CN116925022A - A kind of preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene - Google Patents

Abstract

The invention discloses a preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene, which comprises the following steps: (1) 2-oxoglutarate dicarbonyl methyl ester (M8) and 2-iodine-1-ethanol acetate (M2) are alkylated in anhydrous acetone, and then are cyclized at p-TsOH to obtain M9; (2) The obtained M9 is subjected to alkaline hydrolysis, and is resolved in a solvent by using alpha-phenethylamine to obtain M10a; (3) condensing the obtained M10a with Mi's acid to obtain M11a; (4) reducing the obtained M11a to obtain M12a; (5) Dehydrating the obtained M12a under the action of acetyl chloride and triethylamine to obtain (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene. The method has the advantages of short reaction route, easily obtained raw materials, fewer byproducts, stable reaction conditions, simple and convenient operation and suitability for large-scale production.

Description

A kind of preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene

Technical field

The invention belongs to the technical field of chemical drug intermediate preparation methods, and particularly relates to a preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene.

Background technique

(S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene (CAS number: 1052236-86-8), whose structure is shown in formula (A), is an important Chemical intermediate, often used as resolving agent in the production of chiral alcohols. (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene stereospecifically generates asymmetric acetal B, with almost no trans-bicyclo[3.3.0]octane skeleton C is formed, so the asymmetric center of the bicyclic C1 is well controlled.

The preparation methods of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene disclosed at home and abroad mainly include the following:

(1) The method reported by Tetrahedron Letters (1994) is:

Alkenyl ether P1 was synthesized in 5 steps starting from 2-allyloxycarbonylated cyclopentan-1-one (M1). M1 and M2 were alkylated in dry acetone to obtain M3 with a yield of 89%. Allyl ketone ester M3 was subjected to Shimizu-Tsuji reaction to give allyl ketone M4, which was then treated with a catalytic amount of p-TsOH in methanol to give cyclic acetal M5 in an overall yield of 74%. M5 was treated with acetyl chloride in chloroform for 20 hours to obtain chloride M6. During reflux, triethylamine in dichloromethane was used to immediately obtain the racemate of the target product alkenyl ether P1, with a total yield of 95%. Alkenyl ether P1 can be decomposed in silica gel, but can be purified by alumina gel column chromatography.

(2) The method reported in EP1535917A1 is:

Using M3 as raw material, allyl ketone M4 is obtained through Shimizu-Tsuji reaction, and then treated with a catalytic amount of p-TsOH in methanol to obtain cyclic acetal M5, and then L-lactic acid is used to split P1, and finally P1 is obtained Two enantiomers.

However, the above scheme has technical problems such as high raw material cost, unstable reaction conditions, difficult operation, and difficulty in realizing industrial production.

Contents of the invention

In view of the shortcomings of the existing technology, the purpose of the present invention is to provide a kind of (S)-5-allyl-2-oxabicyclo [3.3 .0] Preparation method of oct-8-ene.

A preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene, including the following steps:

The synthetic route adopted in the present invention can be expressed by a chemical equation as follows:

The present invention is further configured as follows:

In step (1): Add potassium carbonate to M8 and M2 in anhydrous acetone solution, then filter and concentrate, add methanol and p-TsOH to cyclize to obtain M9;

Preferably, the alkylation reaction temperature in step (1) is 30 to 70°C, and the reaction time is 10 to 30 hours. The cyclization reaction temperature is 30 to 70°C, and the reaction time is 2 to 6 hours.

