CN1305849C - Method for preparing 3-methylamino piperidine and its salt - Google Patents

Abstract

The present invention relates to the preparation method of 3-methylaminopiperidine (I) and its salt. It is characterized in that: 3-methylaminopyridine is prepared through methylation reaction with 3-aminopyridine as the starting material, and 3-methylaminopyridine is reduced in metal sodium-alcohol system to obtain 3-methylaminopiperidine. 3-Methylaminopiperidine is combined with various acids to obtain its salts.

Description

Preparation method of 3-methylaminopiperidine and salt thereof

technical field

The present invention relates to the preparation method of the compound 3-methylaminopiperidine represented by formula (I) and salts thereof.

Background technique

Balofloxacin (Balofloxacin) is a fluoroquinolone antibacterial drug jointly developed by Chugai Pharmaceutical Co., Ltd. of Japan and Choongwae Company of Korea. It was first listed in South Korea at the end of 2002. ): 190-193]. The in vitro activity of this product against G+ bacteria such as methicillin-resistant S. ) similar to [Nippon Kagaku Ryoho Gakkai Zasshi, 1995, 43 (S-5): 1-9], and low phototoxicity [AntimicrobAgents Chemother, 1993, 37 (10): 2217-2223], clinically used to treat system infections. 3-Methylaminopiperidine is the key intermediate for the synthesis of baloxacin. The literature search for the synthesis method of 3-methylaminopiperidine was found in November 2004. The researchers reported the synthesis of 3-methylaminopiperidine [Chinese Journal of Pharmaceutical Industry, 2004, 35(7): 385-388]. They used γ-butyrolactone as the starting material to obtain the product through eight steps of reaction, The total yield is 11.5%, during which noble metal catalyst PtO ₂ is used, and the cost is very high.

Contents of the invention

The purpose of the present invention is to provide a kind of simple and easy synthetic method for preparing 3-methylaminopiperidine and salt thereof. The method has short synthesis route, cheap and easy-to-obtain raw materials, and is suitable for industrial production.

The object of the present invention can be achieved through the following measures:

The synthetic route of 3-methylaminopiperidine is as follows:

Wherein, R ₁ is (C ₁ -C ₂ ) alkyl, R ₂ is (C ₁ -C ₃ ) alkyl, R ₃ is (C ₂ -C ₅ ) alkyl, and M is metal Na or metal K.

The specific operation steps are:

(1) With 3-aminopyridine as the starting material, react with orthoformate reagents to obtain the compound of formula II

(2) Formula II compound is in alcoholic solution, obtains formula III compound with borohydride reduction

(3) compound of formula III is reduced in metal sodium-alcohol system to prepare compound of formula I

(4) reacting the compound of formula I with various acids to obtain various salts of the compound of formula I.

In the reaction to obtain the compound of formula II, the orthoformate reagents are trimethyl orthoformate and triethyl orthoformate. Triethyl orthoformate is preferred.

In the reaction to obtain the compound of formula II, the molar ratio of 3-aminopyridine to orthoformate ranges from 1:1.5 to 10. Preferably it is 1:4-7.

In the reaction to obtain the compound of formula II, the reaction is carried out under reflux.

In the reaction to obtain the compound of formula III, the alcoholic solvent is methanol, ethanol, isopropanol. Ethanol is preferred.

In the reaction to obtain the compound of formula III, borohydride is sodium borohydride, potassium borohydride. Preference is given to potassium borohydride.

In the reaction to obtain the compound of formula I, the alcoholic solvent is ethanol, isopropanol, n-butanol, isobutanol, n-amyl alcohol, isoamyl alcohol. Preference is given to n-butanol.

In the reaction to obtain the compound of formula I, the volume ratio of the raw material and the alcohol ranges from 1:10 to 40. Preferably it is 1:20-30.

In the reaction to obtain the compound of formula I, the reducing agent used is sodium metal.

Pass dry hydrogen chloride into the alcohol solution of trimethylaminopiperidine or add 3 mol/l hydrochloric acid aqueous solution dropwise into the aqueous solution of trimethylaminopiperidine to obtain trimethylaminopiperidine dihydrochloride after treatment. Trimethylaminopiperidine is combined with various other acids to obtain various salts, such as bishydrochloride, oxalate, and picrate.

The advantages of the present invention are as follows:

In order to reduce the production cost of baloxacin bulk drug and make it an acceptable price drug, the applicant has conducted research on the synthesis of 3-methylaminopiperidine and proposed a new synthetic route. The invention greatly shortens the reaction steps, the raw materials and reagents used in the route are cheap and easy to obtain, significantly reduces the production cost of 3-methylaminopiperidine, and simplifies the process operation.

