CN115819171B - A chiral resolution method for key intermediates in the synthesis route of MOR receptor agonists - Google Patents

Abstract

The present invention provides a chiral separation method of a key intermediate in a synthetic route of a MOR receptor agonist. Specifically, it relates to a chiral separation method of a racemic 6-oxaspiro[4.5]decaneethylamine derivative, which mainly includes three steps of separation, purification, and freeing. By this method, a 6-oxaspiro[4.5]decaneethylamine derivative with high optical purity can be prepared. The method solves the problems of high equipment requirements, high cost, low preparation efficiency, and difficulty in industrial scale-up in the prior art, and solves the problem of industrial scale-up of the key intermediate.

Description

A chiral resolution method for key intermediates in the synthesis route of MOR receptor agonists

Technical Field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a chiral resolution method for a key intermediate in a synthesis route of a MOR receptor agonist.

Background technique

Compounds with chiral centers usually have very similar physical and chemical properties, but their pharmacological and toxicological effects are very different. Often one stereoisomer is effective while its mirror image is very small, or even completely ineffective or has side effects. As early as 1992, the U.S. Food and Drug Administration stipulated that any drug with an asymmetric center must provide chiral resolution results.

So far, opioid drugs represented by morphine are still the main effective drugs for treating severe pain. These drugs have good analgesic activity, but their clinical application is greatly limited due to serious adverse reactions in the central nervous system, especially respiratory depression, constipation, tolerance and addiction. There are three molecularly and pharmacologically different types of opioid receptors (OR): δ, κ and μ. Opioid drugs are mainly transmitted through opioid μ receptors.

The invention relates to a key intermediate in a synthetic route of a MOR receptor agonist, namely: 6-oxaspiro[4.5]decaneethylamine derivatives, which are a class of μ receptor biased agonists with better efficacy, longer analgesic duration and lower side effects. The synthesis of compounds with similar structures reported currently mainly adopts a chiral supercritical fluid preparation and separation method (SFC) for chiral separation, which has high equipment requirements, high cost, low preparation efficiency, and is difficult to achieve industrial scale-up, which greatly limits the industrial scale-up and related research and application of this type of compound.

Summary of the invention

In order to overcome the above technical defects, the purpose of the present invention is to provide a method for the chiral separation of racemic 6-oxaspiro[4.5]decaneethylamine derivatives, which solves the problems of high equipment requirements, high cost, low preparation efficiency and difficulty in industrial scale-up in the prior art, and realizes the industrial scale-up of the key intermediate.

The present invention provides a method for chiral separation of racemic 6-oxaspiro[4.5]decaneethylamine derivatives, and the specific separation route is as follows:

Wherein, R is hydrogen or halogen, and the halogen is preferably fluorine;

The first step: the compound of formula (1) reacts with a resolution agent in an organic solvent 1 to form a salt, wherein the resolution agent is selected from D-tartaric acid, D-camphorsulfonic acid, D-(+) dibenzoyltartaric acid or D-di-p-methoxybenzoyltartaric acid, preferably D-(+) dibenzoyltartaric acid or D-di-p-methoxybenzoyltartaric acid;

Step 2: react the salt obtained in the first step with a base in an organic solvent 2 to obtain a compound of formula (2).

In certain specific embodiments, the resolution reaction may further include a refining operation, wherein the refining operation steps are: dissolving the salt obtained in the first step reaction with an organic solvent 1, heating and stirring the reaction, then cooling and crystallizing, and centrifuging to obtain a refined salt product.

In certain specific embodiments, the chiral separation method of 6-oxaspiro[4.5]decaneethylamine derivatives provided by the present invention specifically comprises the following steps:

Wherein, R is hydrogen or halogen, and the halogen is preferably fluorine;

1) The first step: dissolving the compound of formula (1) in an organic solvent 1, adding a resolution agent D-(+) dibenzoyl tartaric acid, stirring the reaction, and centrifuging to obtain a crude product of D-(+) dibenzoyl tartaric acid salt of the compound of formula (1).

2) The second step: the crude D-(+) dibenzoyl tartrate obtained in the first step is subjected to a refining operation, wherein the refining operation comprises adding organic solvent 1 to the crude D-(+) dibenzoyl tartrate obtained in the first step, heating and stirring, then cooling and crystallizing, and centrifuging to obtain a refined D-(+) dibenzoyl tartrate.

