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Method for synthesizing zaleplon

A technology for zaleplon and a synthesis method, which is applied in the field of chemical drugs, can solve the problems of poor ring-forming reaction regioselectivity, difficult separation and purification of isomers, unfavorable industrial production and the like, and achieves easy control, easy acquisition and wide application. Effect

Inactive Publication Date: 2015-02-11
ARROMAX PHARMATECH
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0004] The synthetic method of this product that has been reported mostly concentrates on using compound 2 and compound 3 to condense under acidic conditions to synthesize the method of 5,6-and nitrogen-containing heterocyclic ring, and the linear method route used in these synthetic methods is longer, and the synthesis method is relatively long. The regioselectivity of the ring reaction is poor (isomer 4 is generated), and there are disadvantages such as low overall yield and difficulty in isomer separation and purification, which is not conducive to industrial production

Method used

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  • Method for synthesizing zaleplon
  • Method for synthesizing zaleplon
  • Method for synthesizing zaleplon

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Synthesis of compounds of formula (III).

[0023]

[0024] Example 1-1: Add 250 milliliters of dichloromethane, 10.0 grams of formula (I) compound and 11.716 grams of triethylamine in the reaction flask, the resulting solution is cooled to 0°C, and then 5.46 grams of ethyl alcohol are added dropwise to the solution Acid Chlorides (Formula II). The above solution was stirred at room temperature for 3 hours. The reaction solution was washed twice with dilute hydrochloric acid, washed with water, washed with saturated brine, dried and concentrated to obtain 12.0 g of the compound of formula 3 with a yield of 97.3%.

[0025] 1 H NMR (300MHz, CDCl 3 , ppm):7.94(d,J=6Hz,1H),7.54-7.44(m,2H),7.36-7.33(m,4H),7.28-7.24(m,6H),7.11(d,J=6Hz, 2H), 6.92(d, J=6Hz, 2H), 6.76(d, J=6Hz, 6H), 5.09(s, 2H), 4.31(d, J=7.2Hz, 2H), 2.50(t, J= 6Hz, 2H), 1.67-1.55(m, 2H), 1.32-1.24(m, 2H), 0.86(t, J=6Hz, 3H).

Embodiment 2

[0027] Synthesis of compounds of formula (V).

[0028]

example 2-1

[0029] Example 2-1: Add 12 grams of the compound of formula 3, 90 milliliters of N,N-dimethylformamide and 1.22 grams of potassium iodide into a three-necked flask, and then add 4.5 grams of 60% sodium hydrogen. After stirring at room temperature for 30 minutes, 12.18 g of bromoethane (formula IV) were added. The resulting solution was stirred at room temperature for 2 hours, then the reaction solution was poured into ice water, extracted with 200 ml of ethyl acetate, washed 4 times with water, washed once with saturated brine, dried, concentrated, and passed through the column (petroleum ether:ethyl acetate= 5:1) to obtain 11.6 grams of colorless oily liquid, namely the compound of formula (V), with a yield of 85.3%.

[0030] 1 H NMR (300MHz, CDCl 3 ,ppm):9.73(s,1H),7.92(d,J=5.7Hz,1H),7.56-7.40(m,2H),7.35-7.32(m,4H),7.29-7.23(m,6H), 7.10(d, J=6Hz, 2H), 6.92(d, J=6Hz, 6H), 6.83(d, J=6Hz, 2H), 5.45(s, 2H), 2.52(t, J=6Hz, 2H) , 1.72-1.58 (m, 2H), 1.33-1.26 (m, 2H), 0.86 (t, ...

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Abstract

The invention provides a method for synthesizing zaleplon. The method comprises the following steps: (a) reacting a compound of the formula (VIII) as shown in the specification with hydrazine hydrate to generate a compound of the formula (IX) as shown in the specification, reacting the compound of the formula (IX) with a compound of the formula (X) as shown in the specification to generate a compound of the formula (XI) as shown in the specification, and performing halogenating reaction on the compound of the formula (XI) with phosphorus oxychloride to obtain a compound of the formula (XII) as shown in the specification; performing acylation reaction on the compound of the formula (I) as shown in the specification to generate a compound of the formula (III) as shown in the specification, performing alkylation reaction on the compound of the formula (III) to obtain a compound of the formula (V) as shown in the specification, and reacting the compound of the formula (V) with combined boric acid pinacol ester to obtain a compound of the formula (VII) as shown in the specification or a solution of the compound; and (b) performing coupling reaction on the compound of the formula (XII) with the compound of the formula (VII) or the solution of the compound, thereby obtaining zaleplon. The method provided by the invention adopts a gathering method strategy, is short in operation step, simple and convenient to operate and applicable to industrialized production.

Description

technical field [0001] The invention relates to the field of chemical drugs, and more particularly relates to a synthesis method of a small molecule drug zaleplon, which can be used for treating sleep disorders. Background technique [0002] Zaleplon (Zaleplon), the chemical name is 3-[3-cyanopyrazole (1,5-a) pyrimidine-7]-N-ethylacetanilide, which was produced by Wyeth Corporation of the United States in March 1999 And listed non-benzodiazepine sedative hypnotics. Zaleplon is a benzodiazepine (BZ) omega 1 A full agonist of type receptors, acting on the benzodiazepine GABA subtype A receptor complex, producing central inhibitory effects on omega 1 Type receptors are highly selective and can also bind to ω-type receptors, but not to other neurotransmitters. In March 1999, the European Union approved zaleplon for the treatment of insomnia, and in August 1999, the US FDA approved zaleplon for adult insomnia. It has been proved that zaleplon has a short half-life, good curat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 洪健许忻李建
Owner ARROMAX PHARMATECH
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