61-25-6

The invention relates to a preparation method of papaverine compounds. Specifically, the invention relates to a preparation method of a compound as shown in a formula II, and the preparation method comprises a step of reacting a compound as shown in a formula III in the presence of an oxidizing agent. The method is high in yield, mild in reaction condition and suitable for industrial production.

The invention discloses a preparation method of papaverine. The invention provides a preparation method of papaverine, which comprises the following steps: (1) in a solvent, in the presence of a cyclization agent, carrying out cyclization reaction as shown in the specification on a compound as shown in a formula I to obtain a compound as shown in a formula II; and (2) in a solvent, in the presence of a dehydrogenation catalyst, carrying out dehydrogenation reaction as shown in the specification on the compound as shown in the formula II to obtain papaverine. The compound as shown in the formula II prepared in the step (1) is directly used in the step (2) without being purified. The method is simple in process, easy to operate, low in cost and suitable for industrial production, and the product is high in yield and purity.

Abstract: A one-pot synthesis of papaverine hydrochloride with 99.6% purity was performed using xylene as solvent for the entire process. The critical parameters of each step, as well as the impurities generated, were identified. The overall yield was improved to 63%. The proposed synthetic procedure is suitable for industrial production.

The invention relates to preparation of a powder injection pharmaceutical composition from high-purity papaverine hydrochloride, in particular to a preparation method of papaverine hydrochloride. Themethod comprises the following steps of: heating 3, 4-dimethoxy-beta-phenyl-ethylamine and 3, 4-dimethoxy-phenyl-acetic acid to melting, and then carrying out reaction in a mixture of benzene and chlorethoxyfos to obtain 6, 7, 3', 4'-tetramethoxy-1-benzyl-dihydro-isoquinoline hydrochloride; then dissolving the wet product in tetrahydronaphthalene after the wet product becomes free alkali, and carrying out dehydrogenation reaction at 180DEG C in the presence of a Raney nickel catalyst; after dehydrogenation is finished, directly filtering the tetrahydronaphthalene reaction mixture from the Raney nickel catalyst into a mixture of a hydrochloric acid aqueous solution and methanol; filtering out precipitates, and performing recrystallizing from the ethanol-water solution in an inert gas environment to obtain off-white 6, 7, 3', 4'-tetramethoxy-1-benzyl isoquinoline hydrochloride, namely papaverine hydrochloride. The invention also relates to a papaverine hydrochloride powder injection pharmaceutical composition, and a preparation method and a quality detection method thereof. The invention achieves excellent technical effects as described in the specification.

Papaverine HCl was successfully suspended by slurry reactive crystallization with the use of isopropyl alcohol (IPA) at 25 °C, a solid-to-liquid ratio of 0.19 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 200-400 μm, and the value for enthalpy of fusion of 154.5 J/g. The poor solubility of papaverine in IPA and better solubility of papaverine HCl in water-containing IPA had made the homogeneous nucleation of papaverine HCl dominate. Crystal size and crystallinity of papaverine HCl were time and temperature dependent. However, the 1:1 haloperidol-maleic acid salt was also successfully suspended and generated by slurry reactive crystallization with the use of water at 25 °C, a solid-to-liquid ratio of 0.18 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 500-1000 μm, and the value for enthalpy of fusion of 84.9 J/g. The poor solubility of haloperidol and 1:1 haloperidol-maleic acid salt in water had made the heterogeneous nucleation of 1:1 haloperidol-maleic acid salt dominate. Crystal size and crystallinity of 1:1 haloperidol-maleic acid salt became less sensitive to time and temperature. Comparing with grinding, solution reactive crystallization by cooling, and solution recrystallization by cooling, slurry reactive crystallization was a simple, robust, straightforward, low-constant-temperature, low-solvent-volume, and environmentally benign process giving comparable yield, particle size distribution, and crystallinity. Moreover, the use of a poor solvent in the slurry reactive crystallization enabled the recycling of the mother liquor without any significant loss in yield and crystallinity up to three cycles.

The invention discloses a preparation method of papaverine. The preparation method comprises 1, dissolving 3, 4-dihydropapaverine hydrochloride in water and adjusting pH of the solution to greater than 7, 2, through trimethylbenzene, carrying out extraction on the aqueous solution obtained through the step 1, and 3, adding a dehydrogenation reaction catalyst into the obtained organic phase, carrying out a dehydrogenation reaction process at a temperature of 50-180 DEG C and then treating the product to obtain papaverine. The invention also discloses a method for preparing papaverine hydrochloride from the papaverine. Through use of trimethylbenzene as a dehydrogenation reaction solvent, a dehydrogenation reaction temperature is reduced, peroxide production is avoided and production safety is greatly improved. The preparation method realizes recycle of trimethylbenzene and reduces a production cost of papaverine or papaverine hydrochloride.

Compounds having the structure: SPC1 In which R1 and R2 are alkoxy groups of one to four carbon atoms, R3 and R4 each is hydrogen or an alkoxy group of one to four carbon atoms, and R5 and R6 each is an alkyl group of one to four carbon atoms or an arylalkyl group such as benzyl or R5 taken with R6 and N are pyrrolidinyl, piperidino, or morpholino groups and the pharmaceutically acceptable salts thereof and processes for preparing these compounds. These compounds are useful as vasodilators.