CN115611779A - Preparation method and application of radiopharmaceutical precursor intermediate - Google Patents
Preparation method and application of radiopharmaceutical precursor intermediate Download PDFInfo
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- CN115611779A CN115611779A CN202211646332.8A CN202211646332A CN115611779A CN 115611779 A CN115611779 A CN 115611779A CN 202211646332 A CN202211646332 A CN 202211646332A CN 115611779 A CN115611779 A CN 115611779A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The application discloses a preparation method and application of an intermediate of a radiopharmaceutical precursor, wherein the preparation method comprises the following steps: diazotization reaction: carrying out diazotization reaction on N-Boc-2-tolidine, hydrochloric acid and sodium nitrite to obtain a reaction solution I; coupling reaction: carrying out coupling reaction on the reaction liquid I and 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt to obtain a reaction liquid II containing Boc-EB, and carrying out nanofiltration to obtain a filtrate II; deprotection reaction: adding acid into the filtrate II to perform deprotection reaction to obtain a reaction solution III, and freeze-drying to obtain an intermediate of the radiopharmaceutical precursor, wherein the structure of the intermediate is shown as a formula (I),
Description
Technical Field
The application relates to the technical field of pharmaceutical chemical industry. In particular, the application relates to a preparation method and application of an intermediate of a radiopharmaceutical precursor.
Background
The details of the synthesis of the compound (I) have not been reported so far, and in patents of patent publications CN109153641A1 and CN11741451A, diazotization coupling is adopted, then lyophilization is carried out to obtain Boc-EB, lyophilization is carried out to obtain diazotized intermediate, then high-concentration trifluoroacetic acid solution is further used for deprotection, and then preparation and purification are carried out to obtain target intermediate. The synthesis process of the prior art has the following problems: (1) After the Boc-EB is generated by reaction, a large amount of salt and a reaction solvent are contained, and a crude product is obtained by direct freeze drying and contains a large amount of inorganic salt, so that the scale of large-scale production is limited, and the production cost is greatly improved; (2) The Boc-EB crude product is not purified after being freeze-dried, and is directly fed in the subsequent step, so that the difficulty of the next step of intermediate purification is greatly increased, and the qualified compound (I) can be obtained only by secondary preparative chromatographic purification; (3)
The instability of diazo compounds greatly increases the safety risk of production during the transfer process for diazotized structures; (4) The Boc-EB product uses 80 percent TFA solution to remove the protection reagent, and is diluted by a large amount of purified water after the reaction is finished, so that a large amount of three wastes are generated, and the environmental protection pressure is increased; (5) After the deprotection product is prepared and purified by adopting a high-pressure liquid phase, the purity of the deprotection product can only reach about 80 percent in one-time purification, the product with the purity of more than 95 percent can be obtained by more preparation liquid phase purification, the production cost is greatly increased, and the total yield is lower.
Disclosure of Invention
In order to overcome the defects in the prior art, the application provides a preparation method of a novel intermediate of a radioactive prodrug.
The specific technical scheme of the application is as follows:
1. a method for preparing an intermediate of a radiopharmaceutical precursor comprising the steps of:
diazotization reaction: carrying out diazotization reaction on N-Boc-2-tolidine, hydrochloric acid and sodium nitrite to obtain a reaction solution I;
coupling reaction: carrying out nanofiltration on the reaction liquid I, then carrying out coupling reaction on the reaction liquid I and 1-amino-8-naphthol-2, 4-disulfonic acid or monosodium salt thereof to obtain a reaction liquid II containing Boc-EB, and then carrying out nanofiltration;
deprotection reaction: nano-filtering, adding acid to perform deprotection reaction to obtain a reaction solution III, freeze-drying to obtain an intermediate of the radioactive prodrug, wherein the structure of the intermediate is shown as a formula (I),
the formula (I).
2. The production method according to item 1, characterized in that, in the diazotization reaction step and the coupling reaction step, a cut-off molecular weight of a filter membrane used for nanofiltration is 100 to 300Da.
3. The production method according to item 1, characterized in that a quencher is added to the second reaction solution, followed by nanofiltration.
4. The method according to item 3, wherein the quencher is dithiothreitol DTT.
5. The production method according to item 1, wherein in the deprotecting reaction step, an acid is added to adjust pH 2 or less.
6. The production method according to any one of items 1 to 5, characterized in that, in the deprotecting reaction step, the reaction solution is diluted with three-purpose water to a concentration of 0.02 to 0.08g/mL and then lyophilized.
