CN107474105B - Preparation method of bulk drug obitasvir - Google Patents
Preparation method of bulk drug obitasvir Download PDFInfo
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- CN107474105B CN107474105B CN201710644963.9A CN201710644963A CN107474105B CN 107474105 B CN107474105 B CN 107474105B CN 201710644963 A CN201710644963 A CN 201710644963A CN 107474105 B CN107474105 B CN 107474105B
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- C—CHEMISTRY; METALLURGY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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Abstract
The invention discloses a preparation method of bulk drug obipitavir, which comprises a reduction reaction S1 of a double nitro group in an intermediate 1- (4- (tert-butylphenyl) -2, 5-bis (4-nitrophenyl)) pyrrolidine, a proline peptide coupling reaction S2 of a double amino group, a deprotection reaction S3 of a pyrrolidine amino group and a valine peptide coupling reaction S4 of the pyrrolidine amino group. The preparation method of the bulk drug obitasvir adopts 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride as a valine peptide coupling reagent, and compared with peptide coupling reagents such as EDAC/HOBT, PyBOP, HATU, T3P and the like disclosed in the prior art, the final product synthesis step has higher yield, and the product separation and purification are simpler and more convenient.
Description
Technical Field
The invention relates to the field of medicine synthesis, and particularly relates to a preparation method of bulk drug obitasvir.
Background
Orbetavir, also known as pulsatilla beavatavir, is one of the main components in ABT triple anti-hepatitis c drugs, and has the following structure:
CN 102333772A, CN 103172620A, CN 103819459A discloses a series of synthesis methods of antiviral compounds, which comprises reduction of di-nitro group in intermediate 1- (4- (tert-butylphenyl) -2, 5-bis (4-nitrophenyl)) pyrrolidine, proline peptide coupling reaction of di-amino group and deprotection of pyrrolidine amino group and valine peptide coupling of pyrrolidine amino group.
Among them, the following are disclosed in patent documents regarding the coupling reaction of a proline peptide having a double amino group and the coupling treatment of a valine peptide having a pyrrolidino group as a final step: the compounds of the invention can be prepared by intermediate reactions using standard peptide coupling reagents and de-pyrrolidino-amino protecting agents. Specifically, the intermediate can be reacted with N-substituted proline or valine in the presence of a peptide coupling reagent such as EDAC (carbodiimide)/HOBT (1-hydroxybenzotriazole), PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), HATU (2- (7-azobenzotriazol) -tetramethyluronium hexafluorophosphate), T3P (propylphosphoric anhydride), or DEBPT in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as Hunig's base, pyridine, 2, 6-lutidine, or triethylamine to directly give the peptide coupling product.
However, the activities of peptide coupling nitrogen atoms of aniline and pyrrolidine amino are different, and the reaction yield is low because the peptide coupling of pyrrolidine amino is treated by adopting a solvent environment the same as or similar to the peptide coupling reaction of aniline and a peptide coupling reagent in the actual synthesis.
Disclosure of Invention
One of the purposes of the invention is to overcome the defects in the prior art and provide a preparation method of a bulk drug obitasvir, so as to solve the problems of high cost and complex process in the prior art.
In order to achieve the purpose, the technical scheme of the invention is as follows: a preparation method of bulk drug obitasvir is characterized by comprising a reaction formula of reduction reaction S1 of a double nitro group in intermediate 1- (4- (tert-butylphenyl) -2, 5-bis (4-nitrophenyl)) pyrrolidine, coupling reaction S2 of a double amino proline peptide, deprotection reaction S3 of a pyrrolidino group, and coupling reaction S4 and S4 of a pyrrolidino valine peptide:
wherein the peptide coupling reagent in S4 is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the molar ratio of the valine peptide coupling reagent to A4 is (2.5-3.2): 1.
The preferred technical scheme is that the peptide coupling reaction of S2 and/or S4 is carried out in the presence of nitrogen methyl morpholine. The nitrogen methyl morpholine has catalytic effect on the peptide coupling reaction, can accelerate the peptide coupling reaction and improve the conversion rate of the product to a certain extent.
The preferable technical scheme is that the solvent in S4 is at least one of dichloromethane, THF, chloroform and dichloroethane, and the volume ratio of the solvent of valine peptide coupling reaction to nitrogen methylmorpholine is (1.5-2.5): 1.
