WO2010083722A1 - A process for one-pot synthesis of corey lactone - Google Patents

Abstract

A process for one-pot synthesis of Corey lactone, characterized in that it comprises selecting 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid and ester derivatives having the formula I as raw material, adding oxidant, alkalizing with base, acidifying with acid, completing the oxidation of material, ring-opening, cyclization continuously in the same reactor, and purifying to obtain the production 5-hydroxy-hexahydro-2-oxo-2H-cyclopenta[b]furan-4-carboxylic acid having the formula II, i.e. Corey lactone. In the process for one-pot synthesis of Corey lactone having the formula II, Corey lactone is easy to be resolved and is the key intermediate for synthesis of prostaglandins. The method is simple to operate and the raw materials are cheap and easy to be obtained. The method has low pollution to environment and can reduce the cost for producing Corey lactone with large range.

Description

 Process for synthesizing COREY lactone by one-pot method

 This patent relates to a method for synthesizing Corey lactone, a key intermediate in the total synthesis of prostaglandins. Background technique ,

 Prostaglandins (PGs) are an important endogenous physiologically active natural product, which is extremely low in biological tissues. It was discovered by von Enler in 1930, and its skeleton is composed of a five-membered ring. The carboxylic acid of 20 carbon atoms, according to the structural difference of the five-membered ring, the natural prostate can be of the PGA, PGB, PGC, PGE and PGF types, prostaglandins on the reproductive system, nervous system, respiratory system, endocrine and other systems. has an effect.

A large number of prostaglandins have been developed through the study of natural prostaglandins and their structural modifications. For example, the drug for the induction of labor, dinoprostone (PGE ₂ ), is used in the forefront of cardiovascular disease treatment. (PGE is used for glaucoma treatments such as Travoprost and Latanoprost.

 figure 1

It has been more than 30 years since RJ. Corey completed the natural synthesis of prostaglandins. During this period, organic synthetic chemists and biochemists have done a lot of work and developed a number of fully synthetic routes using a variety of starting materials, including cyclopentadiene, bridged dicyclopentadiene, and norbornene. Alkene, indanol, D-glucose, and L-erythrose. The key intermediates in these routes are Corey' alcohol, γ-lactone, bicyclohexane, and the like. Among them, rey Corey's route disclosed in US 3992438 uses norbornadiene as a raw material to synthesize an important intermediate Corey lactone compound. This route has mild reaction conditions and few steps, so it has certain advantages and has become a natural preparation. One of the common routes for prostaglandins and their derivatives, 6-chloro-3-oxo-2-oxabicyclo[3.2.1]octane-8-carboxylic acid represented by the hydrazine compound (Fig. 2) Both ester derivatives and the compound of formula II, Corey lactone, are key intermediates in this route.

The trade name of Corey lactone acid of formula II: 5-hydroxy-hexahydro-2-oxo-277-cyclopenta[b]furan-4-carboxylic acid, the molecular formula is: C ₈ H ₁₍₎ 0 ₅ , the molecular weight is 186.05. The racemate of Corey lactone is resolved by S-((x)-phenethylamine (Liu Zhizhen et al., Organic Chemistry, 1985, 371-372), which readily forms an anti-imiding salt, is easily crystallized, and can be non- The same amount of salt, more economical when split, the free optical pure (-)-Corey lactone acid can be used to synthesize various prostaglandins (PGs).

The Corey lactone acid represented by the formula II is mainly obtained by oxidation reaction of 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid represented by the formula I and an ester derivative thereof. 6-Chloro- _3- oxo-2-oxabicyclo[3.2.1]octane-8-carboxylic acid and its ester derivative are shown in hydrazine, and then hydrolyzed by ring opening and cyclized.

 figure 2

 The main difference between the existing Corey lactone acid preparation methods is that the oxidizing agent used in the first oxidation reaction is different, and can be roughly classified into the following two categories:

 1. With m-perfluorobenzoic acid (m-CPBA) as an oxidizing agent, the oxidation reaction has a single step yield of 70%;

 (Tetrahedron, 37, 1981, 411-420)

2. With 40% or 1M peracetic acid (CH ₃ COOOH) as the oxidant, the oxidation reaction yield is 60-70% in a single step. (US 3992438 & Synthesis, 1985, 5, 491-492) Existing methods for preparing Corey lactone acids of Formula II have the following disadvantages:

1. Using step-by-step synthesis, 3 steps can be completed using 2 or even 3 reaction vessels. The synthesis of Corey lactone acid, the separation and purification of each step is troublesome;

 2. The domestic quality of m-chloroperoxybenzoic acid used in the oxidation reaction is generally high, while the import price is relatively expensive, and high-concentration peracetic acid is difficult to purchase;

 3. M-chloroperoxybenzoic acid and peracetic acid are easy to release oxygen. It is unsafe to store and transport. The higher the purity, the greater the risk, especially the high concentration of peracetic acid, which is extremely explosive;

 4. The reaction of m-chloroperbenzoic acid to form m-chlorobenzoic acid is difficult to separate from the target product. The separation of silica gel column chromatography is good, but it requires a large amount of solvent to be eluted. The cost is high, which limits the industrial production.

 5. With m-chloroperoxybenzoic acid or peracetic acid as the oxidant, the yield is not very high. Summary of the invention

 SUMMARY OF THE INVENTION The object of the present invention is to overcome the deficiencies of the above-mentioned techniques and to provide a novel process for synthesizing Corey lactone acid by a one-pot method. The present invention uses a potassium persulfate preparation (OXONE) as an oxidant, and the one-pot process for preparing the Corey lactone acid of the formula II includes the following steps:

 1. The 2-halo-5-oxobicyclo[2.2.1]heptan-7-carboxylic acid of formula I and its ester derivative are dissolved in a reaction solvent at 0 ° C to 100 ° C. Potassium persulfate preparation in batches under conditions

(OXONE) powder;

 2. After the TLC plate detects the disappearance of the raw materials, it is quenched by adding sodium hydrogen sulfite, and the stirring reaction is continued;

3. Drip the alkaline aqueous solution to PH value: 8~12, continue to stir the reaction for 10 minutes~12 hours;

4. Drip the acidic aqueous solution, adjust the pH value: 1~6, continue to stir the reaction for 10 minutes~12 hours;

5. After the reaction is completed, it can be treated by conventional methods and purified to obtain the desired formula II. Corey lactone acid. The method for preparing a compound of formula III using the potassium peroxodisulfate formulation (OXONE) as an oxidizing agent comprises the following steps:

 1. Dissolving 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid of formula I and its ester derivative in a reaction solvent with or without addition of 4-butyl Ammonium bromide, stirred, batchwise added potassium persulfate preparation (OXO E), 0~100Ό stirred for 1~3 days;

 2. After the reaction is completed, the compound of the formula III can be obtained by a conventional method of treatment and purification. Compared with the prior art, the advantages of the invention are as follows:

 1. The synthesis of Corey lactone can be completed in the same reaction vessel, avoiding product loss caused by intermediate post-treatment and transfer, simplifying operation, reducing the type and quantity of solvent used, and reducing industrialization. Equipment investment, reducing the production cost of the factory production;

2. The oxidizing agent potassium persulfate preparation (OXO E) used in the new process described in the present invention is one-tenth the price of m-chloroperoxybenzoic acid, so that the production cost can be greatly reduced;

3. 0 0 ^ The chemical properties of the oxidant are relatively stable, not easy to deteriorate, safe to store or transport at room temperature, not easy to explode, which is conducive to industrial large-scale production;

 4. In the process of one-pot boiling reaction and post-treatment, some inorganic sodium salts and potassium salts are mainly formed, which have little environmental pollution;

 5. The yield of this reaction is significantly higher than the use of m-chloroperoxybenzoic acid or peracetic acid as the oxidant. BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 shows dinoprostone (PGE ₂ ), alprostadil (PGE^ travoprost) (Travoprost) and the structure of Latanoprost;

 Figure 2 shows the 2-chloro-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid of formula I and its ester derivative obtained by oxidation to give 6-chloro- represented by formula III. 3-oxo-2-oxabicyclo[3.2.1]octane-8-carboxylic acid and its ester derivatives, which are then hydrolyzed to ring-opening and cyclized to give Corey lactone acid. The structure of the compound prepared by the method of the present invention has been confirmed by hydrogen spectrum, carbon spectrum and mass spectrometry, and the structure is correct. In the present invention, Corey lactone is the same term as Corey lactone acid.

