CN107365275A - The Sai Lexipa of high-purity - Google Patents
The Sai Lexipa of high-purity Download PDFInfo
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- CN107365275A CN107365275A CN201710449906.5A CN201710449906A CN107365275A CN 107365275 A CN107365275 A CN 107365275A CN 201710449906 A CN201710449906 A CN 201710449906A CN 107365275 A CN107365275 A CN 107365275A
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- 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
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Abstract
The invention discloses a kind of Sai Lexipa of high-purity.Reacted and be made under conditions of organic base with CDI, Methanesulfomide in organic solvent by Sai Lexipa key intermediate 2 (4 ((base of 5,6 diphenyl pyrazine 2) isopropylamino) butoxy) acetic acid.The operation is simple, and cost is low, environment-friendly, yield ＞ 95%, suitable for industrialized production, obtained Sai Lexipa purity >=99.9%, can meet the requirement of medicine production well.The Sai Lexipa purity that the present invention is prepared is high, and the medicine of higher quality is obtained so as to be advantageous to postorder.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of prostacyclin receptor activator Sai Lexipa height
Imitate preparation method, gained Sai Lexipa purity >=99.9%, yield ＞ 95%.
Background technology
Sai Lexipa (West pa lattice, Selexipag) is a kind of long-acting PGI2 receptor stimulating agents of new oral, by Switzerland
Actelion biopharmaceutical companys research and develop, and are ratified in 2015 by U.S. FDA, for treating adult pulmonary's high pressure.Match pleasure
Western pa chemical name is：2- { 4- [N- (5,6- diphenyl pyrazine -2- bases)-N- isopropylaminos] butoxy }-N- (methylsulfonyls
Base) acetamide, there is following structural formula：
Formula (S-I) compound is Sai Lexipa important intermediate, at present itself and Methanesulfomide of existing more document reports
React the technique for preparing Sai Lexipa.
WO2002088084 (Heterocyclic compound derivatives and medicines) is reported at first
(S-I) and Methanesulfomide generation Sai Lexipa reaction.The operation step is：(S-I) exist with carbonyl dimidazoles (CDI)
After 1 hour (room temperature and be heated to reflux each half an hour) is reacted in anhydrous tetrahydro furan, then it is double in 1,8- diazas with Methanesulfomide
Carbon -7- the alkene (DBU) of ring [5.4.0]-ten one is made to react overnight under conditions of alkali, is extracted after reaction completely through ether, column chromatography point
Product is obtained from purifying.The yield of the reaction is 76.6%, does not disclose product Sai Lexipa purity.
WO2011017612 (Substituted diphenylpyrazine derivatives) has used same side
(S-I) derivative that method is substituted by deuterium prepares corresponding deuterated Sai Lexipa, yield 52%-58%.
WO2017060827(An improved process for the preparation of selexipag or
Its pharmaceutically acceptable salts) disclosed the step of preparing Sai Lexipa is：(S-I) elder generation and CDI
It is heated to reflux in tetrahydrofuran solution 2 hours, then half an hour is reacted at room temperature with Methanesulfomide, is eventually adding DBU stirrings 40
Minute, 1N hydrochloric acid regulation system pH are added after the completion of reaction, are extracted with ethyl acetate, water and brine It, most afterwards through heptane
It is recrystallized to give Sai Lexipa, yield 84.5%.
Method made above uses DBU to participate in reacting as alkali.Make the reaction of alkali with DBU, all exist yield it is low lack
Fall into., the impurity shown in the formula (Z-II) for not only generating and being introduced as DBU is reacted, the content of impurity is also higher shown in formula (Z-I).
The present inventor study find, even if optimize such reaction reaction condition and aftertreatment technology, by its yield improve to 90% with
On, but because the content of impurity (Z-I) and impurity (Z-II) can not be reduced to less than 0.1% during product purification, institute
Also it is difficult to reach 99.9% with obtained Sai Lexipa purity, therefore the requirement of pharmaceutical preparation can not be met.
CN106279047 (a kind of preparation method of prostacyclin receptor activator) disclose by (S-I) and POCl3,
The acetonitrile of acyl chlorides or chloroformic solution are added dropwise to mesyl chloride and triethylamine etc. obtained by the chlorination reactions such as ethanedioly chloride, solid phosgene
In the acetonitrile solution of acid binding agent, insulation reaction 5 hours at 10 DEG C, ethyl alcohol recrystallization is used after extraction, obtains the pure of Sai Lexipa
Spend for 99.1%-99.5%, the yield of reaction is 80%-88%.The reaction makees intermediate using acyl chlorides, and course of reaction needs to grow
Time keeping temperature is 10 DEG C, is not suitable for industrialized production.
