Synthetic method of omipag isopropyl ester
By using the Buchwald coupling reaction of bromo-omepag isopropyl ester precursor with 2-aminoacetic acid isopropyl ester hydrochloride, the problems of unstable raw materials and complex synthesis in the prior art were solved, and the efficient synthesis of omepag isopropyl ester was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-31
- Publication Date
- 2026-04-14
AI Technical Summary
In the existing omepag isopropyl ester synthesis route, the synthesis of the starting material (6-chloromethylpyridine-2-amino) isopropyl acetate is complex and unstable, resulting in low yield and difficulty in commercial application.
Omepag isopropyl ester was synthesized via a Buchwald coupling reaction using bromoomepag isopropyl ester precursor and 2-aminoacetic acid isopropyl ester hydrochloride, avoiding unstable precursors by employing a carbon-nitrogen coupling method.
The synthesis route has been successfully simplified, and the stability and yield of the raw materials have been improved, showing promising prospects for commercial application.
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Figure CN121850985A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical pharmaceutical synthesis technology, specifically to a method for synthesizing omepag isopropyl ester. Background Technology
[0002] Omidenepag isopropyl ester was developed by UBE. @ The active pharmaceutical ingredient in this product is a relatively selective prostaglandin E2 (EP2) receptor agonist, indicated for lowering elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. It is designed to increase aqueous humor drainage via the conventional (or trabecular) and uveal-scleral outflow pathways, and is the only drug with this pharmacological effect. In September 2022, Santen and UBE jointly announced that the U.S. Food and Drug Administration (FDA) approved Omlonti (Omidenepag isopropyl) 0.002% eye drops for lowering elevated intraocular pressure (IOP) in patients with primary open-angle glaucoma or ocular hypertension.
[0003] According to the research report on omepag-isopropyl ester by UBE INDUSTRIES and Masayuki Tanaka et al. in the Journal of Medicinal Chemistry, the synthetic route of omepag-isopropyl ester is as follows: However, the above process has problems such as the complex synthetic route of the raw material (6-chloromethylpyridine-2-amino) isopropyl acetate and the poor stability of its precursor. Summary of the Invention
[0004] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing omepipag isopropyl ester. The present invention creatively constructs an omepipag isopropyl ester bromide precursor and synthesizes omepipag isopropyl ester by reacting the omepipag isopropyl ester bromide precursor with 2-aminoacetic acid isopropyl ester hydrochloride via a carbon-nitrogen coupling method through a Buchwald coupling reaction.
[0005] To achieve the above objectives, the present invention adopts the following technical solution: A method for synthesizing omepag isopropyl ester, comprising the following steps: S1. Preparation of pyridinesulfonamide intermediate 4-(1H-pyrazolyl)benzylamine and an acid-binding agent were dissolved in an organic solvent, and 3-pyridinesulfonyl chloride was added under ice bath conditions. The mixture was stirred to obtain a pyridinesulfonamide intermediate.
[0006] In this step, the molar ratio of 4-(1H-pyrazolyl)benzylamine to 3-pyridinesulfonyl chloride is 1:1-1.3; the molar ratio of 3-pyridinesulfonyl chloride to the acid binder is 1:1-1.5.
[0007] In this step, the acid-binding agent is selected from organic or inorganic bases, such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide.
[0008] In this step, the reaction is carried out with stirring at room temperature. After the reaction is completed, the reaction system is washed with water, extracted with an organic solvent, concentrated to obtain a crude product, and then recrystallized to obtain a pyridine sulfonamide intermediate.
[0009] S2. Preparation of bromo-omepag isopropyl ester precursor Bromopyridine methanol was dissolved in an organic solvent, and under ice bath conditions, phosphine ligands and condensing agents were added and stirred until homogeneous. Then, a pyridine sulfonamide intermediate solution was added dropwise to carry out the reaction, yielding the bromoomepag isopropyl ester precursor.
[0010] In this step, the molar ratio of the bromopyridine methanol and pyridine sulfonamide intermediate is 1:1-1.2; the molar ratio of the phosphine ligand and the condensing agent is 1-1.2:1.
[0011] In this step, the bromopyridine methanol is selected from 6-bromopyridine-2-methanol.
[0012] In this step, the phosphine ligand is selected from one or more of triphenylphosphine, tributylphosphine, and 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene.
