CN104311492B - The preparation method that a kind of ACT-064992 intermediate is new - Google Patents

The preparation method that a kind of ACT-064992 intermediate is new Download PDF

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CN104311492B
CN104311492B CN201410563759.0A CN201410563759A CN104311492B CN 104311492 B CN104311492 B CN 104311492B CN 201410563759 A CN201410563759 A CN 201410563759A CN 104311492 B CN104311492 B CN 104311492B
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propylcarbamic
preparation
sulfonamide
bromophenyl
rom
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CN104311492A (en
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叶丁
龚义
丁诚
王晓玲
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Chengdu Ke Lai Mongolia Medicine Science And Technology Ltd
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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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the preparation method of N (5 (4 bromophenyl) 6 chlorine 4 pyrimidine radicals) N ' propylcarbamic sulfonamide, comprise the following steps: by N propylcarbamic sulfonamide and 5 (4 bromophenyls) 4,6 dichloro pyrimidines join in dimethyl sulfoxide, it is subsequently adding alcoxyl metallic compound (ROM), stirring, reaction, to obtain final product.The preparation method of the present invention is one kettle way, both the reactions steps being prepared N propylcarbamic sulfonamide potassium salt by N propylcarbamic sulfonamide had been eliminated, and do not use N propylcarbamic sulfonamide potassium salt to participate in reaction, and then avoid the N propylcarbamic sulfonamide potassium salt easily moisture absorption to bring transfer, preserve the problems such as difficulty, achieve raising yield and product purity, reduce solvent load, reduce cost, be beneficial to the technique effects such as environmental protection.

Description

The preparation method that a kind of ACT-064992 intermediate is new
Technical field
The invention belongs to technical field of compound preparation, be specifically related to a kind of ACT-064992 intermediate N (5-(4- Bromophenyl)-6-chloro-4-pyrimidine radicals) preparation method of-N '-propylcarbamic sulfonamide.
Background technology
ACT-064992 (macitentan, structure is as shown in formula I) for have highly lipophilic property, the most effective Tissue target to endothelin-receptor antagonists, this compound is to endothelin-1 (ET-1) and ETA receptor, ETB Receptor has double inhibition effect, and has tissue-targeting.After Endothelin is combined with its receptor, it is possible to promote Enter the contraction of vascular smooth muscle, by propagation and the fibrosis of organization mechanism induction of vascular smooth muscle cell, draw Play vascular inflammation, change organizational structure, and then play in the generation, evolution of numerous cardiovascular disease Important function.Clinically, ACT-064992 can be used for treating the disease such as pulmonary hypertension, pulmonary fibrosis, one Range of clinical research demonstrates good treatment prospect, and its effectiveness, safety and toleration all show Preferably.
Document 1 (J.Med.Chem, 2012,55,7849-7861) and CN100432070A disclose Ma Xi and replace Smooth preparation method, wherein, intermediate N (5-(4-bromophenyl)-6-chloro-4-the pyrimidine radicals)-N '-the third of ACT-064992 The preparation method of base sulfamide is as it is shown in figure 1, the method is prepared N-propyl group by N-propylcarbamic sulfonamide Sulfamide potassium salt, then from 5-(4-bromophenyl)-4,6-dichloro pyrimidine prepares N-(5-(4-bromophenyl) the chloro-4-of-6- Pyrimidine radicals)-N '-propylcarbamic sulfonamide, do not only exist the defect of manufacturing cycle length, and preparation method generates Intermediate be both needed to isolated and purified, the N-propylcarbamic sulfonamide potassium salt of the purification the most to be separated easily moisture absorption, And then the N-after causing N-propylcarbamic sulfonamide potassium salt to there is the problem, and the moisture absorption such as transfer, preservation difficulty Propylcarbamic sulfonamide potassium salt has a strong impact on N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulphonyl Amine prepare yield and product purity, and then cause that manufacturing cycle length, yield are low, solvent load is big, the three wastes The defects such as treating capacity is big, cost is high, industrialization has difficulties.Such as, the method uses N-propylcarbamic sulphur Amide potassium salt feeds intake, the yield of synthesis N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide Less than 50% (with 5-(4-bromophenyl)-4,6-dichloro pyrimidine meter), N-(5-(4-bromophenyl) the chloro-4-of-6-prepared Pyrimidine radicals) purity of-N '-propylcarbamic sulfonamide is less than 94%.
Summary of the invention
It is an object of the invention to provide a kind of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulphur The preparation method of amide, it is characterised in that said method comprising the steps of:
By N-propylcarbamic sulfonamide and 5-(4-bromophenyl)-4,6-dichloro pyrimidine joins in organic solvent, then adds Enter alcoxyl metallic compound ROM, stirring, reaction, prepared N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '- Sulfonyl propyl.
