CN113603625B - Synthetic method of ketorolac intermediate - Google Patents
Synthetic method of ketorolac intermediate Download PDFInfo
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- CN113603625B CN113603625B CN202110924258.0A CN202110924258A CN113603625B CN 113603625 B CN113603625 B CN 113603625B CN 202110924258 A CN202110924258 A CN 202110924258A CN 113603625 B CN113603625 B CN 113603625B
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- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960004752 ketorolac Drugs 0.000 title claims abstract description 17
- 238000010189 synthetic method Methods 0.000 title description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 80
- 239000002808 molecular sieve Substances 0.000 claims abstract description 42
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- NFGGQMYSOLVBLF-UHFFFAOYSA-N phenyl(1h-pyrrol-2-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CN1 NFGGQMYSOLVBLF-UHFFFAOYSA-N 0.000 claims abstract description 31
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001308 synthesis method Methods 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- CSDREXVUYHZDNP-UHFFFAOYSA-N alumanylidynesilicon Chemical compound [Al].[Si] CSDREXVUYHZDNP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 34
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 54
- 238000002425 crystallisation Methods 0.000 description 18
- 230000008025 crystallization Effects 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- 239000002994 raw material Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
Abstract
The invention discloses a synthesis method of 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 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.
Description
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): 1697-1702 reported the preparation of compounds of formula I using 1H-pyrrol-2-yl-phenyl methanone with 1,2-dichloroethane under 50% sodium hydroxide solution, using 1 equivalent of tetrabutylammonium iodide as a phase transfer catalyst, after the reaction is complete, purification on silica gel column gives compounds of formula I.
In the 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 resulting crude product purified by silica gel chromatography to give compounds of formula I.
Methods for synthesizing compounds of formula I are reported in J.PharmacoHem. 2002,12 (4): 228-229,232. 1H-pyrrol-2-yl-phenyl methanone is reacted with 1,2-dichloroethane using potassium carbonate as the base and tetrabutylammonium bromide as the phase transfer catalyst under conditions of heating under 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 greatly affects 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 ketorolac intermediate is carried out by reacting 1H-pyrrole-2-yl-phenyl ketone with 1,2-dichloroethane and potassium carbonate, adding NaY type molecular sieve into reaction system, reacting at 0-40 deg.C to obtain ketorolac intermediate as shown in formula I;
preferably, the temperature range is 20 to 30 ℃.
Preferably, the dosage of the NaY molecular sieve is 0.1 to 2.0 times of the total weight of the 1H-pyrrole-2-yl-phenyl ketone; more preferably from 0.1 to 0.5 times the total weight of 1H-pyrrol-2-yl-phenyl methanone.
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 to volume ratio of 1H-pyrrol-2-yl-phenyl methanone to 1,2-dichloroethane is 1 g.
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 5g to 100g of NaY molecular sieve, stirring the mixture at the temperature of 0 to 40 ℃, monitoring the reaction by using TLC (thin layer chromatography), filtering the potassium carbonate and the NaY molecular sieve until 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 (+) =234.2m/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 (thin layer chromatography), filtering the potassium carbonate and the NaY molecular sieve until 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, cooling to below 25 ℃ for crystallization, filtering and drying to obtain the compound of the formula I. ESI-MS (+) =234.2m/z.
The developing agent for monitoring the reaction by TLC is ethyl acetate, petroleum ether (v/v) =1:1, and a GF254 silica gel plate is used for observation under an ultraviolet lamp.
Has the advantages that: the invention discloses a synthesis method of 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 NaY molecular sieve to obtain the intermediate shown in 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 indicated. 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 Lian Hai Xin chemical Co., ltd. And had a silica to alumina ratio of 4.5 to 5.0. Comparative example 1:
the compounds of formula I are prepared according to the methods in J.Pharmacochem. 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, 5 mmol) 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 matter 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.
1H-pyrrol-2-yl-phenyl methanone (15.0 g, 0.087mol), potassium carbonate (53.0 g,0.386 mol), tetrabutylammonium bromide (7.0 g, 22mmol) were added to a reaction flask, 300ml of 1, 2-dichloroethane was added, stirred and heated to reflux for 4 hours, reacted, 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:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 5g NaY molecular sieve was added, the mixture was stirred at 25 ℃, the reaction was monitored by TLC, after 2 hours the material spots disappeared, potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heating was allowed to clear, cooling was cooled to below 25 ℃ for crystallization, filtration, and drying gave the compound of formula I as an off-white solid, 64.2g total, 94% yield.
Example 2:
1H-pyrrol-2-yl-phenyl methanone (150g, 0.88mol) was dissolved in 900ml 1,2-dichloroethane, potassium carbonate (121.1g, 0.88mol) was added, 75g NaY molecular sieve was added, the mixture was stirred at 0 deg.C, the reaction was monitored by TLC, after 4 hours the material spot disappeared, potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 300ml ethyl acetate and 300ml n-heptane were added, heating to clear, cooling to below 25 deg.C for crystallization, filtration, and drying to give the compound of formula I as an off-white solid, total 186.3g, 91% yield.
Example 3:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 50g of NaY molecular sieve was added, the mixture was stirred at 40 ℃, the reaction was monitored by TLC, after 1 hour the spots of raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid in total 64.8g, yield 95%.
Example 4:
dissolving 1H-pyrrol-2-yl-phenyl methanone (250g, 1.46mol) in 1500ml 1,2-dichloroethane, adding potassium carbonate (201.8g, 1.46mol), adding 375g NaY molecular sieve, stirring the mixture at 20 ℃, monitoring the reaction by TLC, after 3 hours the raw material spots disappear, filtering off the potassium carbonate and NaY molecular sieve, concentrating the filtrate under reduced pressure to dryness, adding 500ml ethyl acetate and 500ml n-heptane, heating to clear, cooling to below 25 ℃ for crystallization, filtering, drying to obtain the compound of formula I as an off-white solid with total 317.4g and 93% yield.