The preferable technical scheme is that the post-processing of S4 is as follows: and sequentially extracting an organic layer of the reaction solution after water quenching by adopting water, an organic acid aqueous solution and a sodium bicarbonate aqueous solution, and recovering dichloromethane from the organic layer to obtain an obitacvir crude product A5. Sodium bicarbonate reacts with trace amounts of organic acid in the organic phase, resulting in a salt of the organic acid with greater solubility in the aqueous phase and less residue in the organic phase.
Preferably, the organic acid is one or a combination of two or more selected from citric acid, tartaric acid and malic acid.
The preferred technical scheme is that the reaction formula of S3 is as follows:
the reaction solvent in S3 is one or more mixed solution selected from ethanol, methanol, isopropanol and n-propanol, the reactant hydrochloric acid is added into the reaction solution by the mixed solvent of hydrochloric acid and the reaction solvent, and the reaction temperature of S3 is 10-15 ℃.
The preferred technical scheme is that the reaction formula of S2 is as follows:
in the reaction of S2, the proline peptide coupling reagent is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and diisopropylethylamine, and the reaction solution after being quenched by adding water is sequentially extracted by water, citric acid solution and ammonia water solution. The ammonia water is adopted to react with a trace amount of citric acid in the extracted organic phase, and the obtained organic phase is alkalescent unlike S4 post-treatment, which is beneficial to improving the stability of the S2 product in the post-treatment process.
The preferable technical scheme is that the molar ratio of diisopropylethylamine to A2 is (2.8-3.1): 1, the molar ratio of proline peptide coupling reagent to A2 is (2-2.4): 1, and the molar ratio of BOC-L-proline to A2 is (2-2.4): 1.
The preferred technical scheme is that the reaction formula of S1 is as follows:
s1 hydrogenation reducing agent hydrogen, the catalyst is Raney nickel, the reaction solvent is formed by mixing tetrahydrofuran and methanol, and the mixing volume ratio of the tetrahydrofuran to the methanol is (3.8-4.5): 1.
The second purpose of the invention is to overcome the defects in the prior art and provide a preparation method of the obitasvir tablet, which is characterized by comprising the preparation method of the bulk drug obitasvir and the process step of mixing and pressing the active ingredient obitasvir and auxiliary materials into tablets.
The invention has the advantages and beneficial effects that:
the preparation method of the bulk drug obitasvir adopts 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride as a valine peptide coupling reagent, and compared with peptide coupling reagents such as EDAC/HOBT, PyBOP, HATU, T3P and the like disclosed in the prior art, the final product synthesis step has higher yield, and the product separation and purification are simpler and more convenient.
Detailed Description
The following further describes embodiments of the present invention with reference to examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
The production process of the orbetavir comprises the following steps:
s1: hydrogenation reduction of A1
Sequentially adding an intermediate 1- (4- (tert-butylphenyl) -2, 5-bis (4-nitrophenyl)) pyrrolidine (A1), tetrahydrofuran, methanol and a catalyst Raney nickel into a clean dry hydrogenation kettle, covering a hydrogenation kettle cover, and closing valves; detecting the air tightness of the device; purging (5 times of nitrogen replacement and 5 times of hydrogen replacement at 5 atm); heating to raise the temperature in the kettle to 29-32 ℃, and reacting overnight under the condition of 5 atmospheres of hydrogen; the next day, open, spot plate to check if the reaction is complete. TLC showed the reaction was complete, ready for post-treatment;
and (3) post-treatment: raney nickel was recovered by filtration and the solvent was recovered to give intermediate A2.
S2: a2 diamino proline peptide coupling
Dichloromethane is added into a clean reaction kettle and stirred. Adding the raw material BOC-L-proline at room temperature of 20 ℃, and uniformly stirring; adding diisopropylethylamine, and stirring uniformly to generate heat; adding 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, and stirring; intermediate a2 was added portionwise with an exotherm. Controlling the temperature to be 20-25 ℃; the reaction was 4 hours monitored by TLC which showed the reaction was complete and ready for work-up.
And (3) post-treatment: adding water for extraction and sterilization, adding dichloromethane, and extracting and layering; adding water into the organic layer, extracting and separating liquid; adding 10% citric acid aqueous solution into the dichloromethane layer, extracting, and layering; then 2.5% ammonia water is used for extraction and delamination; the organic layer was dried over anhydrous sodium sulfate; the dichloromethane was recovered by concentration to obtain A3.
