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New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride

A technology of hydrochloric acid and compounds, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, and can solve problems such as increasing the difficulty of industrial production, difficult practical operation, and unfavorable industrial production.

Active Publication Date: 2012-07-11
ANHUI NEW STAR PHARMA DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] CN102002065A (preparation method of tapentadol and its intermediate) provides a new method for preparing tapentadol hydrochloride, which uses 3- tert-butyldimethylsiloxybenzaldehyde is used as the starting material, and under the catalysis of R-proline, it undergoes Aldol condensation reaction with propionaldehyde to obtain (2R, 3S)-3-hydroxy-2-methyl-3- (3-tert-butyldimethylsilyloxyphenyl) propionaldehyde, the compound reacts with dimethylamine hydrochloride to obtain (1S, 2S)-3-(dimethylamino)-2-methyl- 1-(3-tert-butyldimethylsilyloxyphenyl)-1-propanol, the obtained compound reacts with p-toluenesulfonyl chloride to obtain (1S, 2S)-3-(dimethylamino)-2 -Methyl-1-(3-tert-butyldimethylsilyloxyphenyl)propyl-4-toluenesulfonate, and then through Grignard reaction to obtain (2R, 3R)-3-(3-tert-butyl dimethylsilyloxyphenyl)-N,N,2-trimethylpentyl-1-amine, finally deprotected by trifluoroacetic acid to obtain tapentadol, the reaction starting material 3-tert-butyl Dimethylsilyloxybenzaldehyde is not commercially available at present, and at the same time, reactions with harsh conditions such as Grignard reaction are used in the reaction process, which increases the difficulty of industrial production
[0033] WO2011 / 067714A1 (New processes for the preparation of tapetadol and intermediates thereof), the method uses m-nitrobenzaldehyde as a starting material, and obtains 3-(dimethylamino)-1-(3 -Nitrophenyl)-2-methylpropan-1-one, and then resolved by L-(-)-DBTA to obtain (S)-3-(dimethylamino)-1-(3-nitro Phenyl)-2-methylpropan-1-one, reduction gives (S)-3-(dimethylamino)-1-(3-aminophenyl)-2-methylpropan-1-one, ( S)-3-(dimethylamino)-1-(3-aminophenyl)-2-methylpropan-1-one reacts with Grignard reagent to obtain (2S, 3R)-1-dimethylamino- 3-(3-aminophenyl)-2-methylpentan-3-ol, (2S,3R)-1-dimethylamino-3-(3-aminophenyl)-2-methylpentan- After trifluoroacetylation of 3-alcohol and then Pd / C catalytic hydrogenation to obtain (2R, 3R)-[3-(3-aminophenyl)-2-methylpentyl]-dimethylamine, and finally After nitriding, the target product tapentadol is obtained. In this operation, Grignard reagent, expensive acylating reagent trifluoroacetic anhydride, and Pd-C high-pressure catalytic hydrogenation are used, which are not conducive to industrial production and are harmful to practice. operational difficulties

Method used

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  • New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride
  • New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride
  • New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1 Preparation of 1-(3-methoxyphenyl)-propan-1-ol

[0092] Under ice-bath conditions, add 1.5L of methanol and 700g (4.26mol) of 1-(3-methoxyphenyl)propan-1-one into the reaction flask, stir and inject N 2 , when the system drops to about 5°C, add 201.7g (5.34mol) of 96% sodium borohydride in 4 times, continue the heat preservation reaction for 30 minutes after the addition, TLC traces the completion of the reaction, distills off the solvent under reduced pressure, and pours the reactant into 2L of water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 700 g of 1-(3-methoxyphenyl)-propan-1-ol with a yield of 98.9%.

[0093] Molecular formula: C 10 h 14 o 2 , molecular weight: 166.22, MS (m / z): 167.21 (M + +H).

[0094] 1 HNMR (CDCl 3 , 400MH Z )δ: 7.12(t, 1H, J=8.0Hz, Ar-H), 6.81(d, 1H, J=8.0Hz, Ar-H), 6.67(m, 2H, Ar-H), 4.62(t, 1H, J=5.2Hz, CH-O), 3.75(s, 3H, -OCH 3 ), 1.81 (m, 2H,...

Embodiment 2

[0095] Example 2 Preparation of 1-(3-nitrophenyl)-propan-1-ol

[0096] Substitute 1-(3-methoxyphenyl) propan-1-one in Example 1 with 1-(3-nitrophenyl) propan-1-one to obtain compound 1-(3-nitrophenyl)- Propan-1-ol. The yield is 97.1%.

[0097] Molecular formula: C 9 h 11 NO 3 , molecular weight: 181.2, MS (m / z): 182.18 (M + +H).

Embodiment 3

[0098]Example 3 Preparation of 3-(1-bromopropyl) anisole

[0099] in N 2 Under protection, 700g (4.21mol) of 3-(3-methoxyphenyl)-2-pentanol and 2L of dichloromethane were added to the reaction flask, and when the temperature was cooled to about 5°C in an ice bath, 1.14Kg ( 4.21mol) PBr 3 , keep the temperature, continue to insulate and stir the reaction for 1h after the addition is completed, and follow the completion of the reaction by TLC. The reactant is poured into ice water, extracted with dichloromethane, the organic layer is washed with aqueous sodium bicarbonate, then washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 920 g of 3-(1-bromopropyl) anisole was obtained, with a yield of 95.4%.

[0100] Molecular formula: C 10 h 13 BrO, molecular weight: 229.11, MS (m / z): 230.10 (M + +H).

[0101] 1 HNMR (CDCl 3 , 400MH Z )δ: 7.27(t, 1H, J=8.4Hz,, Ar-H), 6.68(m, 2H, Ar-H), 6.51(s, 1H, Ar-H), 4.67(t, 1H, J= 4.8...

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Abstract

The invention provides a new method for synthesizing tapentadol hydrochloride and analogue of the tapentadol hydrochloride, and particularly provides a method for synthesizing a compound with the formula shown as a formula (1). Groups of the compound are defined in the specification. The invention also particularly provides a method for synthesizing the tapentadol hydrochloride and the analogue compound of the tapentadol hydrochloride by using 1-(3-substituted phenyl)-1-ketone compound as an initial raw material. According to the method, the raw materials are easy to obtain, and reaction conditions are mild; and the method is easy to control and operate, reduces production cost and is particularly suitable for industrial production.

Description

technical field [0001] The present invention provides a new method for synthesizing tapentadol hydrochloride and its analogues. Specifically, it provides a method for synthesizing compounds of the following formula (I), especially using 1-(3-substituted phenyl)-1 - A method for preparing tapentadol hydrochloride and its analogue active ingredients using ketone compounds as starting materials, especially a synthesis method for tapentadol hydrochloride, which belongs to the field of medicinal chemistry. [0002] [0003] in: [0004] The R1, R2, R3, R4 are the same or different, each independently selected from hydrogen, C 1～4 Alkyl (preferably methyl, ethyl); [0005] The R is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, nitro, substituted or unsubstituted amino, sulfur-containing groups (such as mercapto, sulfonic acid , sulfonamide, etc.). Background technique [0006] Tapentadol Hydrochloride (Ta...

Claims

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Application Information

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IPC IPC(8): C07B57/00C07C215/54C07C213/10C07C213/08
Inventor 徐自奥赵永海李晓祥李德刚
Owner ANHUI NEW STAR PHARMA DEV
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