Tizanidine intermediate impurity, preparation method and intermediate detection method

Abstract

The invention provides a tizanidine intermediate impurity, namely a compound shown as a formula II and a preparation method, the preparation method is characterized in that a target product is obtained through four-step reaction starting from 4-chloro-3-nitrobenzene-1, 2-diamine, and the compound can be used as a reference substance in quality analysis of tizanidine and an intermediate thereof. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of small molecule compound synthesis, and specifically relates to a method for preparing an imidazole derivative. Background Art

[0002] Tizanidine Hydrochloride is an imidazole derivative. Its Chinese chemical name is 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazole-4-amine hydrochloride, and its English chemical name is 5-Chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-2,1,3-benzothiadiazole-4-aminemonohydrochloride. Its chemical structure is as follows. It is a central skeletal muscle relaxant with an imidazoline structure developed by Novartis of Switzerland. It is used to reduce diseases such as increased skeletal muscle tension, muscle spasms and muscle rigidity caused by brain and spinal cord trauma, cerebral hemorrhage, encephalitis and multiple sclerosis. It is a central muscle relaxant with good clinical evaluation.

[0003]

[0004] The method for synthesizing tizanidine currently adopted all comprises an addition-elimination reaction shown in a reaction formula I, in which the amino group in 4-amino-5-chloro-2,1,3-benzothiadiazole attacks the carbonyl carbon in the five-membered ring in the N-acyl-2-imidazolidinone, and nucleophilic addition occurs, and then a part of water is taken off, and then hydrolyzed under alkaline conditions, takes off acetyl, and obtains tizanidine.

[0005]

[0006] The possible reason for introducing an acyl group into 2-imidazolidinone is that if 2-imidazolidinone is used directly for the reaction, the electron-donating effect of the two nitrogen atoms on both sides of the carbonyl group greatly weakens the electrophilicity of the carbonyl carbon, resulting in low reactivity. However, after the introduction of an acyl group, the reactant N-acetyl-2-imidazolidinone has two carbonyl groups, and the carbonyl group in the acyl group (typically acetyl and benzoyl) will also undergo a condensation reaction with the amino group of thiadiazole, but this has not been reported in the prior art. Summary of the invention

[0007] One of the purposes of the present invention is to provide a pharmaceutical intermediate impurity which has not been reported in the prior art.

[0008] Another object of the present invention is to provide a method for synthesizing the pharmaceutical intermediate impurities.

[0009] The third object of the present invention is to provide the analytical method of above-mentioned medicine intermediate and tizanidine, wherein comprises the use of above-mentioned medicine intermediate impurity as standard sample.

[0010] The pharmaceutical intermediate impurity involved in the first aspect of the present invention has the following structure:

[0011]

[0012] It is hereinafter referred to as Compound 5, and its chemical name is 5-chloro-N-(1′-(2-imidazolidinone-1-yl)ethylidene)-2,1,3-benzothiadiazole-4-amine.

[0013] In the second aspect of the present invention, the method for synthesizing compound 5 is represented by the following route 2:

[0014]

[0015] The steps include:

[0016] 1) Condensation reaction: in the presence of a first solvent, 4-chloro-3-nitrobenzene-1,2-diamine (compound 1) and thionyl chloride undergo a condensation reaction to obtain 4-nitro-5-chloro-2,1,3-benzothiadiazole (compound 2);

[0017] 2) Reduction reaction: reducing 4-nitro-5-chloro-2,1,3-benzothiadiazole in the presence of a second solvent to obtain 4-amino-5-chloro-2,1,3-benzothiadiazole;

[0018] 3) Azide reaction: 4-amino-5-chloro-2,1,3-benzothiadiazole is reacted with sodium nitrite and sodium azide to generate 4-azido-5-chloro-2,1,3-benzothiadiazole;

[0019] 4) AZA-Wittig reaction, wherein compound 4 is reacted with triphenylphosphine and N-acetyl-2-imidazolidinone in sequence to obtain the impurity compound 5-chloro-N-(1'-(2-imidazolidinone-1-yl)ethylidene)-2,1,3-benzothiadiazole-4-amine.

