CN108069863B - Method for synthesizing norepinephrine - Google Patents
Method for synthesizing norepinephrine Download PDFInfo
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- CN108069863B CN108069863B CN201611010389.3A CN201611010389A CN108069863B CN 108069863 B CN108069863 B CN 108069863B CN 201611010389 A CN201611010389 A CN 201611010389A CN 108069863 B CN108069863 B CN 108069863B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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Abstract
The invention discloses a method for synthesizing noradrenaline, which comprises the step of directly reducing noradrenaline to generate levorotatory noradrenaline by using a reducing agent, particularly (-) -diisopinocampheyl chloroborane in an ether solvent at low temperature by using (-) -diisopinocampheyl chloroborane as a catalyst to obtain a solution containing the noradrenaline. The method can directly obtain the levorotatory norepinephrine by using (-) -diisopinocampheylchloroborane as a reducing agent without splitting, and simultaneously reduces the cost and potential safety hazard.
Description
Technical Field
The invention relates to a method for synthesizing noradrenaline, in particular to a method for generating levorotatory noradrenaline by utilizing a reducing agent to react with noradrenalone.
Background
According to the literature report, most of the existing factory production processes take palladium carbon as a hydrogenation catalyst, and reduce noradrenaline ketone in a hydrogen atmosphere to prepare racemic noradrenaline. The palladium-carbon catalyst for the reaction is expensive and flammable, has large hydrogenation hidden danger and high cost, is difficult to inactivate and recycle, obtains a racemate product through the reaction, can obtain a qualified product with a single configuration only by further splitting, and further increases the reaction period and the cost.
Disclosure of Invention
The invention provides a novel process for synthesizing norepinephrine, which directly obtains levonoradrenaline by reacting a reducing agent with norepinephrine ketone without splitting, and simultaneously reduces cost and potential safety hazard.
Specifically, the method for synthesizing norepinephrine provided by the invention comprises the following steps of (1) reducing norepinephrine to generate norepinephrine by using a reducing agent in an ether solvent to obtain a solution containing norepinephrine.
In one embodiment, a solution containing levonoradrenaline is obtained.
In a particular embodiment, the reducing agent is selected from chiral oxazol boranes and/or α -pinene boranes.
In a preferred embodiment, the chiral oxazaborolidines comprise 3, 3-diphenyl-1H, 3H-tetrahydropyrrolo [1,2-c ] [1.3.2] oxazaborolidine and/or 1-methyl-3, 3-diphenyl-1H, 3H-tetrahydropyrrolo [1,2-c ] [1.3.2] oxazaborolidine; the alpha-pinene boron reagent comprises (-) -diisopinocampheylchloroborane.
In a specific embodiment, the molar ratio of norepinephrine to reducing agent is from 1:1.0 to 1: 5.0.
In one embodiment, it is preferred that the molar ratio of norepinephrine to reducing agent is from 1:2.0 to 1: 3.0.
In one embodiment, in the step (1), the ether-based solvent includes at least one of tetrahydrofuran, furan, diethyl ether, 1, 4-dioxane, methyl tert-butyl ether, and ethylene glycol dimethyl ether.
In one embodiment, it is preferable that in the step (1), the ethereal solvent is at least one of methyl tert-butyl ether, diethyl ether and ethylene glycol dimethyl ether.
In one embodiment, in step (1), the reaction temperature is from-30 ℃ to-15 ℃ and the reaction time is from 3 hours to 24 hours.
In a more preferred embodiment, in step (1), the reaction temperature is from-30 ℃ to-20 ℃ and the reaction time is from 3 hours to 5 hours.
In a more preferred embodiment, in step (1), the reaction temperature is from-30 ℃ to-25 ℃ and the reaction time is from 3 hours to 4 hours.
In a specific embodiment, the reaction temperature is adjusted to-30 ℃ to-15 ℃ under a nitrogen atmosphere, or the reaction temperature is adjusted to-30 ℃ to-20 ℃ under a nitrogen atmosphere.
