CN106554354A - The intermediate of Li Gelieting or its analog and Li Gelieting or the preparation method of its analog - Google Patents
The intermediate of Li Gelieting or its analog and Li Gelieting or the preparation method of its analog Download PDFInfo
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- CN106554354A CN106554354A CN201610854917.7A CN201610854917A CN106554354A CN 106554354 A CN106554354 A CN 106554354A CN 201610854917 A CN201610854917 A CN 201610854917A CN 106554354 A CN106554354 A CN 106554354A
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- 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
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Abstract
The invention provides the inorganic acid salt of Formula II compound or acylate intermediate and preparation method thereof；The present invention also disclosed the method for preparing Li Gelieting or its analog using the inorganic acid salt or acylate intermediate of Formula II compound, and the method comprising the steps of：1) solvent is added to the inorganic acid salt or acylate of Formula II compound, add acid, react；2) adjust pH to 7 13；Jing extractions, washing, the crude product for being dried, filtering get profit Ge Lieting or its analog after concentration；3) to step 2) gains is recrystallized get profit Ge Lieting or its analog.The purity that the intermediate announced by the present invention is particularly suitable for the industrialized production of Li Gelieting or its analog, simple production process, low cost, high income, got profit Ge Lieting or its analog is high.
Description
Technical field
The present invention relates to the intermediate and preparation method of Li Gelieting or its analog and Li Gelieting or its analog
Preparation method.
Background technology
Li Gelieting (Linagliptin) and the like can be used to significantly improve type II diabetes (T2DM) adult patients
Different blood glucose levels, its selectivity is high more than other DPP-IV inhibitor, thus with wide market prospects.
The final step reaction of Li Gelieting or its analog in preparation process typically sloughs protection group.Patent
CN201310264236.1 adopts phthalic anhydride for protection group, for the method, not only goes up difficult (the acetic acid backflow of protection group
Harsh conditions, method of the post processing using concentration acetic acid), and when there is Deprotection, use a large amount of monoethanolamine organic reagents
And thus produce accessory substance (phthalyl accessory substance) the drawbacks of；Preparation method disclosed in patent WO 04/018468 be by
Key intermediate (formula II) takes off tertbutyloxycarbonyl (Boc) protection group and obtains, but patent CN201110355112.5 is recognized
It is not appropriate for preparing Li Gelieting for the method, reason is the intrinsic defect of the protection group, using the intermediate compound after BOC protections
Thing cannot carry out purification process, cause follow-up reaction to produce more impurity, be not suitable for industry's enlarging production prepare it is qualified
Bulk drug；Find according to WO2015011609, during using method disclosed in patent WO 04/018468, will produce at concentrations up to
1.19% quinazoline dimethylamino xanthine, more impurity are not suitable for industrialized production.
Although method reduces impurity disclosed in patent WO2015011609, purity is improve, do not solved another
Significant problem-the cost faced during individual industrialized production.It is well known that pharmaceutical industries metaplasia produce carry out when, have two it is heavy
Considerations are wanted, first is the yield and purity of medicine, and second is production cost.
For particularly as Li Gelieting, in order to improve yield and purity, when Li Gelieting crude products are prepared, prior art must
Trifluoroacetic acid (such as WO2015011609, WO2015004599A1, WO2014097314A1) must be used, its consequence is then to need to adopt
With post-processing operation with high costs.As WO2014097314A1 need to use the water of 40 times of raw material inventory and 15 times of dichloromethane
Alkane, whole last handling process need to be performed for more than the lifting control temp step of more than 5 times, and in whole process temperature fluctuation range is only
Within 5 DEG C；For another example it is only 79% that WO2015011609 not only takes off BOC and the yield of refined two steps, and refined in post processing
When, needs use the sodium hydrate aqueous solution of 16 times of raw material inventory and 10 times of water, trifluoroacetic acid use so that after locate
Reason purge process generates substantial amounts of waste water and organic solvent pollution, and whole process trivial operations increased production cost；And
In the method that WO2015004599A1 is announced, the yield for taking off BOC reactions is 79.6% or so, refines the receipts for Li Gelieting finished products
Rate is 65%, and two step total recoverys are only 51.7% or so.
What is more important, during using trifluoroacetic acid, the production cycle of Li Gelieting will be very long, such as WO2015011609
Only take off BOC reactions to be accomplished by more than 20 hours, and it is also more than 16 hours to post-process with the time used by subtractive process, it is at all unfavorable
In industrial production.
Researcher not yet finds the suitable method for not adopting trifluoroacetic acid to improve the purity of Li Gelieting so far.Such as
US20130123282A1 does not adopt trifluoroacetic acid, then which needs to be purified using HPLC (high performance liquid chromatograph), and purifies
Purity afterwards can only reach 98% reluctantly, not only its purification process in industrialized production be it is impossible, it is prior
It is that products obtained therefrom purity is unsatisfactory.
Therefore, find and be adapted to the method for Li Gelieting or its analog industrialized production to be still that this area is urgently to be resolved hurrily ask
Topic.
