CN106892926B - A kind of intermediate of DPP-IV inhibitor, preparation method and the method that DPP-IV inhibitor is prepared by it - Google Patents
- ️Fri Sep 06 2019
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- CN106892926B CN106892926B CN201710059960.9A CN201710059960A CN106892926B CN 106892926 B CN106892926 B CN 106892926B CN 201710059960 A CN201710059960 A CN 201710059960A CN 106892926 B CN106892926 B CN 106892926B Authority
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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
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
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Abstract
The present invention relates to a kind of intermediate of DPP-IV inhibitor (Formulas I), preparation methods and the method for preparing DPP-IV inhibitor by it.Specifically, the method is reacted by cyclic chiral beta-amino arylbutyric acid derivatives (formula II) and compound III, amido protecting group is then removed, DPP-IV inhibitor needed for being made.This method is easy to operate, at low cost, is suitable for large-scale production.
Description
The application is application No. is 201210393435.8, and the applying date is on October 16th, 2012, entitled " a kind of The Chinese patent application of intermediate, preparation method and the method that DPP-IV inhibitor is prepared by it of DPP-IV inhibitor " Divisional application.
Technical field
DPP-IV inhibitor is prepared the present invention relates to a kind of intermediate of DPP-IV inhibitor, preparation method and by it Method.
Background technique
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 cause sugar, protein, A series of metabolic disorder syndromes such as fat, water and electrolyte are one of the principal diseases for threatening human health.Diabetes are usual It is divided to type 1 diabetes and two kinds of diabetes B, wherein diabetes B accounts for 90% or more, studies the side of effectively treatment diabetes B Method is always the important topic of diabetes study work.
The study found that dipeptidyl peptidase-IV (dipeptidyl peptidase IV, DPP-IV) is related to diabetes The important enzyme of one kind, inhibit DPP-IV enzyme that can effectively treat diabetes B, therefore, DPP-IV enzyme inhibitor is a kind of The glycogenetic newtype drug of blood is controlled for treating or improving type 2 diabetic patient, has many DPP-IV enzymes at present and inhibits Agent is applied to clinical test, and have it is some gone through to list, 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 inhibiting effect to DPP-IV enzyme.This DPP-IV disclosed by above-mentioned patent inhibits The disadvantages of in the preparation method of agent, it is long to there is synthesis step, cumbersome, high expensive.
WO2011/127794 describe it is a kind of prepare the cyclic chiral beta-amino arylbutyric acid derivatives 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.
Summary of the invention
The purpose of the present invention is 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, hydroxyl, alkyl or alkoxy The phenyl that group replaces, wherein alkyl or alkoxy are unsubstituted or are further replaced by one or more halogens, preferably Ar1It is 2,4,5- trifluorophenyl；R1Selected from hydrogen atom, alkyl, trifluoromethyl, naphthenic base, aryl or heteroaryl, wherein alkyl, ring Alkyl, aryl, heteroaryl are optionally further by one or more substituent group institutes for being selected from halogen, cyano, aryl, hydroxyl or amino Replace, preferably R1It is trifluoromethyl；R2For hydrogen or substituted or non-substituted C1-10Linear or branched alkyl group, 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 C1-10Linear or branched alkyl group, preferably R3It is hydrogen atom.
Compound of formula I provided by the invention the preparation method is as follows:
Wherein, Ar1、R1、R2、R3As defined in Formulas I；Ar2It is unsubstituted or by 1-5 selected from halogen, cyano, hydroxyl The phenyl that the group of base, alkyl or alkoxy replaces, wherein alkyl or alkoxy be it is unsubstituted or further by one or Multiple halogens replace.
In a preferred embodiment of the present invention, Ar1It is 2,4,5- trifluorophenyl；Ar2It is phenyl；R1It is fluoroform Base；R2It is methyl；R3It is hydrogen atom.
Specifically, this method includes the following steps:
1) cyclic chiral beta-amino arylbutyric acid derivatives (formula II) and compound III react to obtain compound IV；
2) DPP-IV inhibitor shown in formula I is made after removing the amino protecting groups of compound IV.
In step 1), the reaction of compound II and compound III can carry out under the action of an acid, and the acid can be with It is inorganic acid, organic acid or lewis acid.
In one embodiment of the invention, the acid be lewis acid, selected from alchlor, diethyl aluminum chloride, Ethylaluminum dichloride, trimethyl aluminium, triethyl aluminum, zinc chloride etc., preferably diethyl aluminum chloride.
After the amino protecting groups in compound shown in removing formula IV, Formulas I compound represented, amine can be directly obtained The removal methods of base protecting group can be oxidation removal, be also possible to reduction removing；It is preferred specific real at of the invention one It applies in mode, the removal methods of the amido protecting group of compound IV select the removing of Pd/C catalytic hydrogenolysis method.
In order to complete above-mentioned purpose, one aspect of the present invention provides a kind of such as formula IV compound represented, which 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, hydroxyl The phenyl that the group of base, alkyl or alkoxy replaces, wherein alkyl or alkoxy be it is unsubstituted or further by one or Multiple halogens replace, preferably Ar2It is phenyl.