[0020] In a specific embodiment, the first solvent is one or more of toluene, tetrahydrofuran, dichloromethane, dioxane and acetonitrile, preferably toluene and dichloromethane.

[0021] In a specific embodiment, the condensation reaction is carried out in the presence of triethylamine, and the amount used can be 3-5 times the molar amount of 4-chloro-3-nitrobenzene-1,2-diamine, preferably 4 times the molar amount. Preferably, the molar ratio of 4-chloro-3-nitrobenzene-1,2-diamine to thionyl chloride is 1:2.

[0022] In one embodiment, the reducing agent in step 2) is Fe / HCl, Zn / HCl, Na 2 S, NaHS, Na 2 S 2 、Na 2 SO 3 、NaHSO 3 and Na 2 S 2 O 4 As a further preference, in step 2), Fe / HCl reducing agent is used, and the second solvent is selected from N-methylpyrrolidone, toluene, tetrahydrofuran, and dioxane. As a further preference, the molar ratio of iron to reactant is 2 to 5, preferably 1:3.

[0023] In one embodiment, Na is used in step 2). 2 S, NaHS, Na 2 S 2 As a reducing agent, the second solvent is methanol.

[0024] In one embodiment, a solid acid catalyst is used in step 3), which is selected from sulfonic acid type cation exchange resin and SO4 2- / MxOy type solid superacid,

[0025] Furthermore, the solvent used in step 3) is toluene, acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, dimethyl sulfoxide, among which toluene is preferred.

[0026] Furthermore, the SO4 2- / MxOy type solid superacid is SO 4 2- / ZrO 2 -SiO 2 、SO 4 2- / SiO 2 / TiO 2 .

[0027] In a specific embodiment, in step 4), triphenylphosphine is directly added in an equimolar amount to the system after the reaction in step 3), and then reacted at room temperature for a sufficient time to obtain phosphine imide.

[0028] In a specific embodiment, in step 4), N-acetyl-2-imidazolidinone is added to the reaction solution after conversion to phosphine imide, and the mixture is heated to 100-120° C. and the reaction is continued to obtain impurity compound 5.

[0029] The impurity compound 5 according to the present invention can be used as a reference substance for synthesizing a tizanidine intermediate, and is used to determine the content of the impurity compound 5 and other impurities in the intermediate product. The intermediate is 5-chloro-N-(4,5-dihydro-1H-2-acyl imidazole-2-yl)-2,1,3-benzothiadiazole-4-amine, having a structure of formula III,

[0030]

[0031] The detection method uses a high performance liquid chromatograph, and the chromatographic conditions are: a chromatographic column with octadecylsilane bonded silica as a filler, a sodium pentane sulfonate solution-acetonitrile mixed solution as a mobile phase A, and acetonitrile as a mobile phase B, and linear gradient elution is performed as shown in the following table; the flow rate is 0.8-1.0 ml per minute; the column temperature is 25-40°C; the detection wavelength is 220-240 nm; the injection volume is 10-20 μl,

[0032] BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is a hydrogen nuclear magnetic resonance spectrum of the impurity compound 5 obtained in an embodiment of the present invention;

[0034] Figure 2 is a mass spectrum of impurity compound 5 obtained in an embodiment of the present invention;

[0035] Figure 3 is a liquid chromatogram of the test results of Example 6 of the present invention;

[0036] Figure 4 It is the liquid chromatogram of the embodiment of the present invention 7 to tizanidine intermediate formula III compound detection analysis. DETAILED DESCRIPTION

[0037] According to the method of the present invention, the reaction route is shown in the following formula:

[0038]

[0039] The steps include:

[0040] 1) Condensation reaction: in the presence of a first solvent, 4-chloro-3-nitrobenzene-1,2-diamine (compound 1) and thionyl chloride are subjected to a condensation reaction to obtain 4-nitro-5-chloro-2,1,3-benzothiadiazole (compound 2);

[0041] 2) Reduction reaction: reducing 4-nitro-5-chloro-2,1,3-benzothiadiazole (compound 2) in the presence of a second solvent to obtain 4-amino-5-chloro-2,1,3-benzothiadiazole (compound 3);

[0042] 3) Azide reaction: 4-amino-5-chloro-2,1,3-benzothiadiazole (compound 3) is reacted with sodium nitrite and sodium azide to generate 4-azido-5-chloro-2,1,3-benzothiadiazole (compound 4);

[0043] 4) AZA-Wittig reaction, 4-azido-5-chloro-2,1,3-benzothiadiazole is reacted with triphenylphosphine and N-acetyl-2-imidazolidinone in sequence to obtain 5-chloro-N-(1'-(2-imidazolidinone-1-yl)ethylidene)-2,1,3-benzothiadiazole-4-amine (Compound 5).