The content of the invention
For the shortcoming of prior art, an object of the present invention is to provide in a kind of Li Gelieting or its analog
Mesosome, inorganic acid salt or acylate, the Formula II compound and inorganic acid or organic of the intermediate for Formula II compound
The Molecules ratio of acid is 1：1-1:4, wherein
The inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and its any combination；
The organic acid selected from formic acid, acetic acid, acetoacetate, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, enanthic acid,
Hendecanoic acid, laurate, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid,
Lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, flutter acid, nicotinic acid, orotic acid, methyl sulphur
Acid, dodecyl sulphate, methanesulfonic acid, TFMS, ethionic acid, isethionic acid, 1,5- naphthalenedisulfonic acids, 2- naphthalene sulfonic acids,
Camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid and its any combination；
Wherein m=1-5；Preferably, m=1,2, or 3；
L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted purine, xanthine, indoles, oxygen Yin
Diindyl, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I,
Nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6Alkyl, cyano group are monosubstituted or many
Replace；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Preferably, the Formula II structural formula is as follows：
In one preferred embodiment, the structural formula of the intermediate is Formulas I：
Wherein n=1-4, m=1-5, it is preferred that n=1,2, or 3；M=1,2, or 3；
L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted purine, xanthine, indoles, oxygen Yin
Diindyl, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I,
Nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6Alkyl, cyano group are monosubstituted or many
Replace；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Preferably, the Formulas I intermediate structure formula is as follows：
Wherein n=1-4, it is preferred that n=1,2, or 3.
It was found by the inventors of the present invention that be particularly compound of formula I using the inorganic acid or acylate of Formula II compound making
To prepare the intermediate of Li Gelieting or its analog, obtain in high yield, highly purified Li Gelieting or its analog it is same
When, the complexity of preparation technology not only can be greatly reduced, moreover it is possible to production cost is greatly reduced.Such as embodiments of the invention institute
Show, when by the use of compound of formula I as Li Gelieting or its analog intermediate, the purity of got profit Ge Lieting or its analog
More than 99.8% can be readily achieved, without the need for numerous and diverse and with high costs post processing and purification process.
Preferably, the inorganic acid salt of intermediate Formula II compound can be made (to include such as Formulas I chemical combination using the inventive method
Thing) or the purity of acylate reach more than 99.5%, preferably more than 99.8%, more preferably more than 99.9%.The present invention
Inventor have surprisingly found that the intermediate prepared using the inventive method can very easily, directly obtain medicine
0.1% is less than with the list of the Li Gelieting or its analog of rank purity, got profit Ge Lieting or its analog finished product is miscellaneous.More
Importantly, using the inventive method, can be very easy to be controlled the purity of intermediate.
Further object is that the method that the inorganic acid salt or acylate that prepare the Formula II compound are provided,
The method comprises the steps：
1) Formula II compound organic solvent is dissolved, corresponding inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbon is added dropwise
Acid) or organic acid (such as acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) reaction, to precipitation solid；
2) solid that washing is separated out, obtains the inorganic acid salt or acylate of Formula II compound；
Wherein m=1-5, it is preferred that m=1,2, or 3；
In the Formula II compound, L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted fast
Purine, xanthine, indoles, oxindoles, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-
C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6
Alkyl, cyano group are monosubstituted or polysubstituted；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Wherein, step 1) in, the inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid (such as acetic acid,
Trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) rate of addition control in 0.2mL/min-20mL/min；
Preferably, the Formula II structural formula is as follows：
Preferably, step 1) described in organic solvent include methyl tertiary butyl ether(MTBE), dimethyl ether, isopropyl acetate, acetic acid second
One or more in ester, ether, tetrahydrofuran, dichloromethane, preferred tetrahydrofuran and/or dichloromethane, preferably dichloro
Methane；Wherein the consumption of organic solvent is the weight that can dissolve Formula II compound, preferred Formula II compound and organic solvent
Volume ratio is 1:1-40, more preferably 1:5-20.
Preferably, the inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid (such as acetic acid, trifluoro second
Acid, oxalic acid, succinic acid, methanesulfonic acid) concentration be 0.5-10mol/L, preferably 2-6mol/L；
Preferably, the Formula II compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid is (for example
Acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) molar ratio be：1:0.5-10, preferably 1：1-5.
Some preferred embodiment in, there is provided a kind of side of the hydrochloride (compound of formula I) for preparing Formula II compound
Method, comprises the following steps：
1) Formula II compound organic solvent is dissolved, hydrochloric acid reaction is added dropwise, to precipitation solid；
2) solid that washing is separated out, obtains the hydrochloride of Formula II compound；
Wherein, step 1) in, the rate of addition of hydrochloric acid is controlled in 0.2mL/min-20mL/min；
Wherein, Formula II compound is as described above.
Preferably, step 1) described in organic solvent include methyl tertiary butyl ether(MTBE), dimethyl ether, isopropyl acetate, acetic acid second
One or more in ester, ether, tetrahydrofuran, dichloromethane, preferred tetrahydrofuran and/or dichloromethane, preferably dichloro
Methane；Wherein the consumption of organic solvent should be able to dissolve the weight of Formula II compound, preferred Formula II compound and organic solvent
Volume ratio is 1:1-40, more preferably 1:5-20.
Preferably, the concentration of hydrochloric acid is 0.5-10mol/L, preferably 2-6mol/L, the Formula II compound and hydrochloric acid
Molar ratio be：1:0.5-10, preferably 1：1-5.
It should be noted that the inorganic acid salt (such as compound of formula I) or acylate mistake of Formula II compound is prepared in the present invention
Cheng Zhong, the initial purity of Formula II compound will not produce impact to the present invention；Step 1) in reaction temperature be preferred with room temperature, it is but suitable
When can still obtain realizing technical scheme under heating or cooling conditions；Step 2) washing as purification procedures,
Cleaning solvent is preferably but not limited to step 1) the middle organic solvent selected.
