CN112979599A - Preparation method of carboprost tromethamine intermediate - Google Patents

Preparation method of carboprost tromethamine intermediate Download PDF

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CN112979599A
CN112979599A CN202110224037.2A CN202110224037A CN112979599A CN 112979599 A CN112979599 A CN 112979599A CN 202110224037 A CN202110224037 A CN 202110224037A CN 112979599 A CN112979599 A CN 112979599A
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ketone
ethyl acetate
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benzoyl
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范超逸
陈德武
张延峰
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Hebei Saipu Ruisi Pharmaceutical Technology Co ltd
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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
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention provides a preparation method of a carboprost tromethamine intermediate, which comprises the following steps: A) carrying out oxidation reaction on benzoyl-coriolide shown in a formula I under the action of a catalyst and an oxidant to obtain benzoyl-coriolide shown in a formula II; B) reacting benzoylcolactone aldehyde shown as a formula II with (2-oxoheptyl) dimethyl phosphonate under the action of alkali to obtain a 15-ketone crude product shown as a formula III; recrystallizing the crude 15-ketone product to obtain a pure 15-ketone product; C) and carrying out methylation reaction on the pure 15-ketone product to obtain the carboprost tromethamine intermediate shown in the formula IV. The invention avoids using reagents with high toxicity and great environmental pollution. When the carboprost intermediate 15-ketone is prepared, mixed solvent recrystallization is adopted, column chromatography is omitted, operation is simple and convenient, reagents are saved, and cost is reduced. In the process of preparing the methide, ultralow temperature is avoided, the reaction time is shortened, the energy consumption is reduced, and the purity and the yield are higher.

Description

Preparation method of carboprost tromethamine intermediate
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a carboprost tromethamine intermediate.
Background
Prostaglandins are one of a family of fatty acids, widely found in mammalian cells. They are involved in many physiological processes and exhibit very high physiological activities, for example, promotion of fertilization, lowering of blood pressure, protection of the gastrointestinal tract, regulation of neurotransmitter release and activity, constriction of the bronchi, and also influence of hormone synthesis and release.
Natural prostaglandins are low in content, difficult to extract, and have poor stability. Therefore, researchers have used chemical means to synthesize a series of prostaglandins or intermediates, wherein methides are key intermediates in the synthesis process of prostaglandins. The structure is as follows:
Figure BDA0002956189990000011
the existing methods for synthesizing the methylated compounds all have the problem of being not suitable for industrial production. For example, reagents with high pollution and toxicity such as dess-martin reagent, DCC, pyridine and chloroform are required; in the process of preparing the 15-ketone analogue, column chromatography purification is adopted, so that the cost is greatly increased; when the methylated derivatives are prepared, the reaction temperature is below 50 ℃ below zero, the reaction time is more than 6 hours, and the energy loss is large.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing a carboprost tromethamine intermediate, wherein the prepared product has high yield and purity, and the method has the advantages of reduced energy consumption and simple operation.
In order to achieve the aim, the invention provides a preparation method of a carboprost tromethamine intermediate, which comprises the following steps:
A) carrying out oxidation reaction on benzoyl-coriolide shown in a formula I under the action of a catalyst and an oxidant to obtain benzoyl-coriolide shown in a formula II;
B) reacting benzoylcolactone aldehyde shown as a formula II with (2-oxoheptyl) dimethyl phosphonate under the action of alkali to obtain a 15-ketone crude product shown as a formula III;
recrystallizing the crude 15-ketone product to obtain a pure 15-ketone product;
C) carrying out methylation reaction on the pure 15-ketone product to obtain a carboprost tromethamine intermediate shown in a formula IV;
Figure BDA0002956189990000021
the reaction route of the invention is as follows:
Figure BDA0002956189990000022
the present invention first performs an oxidation reaction.
Preferably, the step a) is specifically:
dissolving benzoyl-coriolide in an organic solvent, adding a potassium bromide solution and a sodium bicarbonate solution, keeping the temperature not more than 0 ℃, and reacting with an oxidant under the action of a catalyst to obtain a benzoyl-coriolide aldehyde reaction solution.
In the invention, preferably, the organic solvent is one or more of dichloromethane, ethyl acetate and toluene. More preferably dichloromethane.