 The invention is further illustrated by the following examples, which are not intended to limit the invention. detailed description:

 Example 1

 Preparation of 6-chloro-3-oxo-2-oxabicyclo[3.2.1]methyl octyl-8-carboxylate

5 g of 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid methyl ester, 20 mg of 4-butylammonium bromide, 50 ml of CH ₂ C1 _{2 and} 50 ml of water were added to the reaction flask. 22.5g of oxone was added in portions, the reaction was stirred for 48 hours, and the TLC plate was detected to have no obvious residue of the raw material. The filter cake was washed with C3⁄4C1 ₂ 10 ml× ₂ , and the filtrate was washed with 30 mL× _{2 of a} saturated solution of NaHS0 _{3 to} separate the organic phase to anhydrous sulfuric acid. The sodium is dried, suction filtered, evaporated to dryness, and recrystallized from water to give white crystals. Example 2

 Preparation of 6-chloro-3-oxo-2-oxabicyclo[3.2.1]octane-8-carboxylic acid

5 g of 2-halo-5-oxobicyclo[2.2.1]heptan-7-carboxylic acid, 50 ml of acetone-water mixed solution were added to the reaction flask, and then oxone 22.5 g was added in portions, and the reaction was stirred overnight, TLC plate. No obvious residue of raw materials was detected, suction filtration, filter cake was washed with acetone 10 ml×2, and the filtrate was distilled off under reduced pressure. The mixture was extracted with EtOAc (EtOAc)EtOAc.EtOAc. Example 3

 Preparation of 5-hydroxy-hexahydro-2-oxocyclopenta[b]furan-4-carboxylic acid

 After adding 80 g of 2-chloro-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid to the reaction flask, 500 ml of methanol, and then gradually adding OXONE 270 g, the reaction was stirred at room temperature, and the TLC was detected to be insignificant. The residue of the raw material is quenched by adding sodium hydrogen sulfite, alkalized by adding 10% NaOH, the reaction is continued, concentrated hydrochloric acid is added to adjust the pH value, the reaction liquid is concentrated under reduced pressure, extracted with THF, and the organic layer is separated, sodium anhydrous Dry, suction and dry to give a white solid. Example 4

 Preparation of 5-hydroxy-hexahydro-2-oxo-2 Cyclopenta[b]furan-4-carboxylic acid

 To the reaction flask, 57 g of 2-chloro-5-oxobicyclo[2.2.1]heptan-7-carboxylate methyl ester and 2500 ml of acetone-water mixture were added successively, and then OXONE 180 g was gradually added thereto, and the reaction was stirred at room temperature. TLC detected no obvious residue of raw materials, quenched the reaction by adding sodium hydrogen sulfite, stirring the reaction, adding alkalization with 10% NaOH, continuing the reaction, adding concentrated hydrochloric acid to adjust the acidity, stirring the reaction, and concentrating the reaction solution under reduced pressure. THF:AcOEt (1:1, V/V) was extracted, dried over anhydrous sodium sulfate and evaporated to dryness to afford white crystals. Example 5

 Preparation of 5-hydroxy-hexahydro-2-oxo-2 Cyclopenta[b]furan-4-carboxylic acid

Add 53 g of 2-chloro-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid to the reaction flask, and add 2000 ml of acetone-water mixed solvent, then gradually add OXONE 150 g, stir the reaction at room temperature, TLC No obvious residue of raw materials was detected. The reaction was quenched by adding NaHS0 ₃ , the reaction solution was warmed up, some of the solvent was distilled off, stirring was continued, the temperature was lowered, 10% NaOH was added dropwise to make alkali, the reaction was continued, concentrated hydrochloric acid was added to adjust the acidity, and stirring was continued. The reaction mixture was concentrated under reduced pressure. Example 6

 Preparation of 5-hydroxy-hexahydro-2-oxo-2-cyclopenta[b]furan-4-carboxylic acid

 Add 35 g of 2-chloro-5-oxobicyclo[2.2.1]heptan-7-carboxylic acid to the reaction flask in turn, 1000 ml of water, then gradually add OXONE 135 g, and raise the temperature to 40~50 °C. Overnight, TLC detected no obvious residue of raw materials, quench the reaction by adding sodium hydrogen sulfite, continue to stir the reaction, add 10% KOH, adjust to alkaline, stir the reaction, add concentrated hydrochloric acid to adjust the pH to acidity, stir the reaction, reduce The reaction mixture was concentrated, dried with EtOAc EtOAc EtOAc (EtOAc) Example 7