In general, when inorganic acid or organic acid is added, even if under low temperature or ice bath (such as
CN200680052264.5) BOC protection groups can also come off, and form inorganic acid salt or acylate after deaminizating protection.This
Bright inventor is found surprisingly that, by reaction condition, reaction reagent amount and compound structure Quality Research so that nothing
Machine acid or organic acid preferentially with the intermediate of Li Gelieting or its analog into salt, and while being for example included under sour environment
Under the strong acidic environment of the hydrochloric acid of some embodiments, BOC protection groups on amino simultaneously do not fall off, and have prepared highly purified
The inorganic acid salt or acylate intermediate of BOC protections, such as Formulas I.
The inorganic acid salt or acylate of the ingenious and unexpected utilization Formula II compound of the present invention are easy to be obtained
Highly purified Li Gelieting or its analog, and yield is higher.The present invention prepares the inorganic acid salt or organic acid of Formula II compound
During salt such as compound of formula I, the species of solvent is preferred with the weaker solvent of polarity, and the consumption of solvent can dissolve Formula II chemical combination
Thing；Inorganic acid or organic acid may optionally be the addition of dense and/or dilute inorganic acid or organic acid, inorganic acid or organic acid and change
The amount of compound is related, but the concentration of inorganic acid or organic acid, addition form Formula II for Formula II compound carries out salt-forming reaction
The inorganic acid salt or acylate of compound, still carries out de- BOC and reacts without impact.
What is more important, even it was found by the inventors of the present invention that the other production scale of technical grade, using gained Formula II
The inorganic acid salt or acylate of compound very easy can prepare highly purified Li Gelieting or its analog.Such as this
Shown in bright embodiment, the present invention participates in reacting by the use of such as compound of formula I as intermediate, through the process of simple recrystallization
Afterwards, it is possible to obtain the Li Gelieting of high purity more than 99.9% or its analog, overcome prior art purity it is low and purifying
Difficult defect.
Further object is that providing the preparation method of a kind of Li Gelieting or its analog, the method includes
Following steps：
1) inorganic acid of Formula II compound or acylate are added into organic solvent, adds acid, preferably corresponding inorganic acid
(such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid (such as acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) are anti-
Should；
Preferably, the acid concentration is 0.5-10mol/L, more preferably 2-6mol/L；It is preferable over 20 DEG C of -40 DEG C of reactions；
Wherein, the compound of formula I with the ratio of the molar ratio of acid is：1:0.5-10, preferably 1：1-5；
Wherein, the solvent includes one or more in alcohols, amide-type, sulfone class, water；It is preferred that methyl alcohol, ethanol, isopropyl
One or more in alcohol, N,N-dimethylformamide, dimethyl sulfoxide, 1-METHYLPYRROLIDONE；More preferably methyl alcohol and/or second
Alcohol；Wherein the consumption of organic solvent is preferred with dissolving compound of formula I, the weight of preferred compound of formula I and organic solvent
Volume ratio is 1:1-40, more preferably 1:5-20.
2) pH is adjusted to 7-13, it is preferred to adjust pH to 10-12；After reduced pressure concentration, Jing extraction, washing, be dried, filter, it is dense
Contract Ge Lieting crude products of getting profit；
Wherein, it is preferable to use dichloromethane is extracted, and/or using saturated common salt water washing, it is and/or dry using sodium sulphate
It is dry；
3) to step 2) got profit Ge Lieting or its analog crude product recrystallized；
Preferably, step 3) described in the method that recrystallizes be：To step 2) gains add and good solvent are heated to reflux
Dissolving, add poor solvent at reflux, then cool, until solid separate out finish, filter, be dried after, obtain
Li Gelieting or its analog；
Wherein, the good solvent includes alcohols solvent, the one kind or many in preferred methyl alcohol, ethanol, isopropanol, butanediol
Plant, more preferably methyl alcohol；The poor solvent includes ether solvent, one kind in preferred methyl tertiary butyl ether(MTBE), ether, isopropyl ether or
It is various, more preferably methyl tertiary butyl ether(MTBE)；Wherein, poor solvent and the volume ratio of good solvent are 1-10:1, preferably 5-3:1；
Li Gelieting or its analog crude product and the w/v of recrystallization solvent are 1:6.5-50, preferably 1:10-40；
The Formula II compound is 1 with the Molecules ratio of inorganic acid or organic acid：1-1:4, wherein
The inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and its any combination；
The organic acid selected from formic acid, acetic acid, acetoacetate, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, enanthic acid,
Hendecanoic acid, laurate, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid,
Lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, flutter acid, nicotinic acid, orotic acid, methyl sulphur
Acid, dodecyl sulphate, methanesulfonic acid, TFMS, ethionic acid, isethionic acid, 1,5- naphthalenedisulfonic acids, 2- naphthalene sulfonic acids,
Camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid and its any combination；
Wherein m=1-5；Preferably, m=1,2, or 3；
L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted purine, xanthine, indoles, oxygen Yin
Diindyl, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I,
Nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6Alkyl, cyano group are monosubstituted or many
Replace；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Preferably, the Formula II structural formula is as follows：
Wherein, step 1) the Formula II compound inorganic acid salt or acylate be prepared from for the inventive method.
