CN103664801A - Method of preparing Alogliptin - Google Patents

Method of preparing Alogliptin Download PDF

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CN103664801A
CN103664801A CN201210313836.8A CN201210313836A CN103664801A CN 103664801 A CN103664801 A CN 103664801A CN 201210313836 A CN201210313836 A CN 201210313836A CN 103664801 A CN103664801 A CN 103664801A
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formula
compound
thf
tetrahydrofuran
reaction
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Inventor
邹春兰
邓杰
张强
谢守全
王学瑞
蔡中文
叶文润
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Chongqing Pharmaceutical Research Institute Co Ltd
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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
    • 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to Alogliptin, benzoate thereof and a preparation method of an intermediate of the Alogliptin. The method comprises the following steps: alkylating 6-chlorouracil by using 2-(bromomethyl)benzonitrile on the basis of a tetrahydrofuran solvent and the catalysis of alkali to generate N-benzyluracil derivatives, and further alkylating by using methanol through a Mitsunobu reaction to obtain 1,3-disubstituted uracil (intermediate). The method does not need a NaH risk agent and highly toxic agent methyl iodide in the prior art, and is safe and environment-friendly.

Description

A kind of method of preparing Egelieting
Invention field
The invention belongs to pharmaceutical chemistry field, be specifically related to the preparation method of Egelieting and benzoate thereof and its intermediate.
Background technology
SYR-322 (alogliptin benzoate) is to be developed by Japanese Wu Tian company, and in a kind of dipeptidyl peptidase-IV (DPP-IV) inhibitor of in September, 2011 listing, is used for the treatment of type II diabetes.SYR-322 chemical name 2-[[6-[(3R)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] cyanobenzene benzoate.
Diabetes affects whole world millions of people, is considered to one of chief threat of 21 century mankind death.In 2006, the World Health Organization (WHO) estimated that the whole world has 1.8 hundred million people of surpassing to suffer from diabetes, and this numeral is predicted can be doubled to the year two thousand thirty.Along with time lapse, not controlled diabetes can be damaged body system, comprise heart, blood vessel, eye, kidney and nerve.According to WHO statistics, 1,100,000 people that have an appointment for 2005 die from diabetes, and in future 10 years, the relevant death of diabetes can increase and surpasses 50%.Diabetes have I type and two kinds of main Types of II type, and wherein type II diabetes accounts for 90% of all diabetes in the whole world.Insulin-dependent diabetes mellitus (IDDM) is characterized as insulin deficit, and the beta Cell of islet mainly being mediated by autoimmunization destroys and causes; Type II diabetes is characterized as insulopathic and consequent insulin resistant.By β cell function, weakening the insulin resistant causing is the main challenge of controlling in type II diabetes with the hypoglycemia running down.Evidence demonstration, the patient of insulin resistant can not developed hypoglycemia before its β cell can not produce enough Regular Insulin.Therefore, the new medicament that can strengthen beta Cell of islet excreting insulin in continuable dependence on the glucose mode has the hope for the treatment of type II diabetes.
DPP-IV is rear proline dipeptides aminopeptidase, belongs to proteolytic enzyme S9b peptide enzyme family.Known DPP-IV is by controlling glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic polypeptide (GIP, claim again CIP) incretin active, thereby control emiocytosis Regular Insulin, in maintaining glucose homeostasis, play a key effect.Therefore, suppress DPP-IV and be considered to the treatment approach that type II diabetes is new.
Recently, people have developed a series of DPP-IV inhibitor, and SYR-322 in this compounds (alogliptin benzoate) and analogue thereof demonstrate challenging anti-diabetic effect (WO2005/095381).
