3-droperidol derivative and preparation method thereof

Abstract

The invention provides a 3-droperidol derivative represented by a structural formula (I), wherein R is hydrogen, C1-C6 alkyl, aryl, benzyl, or a structure as the formula; R1 is hydrogen, C1-C18 alkyl, aryl, benzyl or hydroxymethyl; R2 is C1-C6 alkyl, aryl, benzyl or alkoxy; substitution positions of R2 on a benzene ring are 2-, 3-, 4-, 5-, 6- sites or a plurality of sites; and the previous groups are not substituted or substituted by one or more substituents selected from alkyl, alkyl halide, hydroxyalkyl, halogen, alkoxy, or hydroxyl. The invention also provides a preparation method of the 3-droperidol derivative. The preparation method is novel, the raw materials and the reagents are cheap, the reaction conditions are mild, and the operations are easy. With the method, produced 1-substituent-3-droperidol can be used as an important intermediate in novel medicine developing.

Description

technical field

[0001] The present invention relates to 3-fluoropiperidine derivatives and a preparation method thereof. Background technique

[0002] Due to the uniqueness of fluorine atoms, the introduction of organic molecules can bring dramatic changes to the molecular activity and its pharmacological properties, especially in the development of safe and selective drug molecules. Thereby attracting more and more pharmacists and pharmaceutical companies to join the ranks of fluorine-containing drug research and development (Klaus Müller, Christoph Faeh, Francois Diederich, Sceience, 2007, 317, 1881, O'Hagan, D., Chem.Soc. Rev., 2008, 37, 308; Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V,. Dev., 2008, 12, 305; Isanbor, C.; O'Hagan, D., J. Fluorine Chem., 2006, 127, 992; Krik, K.L, J. Fluorine Chem., 2006, 127, 992).

[0003] The piperidine structure is a very important class of intermediates in the development of new drugs. This type of structure is contained in ...

Examples

Embodiment 1

[0053] Embodiment 1: Preparation of N-benzyl-3-fluoropyridinium quaternary ammonium salt

[0054]

[0055] 3-Fluoropyridine (291 g, 3 mol) was dissolved in 750 ml of toluene, and benzyl bromide (510 g, 3 mol) was added with stirring at room temperature. The mixture was heated to reflux for 3 hours. The temperature was lowered to room temperature and left overnight, the supernatant was poured out, and the lower solid was washed twice with petroleum ether, dried under vacuum, and directly proceeded to the next step.

Embodiment 2

[0056] Embodiment 2: Preparation of N-benzyl-3-fluoro-1,2,5,6 tetrahydropyridine

[0057]

[0058] Dissolve the N-benzyl 3-fluoropyridine quaternary ammonium salt in the previous step in 2000ml of methanol, add sodium borohydride in batches, and react for about 4 hours. After the reaction is complete as detected by TLC, add petroleum ether and extract three times (1000ml×l, 500ml×2 ). The petroleum ether phase was concentrated and directly distilled under reduced pressure to obtain 198 g of the product, with a two-step yield of 34.6%.

[0059] 1H NMR (300MHz, CDCl 3 )δ7.29~7.37(m, 5H); 5.24~5.33(dt, 1H); 3.66(s, 2H); 3.06~3.08(m, 2H); 2.56~2.59(m, 2H); m, 2H). MS-ESI: theoretical value.191; actual value: 192 (M+1) + .

Embodiment 3

[0060] Embodiment 3: Preparation of 3-fluoropiperidine

[0061]

[0062] Dissolve N-benzyl-3-fluoro-1,2,5,6-tetrahydropyridine (100g, 0.523mol) in 1L methanol, slowly add 10% Pd / C (10g), room temperature, under 1atm hydrogen After hydrogenation for 3 days, Pd / C was removed by filtration, the filtrate was adjusted to pH=1 with 10% hydrochloric acid, the aqueous phase was separated, concentrated to dryness, and recrystallized with tetrahydrofuran / methanol=10:1 to obtain 58 g of white solid with a yield of 75%.

[0063] 1HNMR (300MHz, DMSO-d6) δ9.30~9.41(br, 2H); 4.93(m, J=46Hz, 1H); 3.07~3.22(m, 2H); 2.84~3.01(m, 2H); 1.71~ 1.87 (m, 2H); 1.49-1.53 ​​(m, 2H). MS-ESI: theoretical value.103; actual value: 104(M+1) + .

