CN114409629B - Preparation method and application of high-purity Relugolix key intermediate - Google Patents

Preparation method and application of high-purity Relugolix key intermediate Download PDF

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CN114409629B
CN114409629B CN202210162521.1A CN202210162521A CN114409629B CN 114409629 B CN114409629 B CN 114409629B CN 202210162521 A CN202210162521 A CN 202210162521A CN 114409629 B CN114409629 B CN 114409629B
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purity
relugolix
hydrogen chloride
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CN114409629A (en
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王栋
沈超
于国栋
杨春
杨勇
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Zhejiang Chemtrue Biomedical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
    • B01J23/89—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with noble metals
    • B01J23/892—Nickel and noble metals
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
    • B01J37/08—Heat treatment
    • B01J37/082—Decomposition and pyrolysis
    • B01J37/084—Decomposition of carbon-containing compounds into carbon
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
    • B01J37/08—Heat treatment
    • B01J37/10—Heat treatment in the presence of water, e.g. steam

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Abstract

The invention relates to a preparation method and application of a high-purity Relugolix key intermediate, which develops a high-efficiency catalytic hydrogenation technology by preparing an environment-friendly palladium-based bimetallic biomass supported catalyst, and develops and prepares a high-purity Raffin Lu Geli key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound and dihydrochloride thereof. The invention has the advantages of high catalyst activity, good stability, high dispersity of active components, long service life, repeated use for many times, short flow, simple operation, easy control of reaction, simple equipment requirement and the like; the prepared Relugolix key intermediate has high purity and good stability.