In step (2): the M9 obtained in step (1) is subjected to alkaline hydrolysis, and α-phenylethylamine is used to resolve it in a solvent to obtain M10a;

The alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, and the dosage is 1 to 3 equivalents of M9;

The solvent is one or more of acetone, ethanol, toluene, ethyl acetate and water, and the dosage is 1 mol of M10: 100-500 mL;

In step (3): M10a obtained in step (2) is condensed with Michaelis acid under the action of a condensing agent and a catalyst to obtain M11a;

The condensation agent is CDI (N'N-carbonyldiimidazole), EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide). Imine), one or more of oxalyl chloride and pivaloyl chloride, the dosage is 1 to 3 equivalents of M10a;

The catalyst is one or more of triethylamine, diethylamine, diisopropylamine, pyridine and lutidine, and the dosage is 1 to 3 equivalents of M10a;

In step (4): add the M11a obtained in step (3) to the solvent, and then add a reducing agent for reduction to obtain M12a;

The reducing agent is one or more of potassium borohydride, potassium borohydride, lithium aluminum tetrahydrogen, zinc amalgam and hydrazine hydrate, and the dosage is 1 to 3 equivalents of M11a;

The solvent is one or more of water, methanol, ethanol, tetrahydrofuran and dichloromethane, and the dosage is 1 mol of M11a: 100-500 mL;

In step (5): Treat the M12a and chlorinated reagent obtained in step (4) in chloroform, and then add a base to obtain the target product (S)-5-allyl-2-oxabicyclo[3.3.0]octane -8-ene (P1a);

The chlorinated reagent is one or more of oxalyl chloride, acetyl chloride, acetyl chloride, thionyl chloride and phosphorus oxychloride, and the dosage is 1 to 3 equivalents of M12a;

The alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine and diisopropylamine, and the dosage is 1 mol of M11a: 100-500 mL;

Compared with the existing technology, the beneficial effects of the present invention are reflected in:

(1) Use α-phenylethylamine to split M10 carboxylic acid. The splitting effect is good, reducing the production of by-products, saving energy and reducing emissions;

(2) Using Michaelis acid to extend the carbon chain is easier to operate than the Grignard reaction, with higher yield and lower cost;

Description of the drawings

The drawings are used to provide a further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention. In the attached picture:

Figure 1 is a chemical equation available for the synthetic route adopted in the present invention;

Detailed ways

In order to make the above-mentioned objects, features and advantages of the present invention more obvious and understandable, the specific implementation modes of the present invention will be described in detail below in conjunction with the examples in the description.

Many specific details are set forth in the following description to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described here. Those skilled in the art can do so without departing from the connotation of the present invention. Similar generalizations are made, and therefore the present invention is not limited to the specific embodiments disclosed below.

Second, reference herein to "one embodiment" or "an embodiment" refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. "In one embodiment" appearing in different places in this specification does not all refer to the same embodiment, nor is it a separate or selective embodiment that is mutually exclusive with other embodiments.

Example 1: Preparation of M9

In a 1000mL four-neck reaction flask, add 2-oxocyclopentadicarbonylmethyl ester (M8, 31g, 0.218mol) and 2-iodo-1-ethanol acetate (M2, 51.4g, 0.240mol) in anhydrous acetone (500mL), add potassium carbonate (45g, 0.327mol) to the mixture, stir at 60°C for 24h, cool to room temperature, filter, evaporate acetone under reduced pressure, add methanol (300mL), stir to dissolve, then add p-toluenesulfonic acid (0.17g, 0.001mol), stirred at 70°C for 4h, concentrated, washed and dried to obtain 37.9g of colorless oil, yield 87.2%;

Example 2: Preparation of M10a

In a 1000 mL four-neck reaction bottle, add 20 grams of M9 prepared in Example 1 and 200 grams of 10% sodium hydroxide aqueous solution, stir at 30-40°C for 6 hours, lower to room temperature, adjust the pH to 2-3, filter and dry , then dissolve it in 200 grams of acetone, stir to dissolve, add 13 grams of α-phenylethylamine, raise the temperature to 50-60°C, add dropwise about 15-20 grams of water-soluble clear, slowly cool down to precipitate crystals, filter, and acidify After treatment, 8.0 g of white solid M10a was obtained, with a yield of 43.1%;

