CN105968091A - Method for preparing drug Alogliptin for treating diabetes type II - Google Patents
Method for preparing drug Alogliptin for treating diabetes type II Download PDFInfo
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- CN105968091A CN105968091A CN201610293432.5A CN201610293432A CN105968091A CN 105968091 A CN105968091 A CN 105968091A CN 201610293432 A CN201610293432 A CN 201610293432A CN 105968091 A CN105968091 A CN 105968091A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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Abstract
The invention discloses a method for preparing a drug Alogliptin for treating diabetes type II. The method comprises that 1, in the presence of copper acetate and triethylamine, 6-cholo-3-methyluracil and 2-cyanobenzyl bromide undergo a contact reaction in acetonitrile, then the reaction solution is poured into water, the mixed solution is filtered, the filter residues are washed by water and are dried to form 6-cholo-1-(2-isocyanobenzyl)-3-methylpyrimidine-2, 4-(1H, 3H)-dione, 2, the 6-cholo-1-(2-isocyanobenzyl)-3-methylpyrimidine-2, 4-(1H, 3H)-dione, (R)-3-tert-butyloxocarbonylaminopiperidine and potassium carbonate are mixed in DMF and undergo a reaction, then water is added into the reaction product, the mixture is extracted by dichloromethane, and the extract is concentrated to form (R)-tert-butyl-1-(3-(2-isocyanobenzyl)-1-methyl-2, 6-dioxo-1, 2, 3, 6-tetrahydropyrimidine-4-yl)piperidine-3-yl-carbamate, and 3, the carbamate obtained by the step 2 is dissolved in ethanol, the solution reacts with benzoic acid at a temperature of 65-70 DEG C, the reaction product is cooled to a temperature of -5 to 5 DEG C so that crystals are produced, filtering the crystals and carrying out drying to obtain Alogliptin. The method has simple processes and realizes a high yield and a fast reaction rate.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of method preparing treatment type ii diabetes medicine Egelieting.
Background technology
Diabetes be a kind of because of internal insulin definitely or a series of clinical syndromes of being caused of relative deficiency.Current treatment
Method is predominantly by diet control and coordinate hypoglycemic medicine (to type ii diabetes) or insulin to supplement to combine.Research is sent out
Existing, DPP IV (DPP-IV) is that body is inside and outside mainly promotes glucagon-like-peptide-1 (GLP-1) to degrade, inactivate
One of key enzyme, therefore DPP-IV inhibitor is a kind of novel Remedies for diabetes, and clinical effectiveness has shown that such medicine
Thing has good hypoglycemic effect, does not finds that common body weight produced by other diabetes medicaments increases bad with blood sugar lowering etc. simultaneously
Reaction.
SYR-322 (Alogliptin Benzoate), chemical name is benzoic acid (R)-2-((6-(-3-amino piperidine-1-base)-3-
Methyl-2,4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-yl) methyl) benzonitrile, concrete structure such as following formula, this compound is the military field system of Japan
The DPP-4 activity inhibitor that a kind of height of medicine research and development selects, this inhibitor is exactly based on and improves the plasma concentration of GLP-1 in body
Promote the level of insulin peptide, increase the secretion of insulin thus play blood sugar lowering curative effect.
At present, although the synthetic route of Egelieting is a lot, but similar, most with 6-chlorouracil or 6-chloro-3-methyl urine
Pyrimidine be initiation material then through alkylation, methylate, coupling, the step such as benzoic acid.CN1926128A disclose a kind of Ah
The preparation method of Ge Lieting, the method is with 6-chlorouracil as initiation material, with 2-bromine first under the effect of sodium hydride and lithium bromide
Base benzonitrile generation alkylation, then obtains 2-(6-chloro-3-methyl-2,4-dioxo-3,4-bis-under the effect of sodium hydride with iodomethane reaction
Hydrogen-2H-pyrimidine-1-ylmethyl)-benzonitrile two step yield is all at about 50-70%.The most in the basic conditions with (R)-3-amino piperazine
Pyridine dihydrochloride generation substitution reaction obtains Egelieting free alkali, Egelieting free alkali become with benzoic acid salt prepare benzoic acid Ah
Ge Lieting.Although the method can successfully prepare Egelieting, but alkylation in the method, the multistep that methylates have used hydrogenation
Sodium, system condition requires extremely strict, and the use of sodium hydride can destroy the stability of raw material, and part material pyrimidine ring destroys,
Reducing yield, total recovery only has about 20%.Be not suitable for large-scale commercial production.
