CN103848817B - The iodo method for making of depeptidyl peptidase inhibitors, chloro, iodo intermediate and method for making - Google Patents

The iodo method for making of depeptidyl peptidase inhibitors, chloro, iodo intermediate and method for making Download PDF

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CN103848817B
CN103848817B CN201210508645.7A CN201210508645A CN103848817B CN 103848817 B CN103848817 B CN 103848817B CN 201210508645 A CN201210508645 A CN 201210508645A CN 103848817 B CN103848817 B CN 103848817B
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CN103848817A (en
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钟朝斌
王学超
杜勇华
张斌
朱学军
肖桂平
李伯刚
姬建新
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Chengdu Diao Pharmaceutical Group Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The present invention provides the iodo method for making of a kind of depeptidyl peptidase inhibitors, chloro, iodo intermediate and method for making.The present invention is by making intermediate chlorinated compound through iodide reaction in organic solvent, then pass through iodo compound and prepare compound and salt thereof that Formulas I represents as depeptidyl peptidase inhibitors, wherein, R1 is aryl, heteroaryl and alkyl, or being replaced alkyl or the aryl of alkoxyl replacement, heteroaryl and alkyl that base carbon number is C1-C8, X is carbon number is the alkylidene of C1-C8.The method of the present invention with in the past by compared with bromo compound obtains the compound method that Formulas I represents, productivity being greatly improved, and does not need to carry out column chromatography purification, thus being conducive to industrialization to synthesize.

Description

The iodo method for making of depeptidyl peptidase inhibitors, chloro, iodo intermediate and method for making
Technical field
The preparation method that the present invention relates to a kind of dipeptidyl peptidase-4 inhibitors; inhibitor (s)-1-(2-(2-(3-(3 particularly to dipeptidyl peptidase-4 (DPP-IV); 4-Dimethoxyphenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group) preparation method of-2-Cyanopyrolidine (formula 1) and pharmaceutically-acceptable salts, the invention still further relates to for preparing the intermediate chloro of this inhibitor, iodoimidazole alkane derivatives and their preparation method.
Background technology
Dipeptidyl peptidase-4 (DPP-IV) physiological action in vivo mainly has following 2 points: immunoregulation effect and blood glucose regulation effect.In immunomodulating, Fischer344/CRJ mouse, with the DPP-IV variant enzyme of inactivation, shows in ovalbumin immunity and looks CD4+T lymphopenia, similarly, the T lymphocyte changes in distribution of the mouse display spleen that CD26 removes, and reduce the CD4+NKT lymphocyte in circulation.In the mouse serum carrying out immunity inoculation, the aggregate level of its IgG, IgG1, IgG2a, and IgE reduces.And it is attended by the minimizing that IL-4 and IL-2 generates, the region between the heart and the diaphragm also delaying IFN-β.In blood glucose regulation, Genetic evidence also supports DPP-IV basic role in Regulation of blood glucose.The display of Fiscder344/CRJ mouse increases GLP-1 level and reduces the deviation of glyceride.Similarly, improve glucose tolerance then showing with the mouse of the targeted inactivation with DPP-IV gene, improve GLP-1, GIP and insulin level, increase the susceptiveness of insulin, decrease the generation of obesity.Before clinic and in clinical research, also can play same effect by DPP-IV inhibitor.In the research scheduling to last 4-52 week, the suppression of the DPP-IV activity of type ii diabetes patient can reduce the level of HbA1C, and hinders body weight to increase, and β cell function strengthens, the suppression of blood plasma pancreas hyperglycemia.
Due to the market prospect that the characteristic that DPP-IV selective depressant is excellent is wide with diabetes, promote global Ge great drugmaker and the researcher exploitation dynamics to it.Up to the present substantial amounts of DPP-IV selective depressant is also had to be in the news.Because DPP-IV can be hydrolyzed sweet-dried meat two peptide prod of generation, many substrate analogues (such as first generation inhibitor DPP-NVP-728 and P32/98) based on sweet-dried meat dipeptides in research and development in early days, development along with high flux screening, it is found that multiple micromolecular lead compound, then carries out structure of modification and obtain the DPP-IV selective depressant of various structures type.
Existing DPP-IV selective depressant (see following formula) is broadly divided into plan peptides (substrate analogue class) and non-peptides (non-substrate analogue class).
Part DPP-IV inhibitor
Current DPP-IV selective depressant through more than ten years development, the list marketing at home and abroad such as sitagliptin, vildagliptin, alogliptin and saxagliptin, multiple candidate variety are in the II phase and the III phase is clinical, additionally also have the good compound of many activity carrying out clinical or preclinical research.
Inventor describes a series of compounds of construction features shown in following formula and the selective inhibitory to dipeptidyl peptidase-4 thereof in detail in CN200810161373.1 patent application, but, have a lot of restriction during preparation method industrialization in this patent application.
Summary of the invention
Conventional art (CN200810161373.1 Chinese patent application) is prepared the DPP-IV Selective depression immunomodulator compounds of construction features shown in above formula and the preparation method of pharmaceutically acceptable salt thereof, there is the problem that the purification step that productivity is relatively low, the relatively low needs of purity are special carrys out purification.