Preferably, the sodium bicarbonate solution is a saturated solution.
In the invention, the catalyst is tetramethyl piperidine nitrogen oxide.
Preferably, the oxidant is sodium hypochlorite or hydrogen peroxide. More preferably sodium hypochlorite.
The oxidant adopted in the invention is sodium hypochlorite, compared with the existing Des-Martin reagent and DCC, the price is greatly reduced, and meanwhile, the aftertreatment is simpler and more convenient and more environment-friendly.
In the invention, preferably, after the reaction is finished, the system is post-treated, specifically:
extracting with organic solvent, mixing organic phases, washing with sodium sulfite, drying with anhydrous sodium sulfate, and filtering to obtain benzoylcolelactone aldehyde solution.
The solvent for the extraction is preferably dichloromethane.
Preferably, the number of times of extraction is two or three.
In the present invention, the mass concentration of the sodium sulfite is preferably 10%.
Preferably, the number of washing is two or three.
In the invention, the preferable dosage of the potassium bromide is 0.02-0.03 equivalent.
In the invention, the preferable amount of the sodium bicarbonate is 1-1.5 equivalent.
Preferably, the catalyst is used in an amount of 0.07 equivalent.
Preferably, the amount of the oxidant is 3-3.4 equivalents.
The above dosage is based on benzoylcolactone alcohol.
The reaction time is 1-3 hours, and the preferable reaction time is 1.5-2 hours; the reaction temperature is preferably-5 ℃ to 5 ℃.
Then the benzoylcolactone aldehyde shown in the formula II reacts with (2-oxoheptyl) dimethyl phosphonate under the action of alkali to obtain a crude product of 15-ketone shown in the formula III.
Preferably, the molar ratio of the benzoylcolelactone aldehyde to the dimethyl (2-oxoheptyl) phosphonate is 1: 0.6-0.9, and the preferable molar ratio is 1: 0.7 to 0.8.
Preferably, step B) is specifically:
dissolving (2-oxoheptyl) dimethyl phosphonate in an organic solvent, adding alkali, and dropwise adding the benzoyl colelactone aldehyde solution obtained in the previous step into a reaction system under a cooling condition to carry out reaction.
Preferably, the invention is stirred for 0.5 to 2 hours under the cooling condition, and then the benzoyl colelactone aldehyde solution is dripped.
The organic solvent is preferably one or more of methyl tert-butyl ether, dichloromethane, isopropyl ether and tetrahydrofuran. More preferably methyl tert-butyl ether.
The alkali is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and potassium tert-butoxide. More preferably lithium hydroxide.
Preferably, the cooling conditions are not more than 20 ℃.
Preferably, the reaction temperature is 0-20 ℃; more preferably 0 to 10 ℃. The reaction time is 1-1.5 h.
After the reaction is completed, it is preferable to perform a post-treatment, specifically:
adding a proper amount of water into a reaction system, standing for layering, extracting a water layer by using an organic solvent, combining organic layers, washing by using saturated sodium bicarbonate, drying by using anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product of the 15-ketone.
The organic solvent for the extraction is preferably methyl tert-butyl ether or dichloromethane.
The invention adopts a recrystallization mode to purify the crude product of the 15-ketone.
In a preferred embodiment of the present invention, the solvent for recrystallization comprises a first solvent and a second solvent;
the first solvent is preferably methyl tert-butyl ether or isopropyl ether.
The second solvent is preferably ethyl acetate, isobutyl acetate, isopropyl acetate or butyl acetate.
In a preferred embodiment of the present invention, the solvent for recrystallization includes ethyl acetate and isopropyl ether.
The volume ratio of the ethyl acetate to the isopropyl ether is preferably 1: (6-12); more preferably 1: (8-10).
In a preferred embodiment of the present invention, the solvent for recrystallization includes ethyl acetate and methyl t-butyl ether.
The volume ratio of ethyl acetate to methyl tert-butyl ether is preferably 1: (10-16); more preferably 1: (12-14).
The invention adopts a recrystallization method to replace column chromatography, greatly saves the reagent dosage and improves the efficiency. Meanwhile, the purity can reach 98 percent.
Then, methylation reaction is carried out on the pure 15-ketone product to obtain the carboprost tromethamine intermediate shown in the formula IV.