3) Step 3: Add water, organic solvent 2 and alkali to the refined D-(+) dibenzoyl tartrate obtained in the second step, stir to separate, extract and concentrate to obtain the compound of formula (2).

In certain specific embodiments, the molar ratio of the compound of formula (1) to the resolving agent is 1:0.5 to 1:2.0, preferably 1:0.5 to 1:1.5; more preferably 1:1 to 1:1.2; and even more preferably 1:1.

In certain specific embodiments, the organic solvent 1 is selected from methanol, ethyl acetate, ethanol, isopropanol, acetonitrile or a mixed solvent of the above solvents, preferably ethyl acetate, ethanol, isopropanol, a methanol/ethyl acetate mixed solution or a methanol/acetonitrile mixed solution, more preferably ethanol, isopropanol, a methanol/ethyl acetate mixed solution or a methanol/acetonitrile mixed solution, and most preferably a methanol/ethyl acetate mixed solution.

In certain specific embodiments, the organic solvent 2 is selected from ethyl acetate, isopropyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, methyltetrahydrofuran or 1,4-dioxane, preferably dichloromethane.

In certain specific embodiments, the base includes various inorganic or organic bases, including but not limited to potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide or sodium hydroxide, etc., preferably potassium hydroxide or sodium hydroxide.

In certain specific embodiments, the reaction temperature in the first step reaction is -10 to 35°C, preferably 0 to 20°C.

In certain specific embodiments, the reaction temperature of the refining operation is 45-75°C, preferably 55-65°C; the crystallization temperature is 0-35°C, preferably 10-20°C.

In certain specific embodiments, after the refining operation is completed, based on the ee. value of the product, if the ee. value is lower than 95%, the refining operation may be repeated until the ee. value meets the requirements.

In certain specific embodiments, the chiral separation method of 6-oxaspiro[4.5]decaneethylamine derivatives provided by the present invention specifically comprises the following steps:

The first step: dissolving the compound of formula (1-1) in a methanol/ethyl acetate mixed solution, adding D-(+) dibenzoyl tartaric acid, stirring at 0-20°C for 12 hours, centrifuging, and drying to obtain a crude D-(+) dibenzoyl tartaric acid salt of the compound of formula (1-1), wherein the molar ratio of the compound of formula (1-1) to D-(+) dibenzoyl tartaric acid is 1:1;

The second step: the crude D-(+) dibenzoyl tartrate obtained in the first step is subjected to a refining operation, wherein the refining operation is as follows: a methanol/ethyl acetate mixed solution is added to the crude D-(+) dibenzoyl tartrate obtained in the first step, the mixture is heated to 55-65° C. and stirred for 0.5-1.0 h, then the mixture is cooled to 10-20° C. and crystallized, centrifuged, and dried to obtain a refined D-(+) dibenzoyl tartrate;

Step 3: Add water, dichloromethane and sodium hydroxide to the refined D-(+) dibenzoyl tartrate obtained in the second step, stir, extract and concentrate to obtain a compound of formula (2-1).

In the resolution reaction of the present invention, if the target product is in R configuration, the resolution reagent is D-(+) dibenzoyltartaric acid, and if the target product is in S configuration, L-(-) dibenzoyltartaric acid can also be used as the resolution reagent.

Beneficial effects achieved by the present invention:

The method of the invention uses D-(+) dibenzoyltartaric acid as a resolution reagent, and can obtain the target product of R configuration through three steps of resolution, purification and freeing. The method has low equipment requirements, simple and easy-to-purchase resolution reagents, low cost, mild reaction conditions in each step, and simple operation. The ee value of the product obtained by the preparation method of the invention is greater than 99%, which is conducive to realizing industrial production.

Detailed ways

The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

The structures of the compounds were determined by mass spectrometry (MS) or nuclear magnetic resonance ( ¹ HNMR).

Nuclear magnetic resonance ( ¹ HNMR) measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The measurement solvent was deuterated dimethyl sulfoxide (DMSO), the internal standard was tetramethylsilane (TMS), and the chemical shift was given in units of 10 ^-6 (ppm).

The term "halogen" in the present invention means fluorine, chlorine, bromine or iodine.

The chemical reagents used in the present disclosure can be obtained from commercial sources.

