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Preparation method of 4-chloro-3-(4-ethoxybenzyl)benzaldehyde

A technology of ethoxybenzyl and benzaldehyde, applied in the field of compound preparation, can solve the problems of difficult separation, expensive starting material of formula 1, etc., and achieve the effects of simple synthesis route, good yield, and cheap and easily available reagents

Inactive Publication Date: 2014-07-02
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, there are several problems in this synthetic route: 1) The starting material compound of formula 1 is relatively expensive; 2) There are 7 steps in the whole route, and the total yield is only 7.8%; 3) The synthesis process from compound of formula 2 to compound of formula 3 , only 52% conversion, and very difficult to separate

Method used

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  • Preparation method of 4-chloro-3-(4-ethoxybenzyl)benzaldehyde
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  • Preparation method of 4-chloro-3-(4-ethoxybenzyl)benzaldehyde

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Effect test

Embodiment 1

[0054] Embodiment 1: Preparation of 5-bromo-2-chlorobenzoyl chloride (compound of formula 7)

[0055]

[0056] Under ice-cooling, add 2-chloro-5-bromobenzoic acid (50g, 0.212mol) (compound of formula 6) into dichloromethane (250ml), add N,N-dimethylformamide (2.5ml), drop Add oxalyl chloride (25ml, 0.255mol), stir at room temperature for 12 hours, TLC (thin layer chromatography) detects that the reaction is complete, spin the reaction solution to obtain 55g of crude product (compound of formula 7).

Embodiment 2

[0057] Embodiment 2: Preparation of 5-bromo-2-chlorobenzoyl chloride (compound of formula 7)

[0058]

[0059] Add 2-chloro-5-bromobenzoic acid (50g, 0.212mol) (compound of formula 6) into thionyl chloride (SOCl 2 ) (500ml), heated to 70°C, reacted for 2 hours, and spin-dried the reaction solution to obtain 55g of crude product.

Embodiment 3

[0060] Embodiment 3: Preparation of (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) ketone (compound of formula 8)

[0061]

[0062] The crude compound of formula 7 (55g) was dissolved in dichloromethane, cooled to -5°C, added phenetole (24ml, 0.19mol), and added aluminum chloride (28.5g, 0.212mol) in batches, keeping the temperature below 0 °C, react for 3h. The reaction solution was poured into ice water, extracted with dichloromethane, washed with 1M (molar concentration) aqueous hydrochloric acid solution, 1M (molar concentration) aqueous sodium hydroxide solution, water, and saturated brine, dried, filtered to remove the desiccant, and spin-dried , recrystallized from ethanol to give a white solid (51 g, 71%).

[0063] Compound of formula 8: 1 H NMR (400MHz, CDCl 3 ): δ1.43-1.46(t,3H),4.08-4.13(m,2H),6.92-6.94(m,2H),7.32-7.33(d,1H),7.47-7.48(d,1H),7.52 -7.54(m,1H),7.75-7.78(m,2H).

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Abstract

The invention discloses a preparation method of 4-chloro-3-(4-ethoxybenzyl)benzaldehyde. The preparation method comprises the following steps that 2-chloro-5-bromobenzoic acid is dissolved in an organic solvent, an acylating chlorination reagent is added into the solution, the mixed solution undergoes a reaction to produce 5-bromo-2-chlorobenzoyl chloride, 5-bromo-2-chlorobenzoyl chloride is dissolved in an organic solvent, the solution is cooled, the cooled solution is added with phenetole and acid catalysts, the mixed solution undergoes a reaction to produce (5-bromo-2-chlorphenyl)(4-ethoxyphenyl)ketone, (5-bromo-2-chlorphenyl)(4-ethoxyphenyl)ketone is dissolved in an organic solvent, the solution is added with a reduction reagent system, the solution undergoes a reaction to produce 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene is dissolved in an organic solvent, a formylation reagent is added into the solution and the mixed solution undergoes a reaction to produce 4-chloro-3-(4-ethoxybenzyl)benzaldehyde. The preparation method utilizes cheap and easily available raw materials and reagents and has a simple synthesis route, simple processes and a high yield.

Description

technical field [0001] The present invention relates to a preparation method of a compound, in particular to a sodium-dependent glucose transporter 2 (SGLT-2) inhibitor Ertugliflozin key intermediate 4-chloro-3-(4-ethoxybenzyl)benzene A new preparation method of formaldehyde [compound of formula (I)]. [0002] Background technique [0003] Type 2 diabetes is a group of clinical syndromes characterized by chronic hyperglycemia due to insufficient insulin secretion or insulin resistance leading to carbohydrate, fat and protein abnormalities. greater than 130mg / dL) and diabetes. [0004] In a healthy human body, more than 99% of blood sugar is reabsorbed back into the blood after being filtered by the glomerulus, and less than 1% of the blood sugar is excreted into the urine. This process is completed by the sodium-dependent glucose transporter (SGLT-1 / 2). SGLT-1 with high affinity and low transport capacity is mainly distributed in the stomach, heart and kidney (completes...

Claims

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Application Information

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IPC IPC(8): C07C47/575C07C45/45
CPCC07C45/455C07C41/18C07C45/46C07C51/60
Inventor 陈友喜刘亦斌陆成樑
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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