CN115010593B - Synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid - Google Patents
Synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid Download PDFInfo
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Abstract
The application provides a synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid, which relates to the field of synthesis of medical intermediates; the method adopts bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester as an initial raw material, and obtains a target product 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid under mild and proper conditions through carbonyl reduction, bromination, hydrolysis and dehalogenation steps; compared with the current situation that the existing method is harsh in reaction conditions, unstable in raw materials, difficult to store and unsuitable for industrial production, the synthetic method is ideal in route overall yield, and the used raw materials and auxiliary materials are easily available in the market and high in stability, so that the synthetic method is suitable for industrial scale-up production.
Description
Technical Field
The application relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid.
Background
In recent years, bicyclo [1.1.1] pentanes (BCP) compounds having three-dimensional structures have been attracting attention in the field of pharmaceutical synthesis, and have been widely used in drug design, and have been favored by pharmaceutical chemists, as well as exhibiting unique physiological activities, but also bioisosteres of benzene rings, endoalkynes, and tert-butyl groups. 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid is taken as an important member of bicyclo [1.1.1] pentane (BCP) compounds, has the same wide application prospect, and needs to explore the synthetic strategy.
Currently, by referring to the prior art, in patent US20160075654, there is mentioned a synthetic method of this compound, the synthetic route of which is:
the route method needs more severe conditions and needs to be carried out at a lower temperature, and the tertiary butyl lithium needed in the second step can react violently when meeting water and oxygen and burn rapidly, so that the method has great potential safety hazard; in addition, the initial raw materials are also extremely unstable and difficult to preserve, and the whole synthesis route is not suitable for scale-up production.
Disclosure of Invention
The application aims to provide a synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid, which adopts bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester as an initial raw material, and obtains a target product 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid under mild and proper conditions through carbonyl reduction, bromination, hydrolysis and dehalogenation steps.
In order to achieve the above purpose, the present application proposes the following technical scheme: a synthetic method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid comprises the following synthetic route:
the specific synthesis steps comprise:
1) Dropwise adding a reducing agent into tetrahydrofuran solution of a compound A bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester dissolved at the temperature of-5 ℃ to fully react the mixed solution at room temperature to obtain a compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester;
2) Under the condition of room temperature, the compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester, a brominating reagent, triphenylphosphine and imidazole are fully reacted in methylene dichloride solution to obtain the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester;
3) Under the condition of room temperature, the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester and alkali I are fully reacted in a first solvent to obtain the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid;
4) Under the condition of room temperature and hydrogen protection, the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid, a catalyst and a base II are fully reacted in a second solvent to obtain the compound CP 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid.
Further, the molar ratio of the compound A, namely methyl bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylate, in the step 1) to the reducing agent is 1 (1-2.0).
Further, the molar ratio of the compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester to the brominating reagent, triphenylphosphine and imidazole in the step 2) is 1: (1-2.0): (3.0-6.0): (1.5-3.0).
Further, in the step 3), the molar ratio of the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester to the base I is 1: (1-2.0).
Further, in the step 4), the molar ratio of the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid and the base II is 1: (1.0-2.5), the mass ratio of the catalyst to the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid is 3-15%.
Further, the reducing agent in the step 1) is borane tetrahydrofuran or borane dimethyl sulfide.
Further, the brominating reagent in the step 2) is liquid bromine or carbon tetrabromide.
Further, in the step 3), the base i is lithium hydroxide monohydrate or sodium hydroxide, and the first solvent is a mixed solvent of tetrahydrofuran and water or a mixed solvent of methanol and water.
Further, the catalyst in the step 4) is palladium carbon, the alkali II is triethylamine, sodium bicarbonate or sodium hydroxide, and the second solvent is ethyl acetate, methanol, ethanol or tetrahydrofuran.
According to the technical scheme, the following beneficial effects are achieved:
aiming at the technical problems of harsh reaction conditions, unstable raw materials, difficult storage, inapplicability to subsequent industrial production and the like existing in the synthesis of target compounds in the prior art, the application discloses a synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid, which is characterized in that methyl bicyclo [1.1.1] pentane-1-carboxylate is taken as an initial raw material, and a target product is obtained under mild and proper conditions through carbonyl reduction, bromination, hydrolysis and dehalogenation steps; the synthetic route of the method has the following advantages:
1) Provides a stable route for synthesizing 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid, and the reactions involved in the route are all classical chemical reactions and have higher stability;
2) The raw materials and the reagents are industrially produced, are easily available in the market, have small environmental pollution and have low material cost;
3) The route has the advantages of convenient feeding, simple and convenient operation, hundred gram-grade preparation verification, and suitability for industrial production;
4) The proposal of the route is expected to reduce the production cost of the intermediate and promote the wide application of the bicyclo [1.1.1] pentane (BCP) compounds in the medical field.
