A process for the asymmetric epoxidation of a brassinosteroid intermediate

Abstract

The present application relates to brassinosteroid intermediate preparation and its purification method, belong to the field of medicine and chemical technology. The present application provides the preparation method of formula 1 brassinosteroid intermediate, reaction as follows: wherein, wherein R1 And R2 Independently selected from -COR3, C1-C8 Alkyl or R1 And R2 Together form R3 Selected from C1-C 20 Linear or branched alkyl, substituted C1-C 20 Alkyl, phenyl, substituted phenyl, preferably C1-C8 Linear or branched alkyl, phenyl or substituted phenyl, substituted phenyl is selected from the phenyl group, F, Cl, Br, nitro, methoxy arbitrary substitution C1-C6 Alkyl; comprising the following steps: step 1: formula 2 compound in solvent under the action of oxidant formula 3 obtains formula 1 compound. As described above, the preparation method of brassinosteroid intermediate of the present application, has the advantages of high selectivity, low cost and simplification of post-processing.

Description

Technical Field

[0001] This invention relates to the preparation and purification methods of brassinolide intermediates, belonging to the fields of pharmaceutical and chemical technology. Background Technology

[0002] Brassinolides are a novel plant growth regulator, first discovered by American agricultural scientists in 1970. Publicly known brassinolides include propionyl brassinolide, acetyl brassinolide, butyryl brassinolide, and brassinosteroids.

[0003] The epoxidation of the carbon-carbon double bond in brassinolide intermediates can occur on both sides of the carbon-carbon double bond, thus yielding two isomers. Many reagents are available for oxidizing the carbon-carbon double bond to form an ethylene oxide ring, such as peracetic acid, m-chloroperoxybenzoic acid, and trifluoroperacetic acid. Due to the special environment of the carbon-carbon double bond, choosing the right reagent can result in a higher yield of the product with the desired configuration.

[0004] CN1033057A discloses that a brassinosteroid derivative intermediate is oxidized with m-chloroperoxybenzoic acid (m-CPBA), and the ratio between the target product and impurities is about (1.4-1.67):1, with a product yield between 15% and 45%.

[0005] In CN1042431C, m-CPBA oxidation yielded propionyl brassinolide with a yield of 39%.

[0006] CN1114612C uses peroxytrifluoroacetic acid reagent to obtain propionyl brassinolide, with a yield of 67.3% after column chromatography.

[0007] Existing reports indicate that dual-phase oxidation has poor selectivity, low yield, and cumbersome post-processing, which is not conducive to industrial production. Summary of the Invention

[0008] In view of the above background technology, the present invention provides a method for preparing and purifying brassinolide intermediates that is simple to operate, highly selective, easy to post-process, highly pure, and suitable for industrial production.

[0009] This invention provides a method for preparing a brassinolide intermediate of Formula 1, comprising the following steps:

[0010] Step 1: Compound 2 is reacted in a solvent with oxidizing agent 3 to yield compound 1, as shown in the following reaction:

[0011]

[0012] R1 and R2 are independently selected from -COR3, C1 to C8 straight-chain or branched alkyl groups, or R1 and R2 are formed together. ;

[0013] R3 is selected from C1 to C2. 20 Straight-chain or branched alkyl groups, substituted C1-C2 20 Alkyl, phenyl, or substituted phenyl, preferably C1-C8 straight-chain or branched alkyl, phenyl, or substituted phenyl, wherein the substituted phenyl is selected from phenyl substituted with C1-C6 alkyl, F, Cl, Br, nitro, or methoxy in any way;

[0014] In this invention, "C1~C 20 "Straight-chain or branched alkyl" refers to straight-chain or branched alkyl groups having 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, pteropentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl, etc.

[0015] In this invention, "C1-C8 straight-chain or branched alkyl groups" refers to straight-chain or branched saturated hydrocarbon groups having 1-8 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, sec-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl.

