Preparation method of calcobutrol and intermediate thereof

Abstract

The invention discloses a preparation method of combbutrol calcium and an intermediate thereof, and relates to the technical field of medicines. Comprising the following steps: dissolving a compound 2 in water, carrying out reduced pressure distillation, and stopping distillation until the pH value of a residue is 5.5-6.5; mixing the residues with water, adding cationic resin, stirring, filtering, and collecting mother liquor to obtain a solution containing a compound 3; and mixing the solution containing the compound 3 with calcium carbonate, reacting, cooling, carrying out reduced pressure distillation, adding a solvent into residues, carrying out heat preservation, cooling and separation to obtain a precipitate, and drying to obtain the combbutrol calcium. According to the method disclosed by the invention, few solid wastes are generated, the intermediate butoxide ammonium salt is free to the combbutrol calcium, and the method can be prepared by a one-pot method, so that the cost is reduced, the process is simplified, and the yield and the purity are high.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a preparation method of calcobutrol and its intermediates. Background Art

[0002] Calcium scobutrol is one of the excipients of gadobutrol. It is a calcium coordination compound composed of calcium and the macrocyclic ligand dihydroxy-hydroxy-methylpropyl-tetraazacyclododecane-triacetic acid (butrol). It can solve the problem of free gadolinium release in gadobutrol preparations, thereby effectively solving the toxicity problem of gadolinium ions in the preparations.

[0003] Chinese patent CN113272284A discloses a method for producing butol by a simple production method, then producing high-purity butol by a purification process, and then using the high-purity butol to produce high-purity calcobutrol. The method comprises: a first step: reacting cyclopentane (1,4,7,10-tetraazacyclododecane) with 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane to obtain 3-(1,4,7,10-tetraazacyclododecane-1-yl)butane-1,2,4-triol, and then reacting it with haloacetic acid to produce crude butol; a second step: using an ion exchange resin to preliminarily purify the crude butol; and a third step: performing secondary purification on the preliminarily purified crude butol by crystallization. The method requires first adsorbing butol with a cationic resin column, eluting with a large amount of ammonia water, then freeing with a cationic resin, then dissolving butol to precipitate, and adding calcium carbonate for complexation to obtain calcobutrol. The above process uses a large amount of cationic resin, which is costly and the purification process is complicated.

[0004] Chinese patent CN114573522A discloses a new crystal form of Calcobutrol and a preparation method thereof, comprising the steps of: adding 3600g of purified water, 1200g of gadobutrol and 475g of oxalic acid dihydrate to a reaction bottle. React at 90°C; filter after the reaction, slowly add 285g of sodium hydroxide to the filtrate, filter by suction, and transfer the filtrate to a reaction bottle. Add 9800g of anhydrous ethanol at 85°C and filter by suction; concentrate the filtrate under reduced pressure, add 520g of purified water and 1600g of anhydrous ethanol, beat, and then transfer the feed liquid to the reaction bottle and stir evenly at 85°C, and add 3600g of ethanol by suction. Filter by suction, dry, and obtain 750g of ligand sodium salt with a molar yield of 75.4%. This method involves nanofiltration to remove sodium chloride, which is difficult to achieve large-scale production and has high cost.

[0005] Chinese patent CN109803958A discloses a method for producing a crystalline form of modification A of calcobutrol calcium, which comprises decomplexing a gadolinium complex of dihydroxy-hydroxy-methylpropyl-tetraazacyclododecane-triacetic acid (gadobutrol), removing the precipitated gadolinium salt, and then binding the solution containing the free ligand to an acidic ion exchanger, eluting it with an alkaline aqueous solution, and then complexing it with calcium ions, crystallizing it from an ethanol aqueous solution, and then drying and separating the product. Gadobutrol is first decomplexed to remove gadolinium, and then purified by an ion exchange column, which is a cumbersome process and high cost.