In order to solve above-mentioned technical problem, the present inventor is after a series of researchs, it is provided that following technical scheme:
First aspect, the preparation method that the present invention provides the compound that a kind of Formulas I represents, wherein, R1For aryl, heteroaryl and alkyl, or being replaced alkyl that base carbon number is C1-C8 or aryl, heteroaryl and alkyl that alkoxyl replaces, X is carbon number is the alkylidene of C1-C8；
Wherein, the method includes following operation:
1) in organic solvent, the chlorinated compound generation iodide reaction that Formula II represents is made to obtain the iodo compound that formula III represents,
2) iodo compound that the salt of the dipeptidase derivant represented by formula 3 and formula III represent is in organic solvent, carries out condensation reaction,
Obtain the compound that Formulas I represents.
The preparation method of foregoing compound, preferably, wherein, described aryl is phenyl or naphthyl, described heteroaryl is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, furyl, thienyl, pyrrole radicals, imidazole radicals, thiazolyl, isothiazolyl, azoles base, isoxazole base, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl, it is preferable that selected from pyridine radicals, furyl, thienyl, thiazolyl, azoles base, benzofuranyl and benzimidazolyl；Described substituent group is carbon number is the alkoxyl of C1-C8；X is carbon number is the alkylidene of C1-C6.
The preparation method of foregoing compound, it is further preferred that wherein, R1For phenyl or naphthyl, or it is replaced alkyl that base carbon number is C1-C8 or the phenyl or naphthyl that alkoxyl replaces；X is methylene or ethylidene or propylidene.
The preparation method of foregoing compound, further it is further preferred that wherein, R1For being replaced the phenyl that the alkoxyl that base carbon number is C1-C8 replaces；X is methylene or ethylidene or propylidene.
The preparation method of foregoing compound, further it is further preferred that wherein, R1For the phenyl replaced by the alkoxyl that two or more carbon numbers are C1-C8；X is methylene or ethylidene or propylidene.
The preparation method of foregoing compound, further it is further preferred that wherein, R1For by alkoxyl that two carbon numbers are C1-C8 respectively at 3,4 phenyl replaced；X is methylene or ethylidene.Wherein, it is most preferred that R1For by two methoxyl groups respectively 3,4 replace phenyl；X is methylene.
Foregoing compounds process for production thereof, further it is further preferred that wherein, operation 1) in, described organic solvent is ketones solvent or esters solvent, it is preferred to anhydrous propanone or methyl acetate；Operation 2) in, described organic solvent is anhydrous acetonitrile, DMF or DMSO；Preferred DMF.
The preparation method of foregoing compound, further it is further preferred that wherein, operation 2) in, the salt of described dipeptidase derivant is trifluoroacetate or hydrochlorate, it is preferable that hydrochlorate.
The preparation method of foregoing compound, further it is further preferred that wherein, operation 2) in, under inorganic base effect, carry out condensation reaction, the preferred sodium carbonate of described inorganic base or potassium carbonate.
The preparation method of foregoing compound, further it is further preferred that wherein, operation 1) at 20-100 DEG C, make the chlorinated compound that Formula II represents carry out iodide reaction with the preferred anhydrous sodium iodide of iodide or potassium iodide；Operation 2) in, at 10-100 DEG C, it is preferable that react at 20-40 DEG C.
Second aspect, the present invention provides the chlorinated compound shown in formula 4
The third aspect, the preparation method that the present invention provides above-mentioned chlorinated compound, it includes following operation: make the compound that formula 8 represents in organic solvent,
Chlorination is occurred to obtain the chlorinated compound shown in formula 4.
The preparation method of foregoing chlorinated compound, wherein, described organic solvent is dichloromethane, N-methylmorpholine, chloroform and/or 1,2-dichloroethanes.
The preparation method of foregoing chlorinated compound, wherein, makes compound and sulfonic acid chloride generation chlorination that formula 8 represents, it is preferable that reaction carries out at 0-10 DEG C；Described sulfonic acid chloride is preferably mesyl chloride.
Fourth aspect, the present invention provides the iodo compound shown in formula 5
5th aspect, the preparation method that the present invention provides the iodo compound shown in above-mentioned formula 5, it includes following operation: in organic solvent, makes the chlorinated compound generation iodide reaction that formula 4 represents obtain the iodo compound that formula 5 represents.
The preparation method of foregoing iodo compound, wherein, makes the chlorinated compound that formula 4 represents occur iodide reaction to obtain the iodo compound of formula 5 expression at 20-100 DEG C with iodide, the preferred anhydrous sodium iodide of described iodide or potassium iodide.
The preparation method of foregoing iodo compound, wherein, described organic solvent is ketones solvent or esters solvent, it is preferred to anhydrous propanone or methyl acetate.
6th aspect, the preparation method that the present invention provides the pharmaceutically acceptable salt of the compound that a kind of Formulas I represents, the compound that Formulas I represents obtains with mineral acid or organic acid reaction, and the compound that wherein Formulas I represents is prepared by the preparation method described in any one of claim 1-10.
The preparation method of the pharmaceutically acceptable salt of foregoing compound, wherein, described organic acid is carboxylic acid or sulfonic acid, it is preferable that carboxylic acid, more preferably acetic acid, oxalic acid, trifluoroacetic acid, citric acid, fumaric acid, benzoic acid, it is most preferred that oxalic acid；Described mineral acid is hydrochloric acid or nitric acid or sulphuric acid or phosphoric acid, it is preferred to hydrochloric acid, oxalic acid.