Description

Preparation method and application of high-purity Relugolix key intermediate
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of bulk drugs, and particularly relates to a preparation method and application of a high-purity Relugolix key intermediate.
Background
The chemical name of rayleigh Lu Geli (Relugolix) is: n- [4- [1- [ (2, 6-difluorophenyl) methyl ] -5- [ (dimethylamino) methyl ] -1,2,3, 4-tetrahydro-3- (6-methoxy-3-pyridazinyl) -2, 4-dioxothieno [2,3-D ] pyrimidin-6-yl ] phenyl ] -N' -methoxyurea, a gonadotropin releasing hormone antagonist (GnRH) developed by the Japanese Wuta-tsi company, marketed in Japan in 2018, is a small molecule gonadotropin releasing hormone (GnRH) receptor antagonist potentially useful for uterine fibroids, endometriosis, prostate cancer and other indications.
The chemical structure is as follows:
the safety and efficacy of Relugolix and leuprorelin (leuprorelin) for treating menorrhagia, as well as the pain symptoms associated with uterine fibrosis, were compared by the martial arts pharmacy through a series of clinical phase III studies conducted in Japan, and finally confirmed for uterine fibroids. Along with the continuous rising of sales, the demand of the bulk drug of Lu Geli also rises continuously, so the requirements on the preparation process of the bulk drug are also higher and higher. The existing preparation process of the Rui Lu Geli still has a series of problems of long route, high cost, environment friendliness, unstable quality and the like. There is a real need to optimize and improve the manufacturing process of the r.p. Lu Geli.
Chinese patent CN 112745304A discloses a preparation method of Relugolix and an intermediate compound, wherein a palladium metal catalyst is used in the preparation method of a key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound of Relugolix, and the synthetic route is as follows:
the prior art mainly has the following problems: 1) The used palladium catalyst has larger dosage (5-10 percent), the production cost is increased along with the rising of the price of the metal palladium, the product is easy to turn black during hydrogenation, the treatment difficulty is increased, and the metal palladium is still remained; 2) The defluorinated impurity which is difficult to remove is easy to generate during hydrogenation reduction, meanwhile, the impurity is difficult to separate in the existing liquid phase analysis method, and is difficult to remove in the subsequent step, so that the method has great quality hidden trouble; 3) Trace defluorinated impurities can affect the purity of subsequent amino groups, affect the salifying quality, cause a mixture of amino-compound monohydrochloride and dihydrochloride, and cannot prepare dihydrochloride of a high-purity Relugolix key intermediate.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method and application of a high-purity Relugolix key intermediate, and the invention develops an efficient catalytic hydrogenation technology by preparing an environment-friendly catalyst, and develops and prepares a high-purity Rayleigh Lu Geli key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a preparation method of a high-purity Relugolix key intermediate comprises the following steps:
(1) The chitosan, palladium salt and other metal salts form a complex, and then the complex is subjected to hydrothermal reaction to prepare the palladium bimetallic biomass supported catalyst;
(2) Taking a compound A with a structural formula shown in (I) and a palladium-based bimetallic biomass supported catalyst, adding a solvent into a reaction kettle, and replacing the system with nitrogen atmosphere;
(3) Introducing hydrogen, replacing the system with hydrogen atmosphere, stirring for 3-12 h at 0-60 ℃, and after the reaction is finished, performing post-treatment (filtering and spin-drying the solvent) to obtain a white solid compound B with a structural formula shown as (II), namely a Relugolix key intermediate.
The synthetic route is as follows:
preferably, the defluorinated impurity in the white solid is less than 0.01%.
The purity grade of the reagent related to the invention is more than Chemical Purity (CP), and palladium salt and chitosan are purchased from the carbofuran technology Co.
Preferably, the palladium salt is any one of palladium chloride, palladium acetate, palladium bromide and palladium nitrate, and more preferably palladium acetate; the other metal salt is nickel salt, copper salt or cobalt salt, wherein the nickel salt is any one of nickel chloride, nickel acetate, nickel bromide and nickel hydroxide, and more preferably is nickel acetate; the copper salt is any one of copper chloride, copper acetate, copper bromide, copper sulfate and copper fluoride; the cobalt salt is any one of cobalt chloride, cobalt acetate, cobalt bromide and cobalt hydroxide.
Preferably, the molar ratio of chitosan, other metal salt and palladium salt is 50:1:0.1 to 1:1:0.1, more preferably 30:1: the hydrothermal reaction temperature is 50 to 80℃and more preferably 70℃at 0.1.
Preferably, the preparation method of the palladium-based bimetallic biomass supported catalyst comprises the following steps:
(a) Adding nickel acetate, palladium acetate and ethanol solvent into a four-mouth flask, slowly adding chitosan, heating the system to 70 ℃, and reacting for 20 hours; cooling to room temperature, filtering to remove ethanol, rinsing the filter cake with ethanol for 3 times, and drying the solid in a vacuum drying oven at 60 ℃ for 12 hours;
(b) Uniformly transferring the dried sample into a porcelain boat, and then placing the porcelain boat into a tube furnace; vacuumizing the tube furnace, and then flushing with nitrogen for half an hour; maintaining the circulation of nitrogen in the tube furnace, heating the tube furnace to 450-750 ℃ with a temperature gradient of 2 ℃/min, and maintaining the tube furnace in a nitrogen atmosphere for 2 hours; then, cooling the tube furnace to room temperature; the palladium-based bimetallic biomass supported catalyst at different temperatures is obtained.
The prepared catalyst was stored at room temperature in a screw-capped vial without any special air protection and was designated as ni—pd@cs- (450,550,650,750).
Preferably, the solvent in the step (2) is any one or any combination of two or more of methanol, ethanol, isopropanol, tertiary butanol, dichloromethane, dioxane, acetic acid ethyl acetate, benzene and toluene; r is any one of ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.
Preferably, the weight ratio of the palladium-based bimetallic biomass supported catalyst to the compound A is 0.001 to 0.01:1.
the application of the high-purity Relugolix key intermediate in preparing 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate dihydrochloride.
Preferably, the compound B is taken and added into an organic solvent for stirring and dissolving, hydrogen chloride gas or hydrogen chloride solution is added at the temperature of 0-40 ℃, after the addition is finished, the temperature is kept at 0-40 ℃ for stirring for 1-3 hours, filtering, washing and drying at 50 ℃ under reduced pressure, thus obtaining an off-white solid.
Preferably, the organic solvent is any one or any combination of more than two of ethyl acetate, ethanol, isopropanol, acetonitrile, dichloromethane, dioxane, acetic acid ethyl acetate, benzene and toluene; the hydrogen chloride solution is any one or any combination of more than two of hydrogen chloride methanol, hydrogen chloride ethyl acetate and hydrogen chloride dioxane solution.
Compared with the prior art, the invention has the beneficial effects that:
1. the catalyst has the advantages of high activity, good stability, high dispersity of active components, long service life, repeated use for a plurality of times, short flow, simple operation, easy control of reaction, simple equipment requirement and the like;
2. the prepared Relugolix key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound has high purity and good stability.
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto. Those skilled in the art can and should appreciate that any simple changes or substitutions based on the true spirit of the invention should fall within the scope of the invention as hereinafter claimed.
Example 1
The synthetic route of the invention is shown in figure 1, chitosan, palladium salt and nickel salt form a complex, and then the complex is subjected to hydrothermal reaction to prepare the palladium bimetallic biomass supported catalyst; dissolving the raw material A by using a solvent, adding a catalyst, introducing hydrogen into the mixture, heating the mixture to the temperature of between 0 and 60 ℃ and stirring the mixture for 3 to 12 hours, carrying out a central control reaction, filtering the mixture after the reaction is finished, and spin-drying the solvent to obtain a white solid.
Preparation of palladium-based bimetallic biomass supported catalyst
Adding nickel acetate, palladium acetate and ethanol solvent into a four-necked flask, and slowly adding chitosan, wherein the molar ratio of the chitosan to the nickel acetate to the palladium acetate is 30:1:0.1, the temperature of the system is raised to 70 ℃ and the reaction is carried out for 20 hours. Cooling to room temperature, filtering to remove ethanol, rinsing the filter cake with ethanol for 3 times, drying the solid in a vacuum drying oven at 60 ℃ for 12 hours, uniformly transferring the dried sample into a porcelain boat, and then placing into a tube furnace. The tube furnace was evacuated and then flushed with nitrogen for half an hour. The nitrogen flow was maintained in the tube furnace, the tube furnace was heated to 450 ℃ (550 ℃,650 ℃,750 ℃) with a temperature gradient of 2 ℃/min, and maintained in a nitrogen atmosphere for 2 hours. Thereafter, the tube furnace was cooled to room temperature. The prepared catalyst was stored at room temperature in a screw-capped vial without any special air protection and was designated Ni-Pd@CS-450 (Ni-Pd@CS-550, ni-Pd@CS-650, ni-Pd@CS-750).
Preparation of Relugolix key intermediates
