CN105985316A - Preparation method for trelagliptin and salt thereof - Google Patents
Preparation method for trelagliptin and salt thereof Download PDFInfo
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- CN105985316A CN105985316A CN201510073686.1A CN201510073686A CN105985316A CN 105985316 A CN105985316 A CN 105985316A CN 201510073686 A CN201510073686 A CN 201510073686A CN 105985316 A CN105985316 A CN 105985316A
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- DVINPEVSHLLESQ-UHFFFAOYSA-N CCC(C)CCc1c(CC)ccc(C)c1 Chemical compound CCC(C)CCc1c(CC)ccc(C)c1 DVINPEVSHLLESQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method for trelagliptin and a salt thereof. The preparation method comprises the following steps: a, subjecting a compound 3, Pd(OAc)2, ligand, K3PO4, 3-tertbutyloxycarbonyl-aminopiperidine, and an organic solvent to a reaction with stirring under the protection of nitrogen so as to obtain a reaction solution; b, carrying out separation and purification so as to obtain a compound 6; c, subjecting the compound 6, ethyl acetate and an ethyl acetate solution of HCl to a reaction with stirring and then carrying out separation and purification so as to obtain a solid; and d, dissolving the solid obtained in the step c in water, adjusting a pH value to 8 to 9 and then carrying out separation and purification so as to obtain a compound 4, i.e., trelagliptin. The preparation method provided by the invention reduces side reactions and production of impurity compounds; the method is simple and convenient in separating and purifying trelagliptin and has the advantages of short production period, high yield, high purity, low cost, etc.; and the yield of trelagliptin in the invention can reach 95% or above, and the preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to a yeast inoculation Ge Lieting and the preparation method of salt thereof.
Background technology
Bent Ge Lieting (Trelagliptin), chemistry is entitled: 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-
Dioxy-1 (2H)-pyrimidine radicals] methyl] the fluoro-benzonitrile of-4-, its structure is shown in formula I；Bent Ge Lieting is a kind of dipeptidyl peptidase
IV (DPP-IV) inhibitor, is the one long-acting DPP-IV suppression developed by Wu Tian company of Japan (Takeda company)
Agent, is mainly used in the treatment (see Chinese patent CN 104003975A) of type 2 diabetes mellitus.
At present, the preparation method of bent Ge Lieting comprises the following steps: by 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-
Pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-, (R)-3-amino-piperadine dihydrochloride and sodium bicarbonate mix in ethanol in sealing pipe
Stirring reaction, after high performance liquid chromatography (HPLC) is isolated and purified, obtains bent Ge Lieting, as shown in synthetic route 1,
Such as: Chinese patent CN 1926128A, CN 101360723A, CN 101573351A are to use said method system
For obtaining bent Ge Lieting；
Molecular structure due to 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) the fluoro-benzonitrile of-4-
In, phenyl ring has a fluorine atom, its para-position also has the strong cyano group inhaling electricity, well leaves away so that fluorine becomes one
Group, easily participates in substitution reaction and generates impurity compound 5, and in real reaction, this impurity compound 5 content in crude product is high
Reaching 12%, the yield causing bent Ge Lieting is low；And this impurity compound 5 is similar with the character of bent Ge Lieting, both separate
Difficulty, the purification procedures of crude product is loaded down with trivial details, is not suitable for industrialized production.
Accordingly, it would be desirable to invention is a kind of, side reaction is few, post-processing approach is easy, yield is high, purity is high, be suitable for industrialized production
The method of the bent Ge Lieting of preparation.
Summary of the invention
It is an object of the invention to provide the preparation method of a yeast inoculation Ge Lieting.
The preparation method of the yeast inoculation Ge Lieting that the present invention provides, its synthetic route is:
It comprises the following steps:
Under the protection of a, nitrogen, compound 3, Pd (OAc)2, ligand, K3PO4, 3-t-butoxycarbonyl-amino piperidines having
In machine solvent, in 40 DEG C～100 DEG C stirring reactions, thin layer chromatography detection reaction is complete, obtains reactant liquor；
Described compound 3, Pd (OAc)2, ligand, K3PO4, the mol ratio of 3-t-butoxycarbonyl-amino piperidines be 1:
(0.01～0.1): (0.015～0.15): (1～10): (1～5)；Described compound 3 is 1 with the mass volume ratio of organic solvent:
(5～12) (m:v)；
B, the reactant liquor of step a is cooled down, filter, obtain filtrate；Filtrate adds water, extracts with halogenated hydrocarbons or ester,
To organic facies；Organic facies is dried, is evaporated, obtain compound 6；
C, take the compound 6 of step b, and ethyl acetate, the ethyl acetate solution of HCl, anti-in 20 DEG C～30 DEG C stirrings
After answering 5h～16h, separate out solid, filter, washing, obtain solid；
In the ethyl acetate solution of described HCl, the content of HCl is 1～4mol/L；
Described compound 6, ethyl acetate, the mass volume ratio of ethyl acetate solution of HCl are 1:(5～8): (5～8) (m:
V:v)；
D, taking the solid of step c, be dissolved in water, regulation pH is 8～9, extracts with halogenated hydrocarbons or ester, obtains organic facies；
Organic facies is dried, is evaporated, obtain compound 4, be bent Ge Lieting.
