equivalent at least three times of intermediate (e), and at the shape of acetonitrile backflow
Under state, so combine interaction and just achieve intermediate (e) and (R)-3-Boc-amino piperidine (f) at temperature 80～85 DEG C
Reaction, is avoided that again the generation of debrominate impurity simultaneously.
The synthetic method of the intermediate (g) of the present invention, avoids the generation of impurity (i) conscientiously, this debrominate impurity (i) in
Mesosome and product are all not detected by.The finished product purity obtained is at least more than 99.5, substantially meets the impurity that medicine is declared
Content requirement.And without adding the dilution of a large amount of water in post-processing step, the most not without adding the use such as dichloromethane and acetic acid
In purification, can avoid producing a large amount of waste water, beneficially environmental protection.The most also solve this intermediate in a solvent because be difficult to separate out and
The problem of purifies and separates difficulty.
(3) the de-Boc protection group method of the present invention, is to carry out under inert gas (such as helium nitrogen) is protected, and system is close
Close, react under pressure or normal pressure.Compared with the conventional method, this method be not required to costliness trifluoroacetic acid-DCM react, only
Use cheap methanol-water solution, and post processing is simple, and the reaction of trifluoroacetic acid-DCM system, generate impurity many, after
Process purge process the most loaded down with trivial details.Furthermore, it is also possible to avoid intermediate (g) and the acid amides in Lie Geliting using strong acid to cause
The impurity such as bond fission.
(4) using the synthetic route of the present invention, the total recovery of final products is high, the final thick simple recrystallization of product warp,
Just can get pharmaceutics acceptable Li Gelieting bulk drug, it is not necessary to other purification processes.
Specific embodiment
For making the purpose of the embodiment of the present invention, technical scheme and advantage clearer, below in the embodiment of the present invention
Technical scheme is clearly and completely described, it is clear that described embodiment is a part of embodiment of the present invention rather than complete
The embodiment in portion.Based on the embodiment in the present invention, those of ordinary skill in the art are not under making creative work premise
The every other embodiment obtained, broadly falls into the scope of protection of the invention.It should be noted that in the case of not conflicting,
Embodiment in the application and the feature in embodiment can mutually be combined.
For can further clearly demonstrate technical scheme, below by by the form pair of specific embodiment
The synthetic method of the Li Gelieting of the present invention carries out concrete, detailed description.
In the present invention, wt% is mass fraction；
Reactant (a) is 8-bromo-3-methyl xanthine, the compound that formula a represents；
Reactant (b) is 1-bromo-2-butine, the compound that formula b represents；
Intermediate (c) is 3-methyl-7-(2-butine-l-base) the bromo-xanthine of-8-, the compound that formula c represents；
Reactant (d) is 2-chloromethyl-4-methylquinazolin, the compound that formula d represents；
Intermediate (e) is that 1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine is yellow
Purine, the compound that formula e represents；
Reactant (f) is (R)-3-Boc-amino piperidine, the compound that formula f represents；
Intermediate (g) is tertbutyloxycarbonyl-Li Gelieting, the compound that formula g represents；
Product (h) is Li Gelieting, the compound that formula h represents；
Debrominate impurity (i) is the compound that formula i represents；
Embodiment 1
The method of formula g compound Li Gelieting, it comprises the steps:
(1) synthesis of intermediate (c)
Bromo-3-methyl xanthine (a) of 8-is reacted with bromo-2-butine (b) of 1-, obtains intermediate (c).
Operating procedure: in a 2L there-necked flask, adds bromo-3-methyl xanthine (a) of 908g (3.7mol) 8-, 574.1g
(4.442mol) bromo-2-butine (b) of DIPEA (DIEA), 591.1g (4.445mol) 1-, acetone 12L.Open
Stirring, is heated to back flow reaction, and after 4～6h, reaction terminates.Reactant liquor cools to room temperature, suction filtration, and filter cake 4L methyl alcohol is washed
Wash, obtain faint yellow solid, dried 1013.7g product, purity 95.7%, yield 105.9%.
