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

Abstract

The present invention discloses a preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene, which comprises the following steps: (1) 2-oxocyclopentanedicarbonyl methyl ester (M8) and 2-iodo-1-ethyl acetate (M2) are alkylated in anhydrous acetone, and then cyclized with p-TsOH to obtain M9; (2) The obtained M9 is hydrolyzed with a base and resolved with α-phenylethylamine in a solvent to obtain M10a; (3) The obtained M10a is condensed with Meldrum's acid to obtain M11a; (4) The obtained M11a is reduced to obtain M12a; (5) The obtained M12a is dehydrated under the action of acetyl chloride and triethylamine to obtain (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene. The reaction route of the present invention is short, the raw materials are easily available, the by-products are less, the reaction conditions are stable, the operation is simple, and it is suitable for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparation methods of chemical drug intermediates, and particularly relates to a preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene. Background Art

[0002] (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene (CAS No.: 1052236-86-8), whose structure is shown in formula (A), is an important chemical intermediate and is often used as a resolving agent for chiral alcohol production. (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene stereospecifically generates an asymmetric acetal B, and the trans bicyclo[3.3.0]octane skeleton C is hardly formed. Therefore, the asymmetric center of bicyclo C1 is well controlled.

[0003]

[0004] The publicly reported preparation methods of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene at home and abroad mainly include the following several:

[0005] (1) The method reported in Tetrahedron Letters (1994) is as follows:

[0006]

[0007] Starting from 2-allyloxycarbonyl cyclopentan-1-one (M1), the vinyl ether P1 is synthesized in 5 steps. M1 and M2 are alkylated in dry acetone to obtain M3 with a yield of 89%. The allyl ketone ester M3 is subjected to the Shimizu-Tsuji reaction to obtain the allyl ketone M4, and then treated with a catalytic amount of p-TsOH in methanol to obtain the cyclic acetal M5 with an overall yield of 74%. M5 is treated with acetyl chloride in chloroform for 20 hours to obtain the chloride M6. At reflux, the racemate of the target product vinyl ether P1 is immediately obtained with triethylamine in dichloromethane, and the overall yield is 95%. The vinyl ether P1 can be decomposed in silica gel but can be purified by alumina gel column chromatography.

[0008] (2) The method reported in EP1535917A1 is as follows:

[0009]

[0010] Using M3 as the raw material, the allyl ketone M4 is obtained through the Shimizu-Tsuji reaction, and then treated with a catalytic amount of p-TsOH in methanol to obtain the cyclic acetal M5. Then, P1 is resolved with L-lactic acid, and finally two enantiomers of P1 are obtained.

[0011] However, the above-mentioned solution has technical problems such as high raw material cost, unstable reaction conditions, great operation difficulty, and being not easy to realize industrial production. Summary of the Invention

[0012] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene, which has cheap and easily available raw materials, stable reaction conditions, simple operation, and is easy to realize industrial production.

[0013] A preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene includes the following steps:

[0014] The synthetic route adopted by the present invention can be represented by the following chemical equation:

[0015]

[0016] The present invention is further arranged as follows:

[0017] In step (1): M8 and M2 are added with potassium carbonate in an anhydrous acetone solution, then filtered, concentrated, and added with methanol and p-TsOH for cyclization to obtain M9;

[0018] Preferably, the alkylation reaction temperature in step (1) is 30-70°C, and the reaction time is 10-30 h. The cyclization reaction temperature is 30-70°C, and the reaction time is 2-6 h.