Preferably, in step a, described ligand be (±)-2,2'-is double-(diphenyl phosphine)-1,1'-dinaphthalene, 1, and 1'-is double (diphenylphosphine)
Ferrocene, tri-butyl phosphine, 2-dicyclohexyl phosphorus-2,4,6-tri isopropyl biphenyls, 2-dicyclohexyl phosphine-2', 6'-dimethoxy joins
Any one or more in benzene；
Described organic solvent is in dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, glycol dimethyl ether
Any one or more.
Preferably, in step a, described compound 3, Pd (OAc)2, ligand, K3PO4, 3-t-butoxycarbonyl-amino
The mol ratio of piperidines is 1:0.01:0.015:3:(1.2～1.5)；Described compound 3 and the quality volume of organic solvent
Ratio is 1:(6～11) (m:v).
Preferably, in step a, described compound 3 is prepared according to following steps:
Chloro-3 methyluracils of i, 6-, potassium carbonate, 2-cyano group-5-fluorine bromobenzyl in organic solvent, in 50 DEG C～60 DEG C reactions
After 3h～8h, obtain reactant liquor；
Chloro-3 methyluracils of described 6-, potassium carbonate, the mol ratio of 2-cyano group-5-fluorine bromobenzyl are 1:(2～5): (1.2～1.5)；
Chloro-3 methyluracils of described 6-, the mass volume ratio of organic solvent are 1:(5～20) (m:v)；
Ii, the reactant liquor of step i being cooled down, add water precipitation solid, filters, and washing is dried, obtains compound 3.
Preferably, in step i, described organic solvent is selected from dimethyl sulfoxide, Isosorbide-5-Nitrae-dioxane, N, N-dimethyl formyl
Any one or more in amine, glycol dimethyl ether；
Chloro-3 methyluracils of described 6-, potassium carbonate, the mol ratio of 2-cyano group-5-fluorine bromobenzyl are 1:3:(1.2～1.3)；Institute
State chloro-3 methyluracils of 6-, the mass volume ratio of organic solvent is 1:(5～15) (m:v).
Preferably, in step b, it is any one that described halogenated hydrocarbons or ester are selected from dichloromethane, chloroform, ethyl acetate
Plant or multiple.
Preferably, in step c, the described response time is 8h；
Described compound 6, ethyl acetate, the mass volume ratio of ethyl acetate solution of HCl are 1:(5～6): (5～6) (m:
V:v).
Preferably, in step d, the reagent of described regulation pH appointing in sodium carbonate, potassium carbonate, ammonia, sodium hydroxide
Anticipate one or more；Described halogenated hydrocarbons or ester any one or more in dichloromethane, chloroform, ethyl acetate.
Present invention also offers the preparation method of a yeast inoculation Ge Lieting succinate.
The preparation method of a yeast inoculation Ge Lieting succinate that the present invention provides, it comprises the following steps:
1., bent Ge Lieting is prepared according to the method described above；
2., step bent Ge Lieting 1. is dissolved in the mixed solvent of oxolane/isopropanol, is warming up to 30 DEG C～70 DEG C,
Obtain the solution of bent Ge Lieting；
In described mixed solvent, oxolane is 3:1 with the volume ratio of isopropanol；
Described bent Ge Lieting, the mass volume ratio of mixed solvent are 1:(5～15) (m:v)；
3., succinic acid is dissolved in the mixed solvent of oxolane/isopropanol, obtains the solution of succinic acid；
In described mixed solvent, oxolane is 3:1 with the volume ratio of isopropanol；
Described succinic acid, the mass volume ratio of mixed solvent are 1:(5～15) (m:v)；
4., by the mixing of the solution of step 2. bent Ge Lieting with the solution of step 3. succinic acid, cooling, filter, washing, dry
Dry, obtain bent Ge Lieting succinate；
In described solution, bent Ge Lieting is 1:1.0～1.3 with the mol ratio of succinic acid.
