Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/20—Nitrogen atoms

Definitions

• the present invention relates to a method for producing type I crystals of selexipag.
• the object of the present invention is to provide highly pure type I crystals of selexipag.
• a method for producing type I crystals of selexipag includes dissolving 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide in a first solvent containing ethanol at a temperature higher than 55°C to obtain a first solution, and precipitating type I crystals of 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide in the first solution at a temperature of 55°C or higher.
• a method for producing type I crystals of 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide is provided.
• 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide is also referred to as selexipag or SXP.
• This manufacturing method includes dissolving selexipag in a first solvent containing ethanol at a temperature higher than 50°C, particularly higher than 55°C, to obtain a first solution, and precipitating type I crystals of selexipag in the first solution at a temperature of 50°C or higher, particularly 55°C or higher.
• type I crystals with high purity can be obtained by precipitating crystals in a first solution at a temperature of 50°C or higher, particularly 55°C or higher.
• the crystal form of selexipag can change depending on the type and temperature of the precipitating solvent.
• the crystal form of the precipitate may be a mixture of type I and type III.
• microcrystals are generated in the first solution in which no crystals are present, selexipag grows around these microcrystals and precipitates as crystals. It is believed that at relatively low temperatures, not only type I crystals but also type III crystals are generated. Therefore, it is believed that when the temperature of the first solution is lowered to a temperature lower than the temperature at which the microcrystals are generated, the microcrystals of the I type crystals and the microcrystals of the III type crystals grow, and the III crystals are mixed into the I type crystals.
• This manufacturing method includes dissolving selexipag in a first solvent containing ethanol at a temperature higher than 50°C to obtain a first solution, and precipitating type I crystals of selexipag in the first solution at a temperature of 50°C or higher, particularly 55°C or higher.
• SX-A03Cl is reacted with 4-(isopropylamino)-1-butanol (SX-E01) in n-methylpyrrolidone to obtain 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol (SX-A04).
• AX-A04 is reacted with tert-butyl bromoacetate to obtain tert-butyl 2- ⁇ 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ acetate (SX-A05Boc).
• the first solvent is a solvent capable of dissolving crude selexipag.
• a solvent containing ethanol is used as the first solvent.
• the first solvent may contain a second solvent other than ethanol, or may be composed of ethanol only.
• the ethanol content in the first solvent is, for example, 90% by volume or more. If the ethanol content in the first solvent is high, the solubility of crude selexipag tends to increase.
• the ethanol content is preferably 92% by volume or more, and more preferably 94% by volume or more.
• the upper limit of the ethanol content is 100% by volume.
• the ethanol content in the first solvent can be measured, for example, by gas chromatography.
• the second solvent it is preferable to use at least one selected from the group consisting of ketones and esters. When these solvents are used, there is a tendency to obtain type I crystals with fewer impurities.
• the order of mixing crude selexipag, ethanol, and the second solvent is not particularly limited.
• a first solvent containing the second solvent in addition to ethanol may be prepared in advance, and crude selexipag may be dissolved in the first solvent.
• crude selexipag may be dissolved in the first solvent to obtain the first solution, and the second solvent may be added to the first solution before precipitating the type I crystals.
• crude selexipag, the first solvent, and the second solvent may be mixed simultaneously to dissolve crude selexipag.
• the amount of the first solvent per 1 g of crude selexipag is, for example, 1 mL or more and 33 mL or less. A large amount of the first solvent tends to produce type I crystals with fewer impurities. A small amount of the first solvent tends to produce type I crystals at a high precipitation rate.
• the amount of the first solvent is preferably 5 mL or more and 30 mL or less, and more preferably 6 mL or more and 15 mL or less.
• the amount of the first solvent per 1 g of crude selexipag may be 10 mL or less, or may be 8 mL or less.
• the temperature at which crude selexipag is dissolved in the first solvent i.e., the temperature at which the first solution is obtained, is, for example, 50°C or higher and 100°C or lower, particularly higher than 50°C and 100°C or lower. If the dissolution temperature is excessively high, the purity of the type I crystals tends to decrease. If the dissolution temperature is low, type I crystals with fewer impurities tend to be obtained.
