CN115340481A - Method for industrially producing deuterated medical intermediate by adopting immobilized nickel catalysis - Google Patents
Method for industrially producing deuterated medical intermediate by adopting immobilized nickel catalysis Download PDFInfo
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- CN115340481A CN115340481A CN202210941633.7A CN202210941633A CN115340481A CN 115340481 A CN115340481 A CN 115340481A CN 202210941633 A CN202210941633 A CN 202210941633A CN 115340481 A CN115340481 A CN 115340481A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention relates to a method for industrially producing a deuterated medical intermediate D by adopting immobilized nickel catalysis, which has the advantages of mild reaction line conditions, high conversion rate and selectivity, high reaction yield and reaction efficiency, high deuterium abundance, low energy consumption, convenient post-treatment and simple reaction operation, and is more suitable for industrial production. The intermediate D can be prepared with high yield, the yield can reach about 90 percent, and the product purity and the deuterium abundance both reach more than 99 percent, thereby reaching the pharmaceutical level.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for industrially producing a deuterated medical intermediate D by adopting supported nickel catalysis.
Background
The novel coronavirus SARS-CoV-2 is a new strain of coronavirus which has not been found in human body before, is found and reported for the first time in 2019, and is not well controlled in many national regions.
After people are infected with coronavirus, the common signs of the person are respiratory symptoms, fever, cough, shortness of breath, dyspnea and the like. In more severe cases, the infection can lead to pneumonia, severe acute respiratory syndrome, renal failure, and even death, and there is currently no specific treatment for the disease caused by the novel coronavirus.
The novel deuterated cyano compound is a micromolecular 3CL protease inhibitor independently developed by Shanghai Gusen pharmaceutical Co., ltd, can prevent viruses from cutting long protein chains into parts required by self-replication by inhibiting main protease, and has the structure as follows:
in vitro experiments prove that the compound has surprising anti-SARS-CoV-2 activity, can effectively inhibit the replication of viruses, and has the more surprising pharmacokinetic characteristic that the oral anti-new crown medicament developed by the Bipicerel and Merck is superior on the basis of equivalent virus antibacterial activity. Further, shanghai Valencon pharmaceutical Co., ltd applied an invention patent for the above novel deuterated cyano compound (application No. CN 202111234708X).
The deuterated pharmaceutical intermediate D is a key intermediate for synthesizing the novel deuterated cyano compound, the quality of the preparation process of the deuterated pharmaceutical intermediate D also has great influence on the quality and the cost of a final product, and the deuterated pharmaceutical intermediate D has the chemical formula as follows:
although the applicant's prior patent CN202111234708X reports deuterated pharmaceutical intermediate D and its synthetic route, i.e. compound B is used as starting material, and is cyclized to obtain D via intermediate state C in the presence of boron deuteride and cobalt chloride. The route is as follows:
however, the above routes fail to provide quality descriptions of intermediates, and after repetition, the deuterium abundance of the intermediates is found to be low, the cost is high, and the intermediates are not suitable for scale-up production, and optimization is performed on the basis of the route of the subsequent applicant patent CN2022100574053 due to production requirements. The route is as follows:
the above route uses Pd/C, ptO 2 Raney nickel catalystThe catalyst is high in activity, flammable and explosive, is stored in water frequently, can bring a hydrogen source to influence the product quality when being directly used, has potential safety hazards and quality risks even if being used after being treated by a deuterated solvent, and can not be amplified particularly in production or needs equipment transformation, so that the cost is greatly increased, and optimization is performed on the basis of the production requirement.
Disclosure of Invention
Based on the method, the invention provides a method for industrially producing the deuterated medical intermediate D by adopting the catalysis of the immobilized nickel, and the method has the advantages of simple preparation process route, safe and easily-obtained catalyst, low cost, high yield and purity and suitability for industrial production.
The specific technical scheme is as follows:
in a solvent, the compound B is subjected to deuteration reduction reaction in the presence of a catalyst/deuterium gas to obtain an intermediate D, and the reaction route is as follows:
the catalyst is selected from solid supported nickel.
The solid supported nickel procatalyst is nickel.
The content of the nickel is 55-70%.
