CN116693440A - Method for removing palladium catalyst in Irelance intermediate VI synthesis process - Google Patents

Abstract

The invention provides a method for removing a palladium catalyst in a synthesis process of an Isomakaposite intermediate VI, which comprises the steps of adding water, standing and separating liquid after the reaction of synthesizing the Isomakaposite intermediate VI from the Isomakaposite intermediate V through the palladium catalyst is finished, taking an organic phase after the liquid separation, and washing the organic phase by using a cysteine aqueous solution and a sodium chloride solution in sequence; adding activated carbon into the washed organic phase, stirring and adsorbing, filtering the activated carbon, adding palladium-removing silica gel, stirring and adsorbing, filtering the palladium-removing silica gel, dripping hydrochloric acid/methanol solution, adding methyl tertiary butyl ether and stirring; filtering out precipitate, and stirring and pulping with a mixed solvent of methanol and ethyl acetate; filtering out a solid filter cake, and drying in vacuum to constant weight to obtain an Irelacasi intermediate VI product after palladium removal. According to the invention, through comprehensively using L-cysteine, activated carbon and palladium-removing silica gel, the residual palladium catalyst in the Iwaneca intermediate VI is effectively removed, the stable quality of the Iwaneca final product is ensured, and the potential safety hazard of medicines is avoided.

Description

A kind of scavenging method of palladium catalyst in Ivankaser intermediate VI synthesis technique

technical field

The invention relates to a synthesis method of an Ivankaser intermediate, in particular to a method for removing a palladium catalyst in the synthesis process of the Ivanassert intermediate VI, and belongs to the technical field of drug synthesis.

Background technique

Secondary hyperparathyroidism (SHPT) is a common and serious complication in patients with chronic kidney disease (CKD), and it is an important pathological basis that directly leads to cardiovascular complications in CKD patients. In SHPT patients, parathyroid hormone (PTH) is oversecreted in response to decreased renal function and impaired mineral metabolism, which leads to massive loss of calcium and phosphate from bone tissue. Current treatments for SHPT include nutritional therapy, nutritional vitamin D, active vitamin D and its analogues, calcimimetics, and phosphorus binders.

Ivankaser is an arylalkylamine compound, the basic information of which is as follows:

Chinese chemical name: 4-((S)-3-(((R)-1-(1-naphthyl)ethyl)amino)-1-pyrrolidinyl)phenylacetic acid;

English chemical name: 4-((S)-3-(((R)-1-(1-naphthalenyl) ethyl) amino)-1-pyrrolidinyl) phenyl acetic acid;

Chemical structure:

;

Molecular formula: C ₂₄ H ₂₆ N ₂ O ₂ ;

Molecular weight: 374.20.

As a calcium-sensing receptor (CaSR) agonist, Ivankacel can increase the sensitivity of CaSR to calcium ions, directly inhibit the secretion of PTH and the proliferation of parathyroid cells, thereby reducing the concentration of PTH in blood. This product will not increase the intestinal absorption of calcium and phosphorus, thus avoiding the increase of blood calcium and phosphorus that may be caused by active vitamin D and other drugs. Ivankaser was first approved in 2018 for the treatment of secondary hyperparathyroidism and in 2019 for the treatment of parathyroid cancer that is not amenable to parathyroidectomy or has recurred after parathyroidectomy or hypercalcemia in patients with primary hyperparathyroidism.

At present, the synthetic method of Ivanka Se mainly adopts the following reaction route to carry out:

Synthetic method one:

This synthetic method has a simple route and high feasibility, but the disadvantages are: the trifluoromethanesulfonic acid used in step (1) has strong acidity, harsh reaction conditions, and relatively expensive; the resolution of the product of step (2) The process is complicated, there are many redundant processes, and the waste is serious.

Synthetic method two:

The characteristics of this synthesis method are similar to the synthesis method 1, but more special raw materials are also used, resulting in high cost and complicated operation.

Synthetic method three:

This synthesis method is relatively proper, the raw materials used are all cheap and easy-to-obtain chemical raw materials, the process operation is reasonable, and there are no obvious redundant steps; but step (4) uses a palladium catalyst, which leads to the residual palladium in the intermediate VI easily exceeding the standard, which affects the I The quality of Vancaser's final product has hidden dangers of drug safety.

