CN113754715B - Optical selective process synthesis method of (5R) -5-hydroxyl triptolide - Google Patents
Optical selective process synthesis method of (5R) -5-hydroxyl triptolide Download PDFInfo
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- OKRSVUYYCJPECG-LFGMFVMYSA-N 5α-hydroxytriptolide Chemical compound O=C1OCC([C@]2(O)C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 OKRSVUYYCJPECG-LFGMFVMYSA-N 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 10
- SWOVVKGLGOOUKI-ZHGGVEMFSA-N triptonide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)C(=O)[C@]21[C@H]3O1 SWOVVKGLGOOUKI-ZHGGVEMFSA-N 0.000 abstract description 4
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000830536 Tripterygium wilfordii Species 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an optical selectivity process synthesis method of (5R) -5-hydroxy triptolide, and particularly discloses a method for obtaining a pure product of (5R) -5-hydroxy triptolide (a compound shown in a formula I) by taking triptonide (a compound shown in a formula II) as a raw material and oxidizing and reducing the triptonide. The method has the advantages of simple and stable raw material source, simple post-treatment operation and easy industrialization.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to an optical selectivity process synthesis method of (5R) -5-hydroxyl triptolide.
Background
The (5R) -5-hydroxyl triptolide tablet (trade name: retengshu) is a new chemical drug developed by Shanghai pharmaceutical group GmbH, and is a compound obtained by purifying, processing and modifying a chemical structure of triptolide. Non-clinical studies show that the rantengshu has a good immunosuppressive effect, produces a significant curative effect in an arthritis disease animal model, and also has stable pharmacokinetic parameters. The rantengshu is expected to take rheumatoid arthritis as a clinical indication, can exert a better curative effect, accords with the therapeutic drug standard with safety, effectiveness and controllable quality, and provides an effective treatment way for a wide range of patients with rheumatoid arthritis.
At present, the methods for preparing (5R) -5-hydroxytriptolide include the following methods:
method (1): CN1511838A discloses using triptolide as raw material, oxidizing to obtain (5R) -5-hydroxy triptolide, reducing with carbonyl to obtain diastereomer mixture, and separating the diastereomer mixture by column chromatography to obtain (5R) -5-hydroxy triptolide pure product.
This method has the disadvantage that the second step of the synthesis (i.e. example 2) is not chiral selective and the final product is a mixture of chiral isomers, where the ratio of the target chiral to the non-target chiral isomer is approximately 1, which can only be separated by preparative separation to obtain the target chiral structure, resulting in low overall yield of the route (about 30%), and post-treatment operations requiring column chromatography separation, which cannot meet the industrial requirements.
Method (2): WO2005/000291A1 discloses a method for preparing (5R) -5-hydroxy triptolide by one-step oxidation by directly using chirally pure triptolide as a raw material. But the process yield is too low (about 46%).
Method (3): CN110759929 discloses a method for obtaining (5R) -5-hydroxy triptolide by taking chiral pure triptolide as a raw material and carrying out three steps of protection, oxidation and deprotection in order to improve the yield. The method has the advantages of greatly improved yield and industrial amplification possibility of each step operation.
However, the methods (2) and (3) avoid the disadvantages of the chromatographic column separation process in the method (1), but both of them use chirally pure triptolide as the starting material. However, triptolide is essentially a natural extract, very expensive (4000 yuan/g), and unstable in source. The triptolide content in the total root of tripterygium wilfordii is 0.0018%, so that the triptolide can not be continuously obtained in large batch and can not meet the clinical medication requirement in the future. In addition, the triptolide has extremely high toxicity, and the synthetic operation process has extremely high requirements on labor personnel protection and environmental protection. In the synthesis process of the methods (2) and (3), triptolide is used as a starting material, so that the process safety risk is high, the requirements on production workshops and equipment are extremely high, and the production cost is increased.
