阅读说明：本技术 一种酮咯酸中间体的合成方法 (Synthetic method of ketorolac intermediate ) 是由 李强 刘子宁 钱金叶 于 2021-08-12 设计创作，主要内容包括：本发明公开了一种酮咯酸中间体的合成方法,1H-吡咯-2-基-苯基甲酮与1,2-二氯乙烷在碳酸钾作为碱的情况下,加入了NaY分子筛,可以降低反应温度,在室温就可以进行,且不需要使用相转移催化剂。由于避免了高温反应,得到的中间体式I化合物的颜色较好。(The invention discloses a synthesis method of a ketorolac intermediate, which is characterized in that under the condition that potassium carbonate is used as alkali, 1H-pyrrole-2-yl-phenyl ketone and 1, 2-dichloroethane are added with an NaY molecular sieve, the reaction temperature can be reduced, the reaction can be carried out at room temperature, and a phase transfer catalyst is not required. The intermediate compound shown in formula I has good color due to the avoidance of high temperature reaction.)

1. A synthesis method of a ketorolac intermediate comprises the steps of reacting 1H-pyrrole-2-yl-phenyl ketone with 1, 2-dichloroethane and potassium carbonate, and is characterized in that a NaY type molecular sieve is added into a reaction system, and the reaction is carried out at the temperature of 0-40 ℃ to obtain the ketorolac intermediate shown in a formula I;

2. the synthesis method according to claim 1, wherein the temperature is in the range of 20-30 ℃.

3. The synthesis method according to claim 1, wherein the amount of the NaY molecular sieve is 0.1-2.0 times of the total weight of 1H-pyrrol-2-yl-phenyl methanone.

4. The synthesis method according to claim 3, wherein the amount of NaY molecular sieve is 0.1-0.5 times of the total weight of 1H-pyrrol-2-yl-phenyl methanone.

5. The synthesis method according to claim 1, wherein the silicon-aluminum ratio of the NaY molecular sieve is 4.5-5.0.

6. The synthesis method according to claim 1, wherein the reaction time is 1 to 6 hours.

7. The synthesis method according to claim 1, wherein the mass volume ratio of 1H-pyrrol-2-yl-phenyl methanone to 1, 2-dichloroethane is 1g:6ml, and the molar ratio of potassium carbonate to 1H-pyrrol-2-yl-phenyl methanone is 1: 1.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a synthesis method of a ketorolac intermediate.

Background

Ketorolac is a nonsteroidal anti-inflammatory drug with potent analgesic effect. The synthesis route of ketorolac is as follows, and the compound of formula I is an intermediate in the synthesis process of ketorolac.

Canadian Journal of Chemistry,1983,61(8): 1697-A1702 reported the preparation of compounds of formula I using 1H-pyrrol-2-yl-phenyl methanone and 1, 2-dichloroethane under 50% sodium hydroxide solution and 1 equivalent of tetrabutylammonium iodide as phase transfer catalyst, after the reaction is complete, purification is carried out using a silica gel column to give compounds of formula I.

In US5082951 patent application filed in 1990, a process for the preparation of compounds of formula I is disclosed, using 1H-pyrrol-2-yl-phenyl methanone reacted with an excess of 1, 2-dichloroethane, using an equivalent amount of a phase transfer catalyst, such as tetrabutylammonium bromide, using an excess of a strong base, such as aqueous NaOH, stirred at room temperature for 5 minutes to 16 hours, preferably 30 minutes, and the crude product obtained is isolated and purified by silica gel chromatography to give the compound of formula I.

Methods for synthesizing the compounds of formula I are reported in journal of Chinese medicinal chemistry 2002,12(4): 228-. 1H-pyrrol-2-yl-phenyl methanone is reacted with 1, 2-dichloroethane using potassium carbonate as base and tetrabutylammonium bromide as phase transfer catalyst under heating reflux.

The reaction can be carried out at a relatively low temperature by using a two-phase solvent in the prior art, but the stirring efficiency has a great influence on the reaction rate due to the two-phase reaction. In the process of industrial production, the stirring efficiency is gradually reduced due to the increase of the reaction volume, resulting in the extension of the reaction time.

The use of potassium carbonate as a base requires a heating reaction to proceed at the boiling point of 1, 2-dichloroethane, resulting in a darker color of the product and affecting the quality of the finished product of ketorolac. If the reaction temperature is lowered, the reaction time is greatly prolonged, and the reaction does not occur at room temperature at all.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a preparation method of a ketorolac intermediate (a compound shown in a formula I) so as to react at a lower temperature and avoid the product from darkening.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a synthesis method of a ketorolac intermediate comprises the steps of reacting 1H-pyrrole-2-yl-phenyl ketone with 1, 2-dichloroethane and potassium carbonate, and is characterized in that a NaY type molecular sieve is added into a reaction system, and the reaction is carried out at the temperature of 0-40 ℃ to obtain the ketorolac intermediate shown in a formula I;

preferably, the temperature range is 20-30 ℃.