[0006] In view of this, the present invention provides a preparation method of a calcobutrol intermediate and calcobutrol with low cost, simple process, high yield and high purity. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing calcobutrol and its intermediates, which avoids the use of high-value gadobutrol as a raw material, avoids the use of ion exchange columns and a large amount of ion exchange resins, has high yield and less solid waste, and can prepare the process of freeing the intermediate butrol ammonium salt to calcobutrol through a one-pot method, does not need to obtain butrol solid in the middle, reduces costs, simplifies the process, and has high yield and purity.

[0008] To achieve the above-mentioned purpose of the invention, the technical solution of the present invention is as follows: In one aspect, the present invention provides a method for preparing calcobutrol, comprising the following steps:

[0009] (1) Compound 2 was dissolved in water and distilled under reduced pressure until the pH of the residue was 5.5-6.5, and then distillation was stopped to obtain residue 1; (2) mixing the residue 1 obtained in step (1) with water, adding a cationic resin, stirring, filtering, and collecting the mother liquor to obtain a solution containing compound 3 (butanol solution); (3) mixing the solution containing compound 3 obtained in step (2) with calcium carbonate, reacting, cooling, and distilling under reduced pressure to collect the residue 2; (4) heating the residue 2 obtained in step (3), adding a solvent, maintaining the temperature, cooling, separating to obtain a precipitate, and drying the precipitate to obtain calcobutrol calcium. The purity of compound 2 is ≥99.0%, preferably ≥99.5%.

[0010] Preferably, in step (1), the mass ratio of the compound 2 to water is 1:4-8, more preferably 1:6.

[0011] Preferably, in step (1), the conditions for the reduced pressure distillation are: temperature ≤50°C, vacuum degree -0.08 to -0.1 MPa.

[0012] Preferably, in step (1), the pH value of the residue is 6.

[0013] Preferably, in step (2), the mass ratio of the water to the compound 2 in step (1) is 1-3:1, more preferably 2:1.

[0014] Preferably, in step (2), the cationic resin is selected from at least one of Amberlite IR120H, FPC22, FPC11, FPC23UPS, and CR99K / 310, and most preferably Amberlite IR120.

[0015] Preferably, the mass ratio of the cationic resin in step (2) to the compound 2 in step (1) is 5-15:5-15, and more preferably 7.1:10.

[0016] Preferably, in step (2), the cationic resin is added in batches, with the mass ratio of the first three additions being 3:3:1, and the amount added each time thereafter being 1% of the mass of compound 2 until the pH is ≤3.8.

[0017] Preferably, in step (2), in order to ensure complete collection, the filtering further comprises the step of: rinsing with water.

[0018] Preferably, the mass ratio of the calcium carbonate in step (3) to the compound 2 in step (1) is 1-3:10, more preferably 1.9:10.

[0019] Preferably, in step (3), the reaction condition is 80-90°C for 1-2h, more preferably 85°C for 1.5h.

[0020] Preferably, in step (3), the cooling refers to cooling to ≤50°C.

[0021] Preferably, in step (3), the conditions for the reduced pressure distillation are: temperature ≤ 50°C, vacuum degree -0.08 to -0.1 MPa.

[0022] Preferably, in step (3), the distillation is stopped when the mass of the distilled fraction is 14-19 times the mass of calcium carbonate; further preferably, the distillation is stopped when the ratio of the mass of the distilled fraction to the mass of calcium carbonate is 30:1.9.

[0023] Preferably, in step (4), the heating temperature is 65-85°C, more preferably 75°C.

[0024] Preferably, in step (4), the solvent is at least one of anhydrous ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and methanol, and more preferably anhydrous ethanol.

[0025] More preferably, the mass ratio of the anhydrous ethanol in step (4) to the compound 2 in step (1) is 10:70-90, and more preferably 10:80.

[0026] Preferably, in step (4), the insulation condition is: insulation at 65-85°C for 0.5-1.5h, more preferably: insulation at 70-80°C for 1h.

[0027] Preferably, in step (4), the cooling refers to cooling to 18-20°C.

[0028] Preferably, in step (4), the separation is specifically: centrifugation, eluting with ethanol to obtain a wet filter cake.

