CN111302953B - Method for synthesizing spermidine hydrochloride - Google Patents
Method for synthesizing spermidine hydrochloride Download PDFInfo
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- CN111302953B CN111302953B CN202010184242.6A CN202010184242A CN111302953B CN 111302953 B CN111302953 B CN 111302953B CN 202010184242 A CN202010184242 A CN 202010184242A CN 111302953 B CN111302953 B CN 111302953B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- 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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Abstract
The invention relates to a method for synthesizing spermidine hydrochloride, wherein the reaction formula is shown as the following formula (I):
in the formula (I), the protecting group R of amino group in 4-amino-1-butanol of the compound 2 1 Is one of Boc-, triphenylmethyl Trt-and p-methoxyl triphenylmethyl Mmt-; protecting group R of propane diamine of compound 2 Is one of Boc-), triphenylmethyl Trt-and p-methoxyl triphenylmethyl (Mmt-); the reagent used in the Mitsunobo reaction condition is one of triphenyl phosphorus, di-tert-butyl azodicarboxylate, diethyl azodicarboxylate and diisopropyl azodicarboxylate. The preparation method provided by the invention has the advantages of simple required process conditions, mild reaction conditions, capability of effectively obtaining spermidine hydrochloride, shorter synthesis steps and higher synthesis yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis methodologies, and particularly relates to a method for synthesizing spermidine hydrochloride.
Background
Spermidine is a polyamine that is widely distributed in the body and can inhibit neuronal NO synthase, bind and precipitate DNA, and can also be used to purify DNA binding proteins and stimulate the activity of T4 polynucleotide kinase. Spermidine is involved in many biological processes in the body, such as regulation of cell proliferation, cell senescence, organ development, immunity, and cancer. The cooperation of scientists in germany and austria on 1/9 in 2013 indicates that spermidine can prevent the onset of senile dementia. The existing method for synthesizing spermidine mainly comprises the following routes:
1.
2.
in the existing method for synthesizing spermidine, the general situation is that the synthetic route is long, a dangerous reducing agent such as lithium aluminum hydride is needed, even a control reagent such as hydrazine hydrate is used, the reaction yield is not high, and the like. Aiming at the problems in the synthesis of spermidine at present, the invention provides a novel method for preparing spermidine hydrochloride.
Disclosure of Invention
1. The technical problem to be solved is as follows:
aiming at the technical problems, the invention provides a method for synthesizing spermidine hydrochloride, which has high safe reaction yield in the synthesis process.
2. The technical scheme is as follows:
a method for synthesizing spermidine hydrochloride, comprising: the reaction formula of the method is shown as the following formula (I):
in the formula (I), the protecting group R of amino group in 4-amino-1-butanol of the compound 2 1 Is one of Boc-, triphenylmethyl Trt-and p-methoxyl triphenylmethyl Mmt-; protecting group R of propylenediamine of compound 2 Is one of Boc-), triphenylmethyl Trt-, and p-methoxyl triphenylmethyl (Mmt-); the reagent used in the Mitsunobo reaction condition is one of triphenyl phosphine, di-tert-butyl azodicarboxylate, diethyl azodicarboxylate and diisopropyl azodicarboxylate.
Further, a method for synthesizing spermidine hydrochloride, characterized by: the method comprises the following steps:
the method comprises the following steps: under the condition of normal temperature, 11mmol of compound 2,10mmol of protected propane diamine and 2.88g, 11mmol of triphenylphosphine are added in sequence, 50ml of tetrahydrofuran is added for dissolution, finally 10mmol of diisopropyl azodicarboxylate or other azo reagents are added, stirring is carried out for 8 hours at room temperature, and the reaction is monitored by TLC.
Step two: and (3) obtaining a compound 3 after the reaction in the step one is finished, and crystallizing and purifying the obtained compound 3 in an organic solvent.
Step three: and (3) removing a protecting group of the purified compound 3 obtained in the step two by using a 4M hydrochloric acid solution to obtain a crude product of the spermidine hydrochloride compound 4, and crystallizing and drying the crude product to obtain a finished spermidine hydrochloride product.
Further, in step one, compound 2: protected propylenediamine: triphenylphosphine: the molar ratio of the azo reagents is 1.1:1:1.1: 1.1.
Further, the following steps: in the second step, the compound 3 is purified by a crystallization method, and the crystallization solvent of the compound 3 is one of ethyl acetate and petroleum ether, ethyl acetate and n-heptane, ethyl acetate and n-hexane, ethyl acetate and cyclohexane, a mixed solution of propyl acetate and petroleum ether, a mixed solution of propyl acetate and n-heptane, a mixed solution of propyl acetate and n-hexane, a mixed solution of propyl acetate and cyclohexane, a mixed solution of butyl acetate and petroleum ether, a mixed solution of butyl acetate and n-heptane, a mixed solution of butyl acetate and n-hexane, a mixed solution of butyl acetate and cyclohexane, a mixed solution of dichloromethane and n-heptane, and a mixed solution of toluene, acetone and n-heptane.
