CN106892926A - A kind of intermediate of DPP IV inhibitor, its preparation method and the method that DPP IV inhibitor is prepared by it - Google Patents
A kind of intermediate of DPP IV inhibitor, its preparation method and the method that DPP IV inhibitor is prepared by it Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
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Abstract
The present invention relates to a kind of intermediate of DPP IV inhibitor (Formulas I), its preparation method and the method that DPP IV inhibitor is prepared by it.Specifically, methods described is reacted by cyclic chiral β aminoaryls butanoic acid derivative (formula II) and compound III, then removes amido protection group, DPP IV inhibitor needed for being obtained.The method is easy to operate, low cost, is suitable to large-scale production.
Description
The application is Application No. 201210393435.8, and the applying date is on October 16th, 2012, entitled " a kind of
The Chinese patent application of the intermediate of DPP-IV inhibitor, its preparation method and the method that DPP-IV inhibitor is prepared by it "
Divisional application.
Technical field
DPP-IV inhibitor is prepared the present invention relates to a kind of intermediate of DPP-IV inhibitor, its preparation method and by it
Method.
Background technology
Diabetes (diabetes mellitus) are by inherent cause, immunologic function disorder, microorganism infection and its poison
The virulence factors such as element, mental element act on body cause hypoinsulinism, insulin resistance and trigger sugar, protein,
A series of metabolic disorder syndromes such as fat, water and electrolyte, are one of principal diseases of threat human health.Diabetes are usual
It is divided to two kinds of type 1 diabetes and diabetes B, wherein diabetes B to account for more than 90%, the side of research effectively treatment diabetes B
Method is always the important topic of diabetes study work.
Research finds that dipeptidyl peptidase-IV (dipeptidyl peptidase IV, DPP-IV) is related to diabetes
A kind of important enzyme, suppress DPP-IV enzymes can effectively treat diabetes B, therefore, DPP-IV enzyme inhibitors are a classes
For treating or improving the diabetes B glycogenetic newtype drug of Patients' rights blood, many DPP-IV enzyme levels are had at present
Agent is applied to clinical test, and has some listings that gone through, for example, sitagliptin (MK-0431, Merck),
Saxagliptin (BMS-477118, BMS), vildagliptin (LAF-237, Norvartis), alogliptin (SYR-
322, Tekada) etc..
WO2009082881 reports a kind of new DPP-IV inhibitor (shown in formula I), patent CN101468988,
CN10141799, WO2010099698, WO2010135944, WO2010111905, WO2011009360 report respectively it or
The preparation method of its composition and its inhibitory action to DPP-IV enzymes.This DPP-IV disclosed by above-mentioned patent suppresses
In the preparation method of agent, it is long to there is synthesis step, cumbersome, the shortcomings of high expensive.
WO2011/127794 describes a kind of cyclic chiral beta-amino arylbutyric acid derivatives prepared as shown in Formula II,
Such cyclic chiral beta-amino arylbutyric acid derivatives can be efficiently used for the preparation of DPP-IV inhibitor shown in formula I.
The content of the invention
It is an object of the invention to provide a kind of preparation method of DPP-IV inhibitor shown in formula I,
Wherein, Ar1It is unsubstituted or further by 1-5 selected from halogen, cyano group, hydroxyl, alkyl or alkoxy
The phenyl of substituent group, wherein alkyl or alkoxy be unsubstituted or further replaced by one or more halogens, preferably
Ar1It is 2,4,5- trifluorophenyls；R1Selected from hydrogen atom, alkyl, trifluoromethyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, ring
Alkyl, aryl, heteroaryl are optionally further selected from the substitution base institute of halogen, cyano group, aryl, hydroxyl or amino by one or more
Substitution, preferably R1It is trifluoromethyl；R2It is hydrogen or substituted or non-substituted C1-10Straight or branched alkyl, substituted or non-substituted
C3-8Cyclic alkyl or substituted or non-substituted C6-10Aryl, preferably R2It is methyl；R3Selected from hydrogen atom or substitution or non-
Substituted C1-10Straight or branched alkyl, preferably R3It is hydrogen atom.
