CN109970673A - The preparation method of SC 69124 sodium impurity - Google Patents
The preparation method of SC 69124 sodium impurity Download PDFInfo
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- CN109970673A CN109970673A CN201711472181.8A CN201711472181A CN109970673A CN 109970673 A CN109970673 A CN 109970673A CN 201711472181 A CN201711472181 A CN 201711472181A CN 109970673 A CN109970673 A CN 109970673A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of preparation method of SC 69124 sodium impurity.The synthetic method of compound PRN073-11 was never mentioned in existing technology, it is that particularly small number of generation is had during preparing Parecoxib Sodium bulk pharmaceutical chemicals, when to obtain the PRN073-11 as standard items, typically can just be obtained using the method being repeatedly enriched with.And synthesising method reacting condition proposed by the invention is mild, also very simple, used reagent are all conventional reagent for operation, are easy to get, no risk, have biggish application value.Compared with the enrichment method reported in the prior art, preparation method of the invention is simpler, accurately, save the cost, and can be mass, product yield greatly improves.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of preparation method of SC 69124 sodium impurity.
Background technique
Parecoxib Sodium chemical structural formula are as follows:
Parecoxib Sodium is a kind of cyclooxygenase-2 (COX-2) specific inhibitor.Belong to the former times cloth in anti-arthritic
Class antalgesic.It can be used for the short of postoperative pain.It can be clinically used for the treatment of moderate or severe postoperative acute pain.
The synthetic method of Parecoxib Sodium is as follows:
4- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide (hereinafter referred to as " compound PARE-004 ") is to prepare
One important intermediate of Parecoxib Sodium, position isomer impurity 4- (5- methyl l-4- phenyl isoxazole -3- base) benzene sulfonyl
Amine (hereinafter referred to as " PRN073-11 ") is an impurity for needing to pay close attention in Parecoxib Sodium quality standard, auspicious for pa
The former times correlative study of cloth sodium is significant.
SC 69124 sodium impurity PRN073-11 structural formula are as follows:
Quality control mainly control active constituent and the content in relation to substance of drug, more particularly to the content of substance
It needs to meet medicinal requirements.Related substance can be described as impurity again, impurity be mainly derived from active constituent preparation process and
It is generated in drug degradation." technological guidance's principle of chemicals impurity research " ([H] GPH3-1, the 6-7 pages) is pointed out: organic miscellaneous
The detection of matter generally mostly uses HPLC method.HPLC method is such as used, peak area method must be used, specific quantitative approach uses external standard method
(impurity Standard reference), quantified by external standard method is more accurate.But in existing HPLC analysis method, if without reference substance, for
Impurity of the content lower than 0.1% carries out structural identification, and there are difficulty.
In existing document, compound PRN073-11 is obtained generally by the method for enrichment, in the prior art simultaneously
The method for obtaining compound PRN073-11 not being simple and efficient.Its main cause are as follows:
During sulphur aminating reaction occurs for compound PARE-013, since the primary product that electronic effect obtains is chemical combination
Object PARE-004 and compound PARE-014, only minimal amount of compound PRN073-11.It is embodied in, it is fragrant first
Sulfonic acid chloride (amine) reaction of ring is electrophilic substitution reaction, the position of electron rich on aromatic rings, easier by sulfonic acid chloride (amine)
Change.In compound PARE-013, due to conjugation, the A ring linked with isoxazole, is integrally electron rich, and B ring
It is electron deficient.So sulfonic acid chloride (amine) reaction can only occur in A ring in the case where reaction condition is not very violent substantially；
And if reaction condition is violent, sulfonic acid chloride (amine) reaction also can preferentially occur in A ring, then occur in B ring, so with this
Method is to be difficult to prepare compound PRN073-11.
Therefore, it is necessary to be improved to the preparation method of Parecoxib Sodium impurity compound PRN073-11, to improve it
Combined coefficient.
Summary of the invention
The present invention provides the conjunctions of the Parecoxib Sodium impurity compound PRN073-11 of simple and effective preparation high-purity a kind of
At method, it is not mentioned in the prior art.
The position of benzsulfamide is first fixed on oxazole ring by the present invention, then the phenyl ring on the position methyl α is introduced, reaction process
Simple and clear, used reagent is all general reagent.