Preferably,
Step 2. in, described bent Ge Lieting, the mass volume ratio of mixed solvent are 1:(8～10) (m:v)；
Step 3. in, described succinic acid, the mass volume ratio of mixed solvent are 1:(10～15) (m:v)；
Step 4. in, bent Ge Lieting is 1:1.0～1.3 with the mol ratio of succinic acid.
In the present invention, " m:v " correspondence " g:ml " or its equal proportion zoom in or out；" m:v:v " correspondence " g:
Ml:ml " or its equal proportion zoom in or out.
The inventive method, has the advantages that
(1) present invention uses 3-t-butoxycarbonyl-amino piperidines to be raw material, 3-t-butoxycarbonyl-amino piperidines and chemical combination
Thing 3 pyrimidine chlorine in ring atom reacts, and not with Fluorine atom, decreases the generation of side reaction and impurity compound；
(2) isolation and purification method of song Ge Lieting of the present invention is easy, have with short production cycle, yield is high, purity is high, become
The advantages such as this is low, are especially suitable for industrialized production.
Song Ge Lieting of the present invention and the preparation method of salt thereof, decrease the generation of side reaction and impurity compound；Qu Gelie
The isolation and purification method in spit of fland is easy, have with short production cycle, yield is high, purity is high, low cost and other advantages；Song lattice of the present invention
The yield in row spit of fland may be up to more than 95%, is especially suitable for industrialized production, has good application prospect.
Obviously, according to the foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the present invention above-mentioned basic fundamental thought premise, it is also possible to make the amendment of other various ways, replace or change.
The detailed description of the invention of form by the following examples, is described in further detail the foregoing of the present invention again.
But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to Examples below.All real based on foregoing of the present invention institute
Existing technology belongs to the scope of the present invention.
Accompanying drawing explanation
Fig. 1 song Ge Lieting succinate1H NMR spectra.
Detailed description of the invention
The raw material, the equipment that use in the specific embodiment of the invention are known product, obtain by buying commercially available prod.
In the present invention, abbreviation or the English Chinese represented are as described below:
DMSO: dimethyl sulfoxide；Boc: tertbutyloxycarbonyl；BINAP:(±)-2,2'-pair-(diphenyl phosphine)-1,1'-dinaphthalene；
Double (diphenylphosphine) ferrocene of DPPF:1,1'-；P (t-Bu) 3: tri-butyl phosphine；X-PHOS:2-dicyclohexyl phosphorus-2,4,6-
Tri isopropyl biphenyl；S-PHOS:2-dicyclohexyl phosphine-2', 6'-dimethoxy-biphenyl；EA: ethyl acetate；THF: tetrahydrochysene
Furan；I-PrOH: isopropanol；TLC: thin layer chromatography.
The synthetic route of the present invention is:
Embodiment 1
Chloro-3 methyluracils of 6-(1.5g), potassium carbonate (3.88g), 2-cyano group-5-fluorine bromobenzyl (2.6g) is dissolved in 20mL
In DMSO, said mixture is heated to 50～60 DEG C of reaction 5h, is cooled to 10 DEG C, and add water in reactant liquor 20mL,
Having faint yellow solid to separate out, filter, solid isopropanol washs, and vacuum drying obtains product (compound 3) 1.6g；
Under nitrogen protection, compound 3 (1g, 3.41mmol) is dissolved in 10mL DMSO, stirs to clarify, Xiang Rong
Liquid adds (Pd (OAc)2(7.7mg, 0.034mmol), BINAP (32mg, 0.051mmol), K3PO4(2.17g,
10.23mmol), said mixture is warming up to 80 DEG C, by 3-Boc-amino piperidine (compound 7,0.82g, 4.1mmol)
Being dissolved in 1mL DMSO and add in above-mentioned reactant mixture, 80 DEG C of stirring 5h, TLC detection compound 3 disappear；Fall
Warming to room temperature, by reacting liquid filtering, filtrate is poured into water, and extracts with dichloromethane, and organic facies is dried, and is evaporated, and is changed
Compound 6 crude product (1.8g), is directly used in next step reaction；
Compound 6 (1.8g) is dissolved in ethyl acetate (9mL), add isopyknic HCl/ ethyl acetate solution (9mL,
In the ethyl acetate solution of HCl, the content of HCl is 4mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, mistake
Filter, washs solid by ethyl acetate；Solid add water (5mL) dissolve, use K2CO3Regulation pH is 8～9, uses dichloro
Methane extracts, and is dried, solvent evaporated, obtains compound 4 (1.13g, yield: 93.8%, purity: 99.06%)；
Compound 4 (1g) is dissolved in THF/i-PrOH (3:1) mixed solvent (10ml), is warming up to 60 DEG C, obtains
The solution of compound 4；Succinic acid (0.363g) is dissolved in THF/i-PrOH (3:1) mixed solvent (5ml),
Solution to succinic acid；Being added dropwise in the solution of above-claimed cpd 4 by the solution of succinic acid, stirring decline warms to room temperature, mistake
Filter, washs solid with THF, vacuum drying, obtains compound 1 (1.2g, purity: 99.93%).
