CN115785062A - Method for preparing intermediate of Rui Lu Geli by continuous hydrogenation - Google Patents
Method for preparing intermediate of Rui Lu Geli by continuous hydrogenation Download PDFInfo
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- CN115785062A CN115785062A CN202211685349.4A CN202211685349A CN115785062A CN 115785062 A CN115785062 A CN 115785062A CN 202211685349 A CN202211685349 A CN 202211685349A CN 115785062 A CN115785062 A CN 115785062A
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- 238000005984 hydrogenation reaction Methods 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000000047 product Substances 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 9
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 238000011049 filling Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 229910018072 Al 2 O 3 Inorganic materials 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 238000005352 clarification Methods 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 1
- 230000014759 maintenance of location Effects 0.000 abstract description 3
- 238000004880 explosion Methods 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 238000006722 reduction reaction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 4
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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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
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing a Rui Lu Geli intermediate by continuously hydrogenating and reducing nitro. The method comprises the following steps: s1, adding a Rui Lu Geli intermediate I into a solvent, stirring and clarifying, adding activated carbon, stirring for 1h, filtering to obtain a filtrate, and filling a reaction tube with a noble metal supported catalyst; s2, conveying the filtrate into a reaction tube through a plunger pump, and carrying out hydrogenation reaction under the action of a metal supported catalyst to generate an intermediate II of the Rui Lu Geli. Wherein the temperature of the continuous hydrogenation reduction reaction is 60-120 ℃. Conversion rate and selectivity of Rui Lu Geli intermediate I are both greater than 98%, and product purity is greater than 98%. The method has the advantages of mild process, simple and convenient operation and small hydrogen carrying capacity, solves the problem of high explosion risk caused by large hydrogen retention in the traditional kettle type process, and greatly improves the product quality and the yield.
Description
Technical Field
The invention relates to a method for preparing a Rui Lu Geli intermediate by continuous hydrogenation
Background
Reg Lu Geli is the first oral gonadotropin releasing hormone receptor antagonist (GnRH) to treat advanced prostate cancer, and is approved by the FDA in us 12 months of 2020 for marketing.
Raey Lu Geli structural formula:
intermediate II (structural formula is shown below) is a key intermediate of Rui Lu Geli
The preparation of the compound II reported at present mainly adopts the traditional intermittent process to add zinc and dilute hydrochloric acid for reaction, so that the nitro group on the molecule of the intermediate I is converted into amino group, the method consumes large amount of zinc and dilute hydrochloric acid, and generates a large amount of waste liquid; the problems of difficult amplification, high safety risk, complex post-treatment operation and the like exist;
when the preparation mode of the intermediate II adopts a kettle type hydrogenation process, the problems of large heat release amount, large hydrogen viscous flow, poor reaction selectivity caused by debenzylation byproducts and the like exist.
Therefore, a method for preparing the intermediate II of Rui Lu Geli through continuous hydrogenation needs to be found, and the requirements of safe production and product quality are met while energy conservation and emission reduction are realized.
Disclosure of Invention
The invention aims to overcome the defects and provides a method for preparing a Rui Lu Geli intermediate by continuous hydrogenation, the inventor can realize the continuous hydrogenation preparation of a Rui Lu Geli intermediate II by using a fixed bed continuous hydrogenation reactor in accidental cases, the conversion rate of the hydrogenation reaction can reach 100%, and the product purity is more than 98%. In addition, the continuous hydrogenation preparation method of the intermediate Rui Lu Geli avoids subsequent operations such as filtration and pH adjustment, has the advantages of simple process, small hydrogen carrying capacity and mild reaction conditions, and solves the problems of high explosion risk caused by large hydrogen retention, poor selectivity quality caused by hydrogenation debenzylation and the like in the traditional kettle type process.