The method that the present invention prepares, by above-mentioned intermediate chlorinated compound and iodo compound, the compound that Formulas I represents, substantially increases productivity, does not need column chromatography purification, is suitable for industrializing implementation and produces DPP-IV selective depressant.
Detailed description of the invention
The compound of construction features shown in Formulas I in CN200810161373.1 patent application; particularly compound (s)-1-(2-(2-(3-(3; 4-Dimethoxyphenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group) preparation method of-2-Cyanopyrolidine (as shown in Equation 1); mainly; condensation is carried out with bromo-derivative and amino-compound (i.e. dipeptidase derivant); but yield is relatively low; complex operation; finished product needs column chromatography purification, also far from being easy to industrializing implementation.
Present inventor finds through a series of research, and with iodo thing and amino-compound condensation, yield is greatly improved, and easy and simple to handle, is suitable for industrializing implementation.
Specifically, the preparation method of the compound that the Formulas I of the present invention represents,
Wherein, R1For aryl, heteroaryl and alkyl, or being replaced alkyl that base carbon number is C1-C8 or aryl, heteroaryl and alkyl that alkoxyl replaces, X is carbon number is the alkylidene of C1-C8；
Described aryl is preferably phenyl or naphthyl, described heteroaryl is preferably selected from pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, furyl, thienyl, pyrrole radicals, imidazole radicals, thiazolyl, isothiazolyl, azoles base, isoxazole base, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl, is more preferably selected from pyridine radicals, furyl, thienyl, thiazolyl, azoles base, benzofuran and benzimidazolyl；Described substituent group is preferably the alkoxyl that carbon number is C1-C8, and described substituent group can be two or more；X is preferably the alkylidene that carbon number is C1-C6；
Wherein, the method includes following operation:
1) in organic solvent, the chlorinated compound generation iodide reaction that Formula II represents is made to obtain the iodo compound that formula III represents,
2) iodo compound that the salt of the dipeptidase derivant represented by formula 3 and formula III represent
In organic solvent, carry out condensation reaction, obtain the compound that Formulas I represents.
Wherein, operation 1) in, described organic solvent is ketones solvent or esters solvent, it is preferred to anhydrous propanone or methyl acetate；Operation 2) in, described organic solvent is anhydrous acetonitrile, DMF or DMSO；Preferred DMF.
Wherein, operation 2) in, the salt of described dipeptidase derivant is organic acid or inorganic acid salt, and described organic acid is carboxylic acid or sulfonic acid, it is preferable that carboxylic acid, more preferably acetic acid, trifluoroacetic acid, citric acid, fumaric acid, benzoic acid, it is most preferred that trifluoroacetic acid；Described mineral acid is hydrochloric acid or nitric acid or sulphuric acid or phosphoric acid, it is preferable that hydrochloric acid.
Wherein, operation 2) in, under inorganic base effect, carry out condensation reaction, the preferred sodium carbonate of described inorganic base or potassium carbonate.
In the preparation method of a preferred above-claimed cpd, wherein, operation 1) in, at 20-100 DEG C, carry out iodide reaction；Operation 2) in, react at 10-100 DEG C, it is preferable that react at 20-40 DEG C.
Below, the preparation method for the salt of the dipeptidase derivant used in the preparation method of the present invention illustrates as follows.
The salt of dipeptidase derivant and the initiation material preparing dipeptidase derivant salt are all dipeptidase derivants that is commercially available or that easily prepared by those of ordinary skill in the art.In the preparation, solvent for use, and reaction temperature and pressure, initiation material etc. is all that those of ordinary skill in the art can select according to known general knowledge.
As the compound that Formulas I represents, in one preferred embodiment, R1For the phenyl replaced by the alkoxyl that two or more carbon numbers are C1-C8；X is methylene or ethylidene or propylidene.In a particularly preferred embodiment, wherein, R1For by two methoxyl groups respectively 3,4 replace phenyl；X is methylene.
In one preferred embodiment, R1Being 3,4-dipropoxy substituted-phenyls, X is ethylidene or propylidene；
In one preferred embodiment, R1For dialkyl substituted base, X is ethylidene or propylidene；
In one preferred embodiment, R1For dialkoxy substituted naphthyl, X is methylene or ethylidene；
In one preferred embodiment, R1For dialkyl group substituted naphthyl, X is methylene or ethylidene；
In one preferred embodiment, R1For heteroaryl such as pyridine radicals or furyl, X is methylene or ethylidene；
In one preferred embodiment, R1For dialkyl group or dialkoxy substituted heteroaryl such as pyridine radicals or furyl；X is methylene or ethylidene.
Below using most preferred compound (s)-1-(2-(2-(3-(3 of the present invention as DPP-IV selective depressant; 4-Dimethoxyphenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group) preparation method of-2-Cyanopyrolidine (shown in formula 1) and salt (as shown in Equation 6) thereof is example; describe the preparation method of compound and pharmaceutically-acceptable salts thereof shown in the Formulas I of the present invention and the preparation method of intermediate chlorinated compound and iodo compound in detail.
