CN106432184A - Trelagliptin derivative and application tereof - Google Patents
Trelagliptin derivative and application tereof Download PDFInfo
- Publication number
- CN106432184A CN106432184A CN201610705695.2A CN201610705695A CN106432184A CN 106432184 A CN106432184 A CN 106432184A CN 201610705695 A CN201610705695 A CN 201610705695A CN 106432184 A CN106432184 A CN 106432184A
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- Prior art keywords
- compound
- lieting
- impurity
- love song
- amber love
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The invention provides a trelagliptin succinate impurity compound, and a preparation method and an application thereof. The compound is obtained with a chemical synthesis method. The compound is subjected to structural confirmation, such that the structure of the compound is determined. The compound is adopted as an impurity reference substance of trelagliptin succinate related substance detection, and assists in directly and effectively monitoring the changes of impurities in drug raw materials or during storage processes.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to a kind of bent Ge Lieting derivative and application thereof.
Background technology
Amber love song Ge Lieting (Trelagliptin succinate) is a kind of DPP IV (DPP-4) suppression
Agent.Wu Tian company of Japan have submitted the bent Ge Lieting amber of Glucovance on March 7th, 2014 to health workfare portion of Japan
The NDA of hydrochlorate, for the treatment of diabetes B, its chemical structural formula is：
The quality control of medicine is mainly the content of control active component and the content having related substance, more particularly to material
Content need to meet medicinal requirements, its impurity mainly medicine produce and store during produce.
The research of related substance and the height to drug quality for the control level is had to play key effect.Compare inorganic impurity and
Dissolvent residual, has the research of related substance complex with control, grinds in the separation qualification of impurity, source analysis, impurity security
Study carefully, the aspect such as limit of impurities determination is required to bound drug design feature, preparation technology, storage stability, clinical practice feature
Etc. carrying out numerous studies.
Patent application CN 105524044 A is in the quality research to bent Ge Lieting, in the bent Ge Lieting of discovery below existence
Four kinds of impurity：
The applicant is found that the brand-new impurity of a kind of structure to amber love song Ge Lieting quality controling research, and it is to finally
The safety and efficacy of medicine of dispatching from the factory has vital impact.
Content of the invention
It is an object of the invention to provide a kind of amber love song Ge Lieting impurity compound and its production and use, logical
Cross chemical synthesis and obtain this compound, and carry out structural identification to it confirming the structure of this compound, thus as
Impurity reference substance during amber love song Ge Lieting Related substances separation, miscellaneous during directly effectively monitoring pharmaceutical raw material or storing
The situation of change of matter.
The purpose of the present invention can be achieved by the following scheme：
A kind of amber love song Ge Lieting derivative compound and salt thereof or isomers, optionally from the one or several of following compound
Kind：
And salt or isomers.
Formulas I-1：(R)-N-(1-(3-(2-itrile group-5-fluorobenzene)-1-first class-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-
4-yl) piperidines-3-base) acetamide
Formulas I-2：(R) (((3-(2-cyano group-5-fluorophenyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydrochysene is phonetic for 1-for-4-
Pyridine-4-base) piperidines-3-base) amino)-4-ketobutyric acid
Formulas I-3：(9R)-14-fluoro-11-imino group-2-methyl-6,7,8,9,10,11-hexahydro-5,9-methyl benzo [j]
Pyrimido [1,6-a] [1,3,8] three azo-cycle dodecane-1,3 (2H, 16H)-diketone
Formulas I-4：N1, N4-bis-((R)-1-(3-(2-cyano group-5-fluorophenyl)-1-methyl-2,6-dioxo-1,2,3,6-
Tetrahydropyrimidine-4-base) piperidines-3-base) succinamide
Present invention also offers a kind of amber love song Ge Lieting derivative compound and salt thereof or isomers as amber love song
The purposes of Ge Lieting quality control impurity reference substance.
Present invention also offers the preparation method of amber love song Ge Lieting derivative compound and salt or isomers, but not only
It is limited to following method：
A kind of method preparing compound I-1, including：By amber love song Ge Lieting and DMF in organic solvent, reaction system
Obtain compound I-1；
Further, amber love song Ge Lieting being heated in DMF solvent more than 40 DEG C, reaction obtains compound I-1.