The inorganic acid salt of Formula II compound or the preparation method of acylate include step：
1) Formula II compound organic solvent is dissolved, corresponding inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbon is added dropwise
Acid) or organic acid (such as acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) reaction, to precipitation solid；
2) solid that washing is separated out, obtains the inorganic acid salt or acylate of Formula II compound；
Wherein m=1-5, it is preferred that m=1,2, or 3；
In the Formula II compound, L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted fast
Purine, xanthine, indoles, oxindoles, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-
C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6
Alkyl, cyano group are monosubstituted or polysubstituted；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Wherein, step 1) in, the inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid (such as acetic acid,
Trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) rate of addition control in 0.2mL/min-20mL/min；
Preferably, the Formula II structural formula is as follows：
Preferably, step 1) described in organic solvent include methyl tertiary butyl ether(MTBE), dimethyl ether, isopropyl acetate, acetic acid second
One or more in ester, ether, tetrahydrofuran, dichloromethane, preferred tetrahydrofuran and/or dichloromethane, particularly preferably
Dichloromethane；Wherein the consumption of organic solvent can dissolve the weight of Formula II compound, preferred Formula II compound and organic solvent
Amount volume ratio is 1:1-40, more preferably 1:5-20.
Preferably, the inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid (such as acetic acid, trifluoro second
Acid, oxalic acid, succinic acid, methanesulfonic acid) concentration be 0.5-10mol/L, preferably 2-6mol/L；
Preferably, the Formula II compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid) or organic acid is (for example
Acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, methanesulfonic acid) molar ratio be：1:0.5-10, preferably 1：1.0-5.
Some preferred embodiment in, there is provided the preparation method of a kind of Li Gelieting or its analog, the method bag
Include following steps：
3) compound of formula I is added into organic solvent, adds hydrochloric acid reaction；
Preferably, the concentration of hydrochloric acid is 0.5-10mol/L, more preferably 2-6mol/L；It is preferable over 20 DEG C -40 DEG C instead
Should；
Wherein, the compound of formula I with the molar ratio of hydrochloric acid is：1:0.5-10, preferably 1：1-5；
Wherein, the solvent includes one or more in alcohols, amide-type, sulfone class, water；It is preferred that methyl alcohol, ethanol, isopropyl
One or more in alcohol, N,N-dimethylformamide, dimethyl sulfoxide, 1-METHYLPYRROLIDONE；More preferably methyl alcohol and/or second
Alcohol；Wherein the consumption of organic solvent is preferred with dissolving compound of formula I, the weight of preferred compound of formula I and organic solvent
Volume ratio is 1:1-40, more preferably 1:5-20.
4) pH is adjusted to 7-13, it is preferred to adjust pH to 10-12；After reduced pressure concentration, Jing extraction, washing, be dried, filter, it is dense
Contract Ge Lieting crude products of getting profit；
Wherein, it is preferable to use dichloromethane is extracted, and/or using saturated common salt water washing, it is and/or dry using sodium sulphate
It is dry；
5) to step 2) got profit Ge Lieting or its analog crude product recrystallized；
Preferably, step 3) described in the method that recrystallizes be：To step 2) gains add and good solvent are heated to reflux
Dissolving, add poor solvent at reflux, then cool, until solid separate out finish, filter, be dried after, obtain
Li Gelieting or its analog；
Wherein, the good solvent includes alcohols solvent, the one kind or many in preferred methyl alcohol, ethanol, isopropanol, butanediol
Plant, more preferably methyl alcohol；The poor solvent includes ether solvent, one kind in preferred methyl tertiary butyl ether(MTBE), ether, isopropyl ether or
It is various, more preferably methyl tertiary butyl ether(MTBE)；Wherein, poor solvent and the volume ratio of good solvent are 1-10:1, preferably 5-3:1；
Li Gelieting or its analog crude product and the w/v of recrystallization solvent are 1:6.5-50, preferably 1:10-40；
Wherein n=1-4, m=1-5；Preferably, n=1,2, or 3；M=1,2, or 3；
L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted purine, xanthine, indoles, oxygen Yin
Diindyl, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I,
Nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6Alkyl, cyano group are monosubstituted or many
Replace；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group.
Preferably, the Formulas I intermediate structure formula is as follows：
Wherein n=1-4, it is preferred that n=1,2, or 3.
Wherein, step 1) compound of formula I is prepared from for the inventive method.
The preparation method of the compound of formula I includes step：
1) Formula II compound organic solvent is dissolved, hydrochloric acid is added dropwise, to precipitation solid；
2) solid that washing is separated out, obtains final product；
Preferably, step 1) described in the mass volume ratio of II compounds and organic solvent be 1:5-15, preferably 1:8-
12；The organic solvent includes methyl tertiary butyl ether(MTBE), dimethyl ether, isopropyl acetate, ethyl acetate, ether, tetrahydrofuran, dichloro
One or more in methane, preferred tetrahydrofuran and/or dichloromethane, more preferably dichloromethane；Wherein organic solvent
Addition can dissolve Formula II compound, and preferred Formula II compound is 1 with the w/v of organic solvent:1-40, it is more excellent
Elect 1 as:5-20.
Preferably, the concentration of hydrochloric acid be 0.5-10mol/L, preferably 2-6mol/L,
Preferably, the Formula II compound with the molar ratio of hydrochloric acid is：1:0.5-10, preferably 1：1.0-5；
Wherein m=1-5, it is preferred that m=1,2, or 3；
In the Formula II compound, L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted fast
Purine, xanthine, indoles, oxindoles, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-
C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6
Alkyl, cyano group are monosubstituted or polysubstituted；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group.
Preferably, the Formula II structural formula is as follows：
It should be noted that preparing profit in the inorganic acid salt (such as compound of formula I) or acylate by Formula II compound
When Ge Lieting or its analog compounds, step 1) in the selection of reaction temperature impact, reaction are produced on reaction speed, yield only
Solvent is preferred with the larger organic solvent of polarity；Step 2) in can select conventional alkaline solution and carry out the regulation of pH value, such as hydrogen
Sodium oxide molybdena, potassium hydroxide, sodium carbonate, potassium carbonate etc., wherein, saturated common salt water washing and/or sodium sulphate are dried only preferably, real
Border operate when can select skilled person will appreciate that conventional reagent replace.