(1) synthesis of the salt of dipeptidase derivant
Organic acid or the inorganic acid salt of this area conventional method synthesis dipeptidase derivant can be adopted, for instance the salt of hydrochloric acid or trifluoroacetic acid.As an example; as shown in following course of reaction; those of ordinary skill in the art can adopt compound (S)-1-(the tertiary fourth oxygen carbon acylamino of 2-) acetyl group-2-Cyanopyrolidine that formula 2 represents in ethyl acetate; in 0 DEG C of ice bath (typical temperature all can react within the scope of 15-30 DEG C); make itself and hydrochloric acid react, prepare the hydrochlorate (formula A) of the dipeptidase derivant that formula 3 represents.
a:HClCH3CO2C2H50℃
Wherein, compound (S)-1-(the tertiary fourth oxygen carbon acylamino of the 2-) acetyl group-2-Cyanopyrolidine represented about formula 2 and the synthetic method of trifluoroacetate thereof; such as, synthesized by following synthetic route described in CN200810161373.1.
That is; with Boc-glycine and proline methyl ester for raw material; with DCC and HOBT condensation; the sweet dried meat methyl ester II of Boc-can be obtained; then the sweet dried meat amide III of Boc-can be obtained with saturated methanol solution aminolysis this ester II of ammonia; this amide III obtains compound IV then through phosphorus oxychloride dehydration, and this compound IV obtains the trifluoroacetate V of dipeptidase derivant again with trifluoroacetic acid Deprotection.
(2) synthesis of chlorinated compound shown in formula 4
a;Triphosgene, C6H6CH3,100-110℃,3-8h;B:NH (CH2CH2OH)2, CH2Cl2, 0-30 DEG C, overnight；C:CH3SO2Cl, NMM, CH2Cl2,0-10℃,2-5h
nullAs shown in course of reaction above，Chlorinated compound shown in formula 4 can be synthesized by following synthetic route: with 3,4-dimethoxyaniline is initiation material，Amine and triphosgene heat to 100-110 DEG C in solvent such as toluene，Reaction 3-8h，Generate 3,4-Dimethylphenyl isocyanate，Without purification，Dihydroxy ethyl urea derivative (shown in formula 8) is generated again with diethanolamine coupling in solvent such as dichloromethane (overnight) (0-30 DEG C of reaction)，In solvent such as NMM and dichloromethane，0-10℃，Ester reaction 2-5h is become through sulfonic acid chloride such as mesyl chloride，Cyclization chloro，One step obtains the chlorinated compound that imidazolidinone derivatives intermediate formula 4 represents，Retrieve through scifinder，This chlorinated compound shown in formula 4 is the compound having novelty that inventor synthesizes first.
Wherein, the method for any routine in this area can be adopted to obtain about dihydroxy ethyl urea derivative (shown in formula 8).Such as, the preparation method adopting the dihydroxy ethyl urea derivative 8 of the middle record of patent application CN200810161373.1 synthesizes.
(3) synthesis of compound and salt thereof shown in the synthesis of iodo compound shown in formula 5, formula 1
a:NaICH3COCH360℃b:K2CO3DMF,Rtc:CH3OH0℃
Imidazoles chlorinated compound shown in formula 4 is low with dipeptidase derivant reactivity, not easily condensation.As shown in course of reaction above, in the present invention, in solvent such as methyl acetate, in 20-100 DEG C, it is preferable that in 60 DEG C, imidazoles chlorinated compound shown in formula 4 is by carrying out ion exchange with iodide such as sodium iodide, obtain the iodide (making shown in 5) of correspondence, this compound again with the salt example hydrochloric acid salt of dipeptidase derivant, in solvent such as DMF, in 10-100 DEG C, preferably in 20-40 DEG C, more preferably in room temperature, under inorganic base such as potassium carbonate effect, it is easy to condensation, obtains target product (shown in formula 1).
Under room temperature, free compound (shown in formula 1) is dissolved in organic solvent such as methanol, under ice bath, the methanol solution of dropping mineral acid or organic acid such as oxalic acid, light purple solid is had to precipitate out, obtain the salt such as oxalates (formula 6) of compound (formula 1), as impure, its organic solvents available such as recrystallizing methanol purification.Described mineral acid can be hydrochloric acid, nitric acid, sulphuric acid or phosphoric acid, it is preferable that hydrochloric acid；Described organic acid can be carboxylic acid or sulfonic acid, it is preferable that carboxylic acid, more preferably acetic acid, oxalic acid, trifluoroacetic acid, citric acid, fumaric acid or benzoic acid, it is most preferred that oxalic acid.
Wherein, in each reactions steps described above, the adding proportion of each reactant and solvent does not all specially require, and carries out as long as can react fully.
Specifically, obtaining compound (formula 1) through " bromo ...-2-oxo-1-imidazolidinyl) ethyl ester " in CN200810161373.1, the present invention be that warp " iodo ...-2-oxo-1-imidazolidinyl) ethyl ester " obtains compound (formula 1)；That is, the method preparing compound (formula 1) in CN200810161373.1 is, after being synthesized bromo compound IX by compound (formula 8), the reactant salt with dipeptidase derivant obtains, but, it is that the reactant salt utilizing iodo compound (formula 5) and the dipeptidase derivant synthesized by compound (formula 8) (through chloro iodo again) obtains compound (formula 1) that the present invention prepares the method for compound (formula 1), compared with the said method in CN200810161373.1, the productivity preparing compound (formula 1) of the present invention is greatly improved.