[0044] In step 1), the condensation reaction needs to be usually carried out in a weakly alkaline environment. Typical weak bases are tertiary amines such as triethylamine and trimethylamine, among which triethylamine is preferred. The tertiary amine is used to absorb HCl and water produced in the condensation reaction. The amount of the tertiary amine can be 3-5 times the molar amount of compound 1, more preferably 4 times the molar amount. The molar ratio of compound 1 to thionyl chloride is 1:1 to 5, preferably 1:2. Low temperature should be controlled in the early stage of the reaction, for example, the temperature is not higher than 5°C. It is usually carried out at low temperature, for example not more than 5°C, and the first solvent preferably used is toluene, tetrahydrofuran, dichloromethane, dioxane, acetonitrile, more preferably toluene and dichloromethane.

[0045] In step 2), there are various methods for reducing the nitro group in compound 2, ie, 4-nitro-5-chloro-2,1,3-benzothiadiazole, to an amino group.

[0046] One is catalytic hydrogenation reduction, which uses precious metal catalysts such as palladium and platinum under pressure. During the process, hydrogen dissociates on the catalyst surface, and then hydrogen atoms are added to nitrobenzene, and finally reduced to aniline This method has the advantage of less by-products.

[0047] The second method is metal reduction under acidic conditions: for example, using iron powder or zinc powder to reduce nitrobenzene under acidic conditions. There is a single electron transfer in the reaction, the iron powder is oxidized to ferrous ions, and the nitro group is reduced to an amino group. This method is simple to operate, but a small amount of nitro reduction may be insufficient, resulting in nitrosobenzene, N-phenylhydroxylamine, etc. When a reducing agent is used, the second solvent is selected from N-methylpyrrolidone, toluene, tetrahydrofuran, dioxane, preferably toluene. When Fe / HCl is used for reduction, the molar ratio of compound 2 to iron is 1:2 to 5, preferably 1:3.

[0048] The third method is to use a sulfur-containing reducing agent. Examples of reducing agents that can be used include Na 2 S, NaHS, Na 2 S 2 、Na 2 SO 3、NaHSO 3 and Na 2 S 2 O 4 . This method has the advantages of short reaction cycle, low energy consumption, mild reaction conditions, simple post-treatment, high yield, and recycled solvent. In the case of using sulfide, the preferred conditions are that the second solvent is methanol, the molar ratio of sulfide to compound 2 is 1.5-2.0, the reaction is carried out in an alkaline environment, and the temperature is preferably 40-70°C. After the reducing agent is added, stirring is continued for 2 hours to complete the reaction.

[0049] Another type of reducing agent is iron catalyst / hydrazine hydrate. Hydrazine hydrate has a strong reducing ability and can reduce nitro groups to amine groups. The reaction needs to be carried out under alkaline conditions to ensure the smooth progress of the reaction. The disadvantage is that hydrazine hydrate is a toxic and flammable liquid.

[0050] In step 3), under acidic conditions, compound 3 is reacted with NaNO 2 reaction, then add an equal molar amount of NaN 3 The reaction can be completed in a short time, usually no more than 1 hour. The solvent used can be toluene, acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, dimethyl sulfoxide. In a specific embodiment, in a reactor, compound 3, solvent, concentrated hydrochloric acid, and water are mixed, the temperature is controlled at about 0°C, and then NaNO is slowly added dropwise 2 After sufficient reaction time, slowly add NaN 3 The amount of hydrochloric acid used is 2-5 times the molar amount of compound 3, more preferably 3 times the molar amount.