[0019] In step (2): M9 obtained in step (1) is hydrolyzed with a base and resolved with α-phenylethylamine in a solvent to obtain M10a;

[0020] The base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate, and the dosage is 1-3 equivalents of M9;

[0021] The solvent is one or more of acetone, ethanol, toluene, ethyl acetate, and water, and the dosage is 1 mol:100-500 mL of M10;

[0022] In step (3): M10a obtained in step (2) is condensed with Meldrum's acid under the action of a condensing agent and a catalyst to obtain M11a;

[0023] The condensing agent is one or more of CDI (N,N'-carbonyldiimidazole), EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), oxalyl chloride, and pivaloyl chloride, and the dosage is 1-3 equivalents of M10a;

[0024] The catalyst described above is one or more of triethylamine, diethylamine, diisopropylamine, pyridine, and dimethylpyridine, and the dosage is 1 to 3 equivalents of M10a;

[0025] In step (4): Add the M11a obtained in step (3) to a solvent, and then add a reducing agent to reduce it to obtain M12a;

[0026] The reducing agent described above is one or more of potassium borohydride, potassium borohydride, lithium aluminum hydride, zinc amalgam, and hydrazine hydrate, and the dosage is 1 to 3 equivalents of M11a;

[0027] The solvent described above is one or more of water, methanol, ethanol, tetrahydrofuran, and dichloromethane, and the dosage is 1 mol of M11a: 100 to 500 mL;

[0028] In step (5): Treat the M12a obtained in step (4) and a chlorinating reagent in chloroform, and then add a base to obtain the target product (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene (P1a);

[0029] The chlorinating reagent described above is one or more of oxalyl chloride, special acyl chloride, acetyl chloride, thionyl chloride, and phosphorus oxychloride, and the dosage is 1 to 3 equivalents of M12a;

[0030] The base described above is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, and diisopropylamine, and the dosage is 1 mol of M11a: 100 to 500 mL;

[0031] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0032] (1) Using α-phenylethylamine to resolve M10 carboxylic acid, the resolution effect is good, reducing the generation of by-products, energy conservation and emission reduction;

[0033] (2) Using Meldrum's acid to extend the carbon chain, which is easier to operate than the Grignard reaction, has a higher yield and lower cost; Description of the Drawings

[0034] The drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation to the present invention. In the drawings:

[0035] Figure 1 is the chemical equation of the synthesis route adopted by the present invention; Detailed Embodiments

[0036] To make the above objects, features, and advantages of the present invention more obvious and understandable, the following detailed description of the specific embodiments of the present invention is provided in conjunction with the embodiments of the specification.

[0037] In the following description, many specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention may be practiced in other ways different from those described herein. Persons skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0038] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation manner of the present invention. The appearances of "in one embodiment" in different places in this specification do not all refer to the same embodiment, nor are they separate or alternative embodiments that exclude each other from other embodiments.

[0039] Example 1: Preparation of M9

[0040] In a 1000 mL four-necked reaction flask, potassium carbonate (45 g, 0.327 mol) was added to a mixture of methyl 2-oxocyclopentanedicarboxylate (M8, 31 g, 0.218 mol) and ethyl 2-iodoacetate (M2, 51.4 g, 0.240 mol) in anhydrous acetone (500 mL). The mixture was stirred at 60 °C for 24 h. After cooling to room temperature, the mixture was filtered, and acetone was distilled off under reduced pressure. Methanol (300 mL) was added and stirred until dissolved. Then p-toluenesulfonic acid (0.17 g, 0.001 mol) was added, and the mixture was stirred at 70 °C for 4 h. After concentration, washing, and drying, 37.9 g of a colorless oily substance was obtained with a yield of 87.2%;

[0041] Example 2: Preparation of M10a

[0042] In a 1000 mL four-necked reaction flask, 20 g of M9 prepared in Example 1 and 200 g of 10% aqueous sodium hydroxide solution were added. The mixture was stirred at 30 - 40 °C for 6 h, cooled to room temperature, the pH was adjusted to 2 - 3, filtered, and dried. Then it was dissolved in 200 g of acetone and stirred until clear. 13 g of α-phenylethylamine was added, the temperature was raised to 50 - 60 °C, about 15 - 20 g of aqueous solution was added dropwise until clear, and the temperature was slowly lowered to precipitate crystals. After filtration and acidification treatment, 8.0 g of white solid M10a was obtained with a yield of 43.1%;