Compound 1 (bent Ge Lieting succinate)1H-NMR data:
1H-NMR (DMSO) δ 7.97～7.94 (m, 1H), 7.37～7.33 (m, 1H), 7.19～7.16 (m, 1H), 5.39 (s,
1H), 5.23～5.09 (ABq, 2H), 3.25～3.08 (m, 5H), 2.90～2.70 (m, 3H), 2.29 (s, 4H), 1.88～1.76 (m,
2H), 1.51～1.48 (m, 2H).
The Ms data of compound 1 (bent Ge Lieting succinate):
Negative ion mode HRESI-, test condition: ionization mode: ESI-；Sweep limits: 100～2000Da；Resolution:
15000(2GHz)；
Bent Ge Lieting succinate anionic molecule amount value of calculation is 474.1789, Low Resolution Mass Spectra (ionization mode: ESI-)
Prove consisting of C22H25N5O6F, this is consistent with the molecular structure of succinum love song Ge Lieting anion.
Embodiment 2
Chloro-3 methyluracils of 6-(30g), potassium carbonate (77.6g), 2-cyano group-5-fluorine bromobenzyl (52g) is dissolved in 200mL
In DMSO, said mixture is heated to 50～60 DEG C of reaction 5h, is cooled to 10 DEG C, and add water in reactant liquor 200mL,
Faint yellow solid is had to separate out.Filtering, solid isopropanol washs, and vacuum drying obtains product (compound 3) 33g；
Under nitrogen protection, compound 3 (10g, 34.1mmol) is dissolved in 50mL DMSO, stirs to clarify, Xiang Rong
Liquid adds Pd (OAc) (77mg, 0.34mmol), BINAP (320mg, 0.51mmol), K3PO4(21.7g,
102.3mmo), said mixture is warming up to 80 DEG C, by 3-Boc-amino piperidine (compound 7,8.2g, 40.9mmol)
Being dissolved in DMSO (10ml) and add in above-mentioned reactant mixture, 80 DEG C of stirring 5h, TLC detection compound 3 disappear；
Being cooled to room temperature, by reacting liquid filtering, filtrate is poured into water, and extracts with dichloromethane, and organic facies is dried, and is evaporated, and obtains
Compound 6 crude product (18.92g), is directly used in next step reaction；
Compound 6 (18.92g) is dissolved in ethyl acetate (100mL), add isopyknic HCl/ ethyl acetate solution (100ml,
In the ethyl acetate solution of HCl, the content of HCl is 2mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, mistake
Filter, washs solid by ethyl acetate；Solid add water (50ml) dissolve, use K2CO3Regulation pH is 8～9, uses dichloro
Methane extracts, and is dried, solvent evaporated, obtain compound 4 (11.65g, yield: 95.5%, purity: 99.70%)；
Compound 4 (10g) is dissolved in THF/i-PrOH (3:1) mixed solvent (80ml), is warming up to 60 DEG C, obtains
The solution of compound 4；Succinic acid (3.63g) is dissolved in THF/i-PrOH (3:1) mixed solvent (50mL),
Solution to succinic acid；Being added dropwise in the solution of above-claimed cpd 4 by the solution of succinic acid, stirring decline warms to room temperature, mistake
Filter, washs solid with THF, vacuum drying, obtains compound 1 (10g, purity: 99.95%).