In a specific embodiment, the method further comprises:
(2) adding 2 to 3 times (e.g., 2.5 times) the molar amount of (-) -diisopinocampheylchloroborane to the solution containing norepinephrine and refluxing;
(3) separating to remove the organic layer, and then adjusting the pH of the aqueous layer to 9.0 to 12.5;
(4) the norepinephrine is filtered off.
In one embodiment, the acid is selected from hydrochloric acid and/or sulfuric acid.
In one embodiment, the acid is hydrochloric acid.
In one embodiment, the reflux time in step (2) is from 1 hour to 2 hours.
In one embodiment, in step (3), the pH of the aqueous layer is adjusted to 9.5 to 10.
In one embodiment, the pH of the aqueous layer is adjusted with ammonia.
In one embodiment, in step (3), after removing the organic layer, the aqueous layer is washed at least 1 time with an ether-based solvent before adjusting the pH of the aqueous layer.
In a specific embodiment, the ethereal solvent in step (3) is at least one selected from the group consisting of tetrahydrofuran, furan, diethyl ether, 1, 4-dioxane, methyl tert-butyl ether and ethylene glycol dimethyl ether.
In one embodiment, it is preferable that the ethereal solvent in the step (3) is at least one of methyl tert-butyl ether, diethyl ether and ethylene glycol dimethyl ether.
In one embodiment, in step (3), after removing the organic layer, the temperature of the aqueous layer is adjusted to 5 ℃ to 15 ℃.
In one embodiment, in step (4), after filtering out the norepinephrine, C is used1-C4The noradrenaline is rinsed with the alcohol and dried in the dark.
In a preferred embodiment, C is as described in step (4)1-C4The alcohol of (a) includes at least one of methanol, ethanol, t-butanol and isopropanol. Wherein the methanol is anhydrous methanol, and the ethanol is anhydrous ethanol.
In the present invention, ee% is the enantiomeric excess and refers to the excess of one enantiomer over the other, usually expressed as a percentage. The beneficial effects of the invention include but are not limited to:
(1) the method provided by the invention improves the chiral purity of the product by using chiral oxazole borane and/or alpha-pinene borane as a reducing agent.
(2) The method provided by the invention avoids the use of palladium carbon, can realize large-scale production and has good safety.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
The raw materials in the examples of the present invention were all purchased from commercial sources unless otherwise specified.
The synthetic route for preparing the levonoradrenaline is as follows:
wherein, (-) -diisopinocampheylchloroborane ((-) DIPCL) can be obtained by self-preparation, and the specific preparation method is as follows:
adding ethylene glycol dimethyl ether and alpha-pinene in the molar ratio of the raw materials shown in the table I into a reaction kettle, uniformly stirring, cooling to below 0 ℃ under the protection of nitrogen, and adding sodium borohydride. Introducing boron trichloride at the temperature of below 0 ℃, naturally heating to 20-25 ℃, preserving heat for 3 hours at the temperature of 20-25 ℃, adding boron trichloride to the mixture to be preserved for 3 hours at the temperature of 37-43 ℃, cooling to 20-25 ℃, preserving heat and stirring for 24 hours at the temperature of 20-25 ℃, and finishing the preparation of the (-) -diisopinocampheylchloroborane. Stored under the protection of nitrogen, and each kilogram of reaction liquid contains 1.6mol of (-) -diisopinocampheylchloroborane.
Table one: preparation of (-) -diisopinocampheylchloroborane
| Raw materials | α -pinene | Sodium borohydride | Boron trichloride | Ethylene glycol dimethyl ether |
| Proportioning (quality ratio) | 1 | 0.07 | 0.238 | 0.96 |
The analysis method in the examples of the present invention is as follows:
in the examples of the present invention, the yield of the finished levonoradrenaline product is calculated as follows:
the yield of the finished product is equal to the weight of the obtained levonoradrenaline multiplied by 0.988/weight of noradrenalone multiplied by 100%
Example 1
Adding 16.7g (100mmol) of norepinephrine and 200mL of methyl tert-butyl ether into a 1L reaction bottle, cooling to minus 25 ℃ under the nitrogen atmosphere, dropwise adding 150g (240mmol) of (-) -diisopinocampheylchloroborane solution at the temperature lower than minus 20 ℃, controlling the temperature to minus 25 ℃ to minus 20 ℃ after dropwise adding to react for 3 hours, gradually heating to room temperature (25 ℃), adding 6M hydrochloric acid (100mL), stirring and refluxing for 1 hour, stirring for 30min at room temperature, separating an organic layer, washing an aqueous layer twice (2X 50mL) with methyl tert-butyl ether, cooling to 10 ℃, stirring, adjusting the pH to 9.5 with ammonia water, performing suction filtration, leaching a filter cake with a small amount of anhydrous ethanol, and drying in the dark to obtain white crystalline powder. The reaction time was checked by TLC.
