CN106966999A - The preparation method of Parecoxib Sodium key intermediate - Google Patents
The preparation method of Parecoxib Sodium key intermediate Download PDFInfo
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- CN106966999A CN106966999A CN201710224433.9A CN201710224433A CN106966999A CN 106966999 A CN106966999 A CN 106966999A CN 201710224433 A CN201710224433 A CN 201710224433A CN 106966999 A CN106966999 A CN 106966999A
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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- 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
- C07D261/10—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 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
- C07D261/14—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
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- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The present invention relates to the preparation method of Parecoxib Sodium key intermediate, belong to pharmaceutical synthesis field.The purpose of the present invention is to overcome defect present in existing synthetic method, there is provided that a kind of reaction condition is gentle, supplementary material it is cheap be easy to get, post-processing operation is simple, the preparation method of the Parecoxib Sodium key intermediate of with short production cycle, product purity and high income, comprise the following steps：Step one, 1 (phenylethylene of 1 methyl 2) pyrrolidines (compound I) is prepared；Step 2, prepares 5 methyl 3,4 diphenyl 5 (base of pyrrolidines 1) 4,5 dihydro-isoxazoles (compound II)；Step 3, prepares 5 methyl 3,4 diphenyl isoxazole (compound III) crude products；Step 4, refining for 53,4 hexichol of methyl 5 base isoxazole (compound III) crude products, a kind of brand-new method is provided to prepare Parecoxib Sodium key intermediate.
Description
Technical field
The present invention relates to the preparation method of Parecoxib Sodium key intermediate, belong to pharmaceutical synthesis field.
Background technology
Parecoxib Sodium (Parecoxib Sodium) is Specific cyclooxygenase-2 inhibitor, the inhibitor by
Pharmacia companies research and develop, and belong to former times dry goods antalgesic.The chemical name of Parecoxib Sodium is N- [[4- (5- methyl -3- benzene
Base -4- isoxazolyls) phenyl] sulfonyl] propionamide sodium salt, concrete structure is as follows：
Preparation method research at present on Parecoxib Sodium is more, is all with the different evil of 5- methyl -3,4- diphenyl mostly
Azoles is key intermediate to carry out preparing Parecoxib Sodium.Comprehensive literature report, current 5- methyl -3,4- diphenyl isoxazole
Preparation method mainly has two kinds：
Method one, document WO2005123701 uses 1,2- benzyl phenyl ketones to be initiation material, is condensed with nafoxidine, then second
It is acylated, then under sodium acetate and hydroxylamine hydrochloride cyclization, through trifluoroacetic acid dehydration obtain 3,4- diphenyl -5- methylisoxazoles.Instead
Answer formula as follows：
The major defect of the route is：The enamine intermediates conversion ratio of first step generation is not high, and routine preservation is unstable, needs
To be purified by way of vacuum distillation, it is higher to the equipment requirement of industrialized production；Second step acetylization reaction, it is necessary to
Acid binding agent is done using 2,6- lutidines costly, the production cost of whole piece process route is improved.Reaction time is relative
Longer, chlorine acetylation needs 24h.4th step, employs trifluoroacetic acid as dehydration mediators, and system is acid very strong, pair sets
It is standby to require high, at the same fluoride for environment pollution also than larger, the cost and difficulty of sewage disposal can be increased.
Method two, document EP1550658 uses 1- phenylacetones for initiation material, with nafoxidine be condensed, then with cyanophenyl N
Oxide reaction cyclization, takes off nafoxidine in concentrated hydrochloric acid, forms double bond and obtains 3,4- diphenyl -5- methylisoxazoles.Reaction
Formula is as follows：
The shortcoming of the route is that the first step reaction time long can increase reaction time；Second step cyanophenyl N oxides come
Source is limited, and the industrially scalable of the route has certain limitation.
In summary, it is contemplated that the deficiency that known preparation method is present, the invention provides a kind of preparation method of improvement,
To make up the defect that above-mentioned preparation method is present, so as to meet the industrial production demand of Parecoxib Sodium key intermediate.
The content of the invention
The purpose of the present invention is to overcome defect present in existing synthetic method crucial middle there is provided a kind of Parecoxib Sodium
The preparation method of body, this method has that reaction condition is gentle, supplementary material it is cheap be easy to get, post-processing operation is simple, production week
Phase is short, the advantage of product purity and high income.
The preparation method of Parecoxib Sodium key intermediate of the present invention, it is characterised in that comprise the following steps：
Step one, 1- (1- methyl -2- phenylethylenes)-pyrrolidines (compound I) is prepared：Reaction dissolvent is hexamethylene, plus
Enter after raw material A 1- phenylacetones and excess raw material B nafoxidines, back flow reaction to raw material A reaction completely, remove reaction dissolvent ring
The raw material B nafoxidines of hexane and excess, obtaining compound I, (gained concentrate is compound I, and the concentrate need not enter one
Step processing is directly used in next step reaction).
