Preparation method of key intermediate of rafenasin

Abstract

The invention discloses a preparation method of a rafenasin intermediate, which comprises the following steps of: adding initial materials SM-1 and SM-2 and alkali according to a specific reaction feeding sequence and reaction temperature, heating to the specific reaction temperature (90-110 DEG C), and dropwise adding diphenyl azide phosphate, so that compared with the prior art (contrast 1, 2), the preparation method has the advantages that the urea impurity 1, 3-bis (1, 2, 3-triazole-1-yl)-1, 3-diketone in the reaction is effectively controlled, and the yield of the rafenasin intermediate is improved. The method can be used for producing (1, 1 '-biphenyl)-2-ylurea (less than 5%), the reaction conversion rate is increased, and the whole synthetic route has the advantages of milder and safer reaction conditions, lower production cost and lower environmental pollution.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing a refennaxine intermediate compound. Background Technology

[0002] Revenacin, chemically known as N-({1,1'-biphenyl}-2-yl)carbamate 1-(2-{4-[(4-carbamoylpiperidin-1-yl)methyl]-N-methylbenzoylamino}ethyl)piperidin-4-yl-1-ester, is a novel long-acting muscarinic antagonist (LAMA) developed by Theravance Biopharmaceuticals in Ireland. It possesses long-lasting bronchodilatory activity and is clinically administered via nebulized inhalation to improve lung function, reduce clinical symptoms of COPD, and prevent further deterioration. It is primarily used for maintenance therapy in COPD patients. Revenacin was approved for marketing in the United States on November 9, 2018, under the brand name YUPELRI. ® It is the first LAMA drug for once-daily nebulized treatment. Its chemical formula is as follows:

[0003]

[0004] After literature review, the following synthetic route for refennacetin has been disclosed:

[0005] Route 1: The original patents CN1930125A and CN102958916A disclose the following synthesis process:

[0006]

[0007] Route 1

[0008] The main limitations of this route are: 1) Using biphenyl-2-isocyanate containing a genotoxic warning structure as the starting material to prepare the key intermediate biphenyl-2-ylcarbamate piperidine-4-yl ester requires separate genotoxic impurity research, and biphenyl-2-isocyanate is expensive and not suitable for large-scale production; 2) Many intermediates in the reaction route are oily substances, which are difficult to purify and are not conducive to quality control.

[0009] Route 2: The literature (Wei Lan et al. Optimization of the synthetic process of refennaxine [J]. Journal of Liaoning Teachers College, 2024(26): 95-103.) discloses an improved synthetic process:

[0010]

[0011] Route 2

[0012] To address the limitations of the original patented route, which uses biphenyl-2-isocyanate as a starting material due to its genotoxicity, high cost, and limited availability, Route 2 uses inexpensive and readily available 4-hydroxypiperidine hydrochloride and triphosgene as starting materials. A nucleophilic substitution reaction generates 4-chloroformic acid piperidine hydrochloride, which then undergoes nucleophilic substitution with o-aminobiphenyl, finally yielding refennaxine via a condensation reaction. While this route avoids using the genotoxic biphenyl-2-isocyanate as a starting material, the triphosgene used in the reaction is asphyxiating and readily produces highly toxic phosgene under heating or alkaline conditions, posing a potential safety risk.

[0013] As shown above, piperidine-4-yl biphenyl-2-ylcarbamate can serve as a key intermediate in the preparation of refennaxine, directly impacting the drug's production, market supply, and quality. The specific structural formula is as follows:

[0014]

[0015] Biphenyl-2-ylcarbamate piperidine-4-yl ester

[0016] Route 3: Patent document WO2023002502A discloses another method for preparing the intermediate refinasine, biphenyl-2-ylcarbamate piperidine-4-yl ester: diphenylphosphohydrazide (DPPA) is reacted with biphenyl-2-carboxylic acid to form an acyl azide intermediate, and then N-tert-butoxycarbonyl-4-hydroxypiperidine is added to react and obtain compound 12, which is further deprotected to obtain biphenyl-2-ylcarbamate piperidine-4-yl ester.