Further, in the third step, the compound 3 is separated from spermidine hydrochloride through the separation of an organic solvent and water after decompression concentration by respectively passing through a hydrochloric acid methanol system, a hydrochloric acid ethanol system, a hydrochloric acid methanol/water system, a hydrochloric acid ethanol/water system for removing tert-butyloxycarbonyl (Boc-), triphenylmethyl (Trt-), and p-methoxytriphenylmethyl (Mmt-) protecting groups, wherein the organic solvent for separation phase extraction is one or a mixture of ethyl acetate, dichloromethane, propyl acetate and butyl acetate; in the above method for preparing spermidine hydrochloride, the solvent for crystallization is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, tetrahydrofuran, and ethyl acetate; wherein the drying mode is vacuum reduced pressure drying, heating forced air drying or infrared drying.
3. Has the beneficial effects that:
the preparation method provided by the invention has the advantages of simple required process conditions, mild reaction conditions, capability of effectively obtaining spermidine hydrochloride, shorter synthesis steps and higher synthesis yield.
Detailed Description
A method for synthesizing spermidine hydrochloride, characterized by: the reaction formula of the method is shown as the following formula (I):
in formula (I), the protecting group R of amino group in 4-amino-1-butanol of compound 2 1 Is one of Boc-, triphenylmethyl Trt-and p-methoxyl triphenylmethyl Mmt-; protecting group R of propane diamine of compound 2 Is one of Boc-), triphenylmethyl Trt-and p-methoxyl triphenylmethyl (Mmt-); the reagent used in the Mitsunobo reaction condition is one of triphenyl phosphorus, di-tert-butyl azodicarboxylate, diethyl azodicarboxylate and diisopropyl azodicarboxylate.
Further, a method for synthesizing spermidine hydrochloride is characterized by comprising the following steps: the method comprises the following steps:
the method comprises the following steps: under the condition of normal temperature, 11mmol of compound 2,10mmol of protected propane diamine and 2.88g, 11mmol of triphenylphosphine are added in sequence, 50ml of tetrahydrofuran is added for dissolution, finally 10mmol of diisopropyl azodicarboxylate or other azo reagents are added, stirring is carried out for 8 hours at room temperature, and the reaction is monitored by TLC.
Step two: and (3) obtaining a compound 3 after the reaction in the step one is finished, and crystallizing and purifying the obtained compound 3 in an organic solvent.
Step three: and (3) removing a protecting group of the purified compound 3 obtained in the step (II) by using a 4M hydrochloric acid solution to obtain a spermidine hydrochloride compound 4 crude product, and crystallizing and drying the crude product to obtain a spermidine hydrochloride finished product.
Further, in step one, compound 2: protected propylenediamine: triphenylphosphine: the molar ratio of the azo reagents is 1.1:1:1.1: 1.1.
Further, the following steps: in the second step, the compound 3 is purified by a crystallization method, and the crystallization solvent of the compound 3 is one of ethyl acetate and petroleum ether, ethyl acetate and n-heptane, ethyl acetate and n-hexane, ethyl acetate and cyclohexane, a mixed solution of propyl acetate and petroleum ether, a mixed solution of propyl acetate and n-heptane, a mixed solution of propyl acetate and n-hexane, a mixed solution of propyl acetate and cyclohexane, a mixed solution of butyl acetate and petroleum ether, a mixed solution of butyl acetate and n-heptane, a mixed solution of butyl acetate and n-hexane, a mixed solution of butyl acetate and cyclohexane, a mixed solution of dichloromethane and n-heptane, and a mixed solution of toluene, acetone and n-heptane.
Further, in the third step, the compound 3 is separated from spermidine hydrochloride through the removal of tert-butyloxycarbonyl (Boc-), triphenylmethyl (Trt-), p-methoxytriphenylmethyl (Mmt-) protecting groups by a hydrochloric acid methanol system, a hydrochloric acid ethanol system, a hydrochloric acid methanol/water system, a hydrochloric acid ethanol/water system, and the phase separation of the removed protecting groups and spermidine hydrochloride by the organic solvent and water after reduced pressure concentration, wherein the organic solvent for phase separation extraction is one or a mixture of ethyl acetate, dichloromethane, propyl acetate and butyl acetate; in the above method for preparing spermidine hydrochloride, the solvent for crystallization is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, tetrahydrofuran and ethyl acetate; wherein the drying mode is vacuum reduced pressure drying, heating forced air drying or infrared drying.
Example 1
(1) Boc protected compound 2a (2.08g, 11mmol), Boc protected propylenediamine (1.74g, 10mmol), triphenylphosphine (2.88g, 11mmol) and 50ml tetrahydrofuran were added sequentially at room temperature to dissolve them, diisopropyl azodicarboxylate (10mmol) was added and stirred at room temperature for a while, and the reaction was monitored by TLC until the reaction was completed.
(2) 10mL of 4M hydrochloric acid solution was added to the reaction system, TLC was performed until the reaction of Compound 3 produced in (1) was completed, 30mL of water was added, EA was used for extraction, the aqueous phase was collected, the organic phase was further extracted with water three times, and the aqueous phases were combined. The water is distilled off under reduced pressure to obtain a crude product of the compound 4, and the crude product is crystallized and purified by a methanol/dichloromethane system to extract the compound 4.