Compound (IX)
It addition, the productivity by obtaining iodo compound (5) after being synthesized compound 4 by compound (formula 8) again of the present invention, also it is significantly larger than the productivity being synthesized bromo compound IX by compound 8.
Furthermore, after being synthesized bromo compound IX by compound (formula 8) in CN200810161373.1, the reactant salt with dipeptidase derivant obtains compound (formula 1), and two steps are required for separating purification by silica gel column chromatography；And the present invention synthesized iodo compound (formula 5) by compound (formula 8), then be synthetically derived compound (formula 1) this two step by iodo compound (formula 5) and all do not need the special purification of silicagel column, can direct reaction, be conducive to commercial synthesis.
When the compound or its salt that the Formulas I made by the method for the present invention is represented is used as the inhibitor of dipeptidyl peptidase-4 (DPP-IV), by this compound or its salt itself or after adding the adjuvant of other components pharmaceutically acceptable or routine in compound or its salt, conventionally can prepare various pharmaceutical preparation further, for treating the disease that can directly or indirectly be produced clinical benefit by the suppression of DPP-IV or CD26, such as autoimmune disease and type ii diabetes etc..It is for instance possible to use the method disclosed in CN200810161373.1 makes tablet, granule, capsule, oral liquid and other dosage forms pharmaceutically acceptable.
Describe in detail below by the preferred specific embodiment of the present invention, the preparation method of compound and pharmaceutically-acceptable salts thereof shown in the Formulas I of the present invention, and the preparation method of intermediate chlorinated compound and iodo compound.These embodiments are used merely to be explained further as an example the present invention, not present invention are limited.
Embodiment
The INSTRUMENT MODEL identifying sample involved in embodiments of the invention and correlation technique and or condition as follows:
Nuclear magnetic resonance measuring instrument and condition
(1) instrument BrukerAvance600
(2) solvent DMSO-d6
Mass spectroscopy instrument and method
(1) instrument: Americanized BrukerDaltonicsDataAnasis3.2.
(2) method is analyzed: ESI positive ion source
HPLC instrument and condition
(1) instrument: GILSON chromatograph of liquid
(2) detector: UV-detector
Chromatographic column: YMCODS-AC18Post (150x4.6mm, 5 μm).
Mobile phase is 0.1mol/L sodium acetate solution (vinegar acid for adjusting pH value to 5.0)-methanol (86:14)；Detection wavelength is 254nm, and flow velocity is 1ml/min, area normalization method.
The synthesis of embodiment 1 (S)-1-(2-(2-(3-(3,4-dimethoxy phenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group)-2-Cyanopyrolidine
(1) synthesis of hydrochlorate (S)-1-(2-amino) acetyl group-2-Cyanopyrolidine hydrochlorate of dipeptidase derivant
By in ethyl acetate solution saturated for the hydrogen chloride of 30g (S)-1-(2-tertiary fourth oxygen carbon acylamino) acetyl group-2-Cyanopyrolidine addition 500mL; after room temperature reacts 5 hours; filter; drain; and wash by 500mL ethyl acetate; dry to obtain title hydrochloride compound 20.1 grams, yield 90%.
(2) synthesis of 3-(3,4-dimethoxy phenyl)-1,1-two (2-ethoxy) urea (shown in formula 8 compound)
By compound 3,4-dimethoxyaniline (229.5 grams, 1.5 moles), toluene 150ml adds in 1000ml there-necked flask, and mechanical agitation heats to 60 DEG C.nullAfter all dissolving，It is cooled to 30 DEG C，In batches，It is slowly added to triphosgene (223.5 grams，0.75 mole)，Heating is to 110 DEG C，Reflux 3 hours，Decompression removes a large amount of toluene，By residue 3,4-dimethoxy-benzene based isocyanate frozen water is cooled to 0 DEG C，Diethanolamine (the 172.5ml that dropping equal-volume dchloromethane is crossed，1.8 moles)，Dropwise，Room temperature reaction is overnight，A large amount of solvent is directly evaporated off，Obtain light oil，Compound 3-(3 is isolated by quick post method (10:1 petrol ether/ethyl acetate),4-dimethoxy phenyl)-1,1-bis-(2-ethoxy) urea 298 grams (1.05mol)，Two step total recoverys 70%,The Mass Spectrometric Identification data of this product are as follows: ESI-MS (+): 307.1279 (M+Na)+。
