Preparation method of treprostinil intermediate

Abstract

The invention relates to the technical field of medicines, in particular to a preparation method of a treprostinil intermediate, which comprises the following steps: in a certain solvent, condensing a compound 1 with ethylene glycol under the catalytic action of p-TsOH to generate a compound 2; carrying out substitution reaction on the compound 2 and 3-bromopropylene under the action of n-butyllithium to generate a compound 3; removing a protecting group from the compound 3 under the action of hydrochloric acid to obtain a target product 4. The method is simple to operate, mild in condition, low in cost of used reagents, easy to obtain, excellent in yield, purity and quality, and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a key intermediate of prostacyclin analog (PGI2) treprostinil. Background Technology

[0002] Treprostinil, developed by United Therapeutics and approved by the FDA in 2002, is a novel prostacyclin derivative that can be administered intravenously or subcutaneously. It has a longer half-life than eprostol and is more stable at room temperature. This drug dilates pulmonary vessels, inhibits platelet aggregation and vascular smooth muscle cell proliferation, and is effective in treating idiopathic pulmonary hypertension (PPH) of heart function class II-IV and PPH associated with connective tissue diseases. It is an important therapeutic and rescue drug. Its structural formula is shown below:

[0003]

[0004] Compound 4 is suitable as an intermediate for the preparation of Treprostinil. Its structural formula is shown below:

[0005]

[0006] The most commonly reported methods for synthesizing pre-stellaria nier from intermediate 4 are as follows:

[0007] First, intermediate 4 and another intermediate 5 react with Grignard to give compound 6, which is then oxidized by pyridine chlorochromate to give diastereoketone 7. Compound 7 is then asymmetrically reduced with R-methyloxazolone and boron-methyl sulfide to give compound 8. The hydroxyl group is then protected with TBDMS-Cl to give compound 9, followed by Pauson-Khand cyclization to give tricycloenone 10. Catalytic hydrogenation is then used to give intermediate 11, followed by reduction with sodium borohydride to give intermediate 12. The side chain is deprotected to give methoxydiol 13, and lithium diphenylphosphine is demethylated to give intermediate 14. Then, chloroacetonitrile is used to give alkylated product 15, which is finally hydrolyzed to give Treprostinil.

[0008]

[0009] The currently reported methods for synthesizing treprostinil intermediate 4 are as follows:

[0010] Method 1: In patent US2012 / 0226076A1, United Therapeutics Inc. used compound 1 as the starting material, first using N,N,N-trimethylethylenediamine, and then protecting the aldehyde group under phenyl lithium or butyl lithium to generate compound 16, followed by ortho-lithiation to obtain compound 17, then conversion to cuprate 18, allylation to generate intermediate 19, and finally hydrolysis to generate target compound 4.

[0011]

[0012] Method 2: In patent WO 03 / 070163A2, United Therapeutics of the United States used compound 20 as the starting material, first protected the hydroxyl group with TBDMS-Cl to obtain compound 21, then ortho-allylated to obtain compound 22, then deprotected with TBAF to obtain intermediate 23, and finally oxidized with Swern to obtain target product 4.

[0013]

[0014] Both of the above synthesis methods have some drawbacks:

[0015] In Route 1, the reaction from compound 1 to target product 4 requires passing through four intermediate states, making the process complex and difficult to control. The use of cuprous cyanide and a significant amount of lithium reagent greatly increases production safety risks and places high demands on operator skills. The use of allyl iodine as a raw material results in high costs. Therefore, Route 1 is not suitable for industrial-scale production.

[0016] Route 2 requires four steps to reach the target product 4 from compound 20, making it a relatively long route. Furthermore, the Swern oxidation reaction requires harsh conditions, is complex and difficult to operate, and produces a foul odor, impacting the environment and creating significant environmental pressure. This route is also unsuitable for industrial scale-up.

[0017] Therefore, finding a convenient and simple method for the industrial production of the key intermediate 4 of treprofen is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0018] To address the problems of long routes, high costs, low safety, and significant environmental issues associated with existing synthetic methods, this invention provides a convenient and simple method for preparing key intermediates of treprostone.

[0019] To achieve the above objectives, the technical solution of the present invention is: a method for preparing a treprostone intermediate, comprising the following steps:

[0020] (1) Compound 1 condenses with ethylene glycol under the catalysis of p-TsOH to form compound 2;

[0021] (2) Compound 2 undergoes a substitution reaction with 3-bromopropene under the action of n-butyllithium to generate compound 3;

[0022] (3) Compound 3 was deprotected by hydrochloric acid to give the target product 4;

[0023] The reaction formula is shown below:

[0024]

[0025] The solvent used in step (1) is selected from dichloromethane and toluene.

[0026] In step (1), the molar ratio of compound 1 to ethylene glycol is 1:(2-5).

[0027] In step (1), the molar ratio of compound 1 to p-TsOH is 1:(0.05-0.2).

[0028] The reaction temperature in step (1) is 20-35℃.

[0029] The reaction time in step (1) is 6-14 hours, preferably 7-8 hours.