(2) synthesis of intermediate (e)
Intermediate (c) reacts with 2-chloromethyl-4-methylquinazolin (d), obtains intermediate (e).
Operating procedure: add 550g (1.851mol) intermediate (c), 463.3g (2.405mol) 2-in 10L reactor
Chloromethyl-4-methylquinazolin (d), 332.6g (2.407mol) potassium carbonate and 6L (dimethylacetylamide, DMAC).Stirring, adds
Heat is to 75～95 DEG C of reactions, and after 7～10h, reaction terminates, and cools to 65 DEG C once, adds 3L methyl alcohol stirring 0.5～1h, mistake
Filter, filter cake 1L methyl alcohol washs.Gained filter cake 2L water is pulled an oar, and filters, filter cake 1L water, and 1L methyl alcohol washs, and obtains yellow filter cake,
Dried product 724.9g, yield 86.4%, purity 98.5%.
(3) synthesis of intermediate (g)
Intermediate (e) reacts with (R)-3-Boc-amino piperidine (f), obtains intermediate (g).
Operating procedure: addition 700g (1.54mol) intermediate (e) in 10L reactor, 464.1g (2.32mol) (R)-
3-Boc-amino piperidine (f), 854g (6.18mol) potassium carbonate, acetonitrile 3.5L.Open stirring, be heated to refluxing (micro-backflow), instead
Answer temperature 80～85 DEG C, react after reaction 28～35h and terminate.It is slowly added to 70 DEG C of hot water of 4.5L, stirring slowly fall under room temperature
Temperature, separates out solid.Filter.Filter gained solid 8L 65～75 DEG C of hot water making beating, filter after being slowly dropped to room temperature.Filter cake is used
Water washs, dried faint yellow solid product 792.7g.Yield 89.6%, purity 99.6%.
(4) synthesis of Li Gelieting
After intermediate (g) deprotection, obtain finished product Li Gelieting.
Operating procedure: add 792.7g intermediate (g), 2.4L methyl alcohol, 1.5L water in 5L reaction bulb, replace three with nitrogen
After secondary, system is airtight, opens stirring, is heated to back flow reaction.After 12～18h, reaction terminates.It is cooled to room temperature, separates out solid.
Filter, filter cake washs with a small amount of methyl alcohol, dried obtain product 586.5g.Yield 92.8%, purity 99.6%.
(5) gained crude product in patent US20130123282 embodiment 23 report method recrystallization both pharmaceutics can
The Li Gelieting bulk drug accepted.
Gained crude product is dissolved in the ethanol of 5 times amount (in this patent being 16 times, product can be caused to lose bigger) volume, adds
Heat, to backflow, after product is completely dissolved, is cooled to less than 50 DEG C, adds the methyl tertiary butyl ether(MTBE) of equal volume amounts, stirring cooling
To 0～5 DEG C and be incubated 1h, suction filtration, filter cake methyl tertiary butyl ether(MTBE) washs, and is drying to obtain finished product in lower 60 DEG C of vacuum.
Or: gained crude product is joined in 3L ethanol, is heated to backflow.After product is completely dissolved, it is cooled to less than 50 DEG C,
Adding 3L methyl tertiary butyl ether(MTBE), stirring is cooled to 0～5 DEG C, and continues insulated and stirred 1h crystallization.Suction filtration, filter cake methyl-tert fourth
Base ether washs, and is dried, in lower 60 DEG C of vacuum, Ge Lieting bulk drug of getting profit.
Embodiment 2
The method of formula g compound Li Gelieting, it comprises the steps:
(1) synthesis of intermediate (c)
Bromo-3-methyl xanthine (a) of 8-is reacted with bromo-2-butine (b) of 1-, obtains intermediate (c).