Prepare the intermediate PARE-004 structural formula of Parecoxib Sodium are as follows:
SC 69124 sodium impurity PRN073-11 structural formula are as follows:
The present invention is achieved through the following technical solutions:
The preparation method of SC 69124 sodium impurity, includes the following steps:
1) compound PRN073-11-102 and compound PRN073-11-003 carries out Buchwald cross-coupling reaction, obtains
To compound PRN073-11-103；
2) compound PRN073-11-103 and NCS and ammonium hydroxide that step 1) is prepared sulphur aminating reaction is carried out to obtain
Compound PRN073-11-104；
3) the compound PRN073-11-104 that step 2) is prepared and NBS generation addition reaction obtains bromide
PRN073-11-105；
4) the compound PRN073-11-105 that step 3) is prepared is reacted with phenyl boric acid generation Suzuki, obtains chemical combination
Object PRN073-11.
In step 1),
According to the present invention, the temperature of Buchwald reaction is 70~120 DEG C, preferably 100~120 DEG C, also preferably
110℃。
According to the present invention, the Buchwald reaction carries out in a solvent, and preferred reaction dissolvent includes toluene, dioxy six
Ring, dimethylbenzene, tetrahydrofuran, DMF, NMP, DMSO equal solvent, further preferably toluene.
According to the present invention, the Buchwald reaction carries out in the presence of a catalyst；The catalyst is the cooperation of palladium phosphorus
Object, such as tetrakis triphenylphosphine palladium, three (double BENZYLIDENE ACETONEs) two palladium (Pd2(dba)3) etc., preferably three (double BENZYLIDENE ACETONEs)
Two palladiums.
According to the present invention, the Buchwald reaction carries out in the presence of base；The alkali is selected from bis- (trimethylsilyl) ammonia
Base sodium, tert butoxide or DIEA etc., preferably DIEA.
According to the present invention, the Buchwald reaction carries out in the presence of ligand；The ligand is selected from for example
Xantphos (the bis- diphenylphosphine -9,9- xanthphos of 4,5-) etc..
According to the present invention, the PRN073-11-102, compound PRN073-11-003, catalyst, ligand and alkali rub
You are than being 1:(1-3): (0.01-0.1): (0.05-0.5): (1.5-2.5), for example, 1:2:0.05:0.1:1.9；According to this hair
Bright, the time of the Buchwald reaction can be 8~12 hours, for example, 10 hours.
Optionally, the Buchwald after the reaction was completed purifies obtained product, such as is chromatographed using column to production
Object is separated, and the eluant, eluent that the column chromatography uses is preferably petroleum ether and ethyl acetate；The eluent petroleum ether and second
The volume ratio of acetoacetic ester is (40~100): 1, preferably (50~70): 1, further preferably 60:1.
In step 2),
According to the present invention, the molar ratio of compound PRN073-11-103 and NCS is 1:(1~5), preferably 1:(2~4),
Further preferably 1:3.
According to the present invention, the sulfanilamide (SN) reaction temperature is 5~35 DEG C, such as 20~55 DEG C；Reaction time is that 4-12 is small
When.
According to the present invention, the dosage of the ammonium hydroxide is determined by the pH of reaction solution, and the dosage of ammonium hydroxide is no more than and makes to react
PH > 8 of liquid.According to the present invention, during ammonium hydroxide is added, the temperature of reaction solution is controlled in the range of 15~20 DEG C.
Optionally, sulfanilamideization after the reaction was completed purifies obtained product, such as is carried out using column chromatography to product
Separation, the eluant, eluent that the column chromatography uses is preferably methylene chloride and methanol；The volume ratio of the methylene chloride and methanol is
(20~60): 1, preferably (20~40): 1, further preferably 30:1.
In step 3),
According to the present invention, the molar ratio of compound PRN073-11-104 and NBS is 1:(2~4), preferably 1:3.
According to the present invention, the temperature of addition reaction is 15~35 DEG C, preferably 25 DEG C.
In step 4),
According to the present invention, the Suzuki reaction carries out in a solvent, and the solvent is toluene, DMF, dioxane etc. pair
Suzuki reacts inert solvent, preferably dioxane.
According to the present invention, suitable water can also be added in reaction solution and do cosolvent, the volume of solvent and cosolvent water
Than for (5~15): 1, preferably 10:1.
According to the present invention, the molar ratio of compound PRN073-11-105 and phenyl boric acid is 1:(1~5), preferably 1:(2~
4), further preferably 1:3.
According to the present invention, the Suzuki reaction carries out in the presence of a catalyst, and the catalyst can be Pd
(OAc)2Equal palladium catalysts.
