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Synthetic method of cis-4-(tetrahydropyrane-2-oxy)-2-butylene-1-ol

A technology of tetrahydropyran and a synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of energy consumption, solvent recovery and environmental protection increase large cost, unsuitable for industrial production, affecting industrial production and other problems, and achieves widening raw material sources and reducing residues. , the effect of reducing production costs

Inactive Publication Date: 2015-11-04
江苏威格瑞斯化工有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These two characteristics cause the single batch output of described method to be very low, must increase a large amount of cost in energy consumption, solvent recovery and environmental protection, are not suitable for suitability for suitability for industrialized production
[0006] (3) In addition, for the synthesis of cis-4-(tetrahydropyran-2-oxygen)-2-buten-1-ol, in order to ensure product quality and yield, high-purity cis-1,4-butanol must be selected Diol is used as a raw material, and domestic cis-1,4-butenediol generally contains more than 5% trans isomers, as well as 1% to 2% butanediol and acetylenic diol, which is suitable for a pharmaceutical For synthetic intermediates, the impact of such a high impurity content on product quality cannot be ignored, and the cost of importing cis-1,4-butenediol increases, which limits the source of this main raw material and affects industrial production

Method used

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  • Synthetic method of cis-4-(tetrahydropyrane-2-oxy)-2-butylene-1-ol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Step 1, refining of 1,4-butenediol

[0032] 394.25 g of crude 1,4-butenediol (89.16% cis content detected by GC) and 1193.47 g of acetone were put into a 2000 mL four-necked flask. Use an ethanol refrigeration system to cool down the solution to -16°C, keep stirring and crystallize for about 4 hours, then quickly filter with suction and rinse with 41g of cold acetone at -6°C (wash the filter funnel with another portion of cold acetone first). Put the filtered crystals into a 1000mL four-neck flask, connect to the vacuum and heat, and distill to the liquid temperature of 65°C under the vacuum of -0.085Mpa, and continue until there is no distillation. Then pump in about 200g of toluene, continue to distill at -0.085Mpa to a liquid temperature of 85°C, and continue until there is no distillation. Cool to room temperature and set aside. GC detection showed that the cis content was 99.76% excluding the residual toluene, and the residual toluene was 4.31%.

[0033] Step 2....

Embodiment 2

[0036] Step 1, refining of 1,4-butenediol

[0037] Put 203.78 g of crude 1,4-butenediol (88.34% cis content as detected by GC) and 613.09 g of acetone into a 2000 mL four-necked flask. Use an ethanol refrigeration system to cool the solution down to -17°C, keep stirring and crystallize for about 4 hours and 30 minutes, then quickly filter it with suction, and rinse it with 23g of cold acetone at -8°C (the filter funnel is first washed with another cold acetone). Put the filtered crystals into a 1000mL four-neck flask, connect to the vacuum and heat, and distill to the liquid temperature of 65°C under the vacuum of -0.085Mpa, and continue until there is no distillation. Then pump in about 100g of toluene, continue to distill at -0.085Mpa to a liquid temperature of 85°C, and continue until there is no distillation, then cool to room temperature for later use. GC detection showed that the cis content was 99.62% excluding the residual toluene, and the residual toluene was 3.59%. ...

Embodiment 3

[0041] Step 1, refining of 1,4-butenediol

[0042]Put 400.97 g of crude 1,4-butenediol (85.42% cis content as detected by GC) and 1206.85 g of acetone into a 2000 mL four-necked flask. Use an ethanol refrigeration system to cool the solution down to -16°C, insulate and stir to crystallize for about 4 hours, then quickly filter it with suction and wash it with 43g of cold acetone at -6°C (the filter funnel is first washed with cold acetone). Put the filtered crystals into a 1000mL four-neck flask, connect to the vacuum and heat, and distill to the liquid temperature of 65°C under the vacuum of -0.085Mpa, and continue until there is no distillation. Then pump in about 200g of toluene, continue to distill at -0.085Mpa to a liquid temperature of 85°C, and continue until there is no distillation. Cool to room temperature and set aside. GC detection showed that the cis content was 99.89% excluding the residual toluene, and the residual toluene was 3.44%.

[0043] Step 2. Addition...

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Abstract

The invention discloses a synthetic method of cis-4-(tetrahydropyrane-2-oxy)-2-butylene-1-ol. The synthetic method comprises the following steps: performing low-temperature recrystallization and desolution by using acetone on 1,4-butendiol which is taken as a raw material to prepare high-purity cis-1,4-butendiol, then performing addition reaction with 2,3-dihydropyrane under the complex catalysis of toluene-p-sulfonic acid monohydrate and pyridine, and performing desolution to obtain a product namely cis-4-(tetrahydropyrane-2-oxy)-2-butylene-1-ol. The method does not need high-purity cis-1-4-butendiol as a raw material anymore, so that the cost is reduced, the raw material source is broadened, and convenience is provided for industrial production. Moreover, the refining process of butendiol is simple and suitable for scale production. The cis content after refining can be improved to more than or equal to 99.5%. The addition process is simple to operate, and the reaction condition is mild. Methylbenzene extraction and water scrubbing are performed, so that the residues of butendiol are greatly reduced, the product quality is improved, the non-rectification content can reach more than or equal to 80%, and the molar yield to 2,3-dihydropyrane after purification reaches more than or equal to 73%.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and relates to a synthesis method of a pharmaceutical intermediate, in particular to a synthesis method of cis-4-(tetrahydropyran-2-oxygen)-2-buten-1-ol. Background technique [0002] Cis-4-(tetrahydropyran-2-oxygen)-2-buten-1-ol is an important intermediate of the drug lafutidine, and is the main side chain of synthetic lafutidine: 4- Key substance of [4-(1-piperidinylmethyl)pyridinyl-2-oxy]-cis-2-butenol. [0003] Chinese patent (Application No.: 201110333367.1) discloses a synthesis process of a pyranyl monoprotected product of cis-1,4-butenediol. The method is based on cis-1,4-butenediol and dihydrogen Pyran is used as raw material for synthesis, and inorganic salt solution is used as catalyst, mainly sulfate, sulfite and carbonate of sodium and potassium. The above method has the following disadvantages: [0004] (1) This method uses a large amount of solvent, which is 10 to 20 t...

Claims

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Application Information

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IPC IPC(8): C07D309/12
CPCC07D309/12
Inventor 王小波
Owner 江苏威格瑞斯化工有限公司
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