The solid supported nickel carrier is at least one of diatomite, alumina, silica and titanium oxide.
Preferably, the support is selected from alumina.
The preparation method of the solid supported nickel comprises the following steps: through precipitation and other techniques, the active component nickel is highly dispersed on the carrier, and then the finished product is formed through the procedures of filtering, washing, drying, roasting, reduction, passivation and the like. The brief flow is as follows:
the solvent is selected from a deuterated solvent, a non-deuterated solvent or a combination of deuterated solvents and non-deuterated solvents.
Preferably, the solvent is selected from deuterated solvents.
Preferably, the deuterated solvent is selected from heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons and deuterated ethers.
Preferably, the deuterated solvent is selected from at least one of deuterium oxide, deuterated methanol-d 1, deuterated methanol-d 4, deuterated ethanol-d 1, deuterated ethanol-d 6, deuterated isopropanol-d 1 and deuterated isopropanol-d 8, including but not limited to mixed solvents in any mixed form of the solvents listed above.
In some embodiments, the solvent is selected from water, alcohols, esters, hydrocarbons, ethers, preferably at least one of methanol, ethanol, tetrahydrofuran, ethyl acetate, and methyl tetrahydrofuran, including but not limited to any mixture of the above listed solvents.
Preferably, compound B needs to be pretreated before the reaction.
Preferably, the treatment is a non-deuterated and deuterated combination solvent wash.
Preferably, the deuterated solvent of the treatment mode is at least one selected from heavy water, deuterated alcohols, deuterated esters, deuterated hydrocarbons and deuterated ethers, and is preferably heavy water; the non-deuterated solvent is at least one selected from water, alcohols, esters, hydrocarbons and ethers, and preferably at least one selected from tetrahydrofuran, ethyl acetate and methyltetrahydrofuran.
Preferably, the weight ratio of the deuterated solvent to the B in the treatment manner is at least 5%.
Preferably, the reaction temperature is 25 to 100 ℃, preferably 30 to 60 ℃.
The preparation route of the deuterated pharmaceutical intermediate D has the following advantages and beneficial effects:
(1) The invention has high reaction conversion rate and selectivity, greatly improves the reaction yield and the deuterium abundance, reduces the cost, ensures that the yield can reach about 90 percent, and ensures that the product purity and the deuterium abundance reach more than 99 percent;
(2) The method has the advantages of high reaction efficiency, low reaction temperature, low energy consumption and simple reaction operation, and multiple steps are carried out at normal temperature;
(3) The synthesis route of the invention has mild conditions and convenient post-treatment, and is more suitable for industrial production.
Drawings
Fig. 1 is a nuclear magnetic hydrogen spectrum diagram of the deuterated pharmaceutical intermediate D.
Fig. 2 is a mass spectrum of the deuterated pharmaceutical intermediate D.
The specific implementation mode is as follows:
the method for industrially producing the deuterated pharmaceutical intermediate D by using the supported nickel catalyst of the invention is further described in detail with reference to specific examples.
The following detailed description is exemplary and explanatory only and is not restrictive.
The following examples, unless otherwise indicated, all solvents and reagents used were commercially available and used as received.
The following abbreviations are used herein:
D 2 : deuterium gas
Synthesis of intermediate D
The chemical formula is as follows: c 13 H 20 D 2 N 2 O 5
Molecular weight: 288.34
Example 1
Pretreating the compound B with a tetrahydrofuran/heavy water mixed solvent, and then spin-drying for later use.
The treated B (1.0kg, 3.24mol) was charged in a 20L hydrogenation reactor, deuterated methanol-d 4 (5.0L, 5V) was added, and nickel supported on alumina (nickel content 63.5%,300g,30wt% of Compound B) was added; sequentially replacing with nitrogen and deuterium for 2 times, and maintaining the pressure of deuterium at 0.5Mpa; the temperature of the system is raised to 55 ℃, and the reaction is kept for 18 hours. After the reaction reaches the end point, the diatomite is filled in for filtration, and the filter cake is leached by methanol. The solvent was removed by concentration under reduced pressure and the crude product was dissolved in 10L of dichloromethane. The organic phase was collected by washing 1 time with 5L of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent from the filtrate. The crude product is crystallized and purified by a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and is filtered to obtain a white solid with the purity of 99 percent, the yield of 90 percent and the deuterium abundance of 99 percent.
