Background and overview[1][2]
Dimethorphan phosphate, also called dimethorphan phosphate, was developed by Fujisawa Pharmaceutical Co., Ltd. of Japan. It was first launched in Japan in 1974. No serious adverse reactions have been reported in clinical applications for many years. It is effective, safe and reliable. At present, it has not been approved for marketing in China, and there is no import. Therefore, there is a certain market prospect for developing this product in China.
Dimethorphan phosphate inhibits the cough center in the brain and is a non-addictive central antitussive. The effect is slightly better than dextromethorphan, about twice that of codeine, but the toxicity is lower, it will not become addictive after repeated use, and it is safer. It takes effect quickly after taking it, lasts for a long time, and does not cause constipation. There is no domestic manufacturer approved to market it, so it has great market potential. The domestic development of this product has broad market prospects.
Preparation[1-2]
Method 1, CN201810199587.1 discloses a preparation process of dimethorphan phosphate. Dimethorphan phosphate is prepared by using dextromethorphan, the base of the drug dextromethorphan hydrobromide, which has been on the market for many years, as the starting material. After methoxymethylation, it is salted with phosphoric acid. The invention has a simple process route, high product purity and low cost, and is suitable for industrial production.
The preparation method of the present invention includes the following steps in sequence:
Polyurethane coating
a. 3,17-dimethyl dextromorphan is produced by reacting 3-methoxy-17-methyl dextromorphan with methylmagnesium bromide,
b. 3,17-dimethyl dextromorphan is then salted with phosphoric acid to obtain dimethorphan phosphate.
The reaction formula is as follows:
Under nitrogen protection, add the starting materials 3-methoxy-17-methyl dextromorphan (5.71g, 20mmol) and dipoloxamer 188 (tricyclohexylphosphine) nickel dichloride (0.70g , 1 mmol) was added to 100 ml of toluene, stirred and dissolved, heated to 65°C, dropwise added methylmagnesium bromide (tetrahydrofuran solution) (1 mol/L, 20 ml, 20 mmol), the dropwise addition was completed and the insulation reaction was completed. TLC detected that the raw material reaction was completed and the temperature dropped to At room temperature, add a small amount of saturated ammonium chloride solution dropwise to quench the reaction, add water to wash the layers, and separate the organic layer; wash the organic layer with saturated brine, and then dry it, and then distill toluene under reduced pressure to obtain dimethorphan; without purification Directly add 25ml of 95% ethanol and stir to dissolve at room temperature, then add 85% phosphoric acid (2.3g, 20mmol) to react and precipitate a white solid. After filtration, washing and drying, 5.46g of dimethorphan phosphate was obtained with a yield of 77.4% and a purity of 96.2%.
Method 2. CN201410104046.8 provides a synthesis method of (9s,13s,14s)-3,17-dimethylmorphine monophosphate. This method is a preparation method with simple process, low cost, high yield, high product purity, strong economic practicability, easily available raw materials and suitable for industrial production.
The technical solution provided by the invention is: (9s, 13s, 14s)-3,17-dimethylmorphine monophosphate synthesis method, combining dextrohydroxymorphan in triethylamine and trifluoromethanesulfonyl chloride The reaction produces dextrohydroxymorphan trifluoromethanesulfonyl ester; dexhydroxymorphan trifluoromethanesulfonyl ester reacts with tetramethyltin in toluene to produce (9s,13s,14s)-3,17-dimethylmorphine ( Or dextrohydroxymorphan triflate is added to a mixed solvent of THF and N-methyl-2-pyrrolidone, iron acetylacetonate catalyst and methylmagnesium bromide are stirred and heated to reflux for 12 hours to prepare (9s,13s ,14s)-3,17-dimethylmorphine), that is, the crude product of dimethorphan, which is directly salted with phosphoric acid and then recrystallized to obtain the target product (9s,13s,14s)-3,17-dimethylmorphine. Phosphate.
Methylation route 1: Add dextrohydroxymorphan trifluoromethanesulfonyl ester into toluene to completely dissolve it, then add (PPh3)2PdCl2, LiCl and PPh3 into the reaction bottle, mix thoroughly, stir at room temperature for 5 minutes, then add (CH3)4Sn into the reaction bottle, the reaction solution is placed in the sealed reaction bottle React for 12 hours. After the reaction is complete, add 10% NaHCO3 solution to quench the reaction, filter, and extract the filtrate with CH2Cl2. Combine the organic phases and use anhydrous for the organic phase. Dry magnesium sulfate and filter. Add 1.5 times the molar amount of H3PO4 to the filtrate to react to form a salt. Stir and react for 0.5h until no more white solid is formed in the solution. The white solid was recrystallized twice with 95% ethanol to obtain white crystals, which is pure dimethorphan phosphate.
Methylation route two: Add dextrohydroxymorphan trifluoromethanesulfonyl ester into THF, stir at room temperature, after complete dissolution, add N-methyl-2-pyrone (NMP), mix evenly and then pass Pour nitrogen into the reaction bottle for 10 minutes to replace the air in the reaction bottle, then add iron acetylacetonate (Fe(acae)3) and methylmagnesium bromide to the reaction bottle, and react under reflux for 12 hours. After the reaction is complete, cool the reaction solution to room temperature. , slowly add 10 mL of water dropwise to quench the reaction, separate the organic phase, extract the aqueous phase with CH2Cl2, and combine the organic phases.
Pour the organic phase into the reaction bottle, add 1.5 times the molar amount of H3PO4 to react to form a salt, and stir for 0.5h until there is no more H3PO4. A white solid is generated, and the white solid is recrystallized twice with 95% ethanol to obtain white crystals, which is pure dimethorphan phosphate. The present invention uses dextrohydroxymorphan as raw material and only needs to undergo three-step reactions of esterification, methylation and salt formation to prepare the target product dimethorphan phosphate. The reaction yield of each step reaches more than 80%, and the operation Simple, economical and feasible.
Main reference materials
[1] CN201810199587.1 A method for preparing dimethorphan phosphate
[2] CN201410104046.8 A safe and effectivePreparation method of antitussive dimethorphan phosphate