Operating procedure: in a 500mL there-necked flask, adds bromo-3-methyl xanthine (a) of 36.75g (0.15mol) 8-,
23.26g (0.18mol) DIPEA (DIEA), bromo-2-butine (b) of 21.94g (0.165mol) 1-, acetone
350mL.Opening stirring, be heated to back flow reaction, after 7h, reaction terminates.Reactant liquor cools to room temperature, suction filtration, and filter cake is used
100mL methyl alcohol washs, and obtains faint yellow solid, dried 52.96g product, purity 92.0%, yield 118.8%.
(2) synthesis of intermediate (e)
Intermediate (c) reacts with 2-chloromethyl-4-methylquinazolin (d), obtains intermediate (e).
Operating procedure: add 29.7g (0.01mol) intermediate (c), 25.0g (0.13mol) 2-chloromethane in 1L reactor
Base-4-methylquinazolin (d), 16.8g (0.13mol) DIPEA (DIEA) and 350mL (dimethylacetylamide,
DMAC).Stirring, is heated to 75～95 DEG C of reactions, and after 10h, reaction terminates, and cools to less than 65 DEG C, adds 180mL methyl alcohol
Stirring 0.5～1h, filters, and filter cake 100mL methyl alcohol washs.Gained filter cake 100mL water is pulled an oar, and filters, filter cake 50mL water,
50mL methyl alcohol washs, and obtains yellow filter cake, dried product 36.9g, yield 81.5%, purity 97.7%.
(3) synthesis of intermediate (g)
Intermediate (e) reacts with (R)-3-Boc-amino piperidine (f), obtains intermediate (g).
Operating procedure: add 100g (0.22mol) intermediate (e), 66.3g (0.33mol) (R)-3-in 2L reactor
Boc-amino piperidine (f), 122g (0.88mol) potassium carbonate, acetonitrile 700mL.Open stirring, be heated to refluxing (micro-backflow), instead
Answer temperature 80～85 DEG C, react after reaction 34h and terminate.It is slowly added to 70 DEG C of hot water of 800mL, under room temperature, stirs slow cooling, analysis
Go out solid.Filter.Filter gained solid 1.5L 65～75 DEG C of hot water making beating, filter after being slowly dropped to room temperature.Filter cake washes with water
Wash, dried faint yellow solid product 108.9g.Yield 86.3%, purity 99.1%.
(4) synthesis of Li Gelieting
After intermediate (g) deprotection, obtain finished product Li Gelieting.
Operating procedure: add 79.3g intermediate (g), 200mL methyl alcohol, 200mL water in 1L reaction bulb, replace three times with nitrogen
After, system is airtight, opens stirring, is heated to back flow reaction.After 12～18h, reaction terminates.It is cooled to room temperature, separates out solid.Cross
Filter, filter cake washs with a small amount of methyl alcohol, dried obtain product 56.1g.Yield 85.7%, purity 98.7%.
Embodiment 3
The method of formula g compound Li Gelieting, it comprises the steps:
(1) synthesis of intermediate (c)
Bromo-3-methyl xanthine (a) of 8-is reacted with bromo-2-butine (b) of 1-, obtains intermediate (c).
Operating procedure: in a 500mL there-necked flask, adds bromo-3-methyl xanthine (a) of 10g (0.04mol) 8-,
6.2g (0.048mol) DIPEA (DIEA), bromo-2-butine (b) of 6.9g (0.052mol) 1-, acetone 120mL.
Opening stirring, be heated to back flow reaction, after 5.5h, reaction terminates.Reactant liquor cools to room temperature, suction filtration, filter cake 50mL first
Alcohol washs, and obtains faint yellow solid, dried 12.9g product, purity 93.6, yield 106.3%.
(2) synthesis of intermediate (e)
Intermediate (c) reacts with 2-chloromethyl-4-methylquinazolin (d), obtains intermediate (e).