A kind of method preparing compound I-2, including：Succinic anhydride and bent Ge Lieting are dissolved and heat in organic solvent
Reaction, prepares compound I-2.
A kind of method preparing compound I-3, including：It is dissolved in amber love song Ge Lieting in organic solvent, heating reaction,
Prepare compound I-3.
A kind of method preparing compound I-4, including：In the basic conditions, succinic acid and condensing agent reaction, generate one and live
Property intermediate, then this reactive intermediate again with Qu Gelie statin response, prepare compound I-4.
The content of the amber love song Ge Lieting impurity of the present invention is that (HPLC detects wavelength by high performance liquid chromatography
230nm) measure, be calculated by area normalization method.
The quality control of the bent Ge Lieting of butanedioic acid and clinical drug safety detection offer standard pair can be by the present invention
According to product, monitor its impurity production during producing and storing, thus improve the quality mark of amber love song Ge Lieting product
Standard, the safe medication for amber love song Ge Lieting provides important directive significance, ensures clinical drug safety reliability.
Detailed description of the invention
For ease of understanding, below by specific embodiment, the present invention will be described in detail.Needs particularly point out
, instantiation is merely to explanation, it is clear that those of ordinary skill in the art can be according to illustrating herein, the present invention's
In the range of correction is made to the present invention.
The preparation of embodiment 1 Formulas I-1
2.50g amber love song Ge Lieting is put in DMF solution, is heated to 50 DEG C and dissolves clarification, at this temperature instead
Answer 3h.Stopping reaction, decompression steams solvent, adds 25mLEA, sodium acid carbonate and saturated aqueous common salt washing organic phase, nothing in raffinate
Aqueous sodium persulfate is dried, and filtering and concentrating obtains 1.82g crude product, purifies to obtain 1.54g compound I-1, productivity 76.24% through column chromatography.1H
NMR：(400MHz, DMSO-d6)：7.99-7.91(m,H),7.88(d,H),7.33(td,H),7.17(dd,H),5.37(s,
H),5.14(dd,H),3.05(s,3H),3.12-2.52(m,4H),2.06-1.91(m,3H),1.59-1.19(m,2H)；MS
(ES+)m/z:386.29[M+H]+.
The preparation of embodiment 2 Formulas I-2
It is stirred at room temperature down, in 100mL reaction bulb, add the succinic anhydride of 0.56g, 5mL1,4 dioxane, N2Protection,
It is warming up to 80 DEG C.Inject the mixing clarified solution of bent to 30mL 1,4 dioxane and 2.00g Ge Lieting in above-mentioned reactant liquor in batches.
After finishing, reflux 3h.Stopping reaction, decompression steams solvent, adds the EA of 15mL, stir after washing 15min in raffinate, filters, and is dried
Obtain 1.32g crude product, purify to obtain 0.88g compound I-2, productivity 34.38% through column chromatography.1H NMR：(400MHz, DMSO-d6)：
12.04(s,H),7.93(dd,H),7.79(d,H),7.34(t,H),7.19(d,H),5.34(s,H),5.15(dd,2H),
3.77-3.61(br,H),3.13-2.93(m,4H),2.98-2.85(m,H),2.77-2.59(m,H),2.55-2.41(m,H),
2.41-2.13(m,4H),1.82-1.67(m,2H),1.61-1.21(m,2H)；MS(ES+)m/z:458.4[M+H]+.
The preparation of embodiment 3 Formulas I-3
In the single port bottle of 25mL, add 2.01g amber love song Ge Lieting, add 3ml acetonitrile and 10ml water, stir molten
Clearly.It is warming up to 80 DEG C, stir 48h.After reactant liquor concentrates, purify to obtain compound I-3 through column chromatography.1H NMR：(400MHz,
DMSO-d6)：7.97(dd,H),7.35(td,H),7.06(dd,H),5.43(d,2H),5.01(s,H),3.81-3.70(m,
2H),3.28-3.08(m,5H),2.75(m,1H),1.87-1.52(m,4H)；MS(ES+)m/z:358.8[M+H]+.