Embodiment 3
Chloro-3 methyluracils of 6-(3g, 18.8mmol), potassium carbonate (12.9g, 94mmol), 2-cyano group-5-fluorine bromine
Benzyl (6g, 28.1mmol) is dissolved in 60mL DMSO, and said mixture is heated to 50～60 DEG C of reaction 5h, fall
Temperature is to 10 DEG C, and add water in reactant liquor 60mL, has faint yellow solid to separate out.Filtering, solid isopropanol washs, vacuum
It is dried, obtains product (compound 3) 2.8g；
Under nitrogen protection, compound 3 (2g, 6.8mmol) is dissolved in 20mL DMSO, stirs to clarify, to solution
Middle addition Pd (OAc) (153mg, 0.68mmol), BINAP (622mg, 1mmol), K3PO4(4.3g, 20.4mmol),
Said mixture is warming up to 80 DEG C, and (R)-3-Boc-amino piperidine (compound 7,2g, 10.2mmol) is dissolved in DMSO
(50ml) and add in above-mentioned reactant mixture, 80 DEG C of stirring 5h, TLC detection compound 3 disappear；It is cooled to room temperature,
By reacting liquid filtering, filtrate is poured into water, and extracts with dichloromethane, and organic facies is dried, and is evaporated, and obtains compound 6 crude product
(3.8g) next step reaction, it is directly used in；
Compound 6 (3.8g) is dissolved in ethyl acetate (30mL), add isopyknic HCl/ ethyl acetate solution (30ml,
In the ethyl acetate solution of HCl, the content of HCl is 3mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, mistake
Filter, washs solid by ethyl acetate；Solid add water (20ml) dissolve, use K2CO3Regulation pH is 8～9, uses dichloro
Methane extracts, and is dried, solvent evaporated, obtain compound 4 (2.2g, yield: 91.2%, purity: 98.91%).
Embodiment 4
Under nitrogen protection, compound 3 (2.93g, 10mmol) is dissolved in 30mL DMSO, stirs to clarify, to
Solution adds (Pd (OAc)2(22.5mg, 0.1mmol), BINAP (93.4mg, 0.15mmol；Entitled: (±)-2,2'-
Double-(diphenyl phosphine)-1,1'-dinaphthalene), K3PO4(6.37g, 30mmol), said mixture is warming up to 80 DEG C, by 3-Boc-
Amino piperidine (compound 7,3g, 15mmol) is dissolved in 5mL DMSO and adds in above-mentioned reactant mixture, 80 DEG C
Stirring 8h, TLC detection compound 3 disappears；Being cooled to room temperature, by reacting liquid filtering, filtrate is poured into water, and uses dichloro
Methane extracts, and organic facies is dried, and is evaporated, and obtains compound 6 crude product, is directly used in next step reaction；
Compound 6 is dissolved in ethyl acetate (30mL), adds isopyknic HCl/ ethyl acetate solution (30mL, HCl
Ethyl acetate solution in, the content of HCl is 4mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, filter,
Solid is washed by ethyl acetate；Solid add water (20mL) dissolve, use K2CO3Regulation pH is 8～9, uses dichloromethane
Extraction, is dried, solvent evaporated, obtains compound 4 (yield: 94.2%).
Embodiment 5
Under nitrogen protection, compound 3 (2.93g, 10mmol) is dissolved in 30mL DMSO, stirs to clarify, to
Solution adds (Pd (OAc)2(22.5mg, 0.1mmol), DPPF (0.15mmol；Entitled: the double (diphenyl of 1,1'-
Phosphine) ferrocene), K3PO4(6.37g, 30mmol), said mixture is warming up to 80 DEG C, (is changed by 3-Boc-amino piperidine
Compound 7,3g, 15mmol) it is dissolved in 5mL DMSO and adds in above-mentioned reactant mixture, 80 DEG C of stirrings 8h, TLC
Detection compound 3 disappears；Being cooled to room temperature, by reacting liquid filtering, filtrate is poured into water, and extracts with dichloromethane, organic
It is dried mutually, is evaporated, obtain compound 6 crude product, be directly used in next step reaction；
Compound 6 is dissolved in ethyl acetate (30mL), adds isopyknic HCl/ ethyl acetate solution (30mL, HCl
Ethyl acetate solution in, the content of HCl is 4mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, filter,
Solid is washed by ethyl acetate；Solid add water (20mL) dissolve, use K2CO3Regulation pH is 8～9, uses dichloromethane
Extraction, is dried, solvent evaporated, obtains compound 4 (yield: 83.2%).