The present inventor is groped to have surprisingly found that by many experiments, is prepared using the intermediate obtained by the present invention sharp
Ge Lieting or its analog, not only can make Li Gelieting or its analog have very outstanding purity, while preparing
Also there is very high yield in journey, the what is more important present invention significantly reduces the complexity of preparation technology and significantly reduces life
Cost is produced, with very good industrial production prospect.
As shown in the embodiment of the present invention, the present invention is without the need for complicated post processing and purification step, it is only necessary to simple to heat up
Backflow and crystallization of lowering the temperature just can obtain highly purified Li Gelieting or its analog, adjust without the need for washing repeatedly, extraction, or even pH
Section and accurate temperature control are walked suddenly, greatly simplified production technology, and greatly reduce production cost.
It is noted that the preferred version using the present invention can also easily, directly obtain medicinal rank purity
Li Gelieting or its analog, it is single miscellaneous to be less than 0.1%.
Beneficial effects of the present invention：
1) inorganic acid salt for having prepared Formula II compound or acylate intermediate of the invention, generally and
Speech, BOC easily come off in sour environment, and we are by reaction condition and compound structure Quality Research so that acid is excellent
First with Li Gelieting or its analog into salt, and while under sour environment, BOC protection groups on amino simultaneously do not fall off.So as to
Prepare the inorganic acid salt or acylate intermediate of BOC protections；
2) inorganic acid salt of Formula II compound or acylate purification of intermediate step are simple, it is only necessary to simple to wash
The purpose of purifying is reached, repeated recrystallize step is eliminated, is substantially reduced process cycle so that production very efficiently, and makes
More than 99.9% be can reach with the inventive method intermediate purity, pole is beneficial to industrial production；
3) present invention process simplicity, cycle is short, low for equipment requirements, environmental protection；The Li Gelieting of the inventive method or its class
Like thing solvent usage amount it is few, a large amount of industrial wastewaters will not be produced, without the need for special temperature control；Li Gelieting of the present invention or its class
The only simple temperature rising reflux of subtractive process, cooling crystallization like thing finished product, without the need for cyclic washing, extraction, need not adjust pH, also without
Temperature control reaction need to be carried out；
4) Li Gelieting or its analog finished product purity and high income obtained by the inventive method；It is during large-scale production, pure
Degree can be up to more than 99.9%, and crude yield is up to more than 97.5%, and refined yield may be up to more than 98.3%.
Li Gelieting of the present invention or its analog include Li Gelieting salt, ester, optical isomer, derivative, this
Inventive method can be applicable to the enantiomter of highly purified Li Gelieting, salt, ester, the preparation of derivative, and its it is related in the middle of
The preparation of body；Select excellent, inventive method of the present invention can be used for the preparation of Li Gelieting and its intermediate.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are simply used
In being further detailed to the present invention, it is impossible to be interpreted as limiting the scope of the invention, the field is skilled in technique
Personnel still fall within protection scope of the present invention according to some nonessential modifications and adaptations that foregoing invention content is made.
Wherein, heretofore described " Molecules ratio (1:N) the Formula II compound and n molecule of each molecule " are referred to
Inorganic acid or organic acid form the inorganic acid salt or acylate of corresponding Formula II compound, it is concrete represent formed for formula
The n molecules inorganic acid of II compounds or acylate, are shown below
Wherein, X is heretofore described organic acid or inorganic acid.
Experimental example 1
1) reaction of tetrahydrofuran (200ml) stirring and dissolving is added in 20g Formula II compounds, with 15mL/min's under room temperature
Speed is added dropwise to 3mol/L hydrochloric acid (17.5ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake tetrahydrofuran
(50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For a hydrochloride, purity 99.9%.
2) methyl alcohol (300ml) is added in above-mentioned intermediate compound I, add 3mol/L hydrochloric acid (50ml), it is little in 40 DEG C of reactions 2
When, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction adjust pH=12, reduced pressure concentration is done, and adds dichloromethane
(200ml) extract, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate are dried, and filter, the dry Ge Lieting that gets profit of reduced pressure concentration
Crude product 16.1g, yield 97.5%.
Take 15.0g Li Gelieting crude products, be added thereto to methyl alcohol (150ml), temperature rising reflux dissolving, at reflux plus
Enter methyl tertiary butyl ether(MTBE) (450ml), then stop heating, naturally cool to room temperature, gradually separate out fluffy solid, filter, decompression
Drying is concentrated to give 14.8g, yield 98.8%, purity 99.9%.
Experimental example 2
1) reaction of dichloromethane (200ml) stirring and dissolving is added in 20g Formula II compounds, with 20mL/min's under room temperature
Speed is added dropwise to 5mol/L hydrochloric acid (28ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake dichloromethane
(50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For tri hydrochloride, purity 99.9%.
2) ethanol (200ml) is added in above-mentioned intermediate compound I, add 6mol/L hydrochloric acid (29ml), it is little in 35 DEG C of reactions 2
When, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction adjust pH=12, reduced pressure concentration is done, and adds dichloromethane
(200ml) extract, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate are dried, and filter, the dry Ge Lieting that gets profit of reduced pressure concentration
Crude product 16.2g, yield 98.1%.
Take 15.0g Li Gelieting crude products, be added thereto to ethanol (75ml), temperature rising reflux dissolving, at reflux plus
Enter ether (375ml), then stop heating, naturally cool to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure concentration
Obtain 14.9g, yield 99.2%, purity 99.9%.
