CN104311492A - New method for preparing macitentan intermediate - Google Patents
New method for preparing macitentan intermediate Download PDFInfo
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- CN104311492A CN104311492A CN201410563759.0A CN201410563759A CN104311492A CN 104311492 A CN104311492 A CN 104311492A CN 201410563759 A CN201410563759 A CN 201410563759A CN 104311492 A CN104311492 A CN 104311492A
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- 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
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Abstract
The invention discloses a new method for preparing a macitentan intermediate and relates to a method for preparing N-(5-(4-bromophenyl)-6-chloro-4-pyrimidyl)-N'-propanesulfonamide. The method comprises the following steps: adding N-propanesulfonamide and 5-(4-bromophenyl)-4,6-dichloropyrimidine into dimethyl sulfoxide, adding an alkoxy metal compound (ROM), stirring, and reacting, thereby obtaining the product. The preparation method disclosed by the invention is a one-pot method, so that the reaction step of preparing potassium N-propanesulfonamide from N-propanesulfonamide is saved, the N-propanesulfonamide does not participate in reaction, the problems such as difficult transfer and preservation due to easy moisture absorption of the potassium N-propanesulfonamide are further solved, and the technical effects of improving the yield and product purity, reducing the solvent amount, reducing the cost and facilitating environment friendliness are achieved.
Description
Technical field
The invention belongs to technical field of compound preparation, be specifically related to the preparation method of a kind of ACT-064992 intermediate N (the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine.
Background technology
ACT-064992 (macitentan, structure is such as formula I Suo Shi) for there is highly lipophilic, highly effective tissue target to endothelin-receptor antagonists, this compound has double inhibition effect to endothelin-1 (ET-1) and ETA acceptor, ETB acceptor, and has tissue-targeting.After endothelin and its receptors bind, the contraction of vascular smooth muscle can be promoted, by propagation and the fibrosis of organization mechanism induction of vascular smooth muscle cell, cause vascular inflammation, change weave construction, and then play a significant role in the generation, evolution of numerous cardiovascular disorder.Clinically, ACT-064992 can be used for disease such as treatment pulmonary hypertension, pulmonary fibrosis etc., demonstrate good treatment prospect, and its validity, security and tolerance all shows better in a series of clinical study.
Document 1 (J.Med.Chem, 2012, 55, the preparation method of ACT-064992 7849-7861) is disclosed with CN100432070A, wherein, the preparation method of intermediate N (the chloro-4-pyrimidyl of 5-(4-bromophenyl)-the 6-)-N '-sulfonyl propyl amine of ACT-064992 as shown in Figure 1, the method prepares N-sulfonyl propyl amine sylvite by N-sulfonyl propyl amine, again from 5-(4-bromophenyl)-4, 6-dichloro pyrimidine prepares N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, not only there is the defect that preparation cycle is long, and the intermediate generated in preparation method all needs separation and purification, especially the N-sulfonyl propyl amine sylvite of the separation and purification very easily moisture absorption is wanted, and then cause N-sulfonyl propyl amine sylvite to there is transfer, preserve the problems such as difficulty, and the N-sulfonyl propyl amine sylvite after the moisture absorption have a strong impact on N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine prepare yield and product purity, and then cause preparation cycle long, yield is low, solvent load is large, three-protection design amount is large, cost is high, the defects such as industrialization has difficulties.Such as, the method adopts N-sulfonyl propyl amine sylvite to feed intake, synthesis N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine yield lower than 50% (with 5-(4-bromophenyl)-4,6-dichloro pyrimidine meter), the purity of obtained N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine is lower than 94%.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, it is characterized in that, said method comprising the steps of:
By N-sulfonyl propyl amine and 5-(4-bromophenyl)-4,6-dichloro pyrimidine joins in organic solvent, then adds alcoxyl metallic compound ROM, stirs, reaction, obtained N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl.
In the preferred technical solution of the present invention, described organic solvent is selected from any one or its combination of dimethyl sulfoxide (DMSO), DMF, tetrahydrofuran (THF), dioxane, is preferably dimethyl sulfoxide (DMSO).
In the preferred technical solution of the present invention, in ROM, R is C1 ~ C4 alkane, is preferably any one or its combination of the tertiary butyl, ethyl, propyl group.
In the preferred technical solution of the present invention, in ROM, M is the first main group element in the periodic table of elements, is preferably potassium or sodium.
In the preferred technical solution of the present invention, ROM is selected from any one or its combination of potassium tert.-butoxide, potassium ethylate, potassium propylate, sodium tert-butoxide, sodium ethylate, sodium propylate.