In the preferred embodiment of the present invention, the methylating agent for the methylation reaction is methyl magnesium bromide.
Preferably, the molar ratio of the methyl magnesium bromide to the 15-ketone is 2.5: 1.
According to the invention, the temperature of the methylation reaction is preferably-40-0 ℃. More preferably-40 to-10 ℃. More preferably from-40 to-30 ℃.
Preferably, the methylation reaction time is 1-2 h.
The dosage of the methylating agent in the invention is 2.5 equivalents, which reduces the cost compared with the existing 3.5 equivalents or 5 equivalents. And the methylation reaction temperature is higher than the existing-50 ℃, so that the energy consumption is reduced.
Preferably, step C) is specifically:
dissolving 15-ketone in an anhydrous organic solvent, dropwise adding a methyl magnesium bromide solution under the conditions of low temperature and nitrogen protection, keeping the temperature and stirring for reaction after dropwise adding, and dropwise adding a saturated ammonium chloride solution for quenching reaction.
In a preferred embodiment of the present invention, the anhydrous organic solvent is one or more of anhydrous tetrahydrofuran and anhydrous diethyl ether. More preferably anhydrous tetrahydrofuran.
Preferably, the methyl magnesium bromide solution is a tetrahydrofuran solution of methyl magnesium bromide.
Preferably, after quenching reaction, adding a proper amount of water into the system, standing for layering, extracting an aqueous layer by using an organic solvent, combining organic layers, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain a crude methylated product.
The solvent for the extraction is preferably ethyl acetate or dichloromethane.
According to the invention, preferably, the obtained crude methylated compound is purified by adopting a column chromatography method.
Preferably, the column chromatography adopts n-hexane-ethyl acetate-dichloromethane system eluent.
The volume ratio of the n-hexane to the ethyl acetate to the dichloromethane is preferably (2-5): 1: (0-1); more preferably (3-4): 1: (0 to 0.5).
The step A) and the step B) are synthesized by a one-pot method, the operation is simple and convenient, the industrialization is easy, and the total molar yield of the first two steps is high and can reach 65%. The crude 15-ketone is purified by adopting a recrystallization mode, the obtained product has good state, is easy to filter, and has high HPLC purity which is more than 98 percent. The methylation step avoids using ultralow temperature below-50 ℃, saves energy consumption and is easy to realize; the eluent adopted by the column chromatography of the crude methylated product has good separation effect, and the purity of the obtained product is high and can reach more than 97 percent.
Compared with the prior art, the invention provides a preparation method of a carboprost tromethamine intermediate, which comprises the following steps: A) carrying out oxidation reaction on benzoyl-coriolide shown in a formula I under the action of a catalyst and an oxidant to obtain benzoyl-coriolide shown in a formula II; B) reacting benzoylcolactone aldehyde shown as a formula II with (2-oxoheptyl) dimethyl phosphonate under the action of alkali to obtain a 15-ketone crude product shown as a formula III; recrystallizing the crude 15-ketone product to obtain a pure 15-ketone product; C) and carrying out methylation reaction on the pure 15-ketone product to obtain the carboprost tromethamine intermediate shown in the formula IV. First, the present invention avoids the use of highly toxic and environmentally polluting reagents such as dess-martin reagent, DCC (dicyclohexylcarbodiimide), etc. Secondly, when the 15-ketone analogue of the carboprost intermediate is prepared, mixed solvent recrystallization is adopted, column chromatography is omitted, operation is simple and convenient, reagents are saved, and cost is reduced. In addition, in the process of preparing the methide, ultralow temperature is avoided, the reaction time is shortened, the energy consumption is reduced, and the purity and the yield are high.
Drawings
FIG. 1 is a chart of HPLC purity of 15-ketone;
FIG. 2 is a chart of HPLC purity of methide.
Detailed Description
To further illustrate the present invention, the following examples are provided to describe the preparation of the carboprost tromethamine intermediate of the present invention in detail.