WO2017042828(Process for the preparation of selexipag and
Intermediates thereof) disclose two methods preparation Sai Lexipa.A kind of method is that (S-I) exists with Methanesulfomide
Reacted under the conditions of CDI, DBU and tetrahydrofuran, obtained Sai Lexipa crude products recrystallized three times through ethanol-isopropanol-ethanol,
Obtain the Sai Lexipa that purity is 99.75%, yield 74%.Another method operating procedure is：(S-I) exist with thionyl chloride
Reacted in dichloromethane 4 hours (25-30 DEG C and 35-40 DEG C is each two hours), Methanesulfomide is added at 25-30 DEG C, then 40 DEG C
Reaction 2 hours, reaction solution is added into water stratification during post processing, organic layer is washed with the sodium acid carbonate of water and 2%, and ethanol is used after concentration
Recrystallization, obtain the Sai Lexipa that purity is 99.6%, yield 67.6%.
In addition, the document for preparing Sai Lexipa using other intermediates has：
CN102459198 (crystal) discloses intermediate (S-II) and 2- chloro- N- (methyl sulphonyl) acetamide reaction system
Standby Sai Lexipa method, but specific embodiment is not provided in document.
CN106008364 (a kind of selexipag preparation method) discloses (S-II) and the chloro- N- of 2- (methyl sulphonyl)
Acetamide reacts the method for preparing Sai Lexipa under the conditions of alkali and 1,4- dioxane.Alkali therein can be potassium tert-butoxide,
Sodium tert-butoxide or both mixture, the crude product obtained after reaction are recrystallized to give match pleasure with tetrahydrofuran/n-hexane mixed solvent
The Sai Lexipa, yield 76%-83.8% that purity is 99.97% can be made in western pa, the technique.
CN106316967 (preparation method of West pa lattice intermediate and West pa lattice) discloses (S-II), the chloro- N- of 2-
(methyl sulphonyl) acetamide and potassium tert-butoxide react 12 hours methods for preparing Sai Lexipa in 1-METHYLPYRROLIDONE.Instead
The crude product that should be obtained is recrystallized to give the Sai Lexipa that purity is 99.2%-99.5% with ethyl acetate/petroleum ether mixed solvent,
Yield is 81%-83%.
CN105949135 (a kind of Sai Lexipa synthetic method) discloses the synthetic method shown in following formula, and this method is received
Rate is 90.5%-92.3%, does not disclose obtained Sai Lexipa purity.
In summary, it is also no in presently disclosed technical scheme simultaneously to meet to prepare high income and match pleasure is made
The also high requirement of western pa purity, it is that a kind of of intermediate reacts especially for disclosing most at present with (S-I), so needing
Develop the Sai Lexipa that new method prepares high-purity in high yield.
The content of the invention
It is an object of the invention to provide a kind of Sai Lexipa preparation method, this method is by Sai Lexipa key intermediate
2- { 4- [N- (5,6- diphenyl pyrazine -2- bases)-N- isopropylaminos] butoxy } acetic acid reacts with Methanesulfomide, passes through selection
Suitable reaction condition and aftertreatment technology so that reaction yield ＞ 95%, obtained Sai Lexipa purity >=99.9%, this hair
Bright purpose can be achieved through the following technical solutions：
The invention provides a kind of method for efficiently preparing high-purity Sai Lexipa, including following operating procedure：
A. compound and 1 shown in formula (S-I), 1 '-carbonyl dimidazoles are added in organic solvent, are heated to reflux 1-2 hours；
B. Methanesulfomide is added at room temperature, is stirred 10-20 minutes, is added organic base, it is purified to obtain Sai Lexipa；
Wherein, organic base described in step b is triethylamine, diisopropyl ethyl amine or both mixture.
In a preferred embodiment, the compound described in step a (S-I) and 1,1 '-carbonyl dimidazoles feed intake
Mol ratio is 1:1.0-1:3.0, preferably 1:1.5.
In a preferred embodiment, the Methanesulfomide described in the compound described in step a (S-I) and step b
Molar ratio be 1:1.0-1:5.0, preferably 1:2.0.
In a preferred embodiment, organic base described in the compound described in step a (S-I) and step b
Molar ratio is 1:0-1:8.0, preferably 1:2.0.