Operating procedure: add 20.8g (0.07mol) intermediate (c), 16.2g (0.084mol) 2-in 500mL reactor
Chloromethyl-4-methylquinazolin (d), 11.6g (0.084mol) potassium carbonate and 200L (dimethylacetylamide, DMAC).Stirring, adds
Heat is to 84～86 DEG C of reactions, and after 16h, reaction terminates, and cools to 65 DEG C once, adds 100mL methyl alcohol stirring 0.5～1h, mistake
Filter, filter cake 30mL methyl alcohol washs.Gained filter cake 120mL water is pulled an oar, and filters, filter cake 120L water, and 50mL methyl alcohol washs,
Yellow filter cake, dried product 24.5g, yield 77.2%, purity 98.9%.
(3) synthesis of intermediate (g)
Intermediate (e) reacts with (R)-3-Boc-amino piperidine (f), obtains intermediate (g).
Operating procedure: addition 700g (1.54mol) intermediate (e) in 10L reactor, 464.1g (2.32mol) (R)-
3-Boc-amino piperidine (f), 854g (6.18mol) potassium carbonate, acetonitrile 3.5L.Open stirring, be heated to refluxing (micro-backflow), instead
Answer temperature 80～85 DEG C, react after reaction 28～35h and terminate.It is slowly added to 70 DEG C of hot water of 4.5L, stirring slowly fall under room temperature
Temperature, separates out solid.Filter.Filter gained solid 8L 65～75 DEG C of hot water making beating, filter after being slowly dropped to room temperature.Filter cake is used
Water washs, dried faint yellow solid product 792.7g.Yield 89.6%, purity 99.6%.
(4) synthesis of Li Gelieting
After intermediate (g) deprotection, obtain finished product Li Gelieting.
Operating procedure: add 25.0g intermediate (g), 50L methyl alcohol, 75L water in 500mL reaction bulb, replace three with nitrogen
After secondary, system is airtight, opens stirring, is heated to back flow reaction.After 29h, reaction terminates.It is cooled to room temperature, separates out solid.Filter,
Filter cake washs with a small amount of methyl alcohol, dried product 17.9g.Yield 86.8%, purity 98.3%.
Comparative example 1
(1) synthesis of intermediate (c) makees solvent with DMF
Under room temperature, in a 5L there-necked flask, add the 8-bromo-3-methyl yellow of the DMF, 100g (0.408mol) of 1000mL
Purine (a), the DIPEA (DIEA) of 62g (0.4797mol), stirring is warming up to 40 DEG C, to all dissolving.Slowly
Bromo-2-butine (b) of 1-of dropping 81.5g (0.6128mol), insulation reaction 7h (HPLC detection).After having reacted, it is slowly added to
2000mL water is to reactant mixture, and is stirred at room temperature 2h, filters.Filter cake 100mL water washs.Gained filter cake is added
700mL methyl alcohol, stirs 1h at 60 DEG C.It is cooled to room temperature, stirs 1h.Filter and use 100mL methyl alcohol to wash, dried
89.3g product, purity 98.3%, yield 83.7%.
(2) the synthesis using method of intermediate (e).
Under room temperature, add in 5L there-necked flask DMSO, 89.3g (0.30mol) of 620mL 3-methyl-7-(2-butine-
1-yl) 2-(chloromethyl)-4-methyl-quinazoline (d) of-8-bromine xanthine (c), 69.5g (0.36mol), 0.5g tetrabutyl bromine
Change ammonium and the Anhydrous potassium carbonate of 49.8g (0.36mol), under stirring, be warming up to 83～86 DEG C.Insulation reaction 9h.After having reacted,
Reactant mixture is cooled to 45～50 DEG C.It is slowly added to 530mL methyl alcohol to reactant mixture and stirs 1h at 45～50 DEG C.Cross
Filter solid also washs with the methyl alcohol of 180mL, pulls an oar with 530mL water subsequently.Filter, add the methyl alcohol of 620mL to filter cake, be warming up to
65 DEG C of insulation 1h, are cooled to 40～45 DEG C and are incubated 1h.Cross filter solid and rinse with 180mL methyl alcohol.Dried product
111.5g, yield 81.8%, purity 99.2%.