[0051] In a preferred embodiment, a solid acid catalyst is used instead of concentrated hydrochloric acid. The advantage of using this catalyst is that the reaction conditions are milder, the reaction can be carried out at room temperature, and the post-treatment is simple, and only the catalyst needs to be filtered out. The preferred solid acid catalyst is a sulfonic acid type cation exchange resin and SO4 2- / M x O y A typical example of the former is a styrene skeleton-loaded sulfonic acid group exchange resin, and an example of the latter is SO 4 2- / ZrO 2 -SiO 2 、SO 4 2- / SiO 2 / TiO 2 .

[0052] In step 4), the AZA-Wittig reaction mainly includes using triphenylphosphine to react with azide to generate phosphinimine through Staudinger reaction, and then the nucleophilic nitrogen atom of phosphinimine attacks the carbonyl group to form a four-membered ring intermediate (oxynitrogen phosphine), which is finally rearranged to compound 5 and triphenylphosphine oxide.

[0053] First, triphenylphosphine reacts with azide to obtain phosphine imide by removing a molecule of nitrogen (Staudinger reaction).

[0054]

[0055] After the Staudinger reaction, there is no need to separate the intermediate phosphine imide. N-acetyl-2-imidazolidinone can be directly added to the system to obtain the intermediate impurity compound 5 after a mild reaction.

[0056]

[0057] In this process, the nucleophilic nitrogen atom of the phosphine imide preferentially attacks the acetyl carbonyl in N-acetyl-2-imidazolidinone to form a four-membered ring intermediate (oxyazaphosphine), which then rearranges into a Schiff base product and triphenylphosphine oxide to complete the AZA-Wittig reaction.

[0058] In this step, the third solvent can be toluene, acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, dimethyl sulfoxide, or a mixture thereof.

[0059] In a specific embodiment, the azide compound 4 is dissolved in toluene, and triphenylphosphine is added in batches at room temperature for about 10 hours. The reaction is monitored by TLC to obtain phosphinimine, and then N-acetyl-2-imidazolidinone is added. After the addition, the reaction solution is heated to reflux temperature and the reaction is continued for 5-15 hours. After the reaction is completed by TLC monitoring, the solvent is concentrated to obtain a crude product of the target compound.

[0060] Example 1 Preparation of Compound 2 (4-nitro-5-chloro-2,1,3-benzothiadiazole)

[0061] Add 15.50 g (82.0 mmol) of 4-chloro-3-nitrobenzene-1,2-diamine (Compound 1) and 250 mL of dichloromethane to a 500 ml three-necked flask, stir for 30 min in an ice-water bath, slowly add 33.12 g (327.9 mmol) of triethylamine, and then slowly add 50 mL of a dichloromethane solution of 19.50 g (163.9 mmol) of thionyl chloride at 0 ° C., react at 40 ° C reflux temperature for 5 h, and after the reaction solution is cooled, add water (3 × 200 mL) and separate the liquid three times. Take the organic layer and purify it with anhydrous Na 2 SO 4The solid was dried, concentrated under reduced pressure, and purified by silica gel column chromatography with ethyl acetate:n-hexane = 1:10 as the eluent. The eluent was concentrated to obtain 15.02 g of 4-nitro-5-chloro-2,1,3-benzothiadiazole as a white crystalline powder with a yield of 84.9%.

[0062] Example 2 Preparation of Compound 3 (4-amino-5-chloro-2,1,3-benzothiadiazole)

[0063] Add 30.00 g (0.14 mol) of 4-nitro-5-chloro-2,1,3-benzothiadiazole (compound 2), 23.31 g (0.42 mol) of iron powder, 41.13 g of 37% concentrated hydrochloric acid, and 120 ml of toluene to a 250 ml three-necked flask, heat to 60 ° C and stir to react for 2 hours. TLC shows that the raw material reacts completely. Cool to room temperature, filter with suction, wash the filter cake with 100 ml of water, stand and separate, adjust the pH value of the aqueous phase to 7-8 with sodium bicarbonate solution, filter with suction, wash the filter cake with 100 ml of water, and dry at 70 ° C to obtain 23.95 g of compound 3, with a yield of 92.7%.