Parallel experiments were performed by replacing the above reducing agent with 3, 3-diphenyl-1H, 3H-tetrahydropyrrolo [1,2-c ] [1.3.2] oxazaborolidine and 1-methyl-3, 3-diphenyl-1H, 3H-tetrahydropyrrolo [1,2-c ] [1.3.2] oxazaborolidine, respectively, and the time required for completion of the reaction and the results are shown in table two.
Table two: effect of reducing Agents on reaction time, purity and yield
The above solvents methyl tert-butyl ether was replaced with tetrahydrofuran, furan, diethyl ether, 1, 4-dioxane and ethylene glycol dimethyl ether, and parallel experiments were conducted, respectively, with the time required for completion of the reaction and the results shown in Table III.
Table three: effect of solvent on reaction time, purity and yield
Example 2
Adding 16.7g (100mmol) of norepinephrine and 200mL of methyl tert-butyl ether into a 1L reaction bottle, cooling to minus 25 ℃ under the nitrogen atmosphere, dropwise adding 150g (240mmol) of (-) -diisopinocampheylchloroborane solution at the temperature lower than minus 20 ℃, controlling the temperature to minus 25 ℃ to minus 20 ℃ after dropwise adding to react for 3 hours, gradually heating to room temperature (30 ℃), adding 6M hydrochloric acid (100mL), stirring and refluxing for 1 hour, stirring for 30min at room temperature, separating an organic layer, washing an aqueous layer twice (2X 50mL) with methyl tert-butyl ether, cooling to 5 ℃, stirring, adjusting the pH to 10 with ammonia water, performing suction filtration, leaching a filter cake with a small amount of tert-butyl alcohol, and drying in the dark to obtain white crystalline powder.
The reaction temperature was adjusted to-20 to-15 ℃ and-30 to-25 ℃ to perform parallel experiments, respectively, and the results are shown in table four.
Table four: effect of reaction temperature on chiral purity
Example 3
Adding 16.7g (100mmol) of norepinephrine and 200mL of methyl tert-butyl ether into a 1L reaction bottle, cooling to minus 30 ℃ under nitrogen atmosphere, dropwise adding 150g (240mmol) of (-) -diisopinocampheylchloroborane solution at the temperature lower than minus 25 ℃, controlling the temperature to minus 30 ℃ to minus 25 ℃ after dropwise adding, reacting for 3 hours, gradually heating to room temperature (20 ℃), adding 6M hydrochloric acid (100mL), stirring and refluxing for 1 hour, stirring for 30 minutes at room temperature, separating an organic layer, washing an aqueous layer twice (2X 50mL) with methyl tert-butyl ether, cooling to 10 ℃, stirring, adjusting the pH to 9.5 with ammonia water, performing suction filtration, leaching a filter cake with a small amount of isopropanol, and drying in the dark to obtain white crystalline powder.
The charging amount of (-) -diisopinocampheylchloroborane in the reaction is adjusted to be 1.0eq to 3.0eq, 9 nodes are selected to carry out parallel experiments respectively, and the results are shown in table five.
Table five: effect of the Charge ratio of (-) -diisopinocampheylchloroborane on the reaction
The above description is only for the purpose of illustrating the present invention and is not intended to limit the present invention in any way, and the present invention is not limited to the above description, but rather should be construed as being limited to the scope of the present invention.