[0017]

[0018] Route 3

[0019] The researchers of this invention conducted an in-depth study of the disclosed synthetic process routes and found that although route 3 overcomes the limitations of routes 1 and 2, in actual production, this synthetic method is greatly affected by the moisture in the reaction system. During the synthesis of the precursor compound 12 of biphenyl-2-ylcarbamate piperidine-4-yl ester, it easily generates a large amount of urea impurities, affecting the conversion rate and the quality of the final product. Although route 3 reduces the generation of urea impurities by controlling the feeding temperature to 0-5℃, the process of cooling and then heating up during scale-up production is cumbersome and energy-intensive. Furthermore, if the temperature is not properly controlled, it cannot effectively prevent the generation of impurities, especially the related substance 1,3-bis(1,1'-biphenyl)-2-ylurea (CAS: 115293-14-6).

[0020] In summary, given the numerous shortcomings in the current method for preparing the refennaxine intermediate biphenyl-2-ylcarbamate piperidine-4-yl ester, there is an urgent need to develop a safe, reliable, simple, high-conversion synthetic method that can effectively avoid the generation of impurities. Summary of the Invention

[0021] Based on this, the present invention provides a method for synthesizing the refennax intermediate biphenyl-2-ylcarbamate piperidine-4-yl ester. This method has the advantages of being safe and environmentally friendly, having a simple process, high conversion rate, and low impurity generation. The target product obtained has high purity and yield.

[0022] The specific technical solution is as follows:

[0023] A method for synthesizing the refennaxine intermediate, biphenyl-2-ylcarbamate piperidine-4-yl ester, as shown in Formula I, with the following reaction formula:

[0024] ,

[0025] Wherein, R is any one of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or triphenylmethyl (Trt).

[0026] A method for synthesizing the refennaxine intermediate, biphenyl-2-ylcarbamate piperidine-4-yl ester, as shown in Formula I, comprises the following steps:

[0027] Step 1) Dissolve intermediates SM-1, SM-2, and alkali in an organic solvent, raise the temperature to the reaction temperature, add diphenyl azidophosphate dropwise, and keep warm until the reaction is complete;

[0028] Step 2) Cool the reaction solution from Step 1 to room temperature, add purified water to wash and separate the liquids, take the organic phase and add acid to react, react at a certain temperature, and after post-treatment, obtain biphenyl-2-ylcarbamate piperidine-4-yl ester.

[0029] Preferably, the reaction temperature in step 1 is 80~120℃, and more preferably 90~110℃.

[0030] Preferably, the SM-2 mentioned in step 1 is N-tert-butoxycarbonyl-4-hydroxypiperidine.

[0031] Preferably, the alkali mentioned in step 1 includes, but is not limited to, one or a combination of K2CO3, Na2CO3, triethylamine, N,N-diisopropylethylamine, and pyridine, and more preferably N,N-diisopropylethylamine.

[0032] Preferably, the organic solvent in step 1 is one or more of benzene, toluene, and xylene, and more preferably toluene.

[0033] Preferably, the molar ratio of SM-1, SM-2, alkali, and diphenyl azidophosphate in step 1 is 1:(1.1~1.5):(1.0~2.0):(1.0~3.0).

[0034] More preferably, the molar ratio of SM-1, SM-2, alkali, and diphenyl azidophosphate in step 1 is 1:(1.1~1.2):(1.0~1.5):(1.0~1.5).

[0035] Preferably, the acid in step 2 is selected from one or more of hydrochloric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid, and more preferably hydrochloric acid.

[0036] Preferably, the reaction temperature in step 2 is 20°C to 60°C, and more preferably 50°C to 60°C.

[0037] Preferably, the post-processing method in step 2 is liquid-liquid extraction, adding alkaline solution to the aqueous phase to adjust the pH to 12-13, cooling, adding organic solvent for extraction, liquid-liquid extraction, washing, vacuum concentration, acetonitrile pulping, centrifugation, washing, and vacuum drying.

