Preparation method of 5-BOC-allhydro-pyrrole[3,4-C]pyridine_Industrial additives

Background and overview of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

5-BOC-Perhydro-pyrrole[3,4-C]pyridine is also called hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylic acid tert-butyl ester, which can be made from 3 , 4-dicarboxylic acid pyridine is used as raw material and is prepared through a seven-step reaction.

Preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

The first step in the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

Dissolve 3,4-dicarboxylic acid pyridine (30.0g, 180mmol) in 250mL acetic anhydride and heat to reflux for 3-4 hours until the reaction solution becomes clear, then cool to room temperature, and evaporate the remaining acetic acid under reduced pressure. The crude product 3,4-dicarboxylic anhydride pyridine is obtained from the anhydride and is directly used in the next reaction.

The second step of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

Add benzylamine (28.9g, 270mmol) dropwise to solid 3,4-dicarboxylic anhydride pyridine (crude product of the first step) at 0°C, then naturally rise to room temperature and let stand for 1 hour. The obtained viscous liquid 4-benzylcarbamoylnicotinic acid was directly used in the next reaction.

The third step of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

Carefully dissolve the crude product of the previous step, 4-benzylaminoformylnicotinic acid zinc carbonate, in 150 mL of acetic anhydride. The resulting solution is heated to 110°C and reacted for 4 hours until the raw materials disappear. After cooling to room temperature, the remaining acetic anhydride was evaporated under reduced pressure. The residue was diluted with water (100 mL) and ethyl acetate (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phase was sequentially washed with saturated sodium bicarbonate aqueous solution ( 1. Bismuth subcarbonate (00 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated on a silica gel column (30%-50% ethyl acetate/petroleum ether) to obtain 2-Benzyl-1H-pyrrole[3,4-o]pyridine-1,3(2H)-dione as a white solid (29.5 g, 69% overall yield over 3 steps).

¹H NMR (MHz, CDCl₃): δ9.17(s,1H),9.07(d,J＝4Hz,1H),7.76(d ,J＝4Hz,1H),7.50-7.40(m,2H),7.30-7.36(m,3H),4.88(s,2H).

The fourth step of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

Add 2-benzyl-1H-pyrrole[3,4-a]pyridine-1,3(2H)-dione (9.60g, 40.3mmol) and wet palladium on carbon (2.0g, 20%) into 300mL In methanol, the reaction solution was placed in a 3MPa hydrogen system and heated to 60°C for overnight reaction. After the reaction is completed, the reaction solution is cooled to room temperature, and the palladium carbon is filtered out through diatomaceous earth. The resulting filtrate is concentrated to obtain a light yellow liquid 2-benzyl-1H-pyrrolo[3,4-c]hexahydropyridine-1,3( 2H)-diketone was used directly in the next reaction.

The fifth step of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

Add lithium aluminum hydride (3.06g, 80.6mmol) in batches to the stirring 2-benzyl-1H-pyrrolo[3,4-c]hexahydropyridine-1 under nitrogen protection and 0°C. A solution of 3(2H)-dione (9.84g, 40.3mmol) in 120mL tetrahydrofuran. After the addition is completed, the reaction solution is heated to reflux for 2 hours until the raw materials disappear, cooled to room temperature, and then cooled to 0°C in an ice-water bath. Water (3mL), NaOH solution (3mL, 15% aqueous solution), and water (9mL) are added dropwise in order to quench. The reaction was extinguished, and the mixture was heated to room temperature and stirred for 30 min, then filtered, and the filtrate was concentrated to obtain light yellow-green 2-benzyl 8-hydrogen-1H-pyrrolo[3,4-c]pyridine, which was directly used in the next reaction.

The sixth step of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

Under nitrogen protection and 0°C, add di-tert-butyl dicarbonate solution (13.06g, 60.45mmol dissolved in 15mL dichloromethane) dropwise to the stirring 2-benzyl 8-hydro-1H-pyrrole and [3,4-c]pyridine (8.70 g, 40.3 mmol) and diisopropylethylamine (11.4 mL, 80.6 mmol) in 100 mL of dichloromethane. After the dropwise addition is completed, remove the ice-water bath and allow the reaction solution to naturally rise to room temperature and continue stirring for 2 hours until the raw materials disappear. Add water (100 mL) to the reaction system, extract with dichloromethane (2 × 50 mL), combine the organic phases and wash with water (50 mL) and saturated brine (50 mL) in sequence, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. After separation on a silica gel column (2% methanol/dichloromethane), 2-benzylhexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylic acid tert-butyl ester was obtained as a pale yellow liquid.

MS-ESI calculated value [M+H] 317, measured value 317.

The seventh step of the preparation method of 5-BOC-perhydro-pyrrole[3,4-C]pyridine

2-Benzylhexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylic acid tert-butyl ester (1.5g, 4.7mmol) and 300mg dry palladium hydroxide (10% ) of 120 mL of tetrahydrofuran solution was placed in a 3MPa hydrogen atmosphere and heated to 60°C for 24 hours. Cool to room temperature, filter out palladium hydroxide, concentrate the filtrate, and separate through silica gel column (50%-100% methanol/dichloromethane) to obtain 5-BOC-perhydro-pyrrole[3,4-C]pyridine (0.5g, Yield: 50%).

MS-ESI calculated value [M+H] 227, measured value 227.

References

[1] [Invented in China, authorized by China] CN201410174893.1 Isoquinolinesulfonyl derivatives as RHO kinase inhibitors