In a preferred embodiment, the organic solvent described in step a is tetrahydrofuran or dichloromethane, preferably two
Chloromethanes.
In a preferred embodiment, the volume mass ratio of the dosage of described organic solvent and compound (S-I) is
5:1-20:1, preferably 8:1-15:1, more preferably 10:1-15:1.
In a preferred embodiment, the purifying described in step b has used recrystallization purifying.
In a preferred embodiment, compound (S-I) is prepared using following methods：
The first step：The bromo- 2,3- diphenyl pyrazines of 5- are heated to 150 with 4- (isopropyl) amino-n-butyl alcohol in the presence of KI
DEG C reaction, obtain 4- ((5,6- diphenyl pyrazine -2- bases)-(isopropyl) amino)-n-butyl alcohol；
Second step：4- ((5,6- diphenyl pyrazine -2- bases)-(isopropyl) amino]-n-butyl alcohol, bromo-acetic acid tert-butyl, four
Butyl ammonium hydrogen sulfate, potassium hydroxide aqueous solution react in toluene, generate 2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyls
Base) amino) butoxy) tert-butyl acetate；
3rd step：2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) tert-butyl acetate is in first
In alcoholic solution, reacted with sodium hydrate aqueous solution, generate (S-I) compound.
Present invention effectively avoids the difficult generation for removing property impurity in the prior art, the product obtained after reaction is through simple
Recrystallization purifying after conventional treatment, the Sai Lexipa of purity >=99.9% is made, the yield ＞ 95% of reaction, has overcome existing
The defects of technology can not meet in high yield with high product purity simultaneously.The present invention is simple to operate, and cost is low, and controllability is strong, safety
Environmental protection, medicine production and the requirement of industrialized production can be met simultaneously.The Sai Lexipa purity that the present invention is prepared is high, so as to
Be advantageous to postorder and obtain the medicine of higher quality.
Brief description of the drawings
Fig. 1 be the gained Sai Lexipa crude products of embodiment 4 HPLC chromatogram, purity 99.16%.
Fig. 2 be the gained Sai Lexipa highly finished product of embodiment 4 HPLC chromatogram, purity 99.93%.
Fig. 3 be the gained Sai Lexipa crude products of embodiment 5 HPLC chromatogram, purity 99.20%.
Fig. 4 be the gained Sai Lexipa highly finished product of embodiment 5 HPLC chromatogram, purity 99.93%.
Fig. 5 be the gained Sai Lexipa crude products of embodiment 6 HPLC chromatogram, purity 99.04%.
Fig. 6 be the gained Sai Lexipa highly finished product of embodiment 6 HPLC chromatogram, purity 99.94%.
The HPLC chromatogram of Fig. 7 Sai Lexipa crude products obtained by comparative example, purity 97.29%.
The HPLC chromatogram of Fig. 8 Sai Lexipa highly finished product obtained by comparative example, purity 99.27%.
Embodiment
Content for a better understanding of the present invention, technical scheme is done into one with reference to specific embodiment
The explanation of step, but specific embodiment is not meant to there are any restrictions to the present invention.
The structure of compound is determined by nuclear magnetic resonance (NMR).Use (the Hes of Bruker Avance III 400
Bruker Avance 600) nuclear magnetic resonance spectrometer, measure solvent is deuterochloroform (CDCl3), inside it is designated as tetramethylsilane (TMS)；
HPLC measure uses Shimadzu high pressure liquid chromatograph (Zorbax SB-C18 250 × 4.6mm, 5 μM)；
Not specified (NS) raw material and reagent of the present invention are bought by conventional method.
Embodiment 1
Bromo- 2, the 3- diphenyl pyrazines (100g, 0.32mol) of 5-, 4- isopropylaminos-n-butyl alcohol are added in reaction bulb
(127g, 0.96mol) and KI (15.9g, 0.096mol), it is heated to 150 DEG C and reacts 16 hours.After system is cooled to room temperature
Ethyl acetate (800mL) is added, is washed with water (800mL × 2), anhydrous sodium sulfate drying, is filtered, filtrate decompression concentration, residual
Thing dichloromethane/heptane (1.2L, v/v=1:5) recrystallize, obtain 4- ((5,6- diphenyl pyrazine -2- bases)-(isopropyls)
Amino)-n-butyl alcohol (75.5g, yield：65.3%).