[0038] Preferably, the alkali mentioned in step 2 includes, but is not limited to, one or more of K2CO3, Na2CO3, NaOH, and KOH.

[0039] Preferably, the organic solvent in step 2 is selected from one or more of dichloromethane, ethyl acetate, chloroform, toluene, and acetonitrile.

[0040] The beneficial effects of this invention are:

[0041] 1. This invention utilizes a specific reaction feeding method and reaction temperature: first, the starting material and alkali are added, and then the reaction temperature is raised to 90~110℃ before diphenyl azidophosphate is added dropwise. Compared with the prior art (Comparative Examples 1 and 2), this effectively controls the generation of urea impurities 1,3-bis(1,1'-biphenyl)-2-ylurea in the reaction (<5%), thus improving the reaction conversion rate. Further controlling the molar ratio of the feed materials can control the amount of urea impurities 1,3-bis(1,1'-biphenyl)-2-ylurea generated to below 1%.

[0042] 2. The synthetic route provided by this invention allows the reaction solution obtained in step 1 to undergo the deprotection reaction in step 2 without post-processing, resulting in minimal material loss. The selected materials are safe and have low toxicity. The entire synthetic route offers advantages such as milder and safer reaction conditions, lower production costs, and less environmental pollution. Attached Figure Description

[0043] Figure 1 The image shows the HPLC chromatogram of the reaction solution used to synthesize intermediate I-1 in Example 1.

[0044] Figure 2 The image shows the HPLC chromatogram of the reaction solution used to synthesize intermediate I-1 in Example 2.

[0045] Figure 3 The image shows the HPLC chromatogram of the reaction solution used to synthesize intermediate I-1 in Example 3.

[0046] Figure 4 The image shows the HPLC chromatogram of the reaction solution used to synthesize intermediate I-1 in Comparative Example 1. Detailed Implementation

[0047] The synthesis method of revanasine intermediate compound I of the present invention will be further described in detail below with reference to specific embodiments. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of the present invention.

[0048] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; and the materials or reagents described are commercially available unless otherwise specified.

[0049] HPLC detection method

[0050] The chromatographic column was ZORBAX Bonus-RP; the mobile phase A was 0.1% trifluoroacetic acid solution-acetonitrile (90:10), and the mobile phase B was 100% acetonitrile; the flow rate was 1.0 mL / min; gradient elution was used (0~5 min: B 5%; 5~10 min: B 5%~20%; 10~20 min: B 20%~40%; 20~30 min: B 40%~90%; 30~35 min: B 90%; 35~36 min: B 90%-5%; 36~40 min: 5%); the column temperature was 30 ℃; the detection wavelength was 220 nm; and the injection volume was 5 μL.

[0051] Example 1 Synthesis of piperidine-4-yl biphenyl-2-ylcarbamate ester (I)

[0052] Step 1: Synthesis of Intermediate I-1

[0053]

[0054] Weigh out biphenyl-2-carboxylic acid (SM-1, 100 g, 0.50 mol), N,N-diisopropylethylamine (DIPEA, 97 g, 0.75 mol), and N-tert-butoxycarbonyl-4-hydroxypiperidine (SM-2, 110.7 g, 0.55 mol), dissolve them in toluene, heat to 100℃ and stir. Control the temperature at 100-110℃ and add diphenyl azide phosphate (DPPA, 178.9 g, 0.65 mol) dropwise. After the addition is complete, maintain the reaction temperature. Detect the reaction by TLC until complete. Analyze the reaction solution by HPLC. The content of impurity 1,3-bis(1,1'-biphenyl)-2-ylurea (retention time 30.367 min) was 0.60%, and the content of intermediate I-1 (retention time 29.370 min) was 90.27%. See [link to relevant documentation]. Figure 1 .