The preparation of embodiment 4 Formulas I-4
In 500mL reaction bulb, addition 0.66g succinic acid, 6.80g triethylamine, 12.88gEDC HCl,
10.08gHOBt, 200mLDMF.Then it is dividedly in some parts the bent Ge Lieting of 4.00g, at 35 DEG C, first reacts 3h, then 25 DEG C stirred
Night.Stopping reaction, pouring reactant liquor in 600mL water, stir 5min, DCM extracts (200mL x 3), the organic phase after merging
Washing (200mL x 2) with saturated common salt, anhydrous sodium sulfate is dried, and filters, and after mother liquor decompression is spin-dried for, purifies to change through column chromatography
Compound I-4, productivity 17.85%.1H NMR：(400MHz, DMSO-d6)：7.93(dd,2H),7.80(d,2H),7.32(td,
2H),7.18(dd,2H),5.34(s,2H),5.15(dd,4H),3.78-3.62(br,2H),3.13-3.01(m,8H),2.95-
2.78(m,2H),2.83-2.71(m,2H),2.52-2.40(m,2H),2.31-2.10(m,4H),1.79-1.68(m,4H),
1.26-1.57(m,4H)；MS(ES+)m/z:797.4[M+H]+.
Embodiment 5 amber love song Ge Lieting impurity compound when Valsartan Related substances separation as impurity reference substance
Application
Chromatographic condition：It is filler with octadecylsilane chemically bonded silica, with 0.1% phosphoric acid as mobile phase A, with acetonitrile be
Mobile phase B；According to the form below gradient elution；Flow velocity is 1.0ml/min, and detection wavelength is 230nm.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 85 | 10 |
| 30 | 50 | 60 |
| 40 | 50 | 60 |
| 40.1 | 85 | 10 |
Experimental procedure：Take amber love song Ge Lieting segmentation appropriate, accurately weighed, add 0.1% phosphoric acid-acetonitrile (85:15) molten
Solution makes the solution of the Ge Lieting of love song containing amber 1.0mg in every 1ml, shakes up, as need testing solution；Precision measures 1ml, puts
In 100ml measuring bottle, with water-acetonitrile (85:15) it is diluted to scale, shakes up, as contrast solution.Take impurity I-1, impurity I-2, miscellaneous
Matter I-3, impurity I-4 and amber love song Ge Lieting reference substance are each in right amount, with water-acetonitrile (85:15) dissolve and quantitatively dilution is made
The solution of about 10 μ g/ml, as system suitability solution.Survey according to high performance liquid chromatography (2015 editions general rules 0512 of Chinese Pharmacopoeia)
Fixed, it is filler with octadecylsilane chemically bonded silica, with 0.1% phosphoric acid as mobile phase A, with acetonitrile as Mobile phase B；According to the form below
Gradient elution；Flow velocity is 1.0ml/min, and detection wavelength is 230nm.Precision measures need testing solution and each 10 μ of reference substance solution
L, is injected separately into liquid chromatograph, records chromatogram, behind deduction butanedioic acid peak, if any impurity in the chromatogram of need testing solution
Peak, impurity I-1, impurity I-2, impurity I-3, impurity I-4 peak area all cannot be greater than 0.15 times of contrast solution main peak area
(0.15%), other single impurity peak area cannot be greater than 0.1 times (0.1%) of the main peak area of contrast solution, each impurity peaks
Area and cannot be greater than contrast solution main peak area 0.5 times (0.5%).
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 85 | 10 |
| 30 | 50 | 60 |
| 40 | 50 | 60 |
| 40.1 | 85 | 10 |
Method with reference to CN 101374523 prepares amber love song Ge Lieting raw material, is taken out two parts as sample
20150801 and sample 20150802, raw material is heated through DMF solvent, obtains sample 20150803, raw material is passed through
High-temperature process obtains sample 20150804, is respectively adopted above-mentioned sample, carries out Related substances separation.