Embodiment 6
Under nitrogen protection, compound 3 (2.93g, 10mmol) is dissolved in 30mL DMSO, stirs to clarify, to
Solution adds (Pd (OAc)2(22.5mg, 0.1mmol), P (t-Bu)3(0.15mmol；Entitled: tri-butyl phosphine),
K3PO4(6.37g, 30mmol), said mixture is warming up to 80 DEG C, by 3-Boc-amino piperidine (compound 7,3g,
15mmol) it is dissolved in 5mL DMSO and adds in above-mentioned reactant mixture, 80 DEG C of stirring 8h, TLC detection compound 3
Disappear；Being cooled to room temperature, by reacting liquid filtering, filtrate is poured into water, and extracts with dichloromethane, and organic facies is dried, and is evaporated,
Obtain compound 6 crude product, be directly used in next step reaction；
Compound 6 is dissolved in ethyl acetate (30mL), adds isopyknic HCl/ ethyl acetate solution (30mL, HCl
Ethyl acetate solution in, the content of HCl is 4mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, filter,
Solid is washed by ethyl acetate；Solid add water (20mL) dissolve, use K2CO3Regulation pH is 8～9, uses dichloromethane
Extraction, is dried, solvent evaporated, obtains compound 4 (yield: 90.2%).
Embodiment 7
Under nitrogen protection, compound 3 (2.93g, 10mmol) is dissolved in 30mL DMSO, stirs to clarify, to
Solution adds (Pd (OAc)2(22.5mg, 0.1mmol), X-PHOS (0.15mmol；Entitled: 2-dicyclohexyl
Phosphorus-2,4,6-tri isopropyl biphenyls), K3PO4(6.37g, 30mmol), said mixture is warming up to 80 DEG C, by 3-Boc-
Amino piperidine (compound 7,3g, 15mmol) is dissolved in 5mL DMSO and adds in above-mentioned reactant mixture, 80 DEG C
Stirring 8h, TLC detection compound 3 disappears；Being cooled to room temperature, by reacting liquid filtering, filtrate is poured into water, and uses dichloro
Methane extracts, and organic facies is dried, and is evaporated, and obtains compound 6 crude product, is directly used in next step reaction；
Compound 6 is dissolved in ethyl acetate (30mL), adds isopyknic HCl/ ethyl acetate solution (30mL, HCl
Ethyl acetate solution in, the content of HCl is 4mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, filter,
Solid is washed by ethyl acetate；Solid add water (20mL) dissolve, use K2CO3Regulation pH is 8～9, uses dichloromethane
Extraction, is dried, solvent evaporated, obtains compound 4 (yield: 82.3%).
Embodiment 8
Under nitrogen protection, compound 3 (2.93g, 10mmol) is dissolved in 30mL DMSO, stirs to clarify, to
Solution adds (Pd (OAc)2(22.5mg, 0.1mmol), S-PHOS (0.15mmol；Entitled: 2-dicyclohexyl
Phosphine-2', 6'-dimethoxy-biphenyl), K3PO4(6.37g, 30mmol), said mixture is warming up to 80 DEG C, by 3-Boc-ammonia
Phenylpiperidines (compound 7,3g, 15mmol) is dissolved in 5mL DMSO and adds in above-mentioned reactant mixture, and 80 DEG C are stirred
Mix 8h, TLC detection compound 3 to disappear；Being cooled to room temperature, by reacting liquid filtering, filtrate is poured into water, and uses dichloromethane
Alkane extracts, and organic facies is dried, and is evaporated, and obtains compound 6 crude product, is directly used in next step reaction；
Compound 6 is dissolved in ethyl acetate (30mL), adds isopyknic HCl/ ethyl acetate solution (30mL, HCl
Ethyl acetate solution in, the content of HCl is 4mol/L), 8h is stirred at room temperature, has off-white color solid to separate out, filter,
Solid is washed by ethyl acetate；Solid add water (20mL) dissolve, use K2CO3Regulation pH is 8～9, uses dichloromethane
Extraction, is dried, solvent evaporated, obtains compound 4 (yield: 77.9%).
In order to beneficial effects of the present invention is described, the present invention provides tests below example as a comparison:
Test example 1
Three-necked bottle is sequentially added into compound 3 (29.3g, 0.1mol), potassium carbonate (60g, 0.435mol), (R)-3-ammonia
Phenylpiperidines dihydrochloride (18.92g, 0.11mol), isopropanol (300mL), after being warming up to 80 DEG C of reactions 8 hours, instead
Answering liquid to be down to 20～30 DEG C, filter, wash solid with isopropanol (50mL × 2), filtrate decompression is evaporated isopropanol, to residual
Excess adds dichloromethane (150mL), water (100mL)；Separating organic facies, aqueous phase extracts with dichloromethane again
(50mL*2), merging organic facies, evaporated under reduced pressure solvent, obtain crude product, wherein major impurity is: impurity compound 5,
Its content is 7%；Crude product column chromatography is purified (eluant: methylene chloride/methanol=100:1～5:1), obtains compound 4
(22.5g, yield 63.2%, purity 98.8%).
