Preparation method of (R)-(1-([1, 1 '-biphenyl]-4-yl)-3-oxopropane-2-yl) tert-butyl carbamate
By using a phosphate system as a buffer and controlling the temperature in the preparation of (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl, the problem of unstable oxidation reaction was solved, and high-yield and low-cost industrial production was achieved.
Patent Information
- Application Number
- CN202511153444.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-18
- Publication Date
- 2025-11-28
AI Technical Summary
In the existing industrial synthesis method of (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester, the sodium bicarbonate buffer system is prone to over-reaction, which is difficult to control, resulting in unstable yield of oxidation reaction and high production cost, making it difficult to industrialize.
A phosphate system was used as a buffer, and the oxidation reaction conditions were optimized by controlling the temperature and adding sodium hypochlorite. TEMPO was used as an oxidation catalyst to control the selectivity and yield of the oxidation reaction.
It increases the yield of oxidation reactions to 90-96%, reduces production costs, and is suitable for large-scale industrial production.
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Figure CN121021340A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of tert-butyl carbamate preparation technology, and more particularly to a method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)tert-butyl carbamate. Background Technology
[0002] (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester is a key intermediate of sacubitril. Sacubitril is a neprilysin inhibitor and is often used in combination with valsartan (an angiotensin receptor antagonist) in clinical practice to treat diseases such as chronic heart failure.
[0003] Most existing industrial synthesis methods for (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate use sodium bicarbonate as a pH stabilizer, TEMPO as an oxidation catalyst, and sodium hypochlorite to oxidize (R)-tert-butyl(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, thereby oxidizing the alcohol group to an aldehyde group.
[0004] Compared to phosphate systems, sodium bicarbonate systems, as pH-adjusting buffers, have significant drawbacks. Firstly, the sodium bicarbonate buffer system is highly susceptible to interference from temperature, solubility, and the reaction itself, making the oxidation process difficult to control and prone to over-oxidation, with the aldehyde group quickly being further oxidized to a carboxyl group. Secondly, the sodium bicarbonate system is less effective at shielding some side reactions than phosphate systems. Currently, oxidation reactions using the sodium bicarbonate buffer system rarely achieve yields exceeding 80%, with most yields remaining between 65-75%, significantly increasing the synthesis cost of sacubitril and hindering its widespread use. Summary of the Invention
[0005] The purpose of this invention is to overcome the above-mentioned defects of the prior art. This invention provides a method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester, which aims to solve the problems mentioned in the background art.
[0006] To achieve the above objectives, the present invention provides a method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester, comprising the following steps:
[0007] S1: Take a four-necked flask, add 1780g of dichloromethane, 165g of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, 1.6g of TEMPO and 2g of tetrabutylammonium bromide to the flask, and stir it.
[0008] S2: Add 33.5g of sodium bromide solution and 146g of mixed phosphate solution to the four-necked flask after stirring in S1, and cool the liquid in the four-necked flask to the specified temperature;
[0009] S3: Add sodium hypochlorite with an effective chlorine content of 9-10% to the four-necked flask after cooling in S2;
[0010] S4: After the dripping in S3 is completed, keep the liquid in the four-necked flask warm, and add 385g of sodium thiosulfate solution to the flask to quench the reaction.
[0011] S5: Sampling and testing.
[0012] The four-necked flask adopts a structure already available in the market and is a common multi-necked glass container in chemical experiments. It is mainly used for assembling apparatus for complex reactions and can simultaneously house a stirrer, thermometer, condenser, and dropping funnel. It is suitable for reactions requiring temperature control, stirring, and continuous feeding (such as organic synthesis and esterification reactions). This technique is common knowledge in the field and will not be elaborated further. A mixed solution of disodium hydrogen phosphate and sodium dihydrogen phosphate is used as the pH buffer, eliminating the use of sodium bicarbonate as a pH adjuster. Using a phosphate-based buffer has advantages that carbonate systems lack, such as significant buffering effect, less susceptibility to solubility changes, less susceptibility to temperature changes, and the ability to shield certain side reactions. The oxidation yield of this process can stably reach 90-96%, which is 20-30% higher than conventional yields.
[0013] The principle of oxidizing (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate to (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl is as follows:
[0014]
[0015] If the oxidizing performance is too weak, it easily leaves behind the alcohol group of the raw material; if the oxidizing performance is too strong, it easily generates the carboxyl group by-product. In the above method for preparing aldehyde group, the oxidant is sodium hypochlorite with an effective chlorine content of 9-10%, the oxidation catalyst is TEMPO, and the amount used is 1% of the amount of the raw material (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate.
[0016] Preferably, the 33.5g sodium bromide solution in S2 comprises 20g water and 13.5g sodium bromide; the mixed phosphate solution comprises 100g water, 38g disodium hydrogen phosphate and 8g sodium dihydrogen phosphate.
[0017] Sodium bromide solution is used as a co-catalyst to generate active bromine species. A mixed phosphate solution (sodium dihydrogen phosphate-disodium hydrogen phosphate complex) serves as a pH buffer system.
[0018] Preferably, the pH value of the phosphate mixed salt solution in S2 is between 7.8 and 9.3.