7. The production method according to any one of items 1 to 5, characterized in that the diazotization reaction step is carried out in a first reaction kettle in the presence of a solvent, and the first reaction kettle is added with the solvent, then N-Boc-o-tolidine is added, hydrochloric acid is added, and finally sodium nitrite is added to obtain a first reaction solution.
8. The preparation method according to item 7, characterized in that the temperature is controlled to be 0 to 15 ℃, and sodium nitrite is added into the first reaction kettle.
9. The production method according to any one of items 1 to 5, wherein a molar ratio of the sodium nitrite to the N-Boc-o-tolidine is 1: 1.
10. The production method according to any one of items 1 to 5, wherein a molar ratio of the sodium nitrite to the N-Boc-o-tolidine is 1 to 1.
11. The production method according to any one of items 1 to 5, wherein a molar ratio of 1-amino-8-naphthol-2, 4-disulfonic acid or a monosodium salt thereof to N-Boc-o-tolidine is (1.1 to 1.5): 1.
12. Use of the method for producing an intermediate for a radiopharmaceutical precursor according to any one of items 1 to 11 for producing a radiopharmaceutical.
ADVANTAGEOUS EFFECTS OF INVENTION
(1) The product (intermediate 1) obtained by diazotization reaction in the method is of a diazonium salt structure, and the aqueous solution after nanofiltration is directly used after preparation, so that the safety risk of operation in the transfer process is greatly reduced, and the production risk is reduced.
(2) According to the method, after the Boc-EB (intermediate 2) is generated through coupling reaction, nanofiltration is carried out without freeze-drying, so that excessive water-soluble raw materials and small molecular byproducts are removed while desalting and dewatering are carried out, column chromatography purification is not needed, the production time is greatly shortened, and the production cost is reduced.
(3) The method has the advantages that the nanofiltration aqueous solution of the intermediate 2 is directly used in the deprotection reaction, the step of adding the diluted acid is carried out in the aqueous solution, the reaction condition is mild, controllable and convenient, the intermediate is not required to be separated, the intermediate is directly freeze-dried after the deprotection is finished, and operations such as solvent removal and purification are not required.
(4) The process has good reproducibility, and the purity can reach more than 96%.
(5) The environment-friendly water is used as a reaction solvent, so that the use of organic solvents and acidic materials is reduced to the maximum extent, and the concept of green chemistry economy and sustainable development is highlighted.
Detailed Description
The following description of exemplary embodiments of the present application is provided to facilitate the understanding that they are considered exemplary only. Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope and spirit of the present application. Also, descriptions of well-known functions and constructions are omitted in the following description for clarity and conciseness.
The present application provides a process for the preparation of an intermediate of a radiopharmaceutical precursor comprising the steps of:
diazotization reaction: carrying out diazotization reaction on N-Boc-o-tolidine, hydrochloric acid and sodium nitrite to obtain a reaction liquid I, wherein the reaction liquid I contains an intermediate 1;
coupling reaction: carrying out nanofiltration on the first reaction solution to obtain a first filtrate, carrying out coupling reaction on the first filtrate and 1-amino-8-naphthol-2, 4-disulfonic acid or monosodium salt thereof to obtain a second reaction solution containing Boc-EB, and carrying out nanofiltration to obtain a second filtrate, wherein the second filtrate contains an intermediate 2;
deprotection reaction: adding acid into the filtrate II to perform deprotection reaction to obtain a reaction solution III, and freeze-drying to obtain an intermediate of the radiopharmaceutical precursor, wherein the structure of the intermediate is shown as a formula (I),
formula (I).
According to the preparation method, after the coupling reaction generates the Boc-EB, freeze-drying and HPLC purification are not carried out, nanofiltration treatment is carried out, and then acid is directly added to remove the protective group, so that the problem that in the prior art, the protective group is removed by sequentially carrying out the steps of feeding, stirring, detection, post-treatment, product obtaining, detection and the like is avoided, and after the protective group is removed, multiple HPLC purification is not required, and the target product can be obtained by direct freeze-drying. The method uses a continuous-feeding new process, the whole reaction process is carried out in aqueous solution, the use of organic solvent is reduced, the environmental pollution is reduced, the safety of the process is greatly improved, the purity of a target product is improved, the production time is greatly shortened, and the production cost is reduced.
