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Preparation method of oxazaspiro compound

A compound, benzyloxycarbonyl technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of unsuitability for large-scale production, potential safety hazards, high toxicity and the like

Active Publication Date: 2020-08-04
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] This method uses OsO 4 , the toxicity is relatively large, there is a certain potential safety hazard, and the yield of the whole route is low (the yield of the first three steps is only 7.7%), so it is not suitable for large-scale production

Method used

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  • Preparation method of oxazaspiro compound
  • Preparation method of oxazaspiro compound
  • Preparation method of oxazaspiro compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]

[0051] Preparation of compound III-1:

[0052] Compound II-1 (94.9g, 366.4mmol, 1.0eq.) was dissolved in MeOH (700mL), and at 0°C, an aqueous solution (30mL) of NaOH (29.3g, 732.8mmol, 2.0eq.) was added dropwise and heated to The reaction was stirred at 60°C for 18h. TLC showed that the reaction of the raw materials was complete, the reaction solution was lowered to room temperature, the reaction solution was concentrated to an oily substance, water was added, EA was extracted twice, the aqueous phase was adjusted to pH 3-4 with saturated citric acid aqueous solution, EA was extracted, the organic phases were combined, and Washed with saturated brine, anhydrous MgSO 4 After drying, filtering and concentrating, compound III-1 was obtained as light yellow solid 83.1 g, yield 92.3%.

[0053] Preparation of compound V-1:

[0054] Compound III-1 (30.0g, 122.3mmol, 1.0eq.) was dissolved in DMF (300mL), cooled to 0°C, and compound IV-1 (2-chloroethylamine hydrochloride) ...

Embodiment 2

[0058]

[0059] Preparation of compound III-2:

[0060] Compound II-2 (90.01g, 292.8mmol, 1.0eq.) was dissolved in EtOH (700mL), at room temperature, an aqueous solution (30mL) of LiOH (7.01g, 292.8mmol, 1.0eq.) was added, heated to reflux and stirred Reaction 18h. TLC showed that the reaction of the raw materials was complete, the reaction solution was lowered to room temperature, the reaction solution was concentrated to an oily substance, water was added, EA was extracted twice, the aqueous phase was adjusted to pH 3-4 with saturated citric acid aqueous solution, EA was extracted, the organic phases were combined, and Washed with saturated brine, anhydrous MgSO 4 After drying, filtering and concentrating, compound III-2 was obtained as 73.1 g of light yellow solid, with a yield of 89.3%.

[0061] Preparation of Compound V-2:

[0062] Compound III-2 (30.0g, 107.4mmol, 1.0eq.) was dissolved in DMF (300mL), cooled to 0°C, and compound IV-2 (1-chloromethylamine) (14.07g, ...

Embodiment 3

[0066]

[0067] Preparation of compound III-3:

[0068] Compound II-3 (90.1g, 324.5mmol, 1.0eq.) was dissolved in MeOH (700mL), at 0 ℃, an aqueous solution (30mL) of KOH (54.6g, 973.5mmol, 3.0eq.) was added, heated to reflux and stirred Reaction 16h. TLC showed that the reaction of the raw materials was complete, the reaction solution was lowered to room temperature, the reaction solution was concentrated to an oily substance, water was added, EA was extracted twice, the aqueous phase was adjusted to pH 3-4 with saturated citric acid aqueous solution, EA was extracted, the organic phases were combined, and Washed with saturated brine, anhydrous MgSO 4 After drying, filtering and concentrating, Compound III-3 was obtained as 76.23 g of light yellow solid, with a yield of 94.3%.

[0069] Preparation of Compound V-3:

[0070] Compound III-3 (30.0g, 120.4mmol, 1.0eq.) was dissolved in DMF (300mL), cooled to 0°C, and compound IV-1 (2-chloroethylamine hydrochloride) (20.9g, 18...

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Abstract

The invention discloses a preparation method of an oxazaspiro compound, which comprises the following steps: by using substituted saturated azaspiro alkane (compound II) as a raw material, performinghydrolyzing under an alkaline condition to obtain a compound III; carrying out condensation reaction on the compound III and a salt of a compound IV (halogenated alkylamine) / compound IV to generate acompound V; and finally, cyclizing the compound V under an alkaline condition to obtain the lactam oxazaspiro compound I.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a method for preparing azaspirocyclic compounds. Background technique [0002] Heterospiro compounds have broad-spectrum biological activities and can be used in the research of pesticides and medicines. Such compounds have the characteristics of spiro conjugation, spiro hyperconjugation or anomeric effect, so the synthesis and biological The study of the activity has aroused great interest. Nitrogen-containing and oxygen-containing heterospirocyclic compounds, as a member of the organic heterospirocyclic ring system, have attracted widespread attention due to their remarkable pharmacological and biological activities, and are an important class of pharmaceutical and new drug research and development intermediates. Patent WO2016122994A1 discloses compounds VI and VII, which are inhibitors of a class of romk (kir1.1) channels, can be used as diuretics and / ...

Claims

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Application Information

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IPC IPC(8): C07D498/10
CPCC07D498/10
Inventor 刘文博周涛余善宝李辉
Owner PHARMABLOCK SCIENCES (NANJING) INC
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