[0019] Adding the buffer reagent disodium hydrogen phosphate (DHP) to the oxidation reactor can suppress the pH value of the stable system over a long period of time, keeping it stable between 7.8 and 9.3. This ensures milder oxidation conditions and more selective oxidation results.
[0020] Preferably, the liquid in the four-necked bottle in S2 is cooled to 0°C.
[0021] Temperature control at 0℃ is a key parameter in pharmaceutical processes, taking into account multiple factors such as solubility regulation, crystal morphology optimization, reaction safety, and production process stability, to ensure that the finished drug meets quality and safety standards.
[0022] Preferably, the sodium hypochlorite in S3 is added over a period of 5-8 hours, and the temperature is controlled at 0-15℃.
[0023] Slow dropwise addition over 5-8 hours avoids a sudden increase in reactant concentration, reduces side reactions, and improves conversion rate. Simultaneously, combined with low-temperature conditions (0-15℃), it ensures temperature stability of the reaction system, preventing decomposition or impurity formation caused by localized high temperatures. Low temperature (0-15℃) can suppress the side reaction of sodium chlorate decomposing into NaCl and NaClO3 (3NaClO→2NaCl+NaClO3), while also reducing other oxidation byproducts (such as ClO). - With ClO3 - (Competitive generation).
[0024] Preferably, the heat preservation time in S4 is 0.5 hours, and the temperature is controlled at 0-15℃.
[0025] Holding the temperature for 0.5 hours ensures that the oxidation reaction is completely completed (such as the formation of sulfone from sulfoxide), while the low temperature limits possible subsequent degradation reactions (such as hydrolysis or polymerization), thus ensuring the chemical stability of the final product.
[0026] Preferably, the 385g sodium thiosulfate solution in S4 comprises 340g water and 45g sodium thiosulfate pentahydrate.
[0027] Sodium thiosulfate solution is used to neutralize residual oxidants (such as sodium hypochlorite) and prevent further degradation of the product.
[0028] The beneficial effects of this invention are:
[0029] In use, this invention can gently oxidize (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate to (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester with a yield of 90-96%. The process of this invention is reasonable, simple to operate, safe to produce, and suitable for large-scale industrial production, providing a feasible method to significantly reduce the cost of synthesizing the drug sacubitril for industrial production. Attached Figure Description
[0030] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0031] Figure 1 This is a process flow diagram of a specific embodiment of the present invention. Detailed Implementation
[0032] Embodiments of the present invention are described in detail below. Examples of these embodiments are shown in the accompanying drawings. Preferably, the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.
[0033] In the description of this invention, it should be understood that the terms "length," "width," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," and "outer," etc., indicating orientation or positional relationships, are based on the orientation or positional relationships shown in the accompanying drawings and are only for the convenience of describing the invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the invention. Furthermore, in the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.
[0034] Please see Figure 1 This invention provides a method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester, comprising the following steps:
[0035] S1: Take a four-necked flask, add 1780g of dichloromethane, 165g of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, 1.6g of TEMPO and 2g of tetrabutylammonium bromide to the flask, and stir it.
[0036] S2: Add 33.5g of sodium bromide solution and 146g of mixed phosphate solution to the four-necked flask after stirring in S1, and cool the liquid in the four-necked flask to the specified temperature;
[0037] S3: Add sodium hypochlorite with an effective chlorine content of 9-10% to the four-necked flask after cooling in S2;
[0038] S4: After the dripping in S3 is completed, keep the liquid in the four-necked flask warm, and add 385g of sodium thiosulfate solution to the flask to quench the reaction.
[0039] S5: Sampling and testing.
[0040] The 33.5g sodium bromide solution in S2 includes 20g water and 13.5g sodium bromide; the mixed phosphate solution includes 100g water, 38g disodium hydrogen phosphate and 8g sodium dihydrogen phosphate.
[0041] The pH value of the mixed phosphate solution in S2 is between 7.8 and 9.3.
[0042] The liquid in the four-necked flask in S2 is cooled to 0°C.
[0043] The sodium hypochlorite in S3 is added over 5-8 hours, with the temperature controlled at 0-15℃.
[0044] The heat preservation time in S4 is 0.5 hours, and the temperature is controlled between 0-15℃.
[0045] The 385g sodium thiosulfate solution in S4 includes 340g of water and 45g of sodium thiosulfate pentahydrate. Specific Implementation Example 1:
[0047] In this embodiment:
[0048] First, take a clean four-necked bottle, add 1780g of dichloromethane, 165g of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, 1.6g of TEMPO and 2g of tetrabutylammonium bromide, and start stirring;
[0049] Next, when the above stirring is complete, add 33.5g of sodium bromide solution (20g of water, 13.5g of sodium bromide) and 146g of mixed phosphate solution (100g of water, 38g of disodium hydrogen phosphate, 8g of sodium dihydrogen phosphate) to the bottle, and cool the liquid in the four-necked bottle to 0℃.
[0050] Next, after the above cooling is completed, add sodium hypochlorite with an effective chlorine content of 9-10% dropwise. Control the dropwise addition rate during the process, with a total dropwise addition time of 5 hours and the temperature controlled at 0-15℃.