CN104592196A discloses the preparation method of a kind of SYR-322, and the method is with 6-chloro-3-methyluracil for rising
Beginning raw material, obtains 2-(6-chloro-3-methyl-2,4-dioxo-3,4-bis-in the basic conditions with toluene for solvent with 2-cyano group benzyl bromine reaction
Hydrogen-2H-pyrimidine-1-ylmethyl)-benzonitrile, then with isopropanol for solvent in the basic conditions with (R)-3-amino piperidine dihydrochloride
There is substitution reaction, then carrying out benzoic acid, purification obtains high-purity SYR-322.Although 6-chloro-3-methyl is urinated
Pyrimidine in the presence of DIPEA with in 2-cyano group benzyl bromine reaction, owing to DIPEA can remain in 2-(6-chloro-3-methyl-2,4-dioxy in a large number
Generation-3,4-dihydro-2H-pyrimidine-1-ylmethyl) in-benzonitrile, hinder the necleophilic reaction of its and amine, while also make by-product such as two
Aggressiveness increases.
Therefore, in view of Egelieting is treating the effect that type ii diabetes is good, this area needs a kind of simple, yield height of exploitation badly
The method of preparation Egelieting.
Summary of the invention
It is an object of the invention to overcome complex steps, response time length and product in the method for existing preparation Egelieting to receive
The defect that rate is low, it is provided that a kind of applicable industrial-scale production and the method that yield is high, Egelieting is prepared in reaction faster.
The present inventor has been surprisingly found that under study for action, and under the catalysis of Schweinfurt green, 6-chloro-3-methyluracil can be with 2-cyanogen
Base benzyl bromine can react rapidly and generate the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone, this is because,
Schweinfurt green can form coordination with N, activates N-H key, the more conducively attack of benzyl bromine；Inventor also finds, if in above-mentioned reaction
During add a small amount of potassium iodide, it is possible to promoting further to react to carry out, the addition of potassium iodide increases ion concentration, more sharp
In reacting to the direction generating the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone.
To achieve these goals, the present invention provides a kind of method preparing treatment type ii diabetes medicine Egelieting, the method
Comprise the following steps:
1) by the presence of Schweinfurt green, triethylamine, chloro-for 6-3-methyluracil and 2-cyano group benzyl bromine are carried out haptoreaction in acetonitrile,
After reaction terminates, reactant liquor is poured in water, filters, washing, it is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine
-2,4-(1H, 3H)-diketone；
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone, (R)-3-t-butyloxycarbonyl amino piperidine,
Potassium carbonate carries out hybrid reaction in DMF, after reaction terminates, adds water, and then dichloromethane extraction, is concentrated to give (R)-tert-butyl group
-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester；
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 65-70 DEG C with benzoic acid in ethanol, be subsequently cooled to-5～5 DEG C of crystallizes,
Filtration drying obtains Egelieting.
Under preferable case, in step 1) in, 6-chloro-3-methyluracil and 2-cyano group benzyl bromine, Schweinfurt green, the mol ratio of triethylamine
For 1:1.05～1.2:0.5～0.8:1.5～3.In the case of Jin Yibuyouxuan, in step 1) in, 6-chloro-3-methyluracil and 2-
Cyano group benzyl bromine, Schweinfurt green, the mol ratio of triethylamine are 1:1.15:0.5:2.5.
In the present invention, Schweinfurt green refers to Salicylaldoxime or the Schweinfurt green with water of crystallization, such as copper acetate monohydrate.
Obtain yield and speed, in step 1 to improve haptoreaction further) in be additionally included in before haptoreaction and add potassium iodide,
The addition of described potassium iodide is 0.2～0.5:1 with the mol ratio of 6-chloro-3-methyluracil.
In the present invention, suitable temperature is highly beneficial to reaction, and inventor finds, temperature is the lowest, and reaction also can be very slow,
And the highest (such as more than more than 60 DEG C), reaction can generate more by-product, the product etc. of such as two molecule dehalogenate couplings, because of
This, under preferable case, in step 1) in, described catalytic temperature is 40～55 DEG C.