Preferably, the dosage of the NaY molecular sieve is 0.1-2.0 times of the total weight of the 1H-pyrrole-2-yl-phenyl ketone; more preferably, the total weight of the 1H-pyrrole-2-yl-phenyl ketone is 0.1 to 0.5 times.

Preferably, the silicon-aluminum ratio of the NaY molecular sieve is 4.5-5.0.

Preferably, the reaction time is 1 to 6 hours.

Preferably, the mass volume ratio of 1H-pyrrol-2-yl-phenyl methanone to 1, 2-dichloroethane is 1g:6ml and the molar ratio of potassium carbonate to 1H-pyrrol-2-yl-phenyl methanone is 1: 1.

The invention can be matched with stirring in the reaction process, and has no special requirement on the stirring speed.

The reaction of the present invention has the following formula:

as a preferred embodiment of the present invention: dissolving 1H-pyrrole-2-yl-phenyl ketone (50g, 0.292mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.35g, 0.292mol), adding 5 g-100 g of NaY molecular sieve, stirring the mixture at 0-40 ℃, monitoring the reaction by using TLC, filtering the potassium carbonate and the NaY molecular sieve when the raw material spots disappear, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear solution, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of the formula I. ESI-MS (+) -234.2 m/z.

As a more preferred embodiment of the present invention: dissolving 1H-pyrrole-2-yl-phenyl ketone (50g, 0.292mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.35g, 0.292mol), adding 5g to 25g of NaY molecular sieve, stirring the mixture at the temperature of 20 to 30 ℃, monitoring the reaction by using TLC, filtering the potassium carbonate and the NaY molecular sieve after raw material spots disappear, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear solution, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of the formula I. ESI-MS (+) -234.2 m/z.

The developing agent for monitoring the reaction by TLC is ethyl acetate and petroleum ether (v/v) ═ 1:1, and the TLC is observed under an ultraviolet lamp by using a GF254 silica gel plate.

Has the advantages that: the invention discloses a synthesis method of a ketorolac intermediate, which is characterized in that under the condition that potassium carbonate is used as alkali, 1H-pyrrole-2-yl-phenyl ketone and 1, 2-dichloroethane are added with an NaY molecular sieve to obtain the intermediate shown in a formula I. In addition, the ketorolac has a long conjugated system, and is easy to generate colored impurities when heated at high temperature, so the color of the ketorolac is a key quality index of the product. Compared with the prior art, the method can reduce the requirement on reaction temperature and avoid the generation of colored impurities under the high-temperature condition.

Detailed Description

The present invention will be further explained with reference to specific examples, but the present invention is not limited to the following examples. The method is a conventional method if not specifically described. The solvent, materials and reagents used are all common reagents which are obtained from public commercial sources.

The NaY molecular sieves used in the following examples were obtained from great company of chemical industry, great company, and had a Si/Al ratio of 4.5 to 5.0. Comparative example 1:

the compound of formula I is prepared according to the method in J.Chem.2002, 12(4):228-229, 232.

1H-pyrrol-2-yl-phenyl methanone (8.5g,0.05mol), potassium carbonate (30g,0.22mol), tetrabutylammonium bromide (1.6g, 5mmol) were added to a reaction flask, 120ml of 1, 2-dichloroethane were added, the mixture was stirred for reaction for 2 hours, cooled to room temperature, insoluble material was filtered off, and the filtrate was concentrated to dryness under reduced pressure to give the compound of formula I (oil).

Comparative example 2:

the compound of formula I was prepared according to the method disclosed in chinese patent 202110177675.3.

To a reaction flask was added 1H-pyrrol-2-yl-phenyl methanone (15.0g, 0.087mol), potassium carbonate (53.0g, 0.386mol), tetrabutylammonium bromide (7.0g, 22mmol), 300ml 1, 2-dichloroethane was added, stirred and heated to reflux for 4 hours, cooled to room temperature, filtered, and the filtrate was concentrated to give the compound of formula I (oil).

Comparative example 3:

17ml of ethyl acetate and 17ml of n-heptane were added to the compound of formula I obtained in comparative example 1 as a brown oil, which was heated to clear, cooled to below 25 ℃ for crystallization, filtered and dried to give the compound of formula I as a light brown solid in a total amount of 7.8g, 67% yield.

Comparative example 4:

the compound of formula I obtained in comparative example 2 as a brown oil was added with 30ml of ethyl acetate and 30ml of n-heptane, heated to clear, cooled to below 25 ℃ for crystallization, filtered and dried to give the compound of formula I as a light brown solid in a total amount of 15.0g with a yield of 74%.

Example 1:

dissolving 1H-pyrrol-2-yl-phenyl ketone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 5g, stirring the mixture at 25 ℃, monitoring the reaction by TLC, after 2 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a yield of 94%, 64.2g in total.

