Formoterol, pharmaceutically acceptable salt thereof and preparation method of intermediate

A formoterol and intermediate technology, applied in the field of pharmaceutical synthesis, can solve the problems of incomplete crystallization, high temperature, affecting the yield of the compound of formula X, etc., and achieve the effects of reducing production costs and short routes

Active Publication Date: 2019-03-29
GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] 1) Intermediates, final products and enantiomeric purity are not disclosed;
[0010] 2) Separation of undesired isomers (RS, SR) at the later stage of synthesis, and unrecyclable isomers are not recyclable, resulting in higher cost and increased pollution
[0014] 1) Harmful reagents such as hydrofluoric acid and crown ether and carcinogenic solvents such as benzene are used in the synthesis process, which are expensive and rare substances, and have serious health and environmental problems, so they are not suitable for scale-up operations
[0015] 2) Unpublished quality information about formoterol fumarate
[0019] 1) During the preparation process from the starting material to the compound of formula X, overnight grinding and repeated purification are required, and the operation is cumbersome
In addition, during the preparation and purification process of the compound of formula X, the adsorption effect of activated carbon is not significant, resulting in difficult crystallization and incomplete crystallization, which seriously affects the yield of the compound of formul

Method used

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  • Formoterol, pharmaceutically acceptable salt thereof and preparation method of intermediate
  • Formoterol, pharmaceutically acceptable salt thereof and preparation method of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] 1) Add the compound of formula II (178.1g) and the compound of formula III (161.7g) into the reaction flask, stir, heat to an internal temperature of 90-100°C, and react for 2-3h; when the internal temperature is 120-130°C, react for 2-3h To complete (HPLC detection, calculated by the normalization method with the peak area, if the compound of formula III in the test sample is less than 10%, it can be considered that the reaction is complete), obtain 320.5g of the compound of formula IV, after cooling to 70 ± 5 ° C, add Water ethanol (220mL) was dissolved for the next reaction.

[0093]

[0094] 2) Add the compound of formula IV dissolved in absolute ethanol (220mL) and absolute ethanol (1280mL) into the reaction flask, stir, add reduced iron powder (199.7g), wash the residue with absolute ethanol (1000mL), and then add chloride Ammonium (191.3g) and water (440mL), heated to an internal temperature of 75-85°C, reacted for 2-3h to complete (HPLC detection, calculated ...

Embodiment 2

[0108] 1) Add V(A) compound (280g) and ethyl acetate (500mL) obtained in step 2) of Example 1 into the reaction flask, stir and dissolve, then add ethyl acetate (340mL), stir, and heat to internal temperature At 65-70°C, add fumaric acid (32.7g) and ethanol (210mL) until the sticky matter is completely dissolved, then cool down to 40°C at a rate of 10°C per hour, then cool down to 30-35°C in a water bath, and stir 1-2h, cool down to internal temperature 0-10°C, stir and crystallize for 1-2h, filter to obtain solid, then wash with ethyl acetate until the filtrate is pale yellow, then vacuum dry at 50±5°C for 4- After 6h, 190g of light yellow solid was obtained.

[0109] Add the light yellow solid (130g) obtained in the previous step, ethyl acetate (650mL) and 15% aqueous sodium carbonate solution (650mL) into the reaction flask, heat to an internal temperature of 30-40°C, a large amount of gas will be generated, stir for 4-6h, until The solid disappeared completely, left to st...

Embodiment 3

[0114] 1) high-purity formula V compound (65g) and ethyl acetate (300mL) are added to reaction flask, under N 2 The reaction solution was cooled to 0-10°C under the condition, and then dicyclohexylcarbodiimide (DCC) (62.3g) and ethyl acetate (25mL) were added, and slowly added dropwise at an internal temperature of 0-10°C without Aqueous formic acid (12.0g), after the dropwise addition, keep the internal temperature at 0-10°C, and react for 1-2h until the reaction is complete (detected by HPLC, calculated by the normalization method based on the peak area, the test product has the formula V compound is less than 0.50%, the reaction can be considered complete.), and then close the cooling equipment, add 10% sodium carbonate aqueous solution (275mL), heat up to 20-30 ° C, stir for 0.5-1.0h, separate the organic layer, and the aqueous layer with acetic acid Ethyl ester (275mL) was extracted, then combined with ethyl acetate layer, stirred and washed with 10% sodium carbonate aque...

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Abstract

The invention relates to formoterol, a pharmaceutically acceptable salt thereof and a preparation method of an intermediate. The method for purifying the formoterol intermediate (a compound shown as aformula V) comprises the following steps of: I) performing a salt forming reaction of the crude compound shown as the formula V and fumaric acid in an organic solvent A to obtain fumarate of the compound shown as the formula V; II) performing a neutralization reaction of the fumarate of the compound of the formula V obtained in the step I) with the base in the organic solvent B to obtain a purified compound of the formula V; and III) crystallizing the purified compound shown as the formula V obtained in the step II) in an organic solvent C to obtain the formoterol intermediate.

Description

field of invention [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of formoterol, its pharmaceutically acceptable salt and its intermediate. Background technique [0002] The chemical name of the pharmaceutically acceptable salt (formula I) of formoterol is: {N-[2-hydroxyl-5-[(RS)-1-hydroxyl-2-[(RS)-2-(4-methyl Oxyphenyl)-1-methylethylamino]ethyl]phenyl]}formamide fumarate dihydrate is a β2 sympathomimetic drug with long-acting, high selectivity, strong anti-inflammatory effect, and It has the characteristics of fast effect and mild side effects; it has the typical basic structure of all sympathomimetic drugs, and the substituent on the amino nitrogen makes it highly selective for the β2 receptor. Pharmacological studies have shown that formoterol fumarate dihydrate exerts anti-inflammatory effects and inhibits pulmonary edema by inhibiting multiple links in the pathological process of asthma and t...

Claims

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Application Information

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IPC IPC(8): C07C231/14C07C231/24C07C213/10C07C51/41C07C217/86C07C233/43C07C57/15
CPCC07C51/412C07C231/14C07C231/24C07C51/43C07C233/43C07C57/15
Inventor 俞雄肖杜政郑广基陈与华袁西伦
Owner GUANGZHOU JOINCARE RESPIRATORY DRUG ENG TECH CO LTD
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