[0029] Preferably, in step (4), the drying is specifically: forced air drying at 45-60°C for 14-20 hours, more preferably forced air drying at 50°C for 16 hours.

[0030] On the other hand, the present invention provides a method for preparing a calcium calcobutrol intermediate (Compound 2), comprising the following steps:

[0031] (1) Compound 1, acid and water are mixed, heated to reflux, reacted to obtain a mixture 1, ammonia water, methanol and ethanol are added to the mixture 1 in sequence, stirred until cloudy, stirred at 15-25°C for 20-24 hours, separated and dried to obtain a crude compound 2; (2) Dissolve the crude compound 2 obtained in step (1) in a solvent, add methanol and ethanol in sequence, stir until it becomes turbid, continue stirring at 15-25° C. for 20-24 hours, separate and dry to obtain the calcobutrol intermediate with a purity of ≥99.5%. in, In step (1), the mass ratio of compound 1, aqueous ammonia, methanol and ethanol is 15-19:10-15:80-90:250-260, preferably 17:11.8:85:255; In step (2), the mass ratio of the crude compound 2, the solvent, methanol and ethanol is 12-14:30-40:50-65:160-180, and more preferably 13.5:34.5:57.5:172.5.

[0032] Preferably, in step (1), the acid is selected from hydrochloric acid, and more preferably hydrochloric acid with a mass concentration of 37%.

[0033] Preferably, in step (1), the mass ratio of the compound 1, the acid and water is 15-20:5-8:40-50, and more preferably 17:7.64:44.5.

[0034] Preferably, in step (1), the reaction is carried out under nitrogen protection for 1-3 hours; more preferably, the reaction time is 2 hours.

[0035] Preferably, in step (1), the volume concentration of the ammonia water is 26%.

[0036] Preferably, in step (1), the sequential addition of ammonia water, methanol and ethanol is specifically as follows: Add aqueous ammonia dropwise, control the temperature not to exceed 25°C, and complete the addition in 1.0-2.0 hours. After the addition is completed, stir at 15-25°C for 10-20 minutes. Add methanol all at once, and then add ethanol dropwise, and complete the addition in 1.5-3.5 hours.

[0037] Preferably, in step (2), the solvent is selected from at least one of water, DMSO and DMF, more preferably water.

[0038] Preferably, in step (2), the sequential addition of methanol and ethanol is specifically: methanol is added all at once, and then ethanol is added dropwise, and the addition is completed over 1.5-3.5 hours.

[0039] Preferably, in step (2), the separation and drying is specifically: centrifuging to dryness, and drying the wet filter cake with air at 45-65° C. for 14-20 hours. More preferably, centrifuging to dryness, and drying the wet filter cake with air at 50° C. for 16 hours.

[0040] The beneficial effects of the present invention are: (1) The present invention uses high-purity butrol ammonium salt to prepare butrol after being freed, and defines specific process conditions, thereby achieving the one-pot method for preparing butrol calcium without separation, simplifying the process and facilitating industrial production.

[0041] (2) The synthesis method of the present invention is easy to purify and only requires a small amount of resin to complete the purification, which saves costs, has high product yield and purity, and reduces solid waste.

[0042] (3) By selecting a specific crystallization solvent (a mixture of methanol and ethanol in a specific ratio) and the amount of ammonia water used, the preparation of high-purity butrol ammonium salt was achieved, which was used to further prepare calcobutrol calcium. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the spectrum of the crude product of compound 2 of the present invention; Figure 2 This is a fine spectrum of compound 2 of the present invention; Figure 3 This is the NMR spectrum of compound 2 of the present invention; Figure 4 The map of calcobutrol prepared by the present invention; Figure 1 , Figure 2 , Figure 4 In the figure, “CAD” represents the peak of the target compound. DETAILED DESCRIPTION

[0044] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present application.

[0045] The present invention is further described below by way of specific embodiments. The various chemical reagents used in the embodiments of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all mass contents. Unless otherwise specified, it is understood that it is carried out at room temperature. In the present invention, the water used can be selected from purified water, ultrapure water, distilled water, drinking water, etc., and as specific embodiments of the present invention, purified water is used.