Example 2
(1) Boc protected compound 2a (2.08g, 11mmol), Boc protected propylenediamine (1.74g, 10mmol), triphenylphosphine (2.88g, 11mmol) and 50ml tetrahydrofuran were added sequentially at room temperature to dissolve them, diisopropyl azodicarboxylate (10mmol) was added and stirred at room temperature for a while, and the reaction was monitored by TLC until the reaction was completed.
(2) After the reaction is finished, the solvent is removed by reduced pressure distillation, and the compound 3 is obtained by column chromatography separation. Dissolving the obtained compound 3 in methanol, adding 10mL of 4M hydrochloric acid solution, monitoring by TLC (thin layer chromatography) until the reaction is finished, removing the solvent and low-boiling-point compounds under reduced pressure, and crystallizing and purifying the obtained crude product by using a methanol/dichloromethane system to obtain a compound 4.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto, and various changes and modifications can be made by one skilled in the art without departing from the spirit and scope of the invention.
Claims (5)
1. A method for synthesizing spermidine hydrochloride, comprising: the reaction formula of the method is shown as the following formula (I):
in formula (I), the protecting group R of amino group in 4-amino-1-butanol of compound 2 1 Is one of Boc-, triphenylmethyl Trt-and p-methoxyl triphenylmethyl Mmt-; protecting group R of propylenediamine of Compound 1 2 Is one of Boc-, triphenylmethyl Trt-and p-methoxyl triphenylmethyl Mmt-; reagents used in the Mitsunobo reaction conditions are triphenylphosphine and an azo reagent; the azo reagent is selected from one of di-tert-butyl azodicarboxylate, diethyl azodicarboxylate and diisopropyl azodicarboxylate.
2. A process for the synthesis of spermidine hydrochloride according to claim 1 wherein: the method comprises the following steps:
the method comprises the following steps: under the condition of normal temperature, sequentially adding 11mmol of compound 2,10mmol of compound 1 and 11mmol of triphenylphosphine, adding 50ml of tetrahydrofuran for dissolving, finally adding 10mmol of diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate or diethyl azodicarboxylate, stirring for 8 hours at room temperature, and monitoring the reaction by TLC;
step two: after the reaction in the step one is finished, obtaining a compound 3, and crystallizing and purifying the obtained compound 3 in an organic solvent;
step three: and (3) removing a protecting group of the purified compound 3 obtained in the step (II) by using a 4M hydrochloric acid solution to obtain a spermidine hydrochloride compound 4 crude product, and crystallizing and drying the crude product to obtain a spermidine hydrochloride finished product.
3. A process for the synthesis of spermidine hydrochloride according to claim 2 wherein in step one, compound 2: compound 1: triphenylphosphine: the molar ratio of the azo reagents is 1.1:1:1.1: 1.1.
4. A process for the synthesis of spermidine hydrochloride according to claim 2 wherein: in the second step, the compound 3 is purified by a crystallization method, and the crystallization solvent of the compound 3 is one of a mixed solution of ethyl acetate and petroleum ether, a mixed solution of ethyl acetate and n-heptane, a mixed solution of ethyl acetate and n-hexane, a mixed solution of ethyl acetate and cyclohexane, a mixed solution of propyl acetate and petroleum ether, a mixed solution of butyl acetate and n-heptane, a mixed solution of butyl acetate and n-hexane, a mixed solution of butyl acetate and cyclohexane, a mixed solution of dichloromethane and n-heptane, and a mixed solution of toluene, acetone and n-heptane.
5. A process for the synthesis of spermidine hydrochloride according to claim 2, characterized in that: in the third step, the compound 3 is separated from spermidine hydrochloride through the separation of an organic solvent and water after decompression concentration by respectively passing through a hydrochloric acid methanol system, a hydrochloric acid ethanol system, a hydrochloric acid methanol/water system and a hydrochloric acid ethanol/water system to remove tert-butyloxycarbonyl Boc-, triphenylmethyl Trt-, p-methoxytriphenylmethyl Mmt-protecting groups, wherein the organic solvent extracted by phase separation is one or more of ethyl acetate, dichloromethane, propyl acetate and butyl acetate; in the above method for preparing spermidine hydrochloride, the solvent for crystallization is one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, tetrahydrofuran and ethyl acetate; wherein the drying mode is vacuum reduced pressure drying, heating forced air drying or infrared drying.
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| CN202010184242.6A CN111302953B (en) | 2020-03-17 | 2020-03-17 | Method for synthesizing spermidine hydrochloride |
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| CN113548971B (en) * | 2021-07-29 | 2023-12-15 | 上海朴颐化学科技有限公司 | Synthesis process of spermidine and intermediate thereof |
| CN113735716B (en) * | 2021-11-08 | 2022-02-11 | 山东盛安贝新能源有限公司 | Preparation method of spermidine |
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Non-Patent Citations (1)
| Title |
|---|
| Conformational change of spermidine upon interaction with adenosine triphosphate in aqueous solution;Keisuke Maruyoshi Dr等;《Chemistry A European Journal》;20090126;第1618-1626页 * |
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