[0016] R4 and R5 are independently selected from C. 1-3 alkyl;

[0017] Equation 3 is shown below:

[0018]

[0019] R6 and R7 are independently selected from any substituted alkyl group, any substituted cycloalkyl group, phenyl group or any substituted phenyl group, preferably phenyl group or phenyl group substituted with 1 to 6 C1 to C6 alkyl groups.

[0020] In this specification, "alkyl" in "arbitrarily substituted alkyl" refers to a straight-chain or branched alkyl group having one or more carbon atoms, and in particular, the range of carbon atoms is limited. If not, C1-C1 is preferred. 20 Alkyl groups, more preferably C1~C 12 Alkyl groups, more preferably C1 to C6 alkyl groups, and particularly preferably C1 to C4 alkyl groups.

[0021] In this specification, "cycloalkyl" in "arbitrarily substituted cycloalkyl" refers to a cycloalkyl group having three or more carbon atoms constituting a ring, and there is no particular limitation on the range of carbon atoms. In this case, it is preferably C3~C4. 10 Cycloalkyl.

[0022] The oxidant in step 1 has the following structural formula:

[0023] .

[0024] The molar ratio of the compound of formula 2 and the oxidant in step 1 is 1: (1-20), preferably 1: (1-15), and more preferably 1: (2-10).

[0025] In step 1, an acidifying agent may also be added, which may be LiClO4, Li2CO3, TfOLi, LiCl, Li2CO3, LiPO4, LiNO3, CaSO4, CaCl2, or KHSO4.

[0026] In step 1, the molar ratio of compound 2 and acidifier is 1:(0.1-3), preferably 1:(0.5-2), and more preferably 1:(0.5-1.5).

[0027] The solvent in step 1 is selected from one or more of alcohols, halogenated hydrocarbons, esters, ethers, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, or water, preferably one or more of acetone, benzene, toluene, xylene, tetrahydrofuran, n-heptane, N,N-dimethylformamide, diethyl ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, acetonitrile, and water; more preferably one or more of tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, and water.

[0028] The reaction temperature in step 1 is -78°C to 0°C, preferably -50°C to -5°C, more preferably -50°C to -15°C, and for example -25°C to -20°C; the reaction time is 3 to 200 hours, preferably 12 to 170 hours, and more preferably 20 to 54 hours.

[0029] The method for preparing the compound of Formula 1 further includes the following steps:

[0030] Step 2: Stir the crude Formula 1 compound in a solvent at a suitable temperature, filter, and evaporate to dryness to obtain the pure Formula 1 compound.

[0031] The solvent mentioned in step 2 is one or more of alcohols or highly polar solvents, preferably one or more of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetonitrile, water, tetrahydrofuran, acetone, dioxane, butanone, toluene, n-heptane, n-hexane, 2-methyltetrahydrofuran, ethyl acetate, and isopropyl acetate.

[0032] The temperature in step 2 is 0°C to 110°C, preferably 20°C to 80°C.

[0033] In step 2, the mixture is first stirred at temperature A, then stirred at temperature B, filtered, and evaporated to obtain a pure compound of formula 1.

[0034] The temperature A is 50°C to 110°C, preferably 50°C to 80°C; the temperature B is 0°C to 50°C, preferably 20°C to 40°C.

[0035] As described above, the present invention provides a method for synthesizing brassinolide that is convenient to operate, easy to control the reaction, highly selective, high in yield and high in purity, and has the following beneficial effects:

[0036] (1) High selectivity: This invention uses a novel epoxy reagent to replace the existing oxidants such as m-CPBA and peroxytrifluoroacetic acid. We use a novel epoxy reagent to increase the selectivity from 1.67:1 to (8.6-9.2):1, which is more than 3 times higher.

[0037] (2) High yield: The yield of this invention is over 85%, which is more than 40% higher than the yield of the prior art using m-CPBA oxidation; and 17.7% higher than the yield using peroxytrifluoroacetic acid.