Example 2:

dissolving 1H-pyrrol-2-yl-phenyl ketone (150g, 0.88mol) in 900ml of 1, 2-dichloroethane, adding potassium carbonate (121.1g, 0.88mol), adding 75g of NaY molecular sieve, stirring the mixture at 0 ℃, monitoring the reaction by TLC, after 4 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 300ml of ethyl acetate and 300ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 186.3g of 91%.

Example 3:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding 50g of NaY molecular sieve, stirring the mixture at 40 ℃, monitoring the reaction by TLC, after 1 hour the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 64.8g and 95%.

Example 4:

dissolving 1H-pyrrol-2-yl-phenyl methanone (250g, 1.46mol) in 1500ml of 1, 2-dichloroethane, adding potassium carbonate (201.8g, 1.46mol), adding NaY molecular sieve 375g, stirring the mixture at 20 ℃, monitoring the reaction by TLC, after 3 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve off, concentrating the filtrate under reduced pressure to dryness, adding 500ml of ethyl acetate and 500ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid, total 317.4g, yield 93%.

Example 5:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 100g, stirring the mixture at 30 ℃, monitoring the reaction by TLC, after 2 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 66.2g and 97%.

Example 6:

dissolving 1H-pyrrol-2-yl-phenyl ketone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 10g, stirring the mixture at 20 ℃, monitoring the reaction by TLC, after 3 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a yield of 90% of 61.4 g.

Example 7:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 10g, stirring the mixture at 25 ℃, monitoring the reaction by TLC, after 3 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 62.8g and 92%.

Example 8:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 20g, stirring the mixture at 20 ℃, monitoring the reaction by TLC, after 3 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 62.1g and 91%.

Example 9:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 25g, stirring the mixture at 25 ℃, monitoring the reaction by TLC, after 4 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 62.1g and 91%.

Example 10:

dissolving 1H-pyrrol-2-yl-phenyl methanone (60g, 0.35mol) in 360ml of 1, 2-dichloroethane, adding potassium carbonate (48.4g, 0.35mol), adding 6g of NaY molecular sieve, stirring the mixture at 25 ℃, monitoring the reaction by TLC, after 4 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 120ml of ethyl acetate and 120ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 76.2g and 93%.

Example 11:

dissolving 1H-pyrrol-2-yl-phenyl methanone (70g, 0.41mol) in 420ml of 1, 2-dichloroethane, adding potassium carbonate (56.5g, 0.41mol), adding NaY molecular sieve 7g, stirring the mixture at 25 ℃, monitoring the reaction by TLC, after 4 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 140ml of ethyl acetate and 140ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 85.0g and 89%.

Example 12:

dissolving 1H-pyrrol-2-yl-phenyl ketone (80g, 0.47mol) in 480ml of 1, 2-dichloroethane, adding potassium carbonate (64.6g, 0.47mol), adding 80g of NaY molecular sieve, stirring the mixture at 25 ℃, monitoring the reaction by TLC, after 2 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 160ml of ethyl acetate and 160ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a total yield of 92.8g and 85%.

Example 13:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding 60g of NaY molecular sieve, stirring the mixture at 40 ℃, monitoring the reaction by TLC, after 2 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid in a total of 63.5g with a yield of 93%.

Example 14:

dissolving 1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) in 300ml of 1, 2-dichloroethane, adding potassium carbonate (40.4g, 0.29mol), adding NaY molecular sieve 5g, stirring the mixture at 0 ℃, monitoring the reaction by TLC, after 6 hours the raw material spots disappear, filtering the potassium carbonate and NaY molecular sieve out, concentrating the filtrate under reduced pressure to dryness, adding 100ml of ethyl acetate and 100ml of n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, and drying to obtain the compound of formula I as an off-white solid with a yield of 64.2g and 94%.

Example 15: color of the Compound of formula I

1g of the compound of the formula I is taken and placed in a 20ml volumetric flask and the volume is determined with dichloromethane. The solution is taken and placed in an ampoule and is compared with the yellow standard colorimetric solution in Chinese pharmacopoeia. The results are shown in Table 1.

TABLE 1

Sample numbering	Colour(s)
		Comparative example 1	Number 6
Comparative example 2	Number 6
		Comparative example 3	Number 4
Comparative example 4	Number 5
		Example 1	Number 2
Example 2	Number 1
		Example 3	Number 1
Example 4	Number 2
		Example 5	Number 2
Example 6	Number 1
		Example 7	Number 1
Example 8	Number 2
		Example 9	Number 1
Example 10	Number 1
		Example 11	Number 1
Example 12	Number 1
		Example 13	Number 1
Example 14	Number 1
		Example 15	Number 1

The test results show that the colour of the samples prepared using the present invention is significantly lighter than that of the samples obtained in the comparative examples.

The present invention provides a method and a concept for synthesizing ketorolac intermediate, and a method and a way for implementing the technical scheme are many, and the above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, a plurality of modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention. All the components not specified in the present embodiment can be realized by the prior art.