CN114213325B - Preparation method and application of 10-methyl-9, 10-acridine dihydride-9-thiocarboxylic acid-4-chlorophenyl ester - Google Patents
Preparation method and application of 10-methyl-9, 10-acridine dihydride-9-thiocarboxylic acid-4-chlorophenyl ester Download PDFInfo
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- CN114213325B CN114213325B CN202111602110.1A CN202111602110A CN114213325B CN 114213325 B CN114213325 B CN 114213325B CN 202111602110 A CN202111602110 A CN 202111602110A CN 114213325 B CN114213325 B CN 114213325B
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- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
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Abstract
The invention provides a preparation method and application of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester, which relates to the technical field of organic synthesis and comprises the following steps: the substituted acridine is activated by an activating agent and then reacts with p-chlorophenylthiol, and then is subjected to reductive amino and N-methylation to obtain 10-methyl-9, 10-acridinium dihydrogenate-9-thiocarboxylic acid-4-chlorophenyl ester; wherein the substituted acridine is substituted acridine at position 9. The invention solves the technical problems of complex starting materials, difficult operation of reaction and use of highly toxic chemicals in the synthesis process of the 10-methyl-9, 10-acridine-9-thiocarboxylate-4-chlorophenyl ester synthesized by the prior art, and achieves the technical effects of simple starting materials, easy operation of reaction and no use of highly toxic chemicals.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method and application of 10-methyl-9, 10-acridine dihydride-9-thiocarboxylic acid-4-chlorophenyl ester.
Background
APS-5 is a chemiluminescent substrate based on 9, 10-dihydroacridine and is mainly used for ELISA detection of compounds with alkaline phosphatase AP conjugation; the 9, 10-dihydroacridine structure in the APS-5 structure can continuously, stably and efficiently emit light under the action of AP, so that the method is very suitable for phosphatase activity solution determination and phosphatase enzyme-linked immunoassay, and has the advantages of high detection sensitivity, high luminous intensity, stable detection result and good reproducibility.
At present, three main synthetic routes of the key intermediate 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl APS-5 are provided:
route 1: in patent CN1312252a, acridine-9-carboxylic acid is used as a raw material, and the target product is obtained through thioesterification, reduction and methylation.
The synthesis of scheme 1 is as follows:
route 2: in CN104230804A, acridone is used as a raw material, and a target product is obtained through methylation, addition, dehydration, reduction and oxidation.
The synthetic procedure of scheme 2 is as follows:
route 3: in CN109928926A, acridone is used as a raw material, and a target product is obtained through methylation, wittig reaction, reduction and oxidation.
The synthesis of scheme 3 is as follows:
however, the above synthetic routes all have certain drawbacks such as complex starting materials, difficult reaction operation and the use of highly toxic chemicals in the synthesis process.
In view of this, the present invention has been made.
Disclosure of Invention
One of the purposes of the present invention is to provide a method for preparing 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester, which can synthesize the target product easily with simple starting materials, does not use toxic chemicals, and has considerable reaction yield.
It is a second object of the present invention to provide the use of said preparation method for the preparation of APS-5.
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
in a first aspect, the present invention provides a process for the preparation of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester, comprising the steps of:
the substituted acridine is activated by an activating agent and then reacts with p-chlorophenylthiol, and then is subjected to reductive amino and N-methylation to obtain 10-methyl-9, 10-acridinium dihydrogenate-9-thiocarboxylic acid-4-chlorophenyl ester;
wherein the substituted acridine is substituted acridine at position 9.
Further, the substituted acridine includes halogenated acridine;
further preferably, the halogenated acridine comprises bromoacridine.
Further, the preparation method of the halogenated acridine comprises the following steps:
reacting acridine with a halogenating reagent to obtain 9-haloacridine;
further preferably, the halogenating reagent comprises a brominating reagent;
further preferably, the brominating reagent comprises N-bromosuccinimide.
Further, the activator includes N, N' -carbonyldiimidazole.
Further, the reducing agent for reducing the amino group comprises zinc powder;
further preferably, the means for reducing amine groups comprises reduction with zinc powder under acidic conditions;
further preferably, the acid that creates the acidic condition includes at least one of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
Further, the N-methylated reagent includes at least one of dimethyl sulfate, methyl iodide, and methyl triflate.
