Preparation method of (S)-1-(3-bromo-2-methoxyphenyl) ethyl-1-ol

A technology of methoxyphenyl and methoxyacetophenone, which is applied in the field of preparation of chiral pharmaceutical intermediates, can solve problems such as unfavorable scale-up production, low overall yield, material waste, etc., and achieves short route and process yield. The effect of high rate and easy industrial amplification

Pending Publication Date: 2022-06-28
SHIJIAZHUANG CHIRALS CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The overall yield of this process is low, material waste is serious, and n-butyllithium is used, which requires -78°C, which is not conducive to industrial scale-up production

Method used

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  • Preparation method of (S)-1-(3-bromo-2-methoxyphenyl) ethyl-1-ol
  • Preparation method of (S)-1-(3-bromo-2-methoxyphenyl) ethyl-1-ol
  • Preparation method of (S)-1-(3-bromo-2-methoxyphenyl) ethyl-1-ol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] like figure 1 As shown, under nitrogen protection, compound 9 (25.0g, 100mmol), methyl iodide (28.4g, 200mmol) and potassium carbonate (20.7g, 150mmol) and 200ml of acetone were added to a 500ml four-necked flask, heated at 42°C The reaction was kept under reflux for 18 hours, then cooled to room temperature, and the solvent was removed under reduced pressure (15 mmHg) at 35°C. After removing acetone, the resulting mixture was poured into 120 ml of water, extracted with 50 ml of dichloromethane, and the organic phase was washed with 100 ml of saturated brine. The phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure (15mmHg) at 35°C, and the 92°C-94°C fraction was collected by high vacuum (2mmHg) distillation to obtain intermediate 7 (25.1g), purity (GC) 97.65%, yield 95.08%.

Embodiment 2

[0084] like figure 2 As shown, under nitrogen protection, compound 9 (25.0g, 100mmol), dimethyl sulfate (18.9g, 150mmol) and potassium carbonate (41.4g, 300mmol) and 300ml of acetone were added to a 500ml four-necked flask, heated The reaction was maintained at 58°C under reflux for 18 hours, then cooled to room temperature, and the solvent was removed at 35°C under reduced pressure (15 mmHg). After removing the acetone, the resulting mixture was poured into 120 ml of water, extracted with 50 ml of dichloromethane, and the organic phase was washed with 100 ml of saturated brine. , the organic phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure (15mmHg) at 35°C, and the 92°C-94°C fraction was collected by high vacuum (2mmHg) distillation to obtain Intermediate 7 (23.5g), purity (GC) 98.25%, Yield 89.02%.

[0085] Preparation of 2-methoxyacetophenone

Embodiment 3

[0087] like image 3 As shown, under nitrogen protection, tetrahydrofuran (240ml), intermediate 7 (26.4g, 100mmol) and the tetrahydrofuran solution (75ml, 150mmol) of isopropylmagnesium chloride were added to a 500ml four-necked flask, maintaining a temperature of 0-5 ℃ , be heated to 25 ℃ after stirring for 4 hours, continue to stir for 2 hours, then add N-methoxy-N-methylacetamide (15.5g, 150mmol) dropwise to the reaction system, keep the temperature not higher than 25 ℃, dropwise After the addition was completed, the reaction was continued for 5 hours, the reaction solution was poured into 5L of ammonium chloride aqueous solution, the layers were separated, the aqueous phase was extracted with 500ml of ethyl acetate, the organic phases were combined, the organic phase was washed with 100ml of saturated brine, and washed with anhydrous sodium sulfate. Dry, remove the solvent under reduced pressure (15mmHg) at 40°C, and collect 95°C-98°C fractions by high vacuum (2mmHg) disti...

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Abstract

The invention relates to a preparation method of (S)-1-(3-bromo-2-methoxyphenyl) ethyl-1-alcohol, which comprises the following steps: (1) methylating 2, 6-dibromophenol to obtain 2, 6-dibromoanisole; (2) carrying out a Grignard reaction on the 2, 6-dibromoanisole to obtain 3-bromo-2-methoxyacetophenone, or carrying out a Heck arylation reaction on the 2, 6-dibromoanisole to obtain 2-methoxyacetophenone; and (3) carrying out asymmetric reduction on the 2-methoxyacetophenone under the action of a chiral catalyst to obtain the (S)-1-(3-bromo-2-methoxyphenyl) ethyl-1-ol. The method is easy to industrially amplify and low in cost.

Description

technical field [0001] The invention relates to a preparation method of a chiral drug intermediate, belongs to the technical field of preparation of chemical raw material drug intermediates, and in particular relates to a key intermediate (S)-1-(3-bromo-2-methoxyl group of Ruxotrope) Preparation method of phenyl)ethan-1-ol. Background technique [0002] (S)-1-(3-Bromo-2-methoxyphenyl)ethan-1-ol is a key intermediate of Lusutrombopag, the structural formula is shown in the following formula 1, Lusutrombopag Popa was developed by Shionogi Company in Japan, and its trade name is Mulpleta. The structural formula is shown in formula 2. [0003] [0004] On August 1, 2018, Lusutrombopag, developed by Japan's Shionogi Company, was approved by the U.S. FDA under the trade name of Mulpleta. The drug is mainly for short-term use before surgery in patients with chronic liver disease with low platelets. Mulpleta, an oral human thrombopoietin (TPO) receptor agonist that upregulates...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C41/26C07C43/23
CPCC07C41/26C07C41/16C07C45/004C07C45/455C07B2200/07C07C43/23C07C43/225C07C49/84
Inventor 靳晓坤温海珊刘娜李娇艳李立斌
Owner SHIJIAZHUANG CHIRALS CHEM CO LTD
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