[0051] Then, after the dripping is complete, keep the reaction at a constant temperature for 0.5 hours, controlling the temperature between 0-15℃, and add 385g of sodium thiosulfate solution (340g of water and 45g of sodium thiosulfate pentahydrate) to quench the reaction.
[0052] Finally, the sampling and testing control showed that the raw material alcohol content was 0%, the target aldehyde content was 93%, and the excessively oxidized carboxyl content was 3%. Specific Implementation Example 2:
[0054] In this embodiment:
[0055] First, take a clean four-necked flask, add 1780g of dichloromethane, 165g of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, 1.6g of TEMPO and 2g of tetrabutylammonium bromide, and start stirring;
[0056] Next, when the above stirring is complete, add 33.5g of sodium bromide solution (20g of water, 13.5g of sodium bromide) and 146g of distilled water (100g of water, 38g of disodium hydrogen phosphate, 8g of sodium dihydrogen phosphate) to the bottle, and cool the liquid in the four-necked bottle to 0℃.
[0057] Next, after the above cooling is completed, sodium hypochlorite with an effective chlorine content of 9-10% is added dropwise. The dropping rate is controlled during the dropping process, the total dropping time is 8 hours, and the temperature is controlled at 0-15℃.
[0058] Then, after the dripping is complete, keep the reaction at a constant temperature for 0.5 hours, controlling the temperature between 0-15℃, and add 385g of sodium thiosulfate solution (340g of water and 45g of sodium thiosulfate pentahydrate) to quench the reaction.
[0059] Finally, the sampling and testing control showed that the raw material alcohol content was 0%, the target aldehyde content was 96%, and the excessively oxidized carboxyl content was 1%. Specific Implementation Example 3:
[0061] In this embodiment:
[0062] First, take a clean four-necked flask, add 1780g of dichloromethane, 165g of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, 1.6g of TEMPO and 2g of tetrabutylammonium bromide, and start stirring;
[0063] Secondly, when the above stirring is completed, add 33.5g of sodium bromide solution (20g of water, 13.5g of sodium bromide) and 146g of mixed phosphate solution (100g of water, 38g of disodium hydrogen phosphate, 8g of sodium dihydrogen phosphate) to the bottle, and cool the liquid in the four-necked bottle to 0℃.
[0064] Next, after the above cooling is completed, sodium hypochlorite with an effective chlorine content of 9-10% is added dropwise. The dropping rate is controlled during the dropping process, the total dropping time is 8 hours, and the temperature is controlled at 0-15℃.
[0065] Then, after the dripping is complete, keep the reaction at a constant temperature for 0.5 hours, controlling the temperature between 0-25℃, and add 385g of sodium thiosulfate solution (340g of water and 45g of sodium thiosulfate pentahydrate) to quench the reaction.
[0066] Finally, the sampling and testing control showed that the raw material alcohol content was 0%, the target aldehyde content was 90%, and the excessively oxidized carboxyl content was 7%.
[0067] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the invention. Those skilled in the art will understand that implementing all or part of the above-described embodiments and making equivalent changes in accordance with the claims of the present invention are still within the scope of the invention.
Claims
1. A method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)tert-butyl carbamate, characterized in that, Includes the following steps: S1: Take a four-necked flask, add 1780g of dichloromethane, 165g of (R)-tert-butyl(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, 1.6g of TEMPO and 2g of tetrabutylammonium bromide to the flask, and stir it. S2: Add 33.5g of sodium bromide solution and 146g of mixed phosphate solution to the four-necked flask after stirring in S1, and cool the liquid in the four-necked flask to the specified temperature; S3: Add sodium hypochlorite with an effective chlorine content of 9-10% to the four-necked flask after cooling in S2; S4: After the dripping in S3 is completed, keep the liquid in the four-necked flask warm, and add 385g of sodium thiosulfate solution to the flask to quench the reaction. S5: Sampling and testing.
2. The method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester as described in claim 1, characterized in that, The 33.5g sodium bromide solution in S2 includes 20g water and 13.5g sodium bromide; the mixed phosphate solution includes 100g water, 38g disodium hydrogen phosphate and 8g sodium dihydrogen phosphate.
3. The method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester as described in claim 1, characterized in that, The pH value of the mixed phosphate solution in S2 is between 7.8 and 9.
3.
4. The method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester as described in claim 1, characterized in that, The liquid in the four-necked flask in S2 is cooled to 0°C.
5. The method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester as described in claim 1, characterized in that, The sodium hypochlorite in S3 is added over 5-8 hours, with the temperature controlled at 0-15℃.
6. The method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester as described in claim 1, characterized in that, The heat preservation time in S4 is 0.5 hours, and the temperature is controlled between 0-15℃.
7. The method for preparing (R)-(1-([1,1'-biphenyl]-4-yl)-3-oxopropane-2-yl)carbamate tert-butyl ester as described in claim 1, characterized in that, The 385g sodium thiosulfate solution in S4 includes 340g of water and 45g of sodium thiosulfate pentahydrate.