According to the present invention, phosphorus ligand, such as Ph can also be used in the Suzuki reaction2P(CH2)2PPh2
(dppe)、Ph2P(CH2)3PPh2(dppp) or the phosphorus ligand such as tricyclohexyl phosphine.
According to the present invention, the Suzuki reaction carries out in the presence of base, and the alkali is selected from Ba (OH)2、Na2CO3、
K2CO3Or CsCO3Deng preferably CsCO3。
According to the present invention, the molar ratio of compound PRN073-11-105, palladium catalyst, phosphorus ligand and alkali is 1:(0.05
~0.5): (0.05~0.5): (2~4), preferably 1:0.1:0.2:3.
According to the present invention, the Suzuki reaction time is 0.5-24 hours, and reaction temperature is 50-150 DEG C.
Optionally, the Suzuki after the reaction was completed purifies obtained product, such as is chromatographed using column to product
It is separated, the eluant, eluent that the column chromatography uses is preferably petroleum ether and ethyl acetate；The eluent petroleum ether and acetic acid
The volume ratio of ethyl ester is (2~8): 1, preferably (3~5): 1, further preferably 4:1.
Preferably, compound PRN073-11-102 used in step 1) is prepared via a method which:
1a) compound PRN073-11-001 is reacted with acetone generation Claisen-Schmidt, and ketenes formula is obtained after condensation
Compound PRN073-11-101；
1b) the compound PRN073-11-101 for obtaining step 1a) and compound PRN073-10-01 carries out ring closure reaction
Obtain compound PRN073-11-102.
Beneficial effects of the present invention
1) synthetic method for never mentioning compound PRN073-11 in existing technology is to prepare pa auspicious former times
There is particularly small number of generation as impurity during cloth sodium raw materials medicine, when to obtain the PRN073-11 as standard items, generally
It is all that can just be obtained using the method being repeatedly enriched with.And the invention proposes a kind of method for synthesizing compound PRN073-11 is anti-
Mild condition is answered, also very simple, used reagent are all conventional reagent for operation, are easy to get, no risk has larger
Application value.
2) compared with the enrichment method reported in the prior art, preparation method of the invention is simpler, accurately, save at
This, and can be mass, product yield greatly improves.
Specific embodiment
Further detailed description is done to technical solution of the present invention below in conjunction with specific embodiment.It should be appreciated that
The following example is merely illustrative the ground description and interpretation present invention, and is not necessarily to be construed as limiting the scope of the invention.
In the range of all technologies realized based on above content of the present invention are encompassed by the present invention is directed to protect.
Unless otherwise indicated, raw materials and reagents used in the following embodiment are commercial goods, or can be by
Perception method preparation.
Embodiment 1
The present embodiment first uses compound PRN073-11-001 that compound PRN073-11-101 is prepared, and then makes again
Raw material compound PRN073-11-102 is prepared with compound PRN073-11-101.By compound PRN073-11-001 through multistep
The specific reaction step that compound PRN073-11 is prepared is as follows:
The preparation of (1. E) -4- (4- bromophenyl) butyl- 3- alkene -2- ketone
It takes PRN073-11-001 (200g, 1.087mol, 1.0eq.), acetone (252.2g, 4.348mmol, 4.0eq.),
2L there-necked flask is added in pure water (252.2g.), and stirring, dissolved clarification, dropwise addition 1% sodium hydrate aqueous solution (250mL), drop do not finish solid,
65 DEG C are warming up to, 2h is reacted.TLC detects (solvent: PE/EA=5/1, Rf=0.6), fully reacting stops reaction, is down to room
Temperature.It is added EA (500mL), stirs liquid separation, organic phase is concentrated into constant weight with saturated common salt water washing (300mL × 2), drying.It is residual
Stay object that methyl tertiary butyl ether(MTBE) (30mL) is added, PE (200mL) stirring to pulp filters, and filter cake is eluted with PE (20mL), and it is solid to obtain yellow
Body, i.e. PRN073-11-101 (174g, yield 72%).
