CN105837557A - Preparation method of alogliptin for treating type-II diabetes - Google Patents
Preparation method of alogliptin for treating type-II diabetes Download PDFInfo
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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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- 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 preparation method of alogliptin for treating type-II diabetes .The method comprises the steps that 1, 1-(2-benzyl isocyanide)-3-methylpyrimidine-2,4,6-(1H,3H,5H)-triketone and a divalent palladium salt and N-chlorosuccinimide are subjected to a contact reaction, dichloromethane extracting, saturated salt water washing, anhydrous sodium sulfate drying and concentrating are conducted, and 6-chloro-1-(2-benzyl isocyanide)-3-methylpyrimidine-2,4-(1H,3H)-diketone is obtained; 2, the product obtained in the first step, (R)-3-N-Boc-aminopiperidine and potassium carbonate are subjected to a mixing reaction in DMF, dichloromethane extracting and concentrating are conducted, and (R)-tert-butyl-1-(3-(2-benzyl isocyanide)-1-methyl-2,6-dioxo-1,2,3,6-ectoine-4-yl)piperidine-3-yl carbamate; 3, the product obtained in the second step is dissolved in ethanol and reacts with benzoic acid at 65 DEG C to 70 DEG C, a reaction product is cooled to -5 DEG C to 5 DEG C for crystallization, filtering and drying are conducted, and alogliptin is obtained.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to the preparation method of a kind of Egelieting for treating type ii diabetes.
Background technology
Diabetes be a kind of because of internal insulin definitely or a series of clinical syndromes of being caused of relative deficiency.At present, glycosuria
Sick treatment is mainly diet control and coordinates hypoglycemic medicine (to type ii diabetes) or insulin to supplement the treatment diabetes that combine.
" diabetes mellitus in China prevalence " report display issued according to U.S.'s " new Scotland medical journal ", diabetes mellitus in China patient is up to
10%, the most every 10 adults just there is an entitled diabetics.And potential diabetes prevalence is more up to 15.5%.Statistics
Data show, the Direct medical cost of inland city type ii diabetes patient and complication thereof accounts for whole nation health care total cost 4%,
Being about 19,000,000,000 yuans, and these data are also persistently riseing, the most most of diabeticss are type ii diabetes.II type
Diabetics can not normally be secreted or the insulin of response regulation blood glucose.Long-time hyperglycemia can increase patient and serious combining occurs
Close the risk of disease, including heart disease, blind, neural and injury of kidney.
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, do not find other diabetes medicaments simultaneously
The untoward reaction such as produced common body weight increase and blood sugar lowering.
At present, the synthetic route of Egelieting is a lot, but is problematic in that, affects its industrialized production.Such as CN1926128A
Disclosing the preparation method of a kind of Egelieting, the method is with 6-chlorouracil as initiation material, at sodium hydride and the work of lithium bromide
With lower and 2-bromomethyl benzonitrile generation alkylation, under the effect of sodium hydride, then obtain 2-(6-chloro-3-methyl-2,4-with iodomethane reaction
Dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile two step yield is all at about 50-70%.The most in the basic conditions with (R)
-3-amino piperidine dihydrochloride generation substitution reaction obtains Egelieting free alkali, and Egelieting free alkali becomes salt to prepare with benzoic acid
SYR-322.Although the method can successfully prepare Egelieting, but alkylation in the method, the multistep that methylates are used
Having arrived sodium hydride, system condition requires extremely strict, and the use of sodium hydride can destroy the stability of raw material, and part material is phonetic
Pyridine ring destroys, and reduces yield, and total recovery only has about 20%.Be not suitable for large-scale commercial production.
CN102361557A discloses the preparation method of a kind of Egelieting, and the method employing 1-(2-isocyanide benzyl)-3-MU is
Raw material and diethyl malonate carry out annulation, mild condition, yield is medium, it is to avoid it is severe to carry out nucleophilic conditions with sodium hydride
Carve the defects such as yield is relatively low.But in follow-up chlorination process, owing to the method uses the phosphoryl chloride phosphorus oxychloride of routine, phosphorus oxychloride etc. quick
Sense reagent, requires the harshest to moisture, air etc., and yield is relatively low, and the method produces a large amount of three wastes, is unfavorable for ring
Border is protected.
Therefore, this area still need that a kind of method is simple badly, mild condition and the method for the high preparation Egelieting of yield.
Summary of the invention
It is an object of the invention to overcome the defect that method conditional is harsh, product yield is low of existing preparation Egelieting, carry
Supply a kind of applicable industrial-scale production and yield is high, the method for the preparation Egelieting of mild condition.
The present inventor has been surprisingly found that under study for action, combines bivalence palladium salt and N-chlorosuccinimide as chlorination reagent,
It is particularly suitable for the chloro of heterocycle hydroxyl, mild condition and substantially increase the chlorination yield of heterocycle hydroxyl.As in key
Mesosome chloride (the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone) yield reaches more than 96, and can
To be directly used in subsequent reactions, thus improve overall yield prepared by Egelieting.