The preparation method of the application relates to a chemical reaction formula as follows:
in this application, boc represents t-butyloxycarbonyl, and N-Boc-2-tolidine has the structural formula
Of the chemical formula C 19 H 24 N 2 O 2 The molecular weight is 312.41. The structural formula of the intermediate 1 is
Of the chemical formula C 19 H 22 ClN 3 O 2 The molecular weight is 359.86. The structural formula of the 1-amino-8-naphthol-2, 4-disulfonic acid is shown in the specification
Of the chemical formula C 10 H 9 NO 7 S 2 The molecular weight is 319.3. The structural formula of the intermediate 2 (Boc-EB) is
Of the chemical formula C 29 H 30 N 4 O 9 S 2 And the molecular weight is 642.7. The object compound of the present application has the formula C 24 H 22 N 4 O 7 S 2 And the molecular weight is 542.58.
In a specific embodiment, in the diazotization reaction step, the molecular weight cut-off of a filter membrane used for nanofiltration is 100 to 300Da, for example, 100Da, 150Da, 200Da, 250Da, 300Da and the like. In the coupling reaction step, the cut-off molecular weight of the filter membrane used for nanofiltration is 100 to 300Da, for example, 100Da, 150Da, 200Da, 250Da, 300Da, etc. Nanofiltration is carried out after the coupling reaction, so that the salt can be removed and the water can be dehydrated, excessive micromolecule water-soluble raw materials and byproducts can be removed, the use of freeze-drying equipment is avoided, and the complicated HPLC purification of the target product is not required in the subsequent process. The trapped molecular weight of the filter membrane is limited in the range, so that the optimal nanofiltration effect can be achieved, inorganic salts and water-soluble micromolecule byproducts are removed to the maximum extent, meanwhile, the loss of the products is avoided, and meanwhile, the purity of the target product is improved. The nanofiltration membrane can adopt a hollow fiber membrane or a roll-type membrane, and the pressure is 0.01 to 1.0MPa.
In one embodiment, in the coupling reaction step, the number of nanofiltration may be selected by one skilled in the art as required, and the number of nanofiltration may be 5 to 15, for example, 5, 7, 9, 10, 12, 14, 15, and the like. Specifically, the concentration can be filtered to 15% -25% each time, then purified water is replenished to the volume of the original solution each time, for example, the concentration can be filtered to 15%, 18%, 20%, 22%, 25% and the like each time, and the nanofiltration end point is set when the conductivity of the final solution is less than 100 mus.
In one embodiment, in the coupling reaction step, a quencher is added to the second mixed solution, and then nanofiltration is performed. "quencher" refers to a substance that rapidly and efficiently quenches excited molecules (singlet oxygen and triplet substances) by intermolecular energy transfer, converts into thermal energy or into fluorescence or phosphorescence, and dissipates radiation to return to the ground state. The quenching agent can be selected as required, and is preferably dithiothreitol DTT.
In one embodiment, in the step of removing protecting group, acid is added to adjust pH to 2 or less, and may be, for example, 1, 1.2, 1.4, 1.6, 1.8, 2.0, etc.
In one embodiment, in the deprotection step, the acid may be hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, or the like, and preferably the acid is hydrochloric acid.
In one embodiment, in the step of removing the protecting group, the reaction solution is diluted with three-way water to a concentration of 0.02 to 0.08g/mL and then lyophilized, for example, to a concentration of 0.02g/mL, 0.04g/mL, 0.06g/mL, 0.08g/mL, or the like. The concentration is low, the total amount of freeze-drying is small each time, and the production efficiency is low; high concentration, bad freeze-drying shape of the product and too high water content.
In one embodiment, the method of the present application, subjecting the first reaction solution to nanofiltration to obtain a first filtrate, and subjecting the first filtrate to a coupling reaction with 1-amino-8-naphthol-2, 4-disulfonic acid to obtain a second reaction solution containing Boc-EB. The application carries out nanofiltration treatment after diazotization reaction, can further remove salt and water, and simultaneously removes excessive water-soluble raw materials, thereby avoiding side reaction and further improving the purity of target products.
In a specific embodiment, in the diazotization reaction step, the number of times of nanofiltration can be selected by one skilled in the art as required, for example, the number of times of nanofiltration can be 5 to 15, for example, 5, 7, 9, 10, 12, 14, 15, etc. Specifically, the concentration can be filtered to be 15% -25% each time, then purified water is supplemented to the volume of the original solution each time, for example, the concentration can be filtered to be 15%, 18%, 20%, 22%, 25% and the like each time, and the nanofiltration end point is set when the conductivity of the solution is less than 100 muS.