[0030] The solvent used in step (2) is selected from n-hexane and methyl tert-butyl ether.

[0031] In step (2), the molar ratio of compound 2 to n-butyllithium is 1:(1-1.5).

[0032] In step (2), the molar ratio of compound 2 to 3-bromopropene is 1:(1-1.5).

[0033] The allylation reaction temperature in step (2) is 20-35℃.

[0034] The reaction time in step (2) is 10-24 hours, preferably 15-18 hours.

[0035] The solvent used in step (3) is selected from acetone and acetonitrile.

[0036] In step (3), the molar ratio of compound 3 to hydrochloric acid is 1:(5-8).

[0037] The reaction temperature in step (3) is 40-60℃, preferably 60℃.

[0038] The reaction time in step (3) is 2-6 hours, preferably 4-5 hours.

[0039] Unless otherwise specified, all reagents and raw materials used in this invention are commercially available. In cases where the Chinese nomenclature of a compound conflicts with its structural formula, the structural formula shall prevail; except where the structural formula is obviously incorrect.

[0040] The beneficial effects of the present invention are as follows: under the catalysis of p-TsOH (p-toluenesulfonic acid), ethylene glycol protects the aldehyde group of compound 1; compound 2 and 3-bromopropene are reacted with n-butyllithium to obtain allylated product 3; and the intermediate is deprotected under the action of hydrochloric acid to obtain compound 4.

[0041] This invention overcomes the problems of excessively long routes and environmental pollution in existing methods. Furthermore, the reaction and post-processing conditions are mild and relaxed, and the reagents are all commercially available, inexpensive, and readily available. In summary, this method is simple to operate, has a convenient route, high atom economy, is safe and environmentally friendly, and is suitable for industrial production. Attached Figure Description

[0042] Figure 1 The image shows the 1H NMR spectrum of compound 2 in Example 1.

[0043] Figure 2 The image shows the 1H NMR spectrum of compound 3 in Example 1.

[0044] Figure 3 The image shows the 1H NMR spectrum of compound 4 in Example 1. Detailed Implementation

[0045] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0046] Example 1

[0047] (1) Preparation of 2-(3-methoxyphenyl)-1,3-dioxopentane (compound 2)

[0048]

[0049] Compound 1 (0.50 g, 3.67 mmol, 1.0 eq) was added to a reaction flask and dispersed in 5 mL of dichloromethane. Ethylene glycol (0.68 g, 11.02 mmol, 3.0 eq) and p-toluenesulfonic acid (0.13 g, 0.73 mmol, 0.2 eq) were then added, and the mixture was stirred at room temperature for 8 h. TLC analysis (PE:EA = 10:1) showed that compound 1 was almost completely consumed, and the reaction was stopped. The mixture was washed with 10 mL of saturated sodium bicarbonate solution, separated, and the aqueous layer was extracted with dichloromethane (10 mL * 3). The combined organic phases were washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum at 45 °C to give 0.61 g of a colorless liquid (yield 92.4%).

[0050] (2) Preparation of 2-(2-allyl-3-methoxyphenyl)-1,3-dioxane (compound 3)

[0051]

[0052] Compound 2 (0.50 g, 2.77 mmol, 1.0 eq) and 5 mL of n-hexane were added to the reaction flask, purged three times with nitrogen, and stirred at room temperature. A solution of n-butyllithium (1.2 mL, 3.05 mmol, 1.1 eq, 2.5 M solution in hexane) was slowly added dropwise to the system. After the addition was complete, the mixture was stirred at room temperature for 2 h. The system temperature was then lowered to 0 °C, and 3-bromopropene (0.39 g, 3.19 mmol, 1.15 eq) was slowly added dropwise, with the addition temperature not exceeding 5 °C. After the addition was complete, the system was brought back to room temperature and stirred for another 18 h. TLC analysis (PE:EA = 3:1) confirmed that the reactants had largely reacted. The mixture was cooled to 0 °C, and 5 mL of saturated ammonium chloride aqueous solution was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was separated, and the organic phase was washed first with 5 mL of purified water, then with 5 mL of saturated brine, and finally dried over anhydrous sodium sulfate. Filter the solution and dry it under vacuum at 45°C to obtain 0.51 g of brown oily substance (yield 83.4%).

[0053] (3) Preparation of 2-allyl-3-methoxybenzaldehyde (compound 4)

[0054]

[0055] Compound 3 (0.50 g, 2.27 mmol, 1.0 eq) was added to a reaction flask and dispersed in 5 mL of acetone. The mixture was stirred and cooled to 0-5 °C. 6N hydrochloric acid (2.3 mL, 13.6 mmol, 6.0 eq) was slowly added dropwise while maintaining the temperature. After the addition was complete, the mixture was refluxed at 60 °C for 5 h. TLC analysis (PE:EA = 3:1) confirmed that the reactants had largely reacted. The reaction solution was concentrated to constant weight under reduced pressure at 45 °C. 10 mL of purified water and 15 mL of ethyl acetate were added, and the mixture was stirred for 10 min. The mixture was separated, and the organic phase was collected. After drying with anhydrous sodium sulfate, the solution was filtered. The filtrate was dried under vacuum at 45 °C to obtain 0.36 g of a light brown oily substance (yield 90.0%).