The isomer content in the present disclosure can be obtained by HPLC detection method, the detection method is:

Chromatographic conditions:

Chromatographic column: CHIRALCH OJ-H, 250mmL CH OJ-H.

Detection wavelength: 266nm

Column temperature: 30:

Flow rate: 1.0mL/min

Mobile phase: n-hexane/ethanol/acetonitrile/diethylamine (920:80:10:1).

Example 1: Preparation of (R)-2-(9-(4-fluorophenyl)-6-oxospiro[4.5]heptane-9-)ethyl-1-amine

1) Split

To a reaction kettle containing 3.06 kg of 2-(9-(4-fluorophenyl)-6-oxospiro[4.5]heptane-9-)ethyl-1-amine, 6.12 kg of methanol, 24.47 kg of ethyl acetate and 3.95 kg of D-(+)dibenzoyltartaric acid were added, and the mixture was stirred at 0-20°C for 12 h, centrifuged and dried to obtain 2.28 kg of a white solid with an ee value of 79.82%.

2) Refining

Refining①：

Add 4.20 kg of methanol and 23.10 kg of ethyl acetate to the reactor, start stirring, add 2.10 kg of the above solid, heat to 60±5°C and stir for 0.5-1.0 h, cool to 15±5°C, centrifuge, and dry to obtain 1.19 kg of white solid.

Refining ②:

Add 3.30 kg of methanol and 8.80 kg of ethyl acetate to the reactor, start stirring, add 1.10 kg of the above solid, heat to 60±5°C and stir for 0.5-1.0 h, cool to 15±5°C, centrifuge, and dry to obtain 681 g of white solid.

3) Free:

Add 1.80 kg of dichloromethane to the reaction flask, start stirring, add 600 g of the above solid and sodium hydroxide aqueous solution, stir, stand, and separate. The aqueous phase is extracted with 1.20 kg of dichloromethane, the organic phases are combined twice, washed once with 1.20 kg of water, and the organic phase is concentrated under reduced pressure at 45±5°C to dryness to obtain 308 g of oil. Yield: 10%, ee value 99.34%.

¹ H-NMR (400MHz, d-DMSO) δppm: 8.00-7.98 (4H, d), 7.68-7.64 (2H, t), 7.55-7.51 (4H, t) 7.3.1-7.28 (2H, m), 7.13-7.09(2H,t), 5.67(2H,s), 3.60-3.46(2H,m), 2.47-2.43(1H,m), 2.08-1.95(3H,m), 1.82-1.66(3H,m ), 1.55-1.34(6H,m), 1.13-1.07(1H,m), 0.80-0.72(1H,m).

LC-MS (ES-API, Pos): m/z: 278.4 (free base +1) ⁺ .

Example 2 to Example 6: Example 1: First step of screening test of the type of splitting reagent

In the process of obtaining the technical solution, the inventors of the present application screened the types of resolution reagents used in step 1), and also conducted statistical analysis on the ee values (%) of the resolution products obtained under different resolution reagent conditions. The results are shown in Table 1 below.

Table 1 Experimental results of different types of resolution reagents

* Note: Except for the change of the type of resolution reagent, the specific operation steps of each example in the table are the same as step 1) in Example 1. The ee value (%) in the table is calculated based on the product obtained in step 1.

Conclusion: From the above experimental results, it can be seen that high-purity (R)-2-(9-(4-fluorophenyl)-6-oxospiro[4.5]heptane-9-)ethyl-1-amine is not easy to obtain. Among the same type of resolution reagents, only D-(+) dibenzoyltartaric acid and D-di-p-methoxybenzoyltartaric acid have relatively good ee values (%) of the resolution products (greater than 15%). Among them, D-(+) dibenzoyltartaric acid has the best effect as the resolution reagent.

Example 7 to Example 15: Example 1 First Step Solvent Screening Test

In the process of obtaining the technical solution, the inventors of the present application conducted a large number of screenings on the types and combinations of solvents used in step 1), and also conducted statistical data on the ee values (%) obtained under different solvent conditions. The results are shown in Table 2 below.

Table 2 Experimental results of different types of solvents

* Note: Except for the change of solvent type, the specific operation steps of each example in the table are the same as step 1) in Example 1. The ee value (%) in the table is calculated based on the product obtained in step 1.