In the preferred technical solution of the present invention, described organic solvent is selected from dimethyl sulfoxide, N, N dimethyl Methanamide, oxolane, any one or a combination thereof, preferably dimethyl sulfoxide of dioxane.
In the preferred technical solution of the present invention, in ROM, R is C1～C4 alkane, preferably the tert-butyl group, second Base, any one or a combination thereof of propyl group.
In the preferred technical solution of the present invention, the first major element during M is the periodic table of elements in ROM, excellent Elect potassium or sodium as.
In the preferred technical solution of the present invention, ROM is selected from potassium tert-butoxide, potassium ethoxide, potassium propoxide, the tert-butyl alcohol Sodium, Sodium ethylate, any one or a combination thereof of sodium propoxide.
In the preferred technical solution of the present invention, the mol ratio of ROM Yu N-propylcarbamic sulfonamide is 1:1～2:1, It is preferably 1:1.
In the preferred technical solution of the present invention, the described response time is 2-10 hour, preferably 3-8 hour, More preferably 4-6 hour.
In the preferred technical solution of the present invention, ROM Yu 5-(4-bromophenyl)-4, the mol ratio of 6-dichloro pyrimidine is 1:0.5～1:1, preferably 1:0.8.
In the preferred technical solution of the present invention, reaction temperature is 0 DEG C～80 DEG C, preferably 20 DEG C-40 DEG C.
In the preferred technical solution of the present invention, dimethyl sulfoxide: (5-(4-bromophenyl)-4,6-dichloro pyrimidine) body Long-pending ratio is 3～50:0.1-5, preferably 10-15:1-2.
In order to clearly state protection scope of the present invention, following term is defined by the present invention as follows:
B2:N-propylcarbamic sulfonamide；
B3:N-propylcarbamic sulfonamide potassium salt；
A4:5-(4-bromophenyl)-4,6-dichloro pyrimidine；
A5:N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide.
One kettle way of the present invention refers to not separate reaction intermediate, but a reaction system (as Reaction vessel) in be gradually completing reaction, until completing the preparation of compound.
The present invention is with reference to the high performance liquid chromatography (Pharmacopoeia of the People's Republic of China (version in 2010) two Annex VD) measure N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide purity, bag Include following step: take N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide appropriate, add second Nitrile dissolves and dilutes makes solution that concentration is 1.0mg/ml as need testing solution.It is molten that precision measures test sample Liquid 10 μ l injects chromatograph of liquid record chromatogram.Chromatographic condition is: with octadecylsilane chemically bonded silica be Filler, and triethylamine phosphate buffer (take triethylamine 0.2ml, add water 1000, mixing, adjust pH with phosphoric acid To 3.0)-acetonitrile (50:50) for flowing phase；Column temperature 40 DEG C；Detection wavelength 220nm；Flow velocity 1.0ml/min.
Except as otherwise noted, when the present invention relates to the percentage ratio between liquid and liquid, described percentage ratio is Volume/volume percentage ratio；When the present invention relates to the percentage ratio between liquid and solid, described percentage ratio be volume/ Percentage by weight；When the present invention relates to the percentage ratio between solid and liquid, described percentage ratio is weight/volume Percentage ratio；Remaining is weight/percentage by weight.
Compared with prior art, N-of the present invention (5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide Preparation method there is following Advantageous Effects:
1, the preparation method of N-of the present invention (5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide saves Omit the reactions steps being prepared N-propylcarbamic sulfonamide potassium salt by N-propylcarbamic sulfonamide, and do not used N-propylcarbamic sulfonamide potassium salt, significantly shortens manufacturing cycle, it is thus also avoided that N-propylcarbamic sulfonamide potassium Transfer that the salt easily moisture absorption is brought, preserve difficulty, yield is low, product purity is undesirable, solvent capacity big, Three-protection design amount is big, cost is high, be unfavorable for the problems such as environmental protection；
2, the present invention uses one kettle way to prepare N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulphonyl Amine, the method is by N-propylcarbamic sulfonamide, dimethyl sulfoxide, alcoxyl metallic compound (ROM) and (5-(4- Bromophenyl)-4,6-dichloro pyrimidine) it is placed in a reaction system and is gradually completing reaction, and not in the middle of separating reaction Product, not only increases the system of (N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide) Standby yield (yield improves more than 60%) and product purity (purity brings up to 99% from 94%), and reduce Solvent load, substantially reduces quantity of three wastes produced by purification of intermediates and processing cost thereof, significantly reduces Cost (cost declines about 50%), beneficially environmental protection and industrialization produce.
