Preparation method of DOTA-PNP

Abstract

The invention relates to a preparation method of DOTA-PNP, and belongs to the technical field of material synthesis. Cheap cycleanine is used as a starting raw material and reacts with tert-butyl bromoacetate to generate a tri-substituted product, the tri-substituted product is further substituted with ethyl bromoacetate to obtain a tetra-substituted product, ethyl ester is further hydrolyzed to obtain substituted carboxylic acid, the substituted carboxylic acid and p-nitrophenol are condensed, and finally tert-butyl is removed to obtain a target product.

Description

Technical Field

[0001] The invention belongs to the technical field of material synthesis and relates to a preparation method of DOTA-PNP. Background Art

[0002] 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTA-PNP) is a key group in nuclear medicine molecules. It is used to chelate radionuclides and has a wide range of uses.

[0003] Patent WO2021 / 195198 discloses a method for preparing 2,2',2"-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid, which is obtained by condensing 2,2',2",2"'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid with p-nitrophenol under the action of DIC. Although there is only one step reaction, the raw materials are expensive and the process cannot be scaled up for production. The scaled-up reaction involves multi-site condensation, which makes purification difficult and greatly reduces the yield. The feasibility of the route for process production is low, and the specific path is as follows. Figure 2 . Summary of the invention

[0004] The object of the present invention is to provide a method for preparing DOTA-PNP, which has the characteristics of simple reaction and post-treatment and can be industrialized.

[0005] The purpose of the present invention can be achieved through the following technical solutions:

[0006] A method for preparing DOTA-PNP, the specific preparation process is as follows:

[0007] S1: Add N,N-dimethylformamide to the reactor, then add cyclopentane, anhydrous sodium acetate and tetrabutylammonium iodide in a mass ratio of 20:38:1, wherein the solid-liquid mass ratio is 0.295:1, stir at a speed of 120r / min, and cool to -10°C while stirring to obtain a mixed solution A, dissolve tert-butyl bromoacetate in N,N-dimethylformamide, the mass ratio of the two is 1.82:1, to obtain a mixed solution B, and drop the mixed solution B into the mixed solution A, the volume ratio of the mixed solution A to the mixed solution B is 4:1, after the dropwise addition is completed, the temperature is raised to 30°C, and the reaction is carried out at a constant temperature overnight. After the reaction is completed, purified water is added, centrifuged and filtered, the filter cake is collected, the filter cake is washed with water again, and the filter cake is transferred to a vacuum oven for drying to obtain a white solid 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tri-tert-butyl ester, which is Figure 1 Intermediate product 2;

[0008] S2: Add acetonitrile to the reactor, add product 2 and anhydrous potassium carbonate in a mass ratio of 1:0.27 to the acetonitrile, wherein the solid-liquid mass ratio is 0.127:1, stir at a speed of 120r / min, cool to -10°C while stirring to obtain a mixed solution C, add ethyl bromoacetate dropwise to the mixed solution C, the volume ratio of the mixed solution C to ethyl bromoacetate is 1:0.0237, after the addition is complete, heat to 30°C, and react at a constant temperature for 48 hours. After the reaction is complete, filter and collect the filtrate, and concentrate the filtrate under reduced pressure under vacuum to obtain brown oily 2,2,2-(10-(2-ethoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate tri-tert-butyl ester, Figure 1 Intermediate product 3;

[0009] S3: Add methanol and purified water in a volume ratio of 1:1 to the reactor, then add product 3, with a solid-liquid mass ratio of 1:10, and stir until completely dissolved to obtain a mixed solution D. Add a concentration of 1 mol / L sodium hydroxide solution, the dropping rate is 1s / drop, the volume ratio of the mixed solution D and the sodium hydroxide solution is 4:1, after the dropwise addition is completed, the temperature is raised to 80℃ for reaction for 8h, after the reaction is completed, 2mol / L hydrochloric acid is added dropwise to adjust the pH value of the mixed solution to 8, the dropping rate is 2s / drop, and the brown-yellow viscous substance E is obtained by reduced pressure concentration. The brown-yellow viscous substance E is dissolved in pure water at room temperature, wherein the mass ratio of the brown-yellow viscous substance E to pure water is 1.6:1, and after stirring until completely dissolved, a mixed solution F is obtained, the temperature is cooled to 0℃ in an ice bath, and the pH value of the mixed solution F is adjusted to 3 with 2mol / L hydrochloric acid, stirred for crystallization for 2h, filtered, the filter cake is collected, washed with ice water, and then transferred to a vacuum state for drying to obtain a white solid 2-(4,7,10-tri(2-tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-ylacetic acid hydrochloride, which is Figure 1 Intermediate product 4;