Further, the preparation method comprises the following steps:
A. reacting acridine with N-bromosuccinimide to obtain 9-bromoacridine;
B. activating 9-bromoacridine by N, N' -carbonyl diimidazole to obtain an activated product;
C. b, reacting the activated product obtained in the step B with p-chlorophenylthiol to obtain a thioesterified product;
D. c, reducing amino groups of the thioesterified product obtained in the step under an acidic condition by zinc powder to obtain a reduced product;
E. the reduction product obtained in the step D is subjected to N-methylation to obtain 10-methyl-9, 10-acridine dihydride-9-thiocarboxylic acid-4-chlorophenyl ester;
wherein the N-methylated reagent is methyl triflate.
Further, the step B includes the steps of:
(a) 9-bromoacridine is dissolved in a solvent to obtain a standby solution (a);
the solvent comprises tetrahydrofuran;
(b) Reacting the standby solution (a) obtained in the step (a) with magnesium under the action of iodine to obtain a standby solution (b);
(c) And (3) reacting the standby solution (b) obtained in the step (b) with N, N' -carbonyl diimidazole to obtain an activated product.
Further, the step (b) includes the steps of:
and (3) adding part of the standby solution (a) obtained in the step (a) and iodine into a reactor containing magnesium for reaction, and then adding the rest of the standby solution (a) for reaction to obtain a standby solution (b).
In a second aspect, the present invention provides the use of a method according to any one of the above in the preparation of APS-5.
Compared with the prior art, the invention has at least the following beneficial effects:
the preparation method provided by the invention comprises the steps of replacing hydrogen on the 9 th position of acridine, activating, then reacting with p-chlorophenylthiol to connect a sulfur aryl fragment, and has the characteristics of simplified reaction steps and mild reaction conditions.
The application of the preparation method provided by the invention in preparing APS-5 has the same advantages as the preparation method, and is not repeated here.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing the synthesis reaction of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester according to one embodiment of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
According to a first aspect of the present invention, there is provided a process for the preparation of 4-chlorophenyl 10-methyl-9, 10-acridine-9-thiocarboxylate, comprising the steps of:
the substituted acridine is activated by an activating agent and then reacts with p-chlorophenylthiol, and then is subjected to reductive amino and N-methylation to obtain 10-methyl-9, 10-acridinium dihydrogenate-9-thiocarboxylic acid-4-chlorophenyl ester;
wherein, substituted acridine in the invention is substituted acridine in the 9-position.
In the invention, the hydrogen at the 9-position of the acridine is substituted and then activated, and then the acridine is reacted with the p-chlorophenylthiol to connect the sulfur aryl fragment, so that the method has the characteristics of simplified reaction steps and mild reaction conditions, and meanwhile, the starting materials used in the method are simple, the reaction process is easy to operate, no toxic chemicals are used, and the method has a considerable reaction yield.
In a preferred embodiment, substituted acridines in the present invention include, but are not limited to, halogenated acridines;
wherein the halogenated acridine of the present invention includes, but is not limited to, bromoacridine.
The bromoacridine selected by the invention can be better activated by an activating agent, and is more beneficial to the connection of subsequent thioaryl fragments.
In a preferred embodiment, the process for the preparation of halogenated acridine according to the present invention comprises the following steps:
reacting acridine with a halogenating reagent to obtain 9-haloacridine;
wherein the halogenating agents of the present invention include, but are not limited to, brominating agents; brominating reagents of the present invention include, but are not limited to, N-bromosuccinimide.
In the invention, acridine reacts with N-bromosuccinimide to obtain 9-bromoacridine, and the specific reaction process comprises the following steps:
under the protection of nitrogen, dissolving acridine in dichloromethane, adding N-bromosuccinimide in batches at the temperature of 0-10 ℃, reacting under the condition of heat preservation, adding water for quenching reaction after the reaction is finished, separating liquid to obtain a water phase, extracting the water phase with ethyl acetate for a plurality of times, merging organic phases, drying with anhydrous sodium sulfate, and concentrating to remove a solvent to obtain the 9-bromoacridine.
