CN109111403A - Horse former times rises smooth related substance, preparation method and the usage - Google Patents
Horse former times rises smooth related substance, preparation method and the usage Download PDFInfo
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- CN109111403A CN109111403A CN201810839815.7A CN201810839815A CN109111403A CN 109111403 A CN109111403 A CN 109111403A CN 201810839815 A CN201810839815 A CN 201810839815A CN 109111403 A CN109111403 A CN 109111403A
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- former times
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- 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
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- General Health & Medical Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention discloses such as following formula (I) compound represented, it rises the purposes of smooth impurity reference substance as horse former times and separation determination horse former times rises smooth and formula (I) compound efficient liquid-phase chromatography method.Preparation method reaction condition provided by the invention is mild, post-processing is simple, and the satisfactory formula of purity (I) compound, the impurity reference substance to rise smooth quality analysis as horse former times can be gone out with prepare with scale.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to horse former times rises smooth related substance, preparation method and purposes.
Background technique
It is the dual endothelin receptor antagonist developed by Actelion that horse former times, which rises smooth, and FDA approval listing in 2013 is clinical
Treatment for pulmonary hypertension.Its structural formula is as follows:
Carrying out quality control to bulk pharmaceutical chemicals and preparation is always the key points and difficulties in medicament research and development, and to miscellaneous Quality Research
It is the most important thing in quality control again.Horse former times rises starting material, intermediate, by-product and catabolite in smooth synthesis process
Deng being likely to become the impurity remained in finished product, and then influence product quality.
The smooth research in relation to object Quality Research and Analysis of quality control method is risen to horse former times at present and rarely has document report.
It is technique side reaction impurity and degradation impurity that Ma Xi, which rises smooth impurity H and impurity I, and synthesis and quality research are to work
The quality of skill controls and stability study is of great significance.
Summary of the invention
The technical problem to be solved by the present invention is to rise issuable related substance in smooth synthesis process to horse former times to grind
Study carefully.
The first aspect of the present invention provides lower formula (I) compound represented:
R is selected from H, Br；
When R is H, Compound nomenclature H, when R is Br, Compound nomenclature J.
The second aspect of the present invention provides above-mentioned formula (I) compounds process for production thereof:
(1) compound H's the preparation method is as follows:
Horse former times is risen into smooth generation debromination and generates compound H；
Preferably, debromination is in ammonium formate/Pd-C system or Pd-C/H2It is carried out under system；
Preferably, reaction dissolvent is selected from anhydrous C1~C4 alcohols solvent, more preferable anhydrous methanol, dehydrated alcohol.
(2) compound J's the preparation method is as follows:
1) debromination is occurred into for compound V and generates intermediate V-6；
2) intermediate V-6 reacts in the presence of alkaline reagent with the bromo- 2- chlorine pyrimidine of 5- generates compound J；
Preferably, in step (1) ammonium formate, Pd/C system under debromination occurs；
Preferably, reaction dissolvent is selected from anhydrous C1~C4 alcohols solvent, more preferable anhydrous methanol, anhydrous second in step (1)
Alcohol；
Preferably, the alkaline reagent in step (2) is selected from sodium hydride, hydrofining, sodium tert-butoxide, potassium tert-butoxide, the tert-butyl alcohol
Lithium；
Preferably, the reaction dissolvent of step (2) is selected from glycol dimethyl ether, tetrahydrofuran, toluene, N, N- dimethyl formyl
Amine, dimethyl sulfoxide, one or both of more preferable tetrahydrofuran, n,N-Dimethylformamide.
Third aspect present invention provides the purposes that formula (I) compound rises smooth bulk pharmaceutical chemicals impurity reference substance as horse former times.
Fourth aspect present invention provide a kind of separation determination horse former times rise it is smooth with formula (I) compound high performance liquid chromatography side
Method, comprising the following steps:
Chromatographic condition setting: using octadecylsilane chemically bonded silica as chromatography column packing, with 8~12mmol/L di(2-ethylhexyl)phosphate
Hydrogen aqueous solutions of potassium-acetonitrile is mobile phase A, using acetonitrile as Mobile phase B, carries out gradient elution；Wherein potassium dihydrogen phosphate aqueous solution is used
It is 4.5~5.5 that sodium hydroxide, which adjusts pH,；
Solution is prepared: being risen smooth raw material using acetonitrile dissolution horse former times, is configured to the solution that concentration is 0.1~1mg/mL；
Detection: it takes the horse former times of preparation to rise smooth solution injection high performance liquid chromatograph, records chromatogram and analyzed.