S3-S4: deprotection of the pyrrolidino group and valine peptide coupling of the pyrrolidino group A3
Adding a reaction solvent into a dry reaction kettle, then adding a raw material intermediate, and controlling the temperature to be 10-15 ℃; adding a mixed solution of hydrochloric acid and a reaction solvent, and releasing heat; stirring for 1 hour; TLC monitoring, TLC shows that the reaction is finished, and preparation post-treatment is carried out; the reaction solvent was concentrated to obtain A4.
Finally adding a peptide coupling solvent and nitrogen methyl morpholine into the product obtained in the previous step; adding MOC-L-valine and a valine peptide coupling reagent; stirring and keeping the temperature at 15-25 ℃. TLC monitored to completion of the reaction, ready for work-up.
And (3) post-treatment: adding water for extraction and sterilization, and performing extraction and layering; adding water into the peptide coupling solvent layer, extracting and separating liquid; adding 10% organic acid aqueous solution into the peptide coupling solvent layer, extracting, and layering; extracting with 10% sodium bicarbonate water solution, and layering; the peptide-coupled solvent layer was dried over anhydrous sodium sulfate; concentrating and recovering the peptide coupling solvent to obtain crude A5.
S5: refining of crude A5 product
Starting stirring, adding ethanol into a reaction kettle, adding the crude product and activated carbon, heating to 50-60 ℃, stirring for dissolving, filtering, introducing the filtrate into a crystallization kettle, cooling to 20-25 ℃, crystallizing, centrifuging, drying at 40-45 ℃ under reduced pressure, and weighing.
Example 1
Taking A4 as a raw material, taking 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride as a valine peptide coupling reagent and dichloromethane as a solvent according to the valine peptide coupling reaction conditions mentioned in CN 102333772A, and the specific technological process comprises the following steps:
50L of dichloromethane, 10kg of N-methylmorpholine 25L, MOC-L-valine and 11kg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added into a reactor containing 11kg of A4, stirred for 3 hours, kept at the temperature of 15-25 ℃, monitored by TLC, and the completion of the reaction is indicated by TLC.
And (3) post-treatment: and (3) starting stirring, adding ethanol into the reaction kettle, adding the crude product and the activated carbon, heating to 50-60 ℃, stirring for 30 minutes, dissolving, filtering, feeding the filtrate into a crystallization kettle, cooling to 20-25 ℃, crystallizing for 4 hours, centrifuging, drying at 40-45 ℃ under reduced pressure for 4-6 hours, weighing to obtain 11kg of white solid, wherein the yield is 64%.
In the process, the peptide coupling reaction solvent adopts dichloromethane, the organic acid is citric acid, and other solvents and organic acids or mixed liquid in the invention can be used for replacing.
Example 2
Example 2 differs from example 1 in that N-methylmorpholine was added to the reaction system in a volume ratio of 1:1 of methylene chloride to N-methylmorpholine.
Example 3
Example 3 lopitavir was prepared from a3 starting with a two-step reaction involving deprotection of the amino group and coupling of valine with peptide.
The process comprises the following steps: adding 45kg of ethanol, 15kg of raw material intermediate and 20L of hydrochloric acid ethanol solution into a dry 500L reaction kettle, controlling the temperature at 10-15 ℃, and stirring for 1 hour to obtain 10.5kgA4 intermediate with the yield of 93%.
In the process, the solvent for amino deprotection reaction is ethanol, and other reaction solvents or solvent combinations in the invention can be used for replacing the solvent.
Example 4
Example 4 lopitavir was prepared from a2 by a three-step reaction of a diamino proline peptide coupling reaction S2, a pyrrolidino deprotection reaction S3, and a pyrrolidino valine peptide coupling reaction S4.
The process comprises the following steps: 140kg of dichloromethane was added to a clean 500L reaction vessel and stirred. The room temperature is 20 ℃; adding 14.7kg of BOC-L-proline serving as a raw material, uniformly stirring, adding 12kg of diisopropylethylamine, and uniformly stirring to generate heat; adding 26kg of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, and stirring for 10 minutes; adding the intermediate 1258235-06-1 in batches, and releasing heat; controlling the temperature to be 20-25 ℃; the reaction was 4 hours monitored by TLC which showed the reaction was complete and ready for work-up.