[0056] Example 2

[0057] (1) Preparation of 2-(3-methoxyphenyl)-1,3-dioxopentane (compound 2)

[0058]

[0059] Compound 1 (100.0 g, 734.5 mmol, 1.0 eq) was added to a reaction flask and dispersed in 500 mL of dichloromethane. Then, ethylene glycol (136.8 g, 2.20 mol, 3.0 eq) and p-toluenesulfonic acid (25.3 g, 146.9 mmol, 0.2 eq) were added, and the mixture was stirred at room temperature for 8 h. TLC analysis (PE:EA = 10:1) showed that compound 1 was almost completely consumed, and the reaction was stopped. The mixture was washed with 500 mL of saturated sodium bicarbonate solution, separated, and the aqueous layer was extracted with dichloromethane (200 mL * 3). The combined organic phases were washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under vacuum at 45 °C to give 123.5 g of a colorless liquid (yield 93.3%) with a purity of 99.72%.

[0060] (2) Preparation of 2-(2-allyl-3-methoxyphenyl)-1,3-dioxane (compound 3)

[0061]

[0062] Compound 2 (100.0 g, 554.9 mmol, 1.0 eq) and 500 mL of n-hexane were added to the reaction flask, purged three times with nitrogen, and stirred at room temperature. A solution of n-butyllithium (244 mL, 610.4 mmol, 1.1 eq, 2.5 M solution in hexane) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. The system temperature was then lowered to 0 °C, and 3-bromopropene (77.2 g, 638.2 mmol, 1.15 eq) was slowly added dropwise, with the addition temperature not exceeding 5 °C. After the addition was complete, the system was brought back to room temperature and stirred for another 18 h. TLC analysis (PE:EA = 3:1) confirmed that the reactants had largely reacted. The mixture was cooled to 0 °C, and 500 mL of saturated ammonium chloride aqueous solution was slowly added dropwise to quench the reaction. After the addition was complete, the mixture was separated, and the organic phase was washed first with 500 mL of purified water, then with 500 mL of saturated brine, and finally dried over anhydrous sodium sulfate. The filtrate was filtered and dried under vacuum at 45°C to obtain 105.6 g of brown oily substance (yield 86.4%) with a purity of 96.89%.

[0063] (3) Preparation of 2-allyl-3-methoxybenzaldehyde (compound 4)

[0064]

[0065] Compound 3 (100.0 g, 454.0 mmol, 1.0 eq) was added to a reaction flask and dispersed in 500 mL of acetone. The mixture was stirred and cooled to 0-5 °C. 6N hydrochloric acid (454 mL, 2.72 mol, 6.0 eq) was slowly added dropwise while maintaining the temperature. After the addition was complete, the mixture was refluxed at 60 °C for 5 h. TLC analysis (PE:EA = 3:1) confirmed that the reactants had largely reacted. Most of the solvent in the reaction solution was concentrated under reduced pressure at 45 °C. 500 mL of purified water and 1000 mL of ethyl acetate were added and stirred for 10 min. The mixture was separated, and the organic phase was collected. After drying with anhydrous sodium sulfate, the solution was filtered. The filtrate was dried under vacuum at 45 °C to obtain 73.3 g of a light brown oily substance (yield 91.6%) with a purity of 98.11%.

[0066] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing a treprostinil intermediate, characterized in that, Includes the following steps: (1) Compound 1 condenses with ethylene glycol under the catalysis of p-TsOH to form compound 2; (2) Compound 2 undergoes a substitution reaction with 3-bromopropene under the action of n-butyllithium to generate compound 3; (3) Compound 3 was deprotected by hydrochloric acid to give the target product 4; The reaction formula is shown below:

2. The preparation method according to claim 1, characterized in that, The solvent used in step (1) is selected from dichloromethane and toluene.

3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound 1 to ethylene glycol is 1:2-5, and the molar ratio of compound 1 to p-TsOH is 1:0.05-0.

2.

4. The preparation method according to claim 1, characterized in that, The reaction temperature in step (1) is 20-35℃ and the reaction time is 6-14h.

5. The preparation method according to claim 1, characterized in that, The solvent used in step (2) is selected from n-hexane and methyl tert-butyl ether.

6. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of compound 2 to n-butyllithium is 1:1-1.5, and the molar ratio of compound 2 to 3-bromopropene is 1:1-1.

5.

7. The preparation method according to claim 1, characterized in that, In step (2), the allylation reaction temperature is 20-35℃ and the reaction time is 10-24h.

8. The preparation method according to claim 1, characterized in that, The solvent used in step (3) is selected from acetone and acetonitrile.

9. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of compound 3 to hydrochloric acid is 1:5-8.

10. The preparation method according to claim 1, characterized in that, The reaction temperature in step (3) is 40-60℃ and the reaction time is 2-6h.

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