[0055] Step 2: Synthesis of piperidine-4-yl biphenyl-2-ylcarbamate (I)

[0056]

[0057] The reaction solution from step 1 was cooled to room temperature, washed with purified water, and separated. The organic phase was added to 6N hydrochloric acid solution, and the temperature was raised to 50-60℃ for 3 hours until intermediate I-1 in the reaction solution was completely reacted and the tert-butyloxycarbonyl (Boc) protecting group was removed. The reaction was confirmed to be complete by TLC. The solution was separated, and the pH of the aqueous phase was adjusted to 12-13 by adding 4N sodium hydroxide aqueous solution. The temperature was lowered to 25-35℃, and DCM was added for extraction. The solution was separated and washed. The organic phase was concentrated under reduced pressure to remove DCM, acetonitrile was added for slurrying, centrifugation was performed, and the solution was washed and dried under vacuum to obtain 115.6 g of piperidine-4-yl biphenyl-2-ylcarbamate (I) with a purity of 99.72%.

[0058] Example 2

[0059] Step 1: Synthesis of Intermediate I-1

[0060] 1.0 eq of compound SM-1 was added, along with 1.5 eq of N,N-diisopropylethylamine (DIPEA) and 1.1 eq of N-tert-butyloxycarbonyl-4-hydroxypiperidine, dissolved in toluene. The mixture was heated to 100 °C and stirred. Diphenyl azide phosphate (DPPA) was added dropwise at 100-110 °C. After the addition was complete, the reaction was maintained at this temperature. TLC was used to monitor the reaction until complete. HPLC analysis of the reaction solution showed that the impurity 1,3-bis(1,1'-biphenyl)-2-ylurea (retention time 30.350 min) was 0.79%, and the intermediate I-1 (retention time 29.351 min) was 90.09%. (See [reference needed]) Figure 2 .

[0061] Step 2, the synthesis of piperidine-4-yl biphenyl-2-ylcarbamate (Ⅰ), was carried out with reference to Example 1.

[0062] Example 3

[0063] Step 1: Synthesis of Intermediate I-1

[0064] 1.0 eq of compound SM-1 was added, along with 1.3 eq of N,N-diisopropylethylamine (DIPEA) and 1.1 eq of N-tert-butoxycarbonyl-4-hydroxypiperidine, dissolved in toluene. The mixture was heated to 100°C and stirred. Diphenyl azide phosphate (DPPA) was added dropwise at 100-110°C. After the addition was complete, the reaction was maintained at this temperature. TLC was used to monitor the reaction until complete. HPLC analysis of the reaction solution showed that the impurity 1,3-bis(1,1'-biphenyl)-2-ylurea (retention time 30.370 min) was 0.72%, and the content of compound I-1 (retention time 29.372 min) was 90.35%. (See [reference needed]) Figure 3 .

[0065] Step 2, the synthesis of piperidine-4-yl biphenyl-2-ylcarbamate (Ⅰ), was carried out with reference to Example 1.

[0066] Example 4

[0067] This example aims to investigate the effects of different material feed amounts on reaction conversion rate and urea impurity content. The feed amount of SM-1 is 1.0 eq. The preparation method of intermediate I-1 is the same as in Example 1. The reaction temperature is 90~110℃. The results are shown in the table below:

[0068]

[0069] Experimental data show that by controlling the reaction feeding sequence and reaction temperature, the formation of urea impurities can be effectively suppressed and its formation amount can be controlled within 2%. Further controlling the molar ratio of SM-1, SM-2, alkali and diphenyl azidophosphate to 1:(1.1~1.2):(1.0~1.5):(1.0~1.5) can reduce the impurity formation amount to less than 1%.

[0070] Comparative Example 1

[0071] This comparative example refers to the existing technology WO2023002502A. The reaction feeding sequence is as follows: DPPA is added dropwise to SM-1 and DIPEA at 0-5℃ first, followed by SM-2, and the temperature is increased to react. The reaction feeding molar ratio is SM-1:SM-2:DIPEA:DPPA=1:1.1:1.3:1.3. The purpose is to investigate the effect of the feeding sequence on the synthesis reaction of intermediate I-1.