To achieve these goals, the present invention provides the preparation method of a kind of Egelieting for treating type ii diabetes, the party
Method comprises the following steps:
1) by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketone and bivalence palladium salt, N-chlorosuccinimide
Carrying out haptoreaction, after reaction terminates, be poured in frozen water by reactant liquor, dichloromethane extracts, and saturated aqueous common salt washs, anhydrous
Sodium sulfate is dried, and is concentrated to give 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.
In the present invention, although bivalence palladium salt and N-chlorosuccinimide are combined realizing chlorination under temperate condition,
In order to improve the yield of chlorination further, under preferable case, in step 1) in, 1-(2-isocyanide benzyl)-3-methylpyrimidine
-2,4,6-(1H, 3H, 5H)-triketones are 1:0.05～0.15:1.2～2 with bivalence palladium salt, the mol ratio of N-chlorosuccinimide.
In the case of Jin Yibuyouxuan, in step 1) in, 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones with
Bivalence palladium salt, the mol ratio of N-chlorosuccinimide are 1:0.1～0.15:1.5～1.8.
In order to improve the efficiency of chlorination further, under preferable case, in step 1) in, described catalytic temperature is 65～85 DEG C；
More preferably 80～85 DEG C.For step 1) catalytic solvent be not particularly limited, such as Isosorbide-5-Nitrae-dioxane
Deng.
Under preferable case, described bivalence palladium salt is Palladous chloride., palladium or palladium sulfate.Under preferable case, described bivalence palladium salt is
Palladous chloride..
In step 2) in, under preferable case, the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone is thick with (R)-3-
T-butyloxycarbonyl amino piperidine, the mol ratio of potassium carbonate are 1:1～1.2:2.2～3.
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.
Under preferable case, described step 1) carry out in the presence of protective gas, described protective gas is nitrogen, helium or argon.
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, mild condition, particularly crucial
Chlorinating step, reduces the destruction to pyrimidine ring, and yield is greatly improved, and solves the defect that prior art reaction is slow,
The yield of Egelieting is greatly improved.
For the technique effect acquired by the present invention, inventor guesses that this is owing to palladium has unfilled 4d track, easy and alkene
The coordination of alcohol of formula double bond and activated hydroxyl groups, weaken double bond so that chlorine atom is easier to attack hydroxyl carbon atom, also makes simultaneously
Hydroxyl after activation is more easy to leave away, thus can complete chlorination under relatively temperate condition.
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 Egelieting, the method comprises the following steps:
1) under nitrogen protection, by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones 25.7g (100mmol)
Enter in 200ml1,4-dioxane with Palladous chloride. 2.7g (15mmol), N-chlorosuccinimide 24.0g (180mmol)
Row haptoreaction 1.5 hours, haptoreaction is carried out at 80 DEG C.After the completion of reaction, reactant liquor is poured in frozen water, dichloro
Methane extracts, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone 27.3g, yield is 98.9%, purity 98.63%.
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,
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 21.6g, yield is 98.2%, pure
Degree 99.20%.
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-5～5 DEG C of crystallizes, mistake
Being filtered dry dry Egelieting, yield is 95.6%, purity 99.79% (HPLC area normalization method).
Embodiment 2
A kind of method preparing Egelieting, the method comprises the following steps:
1) under nitrogen protection, by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones 25.7g (100mmol)
Enter in 200ml1,4-dioxane with Palladous chloride. 1.8g (10mmol), N-chlorosuccinimide 21.4g (160mmol)
Row haptoreaction 1.5 hours, haptoreaction is carried out at 80 DEG C.After the completion of reaction, reactant liquor is poured in frozen water, dichloro
Methane extracts, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone (27.0g, yield is 98.1%, purity 97.94%).
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,
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%, pure
Degree 98.79%.
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-5～5 DEG C of crystallizes, mistake
Being filtered dry dry Egelieting, yield is 95.2%, purity 99.82% (HPLC area normalization method).
Embodiment 3
A kind of method preparing Egelieting, the method comprises the following steps:
1) under nitrogen protection, by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones 25.7g (100mmol)
Enter in 200ml1,4-dioxane with palladium 2.7g (15mmol), N-chlorosuccinimide 20.0g (150mmol)
Row haptoreaction 2.5 hours, haptoreaction is carried out at 85 DEG C.After the completion of reaction, reactant liquor is poured in frozen water, dichloro
Methane extracts, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone (27.0g, yield is 97.9%, purity 98.23%).
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,
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 21.4g, yield is 97.5%, pure
Degree 98.85%.
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-5～5 DEG C of crystallizes, mistake
Being filtered dry dry Egelieting, yield is 96.7%, purity 99.78% (HPLC area normalization method).