Preferably, wherein the gradient elution program is as follows:
Beneficial effects of the present invention: the present invention rises issuable related substance in smooth synthesis process to horse former times and is ground
Study carefully, compound H, compound J have been prepared by above-mentioned preparation method, it is miscellaneous in smooth bulk pharmaceutical chemicals quality research to be risen as horse former times
Matter reference substance.The present invention also provides a kind of separation determination horse former times to rise smooth and high-efficient liquid phase color in relation to substance H and in relation to substance J
Whether spectral analysis method can quickly detect containing related substance H and related substance J in bulk pharmaceutical chemicals, be qualitative and quantitative detection
Horse former times rises smooth bulk pharmaceutical chemicals and provides new selection.
Specific embodiment
The present invention is further explained below, but is not intended to limit the present invention.
Horse former times rises smooth bulk pharmaceutical chemicals and is made by oneself by Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.
Preparation of the embodiment 1 in relation to substance H
Weigh 3.0g horse former times rise it is smooth be added in single port bottle, 30ml dehydrated alcohol and 1.5gPd/C and 0.6g formic acid is added
Ammonium, back flow reaction 4h, is down to room temperature, and reaction solution is poured into 300ml aqueous citric acid solution, stirs 2h, filters, and filtration cakes torrefaction obtains
1.6g solid.Crude product obtains 1.0g solid with recrystallizing methanol.HPLC purity 100%.1H NMR(DMSO-d6): δ 9.35 (1H, s),
8.57(2H,d),8.50(1H,s),7.37(3H,d),7.23(3H,d),7.13(1H,t),4.66(2H,s),4.57(2H,s),
2.81(2H,q),1.42(2H,m),0.80(3H,t).ESI(+)m/z 431.3
Preparation of the embodiment 2 in relation to substance H
Weigh 3.0g horse former times rise it is smooth be added in single port bottle, 30ml anhydrous methanol and 1.5g Pd/C is added, in hydrogen atmosphere
Lower reaction 3h, is down to room temperature, and reaction solution is poured into 300ml aqueous citric acid solution, stirs 2h, filters, and filtration cakes torrefaction obtains 1.5g
Solid.8ml methanol is added, flow back 2h, is down to room temperature, filters, and filtration cakes torrefaction obtains 0.8g solid, HPLC purity 99.5%.
Preparation of the embodiment 3 in relation to substance J
It takes 10.0g intermediate V, 5.1g ammonium formate, 5.0gPd/C and 100ml dehydrated alcohol to add in reaction flask, heats back
2h is flowed, is filtered, the elution of 20ml dehydrated alcohol.Filtrate is poured into 10% aqueous citric acid solution of 300ml, and 50ml ethyl acetate is added to extract
It takes 3 times, organic phase is dry with 40.2g anhydrous magnesium sulfate, and suction filtration is concentrated to give solid, and solid adds 10ml anhydrous methanol, is heated to back
Stream, is cooled to 20 DEG C of stirring and crystallizings, filters, and 5ml anhydrous methanol elution, filtration cakes torrefaction obtains 2.1g V -6.
