A process for the preparation of a key intermediate of cinoxamate
The method for preparing key intermediates of cinuoamine esters by oxidative coupling reaction of tetrabutylammonium iodide and peroxytert-butanol was optimized, which solved the problems of the danger and poor atom economy of using hydrogen bromide gas in the existing technology, and realized the production of key intermediates of cinuoamine esters in a high-efficiency and environmentally friendly manner.
Patent Information
- Application Number
- CN202410169527.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-02-06
- Publication Date
- 2026-01-09
- Estimated Expiration
- 2044-02-06
AI Technical Summary
Existing methods for preparing key intermediates of cinnocyanide involve the use of highly irritating hydrogen bromide gas, which makes industrial production difficult, and also results in poor atom economy, high impurity ratios, and waste.
Tetrabutylammonium iodide was reacted with peroxytert-butanol to generate tert-butoxy radicals and iodine. The major product III-b and minor product III-a were generated through oxidative coupling. The reaction conditions were optimized to increase the proportion of the major product and to avoid the use of bromine reagents.
This method enables the efficient preparation of key intermediates of cinnoamino esters without the need for brominated intermediates, increases the ratio of products III-b and III-a, facilitates industrial production and environmental protection, and improves economic efficiency.
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Figure CN118184595B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a method for preparing a key intermediate of cinoxamate. BACKGROUND
[0002] Cinoxamate is mainly used for partial seizures in adult patients in the clinic, and the main clinical advantage is that in the clinical trials in the research and development stage, the clinical results show that the proportion of patients without seizures in the cinoxamate treatment group is more than 20%, and this range has never been reached or exceeded in the past few decades and other comparable trials.
[0003] Among them, the structural formula of cinoxamate is as follows:
[0004]
[0005] In the prior art, patent CN114901647 and patent CN102803233 disclose a synthetic preparation method of cinoxamate, and the synthetic route is as follows:
[0006]
[0007] The reaction of the alpha-brominated compound I and the potassium salt of 1,2,3,4-tetrazole generates the key intermediate compound III-b, that is, the key intermediate of cinoxamate, which has a chemical formula of 1-(2-chlorophenyl)-2-(2H-tetrazole-2-substituted)ethyl-1-ketone and a structural formula of:
[0008]
[0009] The key intermediate compound III-b of cinoxamate undergoes asymmetric reduction and esterification to prepare cinoxamate. As shown in the synthetic route, the alpha-brominated compound II is prepared from the carbonyl compound I. In the examples of patent CN114901647, it is known that the compound I is reacted with N-bromosuccinimide under the catalysis of p-toluenesulfonic acid to prepare the compound II. However, N-bromosuccinimide can react with p-toluenesulfonic acid to generate highly irritating hydrogen bromide gas, which is harmful to the human body and is not conducive to large-scale industrial production. In addition, in the subsequent process of preparing cinoxamate, the bromine atom (or other halogen molecules) is replaced by tetrazole and removed, which is not an essential element of the final product. Therefore, the synthetic method has poor atom economy. Furthermore, in patent CN114901647, it is known that the preparation of the key intermediate compound III-b of cinoxamate from the compound II will generate more III-a, and the ratio of III-a to III-b is as high as 1:2. III-a must be discarded as an impurity, which causes waste and poor economy of the method.
[0010] Therefore, there is an urgent need for a method for preparing a key intermediate of cinoxamate without preparing bromo intermediate II and with good economy. SUMMARY
[0011] To solve the above problems in the prior art, the present application provides a method for preparing a key intermediate of cinoxamate.
[0012] The key intermediate of cinoxamate has the chemical formula 1-(2-chlorophenyl)-2-(2H-tetrazole-2-substituted)ethyl-1-ketone and the structural formula:
[0013]
[0014] The method for preparing the key intermediate of cinoxamate comprises the following steps:
[0015] S1: mixing o-chlorophenylacetone, tetrazole, acetonitrile, tetrabutylammonium iodide and hydrogen peroxide tert-butyl alcohol, and heating to 70-80℃ for reaction;
[0016] S2: after reacting for 3-8 hours, cooling to 0℃, adding sodium thiosulfate to terminate the reaction, and extracting to obtain a crude product;
[0017] S3: extracting the crude product obtained in step S2 to obtain product III-b.
