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Methods for making simvastatin and intermediates

A new technology of vastatin and lovastatin, applied in the fields of synthetic organic chemistry and medicinal chemistry

Inactive Publication Date: 2012-10-03
VERENIUM CORP (US)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these derivatives, including neovastatin, do not occur naturally and must be prepared synthetically

Method used

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  • Methods for making simvastatin and intermediates
  • Methods for making simvastatin and intermediates
  • Methods for making simvastatin and intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] Example 1: Chemoenzymatic production of nevastatin

[0175] The following examples describe exemplary protocols of the invention, eg, for the chemoenzymatic production of nevastatin.

[0176] Enzymatic hydrolysis of lovastatin

[0177] The enzyme having the sequence of SEQ ID NO:4 (encoded by SEQ ID NO:3) was evaluated in lovastatin or lovastatin acid at a concentration of 0.1 to 0.5M in 7-10% MeOH / buffer by automated Base was added and the reaction was maintained at pH 9-9.5. For example, on a 500ml scale, in 0.5M lovastatin, a lyophilized preparation with the enzyme SEQ ID NO: 4 (centrifugation supernatant from lysed cells) containing 14mg / ml total protein was observed after 48 hours complete transformation of the substance.

[0178] The reaction mixture was acidified (pH 2), and the precipitate was collected by centrifugation and allowed to dry. The filtrate was extracted with iPrOAc and the organic phase extract was added to the dry cake. The resulting susp...

Embodiment 2

[0188] Embodiment 2: lovastatin esterase analysis

[0189] In one aspect, the invention provides methods comprising enzymatically hydrolyzing lovastatin, lovastatin acid, or lovastatin with a hydrolytic enzyme, e.g., an enzyme of the invention, e.g., SEQ ID NO:4 encoded by SEQ ID NO:3 acid salts to produce triol acids. In one aspect, the invention provides methods comprising enzymatically hydrolyzing lovastatin, lovastatin acid, or lovastatin salt to produce neovastatin.

[0190] The following examples describe exemplary lovastatin esterase assays that can be used to practice the methods of the invention. For example, this exemplary assay can be used to determine whether a method of the invention can be performed with a hydrolytic enzyme, such as an esterase.

[0191] (a) Cell Lysis (Analytical Grade)

[0192] From B-PER (4.5L) (Pierce, #78248), lysozyme (200μL) (Sigma, L-6876; stock solution 10mg / ml) and DNase I (40μL) (Sigma, DN-25; stock solution 5mg / ml) mL), prepare ...

Embodiment 3

[0230] Embodiment 3: the synthesis of 4-acetyl glycol lactone

[0231] The invention provides a synthetic method for synthesizing 4-acetyl glycol lactone, such as Figure 18 A example.

[0232] a. Directly acetylated triol acid (20g level)

[0233] 1. In N 2 Next, the crude triol acid (25.82 g, 59.1 mmol) (Note 1, below) was charged into a dry 500 mL round bottom flask, followed by addition of dry CH 2 C1 2 (200mL). in N 2 The slurry mixture was stirred magnetically at room temperature. DMAP (108 g, 8.8 mmol; 15 mol%) was added, followed by slow addition of acetic anhydride (15.8 mL, 2.8 eq.) via syringe pump over 8.5 hours. At 7.75 hours, an additional portion of DMAP (0.36 g, 2.9 mmol) was added (Remark 2, below).

[0234] 2. Closely monitor the progress of the reaction by HPLC (Remark 3, below).

[0235] 3. After 11 hours, water (5 mL) was added to quench the reaction and the mixture was stored at -20°C before working. Filter the mixture through a pad of celit...

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Abstract

The invention provides synthetic chemical and chemoenzymatic methods of producing simvastatin and various intermediates. In one aspect, enzymes such as hydrolases, e.g., esterases, are used in the methods of the invention.

Description

[0001] This application is a divisional application, the filing date of the original application is October 20, 2004, the application number is 2004800362026 (PCT / US2004 / 034913), and the title of the invention is "method for preparing neovastatin and its intermediate". [0002] related application [0003] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application 60 / 513,237, filed October 21, 2003, and U.S. Provisional Application 60 / 542,100, filed February 4, 2004. The aforementioned application is expressly incorporated by reference in its entirety for all purposes. technical field [0004] The present invention relates generally to the fields of synthetic organic chemistry and medicinal chemistry. In one aspect, the present invention provides synthetic chemical and chemoenzymatic methods for the preparation of neovastatin and various intermediates and related compounds. In one aspect, enzymes, such as hydrolases, eg esterases,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/06C12P7/42C07DC07D309/30
CPCC12P17/06C07D309/30
Inventor B·摩根M·伯克M·莱温朱作霖J·查普林K·库什特德约黄子林W·格林伯林
Owner VERENIUM CORP (US)
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