It should be understood that all combinations of the foregoing concepts, as well as additional concepts described in more detail below, may be considered a part of the inventive subject matter of the present disclosure as long as such concepts are not mutually inconsistent.
The foregoing and other aspects, embodiments, and features of the present teachings will be more fully understood from the following description, taken together with the accompanying drawings. Other additional aspects of the application, such as features and/or advantages of the exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of the embodiments according to the teachings of the application.
Drawings
The drawings are not intended to be drawn to scale with respect to true references. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the application will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic resonance spectrum of the target product 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid of the present application.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present application. It will be apparent that the described embodiments are some, but not all, embodiments of the application. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present application fall within the protection scope of the present application. Unless defined otherwise, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this application belongs.
The terms "first," "second," and the like in the description and in the claims, are not used for any order, quantity, or importance, but are used for distinguishing between different elements. Also, unless the context clearly indicates otherwise, singular forms "a," "an," or "the" and similar terms do not denote a limitation of quantity, but rather denote the presence of at least one. The terms "comprises," "comprising," or the like are intended to cover a feature, integer, step, operation, element, and/or component recited as being present in the element or article that "comprises" or "comprising" does not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
Based on the wide attention of bicyclo [1.1.1] pentane (BCP) compounds in the field of medicine synthesis, 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid has wide application prospect as one member, and the existing synthesis strategy has the defects of unstable reaction raw materials, difficult preservation, harsh reaction conditions, potential safety hazard and inapplicability to industrial production; the application aims to provide a method for preparing 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid by adopting a plurality of classical chemical reactions, wherein the method takes bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester as an initial raw material, and the target product is obtained through steps of reduction, bromination, hydrolysis and dehalogenation under mild and proper conditions, so that the defects are effectively avoided.
Specifically, the application discloses a synthesis method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid, which comprises the following synthesis routes:
the specific synthesis steps comprise:
1) Dropwise adding borane tetrahydrofuran or borane dimethyl sulfide serving as a reducing agent into tetrahydrofuran solution of a compound A bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester dissolved at the temperature of-5 ℃ to fully react the mixed solution at room temperature to obtain a compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester; wherein, the mol ratio of the compound A bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester to the reducing agent is 1 (1-2.0);
2) Under the condition of room temperature, the compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester, a brominating reagent, triphenylphosphine and imidazole are fully reacted in methylene dichloride solution to obtain the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester; wherein the brominating reagent is liquid bromine or carbon tetrabromide, and the molar ratio of the compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester to the brominating reagent, triphenylphosphine and imidazole is 1: (1-2.0): (3.0-6.0): (1.5-3.0);
3) Under the condition of room temperature, the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester and alkali I are fully reacted in a first solvent to obtain the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid; wherein the alkali I is lithium hydroxide monohydrate or sodium hydroxide, the first solvent is a mixed solvent of tetrahydrofuran and water or a mixed solvent of methanol and water, and the molar ratio of the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester to the alkali I is 1: (1-2.0), the reaction time is 8-15 h;
4) Under the conditions of room temperature and hydrogen protection, the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid, a catalyst and a base II are fully reacted in a second solvent to obtain a compound CP 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid; wherein the catalyst is palladium carbon, the alkali II is triethylamine, sodium bicarbonate or sodium hydroxide, the second solvent is ethyl acetate, methanol, ethanol or tetrahydrofuran, and the molar ratio of the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid to the alkali II is 1: (1.0-2.5), the mass ratio of the catalyst to the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid is 3-15%; the reaction time is 8-15 h.
The synthesis of 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid disclosed in the present application is described in further detail below with reference to the examples and the accompanying drawings. The chemical reagents adopted in the embodiment of the application are all commercial chemical reagents, and the room temperature is 20-30 ℃.
Example 1
Step 1: preparation of Compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
Compound a (30 g,0.176mol,1 eq) was added to 500ml of tetrahydrofuran, cooled to 0 ℃, borane in tetrahydrofuran (210 ml,0.210mol,1.2 eq) was added dropwise, reacted overnight at room temperature for 12h; cooling to 0 ℃, dropwise adding 200ml of methanol for quenching, and spin-drying to obtain 23.47g of compound B, wherein the yield is 83.53% and the purity is 98.0%.
