KR20150013061A - Novel preparation method of Corey Lactone aldehyde P-Phenyl Benzoate - Google Patents
Novel preparation method of Corey Lactone aldehyde P-Phenyl Benzoate Download PDFInfo
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- KR20150013061A KR20150013061A KR1020140094012A KR20140094012A KR20150013061A KR 20150013061 A KR20150013061 A KR 20150013061A KR 1020140094012 A KR1020140094012 A KR 1020140094012A KR 20140094012 A KR20140094012 A KR 20140094012A KR 20150013061 A KR20150013061 A KR 20150013061A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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Abstract
Description
The present invention relates to a novel process for the preparation of coralactone aldehyde para-phenyl benzoate, and more particularly to a process for the production of coral lactone aldehyde para-phenyl benzoate.
Coriolactone is an important intermediate in prostaglandin synthesis, and coralactone aldehyde para-phenyl benzoate is an important intermediate in linking the prostaglandin side chain.
There has been no known method for mass-producing such a coriolactone aldehyde para-phenylbenzoate from coralactone with high efficiency.
It is an object of the present invention to provide a method for effectively producing coralactone aldehyde para-phenyl benzoate.
The problems to be solved by the present invention are not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
(A) contacting a solvent with an oxidizing agent at -10 to 10 degrees Celsius to obtain a contact; (B) a dropwise addition step of dropwise adding a molten product obtained by dissolving coriolactone in a solvent of the same type as that of the solvent of step (A), at a temperature of -10 to 10 degrees Celsius to the contact material of step (A); (C) a primary agitation step of stirring the drop wort from the step (B) at -20 ° C to 10 ° C to obtain a primary agitated product; And (D) a second stirring step of stirring the mixture at a temperature of 10 to 60 degrees Celsius after the completion of the stirring of step (C) to obtain a final stirred product, Lactone aldehyde para-phenyl benzoate.
In addition, the step of obtaining the final stirred product may further include a third agitation step of adding the same kind of oxidizing agent as the oxidizing agent of the step (A) to the secondary stirring substance and stirring to obtain a tertiary stirring substance.
The final stirred product may not contain the coriolactone.
In addition, the production method may further include (E) neutralizing the final stirred product with a reducing agent to a pH of 7 to 8 to obtain a neutralized product. The final stirred product may be a filtrate filtered through a filter paper.
In addition, the preparation method may further comprise (F) purifying the coralactone aldehyde para-phenyl benzoate from the neutralized product of step (E).
(F) an extraction step of extracting the neutralized product of step (E) with a solvent of the same kind as the solvent of step (A) to obtain an extract; And (Fb) concentrating the extract of step (Fa) to obtain a concentrate.
(E ') Into the final stirred product, water corresponding to 1.5 to 5 times the volume ratio of the solvent of the step (A) and the solvent of the step (B) is added and stirred to produce a solid Separating the filtrate containing the water layer and the solvent layer, separating the solvent layer from the filtrate, removing the solvent from the solvent layer, and removing the solvent.
The solvent may be at least one nonpolar solvent selected from dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether, dimethylformamide, or dimethylsulfoxide.
The oxidizing agent may be at least one selected from Dess-Martin Periodinane, IBX, or iodoperbenzoate derivatives.
In the step (A), the oxidant may be 110 to 160 parts by weight based on 100 parts by weight of the solvent.
The above amount may be in the range of 5 to 8 degrees Celsius.
According to the present invention, coriolactone aldehyde para-phenyl benzoate can be produced with high efficiency.
1 is a flowchart for explaining an embodiment of the present invention.
Hereinafter, advantages and features of the present invention and methods of achieving them will be made clear with reference to the embodiments described below in detail with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. But is only provided to fully inform the owner of the scope of the invention, and the present invention is only defined by the scope of the claims.
Like reference numerals refer to like elements throughout the specification. Also, "and / or" include each and every combination of one or more of the components mentioned.
The terminology used herein is for the purpose of illustrating embodiments and is not intended to be limiting of the present invention. In the present specification, the singular form includes plural forms unless otherwise specified in the specification. It is noted that the terms "comprises" and / or "comprising" used in the specification are intended to be inclusive in a manner similar to the components, steps, operations, and / Or additions.
Corey Lactone is a compound of formula 1 and its name is 4- (hydroxymethyl) -2-oxo-hexahydro-2H-cyclopenta [b] furan-5-yl 4-phenylbenzoate. Coriolactone may be commercially available or synthesized by a known method (PCT patent application publication, WO2010083722A1, etc.).