Use the present invention method, greatly reduce reactions steps 1) response time, general 1.5～2.5h can complete reaction.
Step 2 in the present invention), the ratio of the material of each reaction is not particularly limited, such as, the chloro-1-of 6-(2-isocyanide benzyl
Base)-3-methylpyrimidine-2,4-(1H, 3H)-diketone with (R)-3-t-butyloxycarbonyl amino piperidine, the mol ratio of potassium carbonate is
1:1～1.2:2.2～3.Step 2) reaction temperature be more conducive to when 60～70 DEG C react to carry out.
In step 3) in, benzoic acid and (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidines
-4-base) amount of piperidines-3-aminocarbamic acid ester is not particularly limited, and benzoic amount makes (R)-tert-butyl group-1-(3-(2-isocyanide
Benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-abundant benzoic acid of aminocarbamic acid ester, example
As, benzoic acid and (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-
The mol ratio of aminocarbamic acid ester is 1.2:1.
In the case of in the present invention, it is preferred to, described step 1) carry out in the presence of protective gas, described protective gas can be nitrogen
Gas, helium or argon.The room temperature of indication of the present invention refers to 25 DEG C ± 5 DEG C.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS, GCMS
Deng, react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue less than 2%.
Specifically, the synthetic route of the present invention is as follows:
The method using the preparation Egelieting of present invention offer, operating procedure is simpler, and the response time is greatly shortened, special
It not the step of the 6-chloro-3-methyluracil than relatively time-consuming and 2-cyano group benzyl bromine, and avoids the most dimeric by-product,
Thus ensure that the yield of Egelieting is greatly improved.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently..
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments are only limitted to illustrate rather than this
The further restriction of the protection domain of invention.
Embodiment 1
A kind of method preparing treatment type ii diabetes medicine Egelieting, the method comprises the following steps:
1) nitrogen protection under, by Schweinfurt green 9.1g (50mmol), triethylamine 25.3g (250mmol), potassium iodide 6.6g (40mmol),
6-chloro-3-methyluracil 16.1g (100mmol) and 2-cyano group benzyl bromine 22.5g (115mmol) in 200ml acetonitrile 45 DEG C carry out
Haptoreaction 1.5 hours, after reaction terminates, is poured into reactant liquor in water, filters, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl
Base)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 26.5g, yield is 96.2%, purity 98.79%.
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 13.8g (50mmol), (R)-3-tert-butyl group
Epoxide carbonylamino piperidinyl-1 2.0g (60mmol), potassium carbonate 15.2g (110mmol) in DMF 65 DEG C carry out hybrid reaction 3
Hour, after reaction terminates, adding water, then dichloromethane extraction, concentrate, normal hexane washs, and is dried to obtain (R)-tert-butyl group-1-(3-(2-
Isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-aminocarbamic acid ester 21.5g, yield is
98.1%, purity 98.96%.
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 70 DEG C with benzoic acid in ethanol, be subsequently cooled to-5 DEG C of crystallizes, filter
Being dried to obtain Egelieting, yield is 96.5%, purity 99.46% (HPLC area normalization method).
Embodiment 2
A kind of method preparing treatment type ii diabetes medicine Egelieting, the method comprises the following steps:
1) nitrogen protection under, by Schweinfurt green 9.1g (50mmol), triethylamine 25.3g (250mmol), potassium iodide 5.0g (30mmol),
6-chloro-3-methyluracil 16.1g (100mmol) and 2-cyano group benzyl bromine 23.5g (120mmol) in 200ml acetonitrile 40 DEG C carry out
Haptoreaction 2 hours, after reaction terminates, is poured into reactant liquor in water, filters, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone 26.2g, yield is 95.1%, purity 98.64%.
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 13.8g (50mmol), (R)-3-tert-butyl group
Epoxide carbonylamino piperidinyl-1 1.0g (55mmol), potassium carbonate 20.7g (150mmol) in DMF 70 DEG C carry out hybrid reaction 3
Hour, after reaction terminates, adding water, then dichloromethane extraction, concentrate, normal hexane washs, and is dried to obtain (R)-tert-butyl group-1-(3-(2-
Isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-aminocarbamic acid ester 21.5g, yield is
97.6%, purity 98.71%.