The invention uses brominating reagent N-bromosuccinimide to carry out bromination reaction with acridine to obtain 9-bromoacridine, and has the characteristics of simple reaction operation and good bromination effect.
In a preferred embodiment, the activators used in the present invention include, but are not limited to, N' -carbonyldiimidazole.
The activating agent N, N' -carbonyl diimidazole used in the invention has a better activating effect on halogenated acridine, and the activated product is easier to react with p-chlorophenylthiol to connect with a sulfur aryl fragment.
The invention reduces amino after linking thioaryl fragment and N-methylates to obtain 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester.
In a preferred embodiment, the amine-based reducing agents of the present invention include, but are not limited to, zinc powder; the means for reducing amine groups of the present invention includes, but is not limited to, reduction with zinc powder under acidic conditions, wherein the acid that creates the acidic conditions includes, but is not limited to, at least one of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, preferably acetic acid.
The invention reduces amino by zinc powder under acidic condition, which can obtain better reduction effect, and has simple reaction process and higher yield.
In a preferred embodiment, the N-methylated reagent of the present invention includes, but is not limited to, at least one of dimethyl sulfate, methyl iodide, and methyl triflate, preferably methyl triflate.
The methylation reagent selected by the invention can better realize N-methylation after reduction of the amino, can obtain better reaction effect, and has simple reaction and higher yield.
In a preferred embodiment, the preparation method of the present invention comprises the steps of:
A. reacting acridine with N-bromosuccinimide to obtain 9-bromoacridine;
B. activating 9-bromoacridine by N, N' -carbonyl diimidazole to obtain an activated product;
C. b, reacting the activated product obtained in the step B with p-chlorophenylthiol to obtain a thioesterified product;
D. c, reducing amino groups of the thioesterified product obtained in the step under an acidic condition by zinc powder to obtain a reduced product;
E. the reduction product obtained in the step D is subjected to N-methylation to obtain 10-methyl-9, 10-acridine dihydride-9-thiocarboxylic acid-4-chlorophenyl ester;
wherein the N-methylated reagent is methyl triflate.
The preparation method solves the technical problems of complex starting materials, difficult reaction operation and use of highly toxic chemicals in the synthesis process of the 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester in the prior art, and achieves the technical effects of simple starting materials, easy reaction operation and no use of highly toxic chemicals.
In a preferred embodiment, step B of the present invention comprises the steps of:
(a) Dissolving 9-bromoacridine in a solvent to obtain a ready-to-use solution (a), wherein the solvent includes, but is not limited to, tetrahydrofuran;
(b) Reacting the standby solution (a) obtained in the step (a) with magnesium under the action of iodine to obtain a standby solution (b);
(c) And (3) reacting the standby solution (b) obtained in the step (b) with N, N' -carbonyl diimidazole to obtain an activated product.
In a preferred embodiment, step (b) of the present invention comprises the steps of:
and (3) adding part of the standby solution (a) obtained in the step (a) and iodine into a reactor containing magnesium for reaction, and then adding the rest of the standby solution (a) for reaction to obtain a standby solution (b).
The specific activation process selected by the invention has better activation effect, the reaction operation is relatively simple, no virulent chemical reagent is used, and the obtained activation product can be directly put into the next step of reacting with p-chlorophenylthiol to connect with the thioaryl fragment without purification, thereby simplifying the operation of the reaction.
A typical preparation method of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester, as shown in FIG. 1, comprises the following steps:
s1: under the protection of nitrogen, dissolving acridine (compound A) in methylene dichloride, adding N-bromosuccinimide in batches at the temperature of 0-10 ℃, stirring for reaction under the condition of heat preservation, adding water for quenching reaction after the reaction is finished, then extracting a liquid phase with ethyl acetate, merging organic phases, drying with anhydrous sodium sulfate, concentrating and removing a solvent to obtain 9-bromoacridine (compound B);
s2: under the protection of nitrogen, 9-bromoacridine (compound B) obtained in the step S1 is dissolved in tetrahydrofuran to obtain a standby solution; adding clean magnesium strips into a reaction bottle, adding the part of standby solution and 1 small particle of iodine, heating to reflux under stirring, generating a large amount of gas in the reaction solution, dripping the rest standby solution after the color disappears, reacting after the dripping is finished, cooling the system to 0 ℃, adding N, N' -carbonyl diimidazole again once again, heating to room temperature, reacting under stirring, filtering after the reaction is finished, concentrating the filtrate to obtain oily crude product which is the compound C, and directly putting into the next step for reaction without purification;
s3: dissolving the crude compound C obtained in the step S2 in dichloromethane, adding parachlorothiophenol, stirring at room temperature for reaction, adding water after the reaction is finished, separating liquid, concentrating and drying an organic phase to obtain a compound D;
s4: dissolving the compound D obtained in the step S3 in dichloromethane, adding acetic acid and zinc powder, reacting under stirring, filtering after the reaction is finished, washing filtrate with water, concentrating and drying to obtain a compound E;
s5: and (3) dissolving the compound E obtained in the step (S4) in dichloromethane, adding methyl triflate, reacting at room temperature, washing with water after the reaction is finished, concentrating and drying to obtain the compound F, namely the product of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester.