[0038] (3) The post-processing is simple and the purity is high. This invention does not require column purification. The purity of the compound of formula 1 obtained by using a simple recrystallization method is above 94%.

[0039] (4) The inventors of this application have found through multiple experiments that when the temperature is below -20℃, the selectivity is significantly better than that above -20℃. When the temperature is between -5℃ and 10℃, the selectivity is comparable to that of the prior art. When the temperature is below -45℃, the reaction speed is very slow and the selectivity is not significantly improved.

[0040] (5) The present invention has the characteristics of high atom utilization, high reaction selectivity, simple post-processing operation and high purity. Attached Figure Description

[0041] Figure 1 This is the HPLC chromatogram of the crude product in Example 1 of the present invention.

[0042] Figure 2 This is the HPLC chromatogram of the pure product in Example 1 of the present invention.

[0043] Figure 3 This is the HPLC chromatogram of the crude product in Example 2 of the present invention.

[0044] Figure 4 This is the HPLC chromatogram of the crude product in Example 3 of the present invention.

[0045] Figure 5 This is the HPLC chromatogram of the crude product in Example 4 of the present invention.

[0046] Figure 6 This is the HPLC chromatogram of the crude product in Example 5 of the present invention.

[0047] Figure 7 This is the HPLC chromatogram of the crude product in Example 6 of the present invention.

[0048] Figure 8 This is the HPLC chromatogram of the pure product in Example 7 of the present invention.

[0049] Figure 9 This is the HPLC chromatogram of the pure product in Example 8 of the present invention.

[0050] Figure 10 This is the HPLC chromatogram of the crude product from Comparative Example 1 of the present invention. Detailed Implementation

[0051] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the following detailed description of the technical solutions of the present invention using embodiments will help to further understand the advantages and effects of the technical solutions of the present invention. The embodiments do not limit the scope of protection of the present invention, which is determined by the claims.

[0052] Unless otherwise specified, the experimental methods described in the following examples are generally performed under standard conditions or as recommended by the manufacturer.

[0053] Unless otherwise specified, all raw materials or reagents used in the examples are commercially available.

[0054] Unless otherwise specified, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and are ready for use without treatment.

[0055] Example 1

[0056]

[0057] The epoxidizing agent 4,6-diphenyl-1,3,5-triazin-2-yl hydroperoxide (Triazox) (6.44 g, 24.3 mmol) was dissolved in DCM (130 mL). The reaction system temperature was lowered to -25 to -20 °C, and a DCM solution of compound 2A (compound 2A (2 g, 3.59 mmol) dissolved in 100 mL DCM) was added dropwise over approximately 4 hours. After the addition was complete, the reaction was maintained at -25 to -20 °C for 48 hours. After the reaction was complete, 2-methyl-2-butene (6.5 mL) was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.5 g of crude off-white solid (the ratio of compound 1A to compound 1B was 9.2 / 1, as shown in the figure). Figure 1 (As shown).

[0058] 7 mL of methanol was added to the obtained 2.5 g crude product. The reaction system was heated to 60 °C and stirred for 2 h, then cooled to 35 °C and stirred for 3 h. The mixture was filtered, and the filter cake was collected to obtain 1.6 g of white solid 1A, with a yield of 85%. The HPLC purity of compound 1A was 94.6%. Figure 2 As shown.

[0059] Example 2

[0060]

[0061] The epoxidizing agent Triazox (6.44 g, 24.3 mmol) was dissolved in DCM (32 mL). The reaction system temperature was lowered to -25 to -20 °C. A DCM solution of compound 2 A (2 g of compound 2 A dissolved in 100 mL of DCM) was added dropwise over approximately 4 hours. After the addition was complete, the reaction was maintained at -25 to -20 °C for 48 hours. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.55 g of crude product, an off-white solid (the ratio of compound 1A to compound 1B was 8.6 / 1, as shown in the figure). Figure 3 (As shown).