1H NMR(400MHz,CDCl3) δ 8.01 (s, 1H), 7.45 (d, J=5.8Hz, 2H), 7.35 (d, J=6.8Hz,
2H), 7.28-7.21 (m, 6H), 4.79 (hept, J=6.6Hz, 1H), 3.68 (t, J=6.3Hz, 2H), 3.47-3.38 (m,
2H), 1.86 (s, 1H), 1.80-1.72 (m, 2H), 1.69-1.58 (m, 2H), 1.27 (d, J=6.7Hz, 6H)
13C NMR(100MHz,CDCl3)δ151.6,149.0,139.6,139.5,139.0,129.8,129.3,128.1,
128.0,127.9,127.1,126.9,62.4,46.2,42.2,30.0,25.7,20.4.
Embodiment 2
In reaction bulb add 4- ((5,6- diphenyl pyrazine -2- bases)-isopropylamino)-n-butyl alcohol (72.3g,
0.20mol), toluene (200mL), 4-butyl ammonium hydrogen sulfate (33.9g, 0.10mol) and 40% potassium hydroxide solution (150mL,
W%), bromo-acetic acid tert-butyl (78.0g, 0.40mol) is added dropwise under ice-water bath, drop finishes, and continues insulation reaction 20 hours.Dense salt is added dropwise
Sour regulation system pH to 5-6, extracted with ethyl acetate (500mL), water (500mL × 2) washing, be concentrated under reduced pressure to give 2- (4-
((5,6- diphenyl pyrazine base) (isopropyl) amino) butoxy) tert-butyl acetate crude product, directly carry out next step reaction.
Embodiment 3
Into the gained crude product of above-described embodiment 2 add tetrahydrofuran (300mL) and 10% sodium hydroxide solution (300mL,
W%), it is heated to reflux, TLC detects complete to reaction.It is concentrated under reduced pressure and removes tetrahydrofuran, aqueous phase methyl tertiary butyl ether(MTBE) (300mL
× 2) extract, then extracted, be concentrated under reduced pressure with 1N salt acid for adjusting pH to 2-3, ethyl acetate (800mL), residue acetic acid
Ethyl ester (500mL) is recrystallized to give 2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) acetic acid (S-I)
(55.8g, two step yields：66.5%).
1H NMR(400MHz,CDCl3) δ 8.10 (s, 1H), 7.42 (dd, J=7.6,1.8Hz, 2H), 7.32 (dd, J=
7.4,2.1Hz, 2H), 7.27-7.21 (m, 6H), 4.85 (hept, J=6.6Hz, 1H), 4.07 (s, 2H), 3.61 (t, J=
6.0Hz, 2H), 3.48-3.39 (m, 2H), 1.81-1.70 (m, 4H), 1.26 (d, J=6.7Hz, 6H)
13C NMR(400MHz,CDCl3)δ173.3,152.0,149.6,139.4,138.8,138.4,129.9,129.5,
128.1,128.0,127.9,127.1,126.7,71.4,68.0,46.2,42.3,27.0,26.0,20.3.
Embodiment 4
2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) acetic acid (S-I) is added in reaction bulb
(21.0g, 0.05mol), carbonyl dimidazoles (12.2g, 0.075mol) and dichloromethane (210mL), heating reflux reaction 1 are small
When, be cooled to 20-30 DEG C, add Methanesulfomide (9.5g, 0.10mol), stir 10 minutes, add triethylamine (10.1g,
0.10mol), reaction 5 hours is continued.Water (50mL) is added, 1N hydrochloric acid regulation system pH to 5-6, liquid separation is added dropwise, organic phase is used
Water (50mL × 2) washs, anhydrous sodium sulfate drying, and filtering, filtrate decompression is concentrated to give Sai Lexipa crude product (purity：99.16%,
HPLC chromatogram is as shown in Figure 1), crude product recrystallizes to obtain off-white powder Sai Lexipa (24.0g, receipts with absolute ethyl alcohol (270mL)
Rate：96.8%, purity：99.93%, HPLC chromatogram is as shown in Figure 2).
1H NMR(600MHz,CDCl3) δ 8.00 (s, 1H), 7.43 (d, J=6.9Hz, 2H), 7.34 (d, J=7.4Hz,
2H), 7.29-7.16 (m, 6H), 4.73 (hept, J=6.6Hz, 1H), 3.92 (s, 2H), 3.55 (t, J=5.6Hz, 2H),
3.45-3.40 (m, 2H), 3.25 (s, 3H), 1.78-1.64 (m, 4H), 1.27 (d, J=6.6Hz, 6H)
13C NMR(150MHz,CDCl3)δ169.0,151.6,149.0,139.6,139.4,139.2,129.8,129.3,
128.1,128.0,127.9,127.1,127.0,77.3,77.1 76.9,71.8,69.7 46.4,42.0,41.5,26.9,
25.9,20.4.
