- Synthesis method of selexipag intermediate
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The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of a selexipag intermediate. The preparation method comprises the following steps: reacting a compound as shown in a formula III with 2-aminoacetamidine hydrobromide under the action of a catalyst to obtain a compound as shown in a formula IV; reacting the compound as shown in the formula IV with 4-bromo-1-butanol under the action of alkali to obtain a compound as shown in a formula V; and carrying out N-alkylation reaction on the compound as shown in the formula V under the action of alkali to obtain the selexipag intermediate as shown in the formula I: 4-[(5, 6-diphenylpyrazine-2-yl) (isopropyl alcohol group) amino]-1-butanol. The invention creates a novel synthesis method of the selexipag intermediate, and the method has the advantages of cheap and easily available raw materials, simple operation, mild conditions and high yield.
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- Synthetic method of selexipag intermediate
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The present invention relates to a synthetic method of a selexipag intermediate. The method comprises the following steps: carrying out a nucleophilic substitution reaction on a compound represented by a formula (I) and isopropylamine in an oxygen-free water-free environment in the presence of a hydrogen withdrawing reagent to obtain a compound represented by a formula (II), wherein the structuralformula of the compound represented by the formula (I) is shown in the description, L represents a halogen atom, and the structural formula of the compound represented by the formula (II) is shown inthe description. According to the synthetic method of the selexipag intermediate provided by the invention, in the oxygen-free water-free environment, the compound shown in the formula (I) and the isopropylamine are used as raw materials, the nucleophilic substitution reaction can be performed in the presence of the hydrogen withdrawing reagent to obtain the compound shown in the formula (II), the reaction conditions are mild, the energy consumption is low, the isopropylamine is cheap and easy to obtain, the production costs can be effectively reduced, and the method is suitable for industrial production.
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Paragraph 0085-0088
(2019/11/20)
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- High yield preparation method of selexipag intermediate compound under middle conditions
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The invention relates to a high yield preparation method of a selexipag intermediate compound under middle conditions. According to the method, styracitol and halogen acid carry out halogenation reactions, and the reaction product and N-aminoacetyl-N-isopropyl n-butanol carry out condensation, ammoxidation, and ring forming reactions to obtain 2-(N-isopropyl-N-4-hydroxylbutyl)amino-5,6-diphenylpyrazine. The compound can be used to prepare selexipag. The raw materials are cheap and easily available, the operation is simple, convenient and safe, the reaction selectivity is good, the yield and purity are high, and the cost is low.
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Paragraph 0054-0056; 0061-0062
(2019/03/15)
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- Preparation method for Selexipag intermediate
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The invention provides a method for preparing a Selexipag intermediate 4-((5,6-diphenyl-2-pyrazinyl)(1-methylethyl)amino)-1-butanol. The method includes protecting 4-isopropylamino n-butyl alcohol byusing a hydroxy protecting group reagent, performs addition with 5,6-diphenyl-2-pyrazinyl trifluoromethanesulfonate, and obtains a target compound by removing protecting groups. The preparation methodis high in yield, low in production cost, mild in condition, simple in operation and suitable for industrial production.
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- INHIBITORS OF PLATELET FUNCTION AND METHODS FOR USE OF THE SAME
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Disclosed herein are small molecule inhibitors of platelet function, and methods of using the small molecules to treat diseases, such as platelet hemostasis and thrombosis. In particular, disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein the substituents are as described.
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Paragraph 0083; 0085
(2019/11/12)
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- Preparation method of selexipag intermediate
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The invention relates to a preparation method of a selexipag intermediate, and belongs to the field of chemical preparation. The selexipag intermediate is 4-[N-(5,6-diphenylpiperazine-2-yl)-N-isopropyl amide]-1-butanol. The preparation method of the selexipag intermediate comprises the following steps: dissolving 5-chloro-2,3-diphenylpyrazine and 4-(isopropyl amide)-1-butanol in an organic solvent; and reacting under the effects of a palladium catalyst, a complex catalyst and alkali to obtain the selexipag intermediate. The preparation method of the selexipag intermediate is simple and convenient to prepare and gentle in reaction conditions, is environmentally friendly, and is suitable for industrial production.
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Paragraph 0038; 0041-0045; 0047; 0049-0051; 0053; 0055; 0058
(2018/03/26)
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- METHOD FOR PREPARING PROSTACYCLIN RECEPTOR AGONIST
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The present invention relates to preparation methods of a prostacyclin receptor agonist of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and its intermediates. These methods are simple and convenient to operate, environment-friendly and suitable for industrial production to obtain the product with good yield and high purity.
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Paragraph 0082-0083
(2018/03/01)
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- POLYMORPHIC FORMS AND AMORPHOUS SOLID DISPERSION OF SELEXIPAG
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The present disclosure relates to crystalline forms of selexipag and their processes for preparation. The present disclosure also relates to an amorphous solid dispersion of selexipag and its processes for their preparation as well as premix of crystalline selexipag and their process.
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Page/Page column 37
(2018/02/28)
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- CRYSTALLINE FORM VI OF SELEXIPAG
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The present disclosure relates to solid state forms of Selexipag, processes for preparation thereof and pharmaceutical compositions thereof.
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Paragraph 00129-00134
(2018/02/28)
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- AN IMRPOVED PROCESS FOR THE PREPARATION OF SELEXIPAG OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention provides an improved process for Selexipag of formula (I) or its pharmaceutically acceptable salts.