In one embodiment, the diazotization reaction step occurs in a first reaction kettle in the presence of a solvent, and the first reaction kettle is first charged with the solvent, then N-Boc-2-tolidine, then hydrochloric acid, and finally sodium nitrite to obtain a first reaction solution. The solvent of the present application may be selected from one of acetonitrile, tetrahydrofuran, NMP. The method uses the environment-friendly reaction solvent, reduces the use of acidic materials to the maximum extent, and highlights the concepts of green chemistry and sustainable development.
In a specific embodiment, in the diazotization reaction step, the temperature is controlled to be 0 to 15 ℃, for example, 0 ℃,1 ℃,2 ℃, 3 ℃,4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃, 9 ℃, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃ and the like, sodium nitrite is added into the first reaction kettle and stirred for 0.5 to 3 hours, for example, 0.5 hour, 1 hour, 1.2 hour, 2 hours and the like can be stirred, and preferably, 0.8 to 1.2 hours can be stirred. The reaction temperature range is wide, and the reaction conditions are easy to control.
In one embodiment, the molar amount of sodium nitrite is 1 to 2 times, preferably 1.1 to 1.5 times, for example, 1 time, 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, etc., of the molar amount of N-Boc-2-tolidine. Controlling the amount of the sodium nitrite in the range can reduce the salt content in the reaction system, ensure the complete reaction, reduce the occurrence probability of side reaction and improve the purity of the target product.
In one embodiment, the molar amount of the 1-amino-8-naphthol-2, 4-disulfonic acid or 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt is at least one time, preferably 1.1 to 1.5 times, that of N-Boc-o-tolidine. For example, the amount may be 1 times, 1.01 times, 1.02 times, 1.03 times, 1.04 times, 1.05 times, 1.1 times, 1.15 times, 1.2 times, 1.26 times, 1.3 times, 1.35 times, 1.4 times, 1.45 times, 1.5 times, or the like. The dosage of the 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt is controlled within the range, so that no reaction raw material is left, the utilization rate of the raw material is improved, and the smooth reaction is ensured.
In one embodiment, the preparation method of the present application is performed under an inert atmosphere, which may be selected according to needs, for example, nitrogen, argon, helium, and the like.
In one embodiment, the step of diazotization comprises the steps of:
(1) Controlling the temperature to be 20 to 30 ℃, adding a solvent into the reaction kettle A under the protection of inert atmosphere, and stirring;
(2) Controlling the temperature to be 20 to 30 ℃, adding N-Boc-2-tolidine into the reaction kettle A under the protection of inert atmosphere, stirring, and cooling to 0 to 5 ℃;
(3) Controlling the temperature to be 0 to 10 ℃, and adding HCl into the reaction kettle A under the protection of inert atmosphere;
(4) Controlling the temperature to be 20 to 30 ℃, adding water into the reaction kettle B under the protection of inert atmosphere, and stirring;
(5) Controlling the temperature to be 20-30 ℃, adding sodium nitrite into the reaction kettle B under the protection of inert atmosphere, stirring, and cooling to 0-5 ℃;
(6) Controlling the temperature to be 0-15 ℃, dropping the system in the reaction kettle B into the reaction kettle A under the protection of inert atmosphere, and stirring;
(7) To obtain a first reaction solution containing the intermediate 1.
In one embodiment, the step of diazotization further comprises a step (8) after step (7): and (3) performing nanofiltration on the reaction liquid I by using a 100 to 300Da filter membrane.
In one embodiment, in the diazotization reaction step, the mass to volume ratio of N-Boc-o-tolidine to the solvent is (20 to 30): 1; the molar ratio of N-Boc-2-tolidine to HCl is 1 (2 to 4), and can be, for example, 1; the molar ratio of sodium nitrite to N-Boc-2-tolidine is (1.1 to 1.5) 1, and for example, 1.1; the HCl concentration is 0.2 to 0.5mol/L. As used herein, "mass to volume ratio" refers to the ratio of the mass (g) of one solid to the volume (mL) of another liquid.
In one embodiment, the coupling reaction step comprises the steps of:
(1) Controlling the temperature to be 20 to 30 ℃, adding water into the reaction kettle C under the protection of inert atmosphere, and stirring;
(2) Controlling the temperature to be 20 to 30 ℃, adding 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt and a neutralizing agent into the reaction kettle C under the protection of inert atmosphere, stirring, and cooling to 0 to 5 ℃;
(3) Controlling the temperature to be 0 to 15 ℃, dropwise adding the filtrate into the reaction kettle C, controlling the temperature to be 10 to 20 ℃ for reaction after dropwise adding the filtrate for 20 to 30min;
(4) Sampling is carried out after the reaction is carried out for 2 to 2.5hours, sampling is carried out once every 2 to 4 hours, and HPLC tracking is carried out until the content of the intermediate 1 is less than or equal to 0.5 percent;
(5) And controlling the temperature to be 0-5 ℃, adding a quenching agent into the reaction kettle C after the reaction is finished, stirring and quenching to obtain a second reaction liquid containing the intermediate 2, and performing nanofiltration on the second reaction liquid through a filter membrane of 100-300Da.