Step 2: preparation of the Compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
Solution bromine (35.3, 0.221mol,1.5 eq) was added to 500ml of dichloromethane, triphenylphosphine (173.8 g,0.663mol,4.5 eq) and imidazole (25.1 g,0.369mol,2.5 eq) were added, then a dichloromethane solution of compound B (23 g,0.147mol,1 eq) was added dropwise, the reaction was carried out overnight at room temperature, filtration, washing of the filter cake with dichloromethane, combining the organic phases, spin drying, sample-mixing and column-passing, and purification was carried out to obtain 23.2g of compound C in a yield of 71.29% and a purity of 99%.
Step 3: preparation of Compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid
Compound C (20 g,0.091mol,1 eq) was added to 100ml of water and 50ml of tetrahydrofuran, followed by addition of lithium hydroxide monohydrate (5.75 g,0.137mol,1.5 eq), stirred at room temperature overnight, and reacted for 12h; pouring into ice water, regulating pH to 3-4, extracting with ethyl acetate, backwashing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain 15.4g of compound D with a yield of 80.13% and a purity of 97.3%.
Step 4: preparation of the target product Compound CP 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid
Compound D (3 g,0.0146mol,1 eq) was added to 100ml of ethyl acetate, followed by triethylamine (2.22 g,0.022mol,1.5 eq) and 10% pd/C (0.15 g), hydrogen protected, stirred overnight at room temperature; the reaction is complete, dilute hydrochloric acid backflushing, saturated saline backflushing, drying and spin drying are carried out to obtain 1.54g of compound CP, the yield is 81.27%, and the purity is 97.5%. The nuclear magnetic hydrogen spectrum of the target compound CP is shown in figure 1, 1 H NMR(600MHz,DMSO)δ11.22(s,1H),1.96(s,6H),1.20(s,3H)。
in order to optimize the preparation efficiency of the target product, examples 2-5 explore the influence of each reaction condition in step 2) on the product yield, and the reaction results are shown in table 1; the reaction conditions and the operation of the other synthesis steps of examples 2 to 5 were the same as those of example 1, except that the reaction conditions of step 2) shown in Table 1 were different.
TABLE 1 influence of the reaction conditions in the synthesis step 2) on the yield of Compound C
In comparative examples 1 and 2, the amount of brominating reagent is reduced, the raw materials remain in the same reaction time, and the reaction yield is reduced; in comparative examples 1 and 5, the amount of brominating reagent is increased, the amount of byproducts is increased, and the reaction yield is reduced; in comparative examples 1 and 3, the amount of triphenylphosphine is reduced, the reaction rate is reduced, and the reaction yield is reduced; in comparative examples 1 and 4, the amount of imidazole used as an acid binding agent was reduced, the reaction rate was slowed down, and the reaction yield was reduced.
In order to optimize the preparation efficiency of the target product, examples 6 to 9 explore the influence of each reaction condition in the step 4) on the product yield, and the reaction results are shown in table 2; the reaction conditions and the operation of the other synthesis steps of examples 6 to 9 were the same as those of example 1, except that the reaction conditions of step 4) shown in Table 2 were different.
TABLE 2 influence of the reaction conditions in Synthesis step 2) on the yield of Compound C
Comparative examples 1 and 6 reduced the amount of base II and reduced the reaction yield; in comparative examples 1 and 7, the amount of alkali used was increased, the amount of by-products was increased, and the yield was slightly decreased; in comparative examples 1 and 8, the catalyst consumption is reduced, the reaction rate is slowed down, the conversion rate is reduced within the same reaction time, and the reaction yield is reduced; in comparative examples 1 and 9, the reaction effect of triethylamine in the reaction was superior to that of sodium hydroxide.
Example 10
Step 1: preparation of Compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
Compound a (300 g,1.76mol,1 eq) was added to 5L tetrahydrofuran, cooled to 0 ℃, borane tetrahydrofuran solution (2.1L, 2.10mol,1.2 eq) was added dropwise, reacted overnight at room temperature, for 12h; cooling to 0 ℃, dropwise adding 2L of methanol for quenching, and spin-drying to obtain 224.63g of the compound B, wherein the yield is 80.33% and the purity is 98.3%.