[0010] S4: Add tetrahydrofuran, product 4, pyridine, and p-nitrophenol to the reactor in a mass ratio of 30:3:2:1, stir until completely dissolved to obtain a mixed solution G, and then add N,N'-diisopropylcarbodiimide dropwise, the volume ratio of the mixed solution G and N,N'-diisopropylcarbodiimide is 34.5:1. After the addition is complete, the temperature is raised to 30°C and the reaction is kept at this temperature for 12 hours. After the reaction is completed, filter and collect the filter cake, add methyl tert-butyl ether to the filter cake for pulping treatment, wherein the solid-liquid mass ratio of the filter cake to methyl tert-butyl ether is 1:4, collect the pulped filter cake, put it into a vacuum drying oven at 20°C and dry it for 24 hours to obtain a white solid 2,2,2-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate tri-tert-butyl ester, which is Figure 1 Intermediate product 5;

[0011] S5: The obtained product 5 is placed in a round-bottom flask, cooled to -10°C, and 6 mol / L hydrochloric acid solution is added dropwise while stirring, with a solid-liquid ratio (g / ml) of 1:2. After the addition is completed, the temperature is raised to 30°C and stirred for 12 hours. After the reaction is completed, acetone is added for pulping, with a volume ratio of acetone to hydrochloric acid solution of 1:0.4. The product is filtered, the filter cake is collected, and dried under vacuum to obtain a white solid 2,2,2-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid hydrochloride dry product, i.e., DOTA-PNP.

[0012] Furthermore, the rate at which the mixed solution B in S1 is dripped into the mixed solution A is 1 s / drop.

[0013] Furthermore, the drying parameters in the vacuum box in S1 are a drying temperature of 60° C. and a vacuum degree of 0.01 MPa.

[0014] Furthermore, the rate of adding ethyl bromoacetate to the mixed solution C in S2 is 1 s / drop.

[0015] Furthermore, the parameters of the reduced pressure concentration in S2 are a temperature of 30° C. and a vacuum degree of 30 mbar.

[0016] Furthermore, the parameters of the reduced pressure concentration in S3 are a temperature of 40° C. and a vacuum degree of 30 mbar.

[0017] Furthermore, the dropping rate of N,N'-diisopropylcarbodiimide in S4 is 1 s / drop.

[0018] Furthermore, the methyl tert-butyl ether pulping treatment parameters in S4 are a rotation speed of 300 r / min and a duration of 2 h.

[0019] Furthermore, the acetone beating parameters in S5 are a rotation speed of 200 r / min and a duration of 6 hours.

[0020] Furthermore, the vacuum drying parameters in S5 are a drying temperature of 40° C. and a vacuum degree of 0.01 MPa.

[0021] Beneficial effects of the present invention:

[0022] The present invention makes adjustments in the process route and post-treatment. The new method uses cheap cyclopentane as a starting material, reacts with tert-butyl bromoacetate to generate a trisubstituted product, further replaces with ethyl bromoacetate to obtain a tetrasubstituted product, further hydrolyzes the ethyl ester to obtain a substituted carboxylic acid, then condenses with p-nitrophenol, and finally removes the tert-butyl group to obtain the target product.

[0023] Under acidic catalysis, the hydrogen on the nitrogen atom of cyclopentane is replaced by the acetyl group of tert-butyl bromoacetate to form a tert-butyl ester derivative. The tert-butyl ester group in product 2 is replaced by the acetyl group of ethyl bromoacetate to form a new ester compound, and the tert-butyl ester group in product 3 is hydrolyzed under alkaline conditions to form a carboxylate. Then, by adding hydrochloric acid to adjust the pH value, the carboxylate is converted back into a carboxylic acid and a hydrochloride is generated. The carboxylic acid group in product 4 and the hydroxyl group of p-nitrophenol react with N,N'-diisopropylcarbodiimide (DIC) under the catalysis of pyridine to form an amide bond. In this process, tetrahydrofuran acts as a solvent to facilitate the reaction. Pyridine acts as a base to accept the acid produced in the reaction and push the reaction equilibrium toward the direction of amide formation. The tert-butyl group in product 5 is removed under acidic conditions to form a carboxyl group. Then, the final DOTA-PNP product is obtained by adding acetone for pulping and filtering and drying. In this process, hydrochloric acid plays a role in deprotection, while acetone is used to wash and purify the product.