[0018] It should be noted that the overall reaction formula of the present application is:
[0019]
[0020] The key point of the present application is the oxidative coupling reaction, and the reaction formula is:
[0021]
[0022] The iodine generated in situ reacts with another molecule of peroxyl tert-butyl alcohol (TBHP) and hydroxyl ion to form a tert-butyl peroxy radical and a water molecule.
[0023] The next reaction formula is:
[0024]
[0025] The tert-butoxy radical / peroxy-tert-butoxy radical generated by the oxidative coupling reaction abstracts a hydrogen atom from the keto aryl to form a carbon-centered radical intermediate; the tetrazole abstracts a hydrogen atom from the tetrazole by the tert-butoxy radical / peroxy-tert-butoxy radical to form a nitrogen-centered radical intermediate. Subsequently, the carbon-centered radical intermediate and the nitrogen-centered radical intermediate couple to form the main product III-b and the minor product III-a.
[0026] As a specific embodiment of the present application, in the step S1, the mixing method of the o-chloroacetophenone, the tetrazole, the acetonitrile, the tetrabutylammonium iodide and the tert-butyl hydroperoxide includes: first, mixing the o-chloroacetophenone, the tetrazole and the acetonitrile, adding into the tetrabutylammonium iodide and displacing in an inert atmosphere, and then adding the tert-butyl hydroperoxide.
[0027] As a specific embodiment of the present application, in the step S1, the mixing method of the o-chloroacetophenone, the tetrazole, the acetonitrile, the tetrabutylammonium iodide and the tert-butyl hydroperoxide includes: first, mixing the o-chloroacetophenone, the tetrazole and the acetonitrile, adding into the tetrabutylammonium iodide and displacing in an inert atmosphere, and then adding the tert-butyl hydroperoxide.
[0028] According to the present application, the experimental temperature is room temperature, specifically about 18-26℃.
[0029] As a specific embodiment of the present application, in the step S1, the molar ratio of the o-chloroacetophenone, the tetrazole, the acetonitrile, the tetrabutylammonium iodide and the tert-butyl hydroperoxide is (1-2):(0.5-1.5):(0.5-1.5):(0.1-0.3):(1-4).
[0030] As a specific embodiment of the present application, in the step S1, the molar ratio of the o-chloroacetophenone, the tetrazole, the acetonitrile, the tetrabutylammonium iodide and the tert-butyl hydroperoxide is 1.6:1:1:(0.1-0.2):(1.5-3).
[0031] As a specific embodiment of the present application, in the step S1, the molar ratio of the o-chloroacetophenone, the tetrazole, the acetonitrile, the tetrabutylammonium iodide and the tert-butyl hydroperoxide is 1.6:1:1:0.2:3.
[0032] As a specific embodiment of the present application, in the step S1, the ratio of the first portion of the tetrabutylammonium iodide and the second portion of the tetrabutylammonium iodide is 1:(1-2), preferably 1:1.
[0033] As a specific embodiment of the present application, in the step S1, the ratio of the first portion of tert-butyl hydroperoxide and the second portion of tert-butyl hydroperoxide is 1:(1-2), preferably 1:1.
[0034] As a specific embodiment of the present application, in the step S1, the heating rate is 7-50℃ / h.
[0035] As a specific embodiment of the present application, in the step S1, the heating rate is 10-16℃ / h.
[0036] As a specific embodiment of the present application, in the step S2, the reaction condition further comprises holding reaction.
[0037] As a specific embodiment of the present application, in the step S2, the reaction time is 4-6 hours.
[0038] As a specific embodiment of the present application, in the step S3, the extraction comprises column chromatography.