In one embodiment, in the coupling reaction step, the molar ratio of the monosodium 1-amino-8-naphthol-2, 4-disulfonate to N-Boc-o-tolidine is (1.1 to 1.5) to 1, preferably (1.2 to 1.3) to 1, the molar ratio of the neutralizing agent to N-Boc-o-tolidine is (3 to 5) to 1, the neutralizing agent may be, for example, sodium bicarbonate, the molar ratio of the quencher to N-Boc-o-tolidine is (2 to 4) to 1, and the quencher may be, for example, dithiothreitol DTT.
In one embodiment, hydrochloric acid with a concentration of (0.2 to 0.5) mol/L is added to the second filtrate at room temperature in the deprotection reaction step, and the pH is controlled to be 1 to 2.
In a specific embodiment, in the deprotection reaction step, hydrochloric acid with the concentration of (0.2 to 0.5) mol/L is added into the second filtrate at room temperature, the pH is controlled to be 1 to 2, sampling is started after 2 to 2.5 hours of reaction, sampling is performed every 1 to 2h, HPLC tracking is performed until the content of the second intermediate is less than or equal to 0.5%, a third reaction liquid is obtained, the third reaction liquid is diluted to 0.02 to 0.1g/mL by using water, and the pure intermediate of the target product with the structure shown in the formula (I) is obtained by freeze-drying.
The present application also provides the use of a process for the preparation of an intermediate of a radiopharmaceutical precursor as defined in any of the preceding paragraphs in the preparation of a radiopharmaceutical.
The method for preparing the intermediate compound shown as the formula (I) of the radiopharmaceutical precursor can obtain a pure product shown as the formula (I) with extremely high purity under the condition of high product yield, specifically, the purity of the pure product shown as the formula (I) can reach more than 96%, even 97.23%, and the total yield is more than 48%, even 51.7%.
Examples
The materials used in the tests and the methods of the tests are generally and/or specifically described in the present application, and in the following examples, the materials or instruments used are conventional materials or instruments commercially available without reference to the manufacturer.
Example 1
(1) Controlling the temperature to be 20-30 ℃, adding 80g of acetonitrile into the reaction kettle A under the protection of nitrogen, and starting stirring;
(2) Controlling the temperature to be 20 to 30 ℃, adding 0.016mol of N-Boc-2-tolidine (1.00 eq) into a reaction kettle A under the protection of nitrogen, stirring for 0.5h after adding, and cooling to 0 ℃;
(3) Controlling the temperature to be 0 to 10 ℃, and adding 120mL of HCl (3.00 eq) with the concentration of 0.4M into the reaction kettle A under the protection of nitrogen;
(4) Controlling the temperature to be 20-30 ℃, adding 40mL of purified water into the reaction kettle B under the protection of nitrogen, and starting stirring;
(5) Controlling the temperature to be 20 to 30 ℃, adding 0.0192mol (1.20 eq) of sodium nitrite into the reaction kettle B under the protection of nitrogen, stirring and dissolving the materials after the addition is finished, and cooling to 0 ℃;
(6) Controlling the temperature to be 0-15 ℃, dropping the system in the reaction kettle B into the reaction kettle A under the protection of nitrogen, and stirring for 1h after dropping to obtain a reaction liquid I containing the intermediate 1;
(7) Carrying out nanofiltration on the reaction liquid I by using a 100Da filter membrane until the conductivity is less than 100 mu S, thus obtaining a filtrate containing the intermediate 1;
(8) Controlling the temperature to be 20 to 30 ℃, adding 160mL of purified water into the reaction kettle C under the protection of nitrogen, and starting stirring;
(9) Controlling the temperature to be 20 to 30 ℃, adding 0.020mol (1.25 eq) of 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt and 0.064mol (4.00 eq) of sodium bicarbonate into the reaction kettle C under the protection of nitrogen, stirring and dissolving the materials after the addition is finished, and cooling to 0 ℃;
(10) Controlling the temperature to be 0 to 15 ℃, dripping the filtrate containing the intermediate 1 into the reaction kettle C, controlling the temperature to be 10 to 20 ℃ for reaction after dripping is finished for 20 to 30min;
(11) Sampling is carried out after the reaction is carried out for 2 hours, sampling is carried out once every 2 to 4 hours, and HPLC (AM-1001-01) tracking is carried out until the content of the intermediate 1 is less than or equal to 0.5 percent;
(12) And controlling the temperature to be 0-5 ℃, adding 0.0048mol (0.30 eq) of DTT into the reaction kettle C after the reaction is finished, stirring for 5h, and quenching to obtain a reaction liquid II containing the intermediate 2, and performing nanofiltration by using a 100Da filter membrane until the conductivity is less than 100 mu S to obtain a filtrate containing the intermediate 2.