[0013] In this step, the condensing agent is selected from N,N,N',N'-tetramethylazodicarbonamide and / or diethyl azodicarbonate.
[0014] In this step, the reaction is carried out at room temperature. After the reaction is completed, the reaction system is washed with water, extracted with an organic solvent, concentrated to obtain a crude product, and then subjected to silica gel column chromatography to obtain the bromo-omepag isopropyl ester precursor.
[0015] S3, Preparation of omepag-isopropyl ester In the presence of a catalyst and an acid-binding agent, the bromo-omepag isopropyl ester precursor and 2-aminoacetic acid isopropyl ester hydrochloride are reacted to obtain the omepag isopropyl ester.
[0016] In this step, the molar ratio of the bromo-omepipag isopropyl ester precursor to 2-aminoacetic acid isopropyl ester hydrochloride is 1:2-2.5.
[0017] In this step, the catalyst is selected from palladium-based catalysts, such as Pd(dba)2, Pd(dppf)Cl2 or Pd(PPh3)4.
[0018] In this step, the acid-binding agent is selected from organic or inorganic bases, such as triethylamine, N,N-diisopropylethylamine, 1,8-diazabicycloundec-7-ene, potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide.
[0019] In this step, the reaction temperature is 60-110℃.
[0020] In this step, after the reaction is complete, the reaction system is washed with water, extracted with an organic solvent, concentrated to obtain a crude product, and then subjected to silica gel column chromatography to obtain omepag isopropyl ester.
[0021] The specific synthetic route of omepag isopropyl ester provided by this invention is as follows: Compared with the prior art, the present invention has the following beneficial effects: Existing synthetic methods mainly involve a substitution reaction between isopropyl (6-chloromethylpyridine-2-amino)acetate and pyridinesulfonamide to ultimately obtain omepag-isopropyl ester. However, the lack of commercially available isopropyl (6-chloromethylpyridine-2-amino)acetate severely restricts the development of the original process. Furthermore, during the replication of the original process, the inventors found that there were no reported methods for synthesizing isopropyl (6-chloromethylpyridine-2-amino)acetate, and during attempts at synthesis, they discovered that isopropyl (6-hydroxymethylpyridine-2-amino)acetate is unstable over long periods, resulting in extremely low yields of this intermediate. This invention creatively constructs a bromoomepag-isopropyl ester precursor and, through carbon-nitrogen coupling, synthesizes omepag-isopropyl ester by reacting the bromoomepag-isopropyl ester precursor with isopropyl 2-aminoacetate hydrochloride via a Buchwald coupling reaction.
[0022] Compared with existing synthesis methods, the method provided by this invention successfully avoids the synthesis of unstable precursors, making the raw materials more readily available and showing good prospects for commercial application. Attached Figure Description
[0023] Figure 1 This is a high-performance liquid chromatogram of omepag isopropyl ester obtained in step S3 of Example 1 of the present invention.
[0024] Figure 2 The image shows the hydrogen NMR spectrum of omepag isopropyl ester obtained in step S3 of Example 1 of this invention. Detailed Implementation
[0025] The present invention will be further described in detail below through specific preferred embodiments, but the present invention is not limited to the following embodiments.
[0026] It should be noted that, unless otherwise specified, all chemical reagents involved in this invention were purchased through commercial channels.
[0027] Example 1 A method for synthesizing omepag isopropyl ester, comprising the following steps: Preparation of S1, N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide 20 g of commercially available 4-(1H-pyrazolyl)benzylamine was dissolved in 200 mL of dichloromethane, and 17.53 g of triethylamine was added. After the system cooled to 0 °C, 22.56 g of pyridine-3-sulfonyl chloride was added, and the mixture was heated to room temperature and stirred overnight. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain crude N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide. The crude product was recrystallized from acetonitrile to obtain 27 g of pale yellow solid, with a yield of 74.39%.
