CN112299951A - Synthesis method of DLin-MC3-DMA intermediate - Google Patents
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- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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Abstract
The invention provides a synthesis method of a DLin-MC3-DMA intermediate, wherein the DLin-MC3-DMA intermediate is (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraene-19 alcohol, and the synthesis method comprises the following steps: step S1, carrying out substitution reaction on (6Z,9Z) -18-bromooctadecane-6, 9-diene and nitromethane to obtain (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene; step S2, carrying out hydrolysis reaction on (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to obtain (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraene-19 ketone; and step S3, carrying out reduction reaction on the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone and a reducing agent to obtain the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol, wherein the reducing agent comprises sodium borohydride, potassium borohydride, lithium aluminum hydride or a mixture thereof. The synthesis method has the characteristics of simple process conditions, simple and convenient operation, short route, high repeatability, higher total yield and contribution to industrial production.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a synthesis method of a DLin-MC3-DMA intermediate, and more particularly relates to a synthesis method of (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol.
Background
In RNA liposomes, the novel cationic lipid DLin-MC3-DMA plays an important role. In 2018, the first siRNA liposome product Onpattero for treating familial amyloid polyneuropathy utilizes DLin-MC3-DMA as a material for assembling cationic liposomes. Since then, DLin-MC3-DMA, a cationic lipid material used in Onpattetro, has also begun to be of interest. The ionizable cationic liposome DLin-MC3-DMA is a high-efficiency siRNA transport carrier, which can effectively encapsulate corresponding siRNA and enable the siRNA to enter cytoplasm, and then the two are separated, and the siRNA exerts the efficacy.
The key intermediate for preparing DLin-MC3-DMA is (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol. The synthetic route of (6Z,9Z,28Z,31Z) -heptatriacontan-6, 9,28, 31-tetraen-19 alcohol is described as follows: the (6Z,9Z) -18-bromo-octadecane-6, 9-diene is used as a raw material, and reacts with magnesium chips under the anhydrous and oxygen-free conditions to prepare a Grignard reagent, and then the Grignard reagent reacts with ethyl formate to obtain an intermediate, and the intermediate is synthesized by hydrolysis. Since the Grignard reagent needs to be prepared under anhydrous and oxygen-free conditions, the production equipment required by the route is harsh. And the reaction is poor in reproducibility often due to more by-products in the European Union of oneself when preparing the Grignard reagent.
Disclosure of Invention
In view of the above, the invention provides a method for synthesizing a DLin-MC3-DMA intermediate, namely (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraen-19 alcohol, which has the characteristics of simple and convenient operation, short route, high repeatability, higher total yield and contribution to industrial production.
In order to solve the technical problems, the invention adopts the following technical scheme:
according to the synthesis method of the DLin-MC3-DMA intermediate, the DLin-MC3-DMA intermediate is (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraen-19 alcohol, and the synthesis method comprises the following steps:
step S1, carrying out substitution reaction on (6Z,9Z) -18-bromooctadecane-6, 9-diene and nitromethane to obtain (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene;
step S2, carrying out hydrolysis reaction on (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to obtain (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraene-19 ketone;
and step S3, carrying out reduction reaction on the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone and a reducing agent to obtain the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol, wherein the reducing agent comprises sodium borohydride, potassium borohydride, lithium aluminum hydride or a mixture thereof.
Sodium borohydride, potassium borohydride and lithium aluminum hydride are inorganic compounds with strong selective reducibility, are commonly used as reducing agents and have good chemical selectivity. The method can realize the reduction of aldehyde ketone carbonyl under very mild conditions, and has good reduction effect on aldehyde and ketone. The invention can reduce the intermediate product (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone to obtain (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol by using the reducing agent, can simplify the reaction route and is suitable for industrial production.
The synthesis method has the characteristics of simple process conditions, simple and convenient operation, short route, high repeatability, higher total yield and contribution to industrial production.
Further, in the step S1, the substitution reaction occurs in the presence of an organic base, the organic base comprising Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (LHMDS), or a mixture thereof.
LDA and LHMDS are non-nucleophilic bases, only act with protons and can not perform other nucleophilic reactions, so that the bases can perform deprotonation and can better promote the substitution reaction.
Still further, the (6Z,9Z) -18-bromooctadecane-6, 9-diene: nitromethane: the molar ratio of the organic base is 1: (0.5-0.6): (1.0-1.2), the reaction temperature is-20-0 ℃, and the reaction time is 3-8 hours. The appropriate increase of the amount of nitrotoluene relative to the molar equivalent contributes to an increase in the yield without causing excessive costs.