In the preferred technical solution of the present invention, the mol ratio of ROM and N-sulfonyl propyl amine is 1:1 ~ 2:1, is preferably 1:1.
In the preferred technical solution of the present invention, the described reaction times is 2-10 hour, is preferably 3-8 hour, is more preferably 4-6 hour.
In the preferred technical solution of the present invention, the mol ratio of ROM and 5-(4-bromophenyl)-4,6-dichloro pyrimidines is 1:0.5 ~ 1:1, is preferably 1:0.8.
In the preferred technical solution of the present invention, temperature of reaction is 0 DEG C ~ 80 DEG C, is preferably 20 DEG C-40 DEG C.
In the preferred technical solution of the present invention, dimethyl sulfoxide (DMSO): (5-(4-bromophenyl)-4,6-dichloro pyrimidines) volume ratio is 3 ~ 50:0.1-5, is preferably 10-15:1-2.
In order to clearly state protection scope of the present invention, the present invention defines as follows to following term:
B2:N-sulfonyl propyl amine;
B3:N-sulfonyl propyl amine sylvite;
A4:5-(4-bromophenyl)-4,6-dichloro pyrimidines;
A5:N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine.
One kettle way of the present invention refers to and is not separated reaction intermediate, but progressively completes reaction in a reaction system (as reaction vessel), until complete the preparation of compound.
The present invention measures the purity of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine with reference to high performance liquid chromatography (Pharmacopoeia of the People's Republic of China (version in 2010) two annex VD), comprise the steps: to get N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine appropriate, add acetonitrile and dissolve and dilute that to make concentration be that the solution of 1.0mg/ml is as need testing solution.Precision measures need testing solution 10 μ l injection liquid chromatography record color atlas.Chromatographic condition is: take octadecylsilane chemically bonded silica as weighting agent, and triethylamine phosphoric acid buffer (get triethylamine 0.2ml, add water 1000, mixing, adjust pH to 3.0 with phosphoric acid)-acetonitrile (50:50) is moving phase; Column temperature 40 DEG C; Determined wavelength 220nm; Flow velocity 1.0ml/min.
Except as otherwise noted, when the present invention relates to the per-cent between liquid and liquid, described per-cent is volume/volume per-cent; When the present invention relates to the per-cent between liquid and solid, described per-cent is volume/weight per-cent; When the present invention relates to the per-cent between solid and liquid, described per-cent is weight/volume percent; All the other are weight/weight percent.
Compared with prior art, the preparation method of N-of the present invention (5-(4-bromophenyl)-6-chloro-4-pyrimidyl)-N '-sulfonyl propyl amine has following Advantageous Effects:
1, the preparation method of N-of the present invention (the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine eliminates the reactions steps being prepared N-sulfonyl propyl amine sylvite by N-sulfonyl propyl amine, and do not use N-sulfonyl propyl amine sylvite, both significantly shortened preparation cycle, also avoid N-sulfonyl propyl amine sylvite very easily the moisture absorption bring transfer, preserve difficulty, yield is low, product purity is undesirable, solvent capacity is large, three-protection design amount is large, cost is high, be unfavorable for the problems such as environmental protection;
2, the present invention adopts one kettle way to prepare N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, the method is by N-sulfonyl propyl amine, dimethyl sulfoxide (DMSO), alcoxyl metallic compound (ROM) and (5-(4-bromophenyl)-4, 6-dichloro pyrimidine) be placed in a reaction system and progressively complete reaction, and be not separated reaction intermediate, what not only increase (N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine) prepares yield (yield improves more than 60%) and product purity (purity brings up to 99% from 94%), and decrease solvent load, the quantity of three wastes that remarkable minimizing purification of intermediates produces and processing cost thereof, significantly reduce costs (cost declines about 50%), be beneficial to environmental protection and industrialization production.
Accompanying drawing explanation
The disclosed method being prepared (N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine) by N-sulfonyl propyl amine sylvite of Fig. 1 document 1 (J.Med.Chem, 2012,55,7849-7861);
Preparation technology's flow process of Fig. 2 the present invention (N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine).
Embodiment
The preferred embodiment of the present invention is introduced below in conjunction with embodiment.
embodiment 1the preparation of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine
The preparation method of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, comprises the following steps:
1) 272g (2.00mol) N-sulfonyl propyl amine (moisture 0.2%) is joined the 5-(4-bromophenyl)-4 of 500g (1.65mol), in the dimethyl sulfoxide (DMSO) of 6-dichloro pyrimidine and 5000ml, add the potassium tert.-butoxide of 220g (2.00mol) again, room temperature, stir, react 4 hours;
2) 25000ml saturated aqueous common salt and 25000ml extraction into ethyl acetate is added to reaction solution, get organic layer concentrated after, gained enriched material 2000ml recrystallizing methanol, obtain N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine 473g (in N-sulfonyl propyl amine, molar yield 58.4%).