The preparation method of the compound of formula I that the present invention is provided is as follows：
Wherein, Ar1、R1、R2、R3As defined in Formulas I；Ar2It is unsubstituted or by 1-5 selected from halogen, cyano group, hydroxyl
The phenyl of the substituent group of base, alkyl or alkoxy, wherein alkyl or alkoxy be unsubstituted or further by one or
Multiple halogen substitutions.
In yet other embodiments, Ar1It is 2,4,5- trifluorophenyls；Ar2It is phenyl；R1It is fluoroform
Base；R2It is methyl；R3It is hydrogen atom.
Specifically, the method comprises the following steps：
1) cyclic chiral beta-amino arylbutyric acid derivatives (formula II) and compound III reactions obtains compound IV；
2) DPP-IV inhibitor shown in formula I is obtained after the amino protecting groups of removing compound IV.
In step 1) in, the reaction of compound II and compound III can be carried out under the action of an acid, and described acid can be with
It is inorganic acid, organic acid or lewis acid.
In one embodiment of the invention, described acid is lewis acid, selected from alchlor, diethyl aluminum chloride,
Ethylaluminum dichloride, trimethyl aluminium, triethyl aluminum, zinc chloride etc., preferably diethyl aluminum chloride.
By the way that after the amino protecting groups in removing compound shown in formula IV, the compound shown in Formulas I, amine can be directly obtained
The removal methods of base protection group can be oxidation removal, or reduction removing；It is preferred specific real at one of the invention
Apply in mode, the removal methods of the amido protection group of compound IV are removed from Pd/C catalytic hydrogenolysis method.
In order to complete above-mentioned purpose, one aspect of the present invention provides a kind of compound as shown in formula IV, and the compound can
For easily preparing DPP-IV inhibitor shown in formula I,
Wherein, Ar1、R1、R2、R3As defined in Formulas I；Ar2It is unsubstituted or by 1-5 selected from halogen, cyano group, hydroxyl
The phenyl of the substituent group of base, alkyl or alkoxy, wherein alkyl or alkoxy be unsubstituted or further by one or
Multiple halogen substitutions, preferably Ar2It is phenyl.
Another aspect of the present invention provides a kind of preparation method of the compound as shown in formula IV, and the method is used such as Formula II institute
Cyclic chiral beta-amino arylbutyric acid derivatives and compound the III reaction shown obtain compound IV,
Ar1、Ar2、R1、R2、R3As defined in formula IV.
In the method, the reaction of compound II and compound III can be carried out under the action of an acid, and described acid can be with
It is inorganic acid, organic acid or lewis acid, preferably lewis acid, for example, alchlor, diethyl aluminum chloride, ethyl dichloro
Change aluminium, trimethyl aluminium, triethyl aluminum, zinc chloride etc.；In a preferred embodiment of the invention, described Louis
This acid is preferably diethyl aluminum chloride.
Present invention also offers a kind of compound as shown in formula III, it can be used to prepare the compound as shown in formula IV,
Wherein, R1、R2、R3As defined in formula IV.
The present invention also provides a kind of preparation method of compound III, the hydrogenation that described compound III passes through compound V
It is obtained after reduction,
Wherein, R1、R2、R3As defined in formula IV.
In a preferred embodiment of the invention, compound V is hydrogenated in the presence of catalyst Pd/C
To compound III.
The present invention also provides a kind of compound shown as a formula V, and it can be used for easily prepare compound III,
Wherein, R1、R2、R3As defined in formula IV.
Present invention also offers a kind of preparation method of compound V, by compound VI disclosed in prior art in POX3
Intramolecular cyclization, then obtains compound V in the presence of dehydrating agent in the presence of (X is halogen),
Wherein, R1、R2、R3As defined in formula IV.
The synthesis of compound VI can refer to document J.Med.Chem.1994,37,4567.
