CN115819171A - Chiral resolution method of key intermediate in MOR receptor agonist synthetic route - Google Patents
Chiral resolution method of key intermediate in MOR receptor agonist synthetic route Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 33
- 108020001612 μ-opioid receptors Proteins 0.000 title abstract description 7
- 239000000018 receptor agonist Substances 0.000 title abstract description 4
- 229940044601 receptor agonist Drugs 0.000 title abstract description 4
- 238000007670 refining Methods 0.000 claims abstract description 16
- -1 6-oxaspiro [4.5] decane ethylamine derivatives Chemical class 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
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- 238000006243 chemical reaction Methods 0.000 claims description 16
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- 239000012043 crude product Substances 0.000 claims description 3
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- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a chiral resolution method of a key intermediate in a MOR receptor agonist synthetic route. In particular to a chiral resolution method of racemic 6-oxaspiro [4.5] decane ethylamine derivatives, which mainly comprises three steps of resolution, refining and dissociation, and the 6-oxaspiro [4.5] decane ethylamine derivatives with high optical purity can be prepared by the method. The method solves the problems of high equipment requirement, high cost, low preparation efficiency and difficulty in realizing industrial amplification in the prior art, and solves the problem of industrial amplification of the key intermediate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a chiral resolution method of a key intermediate in a MOR receptor agonist synthetic route.
Background
The enantiomers of compounds containing chiral centers usually have very similar physicochemical properties, but the pharmacological and toxicological effects are very different, often one stereoisomer has drug effect while its mirror image molecule is very small, even no drug effect or side effect. The U.S. food and drug administration, as early as 1992, stipulated that chiral resolution must be given whenever a drug with an asymmetric center was developed.
Until now, opioid drugs (opioid drugs) represented by morphine are still effective drugs mainly for treating severe pain, and such drugs have good analgesic activity, but have greatly limited clinical application due to serious adverse reactions of the central nervous system, especially side effects such as respiratory depression, constipation, tolerance, addiction and the like. Opioid Receptors (ORs) exist in three molecularly and pharmacologically distinct classes: delta, kappa and mu, opioids are primarily conducted through opioid mu receptors.
The key intermediate in the MOR receptor stimulant synthetic route, namely 6-oxaspiro [4.5] decane ethylamine derivatives, is a mu receptor bias stimulant with better drug effect, longer analgesic duration and lower side effect. The synthesis of the compounds with similar structures reported at present mainly adopts a chiral supercritical fluid preparation separation method (SFC) to carry out chiral resolution, and the method has the advantages of high equipment requirement, high cost, low preparation efficiency and difficulty in realizing industrial amplification, thereby greatly limiting the industrial amplification and related research and application of the compounds.
Disclosure of Invention
In order to overcome the technical defects, the invention aims to provide a chiral resolution method of a racemic 6-oxaspiro [4.5] decane ethylamine derivative, which solves the problems of high equipment requirement, high cost, low preparation efficiency and difficulty in realizing industrial amplification in the prior art, and realizes industrial amplification of the key intermediate.
The invention provides a chiral resolution method of a racemic 6-oxaspiro [4.5] decane ethylamine derivative, which comprises the following specific resolution route:
wherein R is hydrogen or halogen, preferably fluorine;
the first step is as follows: reacting a compound of formula (1) in an organic solvent 1 with a resolving agent selected from D-tartaric acid, D-camphorsulfonic acid, D- (+) dibenzoyltartaric acid or D-di-p-methoxybenzyltartaric acid, preferably D- (+) dibenzoyltartaric acid or D-di-p-methoxybenzyltartaric acid, to form a salt;
the second step is that: and (3) reacting the salt obtained in the first step with a base in an organic solvent 2 to obtain the compound shown in the formula (2).
In certain specific embodiments, the resolution reaction may further comprise a refining operation comprising the steps of: and (3) dissolving the salt obtained in the first step reaction by using an organic solvent 1, heating, stirring, reacting, cooling, crystallizing and centrifuging to obtain a refined salt product.