0.7g sodium hydrogen, 21ml tetrahydrofuran and above-mentioned 2.1g V -6 are added into single port bottle, 5ml DMF is added after stirring 1h
With the bromo- 2- chlorine pyrimidine of 1.4g5-, 60 DEG C are heated to, reacts 2h.25 DEG C are cooled to, filtrate is poured into 10% citric acid water of 60ml
Solution, stirring are added 150ml ethyl acetate and extract 3 times, and organic addition 38.6g anhydrous magnesium sulfate is dry, filters, and organic phase is dense
It is reduced to dry solid, adds 10ml anhydrous methanol to be heated to flowing back, is cooled to 12 DEG C of stirring and crystallizings, is filtered, filtration cakes torrefaction obtains 1.8g
Solid, HPLC purity: 97.2%.1H NMR(DMSO-d6): δ 9.36 (1H, s), 8.69 (2H, s), 8.49 (1H, s), 7.35
(3H,m),7.22(3H,m),4.64(2H,m),4.57(2H,m),2.78(2H,q),1.41(2H,m),0.80(3H,t).ESI
(+)m/z 509.3
Preparation of the embodiment 4 in relation to substance J
It takes 10.0g intermediate V, 5.1g ammonium formate, 5.0gPd/C and 100ml anhydrous methanol to add in reaction flask, heats back
2h is flowed, reaction solution directly filters, the elution of 20ml dehydrated alcohol.Filtrate is poured into 10% aqueous citric acid solution of 300ml, and 150ml is added
Ethyl acetate extracts 3 times, and organic phase is dry with 40.2g anhydrous magnesium sulfate, and suction filtration is concentrated to give solid, and solid adds 10ml without water beetle
Alcohol is heated to reflux dissolved clarification, is cooled to 20 DEG C of stirring and crystallizings, filters, and 5ml anhydrous methanol elution, filtration cakes torrefaction obtains 2.0g V -6.
0.8g sodium hydrogen, 21ml tetrahydrofuran and above-mentioned 2.0g V -6 are added into single port bottle, 5ml toluene is added after stirring 1h
With the bromo- 2- chlorine pyrimidine of 1.4g5-, 60 DEG C are heated to, reacts 2h.25 DEG C are cooled to, filtrate is poured into 10% citric acid water of 60ml
Solution stirring, adds 150ml ethyl acetate to extract 3 times, and organic addition 38.6g anhydrous magnesium sulfate is dry, filters, and organic phase is concentrated into
Solid is done to obtain, 10ml anhydrous methanol is added to be heated to reflux, is cooled to 12 DEG C, stirring and crystallizing filters, and filtration cakes torrefaction obtains 2.1g solid.
5 analysis method of embodiment
Instrument: 1100/1260 high performance liquid chromatograph of Agilent
Chromatographic column: YMC-Pack ODS-A (250 × 4.6mm, 5 μm)
Mobile phase: 10mmol/L potassium dihydrogen phosphate (it is 5.0 that sodium hydroxide solution, which adjusts pH)-acetonitrile (90:10) is flowing
Phase A；Using acetonitrile as Mobile phase B, according to the form below carries out linear gradient elution:
Detection wavelength: 210nm
Flow velocity: 1mL/min
Column temperature: 30 DEG C
Sample volume: 10 μ L
Related substance H prepared in the above embodiments, appropriate J are taken respectively, it is accurately weighed, it acetonitrile is added dissolves and dilutes and is made
Solution of every 1mL containing about 0.5mg is as positioning solution.
Weighing horse former times rises smooth appropriate, and impurity H, J is added and positions solution, is made former times containing horse in every 1mL and rises smooth about 0.5mg, divides
The solution of not impure about 2.5 μ g of H, J, as system suitability solution.
Weighing horse former times rises smooth appropriate, is placed in measuring bottle, uses acetonitrile dissolve and dilutes the solution of 0.5mg/mL is made as confession
Test sample solution.
Measurement: impurity H, J positioning solution, system suitability solution, horse former times rise each 10 μ L of smooth test solution and are injected separately into
High performance liquid chromatograph records chromatogram.The result shows that this method may be implemented to rise smooth good point in relation to substance H, J and horse former times
Risen from, horse former times smooth in 25.805min appearance, related substance H is in 9.957min appearance, and related substance J is in 18.981min appearance.
Test solution measurement result shows that horse former times made from our company rises in smooth bulk pharmaceutical chemicals without related substance H and related substance J.
Claims (10)
1. lower formula (I) compound represented:
R is selected from H, Br.
2. compound represented according to claim 1, which is characterized in that R H.
3. compound represented according to claim 1, which is characterized in that R Br.
4. the method for preparing compound described in claim 2, which is characterized in that synthetic route is as follows:
Horse former times is risen into smooth generation debromination prepare compound H.
5. the preparation method according to claim 4, which is characterized in that horse former times rises smooth in ammonium formate/Pd-C system or Pd-C/
H2Debromination prepare compound H occurs under system.
6. the method for preparing compound described in claim 3, which is characterized in that synthetic route is as follows:
Debromination is occurred into for compound V and generates intermediate V-6；
(1) intermediate V-6 reacts in the presence of alkaline reagent with the bromo- 2- chlorine pyrimidine of 5- generates compound J.