LC-MS(ESI，m/z，C 13 H 20 D 2 N 2 O 5 ，189.17，[M+1]＝M-100+1)
1 H NMR(500MHz,CDCl 3 )δ:6.16(s,1H),5.51(d,1H),4.30～4.32(m,1H), 3.73(s,3H),2.42～2.48(m,2H),2.10～2.15(m,1H),1.83-1.81(m,2H),1.27(s,9H)。
Example 2
Pretreating the compound B with an ethyl acetate/deuterated methanol-d 1 mixed solvent, and then spin-drying for later use.
The treated B (1.0kg, 3.24mol) was charged in a 20L hydrogenation reactor, deuterated methanol-d 1 (5.0L, 5V) was added, and nickel supported on silica (nickel content 59.5%,300g,30wt% of Compound B) was added; sequentially replacing with nitrogen and deuterium for 2 times, and maintaining the pressure of deuterium at 0.5Mpa; the temperature of the system is raised to 55 ℃, and the reaction is carried out for 18 hours under the condition of heat preservation. After the reaction reaches the end point, the diatomite is filled in for filtration, and the filter cake is leached by methanol. The solvent was removed by concentration under reduced pressure and the crude product was dissolved in 10L of dichloromethane. The organic phase was collected by washing 1 time with 5L of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent from the filtrate. The crude product is crystallized and purified by a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and white solid D is obtained by filtration, wherein the purity is 97%, the yield is 88%, and the abundance of deuterium is 97%.
Example 3
Pretreating the compound B with a mixed solvent of methyltetrahydrofuran and heavy water, and then spin-drying for later use.
The treated B (1.0kg, 3.24mol) was charged into a 20L hydrogenation reactor, deuterated ethanol-d 1 (5.0L, 5V) was added, and diatomaceous earth-supported nickel (nickel content 56.2%,300g,30wt% of Compound B) was added; sequentially replacing with nitrogen and deuterium for 2 times, and maintaining the pressure of deuterium at 0.5Mpa; the temperature of the system is raised to 55 ℃, and the reaction is kept for 18 hours. After the reaction reaches the end point, the diatomite is filled in for filtration, and the filter cake is leached by methanol. The solvent was removed by concentration under reduced pressure and the crude product was dissolved in 10L of dichloromethane. The organic phase was collected by washing 1 time with 5L of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent from the filtrate. The crude product is crystallized and purified by a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and is filtered to obtain a white solid D with the purity of 95 percent, the yield of 81 percent and the deuterium abundance of 96 percent.
Example 4
Pretreating the compound B with an ethyl acetate/deuterated ethanol-d 1 mixed solvent, and then spin-drying for later use.
The treated B (1.0kg, 3.24mol) was charged in a 20L hydrogenation reactor, deuterated ethanol-d 1 (5.0L, 5V) was added, and nickel supported titanium oxide (nickel content 69.2%,300g,30wt% of Compound B) was added; sequentially replacing with nitrogen and deuterium for 2 times, and maintaining the pressure of deuterium at 0.5Mpa; the temperature of the system is raised to 55 ℃, and the reaction is kept for 18 hours. After the reaction reaches the end point, the diatomite is filled in for filtration, and the filter cake is leached by methanol. The solvent was removed by concentration under reduced pressure and the crude product was dissolved in 10L of dichloromethane. The organic phase was collected by washing 1 time with 5L of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent from the filtrate. And crystallizing and purifying the crude product by using a mixed solution of methyl tert-butyl ether, petroleum ether and ethyl acetate, and filtering to obtain a white solid D with the purity of 95%, the yield of 83% and the deuterium abundance of 96%.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent should be subject to the appended claims.
Claims (12)
1. A method for industrially producing a deuterated medical intermediate D by adopting immobilized nickel catalysis is characterized by comprising the following steps:
in a solvent, the compound B is subjected to deuteration reduction reaction in the presence of a catalyst/deuterium gas to obtain an intermediate D, and the reaction route is as follows:
the catalyst is selected from solid supported nickel.
2. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst as claimed in claim 1, wherein the method comprises the following steps: the solid supported nickel procatalyst is nickel.
3. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst as claimed in claim 2, wherein the method comprises the following steps: the content of the nickel is 55-70%.
4. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst as claimed in claim 1, wherein the method comprises the following steps: the solid supported nickel carrier is at least one of diatomite, alumina, silica and titanium oxide, preferably alumina.
5. The method for industrially producing the deuterated pharmaceutical intermediate D by using the immobilized nickel as the catalyst of claim 1, wherein the immobilized nickel is used as the catalyst for the industrial production of the deuterated pharmaceutical intermediate D, and the method comprises the following steps: the solvent is selected from a deuterated solvent, a non-deuterated solvent or a combination of deuterated solvents and non-deuterated solvents.
6. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst as claimed in claim 5, wherein the method comprises the following steps: the deuterated solvent is at least one selected from the group consisting of deuterium oxide, deuterated alcohols, deuterated esters, deuterated hydrocarbons and deuterated ethers, and preferably at least one selected from the group consisting of deuterium oxide, deuterated methanol-d 1, deuterated methanol-d 4, deuterated ethanol-d 1, deuterated ethanol-d 6, deuterated isopropanol-d 1 and deuterated isopropanol-d 8.
7. The method of claim 5, wherein the method comprises the following steps: the non-deuterated solvent is at least one selected from water, alcohols, esters, hydrocarbons and ethers, preferably at least one selected from methanol, ethanol, tetrahydrofuran, ethyl acetate and methyltetrahydrofuran.
8. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst according to any one of claims 1 to 7, wherein the method comprises the following steps: the compound B needs to be pretreated before the reaction.
9. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst as claimed in claim 8, wherein the method comprises the following steps: the treatment mode is non-deuterated and deuterated combined solvent washing.
10. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst as claimed in claim 9, wherein the method comprises the following steps: the deuterated solvent is at least one selected from deuterium oxide, deuterated alcohols, deuterated esters, deuterated hydrocarbons and deuterated ethers, and is preferably deuterium oxide; the non-deuterated solvent is at least one selected from water, alcohols, esters, hydrocarbons and ethers, preferably at least one selected from tetrahydrofuran, ethyl acetate and methyltetrahydrofuran.
11. The method of claim 10, wherein the supported nickel is used for the industrial production of the deuterated pharmaceutical intermediate D by catalysis, and the method comprises the following steps: the weight ratio of the deuterated solvent to the B is at least 5 percent.
12. The method for industrially producing the deuterated pharmaceutical intermediate D by using the nickel-supported catalyst according to any one of claims 1 to 11, wherein the method comprises the following steps: the reaction temperature is 25-100 ℃.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210941633.7A CN115340481A (en) | 2022-08-08 | 2022-08-08 | Method for industrially producing deuterated medical intermediate by adopting immobilized nickel catalysis |
| PCT/CN2022/126723 WO2024031838A1 (en) | 2022-08-08 | 2022-10-21 | Method for industrially producing deuterated pharmaceutical intermediate by means of catalysis of solid-supported nickel |
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| CN202210941633.7A CN115340481A (en) | 2022-08-08 | 2022-08-08 | Method for industrially producing deuterated medical intermediate by adopting immobilized nickel catalysis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024045292A1 (en) * | 2022-09-01 | 2024-03-07 | 广州谷森制药有限公司 | Method for catalytic industrial production of deuterated pharmaceutical intermediate by means of combination of immobilized nickel and organic alkali |
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| AR076936A1 (en) * | 2009-06-02 | 2011-07-20 | Vitae Pharmaceuticals Inc | CARBAMATE AND UREA INHIBITORS OF THE 11 BETA HYDROXIESTEROID DEHYDROGENASE 1 |
| CN115583984A (en) * | 2022-01-11 | 2023-01-10 | 嘉兴安谛康生物科技有限公司 | Azaspiro compound and preparation method, pharmaceutical composition and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024045292A1 (en) * | 2022-09-01 | 2024-03-07 | 广州谷森制药有限公司 | Method for catalytic industrial production of deuterated pharmaceutical intermediate by means of combination of immobilized nickel and organic alkali |
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