Description of drawings

Fig. 1 is the nuclear magnetic resonance spectrogram of the present invention.

Fig. 2 is the mass spectrogram of the present invention.

Detailed ways

Example 1

In a 250ml three-necked flask, add 18.8g (0.2mol) of 3-aminopyridine and 220ml (2mol) of trimethyl orthoformate, and stir and reflux for 10h. After the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to fractional distillation under reduced pressure, and fractions at 58-60°C/100Pa were collected to obtain 20.4 g (0.15 mol) of the compound of formula II (R ₁ is methyl) as a colorless liquid, with a yield of 75%. The progress of the reaction was tracked by TLC, the developer was ethyl acetate, and observed under a 254 nm fluorescent lamp, the product spot R _f =0.8.

Example 2

In a 250ml three-neck flask, add 18.8g (0.2mol) of 3-aminopyridine and 160ml (1.22mol) of triethyl orthoformate, and stir and reflux for 5h. After the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to fractional distillation under reduced pressure, and fractions at 60-62°C/100Pa were collected to obtain 25.5 g (0.17 mol) of the compound of formula II (R ₁ is ethyl) as a colorless liquid, with a yield of 85%. The progress of the reaction was tracked by TLC, the developer was ethyl acetate, and observed under a 254 nm fluorescent lamp, the product spot R _f =0.8.

Example 3

In a 250ml three-necked flask, add 18.8g (0.2mol) of 3-aminopyridine and 40ml (0.3mol) of triethyl orthoformate, and stir and reflux for 6h. After the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to fractional distillation under reduced pressure, and fractions at 60-62°C/100Pa were collected to obtain 18 g of the compound of formula II (R ₁ is ethyl) as a colorless liquid, with a yield of 60%.

Example 4

Take 50 g (0.33 mol) of the compound of formula II (R ₁ is ethyl) and add it to a 500 ml three-necked flask, then add 300 ml of absolute ethanol to it, cool to 0° C. with ice water, add 15 g of sodium borohydride in small amounts under stirring, and then Slowly warm to room temperature, then slowly warm to reflux after half an hour. Continue to react for 3h. After the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 300ml of water, extracted twice with 1000ml of ether, the extracts were combined and dried over anhydrous magnesium sulfate. The solvent was recovered, the residue was fractionally distilled under reduced pressure, and the 80-82°C/100Pa fraction was collected to obtain 28.8g (0.27mol) of 3-methylaminopyridine as a colorless liquid. The progress of the reaction was tracked by TLC, the developer was ethyl acetate, and observed under a 254 nm fluorescent lamp, the product spot R _f =0.5. Yield: 80%.

Example 5

Take 50 g (0.33 mol) of the compound of formula II (R ₁ is ethyl) and add it to a 500 ml three-necked flask, then add 300 ml of absolute ethanol therein, add 20 g of potassium borohydride in small amounts under stirring, and heat up to reflux. Continue to react for 3h. After the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 300ml of water, extracted twice with 1000ml of ether, the extracts were combined and dried over anhydrous magnesium sulfate. The solvent was recovered, the residue was subjected to fractional distillation under reduced pressure, and the 80-82°C/100Pa fraction was collected to obtain 29 g (0.27 mol) of 3-methylaminopyridine as a colorless liquid. Yield: 80%.

Example 6

Take 50 g (0.33 mol) of the compound of formula II (R ₁ is ethyl) and add it to a 500 ml three-necked flask, then add 300 ml of isopropanol to it, add 20 g of sodium borohydride in small portions under stirring, and heat up to reflux. Continue to react for 5h. After the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 300ml of water, extracted twice with 1000ml of ether, the extracts were combined and dried over anhydrous magnesium sulfate. The solvent was recovered, the residue was subjected to fractional distillation under reduced pressure, and the 80-82°C/100Pa fraction was collected to obtain 20 g (0.185 mol) of 3-methylaminopyridine as a colorless liquid. Yield: 55.6%.

Example 7

In a 100ml three-neck flask, add 1g (9.26mmol) of 3-methylaminopyridine and 25ml of n-butanol, stir, and heat up to reflux. 2g (87.0mmol) sodium metal wire was added in small portions. TLC analysis of raw materials After the reaction was completed, the mixture was cooled to room temperature, and 2 ml of water was added. Evaporate to dryness under reduced pressure, extract with 30ml chloroform, and dry over anhydrous magnesium sulfate. The hydrogen chloride gas was dried, and the precipitated solid was recrystallized in ethanol-ether to obtain 650 mg (3.48 mmol) of 3-methylaminopiperidine bishydrochloride as a white powder solid, with a yield of 37.6%. Melting point: 191-193°C. ¹ HNMR (methanol) d: 1.74-2.35 (4H, m, 4, 5-H), 2.80 (3H, s, CH3), 3.05-3.78 (5H, m, 2, 3, 6-H), 4.87 ( 2H, s, NH). MS (m/z): 114 (M ⁺ ). Purity 99.7% (GC method). Developing solvent: 3ml of methanol plus 3 drops of ammonia water, the product spot R _f =0.3. Nuclear Magnetic Resonance Spectrum and Mass Spectrum are shown in Figures 1 and 2.