In a preferred embodiment of the invention, described POX3Preferably POCl3, described dehydrating agent
Preferably P2O5。
The inventive method has synthetic route short, simple to operate, and the optical purity of product is high, and low cost is simultaneously adapted to industrialization
The features such as production, with significant Social benefit and economic benefit.
Term used in the present invention, in addition to having opposite statement, with following implication：
" alkyl " refers to the aliphatic hydrocarbon group of saturation, including 1 to 10 straight chain and branched group of carbon atom, preferably includes 1
To 6 carbon atoms.Non-limiting example include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
The tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls,
2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyls, 1,1- dimethyl butyrates
Base, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl
Amyl group, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, replace base
Can be substituted on any usable tie point, preferably one or more following groups, independently selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" cycloalkyl " refers to that monocyclic 3 to 8 yuan of full carbon, 5 yuan/6 yuan of full carbon or 6 yuan/6 yuan fused rings or polycyclic fused rings are (" thick
Conjunction " ring system means that each ring in system shares a pair of the carbon atoms for adjoining with other rings in system) group, one of them
Or multiple rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.The reality of cycloalkyl
Example has cyclopropyl, cyclobutyl, cyclopenta, cyclopentene, hexamethylene, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene etc.." ring
Alkyl " can be substituted or unsubstituted, and when substituted, substitution base is preferably one or more following groups, independently selects
From alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle
Alkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" Heterocyclylalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 8 ring originals
Son, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not include-O-
The loop section of O- ,-O-S- or-S-S-, remaining annular atom is carbon.5 to 6 annular atoms are preferably included, wherein 1,2,3 or 4 are
Hetero atom." Heterocyclylalkyl " can be substituted or unsubstituted, and when substituted, substitution base is preferably one or more following bases
Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group,
Cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" aryl " refers to that 6 to 14 yuan of full carbon of the pi-electron system with conjugation are monocyclic or fused polycycle (is namely shared and adjoined
The ring of carbon atom pair) group, more preferably preferably 6 to 10 yuan, phenyl and naphthyl.Aryl can be it is substituted or unsubstituted,
When substituted, substitution base is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane
Sulfenyl, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy,
Heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" heteroaryl " refer to comprising 6 to 10 heteroaromatic systems of annular atom, wherein comprising 1,2,3 or 4 hetero atoms, its
Middle hetero atom includes oxygen, sulphur and nitrogen；Such as pyridine radicals, pyrimidine radicals etc.." heteroaryl " can be it is optionally substituted or unsubstituted,
When substituted, substitution base is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane
Sulfenyl, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy,
Heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), and wherein alkyl, cycloalkyl are as defined above institute
State.Non-limiting example comprising methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy,
Cyclohexyloxy etc..Alkoxy can be optionally substituted or unsubstituted, and when substituted, substitution base is preferably one or more
Following group, independently selected from being alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitre
Base, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Specific embodiment
The present invention is explained in detail below with reference to instantiation so that those skilled in the art is more fully understood this hair
Bright, instantiation is merely to illustrate technical scheme, and the present invention is limited never in any form.
Following table is the structural formula of involved compound in embodiment：
Embodiment 1:Prepare compound VIa
By 2- ammonia -2- pyrazines-acetate hydrochloride (13.6g, by literature method prepare J.Med.Chem.1994,37,
4567) dichloromethane (180mL) solution is cooled to 0-10 DEG C, is added dropwise triethylamine (8.0g) in above-mentioned solution, gained it is mixed
The temperature control of liquid is closed at 0-10 DEG C, trifluoro-acetic anhydride (14.6g) is added dropwise, stirred 1-2 hours at 5-15 DEG C, plus sodium acid carbonate is full
With solution (135mL), layering is stirred, separate organic phase, add magnesium sulfate to dry, filtering is concentrated to give compound VIa
(16.2g), yield 92.2%.
VIa：1H-NMR(400MHz,CD3OD)δ8.80(s,1H),8.63(m,2H),5.98(s,1H),3.79(s,3H).
MS (M+H)=263.79.