[0039] The above raw materials in the present application can be self-made or commercially available, and the present application does not make special limitation thereto.
[0040] Compared with the prior art, the present application has the beneficial effects that:
[0041] 1. The method for preparing the key intermediate of cinoxamate in the present application generates tert-butoxy radical, hydroxyl anion and iodine by the reaction of tetrabutylammonium iodide and tert-butyl hydroperoxide (TBHP); the iodine generated in situ forms tert-butyl peroxy radical and water molecules with another molecule of tert-butyl hydroperoxide (TBHP) and hydroxyl ion. The generated tert-butoxy radical / tert-butoxy peroxy radical abstracts a hydrogen atom from the keto aryl to form a carbon-centered radical intermediate; the tetrazole is abstracted by the tert-butoxy radical / tert-butoxy peroxy radical from the tetrazole to form a nitrogen-centered radical intermediate. Subsequently, the carbon-centered radical intermediate and the nitrogen-centered radical intermediate couple to generate the main product III-b and the secondary product III-a. Through screening and optimization of the reaction conditions, the present application optimizes the ratio of the main product III-b and the secondary product III-a to 3.1:1; which is better than the ratio of 2:1 reported in the patent CN114901647.
[0042] 2. The method of the present application only needs 1-step reaction, does not need to prepare the brominated intermediate I, and prepares the key intermediate III-b of cinoxamate from compound I without using bromine reagent, which is conducive to industrialized production, environmental protection and molecular economy. BRIEF DESCRIPTION OF DRAWINGS
[0043] Figure 1H NMR spectrum of compound III-b;
[0044] Figure 2 C NMR spectrum of compound III-b;
[0045] Figure 3 H NMR spectrum of compound III-a;
[0046] Figure 4 C NMR spectrum of compound III-a;
[0047] Figure 5 HPLC control spectrum of crude product in Example 4 of the present application;
[0048] Figure 6 HPLC control spectrum of crude product in Example 5 of the present application. DETAILED DESCRIPTION
[0049] The present application will be further described in conjunction with specific examples, but does not constitute any limitation to the present application.
[0050] The experimental conditions in each embodiment of the present application are room temperature 22℃.
[0051] Example 1
[0052] The present embodiment provides a method for preparing a key intermediate of cinoxamate, and the specific details are as follows:
[0053] S1: Add o-chloroacetophenone (353 mg, 1.6 eq) and tetrazole (100 mg, 1.0 eq) into acetonitrile (2 ml), and stir to add tetrabutylammonium iodide (51.8 mg, 0.1 eq) under argon replacement,
[0054] S2: Under argon protection, add tert-butyl hydroperoxide (193 mg, 1.5 eq), and heat to 77℃ in one hour, and keep the reaction for 4.5 hours.
[0055] S3: Cool to 0℃, add aqueous sodium thiosulfate solution to terminate the reaction, and extract with EA to obtain the crude product (III-a / III-b = 1:1.6),
[0056] S4: The crude product obtained in step S3 is subjected to column chromatography to obtain product III-b 57 mg.
[0057] The yield of product III-b obtained in Example 1 is 28%.
[0058] Example 2
[0059] The present embodiment provides a method for preparing a key intermediate of cinoxamate, and the specific details are as follows:
[0060] S1: o-Chloroacetophenone (353 mg, 1.6 eq), tetrazole (100 mg, 1.0 eq) were added to acetonitrile (2 ml) under stirring and tetrabutylammonium iodide (104 mg, 0.2 eq) was added under argon protection;
[0061] S2: Under argon protection, tert-butyl hydroperoxide (386 mg, 3.0 eq) was added and the temperature was raised to 77 °C over one hour and the reaction was kept for 5 hours;
[0062] S3: The temperature was lowered to 0 °C and an aqueous solution of sodium thiosulfate was added and EA was used for extraction to obtain the crude product (III-a / III-b = 1 :2.1);
[0063] S4: The crude product obtained from step S3 was subjected to column chromatography to obtain the product III-b 137 mg.