As seen from the experiment, the impurity that comparative experimental example 1 produces due to side reaction is many, and the post processing of crude product is complicated, numerous
Trivial, need to use column chromatography or high performance liquid chromatography (HPLC) to carry out isolated and purified to bent Ge Lieting, the production cycle is long,
Preparation cost is high；Meanwhile, the yield (63.2%) of the bent Ge Lieting of comparative experimental example 1 is far below the present invention, its bent Ge Lieting
Purity also not as good as the present invention.
In sum, song Ge Lieting of the present invention and the preparation method of salt thereof, decrease the life of side reaction and impurity compound
Become；The isolation and purification method of bent Ge Lieting is easy, have with short production cycle, yield is high, purity is high, low cost and other advantages；
The yield of song Ge Lieting of the present invention may be up to more than 95%, is especially suitable for industrialized production, has good application prospect.
Claims (10)
1. the preparation method of a yeast inoculation Ge Lieting, it is characterised in that: its synthetic route is:
It comprises the following steps:
Under the protection of a, nitrogen, compound 3, Pd (OAc)2, ligand, K3PO4, 3-t-butoxycarbonyl-amino piperidines having
In machine solvent, in 40 DEG C～100 DEG C stirring reactions, thin layer chromatography detection reaction is complete, obtains reactant liquor；
Described compound 3, Pd (OAc)2, ligand, K3PO4, the mol ratio of 3-t-butoxycarbonyl-amino piperidines be 1:
(0.01～0.1): (0.015～0.15): (1～10): (1～5)；Described compound 3 is 1 with the mass volume ratio of organic solvent:
(5～12) (m:v)；
B, the reactant liquor of step a is cooled down, filter, obtain filtrate；Filtrate adds water, extracts with halogenated hydrocarbons or ester,
To organic facies；Organic facies is dried, is evaporated, obtain compound 6；
C, take the compound 6 of step b, and ethyl acetate, the ethyl acetate solution of HCl, anti-in 20 DEG C～30 DEG C stirrings
After answering 5h～16h, separate out solid, filter, washing, obtain solid；
In the ethyl acetate solution of described HCl, the content of HCl is 1～4mol/L；
Described compound 6, ethyl acetate, the mass volume ratio of ethyl acetate solution of HCl are 1:(5～8): (5～8) (m:
V:v)；
D, taking the solid of step c, be dissolved in water, regulation pH is 8～9, extracts with halogenated hydrocarbons or ester, obtains organic facies；
Organic facies is dried, is evaporated, obtain compound 4, be bent Ge Lieting.
Preparation method the most according to claim 1, it is characterised in that: in step a, described ligand be (±)-2,2'-
Double-(diphenyl phosphine)-1,1'-dinaphthalene, 1,1'-double (diphenylphosphine) ferrocene, tri-butyl phosphine, 2-dicyclohexyl phosphorus-2,4,6-tri-
Isopropyl biphenyl, 2-dicyclohexyl phosphine-2', any one or more in 6'-dimethoxy-biphenyl；
Described organic solvent is in dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, glycol dimethyl ether
Any one or more.
Preparation method the most according to claim 1, it is characterised in that: in step a, described compound 3, Pd (OAc)2、
Ligand, K3PO4, the mol ratio of 3-t-butoxycarbonyl-amino piperidines be 1:0.01:0.015:3:(1.2～1.5)；
Described compound 3 is 1:(6～11 with the mass volume ratio of organic solvent) (m:v).
Preparation method the most according to claim 1, it is characterised in that: in step a, described compound 3 according to
Prepared by lower step:
Chloro-3 methyluracils of i, 6-, potassium carbonate, 2-cyano group-5-fluorine bromobenzyl in organic solvent, in 50 DEG C～60 DEG C reactions
After 3h～8h, obtain reactant liquor；
Chloro-3 methyluracils of described 6-, potassium carbonate, the mol ratio of 2-cyano group-5-fluorine bromobenzyl are 1:(2～5): (1.2～1.5)；
Chloro-3 methyluracils of described 6-, the mass volume ratio of organic solvent are 1:(5～20) (m:v)；
Ii, the reactant liquor of step i being cooled down, add water precipitation solid, filters, and washing is dried, obtains compound 3.
Preparation method the most according to claim 4, it is characterised in that: in step i, described organic solvent is selected from two
Any one or more in methyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide, glycol dimethyl ether；
Chloro-3 methyluracils of described 6-, potassium carbonate, the mol ratio of 2-cyano group-5-fluorine bromobenzyl are 1:3:(1.2～1.3)；Institute
State chloro-3 methyluracils of 6-, the mass volume ratio of organic solvent is 1:(5～15) (m:v).