[Chemical Formula 1]
(3R, 4S, 5R, 6aS) -4-formyl-2-oxohexahydro-2H-cyclopenta [b] thiophene- furan-5-yl [1,1'-biphenyl] -4-carboxylate.
(2)
Referring to FIG. 1 and Reaction Scheme 1, a novel process for preparing coralactone aldehyde para-phenylbenzoate, which is an embodiment of the present invention, will be described in more detail.
1 is a flowchart for explaining an embodiment of the present invention.
As shown in FIG. 1 and Scheme 1, the co-lactone aldehyde para-phenyl benzoate of formula (2) can be prepared by using a coriolactone of formula (1) as a starting material and an oxidizing agent.
[Reaction Scheme 1]
Concretely, a step of reacting the coriolactone of the formula (1) with the coriolactone aldehyde of the formula (2) as a starting material via a contacting step, (B) a dropping step, (C) a primary stirring step, and Para-phenyl benzoate can be prepared.
The contacting step is a step of contacting the solvent and the oxidizing agent at -10 to 10 degrees Celsius to obtain a contact. The solvent may be, for example, but not limited to, a nonpolar solvent, but may be, for example, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether, dimethylformamide, and / or dimethylsulfoxide .
The oxidizing agent may be, for example, Dess-Martin Periodinane, IBX, and / or iodoperbenzoate derivatives, etc., as long as it can cause the reaction of Scheme 1. Dess-Martin Periodinane may be synthesized by a known method (Organic Synthesis, Coll. Vol. 10: 696, etc.), and IBX may also be synthesized by a known method (Journal of Organic Chemistry 64: 4537, etc.).
The oxidizing agent may be 110 to 160 parts by weight based on 100 parts by weight of the solvent. More preferably, the oxidizing agent may be 120 parts by weight based on 100 parts by weight of the solvent.
The contact may preferably be in contact at 0 to 10 degrees Celsius.
The dropwise step is a step of dropwise adding a molten product obtained by dissolving coriolactone in a solvent of the same kind as that of the solvent of step (A) to the contact of step (A) at -10 ° C to 10 ° C.
The droplet is added dropwise, preferably at a temperature of 5 to 8 degrees Celsius.
The primary stirring step is a step of stirring the kneaded material of step (B) at -20 ° C to 10 ° C to obtain a primary stirred material. The stirring of the primary stirring step can be carried out for 10 minutes to 2 hours.
The step of obtaining the final stirrer is a step of obtaining a final stirrer, which includes a second stirring step.
The second agitation step is a step of stirring the mixture at 10 to 60 degrees Celsius after the completion of the agitation in step (C) to obtain a secondary agitated product, wherein the starting material is the coralactone aldehyde para-phenyl benzoate. The final stirrer is in a state that does not contain the starting material. The secondary agitation may be preferably 15 to 32 degrees Celsius when the oxidizing agent is a Dess-Martin periodinane and 20 to 60 degrees Celsius when the oxidizing agent is IBX.
Agitation in the secondary agitation step can be carried out for 20 minutes to 5 hours, preferably 20 minutes to 2 hours when the oxidizing agent is Dess-Martin periodinane, and preferably 1 hour to 5 hours when the oxidizing agent is IBX can do.
When the starting material is contained in the secondary agitator, the step of obtaining the final agitator may further include a third agitating step.
The third stirring step is a step of adding an oxidizing agent of the same kind as that of the oxidizing agent of the step (A) to the secondary stirring material and stirring to obtain a tertiary stirring material. By subjecting to such a third stirring step, coriolactone aldehyde para-phenyl benzoate can be produced with higher purity. The third stirring may be carried out at 10 to 60 degrees Celsius for 20 minutes to 3 hours. The tertiary agitation may preferably be between 20 and 60 degrees Celsius when the oxidizing agent is a Dess-Martin periodinane and between 10 and 30 degrees Celsius when the oxidizing agent is IBX.
Agitation of the third agitation step can be carried out for 20 minutes to 2 hours when the oxidizing agent is Dess-Martin periodinane and preferably for 40 minutes to 3 hours when the oxidizing agent is IBX.
In addition, the final stirred product may be one in which the reaction of Scheme 1 is terminated, and does not contain a starting material.
The final stirred product may be subjected to (E) neutralization step. The neutralization step is a step of neutralizing the final stirred product with a reducing agent to a pH of 7 to 8 to obtain a neutralized product.
The final stirred product may be a filtrate filtered through a filter paper.
The reducing agent may be, for example, sodium hydroxide or the like, as long as it is a substance capable of adjusting the pH by reducing ability.
Further, after the neutralization step, (F) purification step, the coriolactone aldehyde para-phenyl benzoate can be purified from the neutralized product of step (E).
