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Preparation method of (S)-3-hydroxypiperidine

A technology of hydroxypiperidine and hydroxypyridine, which is applied in the field of preparation of (S)-3-hydroxypiperidine, can solve the problems of poor catalytic effect of ruthenium-carbon catalyst, unsuitability for industrial production, and high price of rhodium, and achieve purity and optical purity High, good catalytic effect, low price effect

Pending Publication Date: 2018-05-11
江苏尚莱特医药化工材料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Catalysts commonly used in catalytic hydrogenation include palladium carbon, rhodium carbon, ruthenium carbon and other catalysts. For the above catalytic hydrogenation reaction, rhodium carbon catalyst has the best catalytic effect, but the price of rhodium is relatively high (about 5 times that of ruthenium), and Relatively heavy pollution, not suitable for industrial production
Although the price of ruthenium is relatively low, the catalytic effect of ruthenium carbon catalyst is relatively poor

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0020] This embodiment prepares 3-hydroxypiperidine by catalytic hydrogenation of 3-hydroxypyridine, and the specific method is as follows:

[0021] Add 95g of 3-hydroxypyridine (1.0mol) and 600mL of water into the autoclave, stir and dissolve, then add 5.0g of 5wt% ruthenium / silicon dioxide catalyst and 2.5g of cocatalyst aluminum oxide.

[0022] After nitrogen replacement for three times, hydrogen gas was introduced, and the reaction was carried out at a pressure of 7 MPa and a temperature of 85°C until complete.

[0023] After the reaction, filter and distill the filtrate to remove water and rectify (65-67°C, 2mmHg) to obtain 99.7g of 3-hydroxypiperidine with a yield of 98.7% and a GC content of 99.5%.

Embodiment 2～ Embodiment 5）

[0025] The preparation method of each embodiment is basically the same as that of Example 1, and the differences are shown in Table 1.

Embodiment 6）

[0031] Add 180mL of ethanol, 180mL of ethyl acetate, 90.9g of 3-hydroxypiperidine (0.9mol) and 75g of D-tartaric acid (0.5mol) into the reaction flask, heat to reflux for 30min, then follow the procedure (78℃→1.5h→ 55°C → 2h → 32°C → 3h → 8°C) Slowly cool down to 8°C, keep stirring for 2h, filter, wash the filter cake with a small amount of ethyl acetate, dry to get (S)-3-hydroxypiperidine tartrate .

[0032] Add 30mL of methanol, 150mL of toluene and 69g of potassium carbonate (0.5mol) into another reaction flask, add the above (S)-3-hydroxypiperidine tartrate, keep the temperature at 30°C and stir for 3h, then cool down to 5°C, filter , the filter cake was washed with toluene, the filtrate was distilled under reduced pressure to recover the solvent, and the distillation residue was recrystallized with a mixed solvent of petroleum ether + ethyl acetate to obtain 37.3 g of (S)-3-hydroxypiperidine with a yield of 82.1% and a purity of is 99.5%, and the ee value is 99.3%.

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PUM

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Abstract

The invention discloses a preparation method of (S)-3-hydroxypiperidine. The preparation method comprises the steps of (1) carrying out catalytic hydrogenation on 3-hydroxypyridine to prepare 3-hydroxypiperidine; (2) splitting the 3-hydroxypiperidine for preparing the (S)-3-hydroxypiperidine, wherein catalytic hydrogenation is carried out under the co-catalysis of a ruthenium / silicon dioxide catalyst and a cocatalyst; the weight ratio of the ruthenium / silicon dioxide catalyst to the cocatalyst is 1:1 to 3:1; the total weight of the ruthenium / silicon dioxide catalyst and the cocatalyst is 5 to10 percent of the weight of the 3-hydroxypiperidine; and the cocatalyst is aluminum oxide. According to the method provided by the invention, the ruthenium / silicon dioxide catalyst and the aluminum oxide are adopted as a compound catalyst for catalytic hydrogenation, and the compound catalyst is relatively cheap but has the same better catalysis effect, and pollutes environment less so as to be suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and in particular relates to a preparation method of (S)-3-hydroxypiperidine. Background technique [0002] Piperidinol and its derivatives are an important class of pharmaceutical intermediates, which are widely used in the synthesis of diabetes drugs, antidepressants, antineoplastic drugs, local anesthetics and antihypertensive drugs, among which (S)-3-hydroxypiperidine Due to its special structure, pyridine is widely used in pharmaceutical synthesis. [0003] At present, the most common method for preparing 3-hydroxypiperidine is to directly carry out catalytic hydrogenation of 3-hydroxypyridine. [0004] Catalysts commonly used in catalytic hydrogenation include palladium carbon, rhodium carbon, ruthenium carbon and other catalysts. For the above catalytic hydrogenation reaction, rhodium carbon catalyst has the best catalytic effect, but the price of rhodi...

Claims

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Application Information

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IPC IPC(8): C07D211/42
CPCC07D211/42Y02P20/584
Inventor 胡国宜胡锦平吴建华张培锋黄磊奚小金
Owner 江苏尚莱特医药化工材料有限公司