Example 8

In a 100ml three-necked flask, add 1g (9.26mmol) of 3-methylaminopyridine and 40ml of isoamyl alcohol, stir, and heat up to 120°C. 2g (87.0mmol) sodium metal wire was added in small portions. TLC analysis of raw materials After the reaction was completed, the mixture was cooled to room temperature, and 2 ml of water was added. Evaporate to dryness under reduced pressure, extract with 30ml chloroform, and dry over anhydrous magnesium sulfate. The hydrogen chloride gas was dried, and the precipitated solid was recrystallized in ethanol-ether to obtain 670 mg (3.58 mmol) of 3-methylaminopiperidine bishydrochloride as a white powder solid, with a yield of 38.7%.

Example 9

In a 100ml three-neck flask, add 1g (9.26mmol) of 3-methylaminopyridine and 10ml of ethanol, stir, raise the temperature to 120°C, and add 2g (87.0mmol) of sodium metal wire in small portions. TLC analysis of raw materials After the reaction was completed, the mixture was cooled to room temperature, and 2 ml of water was added. Evaporate to dryness under reduced pressure, extract with 30ml chloroform, and dry over anhydrous magnesium sulfate. The solvent was recovered under reduced pressure, and the resulting oil was recrystallized in ethanol-ether to obtain 300 mg (2.63 mmol) of a white solid, with a yield of 28.4%. Melting point: 188～190℃. Developing solvent: 3ml of methanol plus 3 drops of ammonia water, the product spot R _f =0.3.

Claims (15)

1, the method for following formula I compound of preparation and salt thereof,

It is characterized in that the preparation method of Formula I may further comprise the steps:

(1) is starting raw material and ortho-formiate class reagent react with the 3-aminopyridine, obtains formula II compound

Wherein, R ₁Be (C ₁～C ₂) alkyl;

(2) formula II compound obtains the formula III compound with borohydride reduction in alcoholic solution;

(3) the formula III compound reduces in sodium Metal 99.5-pure system and makes formula I compound;

(4) formula I compound and acid-respons obtain the salt of formula I compound;

Synthetic route is as follows:

Wherein, R ₂Be (C ₁～C ₃) alkyl, R ₃Be (C ₂～C ₅) alkyl, M is metal Na or metal K.

2, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula II compound, and ortho-formiate class reagent ortho-formiate class reagent is trimethyl orthoformate or triethyl orthoformate.

3, preparation method according to claim 2 is characterized in that obtaining in the reaction of formula II compound, and ortho-formiate class reagent is triethyl orthoformate.

4, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula II compound, and the molar ratio range of 3-aminopyridine and ortho-formiate is 1: 1.5～10.

5, preparation method according to claim 4 is characterized in that obtaining in the reaction of formula II compound, and the molar ratio range of 3-aminopyridine and ortho-formiate is 1: 4～7.

6, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula III compound, and alcoholic solvent is methyl alcohol, ethanol or Virahol.

7, preparation method according to claim 6 is characterized in that obtaining in the reaction of formula III compound, and alcoholic solvent is an ethanol.

8, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula III compound, and hydroborate is sodium borohydride or POTASSIUM BOROHYDRIDE.

9, preparation method according to claim 8 is characterized in that obtaining in the reaction of formula III compound, and hydroborate is a POTASSIUM BOROHYDRIDE.

10, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula I compound, and alcohol reagent is ethanol, Virahol, propyl carbinol, isopropylcarbinol, Pentyl alcohol or primary isoamyl alcohol.

11, preparation method according to claim 10 is characterized in that obtaining in the reaction of formula I compound, and alcohol reagent is a propyl carbinol.

12, preparation method according to claim 1 is characterized in that obtaining in the reaction of formula I compound, and the volume ratio scope of raw material and alcohol is 1: 10～40.

13, preparation method according to claim 12 is characterized in that the volume ratio scope of raw material and alcohol is 1: 20～30.

14, according to the preparation method of claim 1, the salt of described formula I compound is: the dihydrochloride of formula I compound, oxalate, picrate.

15, according to the preparation method of claim 14, the salt of described formula I compound is: the dihydrochloride of formula I compound.

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