(F) an extraction step of extracting the neutralized product of step (E) with a solvent of the same kind as the solvent of step (A) to obtain an extract; And (Fb) concentrating the extract of step (Fa) to obtain a concentrate.
Through such purification steps, higher purity coriolactone aldehyde para-phenyl benzoate can be prepared.
The extraction step is a step of extracting the neutralized product with the same kind of solvent as the solvent of step (A) to obtain an extract. Specifically, a method of extracting a neutralized product with a solvent of the same kind as the solvent of step (A) to obtain a solvent layer, and extracting the solvent layer with a saturated solution of NaCl or the like can be used. The concentrating step is a step of removing the solvent contained in the extract and removing the solvent with a rotary condenser or the like to concentrate the concentrate to obtain a concentrate. At this time, water which may be contained in the extract can be removed by using anhydrous MgSO 4 or the like. These concentrates contain enriched coriolactone aldehyde para-phenyl benzoate.
By this method, a large amount of coralactone aldehyde para-phenyl benzoate can be produced at a time up to 200-500 g.
Instead of (E) neutralization step and (F) purification step, (E ') stirring in water may be followed by a solvent removal step.
The step of removing the solvent after stirring in water is carried out at a ratio of 1.5 to 5 times, preferably 1.8 to 5 times, more preferably 2 to 5 times, to the total amount of the solvent of the step (A) and the solvent of the step (B) And stirring the mixture to remove the generated solid, separating the filtrate containing the water layer and the solvent layer, separating the solvent layer from the filtrate, and removing the solvent from the solvent layer. Stirring can be carried out at 180 to 250 rpm, overnight. When the mixture is stirred overnight, the stirring time may be 12 to 18 hours. The stirring temperature may be 17 to 25 degrees Celsius.
The solid can be removed by filtration with a boulet filter or the like at room temperature and separating the filtrate and the solid.
Specifically, the solvent layer may be separated by first separating the solvent layer from the filtrate using a separating funnel or the like, adding water to the separated first solvent layer, re-extracting the solvent layer, and then separating the solvent layer from the added water layer You can do it by going through the process. The process of separating the solvent layer again after such re-extraction can be repeated three times.
The solvent layer separated by such a process can be removed by concentrating the solvent under reduced pressure using a rotary evaporator or the like. Thereafter, the dried phase of the coriolactone aldehyde para-phenyl benzoate can be obtained by carrying out the drying step. The drying may be natural drying, and the drying temperature may be 17 to 25 degrees Celsius and the drying time may be 10 to 48 hours, preferably 20 to 48 hours, and more preferably 20 to 36 hours.
By carrying out the solvent removal step after such stirring in water, the coriolactone aldehyde para-phenyl benzoate can be separated from the final agitator without going through a neutralization process.
Hereinafter, one embodiment of the production method of the present invention will be described in more detail through the first to fourth embodiments.
<First Specific Example>
Place a thermometer and dropping funnel in a three-necked flask with a capacity of 1000 ml and cool with ice water. To the flask was added 26.5 g of 400 ml of dichloromethane (dried) and an oxidizing agent (Dess-Martin Periodinane: 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3 . At this time, the temperature is maintained at 5 degrees Celsius.
Dissolve the corollactone (17.7 g) in dichloromethane (150 ml) in a dropwise funnel and slowly add dropwise. At this time, the falling temperature is maintained at 8 degrees Celsius.
After addition, the mixture is stirred for 10 minutes in an ice water cooled state (5 to 8 degrees Celsius).
Stop the cooling of the ice water, slowly raise the temperature to room temperature (15 to 25 degrees Celsius) and stir at room temperature. After about 2 hours, it is confirmed by TLC (Thin Layer Chromatography) whether the starting material, coriolactone, is completely reacted.
If the starting material remains, add 4-5 g of oxidizing agent (Dess-Martin Periodinane) and stir for 40 minutes.
After confirming that the reaction of Reaction Scheme 1 is completely proceeded by TLC, the reaction solution is filtered through a filter paper, and the filtrate is neutralized to pH 7-8 with 100 ml of NaOH solution (1M).
The neutralized filtrate is extracted three times with 200 ml of dichloromethane, and the organic solvent layer is collected. The organic solvent layer is extracted with 200 ml of saturated NaCl solution. Separate the organic solvent layer and add anhydrous MgSO 4 and leave to stand for about 20 minutes. Thereafter, the next rotational concentrator removed by filtration the solid MgSO 4 and concentrated to remove the organic solvent from the residue.
