Synthesis method of salbutamol salt

Abstract

The invention provides a synthesis method of salbutamol, which takes p-hydroxy benzaldehyde as an initial raw material, and salbutamol is obtained through multi-step reaction. The synthesis route is simple, the cost is low, the yield and the purity are high, aftertreatment is simple, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a synthesis method of salbutamol salt. BACKGROUND

[0002] Salbutamol (structure as follows) is a short-acting beta2 adrenergic receptor agonist, and is used as an anti-asthmatic drug. Salbutamol can effectively inhibit the release of anaphylactic substances such as histamine, and prevent bronchial spasm. Salbutamol has high selectivity to airway smooth muscle beta2 receptors, can effectively inhibit the activity of catechol methyltransferase and monoamine oxidase, prolong the action time, and has no obvious excitatory effect on the heart. Adding trace amounts of salbutamol in livestock feed can increase the lean meat yield of livestock, improve the meat exchange rate, and reduce the fat content, but the toxicity of salbutamol is higher than that of ractopamine and other substances with the same function. Salbutamol is a commonly used drug for various bronchial asthma and bronchial spasm patients; salbutamol is also an effective drug for preventing and treating premature birth in obstetrics, can relieve placental vascular spasm, and increase placental blood flow; salbutamol is also used for sinus arrest, sinus bradycardia, sinoatrial block, atrioventricular block, and other slow arrhythmias and heart failure.

[0003]

[0004] At present, the synthesis methods of salbutamol reported in the literature mainly include the following methods:

[0005] CN103951568A discloses a route. Zheng Yumei et al. use salicylaldehyde and acyl chloride as starting materials to obtain 4-bromoacetyl salicylaldehyde and 4-chloroacetyl salicylaldehyde through Friedel-Crafts acylation. The product does not need to be separated, and is directly subjected to condensation reaction with tert-butylamine, and is subjected to salification with hydrochloric acid, and is then reduced with potassium borohydride-zinc chloride to obtain salbutamol, and finally is subjected to salification with sulfuric acid to obtain salbutamol sulfate. The method uses industrial product bromoacetyl chloride which has a high price, and the reduction treatment using borohydride compound at the end is complex.

[0006]

[0007] The program always group task group is also with p-hydroxybenzaldehyde as raw material, through Mannich reaction to obtain 3-dimethylaminomethyl-4-hydroxybenzaldehyde, then through Wittig reaction to obtain 2-dimethylaminomethyl-4-vinylphenol, through acylation reaction to obtain 2-acetoxy-5-vinylphenyl acetate, through bromination reaction to obtain bromide product 2-acetoxy-5-(2-bromo-1-hydroxyethyl) phenyl acetate, and then through amination reaction to obtain salbutamol. The first step of the method may exist by-product generation, which leads to complex product, and the harsh conditions required in subsequent conversion, the potassium tert-butoxide used in the second step Wittig reaction and the NBS reagent used in the conversion of the double bond of the bromide product are expensive and not suitable for industrial production.

[0008]

[0009] In summary, there is still room for improvement in the synthesis process of salbutamol, and the present application designs a synthesis process with cheap and easily available raw materials, short steps and relatively mild conditions. SUMMARY

[0010] In order to solve the above technical problems existing in the prior art, the present application provides a synthesis method of salbutamol salt, which is cheap and easy to obtain, simple in process operation and suitable for industrial mass production.

[0011] The synthesis method of salbutamol hydrochloride provided by the present application comprises the following steps:

[0012]

[0013] Step (5): Amine reaction of compound 5 with tert-butylamine, and then deacetylation to obtain compound 6;

[0014] The acid in compound 6 is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, phosphoric acid, methanesulfonic acid, succinic acid, benzoic acid, salicylic acid, maleic acid, tartaric acid, citric acid, succinic acid and fumaric acid.

[0015] In some embodiments, the synthesis method further comprises the following steps:

[0016]

[0017] Step (4): Epoxidation reaction of compound 4 under alkaline conditions to obtain compound 5.

[0018] In some embodiments, the synthesis method further comprises the following steps:

[0019]

[0020] Step (3): Witting reaction of compound 3 under basic condition to obtain compound 4.

[0021] In some embodiments, the synthetic method further comprises the following steps:

[0022]

[0023] Step (1): compound 1 reacts with concentrated hydrochloric acid and paraformaldehyde to obtain compound 2;

[0024] Step (2): acetylation reaction of compound 2 to obtain compound 3.

[0025] In some embodiments, the synthetic method comprises 1, 2, 3, 4 or 5 steps in the following synthetic routes:

[0026]

[0027] In some embodiments, in the synthetic method, the mass ratio of compound 1, concentrated hydrochloric acid and paraformaldehyde in step (1) is 1:2-10:0.1-1; preferably, the mass ratio of compound 1, concentrated hydrochloric acid and paraformaldehyde is 1:5:0.44;

[0028] The temperature of the reaction is 10-30℃; for example, 10℃, 15℃, 20℃, 25℃, 30℃;

[0029] The reaction time of step (1) is 2-8h.