Step 2: preparation of the Compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester
To 5L of methylene chloride, added liquid bromine (345.0 g,2.16mol,1.5 eq), triphenylphosphine (1700 g,6.48mol,4.5 eq) and imidazole (245.23 g,3.61mol,2.5 eq) were added, then methylene chloride solution of compound B (224.63 g,1.43mol,1 eq) was added dropwise, the mixture was reacted overnight at room temperature, the mixture was filtered, the filter cake was washed with methylene chloride, the organic phases were combined, dried by spin-drying and column-stirred, and 223.82g of compound C was purified to yield 70.10% and purity 98.12%.
Step 3: preparation of Compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid
Compound C (200 g,0.91mol,1 eq) was added to 1L of water and 500ml of tetrahydrofuran, followed by addition of lithium hydroxide monohydrate (58 g,1.37mol,1.5 eq), stirred overnight at room temperature, and reacted for 12h; pouring into ice water, regulating pH to 3-4, extracting with ethyl acetate, backwashing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain 149.37g of compound D with a yield of 78.13% and 97.6%.
Compound D (120 g,0.585mol,1 eq) was added to 4L of ethyl acetate, followed by triethylamine (90.0 g,0.8mol,1.5 eq) and 10% Pd/C (6 g), hydrogen protected, and stirred overnight at room temperature; the reaction is complete, dilute hydrochloric acid backflushing, saturated saline backflushing, drying and spin drying are carried out to obtain 60.18g of compound CP, the yield is 80.10%, and the purity is 98.06%.
The route for synthesizing 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid is strong in stability, and the involved reactions are classical chemical reactions and have stability; secondly, the raw materials and reagents for reaction design in each step are industrially produced, are easily available in the market, have small environmental pollution and low material cost, are hopeful to reduce the production cost of the target product, and promote the promotion and application of the target product in the medical field; under the reaction conditions of the examples, the total four-step yield of the synthetic route is 39%, and the purity of the product is as high as 97.5%; under the reaction conditions of example 1, hundred gram-scale preparation verification (example 10) is performed, and the method is more suitable for industrial production compared with the existing synthesis scheme.
While the application has been described with reference to preferred embodiments, it is not intended to be limiting. Those skilled in the art will appreciate that various modifications and adaptations can be made without departing from the spirit and scope of the present application. Accordingly, the scope of the application is defined by the appended claims.
Claims (10)
1. A synthetic method of 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid is characterized by comprising the following synthetic route:
the specific synthesis steps comprise:
1) Dropwise adding a reducing agent into tetrahydrofuran solution of a compound A bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid methyl ester dissolved at the temperature of-5 ℃ to fully react the mixed solution at room temperature to obtain a compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester;
2) Under the condition of room temperature, the compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester, a brominating reagent, triphenylphosphine and imidazole are fully reacted in methylene dichloride solution to obtain the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester;
3) Under the condition of room temperature, the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester and alkali I are fully reacted in a first solvent to obtain the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid;
4) Under the condition of room temperature and hydrogen protection, the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid, a catalyst and a base II are fully reacted in a second solvent to obtain the compound CP 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid.
2. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein the molar ratio of the methyl ester of compound A bicyclo [1.1.1] pentane-1-carboxylic acid-3-carboxylic acid to the reducing agent in step 1) is 1 (1-2.0).
3. The method for synthesizing 3-methyl bicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein the molar ratio of the compound B3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester to brominating reagent, triphenylphosphine, imidazole is 1: (1-2.0): (3.0-6.0): (1.5-3.0).
4. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein in the step 3), the molar ratio of the compound C3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl ester to the base i is 1: (1-2.0).
5. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein in the step 4), the molar ratio of the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid to the base ii is 1: (1.0-2.5).
6. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein in the step 4), the mass ratio of the catalyst to the compound D3- (bromomethyl) bicyclo [1.1.1] pentane-1-carboxylic acid is 3-15%.
7. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein the reducing agent in the step 1) is borane tetrahydrofuran or borane dimethyl sulfide.
8. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein the brominating reagent in the step 2) is liquid bromine or carbon tetrabromide.
9. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein the base i in the step 3) is lithium hydroxide monohydrate or sodium hydroxide, and the first solvent is a mixed solvent of tetrahydrofuran and water or a mixed solvent of methanol and water.
10. The method for synthesizing 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid according to claim 1, wherein the catalyst in the step 4) is palladium carbon, the base II is triethylamine, sodium bicarbonate or sodium hydroxide, and the second solvent is ethyl acetate, methanol, ethanol or tetrahydrofuran.
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