Embodiment 5
2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) acetic acid (S-I) is added in reaction bulb
(21.0g, 0.05mol), carbonyl dimidazoles (12.2g, 0.075mol) and dichloromethane (210mL), heating reflux reaction 1 are small
When, 20-30 DEG C is cooled to, adds Methanesulfomide (9.5g, 0.10mol), stirs 10 minutes, adds diisopropyl ethyl amine
(12.9g, 0.10mol), continues stirring reaction 5 hours.Water (50mL) is added, 1N hydrochloric acid regulation system pH to 5-6 is added dropwise, point
Liquid, organic phase are washed with water (50mL × 2), anhydrous sodium sulfate drying, and filtering, it is (pure that filtrate decompression is concentrated to give Sai Lexipa crude products
Degree：99.20%, HPLC chromatogram is as shown in Figure 3), crude product recrystallizes to obtain off-white powder Sai Lexi with absolute ethyl alcohol (270mL)
Pa (23.7g, yield：95.6%, purity：99.93%, HPLC chromatogram is as shown in Figure 4).
Embodiment 6
2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) acetic acid (S-I) is added in reaction bulb
(21.0g, 0.05mol), carbonyl dimidazoles (12.2g, 0.075mol) and tetrahydrofuran (210mL), heating reflux reaction 1 are small
When, be cooled to 20-30 DEG C, add Methanesulfomide (9.5g, 0.10mol), stir 10 minutes, add triethylamine (10.1g,
0.10mol), stirring reaction is continued 5 hours.It is concentrated under reduced pressure and removes solvent, adds dichloromethane (200mL) and water (150mL), drop
Adding 1N hydrochloric acid regulation system pH to 5-6, liquid separation, liquid separation, organic phase washed with water (50mL × 2) is changed, anhydrous sodium sulfate drying,
Filtering, filtrate decompression are concentrated to give Sai Lexipa crude product (purity：99.04%, HPLC chromatogram is as shown in Figure 5).Crude product is with anhydrous
Ethanol (270mL) recrystallizes to obtain off-white powder Sai Lexipa (23.7g, yield：95.7%, purity：99.94%, HPLC chromatogram
Figure is as shown in Figure 6).
Comparative example
2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) acetic acid (S-I) is added in reaction bulb
(21.0g, 0.05mol), carbonyl dimidazoles (12.2g, 0.075mol) and tetrahydrofuran (210mL), heating reflux reaction 1 are small
When, be cooled to 20-30 DEG C, add Methanesulfomide (9.5g, 0.10mol), stir 10 minutes, add DBU (15.2g,
0.10mol), stirring reaction is continued 5 hours.It is concentrated under reduced pressure and removes solvent, adds dichloromethane (200mL) and water (150mL), drop
Add 1N hydrochloric acid regulation system pH to 5-6, liquid separation, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, is filtered, filter
Liquid is concentrated under reduced pressure get Sai Lexipa crude product (purity：97.29%, HPLC chromatogram is as shown in Figure 7).Crude product absolute ethyl alcohol
(270mL) recrystallizes to obtain off-white powder Sai Lexipa (22.9g, yield：92.3%, purity：99.27%, HPLC chromatogram is such as
Shown in Fig. 8).
Sai Lexipa analyze data is shown in Table 1 obtained by above example.
Sai Lexipa product parameters obtained by 1. each embodiment of table
Note：ND represents to be not detected by related impurities.
Claims (8)
1. a kind of method for efficiently preparing high-purity Sai Lexipa, including following operating procedure：
A. compound and 1 shown in formula (S-I), 1 '-carbonyl dimidazoles are added in organic solvent, are heated to reflux 1-2 hours；
B. Methanesulfomide is added at room temperature, is stirred 10-20 minutes, is added organic base, it is purified to obtain Sai Lexipa；
Wherein, organic base described in step b is triethylamine, diisopropyl ethyl amine or both mixture.
2. the method according to claim 1 for efficiently preparing high-purity Sai Lexipa, it is characterised in that：Described in step a
Compound (S-I) and 1,1 '-carbonyl dimidazoles molar ratio be 1:1.0-1:3.0.
3. the method according to claim 1 for efficiently preparing high-purity Sai Lexipa, it is characterised in that：Described in step a
Compound (S-I) and step b described in Methanesulfomide molar ratio be 1:1.0-1:5.0.