[0030] The acetylation reaction in step (2) is carried out in the presence of sodium acetate, acetic acid and / or acetic anhydride, and the optimal feeding mass ratio of compound 2, sodium acetate, acetic acid and / or acetic anhydride is 1:1:2 and / or 1.5;

[0031] The temperature of the acetylation reaction is 100-138℃, for example, 100℃, 105℃, 110℃, 115℃, 120℃, 125℃, 130℃, 135℃, 138℃.

[0032] In some embodiments, in the synthetic method, the basic condition in step (3) is provided in the presence of one of sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide;

[0033] The reagent used in the Wittig reaction further comprises methyltriphenylphosphonium bromide;

[0034] The solvent used in the Wittig reaction is selected from tetrahydrofuran, benzene or toluene;

[0035] The temperature of the Wittig reaction is 30-100°C; preferably 50-80°C, such as 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C.

[0036] In some embodiments, the synthetic method, wherein the basic condition in step (4) is provided by one of sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide;

[0037] The oxidizing agent is selected from the group consisting of hydrogen peroxide, peracetic acid, oxygen, meta-chloroperoxybenzoic acid, sodium peroxide, benzoyl peroxide.

[0038] In some embodiments, the synthetic method, wherein the deacetylation in step (5) is reacted under the action of an acid.

[0039] The acid is selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, phosphoric acid, methanesulfonic acid, succinic acid, benzoic acid, salicylic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric acid; preferably concentrated hydrochloric acid.

[0040] In some embodiments, the synthetic method, wherein the structure of compound 6 is as shown below,

[0041]

[0042] The advantage of the present application is that the product of step (1) Blanc reaction used in the present application is flexible, has relatively less side reactions, and is easier to obtain a single product. In step (2) reaction, the acid anhydride is directly used for protection, which is simple to operate and has high yield. In step (3) Wittig reaction, potassium carbonate is cheap and easy to obtain, and at the same time, hydrogen peroxide used in step (4) double bond conversion to epoxy is also cheap, which is more suitable for industrial production.

[0043] The following examples are provided to assist in understanding the present application. It should be understood that these examples are intended to be illustrative only and are not intended to limit the scope of the present application. The true scope of the present application is set forth in the appended claims. It should be understood that any modifications and variations of the examples can be made without departing from the spirit of the present application. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solutions and advantages of the present application more clear, the following embodiments are further described in detail. The specific embodiments described herein are only used to explain the present application and do not constitute any limitation. In addition, in the following description, the description of well-known structures and techniques is omitted to avoid unnecessary confusion of the concept of the present application. Such structures and techniques are also described in many publications.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The following definitions are applied to the descriptions and claims herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0046] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.

[0047] As used herein, the term "about" means ±20% of the number that it precedes. In some embodiments, the term "about" means ±10% of the number that it precedes. In some embodiments, the term "about" means ±5% of the number that it precedes.

[0048] Solvents used herein are commercially available.

[0049] The following abbreviations are used herein: TLC: thin layer chromatography; THF: tetrahydrofuran; DCM: dichloromethane; NBS: N-bromosuccinimide; MTPPB: methyltriphenylphosphonium bromide; eq: equivalent concentration N: g / L

[0050] Compounds are either commercially available or synthesized by hand Software nomenclature, commercially available compounds use the vendor catalog name. DETAILED DESCRIPTION

[0051] The technical solutions of the present application are described in detail below in combination with examples, but the protection scope of the present application is not limited thereto. Example 1: synthesis method of salbutamol hydrochloride

[0052]

[0053] First step: 25 g of concentrated hydrochloric acid was measured and added to a 100 mL flask, then 5 g of p-hydroxybenzaldehyde (compound 1) and 2.2 g of paraformaldehyde were weighed and added to the flask, a magnetic stirrer was added, and the reaction was carried out in a magnetic stirrer at 30°C in an oil bath. After 8 hours of reaction, TLC monitoring showed that the raw material was completely reacted. The reaction was stopped, then the reaction was filtered, the filter cake was washed with water 3 times, and dried in the air. After weighing, compound 2 was obtained as a white powder with a yield of 6.6 g, a yield of 95%, which can be directly used for the next step.

[0054] Second step: 6.6g of compound 2 was taken in a 10 mL round bottom flask, 6.6g of sodium acetate, 13.2g of acetic anhydride, 9.9g of acetic acid were taken in sequence, the reaction temperature was raised to 138°C, the reflux was observed and the reaction was timed, after 7h of reflux the reaction was monitored by TLC, after completion of the reaction the work up was done, the acid was removed by rotary evaporator, the reaction was extracted with dichloromethane three times, the organic layer was collected, washed with saturated brine, the organic layer was collected, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, concentrated under reduced pressure by rotary evaporator to get compound 3 as yellow oil, 8.5g was weighed, the yield was 93%, 1 H NMR (500 MHz, CDC13) δ 10.00 (s, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.3, 2.1 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 5.14 (s, 2H), 2.36 (s, 3H), 2.11 (s, 3H) ppm.