[0062] Example 3

[0063]

[0064] The novel epoxidizing agent Triazox (6.44 g, 24.3 mmol) was dissolved in DCM (32 mL). The reaction system temperature was lowered to -25 to -20 °C, and a DCM solution of compound 2 A (2 g of compound 2 A dissolved in 10 mL of DCM) was added dropwise over approximately 4 hours. After the addition was complete, the internal temperature was maintained at -25 to -20 °C for 48 hours. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.5 g of crude, off-white solid (the ratio of compound 1A to compound 1B was 8.7 / 1, as shown in the figure). Figure 4 (As shown).

[0065] Example 4

[0066]

[0067] The novel epoxidizing agent Triazox (3.22 g, 11.2 mmol) was dissolved in DCM (16 mL), and the reaction system temperature was lowered to -25 to -20 °C. A DCM solution of compound 2A (2 g of compound 2A dissolved in 10 mL of DCM) was added dropwise over approximately 1 hour. After the addition was complete, the reaction was maintained at -25 to -20 °C for 54 h. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.2 g of crude, off-white solid (the ratio of compound 1A to compound 1B was 9:1, as shown in the figure). Figure 5 (As shown).

[0068] Example 5

[0069]

[0070] The novel epoxidizing agent Triazox (3.22 g, 11.2 mmol) was dissolved in DCM (16 mL). The reaction system temperature was lowered to -45 to -35 °C, and a DCM solution of compound 2A (2 g of compound 2A dissolved in 10 mL of DCM) was added dropwise over approximately 1 hour. After the addition was complete, the reaction was maintained at -45 to -35 °C for 168 h. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -45 to -35 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.2 g of crude, off-white solid (the ratio of compound 1A to compound 1B was 9.05 / 1, as shown in the figure). Figure 6 (As shown).

[0071] Example 6

[0072]

[0073] The novel epoxidizing agent Triazox (3.22 g, 11.2 mmol) was dissolved in dichloromethane (DCM) (16 mL). The reaction system was cooled to -25 to -20 °C, and LiClO4 (0.4 g, 3.6 mmol) was added. Then, a DCM solution of compound 2A (2 g of compound 2A dissolved in 10 mL of DCM) was added dropwise over approximately 1 hour until complete. After the addition was complete, the reaction was maintained at -25 to -20 °C for 48 hours. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.25 g of crude, off-white solid (the ratio of compound 1A to compound 1B was 9.07 / 1). Figure 7 (As shown).

[0074] Example 7

[0075] A mixture of compounds 1A and 1B (5 g, 9.0 mmol; 1A:1B = 9:1) was added to a reaction flask, followed by 15 mL of methanol. The reaction mixture was heated to 60 °C and stirred for 2 h. The temperature was then lowered to 35 °C and stirred for 3 h. The mixture was filtered, and the filter cake was collected to obtain 4.3 g of white solid 1A, with a yield of 86%. The HPLC purity of compound 1A was 97.4%. Figure 8 As shown.

[0076] Example 8

[0077] A mixture of compounds 1A and 1B (5 g, 9.0 mmol; 1A:1B = 9:1) was added to a reaction flask, followed by 15 mL of ethanol. The reaction mixture was heated to 60 °C and stirred for 2 h. The temperature was then lowered to 35 °C and stirred for 3 h. The mixture was filtered, and the filter cake was collected to give 4.1 g of white solid 1A, with a yield of 82%. The HPLC purity of compound 1A was 96.6%. Figure 9 As shown.

[0078] Comparative Example 1

[0079]

[0080] The epoxidizing agent Triazox (6.44 g, 24.3 mmol) was dissolved in DCM (130 mL). The reaction system temperature was lowered to -5 to 0 °C. A DCM solution of compound 2A (2 g of compound 2A dissolved in 100 mL of DCM) was added dropwise over approximately 4 hours. After the addition was complete, the internal temperature was maintained at -5 to 0 °C for 22 hours. After the reaction was complete, 2-methyl-2-butene (6.5 mL) was added dropwise at -5 to 0 °C to quench the reaction, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.4 g of crude off-white solid (the ratio of compound 1A to compound 1B was 1.8 / 1, as shown in the figure). Figure 10 (As shown).