7. preparation method according to claim 6, which is characterized in that in ammonium formate/Pd-C system or Pd- in step (1)
C/H2Debromination occurs under system；Alkaline reagent in step (2) is selected from sodium hydride, hydrofining, sodium tert-butoxide, the tert-butyl alcohol
Potassium, tert-butyl alcohol lithium.
8. compound described in claim 1 is rising the purposes in smooth bulk pharmaceutical chemicals impurity reference substance as horse former times.
9. a kind of separation determination horse former times rises smooth and formula (I) compound efficient liquid-phase chromatography method, which is characterized in that including following
Step:
Chromatographic condition setting: using octadecylsilane chemically bonded silica as chromatography column packing, with 8~12mmol/L potassium dihydrogen phosphate
Aqueous solution-acetonitrile is mobile phase A, using acetonitrile as Mobile phase B, carries out gradient elution；Wherein potassium dihydrogen phosphate aqueous solution hydrogen-oxygen
Changing sodium to adjust pH is 4.5~5.5；
Sample solution is prepared: being risen smooth raw material using acetonitrile dissolution horse former times, is configured to the solution that concentration is 0.1~1mg/mL；
Detection: it takes the horse former times of preparation to rise smooth solution injection high performance liquid chromatograph, records chromatogram and analyzed.
10. according to the method described in claim 9, it is characterized in that, gradient elution program is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810839815.7A CN109111403A (en) | 2018-07-27 | 2018-07-27 | Horse former times rises smooth related substance, preparation method and the usage |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810839815.7A CN109111403A (en) | 2018-07-27 | 2018-07-27 | Horse former times rises smooth related substance, preparation method and the usage |
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| CN109111403A true CN109111403A (en) | 2019-01-01 |
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| CN201810839815.7A Pending CN109111403A (en) | 2018-07-27 | 2018-07-27 | Horse former times rises smooth related substance, preparation method and the usage |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095702A (en) * | 1993-05-21 | 1994-11-30 | 中国科学院大连化学物理研究所 | The reduction dehalogenation reaction of active alkali metal hydride halohydrocarbon under action |
| CN105388244A (en) * | 2015-12-10 | 2016-03-09 | 合肥久诺医药科技有限公司 | High performance liquid chromatography method of macitentan related substances |
| CN105461639A (en) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | Method for refining high-purity macitentan |
| CN106478520A (en) * | 2016-10-11 | 2017-03-08 | 合肥久诺医药科技有限公司 | A kind of synthetic method of ACT-064992 contamination levels product |
-
2018
- 2018-07-27 CN CN201810839815.7A patent/CN109111403A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1095702A (en) * | 1993-05-21 | 1994-11-30 | 中国科学院大连化学物理研究所 | The reduction dehalogenation reaction of active alkali metal hydride halohydrocarbon under action |
| CN105388244A (en) * | 2015-12-10 | 2016-03-09 | 合肥久诺医药科技有限公司 | High performance liquid chromatography method of macitentan related substances |
| CN105461639A (en) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | Method for refining high-purity macitentan |
| CN106478520A (en) * | 2016-10-11 | 2017-03-08 | 合肥久诺医药科技有限公司 | A kind of synthetic method of ACT-064992 contamination levels product |
Non-Patent Citations (7)
| Title |
|---|
| LIXIU YU ET AL.: "Simultaneous determination of macitentan and its active metabolite in human plasma by liquid chromatography-tandem mass spectrometry", 《JOURNAL OF CHROMATOGRAPHY B》 * |
| MARTIN H. BOLLI ET AL.: "The Discovery of N‑ [5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]‑N′‑propylsulfamide(Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| RANDALL B. NELSON AND GORDON W. GRIBBLE: "Reduction of aryl iodides with sodium hydride", 《J. ORG. CHEM.》 * |
| SHELTON BANK AND MARY C. PRISLOPSKI: "The high reactivity of radical-anion-prepared sodium hydride: reaction with benzyl chloride", 《CHEMICAL COMMUNICATIONS》 * |
| 施悦 等: "《环境氧化还原处理技术原理与应用》", 31 August 2013, 哈尔滨工业大学出版社 * |
| 聂忠莉 等: "HPLC测定马西替坦中的有关物质", 《华西药学杂志》 * |
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