Embodiment 2:Prepare compound Va
In compound VIa (16.2g) and POCl3In the mixed liquor of (162g), phosphorus pentoxide (18.0g) is rapidly joined,
It is heated to 105-110 DEG C, stirs 4-6 hour, concentration, plus people's ethyl acetate, concentration is cooled to 0 DEG C, dropwise addition water quenching goes out three
Chlorethoxyfos, are added dropwise 25% ammoniacal liquor regulation pH=7-9, plus ethyl acetate extraction, merge organic phase, are concentrated to give 13.2g crude products, add
The solution of ethyl acetate and petroleum ether, stirs 0.5 hour, filtering, dry compound Va (11.2g), yield 74.2%.
Va：1H-NMR(400MHz,CDCl3)δ9.80(d,1H),8.15(d,1H),8.07(d,1H),4.09(s,3H).
MS (M+H)=246.31.
Embodiment 3:Prepare compound IIIa
Added in ethyl acetate (40mL) solution of compound Va (7.3g) 0.8g 10% palladium carbons (aqueous 60%), plus
Hydrogen (30psi), stirs 4-6 hours at 20-30 DEG C, filtering, and concentration adds petroleum ether, stirs 1.0 hours, filtering, dry
To compound IIIa (6.1g), yield 82.2%.
IIIa：1H-NMR(400MHz,CDCl3)δ4.40(s,2H),4.13(m,2H),3.90(s,3H),3.32(m,2H).
MS (M+H)=250.20.
Embodiment 4:Prepare compound IIIb
Using the same procedure of synthesis compound IIIa, analog IIIb is synthesized.
IIIb：1H-NMR(400MHz,CD3OD)δ4.88(s,2H),4.62(s,2H),4.38-4.37(d,2H),3.88
(s,2H),1.40-1.37(m,3H).
MS (M+H)=264.33.
Embodiment 5:Prepare compound IIIc
Using the same procedure of synthesis compound IIIa, analog IIIc is synthesized.
IIIc：1H-NMR(400MHz,CD3OD) δ 4.79 (s, 2H), 4.54 (s, 2H), 4.16~4.13 (t, 1H), 3.79
(s, 2H), 1.24~1.22 (d, 6H)
MS (M+H)=277.36.
Embodiment 6:Prepare compound IIId
Using the same procedure of synthesis compound IIIa, analog IIId is synthesized.
IIId:1H-NMR(400MHz,CDCl3) δ 7.51~7.37 (m, 5H), 5.43 (s, 2H), 4.41 (s, 2H), 4.18
(s, the 1H) of~4.15 (t, 2H), 3.32~3.30 (t, 2H), 2.15
Embodiment 7:Prepare compound IIIe
Using the same procedure of synthesis compound IIIa, analog IIIe is synthesized.
IIIe：1H-NMR(400MHz,CD3OD)δ7.47-7.24(m,5H),4.61(s,2H),3.86(s,2H),3.35-
3.31(d,2H),2.15-2.14(d,1H).
MS (M+H)=312.21.
Embodiment 8:Prepare compound IIIf
Using the same procedure of synthesis compound IIIa, analog IIIf is synthesized.
IIIf：1H-NMR(400MHz,CD3OD)δ4.77(s,2H),4.54(s,2H),3.79(s,2H),3.31-3.27
(d,1H).
MS (M+H)=258.33.
Embodiment 9:Prepare compound IVa
Dichloromethane (25mL) solution of compound IIIa (4.8g) is cooled to -15 DEG C, 25mL diethyl chlorinations are added
The toluene solution (0.9M) of aluminium, the mixed liquor of gained is stirred 10 minutes at -10 DEG C, and compound IIa is then added dropwise, and (5.0g is pressed
It is prepared by WO2011/127794 methods) dichloromethane (25mL) solution, the mixed liquor of gained is warming up to 10 DEG C and stirring 40 is small
When, 1N HCl (50mL) is added dropwise reaction is quenched, separate organic phase and respectively with the 0.5N NaOH aqueous solution and water washing, dry, it is dense
Compound IVa (7.3g), yield 83.8% are obtained after contracting.