In order to achieve the purpose, the invention provides the following technical scheme, and the method for preparing the intermediate of the Ry Lu Geli by continuous hydrogenation comprises the following steps:
s1, adding Rui Lu Geli intermediate 1 into a solvent, stirring for clarification, adding activated carbon, stirring for 1h, filtering to obtain a filtrate, filling a reaction tube with a noble metal load catalystAn oxidizing agent; wherein the noble metal supported catalyst is Pd/C, pt/C, pd/Al 2 O 3 ，Pt/Al 2 O 3 ，Pd(OH) 2 /Al 2 O 3 ；
And S2, conveying the solution into a reaction tube through a plunger pump, and quantitatively conveying hydrogen into the reaction tube by using a hydrogen mass flow meter to complete hydrogenation reaction.
And S3, concentrating the reaction solution to be dry to obtain a solid target product II.
Wherein the intermediate I is a compound shown as a formula (1), the intermediate II is a compound shown as a formula (2), and the involved reaction equation is as follows:
preferably, the solvent in S1 is any one or more of acetonitrile, ethyl acetate, N-N dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and is further preferably acetonitrile and/or ethyl acetate.
Preferably, the mass ratio of the intermediate i of the rayleigh Lu Geli in S1 to the noble metal supported catalyst is 20.
Preferably, the mass ratio of the intermediate I of Rayleigh Lu Geli in S1 to the solvent is 1:5-1, such as 1:6.
Preferably, the reaction tubes in the S1 and the S2 are fixed bed reactors.
Preferably, the reaction temperature in the fixed bed reactor is 60-120 ℃, the reaction pressure is 1.0-2.5 MPa, the retention time of the filtrate in the fixed bed reactor is 18-54 min, the flow rate of a plunger pump is 0.1ml/min, and the set flow rate of a hydrogen pump is 40-60ml/min.
Compared with the prior art, the invention has the positive effects that:
the method for preparing the intermediate of Rui Lu Geli by continuous hydrogenation can realize continuous hydrogenation preparation of the key intermediate II of Rui Lu Geli, has simple process, can overcome the limitation of batch operation, and reduces the potential safety risk of reaction. The continuous hydrogenation device avoids the occurrence of side debenzylation reaction caused by over hydrogenation, and has higher conversion rate and selectivity of the reaction.
Drawings
The invention is explained in more detail below with reference to the drawings.
FIG. 1 is a schematic diagram of a reaction apparatus for the synthesis of intermediate II, rayleigh Lu Geli, by continuous hydrogenation, according to one embodiment of the present invention;
FIG. 2-1, FIG. 2-2, FIG. 2-3, FIG. 2-4, FIG. 2-5 are liquid chromatograms of the products of examples 1-5 measured by a liquid chromatograph.
Detailed Description
In order to make the technical means implemented by the present invention, and the purposes, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments.
Example 1
The embodiment provides a method for preparing a intermediates of Lu Geli by continuous hydrogenation, which comprises the following steps: to 90g of acetonitrile was added 10g of intermediate I Rayleigh Lu Geli with a substrate mass of 10%. Dissolving and clarifying, adding activated carbon with the mass of 4% of the substrate, stirring for 1 hour, and filtering. With N 2 After purging the fixed bed reactor for 5min, 2.2g of noble metal supported catalyst Pt/C was filled in the fixed bed reactor, and N was continuously used 2 Purging the reaction tube for 5min, and finally closing N 2 . The pressure of the back pressure valve is adjusted to be 2.2-2.5Mpa, and the temperature of the fixed bed reactor is adjusted to be 60 ℃. And simultaneously starting a plunger pump and hydrogen, setting the flow rate of the plunger pump to be 0.1ml/min and the flow rate of the hydrogen to be 40ml/min, continuously feeding the plunger pump and the hydrogen into the reaction system, keeping the reaction material in the reactor for 54min, collecting the product after flowing out of a material outlet, and directly concentrating the product until the solid target product is obtained, wherein the yield is 98% and the purity is 98.7%.
Example 2
The present example differs from example 1 in that: the temperature of the fixed bed reactor was 70 ℃. After the reaction is finished, the product flows out from a material outlet and is collected, and the product is directly concentrated to a solid target product, wherein the yield is 98 percent, and the purity is 98.5 percent.