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 65 DEG C with benzoic acid in ethanol, be subsequently cooled to 0 DEG C of crystallize, filter
Being dried to obtain Egelieting, yield is 95.4%, purity 99.76% (HPLC area normalization method).
Embodiment 3
A kind of method preparing treatment type ii diabetes medicine Egelieting, the method comprises the following steps:
1) nitrogen protection under, by Schweinfurt green 10.9g (60mmol), triethylamine 20.2g (200mmol), potassium iodide 8.3g (50mmol),
6-chloro-3-methyluracil 16.1g (100mmol) and 2-cyano group benzyl bromine 21.6g (110mmol) in 200ml acetonitrile 50 DEG C carry out
Haptoreaction 2 hours, after reaction terminates, is poured into reactant liquor in water, filters, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone 26.2g, yield is 95.1%, purity 97.73%.
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 13.8g (50mmol), (R)-3-tert-butyl group
Epoxide carbonylamino piperidinyl-1 1.0g (55mmol), potassium carbonate 17.3g (125mmol) in DMF 65 DEG C carry out hybrid reaction 2.5
Hour, after reaction terminates, adding water, then dichloromethane extraction, concentrate, normal hexane washs, and is dried to obtain (R)-tert-butyl group-1-(3-(2-
Isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-aminocarbamic acid ester 21.5g, yield is
98.0%, purity 98.70%.
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 70 DEG C with benzoic acid in ethanol, be subsequently cooled to 5 DEG C of crystallizes, filter
Being dried to obtain Egelieting, yield is 96.4%, purity 99.27% (HPLC area normalization method).
Embodiment 4
A kind of method preparing treatment type ii diabetes medicine Egelieting, the method comprises the following steps:
1) nitrogen protection under, by Schweinfurt green 9.1g (50mmol), triethylamine 15.2g (150mmol), potassium iodide 3.3g (20mmol),
6-chloro-3-methyluracil 16.1g (100mmol) and 2-cyano group benzyl bromine 20.6g (105mmol) in 200ml acetonitrile 45 DEG C carry out
Haptoreaction 2.5 hours, after reaction terminates, is poured into reactant liquor in water, filters, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl
Base)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 26.1g, yield is 94.7%, purity 98.12%.
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 13.8g (50mmol), (R)-3-tert-butyl group
Epoxide carbonylamino piperidinyl-1 1.0g (55mmol), potassium carbonate 17.3g (125mmol) in DMF 60 DEG C carry out hybrid reaction 3
Hour, after reaction terminates, adding water, then dichloromethane extraction, concentrate, normal hexane washs, and is dried to obtain (R)-tert-butyl group-1-(3-(2-
Isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-aminocarbamic acid ester 20.1g, yield is
91.4%, purity 97.33%.
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 65 DEG C with benzoic acid in ethanol, be subsequently cooled to-5 DEG C of crystallizes, filter
Being dried to obtain Egelieting, yield is 95.2%, purity 99.74% (HPLC area normalization method).
Embodiment 5
A kind of method preparing treatment type ii diabetes medicine Egelieting, the method comprises the following steps:
1) nitrogen protection under, by Schweinfurt green 14.5g (80mmol), triethylamine 30.4g (300mmol), potassium iodide 5.0g (30mmol),
6-chloro-3-methyluracil 16.1g (100mmol) and 2-cyano group benzyl bromine 20.6g (105mmol) in 200ml acetonitrile 55 DEG C carry out
Haptoreaction 2.5 hours, after reaction terminates, is poured into reactant liquor in water, filters, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl
Base)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 26.0g, yield is 94.3%, purity 97.45%.
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 13.8g (50mmol), (R)-3-tert-butyl group
Epoxide carbonylamino piperidinyl-1 0.0g (50mmol), potassium carbonate 20.7g (150mmol) in DMF 65 DEG C carry out hybrid reaction 3.5
Hour, after reaction terminates, adding water, then dichloromethane extraction, concentrate, normal hexane washs, and is dried to obtain (R)-tert-butyl group-1-(3-(2-
Isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-bases) piperidines-3-aminocarbamic acid ester 20.2g, yield is
91.8%, purity 98.67%.
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 65 DEG C with benzoic acid in ethanol, be subsequently cooled to 5 DEG C of crystallizes, filter
Being dried to obtain Egelieting, yield is 94.7%, purity 99.80% (HPLC area normalization method).