(3) 1-(2-chloroethyl)-3-(3,4-dimethoxy phenyl) synthesis of-2 imidazolidinones
By compound 3-(3,4-dimethoxy phenyl)-1,1-bis-(2-ethoxy) urea (formula 8) (125.3 grams of 0.44mol) dichloromethane 200ml dissolves, ice bath is cooled to 0 DEG C, add N-methylmorpholine (66ml, 0.6 mole), dropping mesyl chloride (23.4ml0.3 mole) dripped Bi Fanying after 3 hours, and TLC detects (developing solvent；Methanol: dichloromethane=1:7, ultraviolet develops the color), react completely, stopped reaction, filters insoluble matter, washes filter cake with water, separatory funnel is layered, and collects organic facies, aqueous phase dichloromethane extraction three times, merging organic facies, pressurization removes solvent, obtains brown solid, wash twice with petrol ether/ethyl acetate 1:1, dry to obtain brown solid (81.5 grams of 0.29mol) compound 1-(2-chloroethyl)-3-(3,4-dimethoxy phenyl)-2-imidazolidinone (formula 4), yield 66%.The fusing point of this product, nuclear-magnetism and MS Mass Spectrometric Identification data are as follows: Mp118.5-120.3 DEG C；1H-NMRδ(CDCl3):7.6357-7.6318(d,1H,J=2.3);6.8279-6.8135(d,1H,J=9.6);6.6634-6.6446(dd,1H,J=2.4,2.5Hz);3.9020(s,3H);3.8557(s,3H);3.8557-3.8163(t,2HJ=7.3,8.6);3.7157-3.6957 (t, 2H, J=6.0Hz) 3.6583-3.6283 (dd, 4HJ=8.7,5.88), MS285(M+H)+。
(4) 1-(2-iodine ethyl)-3-(3,4-dimethoxy phenyl) synthesis of-2-imidazolidinone
Chloride (formula 4) (28.4g, 0.1mol) is dissolved in acetone (300ml), adds NaI (75g, 0.5mol) refluxing at 100 DEG C, every day filters out the NaCl generated, about reaction 3 days, solid is now no longer had to precipitate out, reaction terminates, and is concentrated into dry by this mixture, is subsequently adding THF and dissolves, filter, by mother liquor concentrations to dry, obtain 35g purple wax (0.093mol), yield 93%.This product nuclear-magnetism and Mass Spectrometric Identification data are as follows: 1H-NMR δ (CDCl3): 7.66 (d, 1H, J=2.6Hz);6.86(d,1H,J=8.6Hz),6.69(dd,1H,J=8.6,2.4Hz);3.96(s,3H);3.89(s,3H);3.86(t,2H,J=7.4Hz);3.74(t,2H,J=6.4Hz);3.66(t,2H,J=7.8Hz);3.39 (t, 2H, J=6.2Hz), MS:377 (M+H)+。
(5) synthesis of (S)-1-(2-(2-(3-(3,4-dimethoxy phenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group)-2-Cyanopyrolidine
Method one: by 1-(2-iodine ethyl)-3-(3,4-dimethoxy phenyl)-2-imidazolidinone (formula 5) (30g, 0.08mol) is dissolved in dry acetonitrile (200ml), is then respectively adding K2CO3(22.1g, 0.16mol), the dipeptidase derivant hydrochlorate (18.9g, 0.1mol) of preparation in previous step (1), under room temperature, stirring reaction is overnight, and TLC detection is wholly absent to raw material.Being filtered to remove insoluble matter, concentrating under reduced pressure obtains grease, adds 10%CH3CO2H(500ml) aqueous solution, then uses CH2Cl2(100mlx3) extract impurity, then use Na2CO3Regulate pH to about 8, use CH2Cl2(200mlx3) extract product, merge organic facies, then by water (100mlx2) washing, anhydrous Na2SO4After drying, it is evaporated, obtains lavender oily compound (formula 1) 20g(0.05mol), yield 62.5%.Purity 96% is detected through HPLC.
Nuclear-magnetism and the ESI-MS data of this product are as follows:
null1H-NMRδ(DMSO-d6):δ7.44,δ6.86,δ 6.80(3H multiplet) δ 4.71(1H，Multiplet) δ 3.73(2H，Triplet J=12HZ) δ 3.46 (2H,Triplet J=12HZ) δ 3.72 (3H,Unimodal)，δ3.69(3H,Unimodal) δ 3.56(1H，Multiplet) δ 3.35(1H，Multiplet) δ 3.32(2H，Multiplet) δ 3.24(2H，Triplet J=6HZ)，δ 2.69(2H，Triplet J=6HZ) δ 2.11(2H，Multiplet) δ 2.00(2H，Multiplet) 13C-NMR δ (DMSO-d6): 170.71，158.04，149.16，144.49，135.24，119.85，112.75，109.15，103.54，56.31，55.91，50.89，47.01
ESI-MS:402(M+H+).HRMS(ES+):402.2136(M+H)+,calcdforC20H27N5O4
Method two: by 1-(2-iodine ethyl)-3-(3,4-dimethoxy phenyl)-2-imidazolidinone (formula 5) (30g, 0.08mol) is dissolved in dry DMF(200ml) in, it is then respectively adding K2CO3(22.1g, 0.16mol), the dipeptidase derivant hydrochlorate (18.2g, 0.096mol) of preparation in previous step (1), under room temperature, stirring reaction is overnight, and TLC detection is wholly absent to raw material.It is filtered to remove insoluble matter, adds 10%CH3CO2H(800ml) aqueous solution, then uses CH2Cl2(100mlx3) extract impurity, then use Na2CO3Regulate pH to about 8, use CH2Cl2(200mlx3) extract product, merge organic facies, then by water (100mlx2) washing, anhydrous Na2SO4After drying, it is evaporated, obtains lavender grease 25g(0.0625mol), yield 78%.Purity 96.5% is detected through HPLC.