[0072] The reaction results are as follows:

[0073]

[0074] Conclusion: The experimental data shows that adding SM-1, DIPEA, and DPPA first, then raising the temperature to the reaction temperature, and finally adding SM-2 results in a large amount of residual reactants at lower temperatures (60-70℃) and a more complete reaction at higher temperatures (90-100℃), but the urea content in the reaction solution is greater than 5%. Figure 4 It does not meet the quality control standards.

[0075] Comparative Example 2

[0076] Biphenyl-2-carboxylic acid (SM-1, 100 g, 0.50 mol), N,N-diisopropylethylamine (DIPEA, 97 g, 0.75 mol), and N-tert-butoxycarbonyl-4-hydroxypiperidine (SM-2, 110.7 g, 0.55 mol) were weighed and dissolved in toluene. The mixture was heated to 60 °C and stirred. Diphenyl azide phosphate (DPPA, 178.9 g, 0.65 mol) was added dropwise while maintaining the temperature at 60-70 °C. After the addition was complete, the mixture was kept at this temperature and the reaction was monitored by TLC. A large amount of raw materials remained in the reaction.

[0077] Even though the feeding sequence of adding SM-1, DIPEA, and SM-2 first, followed by heating and then adding DPPA dropwise, the reaction temperature did not meet the requirements, the raw materials did not react completely, and the urea content of the impurities was greater than 5%, which did not meet the requirements.

Claims

1. A method for synthesizing the refennaxine intermediate biphenyl-2-ylcarbamate piperidine-4-yl ester as shown in Formula I, characterized in that, The reaction formula is as follows: ， Step 1) Dissolve SM-1, SM-2, and alkali in an organic solvent, raise the temperature to the reaction temperature, add diphenyl azidophosphate dropwise, and keep the temperature and stir until the reaction is complete; Step 2) Cool the reaction solution from Step 1 to room temperature, add purified water to wash and separate the liquids. Take the organic phase, add acid to react, and after post-treatment, obtain biphenyl-2-ylcarbamate piperidine-4-yl ester (I). Wherein, R is any one of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or triphenylmethyl (Trt).

2. The synthesis method according to claim 1, characterized in that, In step 1, R is tert-butyloxycarbonyl (Boc), and SM-2 is N-tert-butyloxycarbonyl-4-hydroxypiperidine.

3. The synthesis method according to claim 1, characterized in that, The reaction temperature in step 1 is 80~120℃.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of SM-1, SM-2, alkali, and diphenyl azidophosphate in step 1 is 1:(1.1~1.5):(1.0~2.0):(1.0~3.0).

5. The synthesis method according to claim 4, characterized in that, The molar ratio of SM-1, SM-2, alkali, and diphenyl azidophosphate in step 1 is 1:(1.1~1.2):(1.0~1.5):(1.0~1.5).

6. The synthesis method according to claim 1, characterized in that, The base in step 1 is one or a combination of K2CO3, Na2CO3, triethylamine, N,N-diisopropylethylamine, and pyridine.

7. The synthesis method according to claim 1, characterized in that, The organic solvent in step 1 is one or more of benzene, toluene, and xylene.

8. The synthesis method according to claim 1, characterized in that, The acid in step 2 is one or more of hydrochloric acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

9. The synthesis method according to claim 1, characterized in that, The post-processing method in step 2 is liquid-liquid extraction. Alkali solution is added to the aqueous phase to adjust the pH to 12-13, the temperature is lowered, organic solvent is added for extraction, liquid-liquid extraction, washing, vacuum concentration, acetonitrile pulping, centrifugation, washing, and vacuum drying. The alkali is selected from one or more of K2CO3, Na2CO3, NaOH, and KOH, and the organic solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, toluene, and acetonitrile.

10. The use of the refennaxine intermediate biphenyl-2-ylcarbamate piperidine-4-yl ester as described in any one of claims 1-9 in the preparation of refennaxine.

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