(3) synthesis of intermediate (g) uses and makees solvent with DMSO
Operating procedure: add 100g (0.2206mol) intermediate (e), 66.3g (0.3309mol) in 5L there-necked flask
(R)-3-Boc-amino piperidine (f), 61.0g (0.4412mol) potassium carbonate, the DMSO of 800mL.Open stirring, be heated to 120
DEG C, insulation reaction 10h.After having reacted, reactant mixture is cooled to 30～35 DEG C, is slowly added to 1600mL water and in room temperature
Lower stirring 1h.Filter.Filter gained solid 200mL water to wash, dried crude product 124.8g, yield 98.9%, purity
91.7%.
In this solid, add 500mL dichloromethane and 35g activated carbon, be warming up to return stirring decolouring 6h, be cooled to room
Filtering after temperature, filter cake 200mL eluent methylene chloride, filtrate is spin-dried for, and adds dichloromethane 200mL, dissolve clear in residue
After Qing, dripping 400mL isopropyl ether under stirring in this system, 30min dropping is complete, and crystallization 12h, suction filtration, filter cake are stirred at room temperature
Carry out recrystallizing once by the method again.50 DEG C of forced air dryings of filter cake obtain 100.7g yellow powdery solid.This step is always received
Rate about 79.8%, purity 97.8%.
(4) synthesis of Li Gelieting uses trifluoroacetic acid-dichloromethane system.
At room temperature, in 1L there-necked flask, add the tertbutyloxycarbonyl-Li Gelieting of the dichloromethane of 500mL, 100g
G (), stirring is the most molten clearly.Temperature control, at 25～30 DEG C, drips the trifluoroacetic acid of 200mL in 1h.Insulation reaction after dropping
2.5h。
After having reacted, in a 5L there-necked flask, add 4L water, and be cooled to 5 DEG C, reactant is slowly added in water,
It is warming up to room temperature, stirs 1h.With 30% solution of potassium carbonate regulation to PH=8.5～9.0.Layering, water layer the most respectively with 800mL,
300mL dichloromethane extracts.Merge organic layer and wash with saturated aqueous common salt.Solvent evaporated, adds the second of 350mL in residue
Alcohol, is warming up to 70～75 DEG C, and stirring makes solid be completely dissolved and is incubated 0.5h.Then slow cooling is to room temperature crystallization, in room temperature
After lower stirring 4h, add the methyl tertiary butyl ether(MTBE) of 350mL, be cooled to 5 DEG C, insulated and stirred 2h.Filter, the first of filter cake 100mL
Base tertbutyl ether washs.
Repeat above-mentioned post-processing operation, will dissolve by gained solid wet product 500mL dichloromethane, and add 30% carbonic acid
Hydrogen sodium solution is sufficiently stirred for 1h.Separatory, aqueous phase extracts with 300mL, 100mL dichloromethane respectively.Merge organic layer and with saturated
Brine It.Solvent evaporated, adds the ethanol of 350mL in residue, is warming up to 70～75 DEG C, and stirring makes solid be completely dissolved
And it is incubated 0.5h.Then slow cooling is to room temperature crystallization, after being stirred at room temperature 4h, adds the methyl tertiary butyl ether(MTBE) of 350mL, cold
But to 5 DEG C, insulated and stirred 2h.Filter, the methyl tertiary butyl ether(MTBE) washing of filter cake 100mL.Dry under room temperature, obtain 58.5g white
Solid, yield 70.9%, purity 98.7%.