[0046] In the following examples, the mass concentration of the hydrochloric acid used is 37%, the volume concentration of the ammonia water used is 26%, and the cationic resin used is a hydrogen type purchased from Shanghai Titan Technology Co., Ltd., model Amberlite IR120.

[0047] Example 1 Preparation of Compound 2

[0048] (1) Add 37% hydrochloric acid (7.64 kg) (75 mol) and purified water (44.5 kg) to a 100 L reactor and mix well; add compound 1 (17.0 kg), start condensation circulating water, start stirring, and protect with nitrogen; open the steam valve, raise the temperature to reflux, and keep the temperature for reaction for 2 hours; turn off the steam and cool to 10°C; add ammonia water (26%, 11.8 kg) dropwise, control the temperature not to exceed 25°C, and add the solution dropwise over 1.0-2.0 hours. After the addition is completed, stir at 15-25°C for 15 minutes, transfer the feed liquid to a 500 L reactor, and add methanol (85.0 kg) at one time. Ethanol (255.0 kg) was added dropwise, and the dripping was completed in about 2-3 hours. After the dripping was completed, it was stirred for about 1 hour and then began to become turbid. Stirring was continued at 15-25°C for 20-24 hours. The bottom valve of the kettle was connected to the centrifuge and centrifuged until dry to obtain the crude product of butanol ammonium salt (Compound 2) (13.5 kg), with an HPLC purity of 98.45%. The crude product of Compound 2 is shown in the following figure: Figure 1 , in the figure, the specific data of the peak is as follows: Table 1

[0049] (2) The crude butrol ammonium salt was returned to the 500L reactor, purified water (34.5kg) was added, stirred and dissolved, methanol (57.5kg) was added at once, and ethanol (172.5kg) was added dropwise, and the mixture was dripped in about 2-3 hours. After the dripping was completed, the mixture was stirred for about 1 hour and began to become turbid. The mixture was stirred at 20°C for 22 hours, and the bottom valve of the reactor was connected to the centrifuge and centrifuged to dryness. The wet cake was dried at 50°C with forced air for 16 hours and weighed to obtain 10.5kg of the fine butrol ammonium salt (Compound 2), with a yield of 81% and a HPLC purity of 99.71%.

[0050] 1H NMR (400 MHz, D2O) δ2.28-3.09 (m, 16H), 3.33-3.53 (m, 8H), 3.67-3.70 (m, 4H).

[0051] LC_MS: (ES+): m / z 451.85[M+H] +. tR = 0.590min.

[0052] The exquisite spectrum of compound 2 is as follows Figure 2 , Figure 3 , in the figure, the peak results are as follows: Table 2

[0053] Example 2 Preparation of Calcobutrol

[0054] (1) Purified water (60 kg) and butrol ammonium salt (compound 2) (10.0 kg) were added to a 100 L reactor, and the mixture was stirred to dissolve. The pH value was detected to be 8-9, and the mixture was distilled under reduced pressure (temperature ≤ 50 °C, vacuum degree -0.08 to -0.1 MPa). After collecting 45 kg of the fraction, the distillation was stopped and the pH value of the residue was detected to be 6.

[0055] (2) Dilute the collected residue with 20 kg of water, add cationic resin (3.0 kg + 3.0 kg + 1 kg) in batches, stir for 10 minutes, detect the pH of the supernatant at 4.1, add 0.1 kg of cationic resin again, stir for 10 minutes, detect the pH of the supernatant at 3.8, filter, rinse the kettle wall and the filter cake with purified water (10 kg), and collect 51.2 kg of mother liquor, which is the butanol solution.

[0056] (3) Pour the butanol solution into a 200 L reactor, start stirring, add 1.9 kg of calcium carbonate, heat to 85°C, and react for 1.5 hours. Cool down, perform vacuum distillation, collect 30 kg of fractions, and then stop distillation.