Disclosure of Invention
The invention aims to provide a synthetic method of (5R) -5-hydroxy triptolide, which has the advantages of simple and stable raw material source, simple post-treatment operation and easy industrialization.
The invention provides a preparation method of a compound shown as a formula I, which comprises the following steps:
(1) In an inert solvent, in the presence of an oxidant, carrying out an oxidation reaction on a compound shown as a formula II to form a compound shown as a formula III;
(2) Carrying out reduction reaction on the compound shown in the formula III in an inert solvent in the presence of a reducing agent to form a compound shown in the formula I; the reducing agent is not sodium borohydride.
In one embodiment, step (1) is: in an inert solvent, in the presence of an oxidant, carrying out an oxidation reaction on a compound shown as a formula II to obtain a crude product containing a compound shown as a formula III.
In one embodiment, in step (1), after the oxidation reaction is completed, the reaction mixture is filtered, the filtrate is concentrated, and then separated into an organic solvent (e.g., ethyl acetate, dichloromethane, or the like) and water, and the organic phase is concentrated, thereby obtaining a crude product containing the compound represented by formula III.
In one embodiment, step (2) is: and (2) carrying out reduction reaction on the crude product containing the compound shown in the formula III obtained in the step (1) in an inert solvent in the presence of a reducing agent to obtain the compound shown in the formula I.
In one example, in step (2), after the reduction reaction is completed, the reaction mixture is quenched (e.g., with water) and adjusted to neutral (e.g., 6.5 to 8) by adjusting the pH (e.g., using aqueous hydrochloric acid solution) and then separated; concentrating the organic phase to obtain a crude product; and (3) carrying out hot beating purification on the crude alcohol solvent (such as methanol or ethanol) to obtain the compound shown in the formula I.
In one embodiment, the quenching is performed at 0-10 ℃.
In one embodiment, the compound of formula I obtained in step (2) is more than 95% pure.
In one embodiment, the overall yield of step (1) and step (2) is greater than 60%.
In one embodiment, the oxidizing agent in the oxidation reaction is a commercially available oxidizing agent known in the art for such reactions. For example, the oxidizing agent is selenium dioxide.
In one embodiment, the amount of the oxidizing agent used in the oxidation reaction can be the amount conventionally used in the art, for example, the molar ratio of the amount of the oxidizing agent to the compound represented by formula II can be 4 to 20, preferably 4 to 8.
In one embodiment, the oxidation reaction is carried out at reflux temperature or 100 ℃ to 120 ℃.
In one embodiment, the inert solvent in the oxidation reaction may be a solvent conventional in the art for such reactions. For example, the inert solvent is one or more of dioxane, dimethyl sulfoxide or dimethylformamide.
In one embodiment, the reducing agent in the reduction reaction is a commercially available alkyl hydroboration reagent with large steric hindrance known in the art. For example, the reducing agent is one or more of lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, 9-borabicyclo (3, 1) -nonane and the like.
In one embodiment, the reducing agent may be used in an amount conventional in the art for such reactions. For example, the molar ratio of the reducing agent to the compound represented by formula III may be 1 to 3.
In one embodiment, the reduction is carried out at 0-10 ℃.
In one embodiment, the inert solvent may be a solvent conventional in the art for such reactions. For example, the inert solvent can be one or more of acetone, tetrahydrofuran, diethyl ether or methyl tetrahydrofuran; preferably, the inert solvent is anhydrous tetrahydrofuran.
The positive progress effects of the invention are as follows: provides an optical selective process synthesis method of (5R) -5-hydroxyl triptolide.
The raw materials and reagents used in the invention are commercially available, stable in source and low in price. In addition, the method of the invention takes triptonide as the starting material, and compared with triptolide, the toxicity is greatly reduced, so that the protection requirement of experimenters during operation is lower, and the cost can be greatly saved. And the triptonide is independent of the natural product extraction method, so that the problem of raw material source is solved.