Comparative example 2
By (R) 3-Boc-amino piperidine (f) (0.27 mole) of DMSO, 53.2g of 800mL, 100g 1-[(4-methyl-
Quinazoline-2 base) methyl]-3-methyl-7-(2-butine-l-base) bromo-xanthine intermediate (e) of-8-(0.22 mole), 45.8g
Potassium carbonate (0.33 mole) 20-30 DEG C of charging to equipped with overhead stirrer and 5 liters of round-bottomed flasks of hot bag.By mixture
Temperature is increased to 80-85 DEG C and keeps 4-5 hour at the same temperature.After having heated, mixture is cooled to 30-35
DEG C, and be slowly added the cooling DM water of 1600mL and stir 60 minutes at 25-35 DEG C, there is solid to separate out, after filtering
Faint yellow solid, is detected as unreacted raw material, does not obtains intermediate (g).And course of reaction detects, there are no intermediate
G () generates.
Comparative example 3
100g (0.22mol) intermediate (e), 66.3g (0.33mol) (R)-3-Boc-amino piperazine is added in 2L reactor
Pyridine (f), 122g (0.88mol) potassium carbonate, 700mL DMSO.Open stirring, heating-up temperature 80～85 DEG C, slow after heating 34h
Add 70 DEG C of hot water of 800mL, stir slow cooling under room temperature, separate out solid, obtain faint yellow solid after filtration, detection is confirmed
For reaction raw materials, do not obtain intermediate (g).
The situation of table 1 final products
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | |
| Total recovery, % | 76.1 | 71.6 | 63.8 | 38.7 |
| Debrominate impurity (i) | It is not detected by | It is not detected by | It is not detected by | Containing 0.13% |
Note: the total recovery of total recovery that is four step；
Descriptions above can combine enforcement individually or in every way, and these variant all exist
Within protection scope of the present invention.
It should be noted that in this article, term " includes ", " comprising " or its any other variant are intended to non-row
Comprising of his property, so that include that the article of a series of key element or equipment not only include those key elements, but also include not
There are other key elements being expressly recited, or also include the key element intrinsic for this article or equipment.There is no more limit
In the case of system, statement " including ... " key element limited, it is not excluded that in the article including described key element or equipment
There is also other identical element.
Above example is only in order to illustrate technical scheme and unrestricted, reference only to preferred embodiment to this
Bright it is described in detail.It will be understood by those within the art that, technical scheme can be modified
Or equivalent, without deviating from the spirit and scope of technical solution of the present invention, all should contain the claim model in the present invention
In the middle of enclosing.
Claims (6)
1. the synthetic method of Yi Zhong Li Gelieting intermediate, it is characterised in that comprise the following steps:
By 1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e), (R)-3-
Boc-amino piperidine (f), potassium carbonate and acetonitrile addition reactor are interior and mix, and react when being heated to reflux
Obtain tertbutyloxycarbonyl-Li Gelieting (g),
Wherein, reaction temperature is 80～85 DEG C, and the reaction time is 24～48h,
1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e), (R)-3-
Boc-amino piperidine (f), the mol ratio of potassium carbonate are 1:(1.2～1.6): (3～7),
1-[(4-methylquinazolin-2-base) methyl]-3-methyl-7-(2-butine-1-base)-8-bromine xanthine (e) and acetonitrile
Ratio is 100:(400～1000) g/ml.
2. synthetic method as claimed in claim 1, it is characterised in that reaction temperature is 81～82 DEG C, the reaction time be 28～
35h。
3. synthetic method as claimed in claim 1 or 2, it is characterised in that 1-[(4-methylquinazolin-2-base) methyl]-3-
Methyl-7-(2-butine-1-base)-8-bromine xanthine (e), (R)-3-Boc-amino piperidine (f), the mol ratio of potassium carbonate are 1:
(1.3～1.5): (4～5).