• the dissolution temperature is preferably 55°C or higher and 80°C or lower, and more preferably 60°C or higher and 70°C or lower.
• the temperature at which the I-type crystals of selexipag are precipitated i.e., the precipitation temperature
• the precipitation temperature may be 50°C or higher, typically 55°C or higher.
• the precipitation temperature is preferably 60°C or higher, more preferably 65°C or higher.
• the upper limit of the precipitation temperature is, for example, 80°C or lower, and in another example, 70°C or lower.
• the precipitation temperature is the temperature at which the precipitation of crystals can be confirmed in the first solution.
• the type I crystals of selexipag can be precipitated, for example, by maintaining the first solution within the above-mentioned precipitation temperature range for a predetermined maintenance time.
• the maintenance time is, for example, 30 minutes or more, preferably 2 hours or more, and more preferably 4 hours or more. There is no particular upper limit to this maintenance time, but in one example it is 6 hours or less, in another example it is 8 hours or less, and in yet another example it is 13 hours or less. If the maintenance time is 13 hours or less, type I crystals of higher purity tend to be obtained. It is preferable that the first solution is continuously stirred until precipitation begins.
• the type I crystals of selexipag are preferably extracted by the following method. First, the first solution is stirred at a first temperature of 60°C to 80°C for 0.1 to 2 hours, then the first solution is stirred at a second temperature that is 1°C to 10°C lower than the first temperature and is 50°C or higher, particularly 55°C or higher, for 1 to 5 hours, and then the type I crystals of selexipag are extracted from the first solution at the second temperature. By gradually lowering the temperature of the first solution in this manner, type I crystals with higher purity tend to be obtained.
• the first solution is stirred at a third temperature that is 1°C to 10°C lower than the second temperature and is 50°C or higher, particularly 55°C or higher, for 1 to 5 hours, and the type I crystals of selexipag may be extracted from the first solution at the third temperature.
• seed crystals of type I crystals may be added to the first solution.
• the amount of seed crystals per 1 g of crude selexipag is, for example, from 0.0001 g to 0.1 g, and preferably from 0.001 g to 0.01 g.
• the first solution may contain water.
• the water content in the first solution is preferably 10% by volume or less. When the first solution contains water, the purity of selexipag tends to decrease. This is thought to be because selexipag is hydrolyzed and impurities are produced.
• the water content in the first solution is more preferably 1% by volume or less, and even more preferably 0.1% by volume or less.
• the lower limit of the water content is, for example, 0% by volume, and in another example, 500 ppm.
• the water content can be measured, for example, by coulometric titration.
• the temperature of the first dispersion liquid when extracting type I crystals from the first dispersion liquid i.e., the final cooling temperature
• the temperature of the first dispersion liquid when extracting type I crystals from the first dispersion liquid is preferably 50°C or higher, and more preferably 60°C or higher. By setting the temperature of the first dispersion liquid within this range, type III crystals are less likely to be generated, and type I crystals with higher purity are obtained.
• the final cooling temperature of the first dispersion liquid is not limited to 50°C or higher, and may be less than 50°C, 30°C or lower, or 20°C or lower. A lower final cooling temperature tends to increase the yield of type I crystals. There is no particular lower limit for the final cooling temperature, but one example is 0°C or higher.
• Impurity 4 14.6 min.
• Impurity 5 20.2 min.: 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol.
• the amount of the solvent that is, the total amount of ethanol and ethyl acetate contained in the crystals obtained in Example 1 and Comparative Example 10 was measured by gas chromatography.
• Method for preparing a measurement sample A solution of 50 mg of selexipag dissolved in 5 mL of 1,3-dimethyl-2-imidazolidinone is used.
• the amount of solvent in the crystals of Example 1 was 434 ppm, and the amount of solvent in the crystals of Comparative Example 10 was 1597 ppm.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (1)

Applications Claiming Priority (2)

Publications (1)

Family

ID=91717182

Family Applications (1)

Country Status (2)

Citations (4)

• 2023
  • 2023-11-28 WO PCT/JP2023/042456 patent/WO2024142718A1/ja not_active Ceased
  • 2023-11-28 JP JP2024567322A patent/JPWO2024142718A1/ja active Pending

Patent Citations (4)

Also Published As

Similar Documents

Legal Events