Iva：1HNMR(400MHz,CDCl3)δ2.07-2.85(m,4H),3.45-3.56(m,2H),3.67-3.71(m,
1H),3.85-3.88(m,1H),3.94-3.97(m,4H),4.06-4.09(t,2H),4.18-4.21(t,2H),6.84-6.90
(m,2H),7.15-7.17(d,2H),7.23-7.28(m,3H).
MS (M+H)=585.38.
Embodiment 10:Prepare compound IVa
At 15-25 DEG C, triethylamine (550mg) is dropped into the outstanding of alchlor (480mg) and dichloromethane (30mL)
In turbid liquid, stirring is until form the dichloromethane of settled solution, dropwise addition compound IIa (980mg) and compound IIIa (980mg)
(30mL) solution, stirs 2 hours at 15-25 DEG C, is cooled to 0-5 DEG C, 1N HCl is added dropwise reaction is quenched, and separates organic phase and divides
Not Yong saturated sodium bicarbonate aqueous solution and water washing, dry, compound IVa (1.2g), yield 70.2% are obtained after concentration.
Embodiment 11:Prepare compound Ia
10% wet Pd/C (1.5g) and the concentrated sulfuric acid (3.0g) are added to the methyl alcohol (100mL) of compound IVa (9.0g),
Hydrogenation (15psi), stirs 16 hours at 40-50 DEG C, filters away catalyst, and filtrate is neutralized to pH=with saturated sodium bicarbonate
7, extracted with dichloromethane after concentration, organic phase is separated, dry, compound Ia (5.9g), yield are obtained after concentrating and purifying
82.5%.
Compound Ia：1HNMR(400MHz,CDCl3)δ1.26(s,2H),2.46-2.72(m,3H),2.79-2.84(dd,
1H),3.55-3.61(m,1H),3.88-4.25(m,7H),5.03-5.17(m,2H),6.90-6.96(m,1H),7.06-7.12
(m,1H).
MS (M+H)=465.22.
Due to describing the present invention according to its specific embodiment, some modifications and equivalent variations are for being proficient in this neck
The technical staff in domain is obvious and is included within the scope of the invention.
Claims (8)
1. the compound shown in a kind of formula III,
Wherein, R1Selected from hydrogen atom, alkyl, trifluoromethyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, aryl,
Heteroaryl is optionally further replaced by one or more substitution bases for being selected from halogen, cyano group, aryl, hydroxyl or amino；R2For
Hydrogen or substituted or non-substituted C1-10Straight or branched alkyl, substituted or non-substituted C3-8Cyclic alkyl substitution or it is non-
Substituted C6-10Aryl；R3Selected from hydrogen atom or substituted or non-substituted C1-10Straight or branched alkyl；Ar2It is unsubstituted
Or by 1-5 selected from the substituent group of halogen, cyano group, hydroxyl, alkyl or alkoxy phenyl, wherein alkyl or alkoxy
It is unsubstituted or is further replaced by one or more halogens；It is preferred that R1It is trifluoromethyl, R2It is methyl, R3It is hydrogen atom.
2. a kind of method of the compound prepared as shown in formula III, it is characterised in that including compound shown as a formula V through catalysis
The step of compound shown in formula III is obtained after hydrogenation,
Wherein, R1、R2、R3As defined in claim 1.
3. one kind compound shown as a formula V,
Wherein, R1、R2、R3As defined in claim 1.
4. a kind of method for preparing compound shown as a formula V, it is characterised in that de- through cyclisation including the compound shown in Formula IV
The step of compound shown in Formula V is obtained after water,
Wherein, R1、R2、R3As defined in claim 1.