Experimental example 3
1) reaction of ethyl acetate (100ml) stirring and dissolving is added in 20g Formula II compounds, with 5mL/min's under room temperature
Speed is added dropwise to 2moL/L hydrochloric acid (35ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake tetrahydrofuran
(50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For dihydrochloride, purity 99.9%.
2) DMF (100ml) is added in above-mentioned intermediate compound I, add 4moL/L hydrochloric acid (35ml),
React in 35 DEG C 2 hours, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction and adjusts pH=10, reduced pressure concentration
It is dry, add dichloromethane (200ml) extraction, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate to be dried, filter, decompression
The dry Ge Lieting crude product 16.4g that get profit of concentration, yield 99.5%.
To in 15.0g Li Gelieting crude products, add isopropanol (40ml), temperature rising reflux dissolving to add first at reflux
Base tertbutyl ether (110ml), then stops heating, naturally cools to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure
It is concentrated to give 14.7g, yield 98.5%, purity 99.9%.
Experimental example 4
1) reaction of methyl tertiary butyl ether(MTBE) (400ml) stirring and dissolving is added in 20g Formula II compounds, with 1mL/ under room temperature
The speed of min is added dropwise to 4moL/L hydrochloric acid (9ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake tetrahydrochysene furan
Mutter (50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection techniques inspections of pharmacopeia
Survey as a hydrochloride, purity 99.9%.
2) methyl alcohol (100ml) is added in above-mentioned intermediate compound I, add 6moL/L hydrochloric acid (23ml), it is little in 40 DEG C of reactions 2
When, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction adjust pH=11, reduced pressure concentration is done, and adds dichloromethane
(200ml) extract, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate are dried, and filter, the dry Ge Lieting that gets profit of reduced pressure concentration
Crude product 16.1g, yield 97.8%.
To in 15.0g Li Gelieting crude products, add methyl alcohol (150ml), temperature rising reflux dissolving to add first at reflux
Base tertbutyl ether (450ml), then stops heating, naturally cools to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure
It is concentrated to give 14.9g, yield 91.3%, purity 99.9%.
Experimental example 5
1) reaction of tetrahydrofuran (200ml) stirring and dissolving is added in 20g Formula II compounds, with 10mL/min's under room temperature
Speed is added dropwise to 3moL/L hydrochloric acid (58ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake tetrahydrofuran
(50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For tri hydrochloride, purity 99.9%.
2) addition methyl alcohol and ethanol (1 in above-mentioned intermediate compound I:1V/V) (200ml), adds 4moL/L hydrochloric acid
(17ml), react in 20 DEG C 2 hours, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction and adjusts pH=11, subtracted
Pressure concentration is dry, adds dichloromethane (200ml) extraction, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate to be dried, mistake
Filter, the dry Ge Lieting crude product 16.3g that get profit of reduced pressure concentration, yield 98.8%.
To in 15.0g Li Gelieting crude products, add ethanol (40ml), temperature rising reflux dissolving to add methyl at reflux
Tertbutyl ether (60ml), then stops heating, naturally cools to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure concentration
Obtain 14.7g, yield 98.5%, purity 99.9%.
Experimental example 6
1) reaction of dichloromethane (100ml) stirring and dissolving is added in 20g Formula II compounds, with 15mL/min's under room temperature
Speed is added dropwise to 2moL/L hydrochloric acid (26ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake tetrahydrofuran
(50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For a hydrochloride, purity 99.9%.
2) addition methyl alcohol and ethanol (1 in above-mentioned intermediate compound I:1V/V) (100ml), adds 3moL/L hydrochloric acid
(46ml), react in 20 DEG C 2 hours, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction and adjusts pH=10, subtracted
Pressure concentration is dry, adds dichloromethane (200ml) extraction, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate to be dried, mistake
Filter, the dry Ge Lieting crude product 16.3g that get profit of reduced pressure concentration, yield 99.0%.
To in 15.0g Li Gelieting crude products, add methyl alcohol (40ml), temperature rising reflux dissolving to add ether at reflux
(110ml), then stop heating, naturally cool to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure is concentrated to give
14.8g, yield 99.1%, purity 99.9%.
Experimental example 7
1) reaction of tetrahydrofuran (100ml) stirring and dissolving is added in 20g Formula II compounds, with 20mL/min's under room temperature
Speed is added dropwise to 5moL/L hydrochloric acid (21ml), and reaction separates out solid, and reaction in about 3 hours is finished, and filters, filter cake tetrahydrofuran
(50ml) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For a hydrochloride, purity 99.9%.
2) DMF (100ml) is added in above-mentioned intermediate compound I, add 5moL/L hydrochloric acid (35ml),
React in 40 DEG C 2 hours, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction and adjusts pH=10, reduced pressure concentration
It is dry, add dichloromethane (200ml) extraction, saturated aqueous common salt (50ml) washing, organic phase with sodium sulfate to be dried, filter, decompression
The dry Ge Lieting crude product 16.2g that get profit of concentration, yield 98.0%.
To in 15.0g Li Gelieting crude products, add ethanol (50ml), temperature rising reflux dissolving to add ether at reflux
(250ml), then stop heating, naturally cool to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure is concentrated to give
14.7g, yield 98.3%, purity 99.9%.