Contents of the invention

The purpose of the present invention is to solve the above-mentioned defects in the existing Ivankasel synthesis method, and provide a synthesis process for Ivankaset intermediate VI on the basis of the preferred Ivankaset synthesis method (synthesis method 3) The removal method of palladium catalyst in medium.

The chemical structure of the Ivankaser intermediate VI involved in the present invention is as follows:

;

Its corresponding synthetic steps are as follows:

.

Technical solution of the present invention: a method for removing the palladium catalyst in the Ivankaser intermediate VI synthesis process, aiming at the palladium acetate catalyst used in the synthesis process, L-cysteine, activated carbon and palladium-removing silica gel are used comprehensively as The adsorbent completes the control of palladium residues, and the specific steps are as follows:

(1) Ivankaser intermediate VI is synthesized from Ivankaser intermediate V through palladium catalyst, and after the reaction is completed, add water and let it stand for liquid separation; specific operations include:

① Add 10% sodium hydroxide with a mass fraction of 2.5 times (V:m) of Ivankaser intermediate V and 8 times (V:m) of xylene in the amount of Ivankaser intermediate V in the reactor , heat up to 40~60°C, add Ivankaser intermediate V, stir and separate, and take the upper organic phase;

②Wash the organic phase once with purified water that is 2.5 times (V:m) of Ivankaser intermediate V, and then add 4-bromophenylacetic acid methyl ester, 1.25 times (eq) of Ivankaser intermediate V Ivankaser intermediate V 3.5 times (eq) cesium carbonate, Ivankaser intermediate V 0.01 times (m:m) palladium acetate and Ivankaser intermediate V 0.04 times (m:m) Amount of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, replaced by nitrogen three times, heated to 100°C~120°C, and reacted for 4~5 hours;

③After the reaction is finished, add purified water with an amount 10 times (V:m) of Ivankaser intermediate V, stir well and let stand to separate the liquid.

(2) Take the organic phase after liquid separation in step (1), and wash it with cysteine aqueous solution and sodium chloride solution in turn; specific operations include:

①Take the organic phase after liquid separation, add 2% L-cysteine aqueous solution with a mass fraction of 6 times (V:m) of Ivankaser intermediate V, fully stir and separate liquid, repeat the above operation;

②Take the organic phase after liquid separation, add 25% sodium chloride solution with a mass fraction of 6 times (V:m) of Ivankaser intermediate V, fully stir and separate liquids, and complete the washing step.

(3) Take the organic phase after washing in step (2), add activated carbon to stir and absorb, and filter out the activated carbon; specific operations include:

Take the organic phase, add 0.1 times (m:m) activated carbon of Ivankaser intermediate V, stir for 0.5~2 hours, filter the activated carbon with an appropriate amount of diatomaceous earth, rinse the filter cake with an appropriate amount of xylene, and obtain the filtered activated carbon of the filtrate.

(4) Take the filtrate from step (3) to filter out activated carbon, add palladium-removing silica gel to stir and absorb, and filter out palladium silica gel; specific operations include:

Take the organic phase, add 0.1 times (m:m) amount of palladium-removing silica gel of Ivankaser intermediate V, stir at 40-60°C for 0.5-2 hours, filter the palladium-removing silica gel with an appropriate amount of diatomaceous earth, and rinse with an appropriate amount of xylene The filter cake was washed to obtain a filtrate in which the palladium silica gel was removed by filtration.

(5) Take step (4) to filter out the filtrate of palladium silica gel, add hydrochloric acid/methanol solution dropwise, then add methyl tert-butyl ether and stir; filter out the precipitate, stir and beat with methanol/ethyl acetate mixed solvent; Filter out solid, dry in vacuo to constant weight, obtain the Ivankasel intermediate VI product after removing palladium; Concrete operation comprises:

① Add dropwise the hydrochloric acid/methanol solution (hydrochloric acid:methanol=1:2(m:m)) of Ivankasel intermediate V 0.7 times (V:m) to the filtrate from which the palladium silica gel was removed, within 1 hour After dripping; add 6 times (V:m) amount of methyl tert-butyl ether of Ivankaser intermediate V, and stir for 1-2 hours;

②Filter, rinse the filter cake with an appropriate amount of methyl tert-butyl ether, and pump until no obvious droplets flow out; add the wet product to a methanol/ethyl acetate solution that is 5 times (V:m) of Ivankaser intermediate V (methanol: ethyl acetate = 1:4 (V: V)) beating for 0.5~1 hour, filter; rinse with an appropriate amount of ethyl acetate and drain;

③ The filter cake was vacuum-dried at 35-45°C to constant weight to obtain an off-white solid, which was Ivankasel intermediate VI.