Accompanying drawing explanation
Fig. 1 document 1 (J.Med.Chem, 2012,55,7849-7861) is disclosed by N-propylcarbamic sulfonamide The method of (N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide) prepared by potassium salt；
The preparation of Fig. 2 present invention (N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide) Technological process.
Detailed description of the invention
The preferred embodiment of the present invention is introduced below in conjunction with embodiment.
Embodiment 1The preparation of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide
The preparation method of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide, including following Step:
1) 272g (2.00mol) N-propylcarbamic sulfonamide (moisture 0.2%) is joined 500g (1.65 Mol) 5-(4-bromophenyl)-4, in the dimethyl sulfoxide of 6-dichloro pyrimidine and 5000ml, adds 220g (2.00 Mol) potassium tert-butoxide, room temperature, stirring, react 4 hours；
2) add 25000ml saturated aqueous common salt and the extraction of 25000ml ethyl acetate to reactant liquor, take organic layer After concentration, gained concentrate 2000ml recrystallizing methanol, obtain N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine Base)-N '-propylcarbamic sulfonamide 473g (in terms of N-propylcarbamic sulfonamide, molar yield 58.4%).
According to detection method of the present invention, detect N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propyl group The HPLC purity of sulfamide is 99.2%.
Embodiment 2The preparation of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide
The preparation method of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide, including following Step:
1) 272g (2.00mol) N-propylcarbamic sulfonamide (moisture 0.2%) is joined 500g (1.65 Mol) 5-(4-bromophenyl)-4, in the dimethyl sulfoxide of 6-dichloro pyrimidine and 5000ml, adds 168g (2.00 Mol) potassium ethoxide, room temperature, stirring, react 4 hours；
2) add 25000ml saturated aqueous common salt and the extraction of 25000ml ethyl acetate to reactant liquor, take organic layer Concentrate, gained concentrate 2000ml recrystallizing methanol, obtain N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine Base)-N '-propylcarbamic sulfonamide 446g (in terms of N-propylcarbamic sulfonamide, molar yield 55.0%).
According to detection method of the present invention, detect N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propyl group The HPLC purity of sulfamide is 99.5%.
The preparation of embodiment 3 N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide
The preparation method of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide, including following Step:
1) 272g (2.00mol) N-propylcarbamic sulfonamide (moisture 0.2%) is joined 500g (1.65 Mol) 5-(4-bromophenyl)-4, in the oxolane of 6-dichloro pyrimidine and 5000ml, adds 220g (2.00 Mol) potassium tert-butoxide, room temperature, stirring, react 6 hours；
2) add 25000ml saturated aqueous common salt and the extraction of 25000ml ethyl acetate to reactant liquor, take organic layer Concentrate, gained concentrate 2000ml recrystallizing methanol, obtain N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine Base)-N '-propylcarbamic sulfonamide 387g (in terms of N-propylcarbamic sulfonamide, molar yield 47.7%).
According to detection method of the present invention, detect N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propyl group The HPLC purity of sulfamide is 99.3%.
Comparative example 1The preparation of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide
Use method disclosed in document 1 (J.Med.Chem, 2012,55,7849-7861), prepare N-propyl group ammonia Base sulfonamide potassium salt, comprises the steps:
1) potassium tert-butoxide (8.5g, 75.89mmole) is joined N-propylcarbamic sulfonamide (10g, In methanol (100ml) 72.46mmol), being stirred at room temperature 30 minutes, concentrating under reduced pressure is done, and adds ether (200ml) Crystallize, filters, and because the N-propylcarbamic sulfonamide potassium salt moisture absorption is serious, is increasingly becoming muddy in filter process And be difficult to continue to filter；This slurry is difficult to transfer, obtains 12.4g (with N-propylcarbamic sulphonyl after drying reluctantly Amine meter, molar yield 86.0%, moisture 3.2%)；
2) prepared N-propylcarbamic sulfonamide potassium salt 3.54g (19.80mmo) is joined 5-(4-bromobenzene Base)-4, in 6-dichloro pyrimidine (5.0g, i.e. 16.50mmol) and DMSO (50m), room temperature, stirs 48 Hour, add 250ml saturated aqueous common salt and the extraction of 250ml ethyl acetate, take organic layer and be spin-dried for, use 20ml Recrystallizing methanol, prepared 3.2g N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide (with N-propylcarbamic sulfonamide potassium salt meter, molar yield 39.9%).
In terms of N-propylcarbamic sulfonamide, mole total recovery of A5 is: 34.3%.
According to detection method of the present invention, detect N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propyl group The HPLC purity of sulfamide is 93.4%.
