Preparing naphthalene buthanone using 4-digit subsituted 2-buthanone

A kind of arylbutyl and halogen technology, applied in the field of pharmaceutical active compounds and their preparation

Inactive Publication Date: 2002-09-11
CELANESE POLYMER SPECIALTIES COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reaction is often called the Heck reaction

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Methyl vinyl ketone (MVK) was purchased from Janssen Chimica. 2-Bromo-6-methoxynaphthalene (BMON) was obtained from Albemarle PPC Company. Palladium dichloride and 5% Pd / C pre-wetted to 50% by weight water (Engelhard's ESCAT 111) were obtained from Engelhard. N,N-Dimethylformamide (DMF) was purchased from Air Products. Triphenylphosphine was obtained from ElfAtochem North America. Potassium carbonate was purchased from Armand Products and ground so that 95% of it passed through a 325 mesh (44 micron) sieve. Hydrogen was purchased from Big Three Industries. Diatomaceous earth 545 was purchased from Celite Corporation. Isopropanol was purchased from Shell Corporation. 4-Hydroxy-2-butanone was purchased from TCI-EP. Acetic anhydride, methanesulfonyl chloride, 4-acetoxy-2-butanone, acetyl chloride, methylene chloride and triethylamine were purchased from Aldrich Chemical Company. Embodiment 1: prepare nabumetone with MVK

[0040]Coupling reaction BMON (65.16g), DMF ...

Embodiment 2

[0044] Recrystallization of distilled nabumetone Distilled nabumetone (54.85 g) was recrystallized twice from three times the weight of isopropanol. Yield: about 41.61 g; Purity: greater than about 99.9% (analyzed by HPLC and GC). Embodiment 2: prepare nabumetone with 4-acetoxy-2-butanone

[0045] Coupling reaction BMON (65.20g), DMF (469.34g), potassium carbonate (61.74g), palladium dichloride (6.26mg), and triphenylphosphine (18.38mg) were added to a 1-liter A thermocouple in a thermowell, an overhead stirrer, and a three-necked round bottom flask with a reflux condenser connected to nitrogen and a vacuum multi-way valve. The resulting mixture was stirred while the flask was purged by several rounds of evacuation and nitrogen filling. 4-Acetoxy-2-butanone (44.87 g) was then added to the flask by syringe through a slightly separated sidearm port while maintaining the flask at a moderate positive pressure of nitrogen, and the reaction in the flask was stirred and heated to ...

Embodiment 3

[0050] Example 1 was repeated with the following changes to the coupling reaction: Before heating to about 132° C., the added coupling reaction mixture consisted of BMON (81.19 g), DMF (620 ml), potassium carbonate (42.42 g), palladium dichloride (0.0064 g), consisting of triphenylphosphine (0.018g) and 4-hydroxy2-butanone (24.11g) (instead of MVK). Additional 4-hydroxy-2-butanone (18.43 g) was added via the addition funnel through the 4th neck of the reaction flask over approximately two hours from when the coupling reaction mixture reached about 132°C. Stirring was continued at 132°C for a total of about 6.42 hours, at which time about 99.4% of the starting BMON was converted. The ratio of monoaryl adducts to diaryl adducts measured by HPLC peak area ratio was about 88.1:11.9, and monoaryl adducts and diaryl adducts were the only major products detected . Example 4: Replacement of MVK with 4-hydroxy-2-butanone

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PUM

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Abstract

Palladium catalyzed coupling of aryl and alkenyl halides to vinyl compounds is disclosed. A preferred embodiment involving the palladium catalyzed coupling of 4-substituted and 6-substituted 2-methoxynaphthalenes to nabumetone is also disclosed. The advantage of this new reaction is that methyl vinyl ketone, which is generally used directly in the art for the preparation of nabumetone, is formed in situ. We discovered a mechanism to utilize the in situ formed methyl vinyl ketone, thereby avoiding the use of expensive, toxic, and unstable methyl vinyl ketone starting materials. This reaction can be used in the preparation of various pharmaceutically active and non-pharmaceutically active compounds.

Description

field of invention [0001] The present invention relates to pharmaceutically active compounds and their preparation methods and uses, more specifically, the present invention relates to the synthesis and use of nabumetone. Background of the invention [0002] 4-(6'-methoxy-2'-naphthyl)but-3-en-2-one (formula 4) is a -2-ones, a nonsteroidal anti-inflammatory drug known as nabumetone (Formula 1), are valuable intermediates. [0003] The palladium (Pd) catalyzed coupling of 6-bromo-2-methoxynaphthalene (BMON) with methyl vinyl ketone (MVK) is generally followed in the art as described in US 5,225,603 (incorporated herein by reference) To prepare nabumetone. MVK is expensive, has limited (chemical) stability, and has toxicity associated with it. Industry is looking for an alternative to MVK for the synthesis of nabumetone. [0004] US 4,061,779 discloses the hydrogenation of 4-(6'-methoxy-2'-naphthyl)but-3-en-2-one to produce the final product nabumeto...

Claims

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Application Information

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IPC IPC(8): A61K31/12C07B61/00C07C45/62C07C45/68C07C45/71C07C49/255
CPCC07C49/255C07C45/62C07C45/68C07C45/71
Inventor J·R·弗里奇M·阿斯拉姆D·E·里奥斯J·C·史密斯
Owner CELANESE POLYMER SPECIALTIES COMPANY
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