[0064] Example 3 Preparation of Compound 3 (4-amino-5-chloro-2,1,3-benzothiadiazole)

[0065] 30.00 g (0.14 mol) of 4-nitro-5-chloro-2,1,3-benzothiadiazole (Compound 2) and 120 ml of methanol were added to a 250 ml three-necked flask, and a solution prepared by 12.94 g of sodium hydrosulfide (0.23 mol), 15 ml of water and 2 g of sodium hydroxide (0.05 mol) was added dropwise at room temperature. After the addition, the temperature was raised to 65°C and stirred for 2 h. The reaction of the raw material was complete according to TLC. The solvent was concentrated, 100 ml of water was added and stirred for dispersion, and the filter cake was washed with 100 ml of water and dried at 70°C to obtain 24.16 g of Compound 3 with a yield of 93.0%.

[0066] Example 4 Preparation of Compound 4 (4-azido-5-chloro-2,1,3-benzothiadiazole)

[0067] Add 18.5 g (0.10 mol) of compound 3, 100 ml of toluene, and SO into a 250 ml three-necked flask. 4 2- / SiO 2 / TiO 2 To 12 g of a super-strong solid acid catalyst, add a solution consisting of 6.9 g of sodium nitrite (0.1 mol) and 10 ml of water at room temperature. After the addition is complete, stir and react for 2 hours. Then, add a solution consisting of 6.5 g of sodium azide (0.1 mol) and 15 ml of water. After the addition is complete, stir and react for 2 hours at room temperature. Filter to remove the catalyst, let stand to separate the water layer, wash the organic layer with sodium bicarbonate aqueous solution, dry it with anhydrous sodium sulfate, and directly proceed to the next step of reaction.

[0068] Example 5 Preparation of Compound 5 (5-chloro-N-(1'-(2-imidazolidinone-1-yl)ethylidene)-2,1,3-benzothiadiazole-4-amine)

[0069] To the toluene solution obtained in Example 5, 26.2 g (0.1 mol) of triphenylphosphine was added in batches at room temperature, and the reaction was carried out for about 10 h. The reaction was monitored by TLC to obtain phosphinimine, and 8.6 g (0.1 mol) of N-acetyl-2-imidazolidinone was directly added to the system, and the reaction solution was heated to 115° C. and the reaction was continued for 12 h. After the reaction was completed by TLC monitoring, the solvent was concentrated to obtain a crude product of compound 5, which was purified by silica gel column chromatography, and the eluent was ethyl acetate:n-hexane=1:5. The eluent was concentrated to obtain 15.67 g of a yellow solid with a purity of 96.81% and a total yield of 53.0% in two steps. 1H-NMR (DMSO-d6, 400 MHz): δppm 7.77-7.72 (dd, 2H), 7.58 (s, 1H), 4.03-4.00 (t, 2H), 3.46-3.42 (t, 2H), 2.12 (s, 3H). m / z[M]+=295.91. Its hydrogen spectrum and mass spectrum are shown in Figure 1 and Figure 2 .

[0070] Example 6 Detection of Compound 5

[0071] Preparation of test solution: Compound 5 prepared in Example 5 above was accurately weighed and prepared into a solution with a concentration of 0.2 mg / ml using methanol.

[0072] Octadecylsilane bonded silica gel was used as filler, sodium pentane sulfonate solution at pH 3.0-acetonitrile (95:5) was used as mobile phase A, and acetonitrile was used as mobile phase B. Linear gradient elution was performed according to the table below; the flow rate was 1.0 ml per minute; the column temperature was 30°C; the detection wavelength was 230 nm; and the injection volume was 10 μl.

[0073]

[0074] The obtained liquid chromatogram is shown in Figure 3 .

[0075] Example 7 Intermediate Quality Test

[0076] A tizanidine intermediate, a compound of formula III (self-made by the applicant company), was made into a solution with a concentration of 0.2 mg / ml, and the chromatographic conditions of embodiment 6 were adopted to carry out liquid chromatography detection. The results obtained are shown in Figure 4 .

[0077] The above is only an optional implementation method for some implementation scenarios of the present disclosure. It should be pointed out that for ordinary technicians in this technical field, without departing from the technical concept of the scheme of the present disclosure, other similar implementation methods based on the technical ideas of the present disclosure are also within the protection scope of the embodiments of the present disclosure.