The preparation method provided by the invention uses acridine as a starting material, and has the following advantages compared with the existing synthesis process: the starting materials are simple, the reaction is easy to operate, and highly toxic chemicals are not used.
According to a second aspect of the present invention, there is provided the use of the above-mentioned preparation method of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester for preparing APS-5, which has the same advantages as the above-mentioned preparation method and is not described herein.
The invention is further illustrated by the following examples. The materials in the examples were prepared according to the existing methods or were directly commercially available unless otherwise specified.
Example 1
A method for preparing 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester, which comprises the following steps:
s1: under the protection of nitrogen, 10g of acridine is dissolved in 100mL of dichloromethane, 10g N-bromosuccinimide is added in batches at the temperature of 0-10 ℃, stirring is carried out for 3 hours under the heat preservation, then 50mL of water is added for quenching reaction, liquid separation is carried out, the water phase is extracted 3 times with 50mL of ethyl acetate each time, the ethyl acetate of the organic phase is combined, and then the organic phase is dried with anhydrous sodium sulfate and concentrated, thus 12.6 g of 9-bromoacridine is obtained, and the yield is 88%;
s2: 10g of 9-bromoacridine is dissolved in 50mL of tetrahydrofuran under the protection of nitrogen, so as to obtain a standby solution; adding 1.1g of clean magnesium strips into a reaction bottle, adding 3mL of the standby solution and 1 particle of iodine, heating to reflux under stirring, generating a large amount of gas in the reaction liquid, starting to dropwise add 47mL of the rest standby solution after the color disappears, reacting for 3 hours after the dropwise adding is finished, cooling the system to 0 ℃, adding 7g of N, N' -carbonyldiimidazole again, heating to room temperature again, reacting for 5 hours under stirring, filtering after the reaction is finished, concentrating the filtrate to obtain an oily crude product which is an activated product, directly putting into the next step for reaction without purification;
s3: dissolving the activated product of the oily crude product in 50mL of dichloromethane, adding 8.4g of p-chlorophenylthiol, stirring at room temperature for reaction for 8 hours, adding 50mL of water after the reaction is finished, redistributing, concentrating and drying an organic phase to obtain 10.8g of thioesterified product;
s4: adding 10g of the thioesterified product into 100mL of dichloromethane for dissolution, adding 2.5mL of acetic acid and 10g of zinc powder, reacting for 1 hour under stirring, filtering, washing filtrate with water, concentrating and drying to obtain 9.5g of reduced product, and obtaining the yield of 95%;
s5: and adding 5g of the reduction product into 15mL of dichloromethane to dissolve, adding 15g of methyl triflate, stirring for 24 hours at room temperature, washing for 2 times after the reaction is finished, concentrating and drying to obtain 5.1g of final product 10-methyl-9, 10-acridinium dihydrogenate-9-thiocarboxylic acid-4-chlorophenyl ester, wherein the yield is 98%. 1 H NMR(400MHz,CDCl 3 )δ7.33(t,J＝7.6Hz,4H),7.27–7.20(m,2H),7.19–7.11(m,2H),7.05–6.94(m,4H),5.06(s,1H),3.42(s,1H)ppm. 13 C NMR(100MHz,CDCl 3 )δ197.39,142.44,135.64,135.43,129.89,129.18,129.04,126.82,120.86,119.93,112.92,77.41,77.10,76.78,57.86,33.26.HRMS caled for C 21 H 16 ClNOS(MH + )366.0714,found 366.0718。
Example 2
This example differs from example 1 in that the halogenating reagent used in step S1 of this example was N-chlorosuccinimide, the amount of N-chlorosuccinimide added in this example was 10g, 9-chloroacridine was obtained, and further, 9-chloroacridine was used for the subsequent reaction, and 10-methyl-9, 10-dihydroacridine-9-thiocarboxylic acid-4-chlorophenyl ester was obtained by referring to example 1 for the subsequent reaction step.