Still further, the substitution reaction is carried out in a first solvent, and the first solvent is any one selected from tetrahydrofuran, diethyl ether and toluene. By dissolving the raw material in the solvent, the progress of the substitution reaction can be promoted more favorably.
Further, in the step S2, the hydrolysis reaction occurs in an aqueous solution of an inorganic base, and the inorganic base includes sodium hydroxide, potassium hydroxide, or a mixture thereof. By using these inorganic strong bases, the hydrolysis reaction can be promoted without generating by-products that are difficult to remove, and the raw material cost and the process conditions and equipment requirements are low.
Further, the molar ratio of the (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to the inorganic base is 1.0: 2.0-3.0, and the reaction temperature is 50-80 ℃; the reaction time is 3-8 hours. By adding an excess of the inorganic base, the yield can be improved without a significant increase in cost.
Still further, the hydrolysis reaction occurs under the action of a second solvent which is tetrahydrofuran, dioxane, or a mixture thereof. The (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene can be well dissolved in the second solvent, and thus the progress of the hydrolysis reaction can be promoted.
Further, in the step S3, the molar ratio of the (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraen-19-one to the reducing agent is 1.0: 0.5-1.0, and the reaction temperature is 0-25 ℃; the reaction time is 1-6 hours.
Still further, the step S3 is performed in a third solvent, which is methanol, ethanol, or a mixture thereof. The third solvent can be used for well dissolving the reducing agent, has good intersolubility with (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraen-19 ketone and can promote the reduction reaction.
Further, in the step S1, the step S2, and the step S3, purification treatment is performed after the reaction is completed,
wherein the purification process in step S1 comprises evaporating the first solvent to dryness; extracting with dichloromethane; washing with a saline solution; drying with anhydrous sodium sulfate; steaming to dryness and purifying by column chromatography;
the purification process in step S2 includes evaporating the second solvent to dryness; extracting with dichloromethane; washing with water; drying with anhydrous sodium sulfate; steaming to dryness and purifying by column chromatography;
the purification process in step S3 includes evaporating the third solvent to dryness; extracting with dichloromethane; washing the organic phase with 1M hydrochloric acid; dried over anhydrous sodium sulfate.
By performing the purification process after the reaction is completed in step S1, step S2, and step S3, problems such as an excessively low yield due to by-product poisoning can be reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention, are within the scope of the invention.
First, a method for synthesizing (6Z,9Z,28Z,31Z) -heptatriacontan-6, 9,28, 31-tetraen-19-ol according to an embodiment of the present invention will be specifically described.
The synthesis method of (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol comprises the following steps:
step S1, the (6Z,9Z) -18-bromo-octadecane-6, 9-diene and nitromethane are subjected to substitution reaction to obtain (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene.
In particular, (6Z,9Z) -18-bromooctadecane-6, 9-diene, i.e., compound I (compound I shown in reaction formula (1)) undergoes a substitution reaction with nitromethane to produce (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene, i.e., compound II (compound II shown in reaction formula (1)), and the reaction formula of the substitution reaction is shown in formula (1).
Preferably, the substitution reaction occurs in the presence of an organic base comprising LDA, LHMDS, or a mixture thereof. Therefore, LDA and LHMDS can well perform deprotonation reaction with nitromethane, and then perform substitution reaction with the compound I to generate the compound II serving as an intermediate product.
Preferably, the (6Z,9Z) -18-bromooctadecane-6, 9-diene: nitromethane: the molar ratio of the organic base is 1: (0.5-0.6): (1.0-1.2), the reaction temperature is-20-0 ℃, and the reaction time is 3-8 hours. The substitution reaction is controlled to be carried out at the temperature of-20-0 ℃. After 3-8 hours of reaction, the reaction can be quenched by addition of aqueous salt solution. In addition, the addition of more nitromethane relative to the equivalent molar amount tends to improve the yield.
Preferably, the substitution reaction is performed in a first solvent, and the first solvent is any one selected from tetrahydrofuran, diethyl ether and toluene. The compound I and nitromethane as raw materials can be dissolved in the above solvent well, and are advantageous for promoting the progress of the substitution reaction.
After the substitution reaction is completed, it is preferable to purify compound II as an intermediate product. Specifically, the purification treatment comprises evaporating the first solvent; extracting with dichloromethane; washing with a saline solution; drying with anhydrous sodium sulfate; evaporated to dryness and purified by column chromatography. By carrying out purification treatment, unreacted raw materials, solvents and the like can be well removed, the subsequent hydrolysis reaction can be promoted, and unnecessary byproducts can be avoided.
Step S2, hydrolysis reaction is carried out on (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to obtain (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraene-19 ketone.