According to detection method of the present invention, the HPLC purity detecting N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine is 99.2%.
embodiment 2the preparation of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine
The preparation method of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, comprises the following steps:
1) 272g (2.00mol) N-sulfonyl propyl amine (moisture 0.2%) is joined the 5-(4-bromophenyl)-4 of 500g (1.65mol), in the dimethyl sulfoxide (DMSO) of 6-dichloro pyrimidine and 5000ml, add the potassium ethylate of 168g (2.00mol) again, room temperature, stir, react 4 hours;
2) 25000ml saturated aqueous common salt and 25000ml extraction into ethyl acetate is added to reaction solution, get organic layer to concentrate, gained enriched material 2000ml recrystallizing methanol, obtain N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine 446g (in N-sulfonyl propyl amine, molar yield 55.0%).
According to detection method of the present invention, the HPLC purity detecting N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine is 99.5%.
The preparation of embodiment 3N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine
The preparation method of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, comprises the following steps:
1) 272g (2.00mol) N-sulfonyl propyl amine (moisture 0.2%) is joined the 5-(4-bromophenyl)-4 of 500g (1.65mol), in the tetrahydrofuran (THF) of 6-dichloro pyrimidine and 5000ml, add the potassium tert.-butoxide of 220g (2.00mol) again, room temperature, stir, react 6 hours;
2) 25000ml saturated aqueous common salt and 25000ml extraction into ethyl acetate is added to reaction solution, get organic layer to concentrate, gained enriched material 2000ml recrystallizing methanol, obtain N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine 387g (in N-sulfonyl propyl amine, molar yield 47.7%).
According to detection method of the present invention, the HPLC purity detecting N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine is 99.3%.
comparative example 1the preparation of N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine
Adopt the disclosed method of document 1 (J.Med.Chem, 2012,55,7849-7861), preparation N-sulfonyl propyl amine sylvite, comprises the steps:
1) by potassium tert.-butoxide (8.5g, 75.89mmole) join N-sulfonyl propyl amine (10g, in methyl alcohol (100ml) 72.46mmol), stirring at room temperature 30 minutes, concentrating under reduced pressure is done, and adds ether (200ml) crystallization, filters, because the N-sulfonyl propyl amine sylvite moisture absorption is serious, become muddy gradually in filtration procedure and be difficult to continue to filter; This soup compound is difficult to transfer, obtains 12.4g (in N-sulfonyl propyl amine, molar yield 86.0%, moisture 3.2%) after drying reluctantly;
2) obtained N-sulfonyl propyl amine sylvite 3.54g (19.80mmo) is joined 5-(4-bromophenyl)-4,6-dichloro pyrimidine (5.0g, i.e. 16.50mmol) and DMSO (50m) in, room temperature, stir 48 hours, add 250ml saturated aqueous common salt and 250ml extraction into ethyl acetate, get organic layer to be spin-dried for, use 20ml recrystallizing methanol, obtained 3.2g N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine (in N-sulfonyl propyl amine sylvite, molar yield 39.9%).
In N-sulfonyl propyl amine, mole total recovery of A5 is: 34.3%.
According to detection method of the present invention, the HPLC purity detecting N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine is 93.4%.
Method disclosed in reference literature 1 is prepared in B3 process and is found, B3 thoroughly can not have loss because of crystallization, causes the yield being prepared B3 by B2 to be 86.0%; In addition, because the water ratio of sylvite is higher, the yield being prepared A5 by B3 is only 39.9%; Comprehensive two steps, are only 34.3% in the total recovery of B2, A5.