Example 3
This example differs from example 1 in that the halogenating agent used in step S1 of this example is dibromohydantoin, the addition amount of dibromohydantoin of this example is 8g, 9-bromoacridine is obtained, and further, the subsequent reaction is carried out, and the subsequent reaction step is referred to example 1 to obtain 10-methyl-9, 10-dihydroacridine-9-thiocarboxylic acid-4-chlorophenyl ester.
Example 4
This example differs from example 1 in that hydrochloric acid was used in place of acetic acid in step S4 of example 1 in step S4 of this example, the concentration of hydrochloric acid added in this example was 50% and the addition amount was 1.0mL, and the other steps were the same as in example 1, to obtain 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester.
Example 5
This example differs from example 1 in that trifluoroacetic acid was used in place of acetic acid in step S4 of example 1 in step S4 of this example, the amount of trifluoroacetic acid added in this example was 1.0mL, and the other steps were the same as in example 1 to give 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester.
Example 6
This example differs from example 1 in that methyl iodide was used in step S5 of this example in place of methyl triflate in step S5 of example 1, the amount of methyl iodide added was 14g, the amount of triethylamine added was 17 g, and the remaining steps were the same as in example 1 to obtain 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester.
Comparative example 1
The preparation method of the key intermediate of the chemiluminescent substance APS-5 (CN 104230804A) takes acridone as a raw material, and prepares 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester through N-methylation, nucleophilic addition, dehydration, olefin reduction into alcohol and hydroxyl oxidation into ketone. The preparation method of the comparative example has the disadvantages of complex starting materials, harsh reaction conditions and difficult operation.
As can be seen, compared with comparative example 1, the preparation methods of examples 1 to 6 of the present invention have the characteristics of simplified reaction steps and mild reaction conditions, and the starting materials used in the present invention are simple, the reaction process is easy to operate, no highly toxic chemicals are used, and the reaction yield is considerable.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (4)
1. A process for the preparation of 10-methyl-9, 10-acridine-9-thiocarboxylic acid-4-chlorophenyl ester, said process comprising the steps of:
A. reacting acridine with N-bromosuccinimide to obtain 9-bromoacridine;
B. activating 9-bromoacridine by N, N' -carbonyl diimidazole to obtain an activated product;
C. b, reacting the activated product obtained in the step B with p-chlorophenylthiol to obtain a thioesterified product;
D. c, reducing amino groups of the thioesterified product obtained in the step under an acidic condition by zinc powder to obtain a reduced product;
E. the reduction product obtained in the step D is subjected to N-methylation to obtain 10-methyl-9, 10-acridine dihydride-9-thiocarboxylic acid-4-chlorophenyl ester;
wherein the N-methylated reagent is methyl triflate;
the step B comprises the following steps:
(a) 9-bromoacridine is dissolved in a solvent to obtain a standby solution (a);
the solvent comprises tetrahydrofuran;
(b) Reacting the standby solution (a) obtained in the step (a) with magnesium under the action of iodine to obtain a standby solution (b);
(c) And (3) reacting the standby solution (b) obtained in the step (b) with N, N' -carbonyl diimidazole to obtain an activated product.
2. The method according to claim 1, wherein the acid that creates the acidic condition comprises at least one of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
3. The method of claim 1, wherein step (b) comprises the steps of:
and (3) adding part of the standby solution (a) obtained in the step (a) and iodine into a reactor containing magnesium for reaction, and then adding the rest of the standby solution (a) for reaction to obtain a standby solution (b).
4. Use of a preparation method according to any one of claims 1-3 for the preparation of APS-5.
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