That is, the compound II obtained in the above step S1 is hydrolyzed to produce a ketone, i.e., a compound III (a compound represented by III in the following reaction formula (2)), and the chemical reaction formula of the hydrolysis reaction is represented by the following formula (2).
Preferably, the hydrolysis reaction occurs in an aqueous solution of an inorganic base comprising sodium hydroxide, potassium hydroxide, or a mixture thereof.
Preferably, the molar ratio of the (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to the inorganic base is 1.0: 2.0-3.0, and the reaction temperature is 50-80 ℃; the reaction time is 3-8 hours.
Preferably, the hydrolysis reaction occurs under the action of a second solvent, which is tetrahydrofuran, dioxane, or a mixture thereof.
The first solvent and the second solvent are independent of each other, that is, the first solvent and the second solvent may be the same or different, and there is no dependency.
Preferably, from the viewpoint of management of production raw materials and the like, both the first solvent and the second solvent are preferably tetrahydrofuran.
Similarly, after completion of the hydrolysis reaction, it is preferable to purify compound III, and the purification treatment specifically includes: evaporating the second solvent to dryness; extracting with dichloromethane; washing with water; drying with anhydrous sodium sulfate; evaporated to dryness and purified by column chromatography.
And step S3, carrying out reduction reaction on the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone and a reducing agent to obtain the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol, wherein the reducing agent comprises sodium borohydride, potassium borohydride, lithium aluminum hydride or a mixture thereof.
That is, the target product (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol, i.e., compound IV (compound IV shown in the following reaction formula (3)) is obtained by subjecting the ketone obtained by the above reaction to a reduction reaction with a reducing agent, and the reaction formula is shown in the following formula (3).
The sodium borohydride, the potassium borohydride and the lithium aluminum hydride have strong selective reducibility and good chemical selectivity as reducing agents. The compounds can realize the reduction of aldehyde ketone carbonyl under very mild conditions, and have good reduction effect on aldehyde and ketone. The invention can reduce the intermediate product (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone to obtain (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol by using the reducing agent, can simplify the reaction route and is suitable for industrial production.
Further, in the step S3, the molar ratio of the (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraen-19-one to the reducing agent is 1.0: 0.5-1.0, and the reaction temperature is 0-25 ℃; the reaction time is 1-6 hours.
Still further, the step S3 is performed in a third solvent, which is methanol, ethanol, or a mixture thereof. The third solvent can be used for well dissolving the reducing agent, has good intersolubility with (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraen-19 ketone and can promote the reduction reaction.
Likewise, a purification treatment may be performed after the reduction reaction is completed, and the purification treatment in step S3 may include evaporating the third solvent to dryness; extracting with dichloromethane; washing the organic phase with 1M hydrochloric acid; dried over anhydrous sodium sulfate.
The synthesis method of the present invention will be described in further detail below with reference to specific examples.
Example 1
(a) Synthesis of compound II, namely (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene
In a 150mL round-bottom flask, 10g of Compound I was dissolved in 80mL tetrahydrofuran, cooled to-5 ℃ and 0.93g nitromethane was added. Slowly dropwise adding 15.1mL of LDA with the concentration of 2M; after 3h reaction at-5 ℃ the reaction was quenched by addition of 50mL of aqueous saline.
Washing the organic phase with water, drying and evaporating to dryness; the crude product was purified by column chromatography to give 13.1g of compound II in 77% yield.
(b) Synthesis of Compound III, i.e. (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19-one
In a 150mL round-bottomed flask, 13g of the above compound II was added to 40mL of tetrahydrofuran and 10mL of water, and 1.86g of sodium hydroxide was added to react at 50 ℃ for 4 hours.
The tetrahydrofuran is distilled off, 70mL of dichloromethane are added for extraction, the organic phase is washed once again with clear water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography to give compound III 10.1g in 82% yield.
(c) Synthesis of Compound IV (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19-ol
In a 150mL round-bottom flask, 9.2g of compound III are dissolved in 90mL of methanol, the temperature is reduced to 5 ℃, 0.94g of potassium borohydride is added in portions, and the reaction is continued for 2 h. TLC monitoring reaction is complete, methanol is distilled off, 90ml dichloromethane is added for extraction, 1M hydrochloric acid is used for washing, solvent is evaporated after drying, and compound IV 8.31g is obtained with yield of 90%.
Example 2
(a) Synthesis of compound II, namely (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene
In a 150mL round-bottom flask, 10g of Compound I was dissolved in 80mL tetrahydrofuran, cooled to-5 ℃ and 0.93g nitromethane was added. 15.1mL of LHMDS with the concentration of 2M is slowly dripped; after 6h at-5 ℃ the reaction was quenched by addition of 50mL of aqueous saline.