In some specific embodiments, the chiral resolution method of the 6-oxaspiro [4.5] decane ethylamine derivative provided by the invention specifically comprises the following steps:
wherein R is hydrogen or halogen, preferably fluorine;
1) The first step is as follows: dissolving the compound shown in the formula (1) by using an organic solvent 1, adding a resolving reagent D- (+) dibenzoyl tartaric acid, stirring for reaction, and centrifuging to obtain a crude product of the D- (+) dibenzoyl tartrate of the compound shown in the formula (1).
2) The second step is that: and (3) refining the crude D- (+) dibenzoyl tartrate obtained in the first step, wherein the refining operation comprises the following steps: adding an organic solvent 1 into 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 product.
3) The third step: adding water, an organic solvent 2 and alkali into the refined D- (+) dibenzoyl tartrate obtained in the second step, stirring for dissociating, extracting and concentrating to obtain the compound shown in the formula (2).
In certain specific embodiments, the molar ratio of the compound of formula (1) to resolving agent is 1; more preferably 1; still more preferably 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 comprises 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, and the like, preferably potassium hydroxide or sodium hydroxide.
In certain embodiments, the reaction temperature in the first reaction stage is from-10 to 35 deg.C, preferably from 0 to 20 deg.C.
In certain specific embodiments, the refining operation is carried out at a reaction temperature of 45 to 75 ℃, preferably 55 to 65 ℃; the crystallization temperature is 0 to 35 ℃, preferably 10 to 20 ℃.
In certain embodiments, after the refining operation is completed, the refining operation may be repeated until the ee value is satisfactory, depending on the ee value of the product, if the ee value is less than 95%.
In some specific embodiments, the chiral resolution method of the 6-oxaspiro [4.5] decane ethylamine derivative provided by the invention specifically comprises the following steps:
the first step is as follows: dissolving the compound shown in the formula (1-1) by using a methanol/ethyl acetate mixed solution, adding D- (+) dibenzoyl tartaric acid, stirring for 12 hours at the temperature of 0-20 ℃, centrifuging, and drying to obtain a crude product of the D- (+) dibenzoyl tartrate of the compound shown in the formula (1-1), wherein the molar ratio of the compound shown in the formula (1-1) to the D- (+) dibenzoyl tartaric acid is 1:1;
the second step is that: and (3) refining the crude D- (+) dibenzoyl tartrate obtained in the first step, wherein the refining operation comprises the following steps: adding a methanol/ethyl acetate mixed solution into the crude D- (+) dibenzoyl tartrate obtained in the first step, heating to 55-65 ℃, stirring for 0.5-1.0 h, cooling to 10-20 ℃, crystallizing, centrifuging, and drying to obtain a refined D- (+) dibenzoyl tartrate product;
the third step: adding water, dichloromethane and sodium hydroxide into the refined D- (+) dibenzoyl tartrate obtained in the second step, stirring, extracting and concentrating to obtain the compound shown in the formula (2-1).
In the resolution reaction, if the target product is R configuration, the resolution reagent is D- (+) dibenzoyl tartaric acid, and if the target product is S configuration, L- (-) dibenzoyl tartaric acid can also be used as the resolution reagent.
The invention has the following beneficial effects:
the method takes D- (+) dibenzoyl tartaric acid as a resolving reagent, and the target product with the R configuration can be obtained through resolving, refining and dissociating 3 steps, so that the method has the advantages of low equipment requirement, simple and easily-purchased resolving reagent, low cost, mild reaction condition in each step and simple operation, and the ee value of the product obtained by the preparation method is more than 99%, and the method is favorable for realizing industrial production.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
The structure of the compound is determined by Mass Spectrometry (MS) or nuclear magnetic resonance (M) 1 HNMR).
Nuclear magnetic resonance ( 1 HNMR) was determined using a Bruker AVANCE-400 NMR spectrometer with deuterated Dimethylsulfoxide (DMSO) as the solvent, tetramethylsilane (TMS) as the internal standard and chemical shifts of 10 -6 (ppm) is given as a unit.
In the terms of the present invention, "halogen" means fluorine, chlorine, bromine or iodine.
The chemical reagents used in the present disclosure may be commercially available.
The isomer content in the present disclosure can be obtained by HPLC method, the detection method:
chromatographic conditions are as follows:
a chromatographic column: CHIRALCH OJ-H,250mmLCH OJ-H.