Experimental example 8
1) reaction of tetrahydrofuran (160L) stirring and dissolving is added in 10kg Formula II compounds, with 20mL/min's under room temperature
Speed is added dropwise to 3moL/L hydrochloric acid (15L), and reaction separates out solid, and reaction in about 5 hours is finished, and filters, filter cake tetrahydrofuran
(500mL) washed once, suction filtration obtains formula intermediate compound I to dry, using 2010 editions annex VIII A chlorides inspection technique detections of pharmacopeia
For a hydrochloride, purity 99.9%.
2) methyl alcohol (120L) is added in above-mentioned intermediate compound I, add 5moL/L hydrochloric acid (15L), it is little in 20 DEG C of reactions 2
When, 30% NaOH is slowly added dropwise in reactant liquor after completion of the reaction adjust pH=10, reduced pressure concentration is done, and adds dichloromethane
(500mL) extract, saturated aqueous common salt (500ml) washing, organic phase with sodium sulfate are dried, and filter, the dry lattice row of getting profit of reduced pressure concentration
Spit of fland crude product 8.1kg, yield 97.8%.
To in 7kg Li Gelieting crude products, add methyl alcohol (20L), temperature rising reflux dissolving to add methyl- tert at reflux
Butyl ether (800ml), then stops heating, naturally cools to room temperature, gradually separate out fluffy solid, filter, drying under reduced pressure concentration
Obtain 6.9kg, yield 98.6%, purity 99.9%.
In the present invention, the preparation of Formulas I is relevant with hydrochloric acid rate of addition and compound ad hoc structure property, when us
The rate of addition of hydrochloric acid is controlled, in 0.2mL/min-20mL/min, can smoothly obtain highly purified compound of formula I, at this
Invention limit rate of addition outside scope can on the carrying out of salt-forming reaction and into salt product purity produce impact, but
Taken off during BOC protection groups prepare Li Gelieting compounds by compound of formula I, the rate of addition of hydrochloric acid is to reaction
Carry out having no impact.
Test example
The present invention compared for the situation that Li Gelieting is directly prepared using the Formula II compound of different purity, the results are shown in Table 1.
Table 1
As can be seen from the above table, using being suitable for industrial method to prepare qualified Li Gelieting for Formula II
The purity requirement of compound is very high, even if Formula II compound purity is 99.0%, Li Gelieting finished products cannot also pass through simply
Means re-crystallization directly prepares qualified pharmaceutical product.As Formula II compound is due to intrinsic property, it is impossible to pass through
Recrystallization purifying and obtain satisfactory product.Therefore, the present invention by salt-forming conversions into compound of formula I method, very
This defect is cleverly overcome, is suitable for the industrial production of Li Gelieting.
Claims (10)
1. the intermediate of a kind of Li Gelieting or its analog, it is characterised in that the intermediate is inorganic for Formula II compound
Hydrochlorate or acylate, the Formula II compound are 1 with the Molecules ratio of inorganic acid or organic acid：1-1：4, wherein
The inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and its any combination；
The organic acid selected from formic acid, acetic acid, acetoacetate, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, enanthic acid, 11
Alkanoic acid, laurate, stearic acid, palmitic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, breast
Acid, malic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, flutter acid, nicotinic acid, orotic acid, methyl sulphur
Acid, dodecyl sulphate, methanesulfonic acid, TFMS, ethionic acid, isethionic acid, 1,5- naphthalenedisulfonic acids, 2- naphthalene sulfonic acids,
Camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid and its any combination；
Wherein m=1-5；Preferably, m=1,2, or 3；
L be selected from heteroaromatic, the heteroaromatic include but is not limited to substituted or unsubstituted purine, xanthine, indoles, oxindoles,
Quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitre
Base, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6Alkyl, cyano group are monosubstituted or take more
Generation；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Preferably, the Formula II structural formula is following compound：
2. the intermediate of a kind of Li Gelieting according to claim 1 or its analog, it is characterised in that the intermediate
Structural formula be Formulas I：
Wherein n=1-4；Preferably, n=1,2, or 3；
Preferably, the Formulas I intermediate structure formula is as follows：
Wherein n=1-4, it is preferred that n=1,2, or 3.
3. intermediate according to claim 1 and 2, it is characterised in that the purity of the intermediate is more than 99.5%, excellent
Elect more than 99.8%, more preferably more than 99.9% as.
4. the method for preparing intermediate as claimed any one in claims 1 to 3, it is characterised in that methods described include as
Lower step：
1) Formula II compound organic solvent is dissolved, the inorganic acid or organic acid reaction is added dropwise, to precipitation solid；
2) solid that washing is separated out, obtains the inorganic acid salt or acylate of Formula II compound；
Wherein m=1-5, it is preferred that m=1,2, or 3；
In the Formula II compound, L is selected from heteroaromatic, and the heteroaromatic includes but is not limited to substituted or unsubstituted purine, Huang
Purine, indoles, oxindoles, quinoline, isoquinolin；The substituent is optionally hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alcoxyl
Base, F, Cl, Br, I, nitro, cyano group；Preferably, the heteroaromatic is purine or xanthine, independently by hydrogen, C1-C6Alkyl, cyanogen
Base is monosubstituted or polysubstituted；
R1-R9Selected from hydrogen, C1-C6Alkyl, C1-C6Alkylhalide group, C1-C6Alkoxyl, F, Cl, Br, I, nitro, cyano group；
Wherein, step 1) in, the rate of addition of the inorganic acid or organic acid is controlled in 0.2mL/min-20mL/min, further
It is preferred that the inorganic acid be hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, the organic acid be acetic acid, trifluoroacetic acid, oxalic acid, succinic acid,
Methanesulfonic acid；
Preferably, the Formula II structural formula is as follows：
5. method according to claim 4, it is characterised in that step 1) described in organic solvent include methyl tertbutyl
One or more in ether, dimethyl ether, isopropyl acetate, ethyl acetate, ether, tetrahydrofuran, dichloromethane, preferred tetrahydrochysene furan
Mutter and/or dichloromethane, more preferably dichloromethane；The consumption of wherein organic solvent dissolves Formula II compound, preferred formula
II compounds are 1 with the w/v of organic solvent:1-1：40, more preferably 1:5-1：20.