[0024] To facilitate the later process production, the present invention specifically studies the post-processing and refining of each step of the reaction. After optimization, the present invention has simple reaction and post-processing in each step, does not require purification means such as column chromatography, and has a moderate yield. Secondly, a new DOTA-PNP synthesis and refining process is explored and developed in detail, and industrial production can be carried out. The DOTA-PNP amplified according to this method can be used as a starting material for process production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to facilitate understanding by those skilled in the art, the present invention is further described below with reference to the accompanying drawings.

[0026] Figure 1 The synthetic route for preparing DOTA-PNP of the present invention;

[0027] Figure 2 Prior art Synthesis route of DOTA-PNP. DETAILED DESCRIPTION

[0028] In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the specific implementation methods, structures, features and effects of the present invention are described in detail below in conjunction with the accompanying drawings and preferred embodiments.

[0029] Example 1

[0030] S1: Add 20L of N,N-dimethylformamide to the reactor, then add 2.00kg of cyclopentane, 3.8kg of anhydrous sodium acetate and 100g of tetrabutylammonium iodide, stir at a speed of 120r / min, and cool to -10°C while stirring to obtain a mixed solution A. Dissolve 9.1kg of tert-butyl bromoacetate in 5L of N,N-dimethylformamide to obtain a mixed solution B. Add the mixed solution B dropwise into the mixed solution A at a rate of 1:1. The reaction temperature was 1s / drop, the volume ratio of mixed solution A to mixed solution B was 4:1, and the temperature was raised to 30°C after the addition was completed. The reaction was kept at a constant temperature overnight. After the reaction was completed, purified water was added, centrifuged and filtered, the filter cake was collected, and the filter cake was washed with water again. The filter cake was transferred to a vacuum box for drying. The drying parameters were a drying temperature of 60°C and a vacuum degree of 0.01Mpa. 3.0kg of white solid 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tri-tert-butyl ester was obtained. Figure 1 Middle product 2, product 2 yield 50.20%, MS-ESI=515, [M+H]+;

[0031] S2: Add 10L acetonitrile to the reactor, add 1.0kg of product 2 and 270g of anhydrous potassium carbonate to the acetonitrile, stir at a speed of 120r / min, cool to -10°C while stirring to obtain a mixed solution C, add 357g of ethyl bromoacetate dropwise to the mixed solution C, the dropping rate of ethyl bromoacetate is 1s / drop, the temperature is raised to 30°C after the dropwise addition is completed, and the reaction is carried out at a constant temperature for 48h. After the reaction is completed, filter and collect the filtrate, and concentrate the filtrate under reduced pressure under vacuum. The parameters for reduced pressure concentration are temperature 30°C and vacuum degree 30mbar to obtain 1.1kg of brown oily 2,2,2-(10-(2-ethoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, which is Figure 1 The product 3, the yield of product 3 is 94.26%, MS-ESI=601, [M+H]+;

[0032] S3: Add 10 L of methanol and 10 L of purified water in a volume ratio to the reactor, then add 2.0 kg of product 3, stir until completely dissolved, and obtain a mixed solution D. Add 5 L of 1% mol / L sodium hydroxide solution, the dropping rate is 1s / drop, after the dropping is completed, the temperature is raised to 80℃ and the reaction is carried out for 8h, after the reaction is completed, 2mol / L hydrochloric acid is added dropwise to adjust the pH value of the mixed solution to 8, the dropping rate is 2s / drop, and the mixture is concentrated under reduced pressure to obtain 1.6kg of brown-yellow viscous substance E. The parameters for the reduced pressure concentration are temperature 40℃ and vacuum degree 30mbar. At room temperature, 1.6kg of brown-yellow viscous substance E is dissolved in 1L of pure water and stirred until completely dissolved to obtain a mixed solution F, which is cooled to 0℃ in an ice bath, and the pH value of the mixed solution F is adjusted to 3 with 2mol / L hydrochloric acid, stirred and crystallized for 2 hours, filtered, the filter cake is collected, washed with ice water, and then transferred to a vacuum state and dried to obtain 950g of white solid 2-(4,7,10-tri(2-tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl acetic acid hydrochloride, which is Figure 1 The product 4 had a yield of 49.84%, MS-ESI=573, [M+H]+;