5. preparation method according to claim 4, wherein compound VI is in POX3In the presence of intramolecular cyclization, Ran Hou
Compound V is obtained in the presence of dehydrating agent, wherein X is halogen；It is preferred that POX3It is POCl3, dehydrating agent is P2O5。
6. a kind of method for preparing DPP-IV inhibitor shown in formula I, it includes amido protection group removing as follows
Step,
Wherein, Ar1It is unsubstituted or by the 1-5 benzene selected from the substituent group of halogen, cyano group, hydroxyl, alkyl or alkoxy
Base, wherein alkyl or alkoxy are unsubstituted or are further replaced by one or more halogens；R1Selected from hydrogen atom, alkane
Base, trifluoromethyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, cycloalkyl, aryl, heteroaryl optionally further by one or
Multiple is replaced selected from the substitution base of halogen, cyano group, aryl, hydroxyl or amino；R2It is hydrogen or substituted or non-substituted C1-10It is straight
Chain or branched alkyl, substituted or non-substituted C3-8Cyclic alkyl or substituted or non-substituted C6-10Aryl；R3It is former selected from hydrogen
Sub or substituted or non-substituted C1-10Straight or branched alkyl；Ar2Be it is unsubstituted or by 1-5 selected from halogen, cyano group,
The phenyl of the substituent group of hydroxyl, alkyl or alkoxy, wherein alkyl or alkoxy are unsubstituted or further by one
Or multiple halogen substitutions；Wherein also include that also compound shown in Formula II obtains formula IV compound with the reaction of compound shown in formula III
The step of,
And compound shown as a formula V after catalytic hydrogenation be obtained formula III shown in compound the step of,
7. preparation method according to claim 6, is also obtained Formula V institute including the compound shown in Formula IV after cyclodehydration
The step of showing compound,
Wherein, R1、R2、R3As defined in claim 6.
8. preparation method according to claim 7, wherein compound VI is in POX3In the presence of intramolecular cyclization, Ran Hou
Compound V is obtained in the presence of dehydrating agent, wherein X is halogen；It is preferred that POX3It is POCl3, dehydrating agent is P2O5。
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| CN201210393435.8A CN103724352B (en) | 2012-10-16 | 2012-10-16 | A kind of intermediate of DPP IV inhibitor, its preparation method and the method for DPP IV inhibitor is prepared by it |
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| CN101468988A (en) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | Piperazine derivative, preparation thereof and use thereof in medicine |
| CN102212015A (en) * | 2010-04-12 | 2011-10-12 | 上海源力生物技术有限公司 | Method for preparing chiral beta-amino arylbutyric acid derivatives |
| CN102372698A (en) * | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative and its preparation method and use in medicine |
| CN102464661A (en) * | 2010-11-16 | 2012-05-23 | 上海药明康德新药开发有限公司 | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester |
| CN103087067A (en) * | 2012-08-02 | 2013-05-08 | 盛世泰科生物医药技术(苏州)有限公司 | Compound serving as dipeptidyl enzyme inhibitor and composition thereof and applications of compound and composition |
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| CN101417999A (en) * | 2007-10-25 | 2009-04-29 | 上海恒瑞医药有限公司 | Piperazines derivates, preparation method thereof and application thereof in medicine |
| CN101824036A (en) * | 2009-03-05 | 2010-09-08 | 上海恒瑞医药有限公司 | Salt of tetrahydroimidazo [1,5-a] pyrazine derivative, preparation method and pharmaceutical application thereof |
| CN101899048B (en) * | 2009-05-27 | 2013-04-17 | 上海恒瑞医药有限公司 | Salt of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1- carboxylic acid methyl ester |
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| CN101468988A (en) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | Piperazine derivative, preparation thereof and use thereof in medicine |
| CN102212015A (en) * | 2010-04-12 | 2011-10-12 | 上海源力生物技术有限公司 | Method for preparing chiral beta-amino arylbutyric acid derivatives |
| CN102372698A (en) * | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative and its preparation method and use in medicine |
| CN102464661A (en) * | 2010-11-16 | 2012-05-23 | 上海药明康德新药开发有限公司 | Preparation method of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid ethyl ester |
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| CN103724352A (en) | 2014-04-16 |
| CN106892926B (en) | 2019-09-06 |
| TWI628181B (en) | 2018-07-01 |
| CN103724352B (en) | 2017-11-28 |
| TW201416367A (en) | 2014-05-01 |
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