Compared with a synthesis method using a reduction reagent (such as CN 1511838A) with small steric hindrance, the method of the invention adopts the alkyl hydroboration reagent with large steric hindrance, the chiral selectivity of the reaction is close to 100%, the post-treatment does not need chromatographic column separation at all, and the industrial production of the product can be realized completely.
In a word, the method solves the problem of raw material source, the raw materials are safer, the experimental operation is safer, the method has short synthesis steps and high product chiral selectivity, the post-treatment avoids the operations of column chromatography separation and the like, and the industrial production is easy to realize.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the product obtained in example 3.
FIG. 2 is a HPLC chart of the product obtained in example 3.
FIG. 3 is a HPLC chart of the product obtained in example 4.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
50g (1 eq) of triptolide (compound of formula II) and 500mL dioxane were added to a three-neck flask, followed by 124g (8 eq) of selenium dioxide, and the mixture was heated under reflux with stirring until the reaction was complete. After cooling to room temperature, insoluble matter was removed by filtration. After the filtrate was concentrated, methylene chloride and water were added to extract. The organic layer was washed with water and concentrated to give the crude compound of formula III as a pale yellow solid in 88% yield. The crude product was used in the next reaction without purification.
Example 2
3g (1 eq) triptolide (compound of formula II) and 20mL dimethyl sulfoxide were added to a three-necked flask, followed by 3.7g (4 eq) selenium dioxide, heated to 100-120 ℃ and stirred until the reaction was complete. After cooling to room temperature, insoluble matter was removed by filtration. After the filtrate was concentrated, ethyl acetate and water were added to extract. The organic layer was washed with water and concentrated to give the crude compound of formula III in 80% yield. The crude product was used in the next reaction without purification.
Example 3
17g of the compound of formula III (from example 1, 1eq) and 170mL of anhydrous tetrahydrofuran were added to a three-neck flask, and after dissolution, the temperature was lowered to-60 to 50 ℃. While maintaining this temperature, 100mL (2.2 eq) of a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran was added dropwise. After stirring until the reaction is complete, the temperature is raised to 0-10 ℃. 170mL of water was added dropwise while maintaining the temperature, and the pH was adjusted to neutrality with a 5% hydrochloric acid solution, followed by liquid separation. After the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, filtered through 50g of silica gel, the filter cake was rinsed thoroughly with ethyl acetate, and the filtrate was concentrated to give a crude product. The crude product was filtered, hot-pulped with ethanol and purified to give the compound of formula I as a white powder in 83% yield. 1 H NMR(DMSO-d 6 400 MHz) (. Delta. =5.34 (s, 1H), 4.87 (s, 2H), 4.60 (d, J =7.2Hz, 1H), 3.73 (d, J =3.2Hz, 1H), 3.53 (d, J =2.8Hz, 1H), 3.37 (d, J =7.2Hz, 1H), 3.34 (d, J =4.8Hz, 1H), 2.23-2.03 (m, 4H), 2.03-1.92 (m, 1H), 1.82-1.67 (m, 1H), 1.04 (dd, J =12.4,5.2Hz, 1H), 0.99 (s, 3H), 0.89 (d, J =6.9Hz, 3H), 0.76 (d, J =6.9Hz, 3H). The nuclear magnetic spectrum is shown in FIG. 1. HPLC purity 98.5%, as shown in fig. 2.
Example 4
A three-necked flask was charged with 10g of the compound of formula III (from example 1, 1eq) and 100mL of anhydrous tetrahydrofuran, and the mixture was dissolved and cooled to-60 to 50 ℃. While maintaining this temperature, 84mL (3 eq) of a 1M potassium tri-sec-butylborohydride tetrahydrofuran solution was added dropwise. Stirring until the reaction is complete, and then heating to 0-10 ℃. After 100mL of water was added dropwise while maintaining this temperature, the pH was adjusted to neutrality with a 5% hydrochloric acid solution, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were concentrated to give crude product. The crude product is purified by hot beating with ethanol to obtain the compound of formula I with yield of 80% and HPLC purity of 98.2%, and the HPLC chromatogram is shown in FIG. 3.