Further, the raw material A and raw material B mol ratio are 1:1.5~1:2, preferably 1:1.8；Raw material A and hexamethylene
Mass ratio is 1:5~1:10, preferably 1:6.
Further, after being reacted completely to raw material A, cooling system is to 40-50 DEG C, then be concentrated under reduced pressure removing solvent and raw material
B。
Further, remove reaction dissolvent hexamethylene and use vacuum distillation or air-distillation.It is preferred that vacuum distillation.
Step 2, prepares 5- methyl -3,4- diphenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole (compounds
II)：Reaction dissolvent is dichloromethane, acid binding agent, raw material C (E)-N- hydroxyl benzimidoyl chlorine and step one gained concentrate room temperature
Reaction is complete to raw material C reactions, adds water and washes away point liquid after inorganic salts, organic phase is concentrated under reduced pressure to give compound II, and (gained is concentrated
Thing is compound II, and the concentrate is directly used in next step reaction without further processing).
Further, the raw material C and compound I mol ratio is 0.75:1~1:1, preferably 0.8:1；Compound I with
The mol ratio of acid binding agent is 1:1~1:1.25, preferably 1:1.1；Raw material C is 1 with dichloromethane mass ratio:10~1:15, preferably
1:12.5。
Further, the acid binding agent uses triethylamine, DIPEA；It is preferred to use triethylamine.
Further, step 2, which adds water, washes away inorganic salts, and the water is purified water.
The inorganic salts produced in step 2 are that raw material C can generate hydrochloric acid with chemical compounds I reaction, and hydrochloric acid reacts with acid binding agent to be produced
Raw inorganic salts.Therefore inorganic salts are washed with water away.
Step 3, prepares 5- methyl -3,4- diphenyl isoxazole (compound III) crude product：Reaction dissolvent is hydrochloric acid solution,
The heating responses in hydrochloric acid solution of compound II obtained by step 2 are complete to compound II reactions, are cooled to room temperature；Add dichloro
Methane is extracted, and vacuum distillation is removed after dichloromethane, and isopropanol is added in residue and is again heated to crystallization after dissolved clarification, cooling, from
Heart processing obtains compound III crude products.
Further, hydrochloric acid solution is added water to be mixed with by concentrated hydrochloric acid and formed, wherein, the ratio (ml/ of water and compound ii
G) it is 3:1~5:1, preferably 4:1；Hydrochloric acid solution consumption is in terms of hydrochloric acid, and hydrochloric acid and compound II mol ratio are 3:1-6:1, it is excellent
Select 5:1；Reaction temperature is 90~105 DEG C, preferably 90~100 DEG C.
Step 4,5- methyl -3,4- hexichol -5- base isoxazole (compound III) crude product it is refined：Compound III crude products
It is dissolved in after isopropanol and heats, cooling crystallization, centrifugal treating obtains compound III finished products after drying.
Further, the mass ratio of compound III crude products and isopropanol is 1:1~1:3, preferably 1:1.5；Recrystallization temperature is
0~20 DEG C, preferably 0~10 DEG C；The crystallization time is 3~5 hours.
Preparation method reaction equation of the present invention is as follows：
Preparation method of the present invention have gentle, supplementary material it is cheap be easy to get, post-processing operation is simple, it is with short production cycle,
The characteristics of product purity and high income, a kind of brand-new method is provided to prepare Parecoxib Sodium key intermediate.
Embodiment
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright, illustrate but do not limit the present invention.