Example 3
This example differs from example 1 in that: the catalyst of the fixed bed reactor is Pt/Al 2 O 3 . After the reaction is finished, the product flows out from a material outlet and is collected, and the product is directly concentrated to a solid target product, wherein the yield is 97%, and the purity is 98.4%.
Example 4
This example differs from example 1 in that: the mass of the substrate in the filtrate was 5%, and the residence time of the reaction mass in the reactor was 18min. After the reaction is finished, the product flows out from a material outlet and is collected, and the product is directly concentrated to a solid target product, wherein the yield is 97%, and the purity is 98.7%.
Example 5
This example differs from example 1 in that: the mass of the substrate in the filtrate was 5%, and the hydrogen gas set flow rate was 60ml/min. After the reaction is finished, the product is collected after flowing out of a material outlet, and is directly concentrated to a solid target product, wherein the yield is 98%, and the purity is 100%.
Evaluation of effects
In examples 1 to 5, after the experiment was completed, the reaction solution was concentrated to a solid target product and sampled for analysis, and the analysis method used a liquid chromatography area normalization method to analyze the content of the product.
TABLE 1
| Examples | Rui Lu Geli intermediate II content (%) |
| 1 | 98.7 |
| 2 | 98.5 |
| 3 | 98.4 |
| 4 | 98.7 |
| 5 | 100.0 |
Comparative example 1
This comparative example differs from example 1 in that: the plunger pump was set to a flow rate of 0.3ml/min, and the final product content of this comparative example was only 27%, with a hydroxylamine intermediate content of 73% without further conversion. After the reaction is finished, the product flows out from a material outlet and is collected, and the product is directly concentrated to a solid target product, wherein the yield is 25 percent, and the purity is 27 percent.
Comparative example 2
The comparative example differs from example 1 in that: a batch reactor (a 100mL glass reaction bottle) is adopted for reaction, the concentration and the dosage of reactants are the same as those in example 1, the reaction is carried out for 10 hours under the condition of filling hydrogen, the purity of a reaction product is 48 percent, other impurities are all impurities generated by side reaction, and the problems of long time consumption, complex post-treatment operation and the like exist. After the reaction is finished, the reaction solution is filtered and directly concentrated to a solid target product, the yield is 43 percent, and the purity is 48 percent.
Comparative example 3
This comparative example differs from example 1 in that: the noble metal supported catalyst is Pd/C, and a large amount of impurities are generated due to side reaction in the reaction. After the reaction is finished, the reaction solution is filtered and directly concentrated to a solid target product, the yield is 10%, and the purity is 16.3%.
Claims (6)
1. A method for preparing a Rui Lu Geli intermediate by continuous hydrogenation reduction is characterized by comprising the following steps:
s1, putting Rui Lu Geli inAdding the intermediate I into a solvent, stirring for clarification, adding active carbon, stirring for 1h, filtering to obtain a filtrate, and filling a reaction tube with a noble metal supported catalyst; wherein the noble metal supported catalyst is Pd/C, pt/C, pd/Al 2 O 3 ，Pt/Al 2 O 3 ，Pd(OH) 2 /Al 2 O 3 ；
S2, conveying the filtrate into a reaction tube through a plunger pump, and quantitatively conveying hydrogen into a reaction system by using a hydrogen mass flow meter to complete a hydrogenation reaction;
and S3, concentrating the reaction solution to be dry to obtain a solid target product II.
The reaction equation is as follows:
2. the method for preparing the intermediate of Lu Geli by continuous hydrogenation according to claim 1, wherein the solvent in S1 is any one or more of acetonitrile, ethyl acetate, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
3. The method for preparing Rui Lu Geli intermediate by continuous hydrogenation according to claim 1, wherein the mass ratio of Rui Lu Geli intermediate I to the noble metal supported catalyst in S1 is 20.