Conclusion: From the above experimental results, it can be seen that high-purity (R)-2-(9-(4-fluorophenyl)-6-oxospiro[4.5]heptane-9-)ethyl-1-amine has very high requirements for solvent selectivity. Among the screened organic solvents, only ethanol, isopropanol, methanol/ethyl acetate mixed solution and methanol/acetonitrile mixed solution have relatively good ee values (%) of the resolved products (greater than 35%). Among them, the methanol/ethyl acetate mixed solution has the best effect as the solvent.

Example 16 to Example 19: Example 1 First Step Screening Test of Reagent Dosage

In the process of obtaining the technical solution, the inventors of the present application screened the amount of the resolution reagent used in step 1), and statistically analyzed the ee values (%) of the resolution products obtained at different amounts of the resolution reagent. The results are shown in Table 3 below.

Table 2 Experimental results of different amounts of splitting reagents

* Note: Except for the change in the amount of D-(+) dibenzoyltartaric acid, the specific operating steps of each embodiment in the table are the same as step 1) in Example 1, and the ee value (%) in the table is calculated based on the product obtained in step 1.

Conclusion: From the above experimental results, it can be seen that when the molar ratio of 2-(9-(4-fluorophenyl)-6-oxospiro[4.5]heptane-9-)ethyl-1-amine to D-(+)dibenzoyltartaric acid is between 1:1 and 1:1.2, the ee value (%) of the obtained resolution product is higher, and the best effect is achieved when the molar ratio is 1:1.

The embodiments described above are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims (10)

1. A method for chiral resolution of racemic 6-oxaspiro[4.5]decaneethylamine derivatives, characterized in that it comprises the following steps: Wherein, R is hydrogen or halogen; The first step: the compound of formula (1) reacts with a resolution agent in an organic solvent 1 to form a salt; The organic solvent 1 is selected from a methanol/ethyl acetate mixed solution; The resolving agent is selected from D-(+) dibenzoyltartaric acid; The molar ratio of the compound of formula (1) to the resolving agent is 1:1 to 1:1.2; Step 2: reacting the salt obtained in the first step with a base in an organic solvent 2 to obtain a compound of formula (2); The organic solvent 2 is selected from dichloromethane; The base is selected from potassium hydroxide or sodium hydroxide. 2. The separation method according to claim 1, characterized in that the separation method may include a refining operation, which is: dissolving the salt obtained in the first step reaction with an organic solvent 1, heating and stirring the reaction, then cooling and crystallizing, and centrifuging to obtain a refined salt. 3. The separation method according to claim 1 or 2, wherein the halogen is fluorine. 4. The separation method according to claim 1 or 2, characterized in that the reaction temperature in the first step is -10 to 35°C. 5. The separation method according to claim 4, characterized in that the reaction temperature in the first step is 0 to 20°C. 6. The separation method according to claim 2, characterized in that the reaction temperature of the refining operation is 45 to 75°C. 7. The separation method according to claim 6, characterized in that the reaction temperature of the refining operation is 55-65°C. 8. The separation method according to claim 2, characterized in that the crystallization temperature of the refining operation is 0 to 35°C. 9. The separation method according to claim 8, characterized in that the crystallization temperature of the refining operation is 10 to 20°C. 10. The splitting method according to claim 2, characterized in that it comprises the following steps: The first step: dissolving the compound of formula (1-1) in a methanol/ethyl acetate mixed solution, adding D-(+) dibenzoyl tartaric acid, stirring at 0-20°C for 12h, centrifuging, and drying to obtain a crude D-(+) dibenzoyl tartaric acid salt of the compound of formula (1-1), wherein: The molar ratio of the compound of formula (1-1) to D-(+) dibenzoyltartaric acid is 1:1; The second step: the crude D-(+) dibenzoyl tartrate obtained in the first step is subjected to a refining operation, wherein the refining operation is as follows: a methanol/ethyl acetate mixed solution is added to the crude D-(+) dibenzoyl tartrate obtained in the first step, the mixture is heated to 55-65° C. and stirred for 0.5-1.0 h, then the mixture is cooled to 10-20° C. and crystallized, centrifuged, and dried to obtain a refined D-(+) dibenzoyl tartrate; Step 3: Add water, dichloromethane and sodium hydroxide to the refined D-(+) dibenzoyl tartrate obtained in the second step, stir, extract and concentrate to obtain a compound of formula (2-1).