[0064] 3-Fluoropiperidine hydrochloride (10 g) was dissolved in water (10 ml), and the temperature was lowered to 0°C. Adjust pH=10 with sodium hydroxide, extract with dichloromethane (100ml*3), dry the combined organic phase over anhydrous sodium sulfate, fi...

technical field

[0001] The present invention relates to 3-fluoropiperidine derivatives and a preparation method thereof. Background technique

[0002] Due to the uniqueness of fluorine atoms, the introduction of organic molecules can bring dramatic changes to the molecular activity and its pharmacological properties, especially in the development of safe and selective drug molecules. Thereby attracting more and more pharmacists and pharmaceutical companies to join the ranks of fluorine-containing drug research and development (Klaus Müller, Christoph Faeh, Francois Diederich, Sceience, 2007, 317, 1881, O'Hagan, D., Chem.Soc. Rev., 2008, 37, 308; Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V,. Dev., 2008, 12, 305; Isanbor, C.; O'Hagan, D., J. Fluorine Chem., 2006, 127, 992; Krik, K.L, J. Fluorine Chem., 2006, 127, 992).

[0003] The piperidine structure is a very important class of intermediates in the development of new drugs. This type of structure is contained in ...

Examples

Embodiment 1

[0053] Embodiment 1: Preparation of N-benzyl-3-fluoropyridinium quaternary ammonium salt

[0054]

[0055] 3-Fluoropyridine (291 g, 3 mol) was dissolved in 750 ml of toluene, and benzyl bromide (510 g, 3 mol) was added with stirring at room temperature. The mixture was heated to reflux for 3 hours. The temperature was lowered to room temperature and left overnight, the supernatant was poured out, and the lower solid was washed twice with petroleum ether, dried under vacuum, and directly proceeded to the next step.

Embodiment 2

[0056] Embodiment 2: Preparation of N-benzyl-3-fluoro-1,2,5,6 tetrahydropyridine

[0057]

[0058] Dissolve the N-benzyl 3-fluoropyridine quaternary ammonium salt in the previous step in 2000ml of methanol, add sodium borohydride in batches, and react for about 4 hours. After the reaction is complete as detected by TLC, add petroleum ether and extract three times (1000ml×l, 500ml×2 ). The petroleum ether phase was concentrated and directly distilled under reduced pressure to obtain 198 g of the product, with a two-step yield of 34.6%.

[0059] 1H NMR (300MHz, CDCl 3 )δ7.29~7.37(m, 5H); 5.24~5.33(dt, 1H); 3.66(s, 2H); 3.06~3.08(m, 2H); 2.56~2.59(m, 2H); m, 2H). MS-ESI: theoretical value.191; actual value: 192 (M+1) + .

Embodiment 3

[0060] Embodiment 3: Preparation of 3-fluoropiperidine

[0061]

[0062] Dissolve N-benzyl-3-fluoro-1,2,5,6-tetrahydropyridine (100g, 0.523mol) in 1L methanol, slowly add 10% Pd / C (10g), room temperature, under 1atm hydrogen After hydrogenation for 3 days, Pd / C was removed by filtration, the filtrate was adjusted to pH=1 with 10% hydrochloric acid, the aqueous phase was separated, concentrated to dryness, and recrystallized with tetrahydrofuran / methanol=10:1 to obtain 58 g of white solid with a yield of 75%.

[0063] 1HNMR (300MHz, DMSO-d6) δ9.30~9.41(br, 2H); 4.93(m, J=46Hz, 1H); 3.07~3.22(m, 2H); 2.84~3.01(m, 2H); 1.71~ 1.87 (m, 2H); 1.49-1.53 ​​(m, 2H). MS-ESI: theoretical value.103; actual value: 104(M+1) + .

[0064] 3-Fluoropiperidine hydrochloride (10 g) was dissolved in water (10 ml), and the temperature was lowered to 0°C. Adjust pH=10 with sodium hydroxide, extract with dichloromethane (100ml*3), dry the combined organic phase over anhydrous sodium sulfate, fi...

Images