CN115894276A - Synthesis method of 16-hydroxy capsaicin and marker thereof - Google Patents
Synthesis method of 16-hydroxy capsaicin and marker thereof Download PDFInfo
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- OGBQQOBPAFILCJ-YRNVUSSQSA-N (e)-8-hydroxy-n-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)(C)O)=CC=C1O OGBQQOBPAFILCJ-YRNVUSSQSA-N 0.000 title claims abstract description 36
- 238000001308 synthesis method Methods 0.000 title claims description 21
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- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 4
- 239000011986 second-generation catalyst Substances 0.000 claims description 4
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 claims description 3
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 claims description 3
- RWNJOXUVHRXHSD-UHFFFAOYSA-N hept-6-enoic acid Chemical compound OC(=O)CCCCC=C RWNJOXUVHRXHSD-UHFFFAOYSA-N 0.000 claims description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 abstract description 24
- 229960002504 capsaicin Drugs 0.000 abstract description 10
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- LSIRKKJMETWUBA-SOFGYWHQSA-N (6e)-n-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnona-6,8-dienamide Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)=C)=CC=C1O LSIRKKJMETWUBA-SOFGYWHQSA-N 0.000 description 1
- OCVIWAFGWPJVGZ-FNORWQNLSA-N (e)-9-hydroxy-n-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)CO)=CC=C1O OCVIWAFGWPJVGZ-FNORWQNLSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing 16-hydroxy capsaicin and isotope labels thereof, namely a compound 4 and a compound d 3 -3 or d 3 -3, the target compound can be efficiently synthesized by olefin metathesis reaction of the raw material, and the method is simple and easy to operate; wherein the structural formula of the compound 4 is
Structural formula of the compound 3Is composed of
Compound d 3 -3 has the structural formula
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing 16-hydroxy capsaicin and a marker thereof.
Background
Capsaicin, trans-8-methyl-N-vanillyl-6-nonenamide, otherwise known as capsaicin, is the most important pungent ingredient in pepper and is widely used in pepper sprays and crop protection agents. As an active pharmaceutical ingredient, capsaicin is often used to make topical formulations to relieve pain. In addition, capsaicin has been found to have antioxidant, anticancer and anti-inflammatory activities, and is in phase three clinical trials as a drug for the treatment of arthritis, postoperative pain, acute and chronic neuropathy and musculoskeletal pain.
In the body, drugs are generally biotransformed through phase I and phase II metabolic pathways, and since the phase I reaction mainly involves processes such as oxidation, reduction, and hydrolysis, the resulting metabolites may have pharmacological activity, and thus further safety evaluation is required. The phase I metabolism of capsaicin in an organism is mainly mediated by P450 enzymes, and the phase I metabolic process mainly occurs on an alkyl chain, an aromatic ring and an amide to generate capsaicin hydroxylation, demethylation and dehydrogenation metabolites, wherein macrocyclic metabolites (M1), omega- (16-hydroxy capsaicin, M2) and omega-1 (17-hydroxy capsaicin, M3) alcohol and terminal dehydrodiene (16, 17-dehydrocapsaicin, M4) account for 80 percent. Further studies on the pharmacokinetics of capsaicin in vivo and the pharmacological activities of its major metabolites will undoubtedly help to understand more comprehensively the various effects of capsaicin in the body. However, the above studies are currently severely limited by the lack of sufficient standards for capsaicin metabolites and efficient chemical synthesis thereof.
Disclosure of Invention
In view of the above, the present invention provides a method for synthesizing 16-hydroxy capsaicin and its marker.
Specifically, the synthesis method of 16-hydroxy capsaicin provided by the invention comprises the step of synthesizing the 16-hydroxy capsaicin by taking a compound 3 and a compound 4 as raw materials to perform olefin metathesis reaction, wherein the structural formula of the compound 3 is shown in the specification
The compound 4 has the structural formula of->
The structural formula of the 16-hydroxy capsaicin is as follows:
the synthetic route of the reaction is as follows:
based on the synthesis method, the method comprises the following steps: under the action of Grubbs secondary catalyst in nitrogen atmosphere, the compound 3 and the compound 4 undergo olefin metathesis at 25-50 ℃ to synthesize the 16-hydroxy capsaicin. Preferably, the molar ratio of compound 3, grubbs secondary catalyst and compound 4 is 1: (0.01-0.05): (2.0-4.0).
The method for synthesizing the 16-hydroxy capsaicin by olefin metathesis reaction specifically comprises the following steps: and under the action of Grubbs secondary catalyst in nitrogen atmosphere, carrying out reflux reaction on the compound 3 and the compound 4 at 40-50 ℃ until the compound 3 completely reacts, and synthesizing the 16-hydroxy capsaicin.
Based on the synthesis method, the method comprises the steps of purifying by vacuum concentration and column chromatography purification after the olefin metathesis synthesis of the 16-hydroxy capsaicin to prepare the pure 16-hydroxy capsaicin.
Based on the synthesis method, the synthesis method of the compound 3 comprises the following steps: taking 6-heptenoic acid and a compound 2 as raw materials to carry out amidation reaction to synthesize the compound 3, wherein the structural formula of the compound 2 is shown in the specification
The synthetic route of the reaction is as follows:
based on the synthesis method, the synthesis method of the compound 3 comprises the following steps: 6-heptenoic acid and the compound 2 are subjected to amidation reaction at 0-30 ℃ under the action of diisopropylethylamine and benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to synthesize the compound 3. Preferably, the mol ratio of the 6-heptenoic acid, the diisopropylethylamine, the benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to the compound 2 is 1: (2.0-3.0): (1.0-1.5): (1.0-1.5).