CN102134231(WO2005/095381) disclose the preparation method of SYR-322, its reaction scheme is as follows:
According to the method, under DMF and the mixed solvent of methyl-sulphoxide (DMF-DMSO) and the catalysis of NaH and LiBr, 2-cyano-benzyl bromide, by the alkylation of 6-chlorouracil, produces N-benzyluracils derivative, and yield is 54%.With methyl iodide and NaH, further methylate and obtain 1,3-, bis-substituted uracils in DMF and tetrahydrofuran (THF) (DMF-THF) mixed solvent, yield is 72%.Then at NaHCO 3under existing with 4A molecular sieve, in methyl alcohol, reflux, by (R)-3-amino-piperadine dihydrochloride, replaced to obtain Egelieting.Egelieting is processed with phenylformic acid, and the preparation of carrying out SYR-322 by the ordinary method of sour salify is with separated.The total recovery of this scheme is 20%～25%.One of them shortcoming of aforesaid method is that methyl iodide is the poisonous reagent of national management and control, and price is higher; Second shortcoming is to use high boiling mixed solvent DMF and methyl-sulphoxide (DMF-DMSO), causes aftertreatment difficulty and is difficult to separated and these mixed solvents of purifying for recycling, is unfavorable for suitability for industrialized production; The 3rd shortcoming is to use for example NaH of Hazardous substances, and these need anhydrous solvent as reaction medium, are difficult to industrial applications; The 4th shortcoming is to take methyl alcohol as solvent during with the substitution reaction of (R)-3-amino-piperadine dihydrochloride, increased the risk of methoxy substitution, and by product is increased.
CN101360723(WO2007/035629) also disclose a kind of synthetic method of SYR-322, its reaction scheme is as follows:
Figure 852699DEST_PATH_IMAGE003
It is raw material that the method be take the chloro-3-6-Methyl Uracil of 6-, N-Methyl pyrrolidone (NMP) is solvent, under diisopropyl ethyl amine (DIPEA) effect, obtain 1 with 2-cyano-benzyl bromide reacting by heating, 3-bis-substituted uracils, then in isopropanol-water, there is substitution reaction with (R)-3-amino-piperadine dihydrochloride and obtain Egelieting, finally become benzoate.Although the method has reduced single step reaction compared with the disclosed method of CN102134231, avoided the poor problem of the first step reaction preference in CN102134231 method, but total recovery is general (50%～55%) still, and also there is the high boiling solvent NMP of mixing and mixed solvent NMP-DIPEA Separation and Recovery problem in the method.
CN102361557(WO2010/109468) in, MAPI pharmaceuticals discloses two kinds of methods of synthetic Egelieting benzoate, and its synthetic route is as follows, sees reaction circuit 1 and reaction circuit 2:
Figure 632436DEST_PATH_IMAGE004
Reaction circuit 1
It is raw material that the method be take 2-cyano group benzyl amine hydrochlorate, through three-step reaction, builds 1,3-, bis-substituted uracils, three step total recoverys 19%～50%.Shortcoming: reaction circuit is longer, and starting raw material price is more expensive, and has used the poisonous reagents such as phosphorus oxychloride, there is no cost advantage.
Figure 978710DEST_PATH_IMAGE005
Reaction circuit 2
The method first two steps yield 51%～54%, reacts all improvement of circuit 1, but also without explicit costs advantage.
In foregoing prior art, or used high boiling solvent as DMF, methyl-sulphoxide, N-Methyl pyrrolidone and used Hazardous substances NaH etc., being unfavorable for suitability for industrialized production; Or use poisonous reagent methyl iodide and phosphorus oxychloride, increased environmental protection pressure; Or be exactly raw material costliness, and route is long, has increased cost.Obviously, there is significant limitation in existing synthetic method.
Summary of the invention
One of object of the present invention is to provide the preparation method of a kind of Egelieting intermediate (formula IV compound), the method substitutes methyl iodide with methyl alcohol, got rid of Toxic methyl iodide and Hazardous substances NaH, technological operation simplification, more environmental protection, purity is high, yield good, cost is low.
For realizing object of the present invention, provide following embodiment.
In one embodiment, a kind of method of preparation formula IV compound, comprising: formula V compound Mitsunobu occurs in organic solvent with methyl alcohol and reacts, and obtains formula IV compound,
Figure 730766DEST_PATH_IMAGE006
。
In above-mentioned embodiment, the method for preparation formula IV compound of the present invention, described organic solvent is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferred tetrahydrofuran (THF), described Mitsunobu reaction, wherein, reductive agent is trialkyl phosphine, triphenylphosphine; Oxygenant is selected from diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), Cellmic C 121 (TMAD) and tert-butyl azodicarboxylate (DBAD), preferred diisopropyl azodiformate (DIAD), wherein, the mol ratio of described reductive agent or oxygenant and formula V compound is more than or equal to 1.5.