 Preparation of 5-hydroxy-hexahydro-2-oxo-2-cyclopenta[b]furan-4-carboxylic acid

 Add 40 g of 2-chloro-5-oxobicyclo[2.2.1]heptan-7-carboxylic acid to the reaction flask, and then add 1500 ml of a methanol-water mixed solvent, then gradually add OXO1 E160 g, and stir the reaction at room temperature, TLC. No obvious residue of raw materials was detected. The reaction was quenched by adding sodium hydrogen sulfite. The reaction solution was heated to evaporate part of the solvent, stirring was continued, the temperature was lowered, and the reaction was continued by adding 10% NaOH. The reaction was continued, and the pH was adjusted to be acidic by adding concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated.

Claims

Rights request  A process for synthesizing Corey lactone by a one-pot method: characterized by the production of 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid of the formula I and esters thereof The material is used as a raw material, an oxidizing agent is added, and then alkalization and acidification are carried out, and oxidation, ring opening and cyclization of the raw material are continuously performed in the same reaction vessel, and finally, the product shown in Structure II is obtained by 5-hydroxy-6. Hydrogen-2-oxocyclopenta[b]furan-4-carboxylic acid, also known as Corey lactone.

 2. The preparation method according to claim 1, wherein the oxidation reaction is carried out by using 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid of the formula I and an ester derivative thereof. The starting material, including its racemate and optically pure isomer, is reacted with an oxidizing agent to form a 6-halo-3-oxo-2-oxabicyclo[3.2.indole]octane-8-carboxylate of formula III. Acid and its ester derivatives;

In the structure, X represents a halogen atom, and includes: F, Cl, Br, I; In the structure, R represents a straight or branched chain hydrocarbon of 1 to 10 carbons, an alkene, an alkyne, a phenyl group, a benzyl group, a naphthyl group; X and R in the structure of the formula III represent the same as the formula I. 3. Process according to claim 1, characterized in that the oxidizing agent used is m-chloroperoxybenzoic acid, peracetic acid, potassium hydrogen persulfate (OXO E), preferably potassium hydrogen persulfate (OXONE) o 4. The preparation method according to claim 1, characterized in that the oxidizing agent potassium persulfate preparation (OXONE) and the 2-halo-5-oxobicyclo[2.2.1]heptan-7-carboxylic acid of the formula I and The molar ratio of the ester derivative is: 0.5 to 10:1.  The preparation method according to claim 1, wherein the reaction solvent is: water, acetone, methyl ethyl ketone, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, acetonitrile, tetrahydrofuran, dichloro A mixed solvent of formamidine, chloroform, toluene, ethyl acetate, toluene or the above solvent, preferably an acetone/water mixed system.  The process according to claim 1, wherein the reaction temperature is 0 to 150 ° C, preferably the reaction temperature is 0 to 100 ° C.  The preparation method according to claim 1, characterized in that the base used in the alkalization is an inorganic base or an alkali metal salt or an organic base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide or calcium hydroxide (calcium oxide). ), sodium carbonate, potassium carbonate or triethylamine.  8. The preparation method according to claim 1, wherein the acid used in the acidification is an inorganic acid or an organic acid, such as: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyl Acid benzoic acid or p-toluenesulfonic acid.  9. The preparation method according to claim 1, wherein the preferred preparation process is as follows: a. 2-halo-5-oxobicyclo[2.2.1]heptane-7-carboxylic acid or its ester derivative of the formula I is sequentially added to the reaction flask, added to the solvent, and the oxidizing agent is added in portions. Stir the reaction; b. After the disappearance of the raw materials, the reaction is quenched by adding sodium hydrogen sulfite powder, and the reaction is continued, and the reaction temperature is 0 to 100 ° C; c. alkalized the reaction solution, adjust the pH to 8~12, stir the reaction for 10 minutes to 12 hours;  d. acidify the reaction solution, adjust the pH to 1~6, stir the reaction for 10 minutes to 12 hours;  e. After the reaction is completed, it can be processed and purified by conventional methods to obtain the desired Corey.