The relevant content of material of amber love song Ge Lieting checks result
| Lot number | 20150801 | 20150802 | 20150803 | 20150804 |
| Impurity I-1 (%) | 0.02 | 0.03 | 0.09 | Do not detect |
| Impurity I-2 (%) | 0.07 | 0.08 | Do not detect | Do not detect |
| Impurity I-3 (%) | Do not detect | Do not detect | 0.11 | 0.08 |
| Impurity I-4 (%) | 0.06 | 0.05 | Do not detect | 0.09 |
| Other maximum single miscellaneous (%) | 0.06 | 0.06 | 0.08 | 0.05 |
| Always miscellaneous (%) | 0.33 | 0.31 | 0.45 | 0.39 |
Claims (2)
1. amber love song Ge Lieting derivative compound and salt thereof or an isomers, optionally from the one or several of following compound
Kind：
And salt or isomers.
2. the amber love song Ge Lieting derivative compound described in claim 1 and salt or isomers thereof are as amber love song Ge Lieting
The purposes of quality control impurity reference substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610705695.2A CN106432184A (en) | 2016-08-22 | 2016-08-22 | Trelagliptin derivative and application tereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610705695.2A CN106432184A (en) | 2016-08-22 | 2016-08-22 | Trelagliptin derivative and application tereof |
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| Publication Number | Publication Date |
|---|---|
| CN106432184A true CN106432184A (en) | 2017-02-22 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610705695.2A Pending CN106432184A (en) | 2016-08-22 | 2016-08-22 | Trelagliptin derivative and application tereof |
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| Country | Link |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305106A (en) * | 2019-06-20 | 2019-10-08 | 石药集团中奇制药技术（石家庄）有限公司 | Related substance of a kind of amber love song Ge Lieting and preparation method thereof, analysis method and application |
| CN111116560A (en) * | 2019-11-29 | 2020-05-08 | 北京鑫开元医药科技有限公司 | Preparation method of succinamide derivative |
| CN113004244A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Trelagliptin impurity and preparation method and application thereof |
| CN115057846A (en) * | 2022-08-05 | 2022-09-16 | 北京鑫开元医药科技有限公司 | Preparation method of trelagliptin dimer |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105524044A (en) * | 2014-10-22 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Trelagliptin impurity and its composition |
| CN105699547A (en) * | 2016-04-22 | 2016-06-22 | 中山万汉医药科技有限公司 | Method for measuring related substances in succinic acid Trelagliptin raw materials |
| CN105738517A (en) * | 2016-02-24 | 2016-07-06 | 中山万汉医药科技有限公司 | Method for determining related substances in Trelagliptin tablets |
-
2016
- 2016-08-22 CN CN201610705695.2A patent/CN106432184A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105524044A (en) * | 2014-10-22 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Trelagliptin impurity and its composition |
| CN105738517A (en) * | 2016-02-24 | 2016-07-06 | 中山万汉医药科技有限公司 | Method for determining related substances in Trelagliptin tablets |
| CN105699547A (en) * | 2016-04-22 | 2016-06-22 | 中山万汉医药科技有限公司 | Method for measuring related substances in succinic acid Trelagliptin raw materials |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110305106A (en) * | 2019-06-20 | 2019-10-08 | 石药集团中奇制药技术（石家庄）有限公司 | Related substance of a kind of amber love song Ge Lieting and preparation method thereof, analysis method and application |
| CN110305106B (en) * | 2019-06-20 | 2021-05-25 | 石药集团中奇制药技术（石家庄）有限公司 | Trelagliptin succinate related substance, and preparation method, analysis method and application thereof |
| CN111116560A (en) * | 2019-11-29 | 2020-05-08 | 北京鑫开元医药科技有限公司 | Preparation method of succinamide derivative |
| CN113004244A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Trelagliptin impurity and preparation method and application thereof |
| CN115057846A (en) * | 2022-08-05 | 2022-09-16 | 北京鑫开元医药科技有限公司 | Preparation method of trelagliptin dimer |
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Address after: 210012 C3, 9 Wei Di Road, Xianlin University Town, Nanjing, Jiangsu. Applicant after: Nanjing Huawei Medicine Technology Group Co Ltd Address before: 210012 C3, 9 Wei Di Road, Xianlin University Town, Nanjing, Jiangsu. Applicant before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |
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Application publication date: 20170222 |