[0028] Preparation of S2, N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridin-2-yl)methyl)pyridine-3-sulfonamide 10 g of commercially available 6-bromopyridine-2-methanol was dissolved in 100 mL of tetrahydrofuran. After the system was cooled to 0 °C, 10.94 g of tributylphosphine was added in batches, followed by 9.31 g of N,N,N',N'-tetramethylazodicarbonamide. The mixture was stirred for 10 min, and the temperature was maintained at 0 °C. 17 g of N-[4-(1H-pyrazole-1-yl)benzyl]pyridine-3-sulfonamide tetrahydrofuran solution prepared in step S1 was added dropwise. After the addition was complete, the system was heated to room temperature and stirred overnight. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to obtain 21 g of pure white solid N-(4-(1H-pyrazole-1-yl)benzyl)-N-((6-bromopyridine-2-yl)methyl)pyridine-3-sulfonamide, with a yield of 80.17%.
[0029] Preparation of S3 and omepag-isopropyl ester 5 g of N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridin-2-yl)methyl)pyridine-3-sulfonyl obtained in step S2 was dissolved in 50 mL of toluene. 1.9 g of commercially available 2-aminoacetic acid isopropyl hydrochloride, 2.19 g of sodium carbonate, and 100 mg of Pd(dba)2 were added. After nitrogen purging three times, the mixture was heated to reflux at 110 °C. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was then subjected to silica gel column chromatography to obtain 4.5 g of a pale yellow oily substance, omepag-isopropyl ester, with a yield of 83.74%.
[0030] The high-performance liquid chromatography (HPLC) result of omepag isopropyl ester prepared in step S3 of this embodiment is as follows: Figure 1 As shown, the 1H NMR spectrum is as follows Figure 2 As shown.
[0031] Example 2 A method for synthesizing omepag isopropyl ester, comprising the following steps: Preparation of S1, N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide 20 g of commercially available 4-(1H-pyrazolyl)benzylamine was dissolved in 200 mL of dichloromethane, and 17.53 g of triethylamine was added. After the system cooled to 0 °C, 22.56 g of pyridine-3-sulfonyl chloride was added, and the mixture was heated to room temperature and stirred overnight. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain crude N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide. The crude product was recrystallized from acetonitrile to obtain 27 g of pale yellow solid, with a yield of 74.39%.
[0032] Preparation of S2, N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridin-2-yl)methyl)pyridine-3-sulfonamide 3 g of commercially available 6-bromopyridine-2-methanol was dissolved in 30 mL of tetrahydrofuran. After the system was cooled to 0 °C, 4.17 g of triphenylphosphine was added in batches, followed by 2.77 g of diethyl azodicarbonate. The mixture was stirred for 10 min, and the temperature was maintained at 0 °C. 5 g of N-[4-(1H-pyrazole-1-yl)benzyl]pyridine-3-sulfonamide tetrahydrofuran solution prepared in step S1 was added dropwise. After the addition was complete, the system was heated to room temperature and stirred overnight. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was subjected to silica gel column chromatography to obtain 6.97 g of pure white solid N-(4-(1H-pyrazole-1-yl)benzyl)-N-((6-bromopyridine-2-yl)methyl)pyridine-3-sulfonamide, with a yield of 90.47%.
[0033] Preparation of S3 and omepag-isopropyl ester 4 g of N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridin-2-yl)methyl)pyridine-3-sulfonyl obtained in step S2 was dissolved in 50 mL of 1,4-dioxane. 1.4 g of commercially available 2-aminoacetic acid isopropyl hydrochloride, 5.38 g of cesium carbonate, and 200 mg of tetrakis(triphenylphosphine)palladium were added. After purging with nitrogen three times, the mixture was heated to 101 °C. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was then subjected to silica gel column chromatography to obtain 4.38 g of a pale yellow oil, omepag-isopropyl ester, with a yield of 88.39%.
[0034] Example 3 A method for synthesizing omepag isopropyl ester, comprising the following steps: Preparation of S1, N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide 20 g of commercially available 4-(1H-pyrazolyl)benzylamine was dissolved in 200 mL of dichloromethane, and 17.53 g of triethylamine was added. After the system cooled to 0 °C, 22.56 g of pyridine-3-sulfonyl chloride was added, and the mixture was heated to room temperature and stirred overnight. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain crude N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide. The crude product was recrystallized from acetonitrile to obtain 27 g of pale yellow solid, with a yield of 74.39%.