The preparation of 2.3- (4- bromophenyl) -5- methylisoxazole
It takes PRN073-11-101 (50g, 223.25mmol, 1.0eq.) and methanol (625mL) to be added in 2L there-necked flask, stirs
It mixes, solid not stir by dissolved clarification, addition PRN073-10-01 (83.5g, 446.5mmol, 2.5eq.), and dissolved clarification, dropwise addition be not molten for solid
Potassium carbonate (123.25g, 893mmol, 4.0eq.) solution of Yu Shui (125mL), drop finish, and solid dissolved clarification (has a small amount of white crystal
It is precipitated), it is warming up to reflux, reacts 14h.TLC detects (solvent: PE/EA=15/1, Rf=0.4), raw material fundamental reaction is complete
Entirely, stop reaction, be down to room temperature.EA (1000mL) is added and pure water (500mL) stirs liquid separation, organic phase is washed with saturated common salt
It washs (300mL × 2), it is dry, it is concentrated into constant weight.Column chromatography purifying, residue are added DCM (10mL) and dissolve, dry method upper prop,
PE/EA elution rinses product with PE/EA=90/1, is concentrated (40 DEG C of bath temperature <), obtains PRN073-11-102, yellow solid
(17g, yield 30.7%).
The preparation of 3.3- (4- (benzylthio) phenyl) -5- methylisoxazole
It takes PRN073-11-102 (24g, 101.2mmol, 1.0eq.), toluene (200mL.), benzyl mercaptan (12.58g,
202.4mmol, 2.0eq.), Pd2(dba)3(4.632g, 5.06mmol, 0.05eq.), DIEA (32.2mL, 1.9eq.) and
Xantphos (5.86g, 10.12mmol, 0.1eq.), is added 2L there-necked flask, and stirring is warming up to reflux under argon gas protection, flows back
React 10h.TLC detects (solvent: PE/EA=15/1, Rf=0.2), raw material fully reacting stops reaction, is down to room temperature.Add
Enter DCM (1000mL) and pure water (500mL) stirring liquid separation, organic phase saturated common salt water washing (500mL × 2), dry, concentration
To constant weight.DCM (30mL) dissolution, dry method loading, PE/EA elution, with PE/EA=60/1 is added in column chromatography purifying, residue
It rinses product (having hangover, can suitably increase polarity), concentration obtains PRN073-11-103, (27g, yield are yellow solid
94.9%).
The preparation of 4.4- (5- methylisoxazole -3- base) benzsulfamide
1L there-necked flask is taken, is added PRN073-11-103 (24g, 85.44mmol, 1.0eq.), acetic acid (150mL), stirring,
Solid portion dissolution, is added pure water (50mL), and stirring has a solid precipitation, be added NCS (34.22g, 256.32mmol,
3.0eq.), it is stirred at room temperature, reacts 8h.TLC detection (ammonium hydroxide does derivatization reaction, EA extraction) (solvent: PE/EA=10/1, Rf
=0.5), raw material fully reacting.
Reaction solution is slowly dropped into ammonium hydroxide, temperature control is lower than 15~20 DEG C, and 1~2h is stirred at room temperature, and keeps pH > 8, TLC inspection
Survey (solvent: PE/EA=10/1, Rf=0.5), raw material fully reacting stops reaction.It is added EA (300mL), stirs liquid separation,
Organic phase is concentrated into a small amount of solvent, is there is solid precipitation with saturated common salt water washing (100mL × 2), drying, is filtered, is obtained white solid
Body (16g), i.e. PRN073-11-104.Filtrate is concentrated into constant weight.DCM (10mL) dissolution is added in column chromatography purifying, residue,
Dry method loading, DCM/MeOH elution rinse product with DCM/MeOH=30/1, are concentrated to give yellow solid, i.e. PRN073-11-
104, yellow solid (2g, yield 88.5%).
The preparation of 5.4- (the bromo- 5- methylisoxazole -3- base of 4-) benzsulfamide
PRN073-11-105 (5g, 21mmol, 1.0eq.) and DMF (50mL) are taken, is added in 250mL there-necked flask, stirring is extremely
Dissolved clarification is added portionwise NBS (11.22g, 63mmol, 3.0eq.), is stirred at room temperature, and reacts 4.5h.TLC detects (solvent: DCM/
MeOH=15/1, Rf=0.4), raw material fully reacting stops reaction.Reaction solution is poured into ice water (300mL), there is solid analysis
Out, 1h is stirred, filters, obtains faint yellow solid, i.e. PRN073-11-105 (1.7g, yield 25.6%).