[0043] Example 3: Preparation of M11a

[0044] In a 1000 mL four-necked reaction flask, 18.6 g of M11a prepared in Example 2, 200 mL of acetonitrile, 17.3 g of Meldrum's acid, 1.0 g of dimethylpyridine, and 30.9 g of diisopropylamine were added. The temperature was controlled at 0 - 10 °C, and 15.1 g of pivaloyl chloride was added dropwise. After the addition was complete, the temperature was controlled at 50 - 55 °C and kept warm for 3 h. Then it was acidified and cooled to crystallize to obtain 19.1 g of M11a with a yield of 83.8%;

[0045] Example 4: Preparation of M12a

[0046] In a 1000 mL four-necked reaction flask, 22.8 g of M12a prepared in Example 3 and 200 mL of tetrahydrofuran were added. The temperature was controlled at 0 - 10°C, and lithium aluminum hydride was added in batches. After addition, the temperature was raised to 20 - 30°C and kept warm for 3 hours. Then, a small amount of water and a small amount of sodium hydroxide solution were slowly added, a small amount of anhydrous sulfuric acid solid was added, filtered, and concentrated under reduced pressure to obtain 15.9 g of M12a, with a yield of 79.5%;

[0047] Example 5: Preparation of P1a

[0048] In a 1000 mL four-necked reaction flask, 20.0 g of M12a prepared in Example 4, 300 mL of chloroform, and 92.4 g of acetyl chloride were added. The temperature was controlled at 10 - 30°C and stirred for 20 hours. Volatiles were removed under reduced pressure. 119.2 g of triethylamine, 0.5 g of butanol, and 170 g of dichloromethane were added, and refluxed for 2 h. After cooling, filtered, and the solvent was concentrated under reduced pressure to obtain 13.7 g of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene (P1a), with a yield of 91.3%;

[0049] Gas phase detection showed that the content of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene was more than 99.5%, and the retention time was consistent with that of the standard product.

[0050] The above are only the preferred embodiments of the present invention and are not used 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 technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene, characterized in that, It includes the following steps: In step (1): Potassium carbonate is added to M8 and M2 in an anhydrous acetone solution, then filtered, concentrated, and methanol and p-TsOH are added for cyclization to obtain M9; wherein, the alkylation reaction temperature is 30-70 °C, and the reaction time is 10-30 h; the cyclization reaction temperature is 30-70 °C, and the reaction time is 2-6 h; In step (2): M9 obtained in step (1) is subjected to base hydrolysis and resolved with α-phenylethylamine in a solvent to obtain M10a; In step (3): M10a obtained in step (2) is condensed with Meldrum's acid under the action of a condensing agent and a catalyst to obtain M11a; wherein, the condensing agent is one or more of N'N-carbonyldiimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, oxalyl chloride, and pivaloyl chloride, and the dosage is 1-3 equivalents of M10a; the catalyst is one or more of triethylamine, diethylamine, diisopropylamine, pyridine, and dimethylpyridine, and the dosage is 1-3 equivalents of M10a; In step (4): M11a obtained in step (3) is added to a solvent, and then reduced with a reducing agent to obtain M12a; In step (5): M12a obtained in step (4) and a chlorinating reagent are treated in chloroform, and then a base is added to obtain the target product P1a; The synthetic route of the (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene can be represented by a chemical formula as follows:

2. The preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene according to claim 1, characterized in that, The base described in step (2) is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate, and the dosage is 1-3 equivalents of M9.

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

4. The preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene according to claim 1, characterized in that, In step (4), the reducing agent is one or more of potassium borohydride, potassium borohydride, lithium aluminum hydride, zinc amalgam, and hydrazine hydrate, and the dosage is 1-3 equivalents of M11a.

5. The preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene according to claim 1, characterized in that, In step (4), the solvent is one or more of water, methanol, ethanol, tetrahydrofuran, and dichloromethane, and the dosage is 1 mol of M11a:100-500 mL.

6. The preparation method of (S)-5-allyl-2-oxabicyclo[3.3.0]oct-8-ene according to claim 1, characterized in that, In step (5), the chlorinating reagent is one or more of oxalyl chloride, pivaloyl chloride, acetyl chloride, thionyl chloride, and phosphorus oxychloride, and the dosage is 1-3 equivalents of M12a.

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