Example 5:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 100g of NaY molecular sieve was added, the mixture was stirred at 30 ℃, the reaction was monitored by TLC, after 2 hours the spots of raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid in total 66.2g, 97% yield.
Example 6:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml of 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 10g of NaY molecular sieve was added, the mixture was stirred at 20 ℃, the reaction was monitored by TLC, after 3 hours the spots of the raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml of ethyl acetate and 100ml of n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid, total 61.4g, yield 90%.
Example 7:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 10g of NaY molecular sieve was added, the mixture was stirred at 25 ℃, the reaction was monitored by TLC, after 3 hours the spots of raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid in a total of 62.8g, 92% yield.
Example 8:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 20g of NaY molecular sieve was added, the mixture was stirred at 20 ℃, the reaction was monitored by TLC, after 3 hours the spots of raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid in total 62.1g, 91% yield.
Example 9:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 25g of NaY molecular sieve was added, the mixture was stirred at 25 ℃, the reaction was monitored by TLC, after 4 hours the spots of raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid in total 62.1g, 91% yield.
Example 10:
dissolving 1H-pyrrol-2-yl-phenyl ketone (60g, 0.35mol) in 360ml 1,2-dichloroethane, adding potassium carbonate (48.4 g, 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 off the potassium carbonate and NaY molecular sieve, concentrating the filtrate under reduced pressure to dryness, adding 120ml ethyl acetate and 120ml 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:
1H-pyrrol-2-yl-phenyl methanone (70g, 0.41mol) was dissolved in 420ml 1,2-dichloroethane, potassium carbonate (56.5 g, 0.41mol) was added, 7g of NaY molecular sieve was added, the mixture was stirred at 25 ℃, the reaction was monitored by TLC, after 4 hours the spots of raw material disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 140ml ethyl acetate and 140ml n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid in a total of 85.0g, 89% yield.
Example 12:
dissolving 1H-pyrrol-2-yl-phenyl ketone (80g, 0.47mol) in 480ml 1,2-dichloroethane, adding potassium carbonate (64.6 g, 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 off the potassium carbonate and NaY molecular sieve, concentrating the filtrate under reduced pressure to dryness, adding 160ml ethyl acetate and 160ml 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:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml of 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 60g of NaY molecular sieve was added, the mixture was stirred at 40 ℃, the reaction was monitored by TLC, after 2 hours the raw material spots disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml of ethyl acetate and 100ml of n-heptane were added, heated to clear, cooled to below 25 ℃ for crystallization, filtered, and dried to give the compound of formula I as an off-white solid, total 63.5g, 93% yield.
Example 14:
1H-pyrrol-2-yl-phenyl methanone (50g, 0.29mol) was dissolved in 300ml 1,2-dichloroethane, potassium carbonate (40.4 g, 0.29mol) was added, 5g NaY molecular sieve was added, the mixture was stirred at 0 deg.C, the reaction was monitored by TLC, after 6 hours the raw material spots disappeared, the potassium carbonate and NaY molecular sieve were filtered off, the filtrate was concentrated to dryness under reduced pressure, 100ml ethyl acetate and 100ml n-heptane were added, heating was allowed to clear, cooling was cooled to below 25 deg.C for crystallization, filtration, and drying gave the compound of formula I as an off-white solid in total 64.2g, 94% yield.
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.
Claims (7)
1. A synthesis method of ketorolac intermediate is carried out by reacting 1H-pyrrole-2-yl-phenyl ketone with 1,2-dichloroethane and potassium carbonate, adding NaY type molecular sieve into reaction system, reacting at 0-40 deg.C to obtain ketorolac intermediate as shown in formula I;
2. the method of claim 1, wherein the temperature is in the range of 20 to 30 ℃.
3. The synthesis method according to claim 1, characterized in that the NaY type molecular sieve is used in an amount of 0.1 to 2.0 times the total weight of 1H-pyrrol-2-yl-phenyl methanone.
4. A synthesis process according to claim 3, characterized in that the NaY-type molecular sieve is used in an amount of 0.1 to 0.5 times 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 type molecular sieve is 4.5-5.0.
6. The method of claim 1, wherein the reaction time is 1 to 6 hours.
7. The synthesis method according to claim 1, wherein the mass-to-volume ratio of 1H-pyrrol-2-yl-phenyl methanone to 1,2-dichloroethane is 1 g.
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| US5082951A (en) * | 1990-10-12 | 1992-01-21 | Syntex (U.S.A.) Inc. | Process for preparing 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates (I) and intermediates therefor |
| CN101668747A (en) * | 2007-05-28 | 2010-03-10 | 安斯泰来制药株式会社 | Tetrahydroisoquinolin-1-one derivative or salt thereof |
| US20150010474A1 (en) * | 2011-12-23 | 2015-01-08 | Auckland Uniservices Limited | Compounds And Methods For Selective Imaging And/Or Ablation |
| CN112898307A (en) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Ketorolac impurity C and preparation method and application thereof |
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| US5082951A (en) * | 1990-10-12 | 1992-01-21 | Syntex (U.S.A.) Inc. | Process for preparing 5-aroyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylates (I) and intermediates therefor |
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| US20150010474A1 (en) * | 2011-12-23 | 2015-01-08 | Auckland Uniservices Limited | Compounds And Methods For Selective Imaging And/Or Ablation |
| CN112898307A (en) * | 2021-02-07 | 2021-06-04 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Ketorolac impurity C and preparation method and application thereof |
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