Compared with the prior art, the present invention has the advantages of: through the comprehensive use of L-cysteine, activated carbon and palladium-removing silica gel, under the joint action of various adsorbents, effectively remove the residual The palladium catalyst ensures the stable quality of Ivankaser's final product and eliminates potential drug safety hazards.

Implementation

The technical solution of the present invention will be further described below according to the embodiments. In the description of this specification, the content of each embodiment means that the specific technical features described in conjunction with it are included in at least one embodiment of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific technical features may be combined in any one or more implementations or examples in a proper manner.

(1) Synthesis of Ivankaser Intermediate VI

Add 75 mL of 10% sodium hydroxide and 240 mL of xylene into a 1 L three-necked flask, heat up to 45~55 °C; add 30 g of Ivankaser intermediate V, stir for 10 min, separate the liquids, and take the upper organic phase; The organic phase was washed once with 75 mL of purified water; 23 g of methyl 4-bromophenylacetate, 90 g of cesium carbonate, 0.3 g of palladium acetate and 2-dicyclohexylphosphine-2',4',6'-triiso Propyl biphenyl 1.2 g, nitrogen protection; heat up to 100°C, react for 4 hours.

(2) L-cysteine adsorption to remove palladium

After the reaction, add 300 mL of purified water, stir for 30 min, and let stand to separate the liquid; take the organic phase, add 180 mL of 2% L-cysteine aqueous solution, stir for 0.5 hours, and separate the liquid; take the organic phase, add 2% L-cysteine Take 180 mL of cysteine aqueous solution, stir for 0.5 hours, and separate the liquids; take the organic phase and add 180 mL of 25% sodium chloride solution, stir for 1 hour, and separate the liquids.

(3) Palladium removal by activated carbon adsorption

Add 3 g of activated carbon to the organic phase, stir for 0.5 hours, filter with 15 g of diatomaceous earth, and rinse the filter cake with 18 mL of xylene.

(4) Palladium removal silica gel adsorption to remove palladium

Add 3 g of palladium-free silica gel to the filtrate, stir at 40°C for 0.5 hour, filter with 15 g of diatomaceous earth, and rinse the filter cake with 18 mL of xylene.

(5) Product collection

Add hydrochloric acid/methanol solution (6.6 mL hydrochloric acid, 20 mL methanol) dropwise to the filtrate, add 180 mL methyl tert-butyl ether, and stir for 1 hour;

Filter, wash the filter cake with 30 mL of methyl tert-butyl ether, and pump until no obvious liquid drops flow out; the filter cake is vacuum-dried at 35-40 °C for 10 hours, and the weight is constant to obtain 21.3 g of off-white solid.

The intermediate VI produced in this example is used for the preparation of Ivankaser, and the residual amount of palladium in the final Ivankaser finished product is less than 2 ppm.

The above is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto, any person familiar with the technical field within the technical scope disclosed in the present invention, according to the technical solution of the present invention Any equivalent replacement or change of the inventive concepts thereof shall fall within the protection scope of the present invention.

Claims (10)

