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Preparation method of metaraminol bitartrate

A technology for meta-hydroxylamine bitartrate and a compound is applied in the field of preparation of meta-hydroxylamine bitartrate, can solve the problems of high amplification risk, uneasy industrial production, low yield and the like, achieves high enantioselectivity, easy control of reaction operations, The effect of fewer synthesis steps

Active Publication Date: 2022-08-02
BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is: the yield of the target product is low (7-15%), the risk of amplification is high, and it is not easy to realize industrial production

Method used

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  • Preparation method of metaraminol bitartrate
  • Preparation method of metaraminol bitartrate
  • Preparation method of metaraminol bitartrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of compound VII:

[0037]

[0038] In 1L of ethyl acetate, 100g of L-camphorsulfonic acid, 70g of 2-aminomethylpyridine and an appropriate amount of p-toluenesulfonic acid were respectively added, a water separator was added, and a reflux reaction was performed. g Compound VII, yield 75%.

[0039] Preparation of Compound VI:

[0040]

[0041] In 100 mL of methanol, 10 g of compound VII and 0.2 g of glacial acetic acid were respectively added, the temperature was lowered to -10 to -5 °C under nitrogen atmosphere, 0.4 g of nickel chloride was added, and 2.4 g of sodium borohydride were added in batches. Ethyl ester / n-hexane=5 / 1 was used as the mobile phase for column chromatography to obtain compound VI with a yield of 61%.

Embodiment 2

[0043] Preparation of compound III:

[0044]

[0045] Add 1L absolute ethanol, 16.5g copper acetate monohydrate, 26.5g compound VII to the reaction flask in sequence, stir at room temperature for 10min, then add 100g compound V, lower the temperature to -40~-50°C under nitrogen atmosphere, add 615g nitrile Ethyl ethane, 212g diisopropylethylamine, 1L ethyl acetate was added after the reaction was completed, 1M hydrochloric acid was adjusted to pH 3-4, the layers were separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, saturated sodium chloride Washed, dried and concentrated to dryness to give compound III. dr value=2.25:1, ee value=95.6%.

[0046] Preparation of compound II:

[0047]

[0048] Add compound III, 750mL anhydrous methanol, 12g water-containing 10% palladium carbon to the hydrogenation reaction kettle, control the pressure to 4MPa, stir the reaction at 25~30°C to complete the reaction, suction filter, and remove ...

Embodiment 3

[0052] Preparation of compound III:

[0053] 100 mL of absolute ethanol, 1.65 g of copper acetate monohydrate, and 2.65 g of compound VI were sequentially added to the reaction flask, stirred at room temperature for 10 min, then 10 g of compound V was added, the temperature was lowered to -40 to -50 °C under a nitrogen atmosphere, and 61.5 g of Nitroethane, 21.2g diisopropylethylamine, 100mL ethyl acetate was added after the reaction was completed, 1M hydrochloric acid was adjusted to pH 3-4, the layers were separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, saturated chlorine washed with sodium chloride, dried and concentrated to dryness to obtain compound III. Forward HPLC detection, dr value = 2.13:1, ee value = 93.4%. Preparation of compound II:

[0054] Add the residue compound III of the previous step, 75 mL of anhydrous methanol, 1.2 g of 10% palladium carbon with water to the hydrogenation reaction kettle, control the pre...

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Abstract

The invention belongs to the technical field of drug synthesis, and discloses a preparation method of metaraminol bitartrate, which comprises the following steps: under an alkaline condition, a compound V and a compound IV are subjected to a Henry reaction under the action of a metal catalyst and a chiral ligand to obtain a compound III, the compound III is subjected to catalytic hydrogenation to obtain a compound II, and the compound II is subjected to recrystallization to obtain metaraminol bitartrate. And salifying the compound II and L-tartaric acid to obtain metaraminol bitartrate I, wherein the chiral ligands are a compound VI and a compound VII. The method can effectively control the three-dimensional configuration in the production process, can obviously improve the product quality, and is simple in production process, high in yield, low in cost and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of metahydroxylamine bitartrate. Background technique [0002] Metahydroxylamine bitartrate is an α-adrenergic receptor agonist developed by Fresenius Kabi Company in the United States. It mainly acts on α-receptors and is suitable for the early treatment of shock and prevention and treatment of acute hypotension during spinal anesthesia. [0003] Due to the existence of two chiral carbon atoms in m-hydroxylamine, it has four stereo configurations (R,S), (S,R), (R,R), (S,S), of which (R,S) is effective Configuration, (S,R) is its enantiomer, (R,R) and (S,S) are its diastereomers. [0004] At present, the method for industrially producing meta-hydroxylamine bitartrate is mainly biological fermentation method, and its disadvantage is that the output is small and the cost is relatively high. Some researchers have also tried the reduction met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C213/08C07C215/60C07C59/255C07C51/41C07C201/12C07C205/17C07D213/38B01J31/18
CPCC07C213/02C07C213/08C07C51/412C07C201/12C07D213/38B01J31/1815C07B2200/07B01J2531/16B01J2531/0261B01J2231/34C07C205/17C07C215/60C07C59/255Y02P20/584
Inventor 胡卫东杜宝权郑江
Owner BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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