[0055] Third step: 5g of compound 3 was dissolved in 20 mL of THF and taken in a 50 mL round bottom flask, 4.38g of anhydrous potassium carbonate was added, 11g of MTPPB was added under stirring, the reaction was heated to 60-70°C, the reaction was monitored by TLC, after 12h the reaction was complete. The product was worked up, a small amount of water was added to quench, extracted with ethyl acetate, extracted three times, the organic layer was washed with saturated brine solution, the organic layer was collected, dried over anhydrous sodium sulfate, finally concentrated under reduced pressure by rotary evaporator to get compound 4 as yellow oil, 4.2g was weighed, the yield was 85%, 1 H NMR (500 MHz, CDC13) δ 10.00 (s, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.3, 2.1 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 5.14 (s, 2H), 2.36 (s, 3H), 2.11 (s, 3H) ppm.

[0056] Fourth step: 5 g of compound 4 was dissolved in 25 mL of DCM, added to a 50 mL round-bottom flask, the reaction bottle was placed in an ice water bath, and 1.79 g of pre-prepared peroxoacetic acid was slowly added. Start stirring, react for 1 hour, monitor the reaction by TLC, the reaction is complete, perform post-processing, wash with saturated sodium sulfite solution for 2 times, wash with water for 3 times, collect the organic phase, add anhydrous sodium sulfate for drying, rotary evaporation under reduced pressure to concentrate to obtain compound 5, weighing 4.8 g, the yield is 90%, 1 H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 2.2 Hz, 1H), 7.42-7.38 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 5.19 (s, 2H), 4.11-3.91 (m, 1H), 3.27 (dd, J = 5.5, 4.0 Hz, 1H), 2.90 (dd, J = 5.5, 2.5 Hz, 1H), 2.45 (s, 3H), 2.20 (s, 3H) ppm.

[0057] Fifth step: 10 g of compound 5 was added to a round-bottom flask, 33 mL of tert-butylamine was added, and the temperature was raised to reflux for 12 hours. TLC was used to monitor the reaction, and after the reaction was completed, the tert-butylamine was removed by vacuum concentration. Then 50 mL of isopropyl alcohol was added, and 1 equivalent of concentrated hydrochloric acid was slowly added to precipitate white solids. Filtration and drying yielded compound 6, weighing 8.8 g, with a yield of 80%. 1 H NMR (500 MHz, D2O) δ: 6.74-7.28 (m, 3H), 4.92-4.96 (m, 1H, CH), 4.83 (s, 2H), 3.11-3.20 (m, 2H), 1.39 (s, 9H) ppm.

[0058] The above is only a specific embodiment of the present application, and cannot limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing salbutamol salt, comprising the following steps: Step (5): Compound 5 undergoes an amination reaction with tert-butylamine, followed by deacetylation to obtain compound 6; The acid in compound 6 is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, phosphoric acid, methanesulfonic acid, succinic acid, benzoic acid, salicylic acid, maleic acid, tartaric acid, citric acid, succinic acid, and fumaric acid.

2. The synthesis method according to claim 1, further comprising the following steps: Step (4): Compound 4 undergoes an epoxidation reaction with an oxidant under alkaline conditions to obtain compound 5.

3. The synthesis method according to claim 1 or 2, further comprising the following steps: Step (3): Compound 3 undergoes a witting reaction under alkaline conditions to obtain compound 4.

4. The synthesis method according to any one of claims 1-3, further comprising the following steps: Step (1): Compound 1 reacts with concentrated hydrochloric acid and paraformaldehyde to obtain compound 2; Step (2): Compound 2 undergoes an acetylation reaction to obtain compound 3.

5. The synthesis method according to any one of claims 1-4, comprising one, two, three, four, or five steps of the following synthetic routes:

6. The synthesis method according to claim 4 or 5, wherein, The mass ratio of compound 1, concentrated hydrochloric acid and paraformaldehyde in step (1) is 1:2 to 10:0.1 to 1; The acetylation reaction described in step (2) is carried out in the presence of sodium acetate, acetic acid and / or acetic anhydride.

7. The synthesis method according to claim 3 or 5, wherein, The alkaline conditions described in step (3) are provided in the presence of one of the following bases: sodium carbonate, potassium carbonate, potassium tert-butoxide, and sodium tert-butoxide. The reagents used in the Wittig reaction also include methyltriphenylphosphine bromide.

8. The synthesis method according to claim 2 or 5, wherein, The alkaline conditions described in step (4) are provided in the presence of one of the following bases: sodium carbonate, potassium carbonate, potassium tert-butoxide, and sodium tert-butoxide. The oxidant is selected from hydrogen peroxide, peracetic acid, oxygen, m-chloroperoxybenzoic acid, sodium peroxide, and benzoyl peroxide.

9. The synthesis method according to claim 1 or 5, wherein, The deacetylation described in step (5) is a reaction under acidic conditions; The acid is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, phosphoric acid, methanesulfonic acid, succinic acid, benzoic acid, salicylic acid, maleic acid, tartaric acid, citric acid, succinic acid, and fumaric acid.

10. The synthesis method according to claim 9, wherein, The structure of compound 6 is shown below.

Images