Adding 200L of water for extraction and sterilization, adding 300L of dichloromethane for extraction and layering; adding 300L of water into the dichloromethane layer, extracting and separating liquid; adding 200L of 10% citric acid aqueous solution into the dichloromethane layer, extracting, and layering; extracting with 300L of 2.5% ammonia water, and layering; the dichloromethane layer was dried over anhydrous sodium sulfate, and dichloromethane was recovered by concentration to obtain 20kg of a white solid with a yield of 83%.
Example 5
Example 5 differs from example 4 in that example 5 uses a1 as a starting material and sequentially comprises four steps of hydrogenation reduction-proline peptide coupling-amino deprotection-valine peptide coupling.
The hydrogenation reduction process comprises the following steps: adding 26kg of intermediate into a clean and dry hydrogenation kettle of 1000L, adding 400L of tetrahydrofuran, 100L of methanol and 4kg of Raney nickel, covering the hydrogenation kettle, and closing valves; detecting the air tightness of the device; ventilating (5 times of nitrogen replacement and 5 times of hydrogen replacement under 5 atmospheric pressures), keeping the temperature at 30 ℃, and reacting overnight under 5 atmospheric pressure hydrogen; the next day, open, spot plate to check if the reaction is complete. TLC showed the reaction was complete; raney nickel is recovered by filtration, and the solvent is recovered to obtain 14kg of product with the yield of 63%.
Example 6
The molar ratio of valine peptide coupling reagent to a4 in example 5 was 2.96: 1; the volume ratio of the S4 solvent to the N-methylmorpholine is 2: 1; the molar ratio of diisopropylethylamine to A2 was 3:1, the molar ratio of proline peptide coupling reagent to A2 was 2.2:1, the molar ratio of BOC-L-proline to A2 was 2.2:1, and the mixing volume ratio of tetrahydrofuran and methanol was 4: 1.
The molar ratio of valine peptide coupling reagent to a4 in example 6 was 2.5: 1; the volume ratio of the S4 solvent to the N-methylmorpholine is 1.5: 1; the molar ratio of diisopropylethylamine to A2 was 2.8:1, the molar ratio of proline peptide coupling reagent to A2 was 2:1, the molar ratio of BOC-L-proline to A2 was 2:1, and the mixing volume ratio of tetrahydrofuran and methanol was 3.8: 1.
Example 7
The molar ratio of valine peptide coupling reagent to a4 in example 7 was 3.2: 1; the volume ratio of the S4 solvent to the N-methylmorpholine is 2.5: 1; the molar ratio of diisopropylethylamine to A2 was 3.1:1, the molar ratio of proline peptide coupling reagent to A2 was 2.4:1, the molar ratio of BOC-L-proline to A2 was 2.4:1, and the mixing volume ratio of tetrahydrofuran and methanol was 4.5: 1.
The yield of example 5 is slightly higher than that of examples 6 and 7, compared to examples 5-7.
The valine peptide coupling reaction yields of the examples 1 and 2 are 85% and 93%, respectively, so that the yield is greatly improved by adopting the nitrogen methylmorpholine as a catalyst.
Comparative example
Comparative example the reaction of S4 was carried out under the same reaction conditions as S2, in which the same reaction conditions were dichloromethane and amine, and the peptide coupling reagent was EDAC (carbodiimide)/HOBT (1-hydroxybenzotriazole), PyBOP (benzotriazole-1-oxytripyrrolidinophosphonium hexafluorophosphate), HATU (2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate), T3P (propylphosphoric anhydride), and the single step reaction yield of S4 was 40 to 60%.
In S3, N-methylmorpholine is used for replacing diisopropylethylamine, or N-methylmorpholine with the volume ratio of 1:1 to dichloromethane is added into a reaction system, the yield of S3 is improved by 2-3% in the extraction of 83%, and the improvement amplitude is not obvious.