Preparation method the most according to claim 1, it is characterised in that: in step b, described halogenated hydrocarbons or ester are selected from
Any one or more in dichloromethane, chloroform, ethyl acetate.
Preparation method the most according to claim 1, it is characterised in that: in step c, the described response time is 8h；
Described compound 6, ethyl acetate, the mass volume ratio of ethyl acetate solution of HCl are 1:(5～6): (5～6) (m:
V:v).
Preparation method the most according to claim 1, it is characterised in that: in step d, the reagent of described regulation pH
Any one or more in sodium carbonate, potassium carbonate, ammonia, sodium hydroxide；Described halogenated hydrocarbons or ester selected from dichloromethane,
Any one or more in chloroform, ethyl acetate.
9. the preparation method of a yeast inoculation Ge Lieting succinate, it is characterised in that: it comprises the following steps:
1., according to the bent Ge Lieting of claim 1～8 any one method preparation；
2. the bent Ge Lieting, by step 1. prepared is dissolved in the mixed solvent of oxolane/isopropanol, be warming up to 30 DEG C～
70 DEG C, obtain the solution of bent Ge Lieting；
In described mixed solvent, oxolane is 3:1 with the volume ratio of isopropanol；
Described bent Ge Lieting, the mass volume ratio of mixed solvent are 1:(5～15) (m:v)；
3., succinic acid is dissolved in the mixed solvent of oxolane/isopropanol, obtains the solution of succinic acid；
In described mixed solvent, oxolane is 3:1 with the volume ratio of isopropanol；
Described succinic acid, the mass volume ratio of mixed solvent are 1:(5～15) (m:v)；
4. the succinic acid solution mixing that 3. the bent Ge Lieting solution, by step 2. prepared and step are prepared, cooling, filter, wash
Wash, be dried, obtain bent Ge Lieting succinate；
Described step 4. in, bent Ge Lieting is 1:1.0～1.3 with the mol ratio of succinic acid.
Preparation method the most according to claim 9, it is characterised in that: step 2. in, described bent Ge Lieting, mixing
The mass volume ratio of solvent is 1:(8～10) (m:v)；
Step 3. in, described succinic acid, the mass volume ratio of mixed solvent are 1:(10～15) (m:v)；
Step 4. in, bent Ge Lieting is 1:1.0～1.3 with the mol ratio of succinic acid.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106749176A (en) * | 2016-12-08 | 2017-05-31 | 郑州明泽医药科技有限公司 | The purification process of one koji Ge Lieting succinates |
| CN109970706A (en) * | 2017-12-27 | 2019-07-05 | 徐州万邦金桥制药有限公司 | A kind of preparation and refining methd of amber love song Ge Lieting A crystal form |
| CN112480075A (en) * | 2020-12-22 | 2021-03-12 | 山东永丞制药有限公司 | Refining method of trelagliptin succinate |
| CN116478163A (en) * | 2022-01-13 | 2023-07-25 | 成都赜灵生物医药科技有限公司 | Process for preparing (R) -N- (1- (9H-purin-6-yl) piperidin-3-yl) acrylamides |
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| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| EP2682110B1 (en) * | 2011-03-03 | 2019-12-04 | Takeda Pharmaceutical Company Limited | Laminated tablet and manufacturing method therefor |
| CN102532061A (en) * | 2011-12-07 | 2012-07-04 | 华东理工大学 | Method for easily preparing aryl morpholine and aryl piperidine |
| CN103172615A (en) * | 2013-03-29 | 2013-06-26 | 山东罗欣药业股份有限公司 | Benzoic acid alogliptin crystal form compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749176A (en) * | 2016-12-08 | 2017-05-31 | 郑州明泽医药科技有限公司 | The purification process of one koji Ge Lieting succinates |
| CN109970706A (en) * | 2017-12-27 | 2019-07-05 | 徐州万邦金桥制药有限公司 | A kind of preparation and refining methd of amber love song Ge Lieting A crystal form |
| CN112480075A (en) * | 2020-12-22 | 2021-03-12 | 山东永丞制药有限公司 | Refining method of trelagliptin succinate |
| CN116478163A (en) * | 2022-01-13 | 2023-07-25 | 成都赜灵生物医药科技有限公司 | Process for preparing (R) -N- (1- (9H-purin-6-yl) piperidin-3-yl) acrylamides |
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