6. method according to claim 4, it is characterised in that the concentration of the inorganic acid or organic acid is 0.5-10mol/
L, preferably 2-6mol/L；And/or the Formula II compound and the molar ratio of inorganic acid or organic acid are 1:0.5-10, it is excellent
Elect 1 as：1-5.
7. the preparation method of a kind of Li Gelieting or its analog, it is characterised in that methods described comprises the steps：
1) inorganic acid salt of Formula II compound or acylate are added into solvent, adds acid reaction, be preferably added to corresponding inorganic
Acid or organic acid reaction；
Preferably, in 20 DEG C of -40 DEG C of reactions；
Preferably, the solvent includes one or more in alcohols, amide-type, sulfone class, water；It is preferred that methyl alcohol, ethanol, isopropyl
One or more in alcohol, N,N-dimethylformamide, dimethyl sulfoxide, 1-METHYLPYRROLIDONE；More preferably methyl alcohol and/or second
Alcohol；Wherein the consumption of organic solvent can dissolve the w/v of compound of formula I, preferred compound of formula I and organic solvent
For 1:1-40, more preferably 1:5-20；
2) pH is adjusted to 7-13, it is preferred to adjust pH to 10-12；After reduced pressure concentration, Jing is extracted, is washed, be dried, filter, being concentrated to give
The crude product of Li Gelieting or its analog；
Wherein, it is preferable to use dichloromethane is extracted, and/or using saturated common salt water washing, and/or it is dried using sodium sulphate；
3) to step 2) obtained by crude product recrystallized；
Preferably, step 3) described in the method that recrystallizes be：To step 2) gains add good solvent and be heated to reflux dissolving,
Add poor solvent at reflux, then cool, until solid separate out finish, filter, be dried after, obtain Li Gelie
Spit of fland and and the like；
Wherein, the good solvent includes alcohols solvent, one or more in preferred methyl alcohol, ethanol, isopropanol, butanediol, more
Preferably methyl alcohol；The poor solvent includes ether solvent, the one kind or many in preferred methyl tertiary butyl ether(MTBE), ether, isopropyl ether
Plant, more preferably methyl tertiary butyl ether(MTBE)；
Wherein, the inorganic acid salt or acylate of the Formula II compound is selected from the centre any one of claim 1-3
Body.
8. method according to claim 7, it is characterised in that the inorganic acid salt or acylate of the Formula II compound
Preparation method is selected from the method any one of claim 4-6.
9. method according to claim 7, it is characterised in that：The poor solvent is 1-10 with the volume ratio of good solvent:
1, preferably 5-3:1；Li Gelieting crude products are 1 with the w/v of recrystallization solvent:6.5-50, preferably 1:10-40.
10. method according to claim 7, it is characterised in that comprise the following steps：
1) compound of formula I is added into solvent, adds hydrochloric acid reaction；
2) pH is adjusted to 7-13, it is preferred to adjust pH to 10-12；After reduced pressure concentration, Jing is extracted, is washed, be dried, filter, being concentrated to give
The crude product of Li Gelieting or its analog；
3) to step 2) obtained by crude product recrystallized；
Preferably, the preparation method of the compound of formula I includes：
1) Formula II compound organic solvent is dissolved, hydrochloric acid reaction is added dropwise, to precipitation solid；
2) solid that washing is separated out, obtains compound of formula I；
Wherein, step 1) in, the rate of addition of hydrochloric acid is controlled in 0.2mL/min-20mL/min.
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| CN107641120A (en) * | 2017-06-01 | 2018-01-30 | 合肥远志医药科技开发有限公司 | A kind of unqualified Li Gelieting of purity recovery and treatment method |
| 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 |
| JP2020070296A (en) * | 2018-10-31 | 2020-05-07 | ヤマサ醤油株式会社 | Method for producing linagliptin |
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| CN103319483A (en) * | 2012-10-19 | 2013-09-25 | 药源药物化学（上海）有限公司 | Preparation method of important intermediate of linagliptin |
| WO2015004599A1 (en) * | 2013-07-11 | 2015-01-15 | Wockhardt Limited | An improved process for preparing linagliptin and its key intermediates |
| CN105936634A (en) * | 2016-03-28 | 2016-09-14 | 赤峰赛林泰药业有限公司 | Synthetic method of linagliptin |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319483A (en) * | 2012-10-19 | 2013-09-25 | 药源药物化学（上海）有限公司 | Preparation method of important intermediate of linagliptin |
| WO2015004599A1 (en) * | 2013-07-11 | 2015-01-15 | Wockhardt Limited | An improved process for preparing linagliptin and its key intermediates |
| CN105936634A (en) * | 2016-03-28 | 2016-09-14 | 赤峰赛林泰药业有限公司 | Synthetic method of linagliptin |
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| CN107641120A (en) * | 2017-06-01 | 2018-01-30 | 合肥远志医药科技开发有限公司 | A kind of unqualified Li Gelieting of purity recovery and treatment method |
| 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 |
| 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 |
| JP2020070296A (en) * | 2018-10-31 | 2020-05-07 | ヤマサ醤油株式会社 | Method for producing linagliptin |
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