Wherein, the nuclear-magnetism of this product and ESI-MS data are as follows:
1H-NMRδ(DMSO-d6): δ 7.44, δ 6.86, δ 6.80(3H multiplet) δ 4.71(1H, multiplet) δ 3.73(2H, triplet J=12HZ) δ 3.46 (2H, triplet J=12HZ) δ 3.72 (3H, unimodal), δ 3.69 (3H, unimodal) δ 3.56(1H, multiplet) δ 3.35(1H, multiplet) δ 3.32(2H, multiplet) δ 3.24(2H, triplet J=6HZ), δ 2.69(2H, triplet J=6HZ) δ 2.11(2H, multiplet) δ 2.00(2H, multiplet)13C-NMR δ (DMSO-d6): 170.71,158.04,149.16,144.49,135.24,119.85,112.75,109.15,103.54,56.31,55.91,50.89,47.01ESI-MS:402 (M+H)+, HRMS (ES+):402.2136(M+H)+,calcdforC20H27N5O4。
The synthesis of embodiment 2 (S)-1-(2-(2-(3-(3,4-dimethoxy phenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group)-2-Cyanopyrolidine oxalates
Accurate Weigh Compound (formula 1) (20 grams 0.05 mole) is dissolved in methanol (160ml), under mechanical agitation, ice bath cools after 0-5 DEG C, starts to drip after the oxalic acid (6.3 grams 0.05 mole) dissolved with 40ml methanol dropwises, reacts 2 hours, precipitate out a large amount of light purple solid, filter, collect solid, wash 2 times with methanol, crude product, 50 DEG C of forced air dryings 5 hours, obtains crude product 13 grams.Lilac sterling (formula 6 compound) 9.7 grams is obtained by the 130ml recrystallizing methanol containing 10% water.Yield 39.5%.
Comparative example
(S) synthesis of-1-(2-(2-(3-(3,4-dimethoxy phenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group)-2-Cyanopyrolidine
Adopt CN200810161373.1 records synthesized bromo compound IX by compound 8 after react with the hydrochlorate of dipeptidase derivant and to synthesize (S)-1-(2-(2-(3-(3; 4-dimethoxy phenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group)-2-Cyanopyrolidine, specifically include following experimental procedure:
(1) synthesis of hydrochlorate (S)-1-(2-amino) acetyl group-2-Cyanopyrolidine hydrochlorate of dipeptidase derivant
This synthesis is identical with the operation of the step of embodiment 1 (1).
(2) synthesis of 1-(2-bromoethyl)-3-(3,4-dimethoxy phenyl)-2-imidazolidinone
By 3-(3,4-dimethoxy benzene)-1,1-dihydroxy ethyl urea (41.1g, 145mmol) is dissolved in 300mLCH2Cl2In, drip PBr under ice bath cooling3(39.2g, 145mmol), after finishing insulated and stirred 3 hours, is slowly added dropwise saturated NaHCO3Solution, regulating pH value is after alkalescence, and stirring is overnight.Organic facies separates, aqueous phase CH2Cl2Extract 2 times, merge organic facies, and wash with saturated brine, anhydrous Na2SO4Dry, filter, concentrate to obtain oily mixture, silica gel column chromatography, petroleum ether: ethyl acetate=10/1 to 3/1 eluting, obtain header destination compound 11.78g(35.9mmol), yield 25%.
(3) synthesis of (S)-1-(2-(2-(3-(3,4-dimethoxy phenyl)-2-oxo-1-imidazolidinyl) ethylamino) acetyl group)-2-Cyanopyrolidine
(S)-1-(2-glycyl)-2-Cyanopyrolidine hydrochlorate (45.4g, 240mmol) is dissolved in 80mL acetonitrile, adds anhydrous K2CO3(88g, 640mmol), after strong stirring half an hour, it is released into out free alkali, add 1-(2-bromoethyl)-3-(3,4-dimethoxy phenyl)-2-imidazolidinone (26.2g, 80mmol) acetonitrile solution, it is filtered to remove insoluble matter after being stirred at room temperature 48 hours, concentrating under reduced pressure obtains oily mixture, gained grease is very assorted, separates through silicagel column, CHCl3/ MeOH=10/1 eluting, obtains compound (shown in the formula 1) 10.7g of the product present invention, yield 33%.This product detects purity 94% through HPLC.Nuclear-magnetism and the MS qualification result of this product are as follows:
1H-NMRδ(DMSO-d6): δ 7.43, δ 6.84, δ 6.79(m, 3H) δ 4.70(m, 1H) δ 3.71(t, 2H, J=12HZ) δ 3.43 (t, 2H, J=12HZ) δ 3.70 (s, 3H), δ 3.65 (s, 3H) δ 3.55(m, 1H) δ 3.36(m, 1H) δ 3.32(m, 2H) δ 3.23(t, 2HJ=6HZ), δ 2.67(t, 2HJ=6HZ) δ 2.10(m, 2H) δ 2.00(m, 2H)13C-NMRδ(DMSO-d6): 170.70,158.02,149.15,144.46,135.21,119.82,112.75,109.14,103.53,56.30,55.91,50.87,47.00
ESI-MS:402(M+H)+
Although having focused on preferred embodiment the present invention is described, but obviously can adopt the various modification of preferred embodiment and method for those of ordinary skill in the art, and the present invention can implement with being different from mode described herein.Therefore, the present invention will be included all variations being encompassed within spirit and scope of the present invention.For example it should be clear that, the reactions steps stated in the following claims need not carry out with the order that they occur, those skilled in the art can change the order of reactions steps.Additionally some reaction sequence can carry out simultaneously.Or these reactions can carry out in step respectively, without departing from the spirit and scope of the present invention.All these variations should be construed as being included within appended scope of the claims.