The preparation of 6.4- (5- methyl 4-phenyl isoxazole -3- base) benzsulfamide
Under argon gas protection, PRN073-11-105 (1.5g, 4.75mmol, 1.0eq.) and dioxane (30mL.) is taken to be added
Into 250mL single port bottle, pure water (3mL) then is added, cesium carbonate (4.64g, 14.24mmol, 3.0eq.), phenyl boric acid
(1.74g, 14.24mmol, 3.0eq.), stirring to dissolved clarification are added tricyclohexyl phosphine (266.38mg, 0.95mmol, 0.2eq.),
Pd(OAc)2(106.4mg, 0.475mmol, 0.1eq.), stirring are warming up to 100 DEG C, react 5.5h.TLC detection (solvent:
PE/EA=3/1, Rf=0.3) (more expansion are several times), raw material fully reacting stops reaction, is down to room temperature.It is added EA (100mL)
Liquid separation is stirred with pure water (50mL), organic phase is concentrated into constant weight with saturated common salt water washing (50mL × 2), drying.Column chromatography
DCM (10mL) dissolution, dry method loading is added in purifying, residue, and PE/EA elution is rinsed product with PE/EA=4/1, is concentrated to give white
Color solid.Isopropyl ether (4mL) mashing is added, filters up to PRN073-11, white solid (1.0g, yield 67%).
LCMS(ES+): m/z [M+H]+: 315.14.1H-NMR (400MHz, DMSO) δ: 7.84~7.86 (d, J=8.8Hz,
2H), 7.56~7.59 (d, J=8.4Hz, 2H), 2.49 (s, 3H), 7.38~7.40 (t, J=3.6Hz, 2H), 7.14~7.16
(m,2H),4.93(s,2H),2.47(s,3H)。
More than, embodiments of the present invention are illustrated.But the present invention is not limited to above embodiment.It is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in guarantor of the invention
Within the scope of shield.
Claims (10)
1. the preparation method of Parecoxib Sodium impurity compound PRN073-11, includes the following steps:
1) compound PRN073-11-102 and compound PRN073-11-003 carries out Buchwald cross-coupling reaction, is changed
Close object PRN073-11-103；
2) compound PRN073-11-103 and NCS and ammonium hydroxide that step 1) is prepared are subjected to sulphur aminating reaction and obtain chemical combination
Object PRN073-11-104；
3) the compound PRN073-11-104 that step 2) is prepared and NBS generation addition reaction obtains bromide PRN073-
11-105；
4) the compound PRN073-11-105 that step 3) is prepared is reacted with phenyl boric acid generation Suzuki, obtains compound
PRN073-11。
2. preparation method as described in claim 1, which is characterized in that in step 1), the Buchwald reaction is in catalyst
In the presence of carry out；The catalyst is palladium phosphorus complex, such as tetrakis triphenylphosphine palladium, three (double BENZYLIDENE ACETONEs) two palladiums
(Pd2(dba)3) etc., preferably three (double BENZYLIDENE ACETONEs) two palladiums；
Preferably, the Buchwald reaction carries out in the presence of base；The alkali is selected from bis- (trimethylsilyl) Sodamides, tertiary fourth
Alkoxide or DIEA etc., preferably DIEA；
Preferably, the Buchwald reaction carries out in the presence of ligand；The ligand is selected from such as Xantphos, and (4,5- is bis-
Diphenylphosphine -9,9- xanthphos)；
Preferably, the molar ratio of the PRN073-11-102, compound PRN073-11-003, catalyst, ligand and alkali is 1:
(1-3): (0.01-0.1): (0.05-0.5): (1.5-2.5), for example, 1:2:0.05:0.1:1.9.
3. preparation method as claimed in claim 1 or 2, which is characterized in that in step 1), the Buchwald is after the reaction was completed
Obtained product is purified, such as product is separated using column chromatography, the eluant, eluent that the column chromatography uses is preferred
For petroleum ether and ethyl acetate；
Preferably, the volume ratio of the eluent petroleum ether and ethyl acetate is (40~100): 1, also preferably (50~70):
1, further preferably 60:1.
4. preparation method as described in any one of claims 1-3, which is characterized in that in step 2), compound PRN073-11-
103 with the molar ratio of NCS be 1:(1~5), preferably 1:(2~4), also preferably 1:3；
Preferably, the dosage of the ammonium hydroxide is no more than pH > 8 for making reaction solution；
Preferably, during ammonium hydroxide is added, the temperature of reaction solution is controlled in the range of 15~20 DEG C.