100 g of compound A (R=isopropyl) is weighed, 0.5 g of catalyst Ni-Pd@CS-550 is added into a 2L hydrogenation kettle, 500mL of methanol is added, the system is replaced by nitrogen atmosphere, then the system is replaced by hydrogen atmosphere, stirring is carried out at room temperature for 3 hours, the catalyst is filtered, and the catalyst is used for preparing the catalystEluting with methanol, concentrating the filtrate under reduced pressure to dryness, and drying under reduced pressure to obtain 92.23 g of a product compound B (R=isopropyl), wherein the yield is 98.5%, the chemical purity is 99.6%, and the defluorinated impurity is 0.008%. 1 H NMR(500MHz,DMSO d6 )δ8.43(d,J＝8.0Hz,1H),8.29(s,1H),8.27(d,J＝5.3Hz,1H),7.78(s,1H),7.51(d,J＝6.5Hz,2H),7.27–7.23(m,1H),7.19–7.14(m,2H),6.76(s,1H),4.58(s,2H),3.88(s,3H),3.74(s,3H),2.89(t,J＝6.7Hz,2H),2.63(s,3H),2.36(t,J＝6.7Hz,2H),2.17(s,6H).
Example 2
100 g of compound B (R=isopropyl) in example 1 is added into 0.5L of ethyl acetate to stir and dissolve, 0.5L of 4M hydrogen chloride dioxane solution is added dropwise under stirring at the temperature of 20 ℃, a large amount of crystals are separated out along with half of the dropwise addition, the mixture is stirred at the temperature of 20 ℃ for 3 hours after the dropwise addition, the mixture is filtered, washed with a small amount of dioxane, leached with ethyl acetate and washed with n-heptane, and dried under reduced pressure at the temperature of 50 ℃ to obtain an off-white solid (compound D), the off-white solid is easy to absorb moisture, the quick bagging and weighing are 103g, the yield is 91%, the HPLC purity is 99.7%, and the defluorinated impurity is 0.007%.
Example 3
100 g of the hydrogenated product in example 1 is added with 0.5L of acetonitrile, stirred and dissolved, 0.5L of 4M ethyl hydrogen chloride acetate solution is added dropwise under stirring at the temperature of 20 ℃, a large amount of crystals are precipitated after the addition is completed, the mixture is stirred at the temperature of 20 ℃ for 3 hours after the addition is completed, filtered, washed with a small amount of acetonitrile, leached with ethyl acetate, washed with n-heptane and dried at the temperature of 50 ℃ under reduced pressure to obtain an off-white solid, the off-white solid is easy to absorb moisture, the yield is 92% after quick bagging and weighing, and the defluorinated impurity is 0.005%.
Example 4
Under the catalysis condition of the example 1, the catalyst can be recycled for 5 times, and the catalysis effect is not obviously reduced, and is shown in the table 1:
TABLE 1
Example 5
100 g of the hydrogenated product in example 1 is added with 0.5L of acetonitrile, stirred and dissolved, 0.5L of 4M hydrogen chloride dioxane solution is added dropwise under stirring at the temperature of 20 ℃, a large amount of crystals are precipitated after the mixture is added dropwise, the mixture is stirred at the temperature of 20 ℃ for 3 hours after the completion of the dropwise addition, filtered, washed with a small amount of acetonitrile, rinsed with dioxane, washed with n-heptane and dried at the temperature of 50 ℃ under reduced pressure to obtain an off-white solid, the off-white solid is easy to absorb moisture, the weight of the off-white solid is 105g after quick bagging and weighing, the yield is 93%, the HPLC purity is 99.6%, and the defluorinated impurity is 0.004%.
Example 6
100 g of the hydrogenated product in example 1 is added with 0.5L of dioxane, stirred and dissolved, 0.5L of 4M hydrogen chloride dioxane solution is added dropwise under stirring at the temperature of 20 ℃, a large amount of crystals are separated out along with half of the dropwise addition, stirring is carried out at the temperature of 20 ℃ for 3 hours after the dropwise addition is finished, filtering is carried out, a small amount of acetonitrile is used for washing, dioxane is used for leaching, n-heptane is used for washing, and the obtained product is dried under reduced pressure at 50 ℃ to obtain an off-white solid, the off-white solid is easy to absorb moisture, the product is rapidly packaged and weighed into 108g, the yield is 95%, the HPLC purity is 99.7%, and the defluorinated impurity is 0.005%.
Example 7
100 g of compound B (hydrogenated product) in example 1 is added with 0.5L of ethyl acetate to be dissolved by stirring, 0.5L of 4M ethyl hydrogen chloride solution is added dropwise under stirring at the temperature of 20 ℃, a large amount of crystals are separated out after the mixture is added dropwise, the mixture is stirred at the temperature of 20 ℃ for 3 hours after the completion of the dropwise addition, the mixture is filtered, washed with a small amount of ethyl acetate, leached with ethyl acetate, washed with n-heptane and dried at the temperature of 50 ℃ under reduced pressure to obtain an off-white solid (compound D), the off-white solid is easy to absorb moisture, the quick package is weighed to 105g, the yield is 93%, the HPLC purity is 99.8%, and the defluorinated impurity is 0.003%
The prepared Relugolix key intermediate 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-formate compound has high purity and small defluorinated impurities, and is easy to prepare hydrochloride with high purity, and the purity and related impurities of the prepared Relugolix key intermediate have no obvious change after being placed for 1 year.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.