4. The method for preparing Rui Lu Geli intermediate by continuous hydrogenation according to claim 1, wherein the mass ratio of Rui Lu Geli intermediate I to the solvent in S1 is 1:5-1, for example 1:6.
5. The method for preparing the intermediate of ri Lu Geli by continuous hydrogenation according to claim 1, wherein the reaction tubes in S1 and S2 are fixed bed reactors.
6. The method for preparing the intermediate of Lu Geli by continuous hydrogenation of claim 1, wherein the reaction temperature in the fixed bed reactor is 60-120 ℃, the reaction pressure is 1.0-2.5 MPa, the residence time of the filtrate in the fixed bed reactor is 18-54 min, the flow rate of the plunger pump is 0.1ml/min, and the set flow rate of the hydrogen pump is 40-60ml/min.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0421878A1 (en) * | 1989-10-04 | 1991-04-10 | Rhone-Poulenc Chimie | Process for the hydrogenation of halogenated nitroaromatic derivatives in the presence of noble metal-based catalysts |
| CN111333633A (en) * | 2020-04-01 | 2020-06-26 | 江西青峰药业有限公司 | Rugosril intermediate compound and preparation method and application thereof |
| CN111423452A (en) * | 2020-03-26 | 2020-07-17 | 江西青峰药业有限公司 | Rugoside intermediate, preparation method and application thereof |
| CN112745304A (en) * | 2019-10-29 | 2021-05-04 | 上海度德医药科技有限公司 | Preparation method of Relugolix and intermediate compound |
| CN113501830A (en) * | 2021-07-14 | 2021-10-15 | 山东百诺医药股份有限公司 | Preparation method of Ruogeli |
| CN113563363A (en) * | 2020-12-30 | 2021-10-29 | 上海博志研新药物技术有限公司 | Rugoside intermediate, preparation method thereof and preparation method of Rugoside |
| CN113717149A (en) * | 2021-09-29 | 2021-11-30 | 成都伊诺达博医药科技有限公司 | Ruogeli key intermediate and preparation method thereof |
| CN114230576A (en) * | 2021-12-21 | 2022-03-25 | 伊诺药物研究(南京)有限公司 | Preparation method of Ruogeli |
| CN115417883A (en) * | 2022-09-16 | 2022-12-02 | 浙江科聚生物医药有限公司 | Crystal form of Rui Lu Geli and preparation method thereof |
-
2022
- 2022-12-27 CN CN202211685349.4A patent/CN115785062A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0421878A1 (en) * | 1989-10-04 | 1991-04-10 | Rhone-Poulenc Chimie | Process for the hydrogenation of halogenated nitroaromatic derivatives in the presence of noble metal-based catalysts |
| CN112745304A (en) * | 2019-10-29 | 2021-05-04 | 上海度德医药科技有限公司 | Preparation method of Relugolix and intermediate compound |
| CN111423452A (en) * | 2020-03-26 | 2020-07-17 | 江西青峰药业有限公司 | Rugoside intermediate, preparation method and application thereof |
| CN111333633A (en) * | 2020-04-01 | 2020-06-26 | 江西青峰药业有限公司 | Rugosril intermediate compound and preparation method and application thereof |
| CN113563363A (en) * | 2020-12-30 | 2021-10-29 | 上海博志研新药物技术有限公司 | Rugoside intermediate, preparation method thereof and preparation method of Rugoside |
| CN113501830A (en) * | 2021-07-14 | 2021-10-15 | 山东百诺医药股份有限公司 | Preparation method of Ruogeli |
| CN113717149A (en) * | 2021-09-29 | 2021-11-30 | 成都伊诺达博医药科技有限公司 | Ruogeli key intermediate and preparation method thereof |
| CN114230576A (en) * | 2021-12-21 | 2022-03-25 | 伊诺药物研究(南京)有限公司 | Preparation method of Ruogeli |
| CN115417883A (en) * | 2022-09-16 | 2022-12-02 | 浙江科聚生物医药有限公司 | Crystal form of Rui Lu Geli and preparation method thereof |
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