Preparation method of phosphodiesterase inhibitor

A technology for phosphodiesterase and inhibitors, which is applied in the field of preparation of phosphodiesterase inhibitors, can solve the problems that are not conducive to large-scale production and the total yield of products is not high, achieve the optimization of reaction conditions and operation methods, and ensure product yield. efficiency and purity, and the effect of shortening the reaction cycle

Pending Publication Date: 2021-11-02
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The total yield of the product in this method is not high, and the co

Method used

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  • Preparation method of phosphodiesterase inhibitor
  • Preparation method of phosphodiesterase inhibitor
  • Preparation method of phosphodiesterase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of Intermediate II

[0028] Add 1.8L of methanol to the reaction kettle, add 361g of starting material 1, add 2.65mol of thionyl chloride dropwise at 20±5°C, after the drop is complete, heat to reflux at 65±3°C for 1 hour, and monitor the start After the reaction of raw material 1 was completed, the solvent was evaporated under reduced pressure, then 1.8L of isopropanol and 265g of piperonal were added, stirred and heated to reflux for 7h, the mixture was cooled to 10±5°C, stirred and crystallized for 2h, centrifuged, and vacuum-dried to obtain The solid powder intermediate II was 596g, the yield was 87.2%, the purity was 99.10%, and the isomer impurity was not detected.

Embodiment 2

[0030] Preparation of Intermediate II

[0031] Add 1.8L of methanol into the reaction kettle, add 353g of starting material 1, add 1.73mol of thionyl chloride dropwise at 20±5°C, after the drop is complete, heat to reflux at 65±3°C for 1 hour, and monitor the start After the reaction of raw material 1 was completed, the solvent was evaporated under reduced pressure, then 1.8L of isopropanol and 260g of piperonal were added, stirred and heated to reflux for 8 hours, the mixture was cooled to 10±5°C, stirred and crystallized for 2 hours, centrifuged, and vacuum-dried to obtain The solid powder intermediate II was 554g, the yield was 82.8%, the purity was 98.53%, and the isomer impurity was not detected.

Embodiment 3

[0033] Preparation of Intermediate II

[0034] Add 1.8L of methanol into the reaction kettle, add 359g of starting material 1, and add 1.76mol of thionyl chloride dropwise under the condition of 20±5°C. After dropping, heat to reflux at 65±3°C for 2 hours, monitor After the reaction of the starting material 1 was completed, the solvent was evaporated under reduced pressure, then 1.8L of isopropanol and 317g of piperonal were added, stirred and heated to reflux for 10h, the mixture was cooled to 10±5°C, stirred and crystallized for 2h, centrifuged, and vacuum-dried , 569g of solid powder intermediate II was obtained, the yield was 83.6%, the purity was 99.22%, and the isomer impurity was not detected.

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Abstract

The invention discloses a preparation method of a phosphodiesterase inhibitor, belonging to the field of medicinal chemistry. The preparation method comprises the following steps: carrying out an esterification reaction on an initial raw material 1 and methanol to prepare an intermediate I, directly carrying out condensation cyclization on the intermediate I and heliotropin to prepare an intermediate II, and carrying out chloracetylation, aminolysis cyclization and refining to prepare a final product, namely a refined tadalafil product. The method improves product yield and quality, greatly shortens a reaction period in a preparation process, reduces operation steps and production cost, and is suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a phosphodiesterase inhibitor. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor. When sexual stimulation leads to the local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the level of cyclic guanosine monophosphate in the cavernous body of the penis, which leads to Smooth muscles relax and blood flows into the penile tissue, producing an erection. The compound was originally developed by GlaxoSmithKline and subsequently transferred to ICOS, and later jointly developed by ICOS and Eli Lilly. Approved by the FDA in 2003, tadalafil was listed in the United States as a drug for the treatment of male erectile dysfunction. At the beginning of 2014, the drug was approved by the US FDA as a new indication for the treatment of benign prostatic hyperplasia, and the future market capacity...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D471/04C07D209/20
CPCC07D471/14C07D471/04C07D209/20
Inventor 陈雨李明杰李晓峰宋良伟郭中明侯善波刘新泉朱全明耿强
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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