In above-mentioned embodiment, the method for preparation formula IV compound of the present invention, further comprises the preparation of described formula V compound, comprise: by 6-chlorouracil (VII) and aryl halide (VI), under the existence of alkali, in solvent, reaction obtains compound V, wherein, Hal is Br, Cl or I, is preferably Br
Figure 553228DEST_PATH_IMAGE007
，
Wherein, described alkali is triethylamine or diisopropyl ethyl amine (DIPEA), preferred DIPEA, and described solvent is 2-methyltetrahydrofuran or tetrahydrofuran (THF), preferably tetrahydrofuran (THF).
Another object of the present invention, the 2-[[6-[(3R of a kind of preparation formula II is provided)-3-amino-piperidino]-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidyl] methyl] method of cyanobenzene benzene (Egelieting) or its salt, comprising:
A) there is Mitsunobu and react in formula V compound in organic solvent with methyl alcohol, obtain formula IV compound;
B) the formula IV compound upper step being obtained reacts with (R)-3-amino-piperadine dihydrochloride of formula III the Egelieting that obtains formula II in solvent,
Figure 940533DEST_PATH_IMAGE009
;
C) optional, Egelieting is further obtained to Egelieting benzoate (I) with phenylformic acid salify.
The method of preparing Egelieting of the invention described above, step a) in, described organic solvent is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferred tetrahydrofuran (THF), described Mitsunobu reaction, wherein, reductive agent is trialkyl phosphine, triphenylphosphine; Oxygenant is selected from diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), Cellmic C 121 (TMAD) and tert-butyl azodicarboxylate (DBAD), preferred diisopropyl azodiformate (DIAD), wherein, the mol ratio of described reductive agent or oxygenant and formula V compound is more than or equal to 1.5; Step b), in, described solvent is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferred acetonitrile, and described alkali is Quilonum Retard, lithium bicarbonate, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood or their mixture.
The method of preparing Egelieting of the invention described above, step a) in, described formula V compound can be prepared by following method, the method comprises: by 6-chlorouracil (VII) and aryl halide (VI) under the existence of alkali, in solvent, reaction obtains compound V, and wherein, Hal is Br, Cl or I, be preferably Br
Figure 812674DEST_PATH_IMAGE010
，
Wherein said alkali is triethylamine or diisopropyl ethyl amine (DIPEA), preferred DIPEA, and described solvent is 2-methyltetrahydrofuran or tetrahydrofuran (THF), preferably tetrahydrofuran (THF).
In one embodiment, a kind of method of preparing Egelieting (II) or its salt (I), comprises the following steps:
　
II　　　　　　　　　　　　I
A) 6-chlorouracil (VII) is reacted and obtains compound V with aryl halide (VI) in solvent under the existence of alkali, wherein Hal is Br, Cl or I, is preferably Br;
Figure 248783DEST_PATH_IMAGE012
B) in organic solvent, be there is to Mitsunobu with methyl alcohol in formula V compound and react, obtain formula IV compound;
C) the formula IV compound upper step being obtained reacts with (R)-3-amino-piperadine dihydrochloride (III) of formula III the Egelieting that obtains formula II in solvent;
;
D) optional, Egelieting is further obtained to Egelieting benzoate (I) with phenylformic acid salify.
In above-mentioned specific embodiments, the method for preparing Egelieting of the present invention, step a) in; described alkali is triethylamine or diisopropyl ethyl amine (DIPEA); preferred DIPEA, described solvent is 2-methyltetrahydrofuran or tetrahydrofuran (THF), preferably tetrahydrofuran (THF); Step b), in, described organic solvent is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferred tetrahydrofuran (THF), and described Mitsunobu reaction, wherein, reductive agent is trialkyl phosphine, triphenylphosphine; Oxygenant is selected from one or more in diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), Cellmic C 121 (TMAD) and tert-butyl azodicarboxylate (DBAD), preferred diisopropyl azodiformate (DIAD), wherein, the mol ratio of reductive agent or oxygenant and formula V compound is more than or equal to 1.5; Step c), in, described solvent is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferred acetonitrile, and described alkali is Quilonum Retard, lithium bicarbonate, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood or their mixture.