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Page/Page column 11
(2017/08/01)
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- PROCESSES FOR PREPARATION OF SELEXIPAG AND ITS AMORPHOUS FORM
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The present application relates to processes for preparation of Selexipag, its amorphous form, amorphous solid dispersion and pharmaceutical composition thereof. Formula (I):
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Page/Page column 20
(2017/03/14)
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- PROCESS FOR THE PREPARATION OF SELEXIPAG AND INTERMEDIATES THEREOF
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The present invention provides processes for the preparation of Selexipag compound of formula (1). The present invention also provides processes for the preparation of 4-[(5,6-diphenyl-pyrazin-2-yl)-isopropyl -amino]-butan-1-ol (2), and 4-isopropylamino-butan-1-ol of formula (3), which are intermediates for the synthesis of Selexipag (1 ).
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Page/Page column 42
(2017/03/28)
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- PROCESS FOR THE PREPARATION OF DIPHENYLPYRAZINE DERIVATIVES
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The present invention relates to a process for the preparation of amorphous Selexipag from Selexipag crystalline salts using a solvent.
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Page/Page column 12
(2017/10/31)
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- Selexipag intermediates and method for preparing selexipag
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The invention belongs to the field of chemical preparation, and relates to selexipag intermediates and a method for preparing selexipag. The selexipag intermediates are a compound SLP-4, a compound SLP-7, a compound SLP-8 and a compound SLP-10. The selexipag intermediates and the method have the advantages that the method for preparing the selexipag includes reasonable routes and is low in cost and operative difficulty and little in environmental pollution, raw materials are easily available, accordingly, requirements of large-scale industrial production can be met by the method, and the like.
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- High-purity match le xipa (by machine translation)
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The invention discloses a high-purity match le xipa. By the match le xipa key intermediate 2 - (4 - ((5, 6 - diphenyl pyrazine - 2 - yl) isopropyl amino) butoxy) acetic acid in the organic solvent with the CDI, a sulfonamide in the organic base under the conditions of the reaction. The reaction operation is simple, low cost, environment-friendly, yield>95%, it is suitable for industrial production, the purity of the prepared match le xipa ≥ 99.9%, can better meet the requirements of drug production. The invention prepared match le xipa high purity, thereby facilitating the subsequent more high-quality drugs. (by machine translation)
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Paragraph 0051; 0052; 0053; 0054
(2017/12/14)
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- Preparation method for therapeutic drug selexipag for treating pulmonary arterial hypertension of adults
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The invention discloses a preparation method for therapeutic drug selexipag for treating pulmonary arterial hypertension of adults. The therapeutic drug selexipag for treating pulmonary arterial hypertension of adults is prepared through 5-step reaction of starting materials 5-chlorine-2 and 3-diphenyl pyrazine. The invention aims to overcome the defect of higher cost of the present method, shorten the preparation process and provide the preparation method for the therapeutic drug selexipag for treating pulmonary arterial hypertension of adults that is mild in reaction, easy in operation and high in chiral purity.
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Paragraph 0019; 0020
(2017/08/31)
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- Preparation method for 4-[(5,6-diphenylpiperazin-2-yl)(isopropyl)amido]-1-butanol
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The invention discloses a preparation method for 4-[(5,6-diphenylpiperazin-2-yl)(isopropyl)amido]-1-butanol. According to the invention, a compound as shown in a formula 3 is mixed with 4-(isopropylamino)butanol under an alkaline or neutral condition and a reaction is carried out at a mild reaction temperature so as to obtain the compound as shown in a formula 1.
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- SOLID STATE FORMS OF SELEXIPAG
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The present disclosure relates to solid state forms of Selexipag, in particular selexipag forms IV and V, and processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Paragraph 0089-0094
(2017/03/21)
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- Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension
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Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.
- Asaki, Tetsuo,Kuwano, Keiichi,Morrison, Keith,Gatfield, John,Hamamoto, Taisuke,Clozel, Martine
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p. 7128 - 7137
(2015/10/05)
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- Structure-activity studies on diphenylpyrazine derivatives: A novel class of prostacyclin receptor agonists
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To develop nonprostanoid prostacyclin receptor agonists with a high degree of metabolic resistance and an extended duration of action, a novel series of diphenylpyrazine derivatives was synthesized and evaluated for their inhibition of ADP-induced human platelet aggregation. Structure-activity relationship studies on the side chain containing the carboxylic acid moiety of the lead compound 5c showed that the length of the linker and the presence of the concatenating nitrogen atom adjacent to the pyrazine ring are critical for the antiaggregatory activity. This study led to the discovery of 2-amino-5,6-diphenylpyrazine derivatives 8c, 15a, and 15b, which showed potent inhibition of platelet aggregation with IC50 values of 0.2 μM. Among these compounds, 15b is an orally available and long-lasting prostacyclin receptor agonist which is promising for the treatment of various vascular diseases.
- Asaki, Tetsuo,Hamamoto, Taisuke,Sugiyama, Yukiteru,Kuwano, Keiichi,Kuwabara, Kenji
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p. 6692 - 6704
(2008/03/27)
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- HETEROCYCLIC COMPOUND DERIVATIVES AND MEDICINES
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The present invention provides a compound which is useful as a PGI2 receptor agonist, and a pharmaceutical composition. The present invention is directed to a pharmaceutical composition comprising a compound represented by the following formula [1]: (R1 and R2 are the same or different and each represents optionally substituted aryl, Y represents N or CH, Z represents N or CH, A represents NH, NR5, O, S, or ethylene, R5 represents alkyl, D represents alkylene or alkenylene, E represents phenylene or single bond, G represents O, S, or CH2, R3 and R4 are the same or different and each represents hydrogen or alkyl, Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, or N-(alkylsulfonyl)carbamoyl), or a pharmaceutically acceptable salt thereof as an active ingredient.
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