[0057] (4) The collected fractions were heated to 75°C, and anhydrous ethanol (80 kg) was added dropwise at a temperature of 70-80°C. After the addition, solids were precipitated. After the temperature was kept at this temperature for 1 hour, the temperature was lowered to 18-20°C, centrifuged, and rinsed with ethanol (5 kg). The wet filter cake was dried at 50°C for 16 hours to obtain 8.7 kg of the product with a yield of 89% and a HPLC purity of 99.72%.

[0058] (5) Characterization data: 1H NMR (400 MHz, D2O) δ2.12-2.34 (m, 4H), 2.62-2.80 (m,4H), 3.04-3.31 (m, 9H), 3.40-3.55 (m, 5H), 3.63-3.80 (m, 5H), 3.86-4.06 (m,1H). LC_MS: (ES+): m / z 489.60[M+H] +. tR = 0.648min.

[0059] Calcium calcobutrol Figure 4 , in the figure, the peak results are as follows: Table 3

[0060] Example 3 Preparation of Compound 2 The difference from Example 1 is that in step (1), 90 kg of methanol is added at one time and 250 kg of ethanol is added dropwise, and the other conditions are the same.

[0061] Example 4 Preparation of Compound 2 The difference from Example 1 is that in step (1), 80 kg of methanol is added at one time and 260 kg of ethanol is added dropwise, and the other conditions are the same.

[0062] Example 5 Preparation of Compound 2 The difference from Example 1 is that in step (2), 50 kg of methanol is added and 180 kg of ethanol is added dropwise, and the other conditions are the same.

[0063] Example 6 Preparation of Compound 2 The difference from Example 1 is that in step (2), 65 kg of methanol is added and 160 kg of ethanol is added dropwise, and the other conditions are the same.

[0064] Example 7 Preparation of Compound 2 The difference from Example 1 is that in step (2), 15 kg of aqueous ammonia is added, and the other conditions are the same.

[0065] Example 8 Compound 2 prepared by the method of Example 1 was used as a raw material to further prepare calcobutrol. The difference from Example 2 was that in step (3), the distillation was stopped after collecting 35 kg of the fraction, and the rest was the same.

[0066] Comparative Example 1 Preparation of Compound 2 The difference from Example 1 is that in step (1), 100 kg of methanol is added at one time and 240 kg of ethanol is added dropwise, and the other conditions are the same.

[0067] Comparative Example 2 Preparation of Compound 2 The difference from Example 1 is that in step (1), 255 kg of methanol is added at one time and 85 kg of ethanol is added dropwise, and the other conditions are the same.

[0068] Comparative Example 3 Preparation of Compound 2 The difference from Example 1 is that in step (2), 20 kg of aqueous ammonia is added, and the other conditions are the same.

[0069] According to the same method as in Example 2, compound 2 prepared in Example 3 to Example 7 and Comparative Example 1 to Comparative Example 3 was used in sequence to prepare calcobutrol.

[0070] The calculation formula of the yield of compound 2 is: the amount of compound 2 / (501.58÷658.88×the amount of compound 1 fed)×100%; The calculation formula of the yield of calcobutrol is: (calcobutrol yield / theoretical amount) × 100%; Wherein, theoretical amount = 0.975 × amount of compound 2 fed.

[0071] Purity detection method: HPLC.

[0072] The results are as follows: Table 4

[0073] Comparative Example 4 Referring to the preparation method of Example 2, the compound 2 with a purity of 89.2% was used for preparation, and the rest were the same.

[0074] Comparative Example 5 Compound 2 prepared by the method of Example 1 was used as a raw material to further prepare calcobutrol. The difference from Example 2 was that in step (1), the distillation was stopped when the pH of the residue was detected to be 7. The rest was the same.

[0075] Comparative Example 6 Compound 2 prepared by the method of Example 1 was used as a raw material to further prepare calcobutrol. The difference from Example 2 was that in step (2), the amount of cationic resin added in the first three times was 12 kg + 12 kg + 10 kg, and the rest was the same.