[0035] Preparation of S2, N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridin-2-yl)methyl)pyridine-3-sulfonamide 3.3 g of commercially available 6-bromopyridine-2-methanol was dissolved in 50 mL of acetonitrile. After the system was cooled to 0 °C, 4.6 g of triphenylphosphine was added in batches, followed by 3.22 g of diisopropyl azodicarbonate. The mixture was stirred for 10 min, and the temperature was maintained at 0 °C. Then, 5 g of an acetonitrile solution of N-[4-(1H-pyrazol-1-yl)benzyl]pyridine-3-sulfonamide prepared in step S1 was added dropwise. After the addition was complete, the mixture was allowed to return to room temperature and stirred overnight. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was then subjected to silica gel column chromatography to obtain 4.5 g of pure N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridine-2-yl)methyl)pyridine-3-sulfonamide, with a yield of 58.41%.
[0036] Preparation of S3 and omepag-isopropyl ester 5g of N-(4-(1H-pyrazol-1-yl)benzyl)-N-((6-bromopyridin-2-yl)methyl)pyridine-3-sulfonyl obtained in step S2 was dissolved in 50mL of DMF. 1.74g of commercially available 2-aminoacetic acid isopropyl hydrochloride, 4g of N,N-diisopropylethylamine, and 500mg of PdCl2 were added. After nitrogen purging three times, the mixture was heated to 100℃. After the reaction was detected by TLC, the reaction system was washed with water, extracted, and the organic phase was dried and concentrated to obtain the crude product. The crude product was then subjected to silica gel column chromatography to obtain 4.7g of a pale yellow oily substance, omepag-isopropyl ester, with a yield of 87.46%.
[0037] Finally, it should be noted that the above embodiments do not limit the present invention in any way. Those skilled in the art can make modifications and improvements based on the present invention. Therefore, any modifications or improvements made without departing from the spirit of the present invention are within the scope of protection claimed by the present invention.
Claims
1. A method for synthesizing omepag-isopropyl ester, characterized in that, Includes the following steps: S1. Preparation of pyridine sulfonamide intermediate: 4-(1H-pyrazolyl)benzylamine and an acid-binding agent were dissolved in an organic solvent, and 3-pyridine sulfonyl chloride was added under ice bath conditions. The mixture was stirred and reacted to obtain the pyridine sulfonamide intermediate. S2. Preparation of bromo-omepipag isopropyl ester precursor: Bromopyridine methanol was dissolved in an organic solvent, and under ice bath conditions, phosphine ligands and condensing agents were added and stirred until homogeneous. Then, pyridine sulfonamide intermediate solution was added dropwise to carry out the reaction and obtain bromo-omepipag isopropyl ester precursor. S3. Preparation of omepag isopropyl ester: Under the action of a catalyst and an acid-binding agent, the omepag isopropyl ester bromide precursor and 2-aminoacetic acid isopropyl ester hydrochloride are reacted to obtain the omepag isopropyl ester.
2. The synthesis method according to claim 1, characterized in that, In step S1, the molar ratio of 4-(1H-pyrazolyl)benzylamine to 3-pyridinesulfonyl chloride is 1:1-1.3; the molar ratio of 3-pyridinesulfonyl chloride to the acid binder is 1:1-1.
5.
3. The synthesis method according to claim 1, characterized in that, In step S1, the acid-binding agent is selected from organic or inorganic bases.
4. The synthesis method according to claim 1, characterized in that, In step S2, the molar ratio of the bromopyridine methanol and pyridine sulfonamide intermediate is 1:1-1.2; the molar ratio of the phosphine ligand and the condensing agent is 1-1.2:
1.
5. The synthesis method according to claim 1, characterized in that, In step S2, the bromopyridine methanol is selected from 6-bromopyridine-2-methanol.
6. The synthesis method according to claim 1, characterized in that, In step S2, the phosphine ligand is selected from one or more of triphenylphosphine, tributylphosphine, and 2,2'-bis(diphenylphosphine)-1,1'-binaphthylene.
7. The synthesis method according to claim 1, characterized in that, In step S2, the condensing agent is selected from N,N,N',N'-tetramethylazodicarbonamide and / or diethyl azodicarbonate.
8. The synthesis method according to claim 1, characterized in that, In step S3, the molar ratio of the bromo-omepipag isopropyl ester precursor to 2-aminoacetic acid isopropyl ester hydrochloride is 1:2-2.
5.
9. The synthesis method according to claim 1, characterized in that, In step S3, the catalyst is selected from palladium-based catalysts.
10. The synthesis method according to claim 1, characterized in that, In step S3, the reaction temperature is 60-110℃.