Embodiment 1
In the there-necked flask for preparing 1- (1- methyl -2- phenylethylenes)-pyrrolidines (compound I) 500ml, 1- phenyl is added
Acetone (40g, 300mmol, 1.0eq) and hexamethylene 240g, be stirring evenly and then adding into nafoxidine (38.5g, 540mmol,
1.8eq), system backflow is heated to, reaction is complete to the reaction of 1- phenylacetones, return time about 8 hours.System is cooled to 40-
After 50 DEG C, vacuum distillation removes the nafoxidine of hexamethylene and excess.It is concentrated to give the compound I crude products of oily, this oily
Thing is directly used in next step reaction without further processing.(55g, purity about 91.5%, GC are detected)
Prepare 5- methyl -3,4- diphenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazoles (compound II) (E)-N-
Added after hydroxyl benzimidoyl chlorine (30.5g, 196mmol, 0.8eq) mixing 250ml dichloromethane in 1L there-necked flask., stirring
0-10 DEG C is cooled to after uniform, triethylamine (27g, 269.5mmol, 1.1eq) is added, add compound I (50g, 245mmol,
1.0eq).20-30 DEG C of reaction is warming up to after stirring complete to the reaction of (E)-N- hydroxyl benzimidoyls chlorine.Reaction time about 2-
3 hours.Purified water 200ml is added, stirring stands a point liquid after 5 minutes, organic phase vacuum distillation removes dichloromethane and obtains chemical combination
Thing II mixture, this mixture is directly used in next step reaction without further processing.(60g, purity about 78%, GC are detected)
Prepare in 5- methyl -3,4- diphenyl isoxazole (compound III) crude product 1L there-necked flasks, concentrated hydrochloric acid (63ml,
765mmol, 5.0eq) purified water 240ml is dissolved in, add compound II (60g, 153mmol, 1.0eq) reaction solutions and be heated to
95-105 DEG C of reaction, reaction is complete to compound II reactions, about 2-3 hours reaction time.Room temperature is cooled to after reaction completely, plus
Enter dichloromethane 100ml. extractions, stand a point liquid, aqueous phase is extracted once with 100ml dichloromethane again, merges organic phase.It is organic
Mutually decompression is distilled off after dichloromethane, adds isopropanol 60ml, dissolved clarification is stirred after being heated to 60 DEG C.0- is cooled to after filtering
10 DEG C of crystallizations are filtered for 3 hours, 50 DEG C of forced air dryings receive within 5 hours compound III crude product 16.8g.HPLC detections purity is
95.7%.
The purified compound III crude product 16g of 5- methyl -3,4- diphenyl isoxazole (compound III) crude product, are added
In 100ml there-necked flasks.Isopropanol 24g is added, 60-65 DEG C is heated to after heat filtering after solution dissolved clarification, filtrate is cooled to 0-10 DEG C
Crystallization 5 hours.50 DEG C of forced air dryings 5 hours after filtering, obtain compound III finished product 13.6g, yield 85%, HPLC detection purity
For 98.8%.
Embodiment 2
In the enamel still for preparing 1- (1- methyl -2- phenylethylenes)-pyrrolidines (compound I) 1000L, 1- phenyl is added
Acetone (45kg, 335.8mol, 1.0eq) and hexamethylene 270Kg, be stirring evenly and then adding into nafoxidine (43Kg, 604.5mol,
1.8eq), system backflow is heated to, reaction is complete to the reaction of 1- phenylacetones, return time about 8-9 hours.System is cooled to
After 40-50 DEG C, vacuum distillation removes the nafoxidine of hexamethylene and excess.The compound I crude products of oily are concentrated to give, this oil
Shape thing is directly used in next step reaction without further processing.(63kg, purity about 93.2%, GC are detected)
Prepare 5- methyl -3,4- diphenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazoles (compound II) (E)-N-
1000L enamel still is added after hydroxyl benzimidoyl chlorine (40g, 256mol, 0.8eq) mixing 300L dichloromethane.Stir
After be cooled to 0-10 DEG C, add triethylamine (35.6kg, 352mol, 1.1eq), add compound I (60kg, 320mol,
1.0eq).20-30 DEG C of reaction is warming up to after stirring complete to the reaction of (E)-N- hydroxyl benzimidoyls chlorine.Reaction time about 3-
4 hours.Purified water 250L is added, stirring stands a point liquid after 10 minutes, organic phase vacuum distillation removes dichloromethane and obtains chemical combination
Thing II mixture, this mixture is directly used in next step reaction without further processing.(78Kg, purity about 81%, GC are examined
Survey)
Prepare in 5- methyl -3,4- diphenyl isoxazole (compound III) crude product 1L there-necked flasks, concentrated hydrochloric acid (86L,
1030mol, 5.0eq) purified water 300L is dissolved in, add compound II (78kg, 206mol, 1.0eq) reaction solutions and be heated to
95-105 DEG C of reaction, reaction is complete to compound II reactions, about 3-5 hours reaction time.Room temperature is cooled to after reaction completely, plus
Enter dichloromethane 120L. extractions, stand a point liquid, aqueous phase is extracted once with 120L dichloromethane again, merges organic phase.Organic phase
Vacuum distillation is removed after dichloromethane, adds isopropanol 80L, dissolved clarification is stirred after being heated to 60 DEG C.0-10 is cooled to after filtering
DEG C crystallization is filtered for 5 hours, 50 DEG C of forced air dryings receive within 5 hours compound III crude product 22.4kg.HPLC detections purity is
96.8%.
The purified compound III crude product 22kg of 5- methyl -3,4- diphenyl isoxazole (compound III) crude product, are added
In 100L enamel stills.Isopropanol 33kg is added, 60-65 DEG C is heated to after heat filtering after solution dissolved clarification, filtrate is cooled to 0-10 DEG C
Crystallization 5 hours.50 DEG C of forced air dryings 5 hours after filtering, obtain compound III finished product 19.2Kg, yield 87%, HPLC detection purity
For 99.1%.