Claims

1. A tizanidine intermediate impurity compound, chemical name is: 5-chloro-N-(1'-(2-imidazolidinone-1-yl)ethylidene)-2,1,3-benzothiadiazole-4-amine, which has the structure of following formula II:

2. A method for preparing the compound according to claim 1, comprising the following routes and steps: 1) condensation reaction: in the presence of a first solvent, compound 1, i.e. 4-chloro-3-nitrobenzene-1,2-diamine (compound 1) and thionyl chloride undergo a condensation reaction to obtain 4-nitro-5-chloro-2,1,3-benzothiadiazole, compound 2; 2) Reduction reaction: reducing compound 2 in the presence of a second solvent to obtain 4-amino-5-chloro-2,1,3-benzothiadiazole, compound 3; 3) Azide reaction: Compound 3 is reacted with sodium nitrite and sodium azide successively to generate 4-azido-5-chloro-2,1,3-benzothiadiazole, compound 4; 4) AZA-Wittig reaction, wherein compound 4 is reacted with triphenylphosphine and N-acetyl-2-imidazolidinone in sequence to obtain the impurity compound 5-chloro-N-(1'-(2-imidazolidinone-1-yl)ethylidene)-2,1,3-benzothiadiazole-4-amine, compound 5.

3. The preparation method according to claim 2, wherein The first solvent is one or more of toluene, tetrahydrofuran, dichloromethane, dioxane and acetonitrile, preferably toluene and dichloromethane.

4. The preparation method according to claim 2, wherein The condensation reaction is carried out in the presence of triethylamine, the amount of which is 3-5 times the molar amount of 4-chloro-3-nitrobenzene-1,2-diamine, preferably 4 times the molar amount. Preferably, the molar ratio of 4-chloro-3-nitrobenzene-1,2-diamine to thionyl chloride is 1:

2.

5. The preparation method according to claim 2, wherein: The reducing agent in step 2) is one of Fe / HCl, Zn / HCl, Na2S, NaHS, Na2S2, Na2SO3, NaHSO3 and Na2S2O4.

6. The preparation method according to claim 2, wherein: In step 2), Fe / HCl reducing agent is used, and the second solvent is selected from N-methylpyrrolidone, toluene, tetrahydrofuran, and dioxane. Preferably, the molar ratio of iron to reactant is 1:

3.

7. The preparation method according to claim 2, wherein: In step 2), Na2S, NaHS, or Na2S2 is used as a reducing agent, and the second solvent is methanol.

8. The preparation method according to claim 2, wherein: In step 3), a solid acid catalyst is used, which is selected from sulfonic acid type cation exchange resin and SO4 2- / MxOy type solid superacid.

9. The preparation method according to claim 8, wherein: The solvent used in step 3) is toluene, acetonitrile, tetrahydrofuran, dimethyltetrahydrofuran, dioxane, dimethyl sulfoxide, among which toluene is preferred. Preferably, the SO4 2- / MxOy type solid superacid is SO4 2- / ZrO2-SiO2, SO4 2- / SiO2 / TiO2.

10. A quality detection method for a tizanidine hydrochloride intermediate, wherein the intermediate is 5-chloro-N-(4,5-dihydro-1H-2-acyl imidazole-2-yl)-2,1,3-benzothiadiazole-4-amine, having a structure of formula III, It is characterized in that The following conditions were used: Test solution: accurately weigh the intermediate and prepare a solution with a concentration of 0.1-1 mg / ml using a diluent. High performance liquid chromatography was used, with a chromatographic column filled with octadecylsilane bonded silica gel, a sodium pentane sulfonate solution-acetonitrile mixed solution as mobile phase A, and acetonitrile as mobile phase B, and linear gradient elution was performed as shown in the following table; the flow rate was 0.8-1.0 ml per minute; the column temperature was 25-40°C; the detection wavelength was 220-240 nm; the injection volume was 10-20 μl, 11. The detection method according to claim 10, wherein: The ratio of sodium pentane sulfonate-acetonitrile mixed solution is 95:5, the diluent can be one or more of methanol, acetonitrile, isopropanol, preferably methanol, the flow rate is preferably 1.0 ml / min, the column temperature is preferably 30° C., the detection wavelength is preferably 230 nm, and the injection volume is preferably 10 μl.

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