[0076] The results are as follows: Table 5

[0077] The results show that the purity of compound 2 has a significant effect on the purity and yield of the subsequent calcobutrol product; and the control of the pH value of the residue in step (1) and the amount of cationic resin added in the first three times in step (2) have a significant effect on the yield of the calcobutrol product.

[0078] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing calcobutrol, characterized in that: The following steps are involved: (1) Compound 2 was dissolved in water and distilled under reduced pressure until the pH of the residue was 5.5-6.5 and then distillation was stopped to obtain residue 1; (2) mixing the residue 1 obtained in step (1) with water, adding a cationic resin, stirring, filtering, and collecting the mother liquor to obtain a solution containing compound 3; (3) mixing the solution containing compound 3 obtained in step (2) with calcium carbonate, reacting, cooling, and distilling under reduced pressure to collect the residue 2; (4) heating the residue 2 obtained in step (3), adding a solvent, maintaining the temperature, cooling, separating to obtain a precipitate, and drying the precipitate to obtain calcobutrol calcium. Wherein, the purity of compound 2 is ≥99.0%.

2. The preparation method according to claim 1, characterized in that: In step (1), the mass ratio of the compound 2 to water is 1:4-8; In step (2), the mass ratio of the residue 1 to water is 2-3:1-4; the mass ratio of the cationic resin to the compound 2 in step (1) is 5-15:5-15, and the cationic resin is added in batches, the mass ratio of the first three additions is 3:3:1, and the amount of each subsequent addition is 1% of the mass of the compound 2 until the pH is ≤3.

8.

3. The preparation method according to claim 1, characterized in that: In step (2), after filtering, the method further comprises the step of rinsing with water.

4. The preparation method according to claim 1, characterized in that: In step (3), the mass ratio of calcium carbonate to compound 2 in step (1) is 1-3:10; the reaction conditions are 80-90° C. for 1-2 hours; and the distillation is stopped when the mass of the distillate is 14-19 times the mass of calcium carbonate.

5. The preparation method according to claim 1, characterized in that: In step (4), the heating temperature is 65-85° C.; the solvent is anhydrous ethanol; and the mass ratio of the anhydrous ethanol to the compound 2 in step (1) is 10:70-90.

6. A method for preparing a calcobutrol intermediate, characterized in that: The following steps are involved: (1) Compound 1, acid and water are mixed, heated to reflux, reacted to obtain a mixture 1, ammonia water, methanol and ethanol are added to the mixture 1 in sequence, stirred until cloudy, stirred at 15-25°C for 20-24 hours, separated and dried to obtain a crude compound 2; (2) Dissolve the crude compound 2 obtained in step (1) in a solvent, add methanol and ethanol in sequence, stir until it becomes turbid, continue stirring at 15-25° C. for 20-24 hours, separate and dry to obtain the calcobutrol intermediate with a purity of ≥99.5%. in, In step (1), the mass ratio of compound 1, aqueous ammonia, methanol and ethanol is 15-19:10-15:80-90:250-260; In step (2), the mass ratio of the crude compound 2, the solvent, methanol and ethanol is 12-14:50-65:160-180.

7. The preparation method according to claim 6, characterized in that: In step (1), the acid is hydrochloric acid; the mass ratio of the compound 1, the acid and water is 15-20:5-8:40-50; the reaction is carried out under nitrogen protection for 1-3 hours.

8. The preparation method according to claim 6, characterized in that: In step (1), the sequential addition of ammonia water, methanol and ethanol is specifically as follows: Add ammonia water dropwise, control the temperature not to exceed 25°C, stir at 15-25°C for 10-20 minutes after the addition is completed, add methanol all at once, and then add ethanol dropwise, and complete the addition in 1.5-3.5 hours.

9. The preparation method according to claim 6, characterized in that: In step (2), the solvent is water.

10. The preparation method according to claim 6, characterized in that: In step (2), the sequential addition of methanol and ethanol is specifically as follows: methanol is added at once, and then ethanol is added dropwise, and the addition is completed over 1.5-3.5 hours.

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