The method of preparing Egelieting (II) or its salt (I) of the invention described above, step reaction a) does not have special requirement to temperature of reaction, but rising temperature can improve speed of response, Reaction time shorten, and therefore, preferably room temperature is to reflux temperature; Step b) reaction does not have particular requirement to temperature yet, and temperature is little on speed of response impact, therefore, and preferred room temperature reaction.
The operational path of aforesaid method is expressed as follows:
Figure 611128DEST_PATH_IMAGE015
The method of preparing Egelieting of the present invention, preferably includes: a) 6-chlorouracil and 2-cyano-benzyl bromide are in tetrahydrofuran (THF) (THF) solvent, and the diisopropyl ethyl amine (DIPEA) of usining carries out substitution reaction as catalyzer, obtains formula V compound, b) by formula V compound and methylating reagent methyl alcohol under the existence of reductive agent and oxygenant, in solvents tetrahydrofurane, carry out methylation reaction (Mitsunobu reaction), production IV compound, wherein, reductive agent is triphenylphosphine, oxygenant is that azoformic acid diester can be diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), Cellmic C 121 (TMAD) or tert-butyl azodicarboxylate (DBAD), preferred DIAD, wherein, triphenylphosphine, DEAD, DIAD, the mol ratio of TMAD or DBAD and formula V compound is more than or equal to 1.5, c) compounds Ⅳ is reacted and generates II formula compound (Egelieting) with (R)-3-amino-piperadine dihydrochloride in solvent acetonitrile under the katalysis of alkali, wherein, alkali is selected from sodium bicarbonate, sodium carbonate and their mixture, d) optional, formula II compound and phenylformic acid salify are obtained to Egelieting benzoate.
Synthetic method provided by the invention, main advantage: be first the introducing because of Mitsunobu reaction, make this reaction conditions gentle, simple to operate, yield improves a lot compared with the yield of prior art, and avoided the use of poisonous reagent methyl iodide, be beneficial to environmental protection; Next is the substitution reaction of 6-chlorouracil and 2-cyano-benzyl bromide, with diisopropyl ethyl amine (DIPEA) and triethylamine, replace NaH, increased selectivity, especially DIPEA can make reaction yield be brought up to more than 70% by 54% of prior art, this external application tetrahydrofuran (THF) replaces N, (mixed solvent is difficult to separating treatment and causes wastewater treatment difficulty dinethylformamide and methyl-sulphoxide (DMF-DMSO) high boiling point mixed solvent, be difficult for reclaiming), simplify the operation, and tetrahydrofuran (THF) can recovery, has alleviated environmental protection pressure when having reduced reagent cost; The 3rd is method of the present invention, and yield obviously improves compared with prior art, and the total recovery of Egelieting benzoate reaches more than 50%.
Mitsunobu reaction is with the Japanese green hill organic chemist of institute, solely to prolong the name reaction of vast sea (Oyo Mitsunobu) professor name, this reaction refers under azodicarboxy acid diesters and trialkyl (virtue) base phosphine exist, the dehydration condensation that alcohol and various front nucleophilic reagent with active hydrogen carry out.In reaction process, azodicarboxy acid diesters is reduced to hydrazine dicarboxylic diester, and trialkyl (virtue) base phosphine is oxidized to oxidation trihydrocarbyl phosphine, so Mitsunobu reaction belongs to redox reaction category.Mitsunobu reaction conditions is gentle, easy to operate, compatible with a lot of functional groups, can build the keys such as C-O, C-N, C-S, C-X, C-C, therefore develop rapidly and become one of conventional organic synthesis, widespread use in medicine, natural product and other biological active compound synthetic.
Starting raw material 6-chlorouracil and 2-cyano-benzyl bromide all have commercially available product, therefore, can buy through commercial sources.
Synthetic method provided by the invention be take commercially available cheap products as starting raw material, has avoided the use of high boiling solvent and high-risk reagent, has simplified operation, has reduced cost, is applicable to industrialized production.
