Preparation method of lysine specific demethylase 1 (LSD1) inhibitor key intermediate

Abstract

The invention relates to the technical field of drug synthesis, and discloses a preparation method of a lysine-specific demethylase 1 (LSD1) inhibitor key intermediate, and the preparation method of the intermediate comprises the following steps: 1, carrying out a ylide reaction; step 2, double-bond addition and bromination reaction; step 3, substitution reaction; step 4, hydrolysis reaction; step 5, carrying out amide dissociation reaction; and step 6, substitution reaction. The fluorine-substituted cyclopropylamine compound with LSD1 inhibitory activity can be obtained by oxidizing a key intermediate of the LSD1 inhibitor, connecting the key intermediate with an amine fragment and then performing functional group modification, so that the beneficial effect of conveniently and quickly synthesizing the fluorine-substituted cyclopropylamine compound with LSD1 inhibitory activity is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor. Background Art

[0002] LSD1 (also known as BHC110, p110b, and NPAO) was identified by Shi's group in 2004, and its structure is highly conserved from yeast to humans. In cells, LSD1's demethylation ability is highly gene-, substrate-, and environmental-specific, producing different (or even opposite) effects on gene expression at different loci. Studies have found that LSD1 plays an important role in promoting normal cell differentiation, and LSD1 has also been found to be abnormally recruited to produce inappropriate repression of abnormal gene targets downstream of leukemic gene damage (such as MLL-AF9). In this case, LSD1 maintains the activity of leukemic stem cells (LSCs) conferred by the initial injury, and the cellular effects downstream of LSD1 are also significantly different from the normal cell state. In normal hematopoiesis, no changes in gene expression were found at the level of the most primitive hematopoietic stem cells (HSCs), which is consistent with the observation that hematopoiesis is induced by the exact opposite LSD1 depletion. Therefore, if LSD1 can produce controllable and reversible toxicity to normal hematopoietic cells, it can serve as a potential drug target for the treatment of leukemia. CN 107200706A reports a class of fluorine-substituted cyclopropylamine compounds and preparation methods, pharmaceutical compositions and uses thereof. However, the patent is complex in the preparation of intermediates of the target compound and the key starting raw material cyclopropylamine compound by reductive amination. Summary of the invention

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[0005] DETAILED DESCRIPTION

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[0013] According to the method for synthesizing I1, the phenyl group in the starting material G1 is replaced with 4-phenyl carboxylate to obtain compound I17. Total yield: 6%. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor, characterized in that: The intermediate preparation route is: ， The intermediate preparation method is: Step 1, ylide reaction: Compound A reacts with a ylide reagent or a phosphine salt under alkaline conditions to generate an ethylene derivative B; Step 2, double bond addition and bromination reaction: the double bond in compound B is added with hydrofluoric acid, and then reacted with a bromination reagent to generate bromide C; Step 3, substitution reaction: the bromine in compound C is replaced by a base to generate the acetoxy group in compound D; Step 4: Hydrolysis reaction: The acetoxy group in compound D is hydrolyzed into the hydroxyl group in compound E under alkaline conditions; Step 5, amide dissociation reaction: under the action of hydrochloric acid, the amide bond in compound E is debonded to convert into the amino group in compound F; Step 6, substitution reaction: the hydroxyl group in compound G and N,N'-succinimidyl carbonate are desuccinimide under alkaline conditions to generate compound H; Step 7, amine ester exchange reaction: the ester group in compound F and the amino group in compound F undergo amine ester exchange under alkaline conditions to generate the target intermediate I; in: R1 is selected from the group consisting of ethyl, benzyl, phenyl, cyclohexylmethyl, 4-pyridylmethyl, phenylethyl, 1H-indol-5-ylmethyl, 2-thienylmethyl, 2-furylmethyl, 4-fluorophenylmethyl, 4-chlorophenylmethyl, 4-bromophenylmethyl, 4-methoxyphenyl, 4-trifluoromethylphenylmethyl, 3,5-dimethoxyphenylmethyl, 4-formylphenylmethyl, cyclopentylmethyl, cyclobutylmethyl, 4-piperidinylmethyl, 3-chlorophenylmethyl, 2-chlorophenylmethyl, or 4-tert-butylphenylmethyl; R2 is selected from: methyl; n is 0-2, and when n is 0, it means that there is no methyl substitution on the ring.

2. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: In the step 1, the ylide reagent (phosphonium salt) is methylenetriphenylphosphine, methyltriphenylphosphine bromide, methyltriphenylphosphine chloride, or methyltriphenylphosphine iodide; and the base is potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium amide, lithium diisopropylamide, or sodium hydride.

3. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 2, characterized in that: The solvent in step 1 is tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, dimethylformamide, methyl tert-butyl ether or dioxane; and the reaction temperature in step 1 is 0-25°C.

4. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: In the step 2, the bromination reagent is N-bromosuccinimide, bromine, dibromohydantoin, or pyridinium tribromide; the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, toluene, dimethylformamide, acetonitrile, or dioxane; and the reaction temperature in the step 2 is 0-25°C.

5. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: In the step 5, the tert-butyloxycarbonyl removal agent is hydrochloric acid.

6. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: The solvent in step 5 is ethyl acetate, methanol, ethanol, tetrahydrofuran or dichloromethane, and the reaction temperature in step 5 is -10-25°C.

7. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: The base used for substitution in step 6 is triethylamine, diisopropylamine, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium amide, lithium diisopropylamide or sodium hydride.

8. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: The solvent in step 6 is acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or toluene; and the reaction temperature in step 6 is 0-25°C.

9. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: The base used for the amine ester exchange in step seven is triethylamine, diisopropylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

10. The method for preparing a key intermediate of a lysine-specific demethylase 1 (LSD1) inhibitor according to claim 1, characterized in that: The solvent in step 7 is tetrahydrofuran, 2-methyltetrahydrofuran, water, methyl tert-butyl ether or toluene; the reaction temperature in step 7 is 0-25°C.

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