Claims

1. A method for preparing a brassinolide intermediate, comprising the following reaction: It includes the following steps: Step 1: Compound 2A is reacted with an oxidizing agent to yield compounds 1A and 1B; The oxidant is Triazox, and its structural formula is as follows: ; The reaction temperature in step 1 is -25 to -20°C or -45 to -35°C.

2. The preparation method according to claim 1, characterized in that, When the reaction temperature in step 1 is -25 to -20°C, an acidifying agent is added in step 1, and the acidifying agent is LiClO4.

3. The preparation method according to claim 1, characterized in that, The solvent in step 1 is dichloromethane.

4. A method for preparing a brassinolide intermediate, comprising the following reaction: Its features are, 6.44 g of Triazox was dissolved in 130 mL of DCM. The internal temperature of the reaction system was lowered to -25 to -20 °C. 2 g of compound 2A was added dropwise to 100 mL of DCM solution over 4 hours. After the addition was completed, the internal temperature was maintained at -25 to -20 °C for 48 hours. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.5 g of crude, off-white solid compound.

5. A method for preparing a brassinolide intermediate, comprising the following reaction: Its features are, Dissolve 6.44 g of the epoxidizing agent Triazox in 32 mL of DCM. Lower the internal temperature of the reaction system to -25 to -20 °C. Add the solution dropwise to 100 mL of DCM containing 2 g of compound 2A over 4 h. After the addition is complete, maintain the internal temperature at -25 to -20 °C for 48 h. After the reaction is complete, quench the reaction by adding 6.5 mL of 2-methyl-2-butene dropwise at -25 to -20 °C and stirring for 30 min. Filter the solution, collect the filtrate, and concentrate the filtrate under reduced pressure at 30 to 35 °C to obtain 2.55 g of crude white solid compound.

6. A method for preparing a brassinolide intermediate, comprising the following reaction: Its features are, 3.22 g of the epoxidizing agent Triazox was dissolved in 16 mL of DCM, and the internal temperature of the reaction system was lowered to -25 to -20 °C. 2 g of compound 2 A was added dropwise to 100 mL of DCM solution over 1 hour. After the addition was complete, the internal temperature was maintained at -25 to -20 °C for 54 h. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.2 g of crude product, a white solid.

7. A method for preparing a brassinolide intermediate, comprising the following reaction: Its features are, 3.22 g of the epoxidizing agent Triazox was dissolved in 16 mL of DCM. The internal temperature of the reaction system was lowered to -45 to -35 °C. 2 g of compound 2 A was added dropwise to 100 mL of DCM solution over 1 hour. After the addition was complete, the internal temperature was maintained at -45 to -35 °C for 168 h. After the reaction was complete, 6.5 mL of 2-methyl-2-butene was added dropwise at -45 to -35 °C to quench the reaction, and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.2 g of crude product, a white solid.

8. A method for preparing a brassinolide intermediate, comprising the following reaction: Its features are, 3.22 g of the epoxidizing agent Triazox was dissolved in 16 mL of DCM. The internal temperature of the reaction system was lowered to -25 to -20 °C. 0.4 g of LiClO4 was added, followed by the dropwise addition of 2 g of compound 2 A in 100 mL of DCM solution. The addition was completed in 1 h. After the addition was completed, the internal temperature was maintained at -25 to -20 °C for 48 h. After the reaction was completed, 6.5 mL of 2-methyl-2-butene was added dropwise at -25 to -20 °C to quench the reaction and the mixture was stirred for 30 min. The mixture was filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure at 30 to 35 °C to obtain 2.25 g of crude product, which is an off-white solid.

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