As a result, 13.0 g of a white solid was obtained. The yield is 73%. At this time, the obtained water NMR values {1 H-NMR, 500MHz: δ 9.88 (s, 1H), 8.09 (d, 2H), 7.77 (d, 2H), 7.62 (d, 2H), 7.48 (t, 2H) , 7.42 (t, 2H), 7.39 (t, IH), 5.80 (d, IH), 5.17 (t, IH), 3.56 2.51 (t, 2H), 2.08 (m, 1H)} was confirmed, and it was confirmed that the desired compound was obtained.
≪ Second Embodiment &
Place a thermometer and dropping funnel in a three-necked flask with a capacity of 1000 ml and cool with ice water. To the flask is added 400 ml of dichloromethane (dried) and 23.0 g of an oxidizing agent (IBX; 2-Iodoxybenzoic acid). At this time, the temperature is maintained at 5 degrees Celsius.
Dissolve the corollactone (17.7 g) in dichloromethane (150 ml) in a dropwise funnel and slowly add dropwise. At this time, the falling temperature is maintained at 8 degrees Celsius.
After addition, the mixture is stirred for 10 minutes in an ice water cooled state (5 to 8 degrees Celsius).
Stop cooling the ice water, slowly raise the temperature to 40 ° C, and stir for 3 hours. TLC is used to confirm whether the starting material, coriolactone, has completely reacted.
If the starting material remains, add 4-5 g of an oxidizing agent (IBX) and stir for 1.5 hours.
After confirming that the reaction of Reaction Scheme 1 is completely proceeded by TLC, the reaction solution is filtered through a filter paper, and the filtrate is neutralized to pH 7-8 with 100 ml of NaOH solution (1M).
The neutralized filtrate is extracted three times with 200 ml of dichloromethane, and the organic solvent layer is collected. The organic solvent layer is extracted with 200 ml of saturated NaCl solution. Separate the organic solvent layer and add anhydrous MgSO 4 and leave to stand for about 20 minutes. Thereafter, the next rotational concentrator removed by filtration the solid MgSO 4 and concentrated to remove the organic solvent from the residue.
As a result, 12.0 g of a white solid was obtained. The yield is 68%. At this time, the obtained water NMR values {1 H-NMR, 500MHz: δ 9.88 (s, 1H), 8.09 (d, 2H), 7.77 (d, 2H), 7.62 (d, 2H), 7.48 (t, 2H) , 7.42 (t, 2H), 7.39 (t, IH), 5.80 (d, IH), 5.17 (t, IH), 3.56 2.51 (t, 2H), 2.08 (m, 1H)} was confirmed, and it was confirmed that the desired compound was obtained.
≪ Third Specific Example &
Place a thermometer and a dropping funnel in a three-necked flask with a capacity of 3000 ml and cool with ice water. To the flask was added 26.5 g of 400 ml of dichloromethane (dried) and a Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 . At this time, the temperature is maintained at 5 degrees Celsius.
Dissolve the corollactone (17.7 g) in dichloromethane (150 ml) in a dropwise funnel and slowly add dropwise. At this time, the falling temperature is maintained at 8 degrees Celsius.
After addition, the mixture is stirred for 10 minutes in an ice water cooled state (5 to 8 degrees Celsius).
Stop the cooling of the ice water, slowly raise the temperature to room temperature (15 to 25 degrees Celsius) and stir at room temperature. After about 2 hours, TLC is used to confirm whether the starting material, coriolactone, is fully reacted.
If the starting material remains, add 4-5 g of oxidizing agent (Dess-Martin Periodinane) and stir for 40 minutes.
After confirming that the reaction of Scheme 1 was completely proceeded with TLC, 1000 ml of water was added to the final stirred solution, and stirred at 180 to 250 rpm at 17 to 25 ° C overnight (12 to 18 hours). At this time, it was confirmed that a white solid was produced, and the solid was removed by filtration under reduced pressure (burette funnel). The filtrate after filtration under reduced pressure contains water and a solvent. The solvent layer (dichloromethane layer) is separated therefrom, and 500 ml of water is added to the solvent layer and re-extracted. The re-extraction process is repeated two more times, and the solvent layer is separated and concentrated under reduced pressure using a rotary evaporator to remove the solvent. Thereafter, natural drying (normal pressure, 17-25 DEG C for 20 hours) yields 14.0 g of coriolactone aldehyde para-phenyl benzoate in the form of an impure white solid. At this time, the obtained water NMR values {1 H-NMR, 500MHz: δ 9.88 (s, 1H), 8.09 (d, 2H), 7.77 (d, 2H), 7.62 (d, 2H), 7.48 (t, 2H) , 7.42 (t, 2H), 7.39 (t, IH), 5.80 (d, IH), 5.17 (t, IH), 3.56 2.51 (t, 2H), 2.08 (m, 1H)} was confirmed, and it was confirmed that the desired compound was obtained.