Embodiment 6
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, do not use potassium iodide, obtain 6-chlorine
-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 24.2g, yield is 87.8%, purity 96.98% (HPLC area
Normalization method).
Embodiment 7
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, the amount using potassium iodide is 1.7g
(10mmol), obtaining the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 25.0g, yield is 90.7%, purity
98.02% (HPLC area normalization method).
Embodiment 8
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, the consumption of Schweinfurt green is 1.8g
(10mmol), obtaining the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 24.0g, yield is 87.2%, purity
98.15% (HPLC area normalization method).
Embodiment 9
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, the consumption of Schweinfurt green is 18.2g
(100mmol), obtaining the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 26.6g, yield is 96.4%, pure
Degree 96.91% (HPLC area normalization method).
Comparative example 1
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, do not use Schweinfurt green, obtain 6-chlorine
-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 21.8g, yield is 79.2%, purity 90.37% (HPLC area
Normalization method).Comparative example 1 step 1) response time is 5.5 hours.
Comparative example 2
Such as the preparation method of the Egelieting in embodiment 6, except that, step 1) in, do not use Schweinfurt green, obtain 6-chlorine
-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 19.8g, yield is 71.8%, purity 87.35% (HPLC face
Long-pending normalization method).Comparative example 1 step 1) response time is 6 hours.
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited to the tool in above-mentioned embodiment
Body details, in the technology concept of the present invention, can carry out multiple simple variant to technical scheme, these
Simple variant belongs to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, in reconcilable feelings
Under condition, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention is to various possible groups
Conjunction mode illustrates the most separately.Additionally, combination in any can also be carried out between the various different embodiment of the present invention, as long as
It is without prejudice to the thought of the present invention, and it should be considered as content disclosed in this invention equally.
Claims (7)
1. the method preparing treatment type ii diabetes medicine Egelieting, it is characterised in that the method comprises the following steps:
1) by the presence of Schweinfurt green, triethylamine, chloro-for 6-3-methyluracil and 2-cyano group benzyl bromine are carried out haptoreaction in acetonitrile,
After reaction terminates, reactant liquor is poured in water, filters, washing, it is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine
-2,4-(1H, 3H)-diketone；
2) by chloro-for 6-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone, (R)-3-t-butyloxycarbonyl amino piperazine
Pyridine, potassium carbonate carry out hybrid reaction in DMF, after reaction terminates, add water, and then dichloromethane extraction, is concentrated to give (R)-uncle
Butyl-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-base) piperidines-3-aminocarbamic acid ester；
3) by step 2) (R)-tert-butyl group-1-(3-(2-isocyanide benzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-of obtaining
Base) piperidines-3-aminocarbamic acid ester dissolve react at 65-70 DEG C with benzoic acid in ethanol, be subsequently cooled to-5～5 DEG C of crystallizes,
Filtration drying obtains Egelieting.
Method the most according to claim 1, it is characterised in that in step 1) in, 6-chloro-3-methyluracil and 2-
Cyano group benzyl bromine, Schweinfurt green, the mol ratio of triethylamine are 1:1.05～1.2:0.5～0.8:1.5～3.
Method the most according to claim 1, it is characterised in that in step 1) in, 6-chloro-3-methyluracil and 2-
Cyano group benzyl bromine, Schweinfurt green, the mol ratio of triethylamine are 1:1.15:0.5:2.5.
Method the most according to claim 1, it is characterised in that in step 1) in be additionally included in before haptoreaction and add iodate
Potassium, the addition of described potassium iodide is 0.2～0.5:1 with the mol ratio of 6-chloro-3-methyluracil.
Method the most according to claim 4, it is characterised in that in step 1) in, described catalytic temperature is 40～55 DEG C.
Method the most according to claim 1, it is characterised in that in step 2) in, the chloro-1-of 6-(2-isocyanide benzyl)-3-methyl
Pyrimidine-2,4-(1H, 3H)-diketone is 1:1～1.2:2.2～3 with (R)-3-t-butyloxycarbonyl amino piperidine, the mol ratio of potassium carbonate.
Method the most according to claim 1, it is characterised in that described haptoreaction is carried out in the presence of protective gas, institute
Stating protective gas is nitrogen, helium or argon.
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