Claims (10)
1. the preparation method of Parecoxib Sodium key intermediate, it is characterised in that：Comprise the following steps：
Step one, 1- (1- methyl -2- phenylethylenes)-pyrrolidines (compound I) is prepared：Reaction dissolvent is hexamethylene, is added former
Expect after A1- phenylacetones and excess raw material B nafoxidines, back flow reaction to raw material A reaction completely, remove reaction dissolvent hexamethylene
And excessive raw material B nafoxidines, obtain compound I；
Step 2, prepares 5- methyl -3,4- diphenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazoles (compound II)：Instead
It is dichloromethane to answer solvent, acid binding agent, raw material C (E)-N- hydroxyl benzimidoyl chlorine and step one gained concentrate react at room temperature to
Raw material C reactions are complete, add water and wash away point liquid after inorganic salts, and organic phase is concentrated under reduced pressure to give compound II；
Step 3, prepares 5- methyl -3,4- diphenyl isoxazole (compound III) crude product：Reaction dissolvent is hydrochloric acid solution, step
Two gained compound II heating responses in hydrochloric acid solution are complete to compound II reactions, are cooled to room temperature；Add dichloromethane
Extraction, vacuum distillation is removed after dichloromethane, and isopropanol is added in residue and is again heated at crystallization after dissolved clarification, cooling, centrifugation
Reason obtains compound III crude products；
Step 4,5- methyl -3,4- hexichol -5- base isoxazole (compound III) crude product it is refined：Compound III crude products are dissolved in
Heated after isopropanol, cooling crystallization, centrifugal treating obtains compound III finished products after drying.
2. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：Described in step one
Raw material A and raw material B mol ratio are 1:1.5~1:2, preferably 1:1.8；Raw material A is 1 with hexamethylene mass ratio:5~1:10, it is excellent
Select 1:6.
3. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：Described in step one
To raw material A reaction completely, system is first cooled down to 40-50 DEG C, then be concentrated under reduced pressure removing solvent and raw material B.
4. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：Described in step one
Remove reaction dissolvent hexamethylene and use vacuum distillation or air-distillation；It is preferred to use vacuum distillation.
5. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：Described in step 2
Raw material C and compound I mol ratio is 0.75:1~1:1, preferably 0.8:1；The mol ratio of compound I and acid binding agent is 1:1~
1:1.25, preferably 1:1.1；Raw material C is 1 with dichloromethane mass ratio:10~1:15, preferably 1:12.5.
6. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：Described in step 2
Acid binding agent uses triethylamine, N, N- diisopropylethylamine；It is preferred to use triethylamine.
7. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：Step 2, step
Rapid two, which add water, washes away inorganic salts, and the water is purified water.
8. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：At least meet with
Lower any one：
Hydrochloric acid solution described in step 3 is added water to be mixed with by concentrated hydrochloric acid and formed, wherein, the ratio (ml/g) of water and compound ii
For 3:1~5:1, preferably 4:1；
Hydrochloric acid solution consumption described in step 3 is in terms of hydrochloric acid, and hydrochloric acid and compound II mol ratio are 3:1-6:1, preferably 5:1；
Step 3 reaction temperature is 90~105 DEG C, preferably 90~100 DEG C.
9. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：The step 4
The mass ratio of compound III crude products and isopropanol is 1:1~1:3, preferably 1:1.5.
10. the preparation method of Parecoxib Sodium key intermediate according to claim 1, it is characterised in that：The step
Four recrystallization temperatures are 0~20 DEG C, preferably 0~10 DEG C；The crystallization time is 3~5 hours.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1550658A1 (en) * | 2003-12-30 | 2005-07-06 | Dr. Reddy's Laboratories Ltd. | Method for preparing 3,4-diphenyl-substituted isoxazole compounds |
-
2017
- 2017-04-07 CN CN201710224433.9A patent/CN106966999A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1550658A1 (en) * | 2003-12-30 | 2005-07-06 | Dr. Reddy's Laboratories Ltd. | Method for preparing 3,4-diphenyl-substituted isoxazole compounds |
Non-Patent Citations (3)
| Title |
|---|
| ANUMULA RAGHUPATHI REDDY ，等: "Application of [3+2]-Cycloaddition in the Synthesis of Valdecoxib", 《SYNTHETIC COMMUNICATIONS》 * |
| LEONARDO DI NUNNO，等: "Novel Synthesis of 3,4-Diarylisoxazole Analogues of Valdecoxib: Reversal Cyclooxygenase-2 Selectivity by Sulfonamide Group Removal", 《J.MED.CHEM.》 * |
| 宁国慧，等: "3,5-二取代的异噁唑啉类衍生物的合成及杀菌活性研究", 《有机化学》 * |
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