≪ Fourth Embodiment &
Place a thermometer and a dropping funnel in a three-necked flask with a capacity of 3000 ml and cool with ice water. To the flask is added 400 ml of dichloromethane (dried) and 23.0 g of an oxidizing agent (IBX; 2-Iodoxybenzoic acid). At this time, the temperature is maintained at 5 degrees Celsius.
Dissolve the corollactone (17.7 g) in dichloromethane (150 ml) in a dropwise funnel and slowly add dropwise. At this time, the falling temperature is maintained at 8 degrees Celsius.
After addition, the mixture is stirred for 10 minutes in an ice water cooled state (5 to 8 degrees Celsius).
Stop cooling the ice water, slowly raise the temperature to 40 ° C, and stir for 3 hours. TLC is used to confirm whether the starting material, coriolactone, has completely reacted.
If the starting material remains, add 4-5 g of an oxidizing agent (IBX) and stir for 1.5 hours.
After confirming that the reaction of Scheme 1 was completely proceeded with TLC, 1000 ml of water was added to the final stirred solution, and stirred at 180 to 250 rpm at 17 to 25 ° C overnight (12 to 18 hours). At this time, it was confirmed that a white solid was produced, and the solid was removed by filtration under reduced pressure (burette funnel). The filtrate after filtration under reduced pressure contains water and a solvent. The solvent layer (dichloromethane layer) is separated therefrom, and 500 ml of water is added to the solvent layer and re-extracted. The re-extraction process is repeated two more times, and the solvent layer is separated and concentrated under reduced pressure using a rotary evaporator to remove the solvent. Thereafter, natural drying (normal pressure, 17-25 DEG C for 20 hours) yields 13.0 g of coriolactone aldehyde para-phenyl benzoate in the form of an impure white solid. At this time, the obtained water NMR values {1 H-NMR, 500MHz: δ 9.88 (s, 1H), 8.09 (d, 2H), 7.77 (d, 2H), 7.62 (d, 2H), 7.48 (t, 2H) , 7.42 (t, 2H), 7.39 (t, IH), 5.80 (d, IH), 5.17 (t, IH), 3.56 2.51 (t, 2H), 2.08 (m, 1H)} was confirmed, and it was confirmed that the desired compound was obtained.
Claims (10)
(B) a dropwise addition step of dropwise adding a molten product obtained by dissolving coriolactone in a solvent of the same type as that of the solvent of step (A), at a temperature of -10 to 10 degrees Celsius to the contact material of step (A);
(C) a primary agitation step of stirring the drop wort from the step (B) at -20 ° C to 10 ° C to obtain a primary agitated product; And
(D) a second agitating step of agitating at 10 to 60 degrees Celsius after the completion of the agitation in step (C) to obtain a second agitated product, thereby obtaining a final agitated product; A process for preparing aldehyde para-phenyl benzoate.
The step of obtaining the final agitated product may further comprise a third agitating step of adding a third agitating step to the second agitated product by adding an oxidizing agent of the same kind as that of the step (A) and stirring to obtain a third agitated product, ≪ / RTI >
(E) neutralizing the final stirred product with a reducing agent to a pH of 7 to 8 to obtain a neutralized product.
(F) a step of purifying coriolactone aldehyde para-phenyl benzoate from the neutralized product of step (E).
The purification step
(Fa) an extraction step of extracting the neutralized product of step (E) with a solvent of the same kind as the solvent of step (A) to obtain an extract; And
(Fb) a step of concentrating the extract of step (Fa) to obtain a concentrate; and a step of concentrating the extract of step (Fa) to obtain a concentrate.
(E ') 1.5 to 5 times the volume ratio of the solvent of the step (A) and the solvent of the step (B) is added to the final stirred solution, and the resulting solid is removed, Separating the filtrate from the filtrate, separating the solvent layer from the filtrate, and removing the solvent from the solvent layer, followed by removing the solvent, followed by removing the solvent.
Wherein the solvent is at least one nonpolar solvent selected from the group consisting of dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether, dimethylformamide or dimethylsulfoxide.
Wherein the oxidizing agent is at least one selected from Dess-Martin Periodinane, IBX, or iodoperbenzoate derivatives.
In the step (A), the oxidizing agent is 110 to 160 parts by weight based on 100 parts by weight of the solvent.
The process for producing coriolactone aldehyde para-phenyl benzoate according to claim 1, wherein said aldehyde is in the range of from 5 to 8 degrees Celsius.
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