(13) Adding 0.4mol/L hydrochloric acid into the filtrate containing the intermediate 2 at room temperature, adjusting the pH value to be between 1 and 2, starting to sample after reacting for 2 hours, sampling every 1 to 2h, tracking by HPLC (high performance liquid chromatography) until the content of the intermediate 2 is less than or equal to 0.5% to obtain a reaction liquid III, diluting the reaction liquid III with water to about 0.02g/mL (namely about 5% concentration), and freeze-drying to obtain the pure product of the formula (I), wherein the yield is 51.7% and the purity is 96.01%.
Example 2
This example differs from example 1 in that: the molecular weight cut-off of the filter membrane used in the nanofiltration in the step (7) and the step (12) is 300Da. The yield of the final pure product of formula (I) was 48.6% and the purity was 97.23%.
Comparative example 1
The comparative example differs from example 1 in that: after the reaction liquid I containing the intermediate 1 is obtained, nanofiltration is not carried out, and the reaction liquid I is dripped into the reaction kettle C. The final product of formula (I) was obtained in 70.1% yield and 82.35% purity.
Comparative example 2
The comparative example differs from example 2 in that: performing HPLC (AM-1001-01) tracking until the content of the intermediate 1 is less than or equal to 0.5%, directly obtaining a reaction liquid II containing the intermediate 2 without quenching, performing nanofiltration after obtaining the reaction liquid II, and performing freeze-drying on the reaction liquid II to obtain a crude product of the intermediate 2; adding 100ml of water, 10mL of TFA10ml of water and 0.0048mol (0.30 eq) of DTT into the crude product of the intermediate 2, controlling the temperature to be 20-30 ℃, stirring and reacting for 2 hours, starting sampling after reacting for 2 hours, sampling every 1-2h, tracking by HPLC (high performance liquid chromatography) until the content of the intermediate 2 is less than or equal to 0.5 percent to obtain a reaction liquid III, diluting the reaction liquid three-way water to about 0.02g/mL (namely about 5 percent concentration), and freeze-drying to obtain the product of the formula (I), wherein the yield is 65.4 percent and the purity is 85.42 percent.
Comparative example 3
This comparative example differs from example 2 in that: after the reaction solution one containing the intermediate 1 was obtained, nanofiltration was not performed, and it was the reaction solution one that dropped into the reaction kettle C. The final product of formula (I) was obtained in 66.3% yield and 84.83% purity.
Comparative example 4
This comparative example is different from example 1 in that nanofiltration was not performed after obtaining the second reaction solution containing the intermediate 2, and 0.4mol/L hydrochloric acid was directly added to the second reaction solution at room temperature and the subsequent steps were performed. The final product of formula (I) was obtained in 68.3% yield and 82.82% purity.
Comparative example 5
The comparative example differs from example 1 in that nanofiltration was not performed after the reaction liquid one containing the intermediate 1 was obtained, and it was the reaction liquid one that was dropped into the reaction vessel C; and directly adding 0.4mol/L hydrochloric acid into the reaction liquid II at room temperature without nanofiltration after obtaining the reaction liquid II containing the intermediate 2, and carrying out subsequent steps. The final product of formula (I) was obtained in 75.4% yield and 76.50% purity.