Another aspect of the present invention provides a kind of preparation method of compound as shown in formula IV, and this method is used such as Formula II institute The cyclic chiral beta-amino arylbutyric acid derivatives and compound III shown react to obtain compound IV,
Ar1、Ar2、R1、R2、R3As defined in formula IV.
In the method, the reaction of compound II and compound III can carry out under the action of an acid, and the 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, the Louis This acid is preferably diethyl aluminum chloride.
The present invention also provides a kind of such as formula III compound represented, can be used for preparing such as formula IV compound represented,
Wherein, R1、R2、R3As defined in formula IV.
The present invention also provides the preparation method of compound III a kind of, the compound III passes through the hydrogenation of compound V It is made after reduction,
Wherein, R1、R2、R3As defined in formula IV.
In a preferred embodiment of the invention, compound V is hydrogenated under the action of catalyst Pd/C To compound III.
The present invention also provides a kind of compounds shown as a formula V, can be used for easily prepare compound III,
Wherein, R1、R2、R3As defined in formula IV.
The present invention also provides the preparation methods of compound V a kind of, by compound VI disclosed in the prior art in POX3 Intramolecular cyclization, then obtains compound V under the action of dehydrating agent under the action 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, the POX3Preferably POCl3, the dehydrating agent Preferably P2O5。
The method of the present invention has synthetic route short, easy to operate, and the optical purity of product is high, at low cost and suitable industrialization The features such as production, has significant Social benefit and economic benefit.
Term used in the present invention has following meaning in addition to having opposite statement:
" alkyl " refers to the aliphatic hydrocarbon group of saturation, and straight chain and branched group including 1 to 10 carbon atom preferably include 1 To 6 carbon atoms.Non-limiting embodiment include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrate Base, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl Amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be substituted or unsubstituted, when substituted, substituent group It can be substituted on any workable 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, naphthenic base, Heterocyclylalkyl, aryl, Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" naphthenic base " refers to that 3 to 8 yuan of full carbon monocycles, 5 yuan/6 yuan of full carbon or 6 yuan/6 yuan fused rings or polycyclic fused rings are (" thick Conjunction " ring system means each ring in system and shared a pair of of the carbon atom adjoined of other rings in system) group, one of them Or multiple rings can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.The reality of naphthenic base Example has cyclopropyl, cyclobutyl, cyclopenta, cyclopentene, hexamethylene, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene etc.." ring Alkyl " can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups, is independently selected From alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, heterocycle Alkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" Heterocyclylalkyl " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent comprising 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 are carbon.5 to 6 annular atoms are preferably included, wherein 1,2,3 or 4 is Hetero atom." Heterocyclylalkyl " can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following bases Group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, Naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared to adjoin The ring of carbon atom pair) group, preferably 6 to 10 yuan, more preferable phenyl and naphthalene.Aryl can be substituted or unsubstituted, When substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Sulfenyl, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, Heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" heteroaryl " refers to the heteroaromatic system comprising 6 to 10 annular atoms, wherein include 1,2,3 or 4 hetero atom, Middle hetero atom includes oxygen, sulphur and nitrogen；Such as pyridyl group, pyrimidine radicals etc.." heteroaryl " can be optionally it is substituted or unsubstituted, When substituted, substituent group is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Sulfenyl, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, Heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted naphthenic base), and wherein alkyl, naphthenic base are as defined above institute It states.Non-limiting embodiment include methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, Cyclohexyloxy etc..Alkoxy can be optionally it is substituted or unsubstituted, when substituted, substituent group be preferably one or more Following group, independently selected from for alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitre Base, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Specific embodiment
The present invention is explained in detail below with reference to specific example so that this hair is more fully understood in those skilled in the art Bright, specific example is only used to illustrate the technical scheme of the present invention, and does not limit the present invention in any way.
Following table is the structural formula of involved compound in embodiment:
Embodiment 1: prepare compound VIa
By 2- ammonia -2- pyrazine-acetate hydrochloride (13.6g, by literature method prepare J.Med.Chem.1994,37, 4567) methylene chloride (180mL) solution is cooled to 0-10 DEG C, and triethylamine (8.0g) is added dropwise in the above solution, resulting mixed Close liquid temperature control at 0-10 DEG C, be added dropwise trifluoro-acetic anhydride (14.6g), 5-15 DEG C stirring 1-2 hours, add sodium bicarbonate satisfy With solution (135mL), stirring layering separates organic phase, and magnesium sulfate is added and dries, filters, is concentrated to get 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 adds people's ethyl acetate, is concentrated, and is cooled to 0 DEG C, and dropwise addition water quenching goes out three Chlorethoxyfos are added dropwise 25% ammonium hydroxide and adjust pH=7-9, ethyl acetate is added to extract, merge organic phase, be concentrated to give 13.2g crude product, are added 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
10% palladium carbon of 0.8g is added in ethyl acetate (40mL) solution of compound Va (7.3g), and (aqueous 60%), adds Hydrogen (30psi) stirs 4-6 hours at 20-30 DEG C, filters, and petroleum ether is added in concentration, 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 has been 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 has been 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 has been synthesized.