4. synthetic method as claimed in claim 1 or 2, it is characterised in that 1-[(4-methylquinazolin-2-base) methyl]-3-
Methyl-7-(2-butine-1-base)-8-bromine xanthine (e) is 100:(500～700 with the ratio of acetonitrile) g/ml.
5. synthetic method as claimed in claim 1, it is characterised in that include also following steps: after the completion of reaction, slowly add
Enter 65～80 DEG C of hot water, stir slow cooling under room temperature, separate out solid, be filtrated to get solid.
6. synthetic method as claimed in claim 5, it is characterised in that after being filtrated to get solid, in addition it is also necessary to walk as follows
Rapid: solid is pulled an oar with 65～75 DEG C of hot water, filter after being slowly dropped to room temperature.Filter cake washes with water, is dried, obtains tertiary butyloxycarbonyl
Ji-Li Gelieting (g).
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110563728A (en) * | 2019-09-23 | 2019-12-13 | 南京奇可药业有限公司 | Preparation method of linagliptin intermediate |
| CN110894198A (en) * | 2018-09-13 | 2020-03-20 | 齐鲁制药有限公司 | Xanthine compound and preparation method and application thereof |
| CN110964013A (en) * | 2018-09-29 | 2020-04-07 | 甘李药业江苏有限公司 | Preparation method of linagliptin and intermediate thereof |
| CN110964014A (en) * | 2018-09-29 | 2020-04-07 | 甘李药业江苏有限公司 | Crystal form of linagliptin intermediate and preparation method thereof |
| CN111574520A (en) * | 2019-02-19 | 2020-08-25 | 鲁南制药集团股份有限公司 | Riagliptin intermediate compound V |
| CN111574463A (en) * | 2019-02-19 | 2020-08-25 | 鲁南制药集团股份有限公司 | Riagliptin intermediate compound IV |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105073749A (en) * | 2012-12-17 | 2015-11-18 | 迈兰实验室有限公司 | An improved process for the preparation of Linagliptin |
-
2016
- 2016-03-28 CN CN201610189177.XA patent/CN105906627B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105073749A (en) * | 2012-12-17 | 2015-11-18 | 迈兰实验室有限公司 | An improved process for the preparation of Linagliptin |
Non-Patent Citations (2)
| Title |
|---|
| JIA WANG ET AL.: "Boiling water-catalyzed neutral and selective N-Boc deprotection", 《CHEMCOMM》 * |
| 刘明媚等: "利拉利汀的合成工艺研究", 《中国药物化学杂志》 * |
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| CN110894198A (en) * | 2018-09-13 | 2020-03-20 | 齐鲁制药有限公司 | Xanthine compound and preparation method and application thereof |
| CN110964013A (en) * | 2018-09-29 | 2020-04-07 | 甘李药业江苏有限公司 | Preparation method of linagliptin and intermediate thereof |
| CN110964014A (en) * | 2018-09-29 | 2020-04-07 | 甘李药业江苏有限公司 | Crystal form of linagliptin intermediate and preparation method thereof |
| 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 |
| CN111574520A (en) * | 2019-02-19 | 2020-08-25 | 鲁南制药集团股份有限公司 | Riagliptin intermediate compound V |
| CN111574463A (en) * | 2019-02-19 | 2020-08-25 | 鲁南制药集团股份有限公司 | Riagliptin intermediate compound IV |
| CN111574520B (en) * | 2019-02-19 | 2022-08-26 | 鲁南制药集团股份有限公司 | Riagliptin intermediate compound V |
| CN111574463B (en) * | 2019-02-19 | 2023-07-14 | 鲁南制药集团股份有限公司 | Rivastigmine intermediate compound IV |
| CN110563728A (en) * | 2019-09-23 | 2019-12-13 | 南京奇可药业有限公司 | Preparation method of linagliptin intermediate |
| CN110563728B (en) * | 2019-09-23 | 2020-09-25 | 安庆奇创药业有限公司 | Preparation method of linagliptin intermediate |
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