Comparative example 6
(1) Controlling the temperature to be 20-30 ℃, adding 80g of acetonitrile into the reaction kettle A under the protection of nitrogen, and starting stirring;
(2) Controlling the temperature to be 20 to 30 ℃, adding 0.016mol of N-Boc-2-tolidine (1.00 eq) into a reaction kettle A under the protection of nitrogen, stirring for 0.5h after adding, and cooling to 0 ℃;
(3) Controlling the temperature to be 0-10 ℃, and adding 120mL of HCl (3.00 eq) with the concentration of 0.4M into the reaction kettle A under the protection of nitrogen;
(4) Controlling the temperature to be 20-30 ℃, adding 40mL of purified water into the reaction kettle B under the protection of nitrogen, and starting stirring;
(5) Controlling the temperature to be 20 to 30 ℃, adding 0.0192mol (1.20 eq) of sodium nitrite into the reaction kettle B under the protection of nitrogen, stirring and dissolving the materials after the addition is finished, and cooling to 0 ℃;
(6) Controlling the temperature to be 0 to 15 ℃, dropping the system in the reaction kettle B into the reaction kettle A under the protection of nitrogen, and stirring for 1 hour after dropping to obtain a first reaction solution containing the intermediate 1;
(7) Controlling the temperature to be 20-30 ℃, adding 160mL of purified water into the reaction kettle C under the protection of nitrogen, and starting stirring;
(8) Controlling the temperature to be 20 to 30 ℃, adding 0.020mol (1.25 eq) of 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt and 0.064mol (4.00 eq) of sodium bicarbonate into the reaction kettle C under the protection of nitrogen, stirring and dissolving the materials, and cooling to 0 ℃;
(9) Controlling the temperature to be 0 to 15 ℃, dripping the reaction liquid containing the intermediate 1 into the reaction kettle C, controlling the temperature to be 10 to 20 ℃ for reaction after dripping for 20 to 30min;
(10) Sampling is carried out after the reaction is carried out for 2 hours, sampling is carried out once every 2 to 4 hours, and HPLC (AM-1001-01) tracking is carried out until the content of the intermediate 1 is less than or equal to 0.5 percent;
(11) Controlling the temperature to be 0 to 5 ℃, adding 0.0048mol (0.30 eq) of DTT into the reaction kettle C after the reaction is finished, and stirring for 5 hours for quenching to obtain a reaction liquid II containing the intermediate 2. The conditions for HPLC purification of the second reaction solution are as follows:
mobile phase: aqueous ammonium acetate/ethanol
Filling: c18
A: ammonium acetate aqueous solution (0.5 mol/L)
B: ethanol/H 2 O(9:1)
Carrying out HPLC detection on the eluent, combining the eluents according to the detection result, and purging the eluent at room temperature by using nitrogen to remove the organic reagent ethanol to obtain an aqueous solution containing the intermediate 2;
(12) Adding 0.4mol/L hydrochloric acid into an aqueous solution containing the intermediate 2 at room temperature, adjusting the pH value to be between 1 and 2, starting to sample after reacting for 2 hours, sampling every 1 to 2h, tracking by HPLC (high performance liquid chromatography) until the content of the intermediate 2 is less than or equal to 0.5% to obtain a reaction liquid III, diluting the reaction liquid III with water to about 0.02g/mL (namely about 5% concentration), and freeze-drying to obtain a pure product of the formula (I), wherein the yield is 30.7% and the purity is 98.21%.
Comparative example 7
(1) Controlling the temperature to be 20 to 30 ℃, adding 80g of acetonitrile into the reaction kettle A under the protection of nitrogen, and starting stirring;
(2) Controlling the temperature to be 20 to 30 ℃, adding 0.016mol of N-Boc-2-tolidine (1.00 eq) into a reaction kettle A under the protection of nitrogen, stirring for 0.5h after adding, and cooling to 0 ℃;
(3) Controlling the temperature to be 0-10 ℃, and adding 120mL of HCl (3.00 eq) with the concentration of 0.4M into the reaction kettle A under the protection of nitrogen;
(4) Controlling the temperature to be 20 to 30 ℃, adding 40mL of purified water into the reaction kettle B under the protection of nitrogen, and starting stirring;
(5) Controlling the temperature to be 20 to 30 ℃, adding 0.0192mol (1.20 eq) of sodium nitrite into the reaction kettle B under the protection of nitrogen, stirring and dissolving the materials after the addition is finished, and cooling to 0 ℃;
(6) Controlling the temperature to be 0-15 ℃, dropping the system in the reaction kettle B into the reaction kettle A under the protection of nitrogen, and stirring for 1h after dropping to obtain a reaction liquid I containing the intermediate 1; and removing the organic solvent acetonitrile by nitrogen purging at room temperature to obtain the aqueous solution containing the intermediate 1.
(7) The aqueous solution containing intermediate 1 was diluted with water to about 0.02g/mL (i.e., about 5% strength) and lyophilized to give the crude intermediate 1 product.