Claims (23)

1. a preparation method for the compound that Formulas I represents, wherein, R1For aryl, heteroaryl and alkyl, or being replaced alkyl that base carbon number is C1-C8 or aryl, heteroaryl and alkyl that alkoxyl replaces, X is carbon number is the alkylidene of C1-C8；
Wherein, the method includes following operation:
1) in organic solvent, the chlorinated compound generation iodide reaction that Formula II represents is made to obtain the iodo compound that formula III represents,
2) iodo compound that the salt of the dipeptidase derivant represented by formula 3 and formula III represent is in organic solvent, carries out condensation reaction,
Obtain the compound that Formulas I represents；
Wherein, described aryl is phenyl or naphthyl, and described heteroaryl is selected from pyridine radicals, pyrimidine radicals, pyrazinyl, triazine radical, furyl, thienyl, pyrrole radicals, imidazole radicals, thiazolyl, isothiazolyl, azoles base, isoxazole base, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzimidazolyl and benzothiazolyl；
Wherein, operation 1) in, described organic solvent is ketones solvent or esters solvent, operation 2) in, described organic solvent is anhydrous acetonitrile, DMF or DMSO.
2. the preparation method of compound according to claim 1, wherein, described heteroaryl is selected from pyridine radicals, furyl, thienyl, thiazolyl, azoles base, benzofuranyl and benzimidazolyl；Described substituent group is carbon number is the alkoxyl of C1-C8；X is carbon number is the alkylidene of C1-C6.
3. the preparation method of compound according to claim 1, wherein, R1For phenyl or naphthyl, or it is replaced alkyl that base carbon number is C1-C8 or the phenyl or naphthyl that alkoxyl replaces；X is methylene or ethylidene or propylidene.
4. the preparation method of compound according to claim 3, wherein, R1For being replaced the phenyl that the alkoxyl that base carbon number is C1-C8 replaces；X is methylene or ethylidene or propylidene.
5. the preparation method of compound according to claim 4, wherein, R1For the phenyl replaced by the alkoxyl that two or more carbon numbers are C1-C8；X is methylene or ethylidene or propylidene.
6. the preparation method of compound according to claim 5, wherein, R1For by alkoxyl that two carbon numbers are C1-C8 respectively at 3,4 phenyl replaced；X is methylene or ethylidene.
7. the preparation method of the compound according to any one of claim 1-6, wherein, operation 1) in, described organic solvent is anhydrous propanone or methyl acetate；Operation 2) in, described organic solvent is DMF.
8. the preparation method of the compound according to any one of claim 1-6, wherein, operation 2) in, the salt of described dipeptidase derivant is trifluoroacetic acid or hydrochlorate.
9. the preparation method of compound according to claim 8, wherein, operation 2) in, the salt of described dipeptidase derivant is hydrochlorate.
10. the preparation method of the compound according to any one of claim 1-6, wherein, operation 2) in, under inorganic base effect, carry out condensation reaction.
11. the preparation method of compound according to claim 10, wherein, operation 2) in, under sodium carbonate or potassium carbonate effect, carry out condensation reaction.
12. the preparation method of the compound according to any one of claim 1-6, wherein, operation 1) in, at 20-100 DEG C, make the chlorinated compound that Formula II represents carry out iodide reaction with iodide；Operation 2) in, react at 10-100 DEG C.
13. the preparation method of compound according to claim 12, wherein, operation 1) in, at 20-100 DEG C, make the chlorinated compound that Formula II represents carry out iodide reaction with anhydrous sodium iodide or potassium iodide；Operation 2) in, react at 20-40 DEG C.
14. the chlorinated compound shown in formula 4
15. the preparation method of the chlorinated compound described in claim 14, it includes following operation: make the compound that formula 8 represents in organic solvent,
Occurring chlorination to obtain the chlorinated compound shown in formula 4, wherein, described organic solvent is dichloromethane, N-methylmorpholine, chloroform and/or 1,2-dichloroethanes.
16. the preparation method of chlorinated compound according to claim 15, wherein, make compound and sulfonic acid chloride generation chlorination that formula 8 represents.
17. the preparation method of chlorinated compound according to claim 16, wherein, make the compound that formula 8 represents at 0-10 DEG C and mesyl chloride generation chlorination.
18. the iodo compound shown in formula 5
19. the preparation method of the iodo compound described in claim 18, it includes following operation: in organic solvent, makes the chlorinated compound generation iodide reaction that formula 4 represents obtain the iodo compound that formula 5 represents；
Wherein, described organic solvent is ketones solvent or esters solvent；
20. the preparation method of iodo compound according to claim 19, wherein, the chlorinated compound that formula 4 represents is made to occur iodide reaction to obtain the iodo compound that formula 5 represents at 20-100 DEG C with iodide.
21. the preparation method of iodo compound according to claim 20, wherein, the chlorinated compound that formula 4 represents is made to occur iodide reaction to obtain the iodo compound that formula 5 represents at 20-100 DEG C with anhydrous sodium iodide or potassium iodide.
22. the preparation method of iodo compound according to claim 19, wherein, described organic solvent is anhydrous propanone or methyl acetate.
23. the preparation method of iodo compound according to claim 20, wherein, described organic solvent is anhydrous propanone or methyl acetate.
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