[0033] S4: Add 10L tetrahydrofuran, 950g product 4, 0.67L pyridine, and 297g p-nitrophenol to the reactor, stir until completely dissolved to obtain a mixed solution G, and then add 0.31L N,N'-diisopropylcarbodiimide dropwise at a drop rate of 1s / drop. After the dropwise addition is completed, the temperature is raised to 30°C and the reaction is carried out at a constant temperature for 12h. After the reaction is completed, filter and collect the filter cake. Add 5L methyl tert-butyl ether to the filter cake for pulping treatment. The pulping treatment parameters are a speed of 300r / min and a duration of 2h. Collect the pulped filter cake and put it into a vacuum drying oven at 20°C for drying for 24 hours to obtain 924g of white solid 2,2,2-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate tri-tert-butyl ester, which is Figure 1 The product 5 had a yield of 80.34%, MS-ESI=694, [M+H]+;

[0034] S5: 200 g of the obtained product 5 was placed in a round-bottom flask, cooled to -10°C, and 400 mL of a 6 mol / L hydrochloric acid solution was added dropwise while stirring. After the addition was completed, the temperature was raised to 30°C and stirred for 12 h. After the reaction was completed, 1 L of acetone was added for pulping treatment. The pulping parameters were a speed of 200 r / min and a duration of 6 h. The filter cake was collected and dried under vacuum. The vacuum drying parameters were a drying temperature of 40°C and a vacuum degree of 0.01 MPa. 105 g of a white solid 2,2,2-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid hydrochloride dry product, i.e., DOTA-PNP, was obtained. The yield was 69.53%, and MS-ESI=525, [M+H]+.

[0035] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technical personnel in this field can make some changes or modify the technical contents disclosed above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for preparing DOTA-PNP, characterized in that: The specific preparation process is as follows: S1: Add N,N-dimethylformamide to the reactor, then add cyclopentane, anhydrous sodium acetate and tetrabutylammonium iodide in a mass ratio of 20:38:1, wherein the solid-liquid mass ratio is 0.295:1, stir at a speed of 120r / min, cool to -10°C while stirring, obtain mixed solution A, dissolve tert-butyl bromoacetate in N,N-dimethylformamide, the mass ratio of the two is 1.82:1, obtain mixed solution B, drop mixed solution B into mixed solution A, the volume ratio of mixed solution A to mixed solution B is 4:1, after the dropwise addition is completed, heat to 30°C, react at constant temperature overnight, after the reaction is completed, add purified water, centrifuge and filter, collect filter cake, wash the filter cake with water again, transfer the filter cake to a vacuum oven for drying, and obtain white solid 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid tri-tert-butyl ester, which is product 2 in Figure 1; S2: Add acetonitrile to the reactor, add product 2 and anhydrous potassium carbonate in a mass ratio of 1:0.27 to acetonitrile, wherein the solid-liquid mass ratio is 0.127:1, stir at a speed of 120r / min, cool to -10°C while stirring, obtain mixed solution C, add ethyl bromoacetate dropwise to the mixed solution C, the volume ratio of the mixed solution C to ethyl bromoacetate is 1:0.0237, raise the temperature to 30°C after the addition is complete, and react at a constant temperature for 48h. After the reaction is complete, filter and collect the filtrate, and concentrate the filtrate under reduced pressure under vacuum to obtain brown oily 2,2,2-(10-(2-ethoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, which is product 3 in Figure 1; S3: Add methanol and purified water in a volume ratio of 1:1 to the reactor, then add product 3, the solid-liquid mass ratio is 1:10, stir until completely dissolved to obtain a mixed solution D, add a 1 mol / L sodium hydroxide solution to the mixed solution D, the drop rate is 1s / drop, the volume ratio of the mixed solution D to the sodium hydroxide solution is 4:1, after the drop addition is completed, heat to 80℃ and react for 8h, after the reaction is completed, add 2 mol / L hydrochloric acid to adjust the pH value of the mixed solution to 8, the drop rate is 2s / drop, and reduce the pressure to concentrate to obtain a brown-yellow viscous substance E, which is heated to 80℃ and reacted for 8h. The brown-yellow viscous substance E was dissolved in pure water, wherein the mass ratio of the brown-yellow viscous substance E to pure water was 1.6:1, and after stirring until completely dissolved, a mixed solution F was obtained, which was cooled to 0°C in an ice bath, and then the pH value of the mixed solution F was adjusted to 3 with 2 mol / L hydrochloric acid, and stirred for crystallization for 2 hours, filtered, and the filter cake was collected, washed with ice water, and then transferred to a vacuum state and dried to obtain a white solid 2-(4,7,10-tri(2-tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl acetic acid hydrochloride, which is product 4 in Figure 1; S4: tetrahydrofuran, product 4, pyridine, and p-nitrophenol were added to the reactor in a mass ratio of 30:3:2:1, and stirred until completely dissolved to obtain a mixed solution G, and then N,N'-diisopropylcarbodiimide was added dropwise, and the volume ratio of the mixed solution G to N,N'-diisopropylcarbodiimide was 34.5:

1. After the addition was completed, the temperature was raised to 30°C and reacted at a constant temperature for 12 hours. After the reaction was completed, it was filtered and the filter cake was collected. The filter cake was added to methyl tert-butyl ether for pulping treatment, wherein the solid-liquid mass ratio of the filter cake to methyl tert-butyl ether was 1:

4. The filter cake after pulping treatment was collected and placed in a vacuum drying oven at 20°C for drying for 24 hours to obtain a white solid 2,2,2-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate tri-tert-butyl ester, which is product 5 in Figure 1; S5: The obtained product 5 is placed in a round-bottom flask, cooled to -10°C, and 6 mol / L hydrochloric acid solution is added dropwise while stirring, with a solid-liquid ratio (g / ml) of 1:

2. After the addition is completed, the temperature is raised to 30°C and stirred for 12 hours. After the reaction is completed, acetone is added for pulping, with a volume ratio of acetone to hydrochloric acid solution of 1:0.

4. The product is filtered, the filter cake is collected, and dried under vacuum to obtain a white solid 2,2,2-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid hydrochloride dry product, i.e., DOTA-PNP.

2. A method for preparing DOTA-PNP according to claim 1, characterized in that, The rate of dripping the mixed solution B into the mixed solution A in S1 is 1 s / drop.

3. A method for preparing DOTA-PNP according to claim 1, characterized in that, The drying parameters in the vacuum box in S1 are a drying temperature of 60° C. and a vacuum degree of 0.01 MPa.

4. A method for preparing DOTA-PNP according to claim 1, characterized in that, The rate of adding ethyl bromoacetate to the mixed solution C in S2 is 1 s / drop.

5. A method for preparing DOTA-PNP according to claim 1, characterized in that, The parameters of the reduced pressure concentration in S2 are a temperature of 30° C. and a vacuum degree of 30 mbar.

6. The method for preparing DOTA-PNP according to claim 1, wherein: The parameters for the reduced pressure concentration in S3 are a temperature of 40° C. and a vacuum degree of 30 mbar.

7. A method for preparing DOTA-PNP according to claim 1, characterized in that, The dropping rate of N,N'-diisopropylcarbodiimide in S4 is 1 s / drop.

8. A method for preparing DOTA-PNP according to claim 1, characterized in that, The methyl tert-butyl ether pulping treatment parameters in S4 are a rotation speed of 300 r / min and a duration of 2 h.

9. A method for preparing DOTA-PNP according to claim 1, characterized in that, The acetone beating parameters in S5 are a rotation speed of 200 r / min and a duration of 6 h.

10. The method for preparing DOTA-PNP according to claim 1, characterized in that: The vacuum drying parameters in S5 are a drying temperature of 40° C. and a vacuum degree of 0.01 MPa.

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