(8) Controlling the temperature to be 20-30 ℃, adding 160mL of purified water into the reaction kettle C under the protection of nitrogen, and starting stirring;
(9) Controlling the temperature to be 20 to 30 ℃, adding 0.020mol (1.25 eq) of 1-amino-8-naphthol-2, 4-disulfonic acid monosodium salt and 0.064mol (4.00 eq) of sodium bicarbonate into the reaction kettle C under the protection of nitrogen, stirring and dissolving the materials after the addition is finished, and cooling to 0 ℃;
(10) Controlling the temperature to be 0 to 15 ℃, dissolving a sample of the intermediate 1 in 100ml of water, dripping into the reaction kettle C for 20 to 30min, and controlling the temperature to be 10 to 20 ℃ for reaction;
(11) Sampling is carried out after the reaction is carried out for 2 hours, sampling is carried out once every 2 to 4 hours, and HPLC (AM-1001-01) tracking is carried out until the content of the intermediate 1 is less than or equal to 0.5 percent;
(12) Controlling the temperature to be 0-5 ℃, adding 0.0048mol (0.30 eq) of DTT into the reaction kettle C after the reaction is finished, stirring for 5h, and quenching to obtain a reaction liquid II containing the intermediate 2.
(13) Adding 0.4mol/L hydrochloric acid into an aqueous solution containing the intermediate 2 at room temperature, adjusting the pH value to be between 1 and 2, starting to sample after reacting for 2 hours, sampling every 1 to 2h, tracking by HPLC (high performance liquid chromatography) until the content of the intermediate 2 is less than or equal to 0.5% to obtain a third reaction solution, diluting the third reaction solution with three-purpose water to about 0.02g/mL (namely about 5% concentration), and freeze-drying to obtain the product of the formula (I), wherein the yield is 73.2% and the purity is 75.81%.
The important parameters of the above examples and comparative examples are listed in table 1 below.
TABLE 1
The foregoing is directed to preferred embodiments of the present application, other than the limiting examples of the present application, and variations of the present application may be made by those skilled in the art using the foregoing teachings. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present application still belong to the protection scope of the technical solution of the present application.
Claims (12)
1. A process for the preparation of an intermediate for a radiopharmaceutical precursor comprising the steps of:
diazotization reaction: carrying out diazotization reaction on N-Boc-2-tolidine, hydrochloric acid and sodium nitrite to obtain a reaction solution I;
coupling reaction: carrying out nanofiltration on the reaction liquid I, then carrying out coupling reaction on the reaction liquid I and 1-amino-8-naphthol-2, 4-disulfonic acid or monosodium salt thereof to obtain a reaction liquid II containing Boc-EB, and then carrying out nanofiltration;
deprotection reaction: nano-filtering, adding acid to perform deprotection reaction to obtain a reaction solution III, freeze-drying to obtain the intermediate of the radiopharmaceutical precursor, wherein the structure of the intermediate is shown as a formula (I),
the formula (I).
2. The production method according to claim 1, wherein in the diazotization reaction step and the coupling reaction step, a filtration membrane used for nanofiltration has a molecular weight cutoff of 100 to 300Da.
3. The method according to claim 1, wherein a quencher is added to the second reaction solution, and nanofiltration is performed.
4. The method of claim 3, wherein the quencher is DTT.
5. The method according to claim 1, wherein in the deprotecting reaction step, an acid is added to adjust pH 2 or less.
6. The production method according to any one of claims 1 to 5, wherein in the deprotecting reaction step, the reaction solution is diluted with three-purpose water to a concentration of 0.02 to 0.08g/mL and then lyophilized.
7. The preparation method according to any one of claims 1 to 5, wherein the diazotization reaction step is carried out in a first reaction kettle in the presence of a solvent, and the first reaction kettle is added with the solvent, then N-Boc-o-tolidine, hydrochloric acid and finally sodium nitrite to obtain a first reaction solution.
8. The preparation method according to claim 7, wherein the temperature is controlled to be 0 to 15 ℃, and the sodium nitrite is added into the first reaction kettle.
9. The production method according to any one of claims 1 to 5, wherein the molar ratio of sodium nitrite to N-Boc-o-tolidine is (1 to 2): 1.
10. The production method according to any one of claims 1 to 5, wherein the molar ratio of sodium nitrite to N-Boc-o-tolidine is (1.1 to 1.5): 1.
11. The production method according to any one of claims 1 to 5, wherein the molar ratio of 1-amino-8-naphthol-2, 4-disulfonic acid or a monosodium salt thereof to N-Boc-o-tolidine is (1.1 to 1.5): 1.
12. Use of a process for the preparation of an intermediate of a radiopharmaceutical precursor according to any one of claims 1 to 11 in the preparation of a radiopharmaceutical.
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