Example 1
According to the mixture ratio of table 1, adding benzoyl colelactone alcohol, TEMPO and dichloromethane into a 500ml three-neck flask, stirring and dissolving, adding potassium bromide, adding saturated sodium bicarbonate solution (about 90ml), cooling to below 0 ℃, slowly dropwise adding 10% sodium hypochlorite solution, controlling the temperature of the reaction solution to be not more than 0 ℃, heating to room temperature after dropwise adding, stirring for 0.5h, and monitoring the reaction completion by TLC (PE: EA ═ 1: 2). The mixture was allowed to stand for separation, the aqueous layer was extracted once with 50ml of dichloromethane, the organic layers were combined, and the organic layer was washed twice with 100ml of 10% sodium sulfite, once with 100ml of saturated brine, and dried over 30g of anhydrous sodium sulfate for 0.5 h. Filtering to obtain the benzoyl colelactone aldehyde solution.
TABLE 1 proportioning of the materials
Figure BDA0002956189990000061
Example 2
11.26g of dimethyl (2-oxoheptyl) phosphonate (calculated according to 0.7 equivalent of benzoyl colelactone alcohol) are dissolved in 240ml of methyl tert-butyl ether and put into a 1L reaction bottle, the temperature of the ice salt bath is reduced, the internal temperature is reduced to be below 0 ℃, 2.12g of lithium hydroxide (calculated according to 0.7 equivalent of benzoyl colelactone alcohol) are added, and after the addition is finished, the stirring is continued for 1 hour. The benzoyl colelactone aldehyde solution in the embodiment 1 is slowly added, the internal temperature is kept between 0 and 10 ℃, and after the addition is finished, the reaction is carried out for 1 hour under the heat preservation condition. The completion of the reaction was monitored by TLC (PE: EA ═ 1: 1). 100ml of water was added to the solution, and the mixture was stirred for 10 min. The organic layer was collected by settling, the aqueous layer was extracted with 80ml of methyl t-butyl ether, and the organic layers were combined and washed with 200ml of saturated sodium bicarbonate and 200ml of saturated brine in this order. The organic phase was dried over 40g of anhydrous sodium sulfate for 0.5 h. Filtering, and concentrating under reduced pressure at 30-40 deg.C to obtain orange red oily substance (26.7 g).
Example 3
The red oil obtained in example 2 was dissolved in 1-fold volume of ethyl acetate (i.e., 26.7ml) at room temperature, and then added to 7-fold volume of isopropyl ether (i.e., 186.9ml) to precipitate a little white flaky solid, which was stirred for 1 hour, and then transferred to an ice bath to maintain the internal temperature at 0 ℃ to 10 ℃ and stirred for 1 hour. Filtering, collecting solid, transferring into vacuum drying oven at 40 deg.C, and drying for 4 hr. 14.3g of a white solid, namely 15-ketone, is obtained with a yield of 53.33% and a purity of 97.2%.
Example 4
26g of a red oil was prepared as in example 2, and dissolved in 1-fold volume of ethyl acetate (i.e., 26ml) at room temperature, followed by addition of 10-fold volume of methyl t-butyl ether (i.e., 260ml) to precipitate a little white flaky solid, which was further stirred for 1.5 hours. Filtering, collecting solid, transferring into vacuum drying oven at 40 deg.C, and drying for 4 hr. 17g of white solid, namely 15-ketone, is obtained, the yield is 63.38 percent, and the purity is 98.79 percent. The purity profile is shown in FIG. 1.
Example 5
10g of 15-ketone from example 4 above were taken. Dissolved in 200ml of anhydrous tetrahydrofuran. Adding the mixture into a 500ml reaction bottle, and transferring the reaction bottle into an ethanol bath at the temperature of minus 40 ℃ to keep the internal temperature between minus 40 ℃ and minus 30 ℃. Under the protection of nitrogen, methyl magnesium bromide was slowly added by a constant pressure dropping funnel at a flow rate of 1 second/1 drop. Keeping the internal temperature at-40 ℃ to-30 ℃, and reacting for 1.5h after the addition is finished. TLC (PE: EA 1:1) detection of reaction completion. Preparing 3.6g of ammonium chloride into a saturated aqueous solution, slowly adding the saturated aqueous solution by using a constant-pressure dropping funnel, keeping the internal temperature between minus 40 ℃ and minus 20 ℃, moving a reaction bottle to the room temperature for naturally heating after the addition is finished, and stirring the mixture for 1 hour at the room temperature. Adding 100ml of water, stirring for 10min, standing for layering, collecting an organic phase, extracting an aqueous phase by using 40ml of ethyl acetate multiplied by 3, combining the organic phases, and washing by using 100ml of saturated sodium chloride. Drying 40g anhydrous sodium sulfate for 0.5h, filtering, and concentrating the filtrate at 30-35 deg.C to obtain yellow oily substance (about 12 g). I.e. crude methide.