5. preparation method according to any one of claims 1-4, which is characterized in that in step 2), sulfanilamideization is after the reaction was completed
Obtained product is purified, such as product is separated using column chromatography, the eluant, eluent that the column chromatography uses is preferred
For methylene chloride and methanol；
Preferably, the volume ratio of the methylene chloride and methanol is (20~60): 1, also preferably (20~40): 1, it is further excellent
It is selected as 30:1.
6. preparation method as described in any one in claim 1-5, which is characterized in that in step 3), compound PRN073-11-
The molar ratio of 104 and NBS is 1:(2~4), preferably 1:3.
7. preparation method as claimed in any one of claims 1 to 6, which is characterized in that in step 4), compound PRN073-11-
105 with the molar ratio of phenyl boric acid be 1:(1~5), preferably 1:(2~4), further preferably 1:3.
8. such as the described in any item preparation methods of claim 1-7, which is characterized in that in step 4), the Suzuki reaction exists
It is carried out in the presence of catalyst, the catalyst can be Pd (OAc)2Equal palladium catalysts；
Preferably, the middle of Suzuki reaction uses phosphorus ligand, such as Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2
(dppp) or tricyclohexyl phosphine；
Preferably, the Suzuki reaction carries out in the presence of base；The alkali is selected from Ba (OH)2、Na2CO3、K2CO3Or
CsCO3, preferably CsCO3；
Preferably, the molar ratio of PRN073-11-105, palladium catalyst, phosphorus ligand and alkali is 1:(0.05~0.5): (0.05~
0.5): (2~4), also preferably 1:0.1:0.2:3.
9. such as the described in any item preparation methods of claim 1-8, which is characterized in that in step 4), the Suzuki has reacted
Obtained product is purified at rear, such as product is separated using column chromatography, the column chromatographs the eluant, eluent used
Preferably petroleum ether and ethyl acetate；
Preferably, the volume ratio of the eluent petroleum ether and ethyl acetate is (2~8): 1, also preferably (3~5): 1, into one
Step is preferably 4:1.
10. such as the described in any item preparation methods of claim 1-9, which is characterized in that compound used in step 1)
PRN073-11-102 is prepared via a method which:
1a) compound PRN073-11-001 is reacted with acetone generation Claisen-Schmidt, and ketenes formula chemical combination is obtained after condensation
Object PRN073-11-101；
The compound PRN073-11-101 and compound PRN073-10-01 that step 1a) is obtained 1b) is carried out ring closure reaction to obtain
Compound PRN073-11-102.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1181075A (en) * | 1995-02-13 | 1998-05-06 | G·D·瑟尔公司 | Substituted isoxazoles for the treatment of inflammation |
| US20070060629A1 (en) * | 2003-10-17 | 2007-03-15 | Yasuhiro Imanishi | Large conductance calcium-activated k channel opener |
| WO2012170752A1 (en) * | 2011-06-10 | 2012-12-13 | Glaxo Wellcome Manufacturing Pte Ltd | Novel compounds |
| CN104945343A (en) * | 2015-01-04 | 2015-09-30 | 成都克莱蒙医药科技有限公司 | Synthesis method of parecoxib sodium impurity |
-
2017
- 2017-12-28 CN CN201711472181.8A patent/CN109970673B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1181075A (en) * | 1995-02-13 | 1998-05-06 | G·D·瑟尔公司 | Substituted isoxazoles for the treatment of inflammation |
| US20070060629A1 (en) * | 2003-10-17 | 2007-03-15 | Yasuhiro Imanishi | Large conductance calcium-activated k channel opener |
| WO2012170752A1 (en) * | 2011-06-10 | 2012-12-13 | Glaxo Wellcome Manufacturing Pte Ltd | Novel compounds |
| CN104945343A (en) * | 2015-01-04 | 2015-09-30 | 成都克莱蒙医药科技有限公司 | Synthesis method of parecoxib sodium impurity |
Non-Patent Citations (4)
| Title |
|---|
| MIKHAIL KRASAVIN 等: "Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides synthesized via a direct sulfochlorination of 3- and 4-(hetero)arylisoxazol-5-amine scaffolds", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| ROOZBEH ESKANDARI 等: "A convenient synthesis of 5-alkylthio-3,4-diarylisoxazoles by palladium-catalyzed coupling reactions", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| SHIBING TANG 等: "Efficient and Regioselective One-Pot Synthesis of 3-Substituted and 3,5-Disubstituted Isoxazoles", 《ORGANIC LETTERS》 * |
| 张亮亮 等: "磺酰氯合成方法研究进展", 《合成化学》 * |
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