Claims (4)

1. The preparation method of the high-purity Relugolix key intermediate is characterized by comprising the following steps of:
(1) Preparation of palladium-based bimetallic biomass supported catalyst
Adding nickel acetate, palladium acetate and ethanol solvent into a four-necked flask, and slowly adding chitosan, wherein the molar ratio of the chitosan to the nickel acetate to the palladium acetate is 30:1:0.1, heating the system to 70 ℃ and reacting for 20 hours; cooling to room temperature, filtering to remove ethanol, rinsing the filter cake with ethanol for 3 times, drying the solid in a vacuum drying oven at 60 ℃ for 12 hours, uniformly transferring the dried sample into a porcelain boat, and then placing into a tube furnace; vacuumizing the tube furnace, and then flushing with nitrogen for half an hour; maintaining the nitrogen flowing in the tube furnace, heating the tube furnace to 550 ℃ with a temperature gradient of 2 ℃/min, and maintaining the tube furnace in a nitrogen atmosphere for 2 hours; then, cooling the tube furnace to room temperature; the prepared catalyst was stored in a screw-capped vial at room temperature without any special air protection, and was named ni—pd@cs-550;
(2) Preparation of Relugolix key intermediates
Weighing 100 g of a compound A with a structural formula shown in (I), wherein R is isopropyl, adding 0.5 g of a catalyst Ni-Pd@CS-550 into a 2L hydrogenation kettle, adding 500mL of methanol to replace the system with nitrogen atmosphere, replacing the system with hydrogen atmosphere, stirring at room temperature for reaction for 3 hours, filtering the catalyst, leaching with methanol, concentrating the filtrate under reduced pressure to dryness, and drying under reduced pressure to obtain a product compound B92.23 g with a structural formula shown in (II), wherein R is isopropyl, the yield is 98.5%, the chemical purity is 99.6%, and the defluorinated impurity is 0.008%;
。
2. a method for preparing 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-carboxylic acid ester dihydrochloride, which is characterized by comprising the following steps: the preparation method comprises the preparation method of the high-purity Relugolix key intermediate in claim 1.
3. The process for preparing 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-carboxylic acid ester dihydrochloride according to claim 2, wherein: adding the compound B into an organic solvent, stirring and dissolving, controlling the temperature to be 0-40 ℃, adding hydrogen chloride gas or hydrogen chloride solution, after the addition, keeping the temperature to be 0-40 ℃, stirring for 1-3 hours, filtering, washing, and drying at 50 ℃ under reduced pressure to obtain an off-white solid.
4. A process for the preparation of 2- ((2, 6-difluorobenzyl) (ethoxycarbonyl) amino) -4- ((dimethylamino) methyl) -5- (4-aminophenyl) thiophene-3-carboxylic acid ester dihydrochloride according to claim 3, wherein: the organic solvent is any one or any combination of more than two of ethyl acetate, ethanol, isopropanol, acetonitrile, dichloromethane, dioxane, acetic acid ethyl acetate, benzene and toluene; the hydrogen chloride solution is any one or any combination of more than two of hydrogen chloride methanol solution, hydrogen chloride ethyl acetate solution and hydrogen chloride dioxane solution.
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WO2024126674A1 (en) * 2022-12-15 2024-06-20 Medichem, S.A. Process for the preparation of relugolix
CN116655745B (en) * 2023-07-31 2023-10-13 杭州湃肽生化科技有限公司 Application of intermediate in preparation of buserelin

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Denomination of invention: Preparation method and application of a key intermediate for high-purity Relugolix

Granted publication date: 20231229

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