120g of silica gel (200-300 mesh) is taken and loaded on a column, and a little silica gel is stirred for sample application in yellow oil. N-hexane is selected in sequence: ethyl acetate 5:1, n-hexane: ethyl acetate 3:1, n-hexane: ethyl acetate: dichloromethane ═ 3: 1: 0.5, eluting, collecting high-purity methylated compound eluate, and concentrating by external bath at 30-35 ℃ to obtain 6.8g, wherein the yield is 65.24% and the purity is 97.01%. The methylated compound is racemic, and the sum is calculated. The purity is shown in FIG. 2.
The amounts of the materials are shown in table 2:
TABLE 2 dosage of each material
Figure BDA0002956189990000081
Example 6
The procedure was as in example 5, except that the reaction temperature was adjusted to-20 ℃ and the other conditions were not changed. The reaction time was 50min, TLC (PE: EA ═ 1:1) detection and reaction was complete. Working-up was carried out in the same manner as in example 5, giving 11g of crude methide.
110g of silica gel (200-300 mesh) is taken and loaded on a column, and a little silica gel is stirred for sample application in yellow oil. N-hexane is selected in sequence: ethyl acetate 5:1, n-hexane: ethyl acetate 3:1, n-hexane: ethyl acetate: dichloromethane ═ 3: 1: 0.5, eluting, collecting high-purity methylated compound eluate, and concentrating by external bath at 30-35 deg.C to obtain 5.3g, with yield of 50.84% and purity of 97.1%.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (10)

1. A preparation method of a carboprost tromethamine intermediate comprises the following steps:
A) carrying out oxidation reaction on benzoyl-coriolide shown in a formula I under the action of a catalyst and an oxidant to obtain benzoyl-coriolide shown in a formula II;
B) reacting benzoylcolactone aldehyde shown as a formula II with (2-oxoheptyl) dimethyl phosphonate under the action of alkali to obtain a 15-ketone crude product shown as a formula III;
recrystallizing the crude 15-ketone product to obtain a pure 15-ketone product;
C) carrying out methylation reaction on the pure 15-ketone product to obtain a carboprost tromethamine intermediate shown in a formula IV;
Figure FDA0002956189980000011
2. the preparation method according to claim 1, wherein the step a) is specifically:
dissolving benzoyl-coriolide in an organic solvent, adding a potassium bromide solution and a sodium bicarbonate solution, keeping the temperature not more than 0 ℃, and reacting with an oxidant under the action of a catalyst to obtain a benzoyl-coriolide aldehyde reaction solution.
3. The preparation method according to claim 2, wherein the organic solvent is one or more of dichloromethane, ethyl acetate and toluene.
4. The method of claim 1, wherein the catalyst is tetramethylpiperidine nitroxide.
5. The preparation method according to claim 1, wherein the oxidant is sodium hypochlorite or hydrogen peroxide.
6. The method according to claim 1, wherein the solvents for recrystallization in the step B) include a first solvent and a second solvent;
the first solvent is selected from methyl tert-butyl ether or isopropyl ether;
the second solvent is selected from ethyl acetate, isobutyl acetate, isopropyl acetate or butyl acetate.
7. The production method according to claim 6, wherein the solvent for recrystallization comprises ethyl acetate and isopropyl ether;
or ethyl acetate and methyl tert-butyl ether.
8. The method according to claim 7, wherein the volume ratio of ethyl acetate to isopropyl ether is 1: (6-12);
the volume ratio of the ethyl acetate to the methyl tert-butyl ether is 1: (10-16).
9. The method of claim 1, wherein the methylating agent of the methylation reaction is methyl magnesium bromide;
the molar ratio of methyl magnesium bromide to 15-ketone is 2.5: 1.
10. The method according to claim 1, wherein the temperature of the methylation reaction is-40 to 0 ℃.
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Application publication date: 20210618