阅读说明：本技术 一种鞘氨醇激酶激动剂的合成方法 (Synthetic method of sphingosine kinase agonist ) 是由 马新波 林周 于 2021-11-05 设计创作，主要内容包括：本发明公开了一种鞘氨醇激酶激动剂K6PC-5的合成方法,属于有机合成技术领域,所述合成方法的具体步骤为：(1)以辛酰氯(化合物II)为原料,在三乙胺作用下,在二氯甲烷中反应得到中间体III；(2)中间体III与丝氨醇反应得到化合物I,即所述激动剂K6PC-5。本发明合成方法一种操作简单,经济高效的可用来大规模生产的合成方法,一锅法的使用避免了中间体III形成后过度的暴露在空气中,降低了其变质的可能性,使得整个操作安全可靠,快速高效。(The invention discloses a synthetic method of sphingosine kinase agonist K6PC-5, belonging to the technical field of organic synthesis, and the synthetic method comprises the following specific steps: (1) using octanoyl chloride (compound II) as a raw material, and reacting in dichloromethane under the action of triethylamine to obtain an intermediate III; (2) reaction of intermediate III with serinol gives compound I, the agonist K6 PC-5. The synthetic method is simple to operate, economical and efficient, and can be used for large-scale production, the one-pot method avoids the intermediate III from being excessively exposed to the air after being formed, the possibility of deterioration of the intermediate III is reduced, and the whole operation is safe, reliable, rapid and efficient.)

1. A synthetic method of sphingosine kinase agonist K6PC-5 is characterized by comprising the following steps:

the method comprises the following specific steps:

(1) using octanoyl chloride as a raw material, and reacting in dichloromethane under the action of triethylamine to obtain an intermediate III;

(2) reaction of intermediate III with serinol gives compound I, the agonist K6 PC-5.

2. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of octanoyl chloride to triethylamine is 1: 1-1.2.

3. The synthesis method according to claim 2, wherein the molar ratio of octanoyl chloride to triethylamine is 1: 1.1.

4. The synthesis method according to claim 1, wherein in the step (1), the volume of the dichloromethane is 4-6 times that of the octanoyl chloride.

5. The method of claim 4, wherein the amount of dichloromethane used is 5 times the volume of octanoyl chloride.

6. The synthesis method according to claim 1, wherein in the step (1), the reaction conditions are as follows: reacting for 3-4h at room temperature.

7. The synthesis method according to claim 6, characterized in that the reaction conditions are: the reaction was carried out at 25 ℃ for 4 h.

8. The method of claim 1, wherein in step (2), the molar ratio of serinol to octanoyl chloride is 0.55-0.65: 1.

9. The method of claim 8, wherein the molar ratio of serinol to octanoyl chloride is 0.6: 1.

10. The synthesis method according to claim 1, wherein in the step (2), the reaction conditions are as follows: the reaction is carried out at room temperature for 8-12h, preferably at 25 ℃ for 10 h.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a one-pot synthesis method of sphingosine kinase agonist K6 PC-5.

Background

Sphingosine kinases (sphingases) are key rate-limiting enzymes and intracellular signal transduction enzymes for maintaining intracellular sphingolipid balance, have the functions of maintaining the balance of sphingosine-1-phosphate, ceramide and sphingosine, and participate in regulating various physiological functions of cell proliferation and apoptosis, vasoconstriction and remodeling, inflammation and metabolism and the like. K6PC-5 is a novel unnatural ceramide having an agonistic effect on sphingosine kinase 1, and is effective in enhancing sphingosine-1-phosphate production, controlling keratinocyte proliferation and differentiation, fibroblast proliferation and collagen synthesis, treating skin wound, improving wrinkle and inhibiting skin aging. In addition, it has been reported that K6PC-5, as a sphingosine kinase agonist, has a certain effect on the anti-glucocorticoid-related bone injury, the inhibition of Ebola virus infection in endothelial cells, and the anti-tumor effect.

Disclosure of Invention

Aiming at the blank existing in the prior art, the invention provides a one-pot synthesis method of sphingosine kinase agonist K6 PC-5. The synthesis method disclosed by the invention is efficient and high in yield, and is suitable for large-scale industrial production.

The technical scheme adopted by the invention is as follows:

a synthetic method of sphingosine kinase agonist K6PC-5 is carried out according to the following steps:

the method comprises the following specific steps:

(1) using octanoyl chloride (compound II) as a raw material, and reacting in dichloromethane under the action of triethylamine to obtain an intermediate III;

(2) reaction of intermediate III with serinol gives compound I, the agonist K6 PC-5.

In the step (1), the mol ratio of octanoyl chloride to triethylamine is 1: 1-1.2; preferably, the molar ratio of octanoyl chloride to triethylamine is 1: 1.1.

In the step (1), the volume consumption of the dichloromethane is 4-6 times of that of the octanoyl chloride; preferably, the amount of dichloromethane used is 5 times the volume of octanoyl chloride.

In the step (1), the reaction conditions are as follows: reacting for 3-4h at room temperature; preferably, the reaction is carried out at 25 ℃ for 4 h.

In the step (2), the mol ratio of serinol to octanoyl chloride is 0.55-0.65: 1; preferably, the molar ratio of serinol to octanoyl chloride is 0.6: 1.