Washing the organic phase with water, drying and evaporating to dryness; the crude product was purified by column chromatography to give 13.1g of compound II in 72% yield.
(b) Synthesis of Compound III, i.e. (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19-one
In a 150mL round-bottom flask, 13g of Compound II was added to 40mL of tetrahydrofuran and 10mL of water, 2.61g of potassium hydroxide was added, and the mixture was reacted at 60 ℃ for 4 hours.
The tetrahydrofuran is distilled off, 70mL of dichloromethane are added for extraction, the organic phase is washed once again with clear water, dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography to give 9.57g of compound III in 78% yield.
(c) Synthesis of Compound IV (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19-ol
In a 150mL round-bottom flask, 9.2g of compound III are dissolved in 90mL of ethanol, the temperature is reduced to 5 ℃, 0.66g of sodium borohydride is added in portions, and the reaction is continued for 2 h. TLC monitors the reaction to be complete, ethanol is evaporated, 90ml dichloromethane is added for extraction, 1M hydrochloric acid is used for washing, and the solvent is evaporated after drying, so that 8.03g of a compound IV is obtained, and the yield is 87%.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. A method for synthesizing a DLin-MC3-DMA intermediate, wherein the DLin-MC3-DMA intermediate is (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol, and is characterized by comprising the following steps:
step S1, carrying out substitution reaction on (6Z,9Z) -18-bromooctadecane-6, 9-diene and nitromethane to obtain (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene;
step S2, carrying out hydrolysis reaction on (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to obtain (6Z,9Z,28Z,31Z) -heptadecane-6, 9,28, 31-tetraene-19 ketone;
and step S3, carrying out reduction reaction on the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone and a reducing agent to obtain the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 alcohol, wherein the reducing agent comprises sodium borohydride, potassium borohydride, lithium aluminum hydride or a mixture thereof.
2. The synthesis method of claim 1, wherein in step S1, the substitution reaction occurs in the presence of an organic base, the organic base comprising LDA, LHMDS, or a mixture thereof.
3. The method of claim 2, wherein in step S1, the ratio of (6Z,9Z) -18-bromooctadecane-6, 9-diene: nitromethane: the molar ratio of the organic base is 1: (0.5-0.6): (1.0-1.2), the reaction temperature is-20-0 ℃, and the reaction time is 3-8 hours.
4. The synthesis method according to claim 2, wherein the substitution reaction is carried out in a first solvent, and the first solvent is any one selected from tetrahydrofuran, diethyl ether and toluene.
5. The synthesis method according to claim 1, wherein in the step S2, the hydrolysis reaction occurs in an aqueous solution of an inorganic base, and the inorganic base comprises sodium hydroxide, potassium hydroxide, or a mixture thereof.
6. The synthesis method according to claim 5, wherein the molar ratio of the (6Z,9Z,28Z,31Z) -19-nitro-heptadecane-6, 9,28, 31-tetraene to the inorganic base is 1.0: 2.0-3.0, and the reaction temperature is 50-80 ℃; the reaction time is 3-8 hours.
7. The synthesis method according to claim 5, wherein the hydrolysis reaction is carried out under the action of a second solvent, wherein the second solvent is tetrahydrofuran, dioxane or a mixture thereof.
8. The synthesis method according to claim 1, wherein in the step S3, the molar ratio of the (6Z,9Z,28Z,31Z) -heptatriacontane-6, 9,28, 31-tetraen-19 ketone to the reducing agent is 1.0: 0.5-1.0, and the reaction temperature is 0-25 ℃; the reaction time is 1-6 hours.
9. The synthesis method according to claim 8, wherein the step S3 is carried out in a third solvent, wherein the third solvent is methanol, ethanol, or a mixture thereof.
10. The method of claim 1, wherein the steps S1, S2, and S3 are performed by performing purification treatment after the reaction is completed,
wherein the purification process in step S1 comprises evaporating the first solvent to dryness; extracting with dichloromethane; washing with a saline solution; drying with anhydrous sodium sulfate; steaming to dryness and purifying by column chromatography;
the purification process in step S2 includes evaporating the second solvent to dryness; extracting with dichloromethane; washing with water; drying with anhydrous sodium sulfate; steaming to dryness and purifying by column chromatography;
the purification process in step S3 includes evaporating the third solvent to dryness; extracting with dichloromethane; washing the organic phase with 1M hydrochloric acid; dried over anhydrous sodium sulfate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022246555A1 (en) * | 2021-05-28 | 2022-12-01 | Nanovation Therapeutics Inc. | Method for producing an ionizable lipid |
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