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Synthesis of levomethadone hydrochloride or dextromethadone hydrochloride and methods for use thereof

A technology for methadone and levothadone hydrochloride is applied in the synthesis of levomethadone hydrochloride or dexmethadone hydrochloride and its application field, and can solve the problems of reducing the total yield of levomethadone and the like

Inactive Publication Date: 2018-06-08
CODY LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The resolution step introduces undesired impurities and significantly reduces the overall yield of levmethadone

Method used

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  • Synthesis of levomethadone hydrochloride or dextromethadone hydrochloride and methods for use thereof
  • Synthesis of levomethadone hydrochloride or dextromethadone hydrochloride and methods for use thereof
  • Synthesis of levomethadone hydrochloride or dextromethadone hydrochloride and methods for use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0310] Example 1.A.N,N-dimethyl D-alanine (B)

[0311] Step 1: Dimethylation of D-alanine (A) by hydrogenation with formaldehyde in the presence of Pd / C to form N,N-dimethyl D-alanine (B)

[0312] This step was performed by a modified literature procedure. See WO 2012 / 162635 and Org Lett 2013, 15, 3118-3121 by Paterson et al., each incorporated by reference.

[0313]Formaldehyde (37%, 125 mL, 1,680 mmol) and Pd / C were added to a solution of D-alanine (A) (50.0 g, 561 mmol) in water (800 mL). The flask was purged with Ar for 10 min, followed by H 2 Purge three times at 50 °C in H 2 The reaction mixture was stirred at (35 psi) for 20 hours. The reaction mixture was then heated to reflux for 1 hour and filtered through a short pad of celite while hot. The filtrate was concentrated under reduced pressure. More water was added (3 times 200 mL each) and the reaction was concentrated to remove unreacted formaldehyde. Residual water was azeotroped with toluene (3 x 100 mL). 1 ...

Embodiment 2

[0316] Example 2. (R)-2-(dimethylamino)propan-1-ol (C)

[0317] Step 2: Reduction of N,N-dimethyl D-alanine (B) with lithium aluminum hydride to form (R)-2-(dimethylamino)propan-1-ol (C)

[0318] At 0 °C, the LiAlH 4 (1.14 g, 30 mmol) was added to a stirred solution of N,N-dimethyl D-alanine (B) (2.34 g, 20 mmol) in THF (30 mL) prepared in step 1 and the resulting reaction mixture was heated to reflux for 16 Hour. After cooling to room temperature, dissolve with 10 mL of saturated NaHCO 3 The reaction was carefully quenched and stirred for 10 minutes to form a thick suspension. Then DCM (50 mL) was added and the organic layer was separated by decantation. DCM (50mL) and anhydrous Na 2 SO 4 (ca. 10 g) was added to the remaining pasty residue and the mixture was stirred vigorously. The DCM layer is then separated. The residue was stirred with two further portions of DCM (50 mL each). use Na 2 SO 4 The combined DCM layers were dried and concentrated under reduced press...

Embodiment 3

[0319] Example 3. (R)-4-(Dimethylamino)-2,2-diphenylvaleronitrile. Step 3: Synthesis of levmethadonenitrile (E) from (R)-2-(dimethylamino)propan-1-ol (C) and diphenylacetonitrile

[0320] At 0°C, 1.0 mL SOCl 2 CHCl 3 (5 mL) solution was carefully added to a solution of crude aminoalcohol C (550 mg, 5.33 mmol) prepared in step 2 in chloroform (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, then heated to reflux for 1 hour. Then cooled to room temperature, the solvent and volatiles were removed under vacuum to give 781 mg of crude product D, (R)-1-chloro-N,N-dimethylpropan-2-amine HCl (yield Yield 93%), which was used directly in the following steps.

[0321] KOtBu (617 mg, 5.5 mmol) was added to a stirred solution of the above (R)-1-chloro-N,N-dimethylpropan-2-amine HCl, intermediate D, in DMF (5.0 mL) under Ar. The resulting mixture was stirred at room temperature for 10 minutes. Diphenylacetonitrile Ph in DMF (5.0 mL) 2 In a separate flask ...

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Abstract

Highly efficient methods for synthesis of levomethadone hydrochloride or dextromethadone hydrochloride are provided starting from D-alanine, or L-alanine, respectively, with retention of configuration. Methods for treating a subject are provided comprising administering a composition comprising an effective amount of levomethadone hydrochloride having not more than 10 ppm dextromethadone.

Description

[0001] This application was filed as a PCT International Patent Application on August 24, 2016 and claims priority to U.S. Provisional Patent Application No. 62 / 209,168, filed on August 24, 2015, the entire disclosure of which is incorporated by reference in its entirety . Background technique [0002] Methadone hydrochloride is a long-acting opiate used in the treatment of opiate dependence, for opiate detoxification, and for the treatment of chronic severe pain. Methadone hydrochloride, currently approved for use by the FDA, is a racemic mixture of levmethadone and dexmethadone, also known as DL-methadone or (R,S)-methadone. [0003] The active enantiomer used in the treatment of opiate dependence, in opiate detoxification and in the treatment of chronic severe pain is levmethadone, also known as L-methadone or R-(-)-methadone. Known processes for the preparation of levmethadone may have low overall yields and / or undesired impurity profiles. [0004] Beckett et al. in J Ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C221/00C07C225/16A61P25/04A61K31/135
CPCC07C225/16C07C213/00C07C227/18C07C253/30C07B2200/07C07C221/00A61P25/04C07C229/12C07C215/08C07C255/42
Inventor 格内尔·姆克尔强姚庆伟
Owner CODY LAB
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