Claims (19)
1. A method for synthesizing noradrenaline is characterized by comprising the steps of (1) reducing noradrenaline ketone in an ether solvent by using a reducing agent to generate noradrenaline, and directly obtaining a solution containing levorotatory noradrenaline;
the reducing agent is selected from chiral oxazole borane and/or alpha-pinene borane;
the chiral oxazaborolidines comprise 3, 3-diphenyl-1H, 3H-tetrahydropyrrolo [1,2-c ] [1.3.2] oxazaborolidine and/or 1-methyl-3, 3-diphenyl-1H, 3H-tetrahydropyrrolo [1,2-c ] [1.3.2] oxazaborolidine; the alpha-pinene boron reagent comprises (-) -diisopinocampheylchloroborane.
2. The method of claim 1, wherein the molar ratio of norepinephrine to reducing agent is from 1:1.0 to 1: 5.0.
3. The method of claim 2, wherein the molar ratio of norepinephrine to reducing agent is from 1:2.0 to 1: 3.0.
4. The method according to claim 1, wherein the ether solvent comprises at least one of tetrahydrofuran, furan, diethyl ether, 1, 4-dioxane, methyl tert-butyl ether, and ethylene glycol dimethyl ether.
5. The method according to claim 4, wherein the ethereal solvent is at least one of methyl tert-butyl ether, diethyl ether and ethylene glycol dimethyl ether.
6. The method according to claim 1, wherein in step (1), the reaction temperature is from-30 ℃ to-15 ℃ and the reaction time is from 3 hours to 24 hours.
7. The method according to claim 6, wherein in the step (1), the reaction temperature is from-30 ℃ to-20 ℃ and the reaction time is from 3 hours to 5 hours.
8. The method according to claim 7, wherein in the step (1), the reaction temperature is from-30 ℃ to-25 ℃ and the reaction time is from 3 hours to 4 hours.
9. The method of claim 1, further comprising:
(2) adding 2 to 3 times of acid of the molar weight of (-) -diisopinocampheylchloroborane into the solution containing the norepinephrine, and refluxing;
(3) separating to remove the organic layer, and then adjusting the pH of the aqueous layer to 9.0 to 12.5;
(4) the norepinephrine is filtered off.
10. The process according to claim 9, wherein in step (2), the acid is selected from hydrochloric acid and/or sulfuric acid.
11. The method according to claim 10, wherein in step (2), the acid is hydrochloric acid.
12. The method according to claim 9, wherein in step (3), the pH of the aqueous layer is adjusted to 9.0 to 10.
13. The method of claim 9, wherein the pH of the aqueous layer is adjusted with ammonia.
14. The method according to claim 9, wherein in the step (3), after removing the organic layer, the aqueous layer is washed at least 1 time with the ethereal solvent before adjusting the pH of the aqueous layer.
15. The method as claimed in claim 14, wherein, in the step (3), the ether-based solvent includes at least one of tetrahydrofuran, furan, diethyl ether, 1, 4-dioxane, methyl tert-butyl ether and ethylene glycol dimethyl ether.
16. The method as claimed in claim 15, wherein, in the step (3), the ethereal solvent is at least one selected from the group consisting of methyl t-butyl ether, diethyl ether and ethylene glycol dimethyl ether.
17. The method according to claim 9, wherein in step (3), after removing the organic layer, the temperature of the aqueous layer is adjusted to 5 to 15 ℃.
18. The method of claim 9, wherein in step (4), the noradrenaline is filtered off and then administered with C1-C4The noradrenaline is rinsed with the alcohol and dried in the dark.
19. The method of claim 18, wherein in step (4), C is1-C4The alcohol of (a) includes at least one of methanol, ethanol, t-butanol and isopropanol.
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| EP3725765A1 (en) | 2019-04-18 | 2020-10-21 | Edmond Pharma S.R.L. | A process for the preparation of enantiomerically pure norepinephrine |
| CN112079733B (en) * | 2020-09-25 | 2022-09-06 | 南京仁为医药科技有限公司 | Method for asymmetrically synthesizing noradrenaline bitartrate |
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