Detection wavelength: 266nm
Column temperature: 30:
flow rate: 1.0mL/min
Mobile phase: n-hexane/ethanol/acetonitrile/diethylamine (920.
Example 1: preparation method of (R) -2- (9- (4-fluorophenyl) -6-oxospiro [4.5] heptane-9-) ethyl-1-amine
1) Splitting
6.12kg of methanol, 24.47kg of ethyl acetate and 3.95kg of D- (+) -dibenzoyltartaric acid were added to a reaction vessel containing 3.06kg of 2- (9- (4-fluorophenyl) -6-oxospiro [4.5] heptane-9-) ethyl-1-amine, stirred at 0-20 ℃ for 12 hours, centrifuged and dried to give 2.28kg of a white solid having an ee value of 79.82%.
2) Refining
Refining (1):
adding 4.20kg of methanol and 23.10kg of ethyl acetate into a reaction kettle, starting stirring, adding 2.10kg of the solid, heating to 60 +/-5 ℃, stirring for 0.5-1.0 h, cooling to 15 +/-5 ℃, centrifuging, and drying to obtain 1.19kg of white solid.
Purification (2):
adding 3.30kg of methanol and 8.80kg of ethyl acetate into a reaction kettle, starting stirring, adding 1.10kg of the solid, heating to 60 +/-5 ℃, stirring for 0.5-1.0 h, cooling to 15 +/-5 ℃, centrifuging, and drying to obtain 681g of white solid.
3) Dissociating:
1.80kg of methylene chloride was added to the reaction flask, and stirring was turned on, and 600g of the above solid and an aqueous solution of sodium hydroxide were added, followed by stirring, standing and liquid separation. The aqueous phase was extracted with 1.20kg of dichloromethane, the two organic phases were combined, washed once with 1.20kg of water and the organic phase was concentrated to dryness at 45. + -. 5 ℃ under reduced pressure to give 308g of an oil. Yield: 10% and 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 resolving reagent species screening assay
The inventor of the present application screens the types of the resolution reagents used in step 1) in the process of obtaining the technical scheme, and performs data statistics on ee values (%) of the resolution products obtained under different resolution reagent conditions, and the results are shown in table 1 below.
TABLE 1 Experimental results for different kinds of resolving agents
* Remarking: the concrete procedures in the examples are the same as those in step 1) in example 1 except that the kind of the resolving agent is changed, and the ee value (%) in the table is calculated based on the product obtained in step 1.
And (4) conclusion: from the above experimental results, it can be seen that high purity (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4.5] heptane-9-) ethyl-1-amine is not easily obtained, and of the resolving agents of the same type, the ee value (%) of the resolved product obtained by only D- (+) dibenzoyl tartaric acid and D-di-p-methoxybenzoyl tartaric acid is relatively good (more than 15%), wherein the best effect is achieved by using D- (+) dibenzoyl tartaric acid as the resolving agent.
Example 7 to example 15: example 1 first step resolution solvent screening assay
The inventor of the present application has conducted extensive screening on the types and combinations of the solvents used in step 1) in the process of obtaining the technical solution, and has conducted data statistics on ee values (%) obtained under different solvent conditions, and the results are shown in table 2 below.
TABLE 2 Experimental results for different kinds of solvents
* Remarking: the concrete procedures of the examples in the table were the same as those of step 1) in example 1 except that the kind of the solvent was changed, and the ee value (%) in the table was calculated based on the product obtained in step 1.
And (4) conclusion: from the above experimental results, it can be seen that (R) -2- (9- (4-fluorophenyl) -6-oxospiro [4.5] heptane-9-) ethyl-1-amine of high purity is required to have high selectivity to the solvent, and of the organic solvents to be screened, only ethanol, isopropanol, the mixed solution of methanol/ethyl acetate and the mixed solution of methanol/acetonitrile are used to obtain a relatively good ee value (%) of the resolved product (more than 35%), and among them, the mixed solution of methanol/ethyl acetate is used as the solvent with the best effect.