Example 5
1g of the compound of formula III (from example 1, 1eq) and 10mL of anhydrous tetrahydrofuran were added to a three-neck flask, dissolved and cooled to-60-50 ℃. While maintaining this temperature, 8.4mL (1.5 eq) of a 0.5M 9-borabicyclo (3, 1) -nonane tetrahydrofuran solution was added dropwise. After stirring until the reaction was completed, 1mL of acetone was added, and the mixture was warmed to 0-10 ℃. After 10mL of water was added dropwise while maintaining this temperature, the pH was adjusted to neutrality with a 5% hydrochloric acid solution, and then the solution was separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were concentrated to give crude product. The compound of formula I is obtained after the crude product is purified by hot pulping with ethanol, and the yield is 80%.
Comparative example 1
1g of the compound of the formula III (from example 1,1eq) and 1.4g of Eu (FOD) 3 (0.5 eq) was dissolved in 20mL of anhydrous methanol, cooled to-60 ℃ and 0.2g of sodium borohydride (2 eq) was added. After the mixture was reacted completely at-60 ℃, it was warmed to room temperature and quenched with water. Extraction with ethyl acetate, washing of the organic layer with brine, and concentration of the mixture of (5R) -5-hydroxytriptolide (i.e., the compound of formula I) and (5R) -5-hydroxytriptolide (i.e., the compound of formula IA) in the crude product (HPLC showed a ratio of about 1. Separating the crude product by preparative chromatography to give a compound of formula I as a off-white solid in an amount of about 300mg; the yield thereof was found to be about 30%.
Comparing the synthesis method of the invention with the synthesis method of the comparative example 1 or the embodiment 2 of CN1511838A, the synthesis method of the invention has obviously improved chiral selectivity, can directly obtain the target chiral product (5R) -5-hydroxy triptolide (namely the compound of the formula I) with high yield, avoids operations such as column chromatography and the like in post-treatment steps, and completely meets the industrial production requirements of (5R) -5-hydroxy triptolide.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (4)
1. The preparation method of the compound shown in the formula I is characterized by comprising the following steps:
(1) Carrying out oxidation reaction on a compound shown as a formula II in an inert solvent in the presence of an oxidant to form a compound shown as a formula III; the oxidant is selenium dioxide; the inert solvent is one or more of dioxane, dimethyl sulfoxide or dimethylformamide;
(2) Carrying out a reduction reaction on the compound shown in the formula III in an inert solvent in the presence of a reducing agent to form a compound shown in the formula I; the reducing agent is lithium tri-sec-butyl borohydride or potassium tri-sec-butyl borohydride; the inert solvent can be one or more of tetrahydrofuran, diethyl ether or methyl tetrahydrofuran; after the reduction reaction is finished, quenching the reaction mixture, adjusting the pH value to be neutral, and separating liquid; concentrating the organic phase to obtain a crude product; carrying out hot pulping and purification on the crude product by using an alcohol solvent to obtain a compound shown in a formula I; the quenching is carried out at 0-10 ℃;
the purity of the compound shown in the formula I obtained in the step (2) is over 95 percent;
the total yield of the step (1) and the step (2) is higher than 60 percent.
2. The method according to claim 1, wherein the molar ratio of the oxidizing agent to the compound represented by formula II is 4 to 20.
3. The method according to claim 1, wherein the molar ratio of the reducing agent to the compound represented by formula III is 1 to 3.
4. The method of claim 1, wherein the alcoholic solvent is methanol or ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111256351.5A CN113754715B (en) | 2021-10-27 | 2021-10-27 | Optical selective process synthesis method of (5R) -5-hydroxyl triptolide |
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