JPS6158478B2 - - Google Patents

Description

[Detailed description of the invention]

The 2-piperidinopropane derivative obtained by the present invention is an important substance as an intermediate for pharmaceuticals, and in particular, 1-(o-benzylphenoxy)-2
- Piperidinopropane phosphate has been reported to have antitussive properties (US Patent 3117059;
Brit.patent 914008). Conventionally, synthetic routes for this compound have been developed, such as those shown in parentheses (USpatent 3117059; Brit.patent
914008). However, in this method, twice the molar amount of piperidine and 1-(o-benzylphenoxy)-2-chloropropane are reacted at normal pressure, so the reaction must occur at high temperature and for a long time (over 80 hours). The disadvantage is that the process is not completed and the yield is low at 66%. (See Reference Example) In addition, in this method, piperidine hydrochloride precipitates during the reaction and inhibits the reaction, so the reaction is not completed.Moreover, a resin-like substance is produced, and in order to purify it, it must be distilled under high vacuum. This method is not suitable for industrial use because it also has the disadvantage that it does not. In addition, since the chlorine of the 2-chloropropane derivative is attached to the secondary carbon, the reactivity is low, and when a normal dehydrochlorination agent (for example, potassium acetate, potassium hydroxide, potassium hydrogen carbonate, etc.) is used, the yield is very low. is low and by-products are generated.
Taking the above points into consideration, the present inventors investigated various methods of synthesizing the relevant compound, and found that by reacting piperidine and 2-chloropropane derivatives under pressure, it is possible to synthesize the compound industrially very easily and in a short time. We discovered that it can be synthesized with good yield. After the reaction is complete, remove excess piperidine and piperidine hydrochloride,
By adding phosphoric acid, a crude 2-piperidinopropane phosphate derivative is obtained. By recrystallizing this crude product, a white crystalline 2-piperidinopropane phosphate derivative can be easily obtained in high yield. The conditions used here are as follows. The reaction temperature is
The temperature is 100 to 300°C, the reaction pressure is 2 to 10 atm, and piperidine is used in a molar amount 4 to 100 times that of the 2-chloropropane derivative. Among them, 150~200℃, 2~
It is optimal to use 5 to 10 times the molar amount at 3 atm. Of course, the recovered piperidine can be reused. The 2-chloropropane derivative used here can be easily obtained in high yield by reacting the corresponding 2-hydroxypropane derivative with thionyl chloride. Next, specific methods of the present invention will be illustrated by the following examples. Reference example A mixture of 26.1 g of 1-(o-benzylphenoxy)-2-chloropropane and 17 g of piperidine was heated at 124°C.
Reflux for 32 hours until Then further at 160℃
Reflux for 48 hours. The resulting reaction product is cooled and dissolved in methanol. 3N hydrochloric acid 200 ml after concentration under reduced pressure
ml and wash three times with 100 ml of ether. After washing the ether layer three times with 50 ml of water, combine all the aqueous layers. The aqueous layer was concentrated to dryness under reduced pressure to obtain impure 1-(o-benzylphenoxy)-2-piperidinopropane hydrochloride, which was dissolved in 100 ml of water and 100 ml of 30% caustic soda solution was added. Extract the liberated oil layer with ether (100 ml, 50 ml x 2). ether layer to water
After washing with 50 ml x 4, dehydrate with magnesium sulfate.
After concentrating the ether solution, distill it to 159-161℃/0.2
Obtain a fraction of mmHg. This oil was dissolved in 75 ml of 1 molar phosphoric acid and concentrated to dryness under reduced pressure. The concentrated residue was recrystallized twice with 85 ml of ethanol, dried on a sulfuric acid bath under reduced pressure for 4 hours, and 1-
27 g (yield 66.3%) of (o-benzylphenoxy)-2-piperidinopropane hydrochloride is obtained. mp150
−152℃. Example 1 150 g of 1-(o-benzylphenoxy)-2-chloropropane and 500 ml of piperidine were placed in a pressure cooker and reacted at 150° and 2 atm for 40 hours. After the reaction is complete, the excess piperidine is completely distilled off under reduced pressure, and the precipitated piperidine hydrochloride is filtered. 400 g of 90% acetone-water is added to the obtained filtrate, and 66.4 g of 85% phosphoric acid is added dropwise to this solution. The precipitated crystals were filtered and recrystallized from 90% acetone-water to obtain 190.6 g of purified 1-(o-benzylphenoxy)-2-piperidinopropane phosphate as white crystals. Yield 80.9% Melting point 150.0-152.0℃ Elemental analysis; C ₂₁ H ₃₀ NO ₅ P Theoretical value
C%61.90; H%7.47; N%3.43; P%7.60 Actual value
C% 61.98; H% 7.47; N% 3.39: P% 7.57 NMR spectrum ( _CD3OD , δ value) 1.40 (3H, d, J=7Hz, _-CH3 ), 1.75
(6H, m,

【formula】) 3.05 (4H, m,

[Formula]), 3.40 (1H, d, d, d, J = 6, 6, 7Hz,

[Formula]) 4.05 (2H, S, -CH ₂ -), 4.33 (1H, m,

【formula】) 4.40 (1H, m,

[Formula]), 6.9-7.5 (9H, m, aromatic proton) Examples 2-6 Using 150 g of 1-(o-benzylphenoxy)-2-chloropropane, the reaction was carried out in Example 1 under the reaction conditions shown in the attached table. The reaction was carried out in the same manner, and purified 1-(o-benzylphenoxy)-2-piperidinopropane phosphate was obtained in the yield shown in the attached table.

[Table] Example 7 1-(o-benzylphenoxy)-2 of Example 1
-1-phenoxy-2 instead of chloropropane
- Purified according to Example 1 using 98.2 g of chloropropane and 21.0 g of hydrogen chloride instead of 85% phosphoric acid.
-Phenoxy-2-piperidinopropane hydrochloride
117.7g was obtained. mp145-146℃ Example 8 1-(o-benzylphenoxy)-2 of Example 1
The procedure of Example 1 was repeated, using 125.8 g of 1-(4-chlorophenoxy)-2-chloropropane instead of chloropropane and 66.8 g of fumaric acid instead of 85% phosphoric acid. enoxy)-2-
216.3 g of piperidinopropane fumarate were obtained. mp109℃ Example 9 1-(o-benzylphenoxy)-2 of Example 1
-1-(2,4,6-tribromophenoxy)-2-chloropropane250 instead of chloropropane
g, using 21.0 g of hydrogen chloride instead of 85% phosphoric acid,
The procedure of Example 1 was followed to obtain 241.8 g of purified 1-(2,4,6-tribromophenoxy)-2-piperidinopropane hydrochloride. mp170−171℃.

Claims (1)

[Claims] 1 General formula characterized by condensing piperidine and 1-substituted-2-chloropropane under pressure [Formula] (where R represents a phenoxy group or a substituted phenoxy group) ) A method for producing a 2-piperidinopropane derivative shown in the following.