Embodiment
Following embodiment is to describe in detail the present invention, but not limits the scope of the invention.
Embodiment 1 2-(6-is chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) preparation of-benzonitrile (V)
1a) 6-chlorouracil (50g) is suspended in tetrahydrofuran (THF) (300ml), adds N, N-diisopropyl ethyl amine (80ml), drips tetrahydrofuran (THF) (100ml) solution of 2-cyano-benzyl bromide (66.3g) afterwards.20～65 ℃ of stirring reactions of this mixed solution, there are a large amount of solids to separate out, thin-layer chromatography detection reaction is complete, after reacting completely, filter the solid that reaction generates, with tetrahydrofuran (THF) (30ml), wash, solid is poured in 100ml water and stirred 5 minutes afterwards, washing more after filtration,, drying under reduced pressure obtain 2-(6-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile (V) 50g, tetrahydrofuran (THF) mother liquor is before used tetrahydrofuran (THF) recrystallization target product 15g again, total recovery 72.8% after concentrating again.
1b) 6-chlorouracil (2.92g) is suspended in tetrahydrofuran (THF) (30ml), adds triethylamine (3.03g), drip afterwards tetrahydrofuran (THF) (5ml) solution of 2-cyano-benzyl bromide (3.92g).20～65 ℃ of stirring reactions of this mixed solution, there are a large amount of solids to separate out, thin-layer chromatography detection reaction is complete, after reacting completely, filter the solid that reaction generates, with tetrahydrofuran (THF) (10ml), wash, solid is poured in 30ml water and stirred 5 minutes afterwards, washing more after filtration,, drying under reduced pressure obtain 2-(6-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl)-benzonitrile (V) 2.46g, tetrahydrofuran (THF) mother liquor is before used tetrahydrofuran (THF) recrystallization target product 0.66g again, total recovery 60% after concentrating again.
The embodiment chloro-3-of 2 2-(6-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) preparation of benzonitrile (IV)
2a) compound V (5.22g) is suspended in tetrahydrofuran (THF) (40ml), add successively methyl alcohol (3ml), triphenylphosphine (7.77g), under room temperature, in reaction solution, drip diisopropyl azodiformate (6.02g), mixed solution reacts 3 hours under room temperature, and thin-layer chromatography detection reaction is complete.By reaction solution concentrating under reduced pressure, resistates obtains the chloro-3-of 2-(6-methyl-2 with the mixing solutions recrystallization of methyl alcohol and methyl tertiary butyl ether, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) benzonitrile (IV) 4g, mother liquor concentrated by silica gel column chromatography (take petroleum ether-ethyl acetate carry out gradient elution for elutriant) again target product 1.2g, overall yield of reaction 94.5%.
2b) compound V (2.62g) is suspended in tetrahydrofuran (THF) (30ml), add successively methyl alcohol (2ml), triphenylphosphine (5.24g), under room temperature, in reaction solution, drip diethyl azodiformate (3.48g), mixed solution was in 20～65 ℃ of reactions 2 hours, and thin-layer chromatography detection reaction is complete.By reaction solution concentrating under reduced pressure, resistates obtains the chloro-3-of 2-(6-methyl-2 by re-crystallizing in ethyl acetate, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) benzonitrile (IV) 4g, yield 78.5%.
2c) compound V (5.22g) is suspended in tetrahydrofuran (THF) (40ml), add successively methyl alcohol (3ml), triphenylphosphine (10.36g), under room temperature, in reaction solution, drip diisopropyl azodiformate (8.03g), mixed solution reacts 3 hours under room temperature, and thin-layer chromatography detection reaction is complete.By reaction solution concentrating under reduced pressure, resistates obtains the chloro-3-of 2-(6-methyl-2 with the mixing solutions recrystallization of methyl alcohol and methyl tertiary butyl ether, 4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl) benzonitrile (IV) 4g, mother liquor is concentrated obtains target product 1.0g, overall yield of reaction 90.9% again by silica gel column chromatography.