Example 16 to example 19: EXAMPLE 1 first step resolution reagent dosage screening assay
In the process of obtaining the technical scheme, the inventor screens the dosage of the resolution reagent used in the step 1), and simultaneously performs data statistics on ee values (%) of the resolution products obtained under different dosages of the resolution reagent, and the results are shown in the following table 3.
TABLE 2 Experimental results for different amounts of resolving agent
* Remarking: the procedure was as in step 1 of example 1 except that the amount of D- (+) dibenzoyltartaric acid was changed, and the ee value (%) was calculated based on the product obtained in step 1.
And (4) 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 1 to 1.2, the ee value (%) of the obtained resolved product is high, and the effect is best when the molar ratio is 1.
The above-mentioned embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements of the technical solution of the present invention by those skilled in the art should fall within the protection scope defined by the claims of the present invention without departing from the spirit of the present invention.
Claims (10)
1. A chiral resolution method of racemic 6-oxaspiro [4.5] decane ethylamine derivatives is characterized by comprising the following steps:
wherein R is hydrogen or halogen, preferably fluorine;
the first step is as follows: reacting a compound of formula (1) in an organic solvent 1 with a resolving agent selected from D-tartaric acid, D-camphorsulfonic acid, D- (+) dibenzoyltartaric acid or D-di-p-methoxybenzyltartaric acid, preferably D- (+) dibenzoyltartaric acid or D-di-p-methoxybenzyltartaric acid, to form a salt;
the second step: and (3) reacting the salt obtained in the first step with a base in an organic solvent 2 to obtain the compound shown in the formula (2).
2. The resolution process of claim 1, wherein the resolution process can include a refining operation that: dissolving the salt obtained in the first step with an organic solvent 1, heating and stirring for reaction, and then cooling, crystallizing and centrifuging to obtain a refined salt product.
3. The resolution process according to claim 1, wherein the molar ratio of the compound of formula (1) to the resolving agent in the first reaction stage is from 1; more preferably 1.
4. The resolution process according to any one of claims 1 to 2, wherein the organic solvent 1 is selected from methanol, ethyl acetate, ethanol, isopropanol, acetonitrile or a mixture thereof.
5. The resolution process according to claim 4, wherein the organic solvent 1 is selected from ethyl acetate, ethanol, isopropanol, methanol/ethyl acetate mixed solution or methanol/acetonitrile mixed solution.
6. The resolution process according to claim 1, wherein the organic solvent 2 is selected from ethyl acetate, isopropyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, methyltetrahydrofuran or 1, 4-dioxane, preferably dichloromethane.
7. The resolution process according to claim 1, wherein the base is selected from potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide or sodium hydroxide, preferably potassium hydroxide or sodium hydroxide.
8. The resolution process according to claim 1, wherein the reaction temperature in the first step is-10 to 35 ℃, preferably 0 to 20 ℃.
9. The resolution process according to claim 2, characterized in that the reaction temperature of the refining operation is 45 to 75 ℃, preferably 55 to 65 ℃; the crystallization temperature is 0 to 35 ℃, preferably 10 to 20 ℃.
10. The splitting method according to claim 1, comprising the steps of:
the first step is as follows: dissolving the compound shown in the formula (1-1) by using a methanol/ethyl acetate mixed solution, adding D- (+) dibenzoyl tartaric acid, stirring for 12 hours at the temperature of 0-20 ℃, centrifuging, and drying to obtain a crude product of the D- (+) dibenzoyl tartrate of the compound shown in the formula (1-1), wherein the molar ratio of the compound shown in the formula (1-1) to the D- (+) dibenzoyl tartaric acid is 1:1;
the second step is that: and (3) refining the crude D- (+) dibenzoyl tartrate obtained in the first step, wherein the refining operation comprises the following steps: adding a methanol/ethyl acetate mixed solution into the crude D- (+) dibenzoyl tartrate obtained in the first step, heating to 55-65 ℃, stirring for 0.5-1.0 h, then cooling to 10-20 ℃, crystallizing, centrifuging and drying to obtain a refined D- (+) dibenzoyl tartrate product;
the third step: adding water, dichloromethane and sodium hydroxide into the refined D- (+) dibenzoyl tartrate obtained in the second step, stirring, extracting and concentrating to obtain the compound shown in the formula (2-1).
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