Table 1
| ? | B2 and A4 mol ratio | B3 and A4 mol ratio | A5 yield (%) | A5 purity (%) |
| Comparative example 1 | ———— | 1.2:1 | 34.3 | 93.4 |
| Embodiment 1 | 1.2:1 | ———— | 58.4 | 99.2 |
| Embodiment 2 | 1.2:1 | ———— | 55.0 | 99.5 |
| Embodiment 3 | 1.2:1 | ———— | 47.7 | 99.3 |
From table 1, compared with prior art, the preparation method of N-of the present invention (5-(4-bromophenyl)-6-chloro-4-pyrimidyl)-N '-sulfonyl propyl amine has following Advantageous Effects:
1, the preparation method of N-of the present invention (the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine eliminates and prepares the reactions steps of N-sulfonyl propyl amine sylvite by N-sulfonyl propyl amine and do not use N-sulfonyl propyl amine sylvite, both significantly shortened preparation cycle, also avoid N-sulfonyl propyl amine sylvite very easily the moisture absorption bring transfer, preserve difficulty, yield is low, product purity is undesirable, solvent capacity is large, three-protection design amount is large, cost is high, be unfavorable for the problems such as environmental protection;
2, the present invention adopts one kettle way to prepare N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, the method is by N-sulfonyl propyl amine, dimethyl sulfoxide (DMSO), alcoxyl metallic compound (ROM) and (5-(4-bromophenyl)-4, 6-dichloro pyrimidine) be placed in a reaction system and progressively complete reaction, and be not separated reaction intermediate, what not only increase (N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine) prepares yield (yield improves more than 60%) and product purity (purity brings up to 99% from 94%), and decrease solvent load, the quantity of three wastes that remarkable minimizing purification of intermediates produces and processing cost thereof, significantly reduce costs (cost declines about 50%), be beneficial to environmental protection and industrialization production.
The above embodiment only have expressed the specific embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.
Claims (10)
1. a preparation method for N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine, comprises the following steps:
By N-sulfonyl propyl amine and 5-(4-bromophenyl)-4,6-dichloro pyrimidine joins in organic solvent, then adds alcoxyl metallic compound ROM, stirs, reaction, obtained N-(the chloro-4-pyrimidyl of 5-(4-bromophenyl)-6-)-N '-sulfonyl propyl amine.
2. preparation method according to claim 1, described organic solvent is selected from any one or its combination of dimethyl sulfoxide (DMSO), DMF, tetrahydrofuran (THF), dioxane, is preferably dimethyl sulfoxide (DMSO).
3. preparation method according to claim 1 and 2, in ROM, R is C1 ~ C4 alkane, is preferably any one or its combination of the tertiary butyl, ethyl, propyl group.
4. the preparation method according to any one of claim 1-3, M is the first main group element in the periodic table of elements, is preferably potassium or sodium.
5. the preparation method according to any one of claim 1-4, ROM is selected from any one or its combination of potassium tert.-butoxide, potassium ethylate, potassium propylate, sodium tert-butoxide, sodium ethylate, sodium propylate.
6. the preparation method according to any one of claim 1-5, the mol ratio of ROM and N-sulfonyl propyl amine is 1:1 ~ 2:1, is preferably 1:1.
7. the preparation method according to any one of claim 1-6, the mol ratio of ROM and 5-(4-bromophenyl)-4,6-dichloro pyrimidines is 1:0.5 ~ 1:1, is preferably 1:0.8.
8. the preparation method according to any one of claim 1-7, temperature of reaction is 0 DEG C ~ 80 DEG C, is preferably 20 DEG C-40 DEG C.
9. the preparation method according to any one of claim 1-8, dimethyl sulfoxide (DMSO): (5-(4-bromophenyl)-4,6-dichloro pyrimidines) volume ratio is 3 ~ 50:0.1 ~ 5, is preferably 10 ~ 15:1 ~ 2.
10. the preparation method according to any one of claim 1-9, the described reaction times is 2-10 hour, is preferably 3-8 hour, is more preferably 4-6 hour.
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| CN104897833A (en) * | 2015-05-15 | 2015-09-09 | 成都克莱蒙医药科技有限公司 | Detection method for macitentan intermediate and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524079A (en) * | 2000-12-18 | 2004-08-25 | ������˹ҩƷ��˾ | Novel sulfamides and their use as endothelin receptor antagonists |
| CN101939001A (en) * | 2008-02-20 | 2011-01-05 | 埃科特莱茵药品有限公司 | Combination comprising paclitaxel for treating ovarian cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524079A (en) * | 2000-12-18 | 2004-08-25 | ������˹ҩƷ��˾ | Novel sulfamides and their use as endothelin receptor antagonists |
| CN101939001A (en) * | 2008-02-20 | 2011-01-05 | 埃科特莱茵药品有限公司 | Combination comprising paclitaxel for treating ovarian cancer |
Non-Patent Citations (3)
| Title |
|---|
| ANONYMOUSLY: "Process for preparing N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2- pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl)-N"-propylsulfamide and intermediates thereof", 《IP.COM JOURNAL》 * |
| MARTIN H. BOLLI，等: "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", 《J. MED. CHEM.》 * |
| MARTIN H. BOLLI，等: "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", 《J. MED. CHEM.》, vol. 55, 3 August 2012 (2012-08-03), pages 7849 - 7861, XP 055078934, DOI: doi:10.1021/jm3009103 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104897833A (en) * | 2015-05-15 | 2015-09-09 | 成都克莱蒙医药科技有限公司 | Detection method for macitentan intermediate and application thereof |
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