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Synthetic method of macrocyclic inhibitor intermediate cycloheptane sulfonyl chloride

A technology of cycloheptanesulfonyl chloride and a synthesis method, which is applied in the chemical field, can solve problems such as easy pollution of the environment, high economic cost, and low yield, and achieve the effects of strong operability, simple post-treatment, and easy-to-obtain raw materials

Inactive Publication Date: 2019-11-22
苏州汉德创宏生化科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are many reports on cyclohexylsulfonyl chloride of the six-membered ring, and most of the synthesis methods use cyclohexanethiol, which has a relatively large odor, as a raw material, which is oxidized by an oxidant, chlorinated, etc. to generate cyclohexylsulfonyl chloride, and most of the methods use noble metals. As a catalyst to increase the cost, if it is not handled properly, it will easily cause environmental pollution and it is not easy to scale up production
However, there are few reports on the synthesis of cycloheptanesulfonyl chloride of the macrocyclic seven-membered ring. Among them, the document Russian Journal of Organic Chemistry, volume 53 (6), pages 860-868, in 2017, reported the use of thiol and di Chlorine oxide reacts with vanadyl acetylacetonate, and the product yield is only 30%
The synthesis method of the above-mentioned same type of compound is easy to pollute the environment, the yield is low, the economic cost is high, and it is not conducive to production enlargement

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  • Synthetic method of macrocyclic inhibitor intermediate cycloheptane sulfonyl chloride
  • Synthetic method of macrocyclic inhibitor intermediate cycloheptane sulfonyl chloride

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preparation example Construction

[0021] A synthetic method of macrocyclic inhibitor intermediate cycloheptanesulfonyl chloride, comprising the following reaction steps:

[0022]

[0023] Specifically: the first step: compound I cycloheptyl alcohol is reacted with p-toluenesulfonyl chloride in the first reaction solvent under the action of an acid-binding agent to obtain compound II cycloheptyl 4-methylbenzenesulfonate;

[0024] Second step: Substitution reaction occurs between compound II and potassium thioacetate in the second reaction solvent to generate compound III cycloheptylethane sulfate;

[0025] The third step: the compound III is oxidized with the chlorination reagent in the third reaction solvent to obtain the desired compound cycloheptanesulfonyl chloride.

[0026] In the first step, the first reaction solvent is one or more of dichloromethane, acetone, 1,4-dioxane, tetrahydrofuran, toluene, MTBE, and the acid-binding agent is selected from organic bases, and the acid-binding agent is One or m...

Embodiment 1

[0031] A synthetic method of macrocyclic inhibitor intermediate cycloheptanesulfonyl chloride, comprising the following reaction steps:

[0032] Step 1: Add compound I cycloheptanol (23 g, 0.20 mol, 1.0 eq.) and tetrahydrofuran (120 mL, 6 v / w) and dry pyridine (48 g, 0.60 mol, 3 eq.), under stirring, lower the temperature of the reaction system to 0°C, and slowly add p-toluenesulfonyl chloride (38 g, 0.20 mol, 1.0eq.) in the temperature range of 0~10°C , the dropwise addition is completed in half an hour; maintain the reaction temperature at 0~10°C for 2 h; at 0~-10°C, use 6% HCl aqueous solution to adjust the pH of the reaction solution to 1~2 or adjust to no pyridine odor, and use 150 Extract with ethyl acetate, separate the water phase, wash the organic phase with 200 mL of saturated aqueous sodium bicarbonate solution, 200 mL of brine, dry with 50 g of anhydrous sodium sulfate, filter and concentrate to obtain 44 g of cycloheptyl 4-methylbenzenesulfonate The base ester is...

Embodiment 2

[0036]Step 1: Add cycloheptanol (20 g, 0.17 mol, 1.0 eq.) and dichloromethane (160 mL, 8 v) and dry triethylamine (34 g, 0.34 mol, 2.0 eq.). Under stirring, the temperature of the reaction system was lowered to 0°C, and p-toluenesulfonyl chloride (48.6 g, 0.25 mol, 1.5eq.) was slowly added dropwise within the temperature range of 0-10°C, and the addition was completed in half an hour. Maintain the reaction temperature at 0-10°C for 3 h. At 0~-10°C, use 6% HCl aqueous solution to adjust the pH to 1~2 or adjust to no pyridine odor, extract with 140 mL ethyl acetate, separate the water phase, and use 150 mL saturated sodium bicarbonate for the organic phase Aqueous solution, washed with 150 mL of brine, dried with 40 g of anhydrous sodium sulfate, filtered and concentrated to obtain 40 g of cycloheptyl 4-methylbenzenesulfonate as a colorless liquid with a purity of 98% and a yield of 85%.

[0037] Step 2: In a 500 mL three-neck flask, first add potassium thioacetate (51 g, 0.45...

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Abstract

The invention discloses a synthetic method of a macrocyclic inhibitor intermediate cycloheptane sulfonyl chloride. The synthetic method comprises the following steps of 1, reacting a compound I cycloheptanol with p-toluenesulfonyl chloride to obtain a compound II cycloheptane 4-methyl benzene sulfonate; 2, reacting a compound II with the potassium thioacetate to obtain a compound III cycloheptaneethane sulfate; and 3, oxidizing the compound III to obtain the compound cycloheptane sulfonyl chloride. The synthetic method of the macrocyclic inhibitor intermediate cycloheptane sulfonyl chloride provided by the invention is simple in reaction, simple and convenient in post-treatment, high in yield, low in cost and strong in operability, can obtain the raw materials easily, and is suitable forthe industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemistry, and in particular relates to a method for synthesizing cycloheptanesulfonyl chloride, an intermediate of macrocyclic inhibitors. Background technique [0002] As a series of organic synthesis raw materials, sulfonyl chloride is mainly used as chlorination agent of vat dyes, dry ink, assimilative agent of dyes, dyeing auxiliaries of wool, etc. In addition, it is widely used as intermediate in the synthesis of medicine and pesticide. Important intermediates of drugs and sulfonylurea herbicides. Naphthene sulfonyl chloride is a kind of sulfonyl chloride. The synthesis methods of sulfonyl chloride reported in domestic and foreign literature include mercaptan chlorine oxidation method, thiocyanate chlorination method, sodium thiosulfate chlorination method, etc. There are many reports on cyclohexylsulfonyl chloride of the six-membered ring, and most of the synthesis methods use cyclohexanethiol, wh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/02C07C309/85C07C303/28C07C309/73C07C327/24
CPCC07C303/02C07C303/28C07C327/24C07C2601/18C07C309/85C07C309/73
Inventor 茅仲平马东旭石俊
Owner 苏州汉德创宏生化科技有限公司
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