[0064] The yield of product III-b obtained in Example 2 was 43%.
[0065] Example 3
[0066] This example provides a method for preparing a key intermediate of cinoxamate, the specific details of which are as follows:
[0067] S1: o-Chloroacetophenone (353 mg, 1.6 eq), tetrazole (100 mg, 1.0 eq) were added to acetonitrile (2 ml) under stirring and tetrabutylammonium iodide (51.8 mg, 0.1 eq) was added under argon protection;
[0068] S2: Under argon protection, tert-butyl hydroperoxide (193 mg, 1.5 eq) was added and the temperature was raised to 77 °C over one hour;
[0069] S3: Then tetrabutylammonium iodide (51.8 mg, 0.1 eq) and tert-butyl hydroperoxide (193 mg, 1.5 eq) were dissolved in acetonitrile and added to the reaction, and the reaction was kept for 5 hours;
[0070] S4: The temperature was lowered to 0 °C and an aqueous solution of sodium thiosulfate was added and EA was used for extraction to obtain the crude product (III-a / III-b = 1 :2.1);
[0071] S5: The crude product obtained from step S4 was subjected to column chromatography to obtain the product III-b 163 mg.
[0072] The yield of product III-b obtained in Example 3 was 51%.
[0073] Example 4
[0074] This example provides a method for preparing a key intermediate of cinoxamate, the specific details of which are as follows:
[0075] S1: o-chloroacetophenone (353 mg, 1.6 eq), tetrazole (100 mg, 1.0 eq) were added to acetonitrile (2 ml) and stirred under argon protection, and then tetrabutylammonium iodide (51.8 mg, 0.1 eq) was added under argon protection;
[0076] S2: Under argon protection, tert-butyl hydroperoxide (193 mg, 1.5 eq) was added, and the temperature was raised to 77 °C at a rate of 27.5 °C / h (a total of 2 h);
[0077] S3: Then tetrabutylammonium iodide (51.8 mg, 0.1 eq) and tert-butyl hydroperoxide (193 mg, 1.5 eq) were dissolved in acetonitrile and added to the reaction, and the reaction was incubated for 5 hours;
[0078] S4: The temperature was lowered to 0 °C, and an aqueous solution of sodium thiosulfate was added, and EA was used for extraction to obtain a crude product, and the crude product was subjected to HPLC control spectrum, as shown in Figure 5 , the ratio of III-a: III-b in the crude product was 1:2.6; (reference Figure 1 H spectrum of compound III-b; Figure 2 C spectrum of compound III-b; Figure 3 H spectrum of compound III-a; Figure 4 C spectrum of compound III-a.)
[0079] S5: The crude product obtained in step S4 was subjected to column chromatography to obtain product III-b 188 mg.
[0080] The yield of product III-b obtained in Example 4 was 59%.
[0081] Example 5
[0082] This example provides a method for preparing a key intermediate of cinoxamate, and the specific details are as follows:
[0083] S1: o-chloroacetophenone (353 mg, 1.6 eq), tetrazole (100 mg, 1.0 eq) were added to acetonitrile (2 ml) and stirred under argon protection, and then tetrabutylammonium iodide (51.8 mg, 0.1 eq) was added under argon protection;
[0084] S2: Under argon protection, tert-butyl hydroperoxide (193 mg, 1.5 eq) was added, and the temperature was raised to 77 °C at a rate of 11 °C / h (a total of 5 h);
[0085] S3: Then tetrabutylammonium iodide (51.8 mg, 0.1 eq) and tert-butyl hydroperoxide (193 mg, 1.5 eq) were dissolved in acetonitrile and added to the reaction, and the reaction was incubated for 5 hours;
[0086] S4: cooling to 0°C, adding sodium thiosulfate aqueous solution, EA extraction, obtaining crude product, crude product HPLC control atlas, as shown in Figure 6 the ratio of III-a / III-b in the crude product is 1:3.1;
[0087] S5: column chromatography of the crude product obtained in step S4 to obtain product III-b 229mg.