4. the method according to claim 1 for efficiently preparing high-purity Sai Lexipa, it is characterised in that：Described in step a
Compound (S-I) and step b described in organic base molar ratio be 1:0-1:8.0.
5. the method according to claim 1 for efficiently preparing high-purity Sai Lexipa, it is characterised in that：Described in step a
Organic solvent be tetrahydrofuran or dichloromethane.
6. high-purity Sai Lexipa method is efficiently prepared according to claim 1 or 5, it is characterised in that：Described has
The dosage of solvent is 5 with the volume mass ratio of compound (S-I):1-20:1.
7. the method according to claim 1 for efficiently preparing high-purity Sai Lexipa, it is characterised in that：Described in step b
Purifying used recrystallization purifying.
8. the method according to claim 1 for efficiently preparing high-purity Sai Lexipa, it is characterised in that：Compound (S-I)
Prepared using following methods：
The first step：The bromo- 2,3- diphenyl pyrazines of 5- are heated to 150 with 4- (isopropyl) amino-n-butyl alcohol in the presence of KI
DEG C reaction, obtain 4- ((5,6- diphenyl pyrazine -2- bases)-(isopropyl) amino)-n-butyl alcohol；
Second step：4- ((5,6- diphenyl pyrazine -2- bases)-(isopropyl) amino]-n-butyl alcohol, bromo-acetic acid tert-butyl, the tetrabutyl
Ammonium hydrogen sulfate, potassium hydroxide aqueous solution react in toluene, generate 2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) ammonia
Base) butoxy) tert-butyl acetate；
3rd step：2- (4- ((5,6- diphenyl pyrazine -2- bases) (isopropyl) amino) butoxy) tert-butyl acetate is molten in methanol
In liquid, reacted with sodium hydrate aqueous solution, generate (S-I) compound.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128358A (en) * | 2019-04-08 | 2019-08-16 | 河北科技大学 | 4 [(5,6 diphenyl pyrazine, 2 base) (isopropyl) amino] butyl 2 (sulfonyloxy methyl amino) acetic acid esters preparation methods |
| CN111263754A (en) * | 2017-09-28 | 2020-06-09 | 日本新药株式会社 | Crystallization of |
| CN112500358A (en) * | 2020-11-18 | 2021-03-16 | 江苏豪森药业集团有限公司 | Celecoxib crystal form and preparation method thereof |
| CN112939877A (en) * | 2019-12-11 | 2021-06-11 | 南京理工大学 | Synthesis method of diphenylpyrazine derivative |
| CN113480484A (en) * | 2021-06-30 | 2021-10-08 | 湖南方盛制药股份有限公司 | Preparation method of medical intermediate |
| CN114213343A (en) * | 2022-01-07 | 2022-03-22 | 江苏豪森药业集团有限公司 | Preparation and purification method of celecoxib intermediate |
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| CN111263754A (en) * | 2017-09-28 | 2020-06-09 | 日本新药株式会社 | Crystallization of |
| EP3689854A4 (en) * | 2017-09-28 | 2021-06-09 | Nippon Shinyaku Co., Ltd. | Crystal |
| US11655218B2 (en) | 2017-09-28 | 2023-05-23 | Nippon Shinyaku Co., Ltd. | Crystalline substituted pyrazines as PGI2 receptor agonists |
| CN110128358A (en) * | 2019-04-08 | 2019-08-16 | 河北科技大学 | 4 [(5,6 diphenyl pyrazine, 2 base) (isopropyl) amino] butyl 2 (sulfonyloxy methyl amino) acetic acid esters preparation methods |
| CN112939877A (en) * | 2019-12-11 | 2021-06-11 | 南京理工大学 | Synthesis method of diphenylpyrazine derivative |
| CN112500358A (en) * | 2020-11-18 | 2021-03-16 | 江苏豪森药业集团有限公司 | Celecoxib crystal form and preparation method thereof |
| CN113480484A (en) * | 2021-06-30 | 2021-10-08 | 湖南方盛制药股份有限公司 | Preparation method of medical intermediate |
| CN114213343A (en) * | 2022-01-07 | 2022-03-22 | 江苏豪森药业集团有限公司 | Preparation and purification method of celecoxib intermediate |
| CN114213343B (en) * | 2022-01-07 | 2024-04-16 | 江苏豪森药业集团有限公司 | Preparation and purification methods of celecoxib intermediate |
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