The method has the advantages of high yield, high product purity and simple and convenient separation and purification of the intermediate product. In addition, in the preparation method adopted by the invention, all raw materials are common reagents in the field, and the raw materials are cheap. By combining the factors, the preparation method is more suitable for industrial large-scale application.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A preparation method of bulk drug obitasvir is characterized by comprising a reaction formula of reduction reaction S1 of a double nitro group in intermediate 1- (4- (tert-butylphenyl) -2, 5-bis (4-nitrophenyl)) pyrrolidine, coupling reaction S2 of a double amino proline peptide, deprotection reaction S3 of a pyrrolidino group, and coupling reaction S4 and S4 of a pyrrolidino valine peptide:
wherein the peptide coupling reagent in S4 is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the molar ratio of the valine peptide coupling reagent to A4 is (2.5-3.2): 1; the peptide coupling reaction of S4 is carried out in the presence of nitromethylmorpholine; the solvent in S4 is at least one of dichloromethane, THF, chloroform and dichloroethane, and the volume ratio of the S4 solvent to the N-methylmorpholine is (1.5-2.5): 1.
2. The preparation method of the bulk drug orbitavir according to claim 1, wherein the post-treatment of S4 is: and sequentially extracting an organic layer of the reaction solution after water quenching by adopting water, an organic acid aqueous solution and a sodium bicarbonate aqueous solution, and recovering dichloromethane from the organic layer to obtain an obitacvir crude product A5.
3. The preparation method of bulk drug obitasvir as claimed in claim 2, wherein the organic acid is one or a combination of two or more selected from citric acid, tartaric acid and malic acid.
4. The preparation method of bulk drug orbitavir according to claim 1, wherein the reaction formula of S3 is:
the reaction solvent in S3 is one or more mixed solution selected from ethanol, methanol, isopropanol and n-propanol, the reactant hydrochloric acid is added into the reaction solution as the mixed solvent of hydrochloric acid and the reaction solvent, and the reaction temperature of S3 is 10-15 ℃.
5. The preparation method of bulk drug orbitavir according to claim 1, wherein the reaction formula of S2 is:
in the reaction of S2, the proline peptide coupling reagent is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and diisopropylethylamine, and the reaction solution after being quenched by adding water is sequentially extracted by water, citric acid solution and ammonia water solution.
6. The preparation method of bulk drug orbitavir according to claim 1, wherein the reaction formula of S1 is:
s1 hydrogenation reducing agent hydrogen, the catalyst is Raney nickel, the reaction solvent is formed by mixing tetrahydrofuran and methanol, and the mixing volume ratio of the tetrahydrofuran to the methanol is (3.8-4.5): 1.
7. A preparation method of an obitasvir tablet, which is characterized by comprising the preparation method of the bulk drug obitasvir as claimed in any one of claims 1 to 6, and further comprising the process step of mixing and compressing an effective component obitasvir and auxiliary materials into tablets.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102333772A (en) * | 2009-06-11 | 2012-01-25 | 雅培制药有限公司 | Anti-viral compounds |
| CN105237516A (en) * | 2015-10-13 | 2016-01-13 | 厦门市蔚嘉化学科技有限公司 | Preparation method of Ledipasvir |
| CN105294828A (en) * | 2015-11-11 | 2016-02-03 | 苏州明锐医药科技有限公司 | Preparation method of Ombitasvir |
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2017
- 2017-08-01 CN CN201710644963.9A patent/CN107474105B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102333772A (en) * | 2009-06-11 | 2012-01-25 | 雅培制药有限公司 | Anti-viral compounds |
| CN105237516A (en) * | 2015-10-13 | 2016-01-13 | 厦门市蔚嘉化学科技有限公司 | Preparation method of Ledipasvir |
| CN105294828A (en) * | 2015-11-11 | 2016-02-03 | 苏州明锐医药科技有限公司 | Preparation method of Ombitasvir |
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| Title |
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| Discovery of ABT-267, a Pan-Genotypic Inhibitor of HCV NS5A;David A. DeGoey等;《Journal of Medicinal Chemistry》;20140108;第57卷;第2048页"Scheme 1" * |
| Ombitasvir (ABT-267), a novel NS5A inhibitor for the treatment of hepatitis C;Guido Stirnimann;《Expert Opinion on Pharmacotherapy》;20141027;第15卷(第17期);第2609-2622页 * |
| Patent Highlights: Recently Approved HCV NS5a Drugs;David L. Hughes;《Org. Process Res. Dev.》;20160721;第20卷(第8期);第1404-1415页 * |
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