Embodiment 3 2-{ 6-[3(R)-amino-piperadine-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl } preparation of-benzonitrile benzoate (I)
3a) compounds Ⅳ (5.2g), sodium bicarbonate (4.2g) and (R)-3-amino-piperadine dihydrochloride (3.48g) are suspended in acetonitrile (200ml), back flow reaction 14 hours, thin-layer chromatography detection reaction is complete, reaction solution is down to room temperature, removes by filter most of sodium bicarbonate, mother liquor is concentrated, resistates dissolves with methylene dichloride, washing, anhydrous sodium sulfate drying half hour, removes by filter sodium sulfate.In filtrate, add phenylformic acid (4g), stirring at room reaction 2 hours, concentrating under reduced pressure, a small amount of dissolve with methanol of resistates, adds ether or methyl tertiary butyl ether to make to separate out off-white color solid afterwards.Such white solid leaches and with acetonitrile recrystallization, obtains 2-{ 6-[3(R afterwards)-amino-piperadine-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl }-benzonitrile benzoate (I) 6.5g(white solid, HPLC purity 99.13%, yield 74.7%)
3b) compounds Ⅳ (5.5g), sodium carbonate (3.18g) and (R)-3-amino-piperadine dihydrochloride (4.02g) are suspended in acetonitrile (200ml), back flow reaction, thin-layer chromatography detection reaction is complete, reaction solution is down to room temperature, removes by filter most of sodium carbonate, mother liquor is concentrated, resistates dissolves with methylene dichloride, washing, anhydrous sodium sulfate drying half hour, removes by filter sodium sulfate.In filtrate, add phenylformic acid (4.5g), stirring at room reaction 2 hours, concentrating under reduced pressure, a small amount of dissolve with methanol of resistates, adds ether or methyl tertiary butyl ether to make to separate out off-white color solid afterwards.Such white solid leaches and with acetonitrile recrystallization, obtains 2-{ 6-[3(R afterwards)-amino-piperadine-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl }-benzonitrile benzoate (I) 6.4g(white solid, HPLC purity 99.05%, yield 70%).

Claims (10)

1. a method for preparation formula IV compound, comprising: compound V and methyl alcohol, under reductive agent exists, Mitsunobu reaction occur in organic solvent, obtain formula IV compound
Figure 2012103138368100001DEST_PATH_IMAGE001
。
2. the method for claim 1, described organic solvent is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferably tetrahydrofuran (THF).
3. the method for claim 1, described Mitsunobu reaction, wherein, reductive agent is trialkyl phosphine; Or oxygenant is selected from diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), Cellmic C 121 (TMAD) and tert-butyl azodicarboxylate (DBAD), preferred diisopropyl azodiformate (DIAD).
4. method as claimed in claim 3, described trialkyl phosphine is triphenylphosphine.
5. the method for claim 1, further comprises the preparation of described formula V compound, comprising: by 6-chlorouracil (VII) and aryl halide (VI), under the existence of alkali, in solvent, reaction obtains compound V, and wherein Hal is Br, Cl or I
Figure 671948DEST_PATH_IMAGE002
。
6. method as claimed in claim 5, described alkali is triethylamine or diisopropyl ethyl amine, preferably diisopropyl ethyl amine.
7. method as claimed in claim 5, described solvent is 2-methyltetrahydrofuran or tetrahydrofuran (THF), preferably tetrahydrofuran (THF).
8. preparation formula II (Egelieting) or a method for its salt, comprising:
Figure 2012103138368100001DEST_PATH_IMAGE003
Figure 278510DEST_PATH_IMAGE004
II
A) the formula IV compound of the arbitrary gained of claim 1-7 is reacted to the Egelieting that obtains formula II with (R)-3-amino-piperadine dihydrochloride (III) of formula III in solvent,
Figure 2012103138368100001DEST_PATH_IMAGE005
;
B) optional, Egelieting and phenylformic acid salify are obtained to the Egelieting benzoate of formula I.
9. method as claimed in claim 8, described step solvent a) is acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran or dioxane, preferably acetonitrile.
10. method as claimed in claim 8, described alkali is Quilonum Retard, lithium bicarbonate, sodium bicarbonate, sodium carbonate, saleratus, salt of wormwood or their mixture.
CN201210313836.8A 2012-08-30 2012-08-30 Method of preparing Alogliptin Pending CN103664801A (en)

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