Method disclosed in reference literature 1 finds during preparing B3, and B3 can the most thoroughly have loss because of crystallize, Causing the yield being prepared B3 by B2 is 86.0%；Further, since the moisture content of potassium salt is higher, prepare B3 The yield of A5 is only 39.9%；Comprehensive two steps, in terms of B2, the total recovery of A5 is only 34.3%.
Table 1
From table 1, compared with prior art, N-of the present invention (5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '- The preparation method of propylcarbamic sulfonamide has a following Advantageous Effects:
1, the preparation method of N-of the present invention (5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide saves Omit and prepared the reactions steps of N-propylcarbamic sulfonamide potassium salt by N-propylcarbamic sulfonamide and do not use N-propylcarbamic sulfonamide potassium salt, significantly shortens manufacturing cycle, it is thus also avoided that N-propylcarbamic sulfonamide potassium Transfer that the salt easily moisture absorption is brought, preserve difficulty, yield is low, product purity is undesirable, solvent capacity big, Three-protection design amount is big, cost is high, be unfavorable for the problems such as environmental protection；
2, the present invention uses one kettle way to prepare N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulphonyl Amine, the method is by N-propylcarbamic sulfonamide, dimethyl sulfoxide, alcoxyl metallic compound (ROM) and (5-(4- Bromophenyl)-4,6-dichloro pyrimidine) it is placed in a reaction system and is gradually completing reaction, and not in the middle of separating reaction Product, not only increases the system of (N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide) Standby yield (yield improves more than 60%) and product purity (purity brings up to 99% from 94%), and reduce Solvent load, substantially reduces quantity of three wastes produced by purification of intermediates and processing cost thereof, significantly reduces Cost (cost declines about 50%), beneficially environmental protection and industrialization produce.
Embodiment described above only have expressed the detailed description of the invention of the present invention, and it describes more 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 this area Those of ordinary skill for, without departing from the inventive concept of the premise, it is also possible to make some deformation and Improving, these broadly fall into protection scope of the present invention.

Claims (13)

1. the preparation side of N-(5-(4-bromophenyl)-6-chloro-4-pyrimidine radicals)-N '-propylcarbamic sulfonamide Method, comprises the following steps:
By N-propylcarbamic sulfonamide and 5-(4-bromophenyl)-4,6-dichloro pyrimidine joins in organic solvent, Adding alcoxyl metallic compound ROM, stirring, reaction, (5-(4-bromophenyl) the chloro-4-of-6-is phonetic to prepare N- Piperidinyl)-N '-propylcarbamic sulfonamide,
Wherein, in described ROM, R is C1～C4 alkyl；M is the first main group in the periodic table of elements Element,
Wherein, the mol ratio of ROM Yu N-propylcarbamic sulfonamide is 1:1～2:1,
The mol ratio of ROM Yu 5-(4-bromophenyl)-4,6-dichloro pyrimidine is 1:0.5～1:1.
Preparation method the most according to claim 1, it is characterised in that described organic solvent is selected from Dimethyl sulfoxide, N, N-dimethylformamide, oxolane, any one or a combination thereof of dioxane.
Preparation method the most according to claim 1, it is characterised in that in ROM R be the tert-butyl group, Ethyl, any one or a combination thereof of propyl group.
4. according to the preparation method described in any one of claim 1-3, it is characterised in that M is potassium or sodium.
5. according to the preparation method described in any one of claim 1-3, it is characterised in that ROM is selected from uncle Butanol potassium, potassium ethoxide, potassium propoxide, sodium tert-butoxide, Sodium ethylate, any one or a combination thereof of sodium propoxide.
Preparation method the most according to claim 1, it is characterised in that ROM Yu 5-(4-bromobenzene Base) mol ratio of-4,6-dichloro pyrimidine is 1:0.8.
7. according to the preparation method described in any one of claim 1-3, it is characterised in that reaction temperature is 0 DEG C～80 DEG C.
Preparation method the most according to claim 7, it is characterised in that reaction temperature is 20 DEG C-40 DEG C.
9. according to the preparation method described in any one of claim 1-3, it is characterised in that dimethyl sulfoxide: (5-(4-bromophenyl)-4,6-dichloro pyrimidine) volume ratio is 3～50:0.1～5.
Preparation method the most according to claim 9, it is characterised in that dimethyl sulfoxide: (5-(4- Bromophenyl)-4,6-dichloro pyrimidine) volume ratio is 10～15:1～2.
11. according to the preparation method described in any one of claim 1-3, it is characterised in that described reaction Time is 2-10 hour.
12. preparation methoies according to claim 11, it is characterised in that the described response time is 3-8 hour.
13. preparation methoies according to claim 12, it is characterised in that the described response time is 4-6 hour.
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