In the step (2), the reaction conditions are as follows: reacting for 8-12h at room temperature; the reaction is preferably carried out at 25 ℃ for 10 h.

The beneficial technical effects of the invention are as follows:

the method provided by the invention provides a synthetic method which is simple to operate, economic and efficient and can be used for large-scale production for K6PC-5, the intermediate III has poor stability under conventional conditions and is easy to react with water and nucleophilic reagents to deteriorate, so that the purity and yield of the product are influenced, the intermediate III is prevented from being excessively exposed in the air after being formed by using a one-pot method, the possibility of deterioration of the intermediate III is reduced, and the whole operation is safe, reliable, rapid and efficient. This method has been applied to scale-up production.

Drawings

FIG. 1 shows the NMR spectrum of agonist K6PC-5 prepared in example 1 of the present invention.

Detailed Description

The present invention will be described in detail with reference to the accompanying drawings and examples.

Example 1:

a synthetic method of sphingosine kinase agonist K6PC-5 comprises the following specific steps:

(1) 350L of dichloromethane and 48kg of triethylamine (475mol) are added into a reaction kettle, 70kg of octanoyl chloride (432mol) is dripped under the protection of nitrogen, and the reaction solution containing the intermediate III is obtained after the octanoyl chloride (432mol) is dripped and stirred for 4 hours at 25 ℃.

(2) Adding 24kg of serinol (263mol) into the reaction kettle in batches, keeping the reaction kettle at 25 ℃ for stirring for 10 hours after the addition is finished, adding 1mol/L of dilute hydrochloric acid after the reaction is finished, adjusting the pH to 3-5, standing for layering, removing a water phase, washing an organic phase once by using 100L of saturated saline solution, concentrating to obtain a crude product, adding 70L of acetone, stirring for dissolving, slowly adding 140L of water, controlling the temperature to be 0-5 ℃ for crystallization, filtering, and drying to obtain 42.5kg of a product (I), namely the agonist K6 PC-5.

The nmr hydrogen spectrum of the obtained product is shown in fig. 1, and it can be seen from fig. 1 that the single hydrogen double peak with chemical shift of 6.89ppm corresponds to the amino hydrogen on the amide bond, the single hydrogen multiple peak near 3.93ppm corresponds to the methine group connected to the amino group on the serinol fragment, the multiple peak of four hydrogen at 3.75-3.86ppm corresponds to two methylene groups connected to the hydroxyl group on the serinol fragment, the single hydrogen triple peak at 3.40ppm corresponds to the methine group in the middle of two carbonyl groups, the broad peak of two hydrogen at 2.60ppm corresponds to two hydroxyl hydrogen on the serinol fragment, the double hydrogen triple peak at 2.55ppm corresponds to the methylene group adjacent to the carbonyl group, the two double hydrogen multiple peaks at 1.8ppm and 1.6ppm correspond to two methylene groups with two alkyl chains separated by one carbon from the carbonyl group, the broad peak of 16 hydrogen at 1.27ppm corresponds to the other methylene groups on two alkyl chains, and the hexahydro peak at 0.88ppm corresponds to two terminal methyl groups on two alkyl chains.

Example 2:

a synthetic method of sphingosine kinase agonist K6PC-5 comprises the following specific steps:

(1) 28L of dichloromethane and 4.36kg of triethylamine (43.2mol) are added into a reaction kettle, 7kg of octanoyl chloride (43.2mol) is added dropwise under the protection of nitrogen, and the reaction solution containing the intermediate III is obtained after the dropwise addition is finished and the stirring is carried out for 3 hours at 20 ℃.

(2) Adding 2.16kg serinol (23.8mol) into the reaction kettle in batches, keeping the reaction kettle at 20 ℃ for stirring for 8 hours after the addition is finished, adding 1mol/L diluted hydrochloric acid after the reaction is finished, adjusting the pH to 3-5, standing for layering, removing a water phase, washing an organic phase once by using 10L saturated saline solution, concentrating to obtain a crude product, adding 7L acetone, stirring for dissolving, slowly adding 14L water, controlling the temperature to be 0-5 ℃ for crystallization, filtering, and drying to obtain 4.05kg of a product (I), namely the agonist K6 PC-5.

Example 3:

a synthetic method of sphingosine kinase agonist K6PC-5 comprises the following specific steps:

(1) 42L of dichloromethane and 5.23kg of triethylamine (51.8mol) are added into a reaction kettle, 7kg of octanoyl chloride (43.2mol) is added dropwise under the protection of nitrogen, and the reaction solution containing the intermediate III is obtained after the dropwise addition is kept at 28 ℃ and stirred for 5 hours.

(2) Adding 2.55kg serinol (28.1mol) into the reaction kettle in batches, keeping the reaction kettle at 28 ℃ for stirring for 12 hours after the addition is finished, adding 1mol/L dilute hydrochloric acid after the reaction is finished, adjusting the pH to 3-5, standing for layering, removing a water phase, washing an organic phase once by using 10L saturated saline solution, concentrating to obtain a crude product, adding 7L acetone, stirring for dissolving, slowly adding 14L water, controlling the temperature to be 0-5 ℃ for crystallization, filtering, and drying to obtain 4.12kg of a product (I), namely the agonist K6 PC-5.