1. a kind of scavenging method of palladium catalyst in Ivankaser intermediate VI synthetic technique, it is characterized in that, the method specifically comprises the steps: (1) Synthesize the Ivankaser intermediate VI from the Ivankaser intermediate V through the palladium catalyst, add water after the reaction and let it stand for liquid separation; (2) Take the organic phase after liquid separation in step (1), and wash it successively with aqueous cysteine solution and sodium chloride solution; (3) Take the organic phase after washing in step (2), add activated carbon to stir and absorb, and filter out the activated carbon; (4) Take step (3) to filter out the filtrate of activated carbon, add palladium-removing silica gel to stir and absorb, and filter out palladium silica gel; (5) Take step (4) to filter out the filtrate of palladium silica gel, add hydrochloric acid/methanol solution dropwise, then add methyl tert-butyl ether and stir; filter out the precipitate, stir and beat with methanol/ethyl acetate mixed solvent; The solid filter cake was filtered out, and vacuum-dried to constant weight to obtain the Ivankasel intermediate VI product after palladium removal. 2. the scavenging method of palladium catalyst in a kind of Ivankaser intermediate VI synthesis technique according to claim 1, is characterized in that, described step (1) specifically comprises following operation: ① Add 10% sodium hydroxide with a mass fraction of 2.5 times (V:m) of Ivankaser intermediate V and xylene of 8.0 times (V:m) of Ivankaser intermediate V into the reactor , heat up to 40~60°C, add Ivankaser intermediate V, stir and separate, and take the upper organic phase; ②Wash the organic phase once with purified water that is 2.5 times (V:m) of Ivankaser intermediate V, and then add 4-bromophenylacetic acid methyl ester, 1.25 times (eq) of Ivankaser intermediate V Ivankaser intermediate V 3.5 times (eq) cesium carbonate, Ivankaser intermediate V 0.01 times (m:m) palladium acetate and Ivankaser intermediate V 0.04 times (m:m) Amount of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, replaced by nitrogen three times, heated to 100°C~120°C, and reacted for 4~5 hours; ③After the reaction is finished, add purified water with an amount 10 times (V:m) of Ivankaser intermediate V, stir well and let stand to separate the liquid; Its corresponding synthetic step reaction formula is as follows: . 3. the scavenging method of palladium catalyst in a kind of Ivankaser intermediate VI synthesis technique according to claim 1, is characterized in that, described step (2) specifically comprises following operation: ①Take the organic phase after liquid separation, add 2% L-cysteine aqueous solution with a mass fraction of 6 times (V:m) of Ivankaser intermediate V, fully stir and separate liquid, repeat the above operation; ②Take the organic phase after liquid separation, add 25% sodium chloride solution with a mass fraction of 6 times (V:m) of Ivankaser intermediate V, fully stir and separate liquids, and complete the washing step. 4. the scavenging method of palladium catalyst in a kind of Ivankaser intermediate VI synthesis technique according to claim 1, is characterized in that, the quality that adds activated carbon in the organic phase of described step (3) gained is Ivankaser The amount of intermediate V is 0.1 times (m:m), and the stirring adsorption time is 0.5~2 hours. 5. The method for removing palladium catalysts in a kind of Ivankaser intermediate VI synthesis process according to claim 1, characterized in that, the reaction solution in the step (3) to filter out activated carbon specifically includes the following operations: pad an appropriate amount Filter the activated carbon with diatomaceous earth, rinse the filter cake with an appropriate amount of xylene, and obtain a filtrate that removes the activated carbon. 6. the scavenging method of palladium catalyst in a kind of Ivankasel intermediate VI synthesis technique according to claim 1, is characterized in that, the quality that adds palladium silica gel in described step (4) gained organic phase is Ivan The amount of 0.1 times (m:m) of intermediate V is 0.1 times (m:m), the stirring adsorption temperature is 40~60°C, and the stirring adsorption time is 0.5~2 hours. 7. the cleaning method of palladium catalyst in a kind of Ivankaser intermediate VI synthesis technique according to claim 1, is characterized in that, the reaction solution filtration of described step (4) removes palladium silica gel and specifically comprises the following operations: Pad an appropriate amount of diatomaceous earth to filter out the palladium silica gel, and rinse the filter cake with an appropriate amount of xylene to obtain a filtrate that removes the palladium silica gel. 8. The method for removing palladium catalyst in a kind of Ivankasel intermediate VI synthesis process according to claim 1, characterized in that, the organic phase obtained in the step (5) is added dropwise to Ivankaser intermediate V In 0.7 times (V:m) amount of hydrochloric acid/methanol solution, where hydrochloric acid:methanol=1:2 (m:m), the drop will be completed within 1 hour; the mass of adding methyl tert-butyl ether is the middle 6 times the volume of V (V:m), the stirring time is 1~2 hours. 9. The removal method of palladium catalyst in a kind of Ivankaser intermediate VI synthesis technique according to claim 1, it is characterized in that, when the reaction solution of described step (5) filters out precipitate, filter cake is used appropriate amount Rinse with methyl tert-butyl ether, pump until no obvious droplet flows out; add the wet product to a mixed solvent of methanol/ethyl acetate that is 5 times (V:m) of Ivankaser intermediate V and beat for 0.5~1 hour , filtered, methanol/ethyl acetate solution methanol: ethyl acetate = 1:4 (V:V); finally rinse with an appropriate amount of ethyl acetate and drain. 10. The method for removing palladium catalyst in a kind of Ivankasel intermediate VI synthesis process according to claim 1, characterized in that, the solid filter cake filtered out in the step (5) is at 35~45°C Dry in vacuo to constant weight.