Example 3: Preparation of M11a

In a 1000 mL four-neck reaction bottle, add 18.6 g of M11a prepared in Example 2, 200 mL of acetonitrile, 17.3 g of Melmenic acid, 1.0 g of dipyridine and 30.9 g of diisopropylamine, control the temperature at 0 to 10°C, and add dropwise 15.1 Gram of tivaloyl chloride, after dripping, control the temperature at 50-55°C, keep the temperature for 3 hours, then acidify, cool and crystallize to obtain 19.1 grams of M11a, with a yield of 83.8%;

Example 4: Preparation of M12a

In a 1000 mL four-neck reaction bottle, add 22.8 grams of M12a prepared in Example 3 and 200 mL of tetrahydrofuran. Control the temperature at 0 to 10°C. Add lithium aluminum tetrahydrhydride in batches. After the addition is completed, raise the temperature to 20 to 30°C and keep it warm for 3 hours. Then slowly add a small amount of water and a small amount of sodium hydroxide solution, add a small amount of anhydrous sulfuric acid solid, filter, and concentrate under reduced pressure to obtain 15.9 grams of M12a, with a yield of 79.5%;

Example 5: Preparation of P1a

In a 1000 mL four-neck reaction bottle, add 20.0 g of M12a prepared in Example 4, 300 mL of chloroform, and 92.4 g of acetyl chloride. Control the temperature at 10 to 30°C, stir for 20 hours, remove volatile matter under reduced pressure, and add 119.2 g of triethylamine. , 0.5 g butanol, 170 g methylene chloride, reflux for 2 h, cool down and filter, and concentrate the solvent under reduced pressure to obtain 13.7 g (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene (P1a), yield 91.3%;

Gas phase detection showed that the content of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene was over 99.5%, and the retention time was consistent with the standard.

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the foregoing embodiments. Modify the recorded technical solutions, or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A process for the preparation of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene comprising the steps of:

in step (1): adding potassium carbonate into the anhydrous acetone solution of M8 and M2, filtering, concentrating, adding methanol and p-TsOH, and cyclizing to obtain M9;

in the step (2): carrying out alkaline hydrolysis on M9 obtained in the step (1), and carrying out resolution on the M9 in a solvent by using alpha-phenethylamine to obtain M10a;

in the step (3): condensing the M10a obtained in the step (2) with Mi's acid under the action of a condensing agent and a catalyst to obtain M11a;

in the step (4): adding the M11a obtained in the step (3) into a solvent, and then adding a reducing agent for reduction to obtain M12a;

in the step (5): treating M12a and a chloro reagent obtained in the step (4) in chloroform, and then adding alkali to obtain a target product P1a;

the synthetic route of the (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene can be represented by the chemical formula:

2. the process for the preparation of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, characterized in that the alkylation reaction temperature of step (1) is 30-70 ℃ and the reaction time is 10-30 h; the cyclization reaction temperature is 30-70 ℃ and the reaction time is 2-6 h.

3. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein the base in the step (2) is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, and the amount is 1 to 3 equivalents of M9.

4. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein the solvent in the step (2) is one or more of acetone, ethanol, toluene, ethyl acetate and water, and the dosage is 1 mol:100-500 mL of M10.

5. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (3), the condensing agent is one or more of N' N-carbonyldiimidazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, oxalyl chloride and pivaloyl chloride in an amount of 1 to 3 equivalents of M10 a.

6. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (3), the catalyst is one or more of triethylamine, diethylamine, diisopropylamine, pyridine and lutidine, and the amount of the catalyst is 1 to 3 equivalents of M10 a.

7. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (4), the reducing agent is one or more of potassium borohydride, lithium aluminum hydride, zinc amalgam and hydrazine hydrate, and the dosage is 1-3 equivalents of M11 a.

8. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (4), the solvent is one or more of water, methanol, ethanol, tetrahydrofuran and dichloromethane, and the dosage is 1 mol:100-500 mL of M11 a.

9. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in step (5), the chlorinating agent is one or more of oxalyl chloride, special acyl chloride, acetyl chloride, sulfoxide chloride and phosphorus oxychloride, and the amount is 1 to 3 equivalents of M12 a.

10. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (5), the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine and diisopropylamine, and the dosage is 1mol of M11a to 100-500 mL.