IIId:1H-NMR(400MHz,CDCl3) δ 7.51~7.37 (m, 5H), 5.43 (s, 2H), 4.41 (s, 2H), 4.18 ~4.15 (t, 2H), 3.32~3.30 (t, 2H), 2.15 (s, 1H)
Embodiment 7: prepare compound IIIe
Using the same procedure of synthesis compound IIIa, analog IIIe has been 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 has been 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
Methylene chloride (25mL) solution of compound IIIa (4.8g) is cooled to -15 DEG C, the chlorination of 25mL diethyl is added The toluene solution (0.9M) of aluminium, resulting mixed liquor stir 10 minutes at -10 DEG C, and compound IIa is then added dropwise, and (5.0g is pressed The preparation of WO2011/127794 method) methylene chloride (25mL) solution, resulting mixed liquor is warming up to 10 DEG C and stirs 40 small When, 1N HCl (50mL) quenching reaction is added dropwise, separates organic phase and uses 0.5N NaOH aqueous solution and water washing respectively, it is 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 added dropwise to the outstanding of alchlor (480mg) and methylene chloride (30mL) In turbid, the methylene chloride of compound IIa (980mg) and compound IIIa (980mg) is added dropwise until formation clear solution in stirring (30mL) solution stirs 2 hours at 15-25 DEG C, is cooled to 0-5 DEG C, and 1N HCl quenching reaction is added dropwise, and separates organic phase and divides Not Yong saturated sodium bicarbonate aqueous solution and water washing, it is 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 methanol (100mL) of compound IVa (9.0g), Add hydrogen (15psi), is stirred 16 hours at 40-50 DEG C, filter away catalyst, filtrate is neutralized to pH=with saturated sodium bicarbonate 7, it is extracted with dichloromethane after concentration, separates organic phase, it is 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, certain 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 (10)
1. a kind of formula III compound represented,
Wherein, R1For trifluoromethyl；R2For hydrogen, ethyl, C1-10Branched alkyl, substituted or non-substituted C3-8Cyclic alkyl, Or substituted or non-substituted C6-10Aryl；R3It is hydrogen atom.
2. a kind of prepare the method such as formula III compound represented, it is characterised in that including compound shown as a formula V through being catalyzed The step of compound shown in formula III is made after hydrogenation,
Wherein, R1、R2、R3As defined in claim 1.
3. a kind of 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 it includes the step of compound shown in Formula V is made in Formula IV compound represented after cyclodehydration,
Wherein, R1、R2、R3As defined in claim 1.
5. according to the method described in claim 4, wherein compound VI is in POX3Under the action of intramolecular cyclization, be then dehydrated Compound V is obtained under the action of agent, wherein X is halogen.
6. according to the method described in claim 5, wherein POX3For POCl3, dehydrating agent P2O5。
7. a kind of method for preparing DPP-IV inhibitor shown in formula I comprising Formula V compound represented is after catalytic hydrogenation The step of compound shown in formula III is made, compound shown in Formula II reacts to obtain formula IV compound with compound shown in formula III The step of amino protecting group removes in step and formula IV compound,
Wherein, Ar1It is benzene that is unsubstituted or being replaced by the 1-5 groups selected from halogen, cyano, 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, naphthenic base, aryl or heteroaryl, wherein alkyl, naphthenic base, aryl, heteroaryl optionally further by one or Replaced multiple substituent groups selected from halogen, cyano, aryl, hydroxyl or amino；R2For 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；R3Selected from hydrogen original Sub or substituted or non-substituted C1-10Linear or branched alkyl group；Ar2Be it is unsubstituted or by 1-5 selected from halogen, cyano, The phenyl that the group of hydroxyl, alkyl or alkoxy replaces, wherein alkyl or alkoxy are unsubstituted or further by one Or multiple halogens replace.
8. according to the method described in claim 7, further including that change shown in Formula V is made in Formula IV compound represented after cyclodehydration The step of closing object,
Wherein, R1、R2、R3As defined in claim 7.
9. according to the method described in claim 8, wherein compound VI is in POX3Under the action of intramolecular cyclization, be then dehydrated Compound V is obtained under the action of agent, wherein X is halogen.
10. according to the method described in claim 9, wherein POX3For POCl3, dehydrating agent P2O5。
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| CN113773323B (en) * | 2020-06-10 | 2023-05-12 | 江苏恒瑞医药股份有限公司 | Preparation method of 3R-amino substituted butyramide derivative |
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| CN106892926A (en) | 2017-06-27 |
| CN103724352B (en) | 2017-11-28 |
| TWI628181B (en) | 2018-07-01 |
| TW201416367A (en) | 2014-05-01 |
| CN103724352A (en) | 2014-04-16 |
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