Embodiment 4
A kind of method preparing Egelieting, the method comprises the following steps:
1) under nitrogen protection, by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones 25.7g (100mmol)
Enter in 200ml1,4-dioxane with palladium sulfate 0.9g (5mmol), N-chlorosuccinimide 26.7g (200mmol)
Row haptoreaction 4.5 hours, haptoreaction is carried out at 75 DEG C.After the completion of reaction, reactant liquor is poured in frozen water, dichloro
Methane extracts, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone (25.0g, yield is 90.7%, purity 97.29%).
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,
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 91.7%, pure
Degree 97.36%.
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-5～5 DEG C of crystallizes, mistake
Being filtered dry dry Egelieting, yield is 95.0%, purity 99.91% (HPLC area normalization method).
Embodiment 5
A kind of method preparing Egelieting, the method comprises the following steps:
1) under nitrogen protection, by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones 25.7g (100mmol)
Enter in 200ml1,4-dioxane with Palladous chloride. 0.9g (5mmol), N-chlorosuccinimide 16.0g (120mmol)
Row haptoreaction 2 hours, haptoreaction is carried out at 65 DEG C.After the completion of reaction, reactant liquor is poured in frozen water, dichloromethane
Alkane extracts, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and concentrates, and washing is dried to obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-
Methylpyrimidine-2,4-(1H, 3H)-diketone (25.2g, yield is 91.4%, purity 98.11%).
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,
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 20.4g, yield is 92.7%, pure
Degree 98.50%.
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-5～5 DEG C of crystallizes, mistake
Being filtered dry dry Egelieting, yield is 94.8%, purity 99.76% (HPLC area normalization method).
Embodiment 6
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, the consumption of Palladous chloride. is 0.2g
(1mmol), obtaining the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 19.9g, yield is 72.4%, purity
97.11% (HPLC area normalization method).
Embodiment 7
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, the use of N-chlorosuccinimide
Amount is 40.1g (300mmol), obtains the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 26.7g, and yield is
96.7%, purity 95.79% (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 Palladous chloride., obtain 6-chlorine
-1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 10.1g, yield is 36.7%, purity 89.21% (HPLC area
Normalization method).
Comparative example 2
Such as the preparation method of the Egelieting in embodiment 1, except that, step 1) in, N-chlorosuccinimide is changed
Becoming the phosphoryl chloride phosphorus oxychloride of equimolar amounts, obtain the chloro-1-of 6-(2-isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 14.8g, yield is
53.7%, purity 84.91% (HPLC area normalization method).
Comparative example 3
Such as the preparation method of the Egelieting in CN102361557A embodiment 1, by POCl3(210ml) 1-(the 2-isocyanide benzyl in
Base)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketones 25.7g (100mmol) reflux 1-3 hour, by this solvent concentration and with two
Chloromethanes (700ml) and water (700ml) are separately.Organic layer is washed, at Na with strong brine2SO4Above it is dried and is concentrated to give 6-chloro-1-(2-
Isocyanide benzyl)-3-methylpyrimidine-2,4-(1H, 3H)-diketone 19.4g, yield is 70.4%, purity 86.47% (HPLC area normalization
Method).
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 (9)
1. the preparation method being used for treating the Egelieting of type ii diabetes, it is characterised in that this preparation method includes following step
Rapid:
1) by 1-(2-isocyanide benzyl)-3-methylpyrimidine-2,4,6-(1H, 3H, 5H)-triketone and bivalence palladium salt, N-chlorosuccinimide
Carrying out haptoreaction, after reaction terminates, be poured in frozen water by reactant liquor, dichloromethane extracts, and saturated aqueous common salt washs, anhydrous
Sodium sulfate is dried, and is concentrated to give 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.
Preparation method the most according to claim 1, it is characterised in that in step 1) in, 1-(2-isocyanide benzyl)-3-first
Yl pyrimidines-2,4,6-(1H, 3H, 5H)-triketones are 1:0.05～0.15 with bivalence palladium salt, the mol ratio of N-chlorosuccinimide:
1.2～2.
Preparation method the most according to claim 2, it is characterised in that in step 1) in, 1-(2-isocyanide benzyl)-3-first
Yl pyrimidines-2,4,6-(1H, 3H, 5H)-triketones are 1:0.1～0.15 with bivalence palladium salt, the mol ratio of N-chlorosuccinimide:
1.5～1.8.
Preparation method the most according to claim 1, it is characterised in that in step 1) in, described catalytic temperature is
65～85 DEG C.
Preparation method the most according to claim 4, it is characterised in that in step 1) in, described catalytic temperature is
80～85 DEG C.
6. according to the preparation method described in claim 1-3, it is characterised in that described bivalence palladium salt is Palladous chloride., palladium or sulfur
Acid palladium.
7. according to the preparation method described in any one in claim 6, it is characterised in that described bivalence palladium salt is Palladous chloride..
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.
Preparation method the most according to claim 1, it is characterised in that step 1) haptoreaction protective gas exist
Under carry out, described protective gas is nitrogen, helium or argon.
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