[0088] The yield of product III-b obtained in Example 5 is 72%.
[0089] In summary, the optimal conditions obtained in Example 5 are screened, the ratio of III-a / III-b in the crude product is 1:3.1, and the yield of product III-b is 229mg, which is 72%.
[0090] Any numerical values recited herein include all values from the lower value and the upper value in between. For example, if a component is stated as 50-90, it is intended to mean that every possible number between 51 and 89, and 69 and 71, and 70 and 71, etc. are also specifically recited. For values which are not integers, one-tenth, one-hundredth, one-thousandth, or one-ten-thousandth of the unit are understood to be specifically recited. These are only examples of what is specifically recited herein, and other combinations of numbers can be specifically recited in some contexts. In the application, all possible combinations between the minimum and maximum values recited are considered to have been disclosed in a similar manner.
[0091] It should be noted that the above-described examples are only used to explain the present application and do not constitute any limitation on the present application. The present application is described by referring to typical examples, but it should be understood that the words used therein are descriptive and explanatory words, not limiting words. The present application can be modified within the scope of the claims, and the present application can be revised without departing from the scope and spirit of the present application. Although the present application described therein relates to specific methods, materials and examples, it does not mean that the present application is limited to the specific examples disclosed therein, on the contrary, the present application can be extended to all other methods and applications with the same function.
Claims
1. A process for the preparation of a key intermediate of cinoxamate characterized in that, The method comprises the following steps: S1: first, o-chloroacetophenone, tetrazole, acetonitrile are mixed and added into the first part of tetrabutylammonium iodide to be replaced in an inert atmosphere, the first part of tert-butyl hydroperoxide is added, and the temperature is raised to 70-80℃, then the second part of tetrabutylammonium iodide and the second part of tert-butyl hydroperoxide are dissolved in acetonitrile and added to the reaction; S2: after the reaction for 3-8 hours, the temperature is lowered to 0℃, sodium thiosulfate is added to terminate the reaction, and the crude product is obtained by extraction; S3: the crude product obtained in step S2 is subjected to column chromatography to obtain the key intermediate of cinoxamate represented by III-b; ； In the step S1, the heating rate is 7-50℃ / h.
2. The method of claim 1, wherein, In the step S1, the molar ratio of o-chloroacetophenone, tetrazole, acetonitrile, tetrabutylammonium iodide and tert-butyl hydroperoxide is (1-2):(0.5-1.5):(0.5-1.5):(0.1-0.3):(1-4).
3. The method of claim 2, wherein, In the step S1, the molar ratio of o-chloroacetophenone, tetrazole, acetonitrile, tetrabutylammonium iodide and tert-butyl hydroperoxide is 1.6:1:1:(0.1-0.2):(1.5-3).
4. The method of claim 3, wherein, In the step S1, the molar ratio of o-chloroacetophenone, tetrazole, acetonitrile, tetrabutylammonium iodide and tert-butyl hydroperoxide is 1.6:1:1:0.2:
3.
5. The method according to any one of claims 1 to 4, characterized in that, The ratio of the first part of tetrabutylammonium iodide to the second part of tetrabutylammonium iodide is 1:(1-2); The ratio of the first part of tert-butyl hydroperoxide to the second part of tert-butyl hydroperoxide is 1:(1-2).
6. The method of claim 5, wherein, The ratio of the first part of tetrabutylammonium iodide to the second part of tetrabutylammonium iodide is 1:1; The ratio of the first part of tert-butyl hydroperoxide to the second part of tert-butyl hydroperoxide is 1:
1.
7. The method according to any one of claims 1 to 4, characterized in that, In the step S1, the heating rate is 10-16℃ / h.
8. The method according to any one of claims 1 to 4, characterized in that, In the step S2, the reaction condition further comprises incubation.
9. The method according to any one of claims 1 to 4, characterized in that, In the step S2, the reaction time is 4-6 hours.