The synthesis method of the compound 3 specifically comprises the following steps: in N, N-dimethylformamide solution, 6-heptenoic acid, diisopropylethylamine and benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate are uniformly stirred at the temperature of-5 ℃; then adding the compound 2 in batches, and carrying out amidation reaction at room temperature to synthesize the compound 3; the reaction was then quenched with aqueous hydrochloric acid, extracted with ethyl acetate, the organic phase washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure, and the crude product purified by column chromatography to give pure compound 3.
The invention also provides a synthetic method of the 16-hydroxy capsaicin marker, which comprises the following steps: with compounds d 3 -3 and compound 4 as raw materials to perform olefin metathesis reaction to synthesize d 3 -16-hydroxycapsaicin, wherein the compound d 3 -3 has the structural formula
The structural formula of the compound 4 is as follows: />
d 3 -16-hydroxy capsaicin has the structural formula: />
Based on the synthesis method, the method comprises the following steps: under the action of Grubbs secondary catalyst in nitrogen atmosphere 3 -3 and 4 at 25 ℃ to 50 ℃ for the synthesis of d by olefin metathesis 3 -16-hydroxycapsaicin, and said compound d 3 -3, grubbs' second generation catalyst and compound 4 in a molar ratio of 1: (0.01-0.05): (2.0-4.0).
Based on the above synthesis process, which comprises carrying out the olefin metathesis synthesis d 3 After-16-hydroxy capsaicin, the product is purified by vacuum concentration and column chromatography to obtain d 3 -pure 16-hydroxy capsaicin.
Based on the above synthetic method, the compound d 3 The synthesis method of the-3 comprises the following steps: with 6-heptenoic acid and compound d 3 -2 is taken as raw material to carry out amidation reaction to synthesize the compound d 3 -3, wherein the compound d 3 -2 has the formula:
based on the above synthesis method, the compound d 3 The synthesis method of-3 comprises: in diisopropylethylamine and benzotriazole-N, N6-N-heptenoic acid and compound d under the action of N ', N' -tetramethyluronium hexafluorophosphate 3 -2 amidation reaction at 0-30 ℃ to synthesize the compound 3; and 6-N-heptenoic acid, diisopropylethylamine, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and compound d 3 -2 in a molar ratio of 1: (2.0-3.0): (1.0-1.5): (1.0-1.5).
Therefore, the invention provides a method for synthesizing the 16-hydroxy capsaicin and the isotope label thereof, and the compound 4 and the compound d 3 -3 or d 3 And the target compound can be efficiently synthesized by olefin metathesis reaction of the raw material-3, and the method is simple and easy to operate. In addition, the invention also provides a synthetic method of the 16-hydroxy capsaicin and the isotope markers thereof, which starts from 6-heptenoic acid, efficiently realizes the synthesis of target molecules through amidation reaction and olefin metathesis reaction, has reasonable design of the whole synthetic route, simple and easily obtained raw materials, simple and convenient operation, strong operability, easy purification and high purity of the obtained target product, ensures that the purity of the product reaches more than 95 percent, meets the purity requirement of capsaicin metabolite standard products, provides test samples for the research of the in vivo metabolism mechanism of the capsaicin, and has important application value.
Detailed Description
The technical solution of the present invention is further described in detail by the following embodiments.
Example 1
The embodiment provides a method for synthesizing 16-hydroxy capsaicin, which comprises the following steps: 6.60g of Compound 3 and 0.53g of Grubbs's second generation catalyst were placed in a dry three-necked flask under nitrogen, and then 125mL of dry dichloromethane containing 6.50g of Compound 4 were added by syringe. The reaction system was heated under reflux (removal of ethylene by-product) for 12 hours under a continuous nitrogen flow at 45 ℃; after complete consumption of compound III, the reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography to give 5.30g of 16-hydroxy capsaicin in 66% yield and about 98.5% purity; the synthetic route of this step is shown below:
of which 16-hydroxy capsaicin 1 H NMR(400MHz,CDCl 3 )δ6.86(d,J＝8.0Hz,1H),6.80(d,J＝1.9Hz,1H),6.76(dd,J＝8.0,1.9Hz,1H),5.84–5.71(m,2H),5.62-5.54(m,2H),4.35(d,J＝5.6Hz,2H),3.87(s,3H),2.20(t,J＝7.5Hz,2H),2.06-2.01(m,2H),1.77(br s,1H),1.66(p,J＝7.6Hz,2H),1.40(p,J＝7.5Hz,2H),1.29(s,6H)。
Example 2
This example provides a method of 16-hydroxycapsaicin that is substantially the same as the method provided in example 1, except that, under nitrogen and with the aid of 0.42g of Grubbs's two-generation catalyst, 5.28g of Compound 3 and 5.20g of Compound 4 are subjected to an olefin metathesis reaction at 40 ℃ to synthesize 4.69g of 16-hydroxycapsaicin in 70% yield and a purity of about 95.9%.
Example 3
This example provides a method of synthesizing 16-hydroxypivacin, which is substantially the same as the method provided in example 1, except that 3.95g of compound 3 and 3.90g of compound 4 were subjected to olefin metathesis at 50 ℃ in a nitrogen atmosphere and under the action of 0.32g of Grubbs' second generation catalyst to synthesize 3.2g of 16-hydroxypivacin, with a yield of 64% and a purity of about 96.7%.
Example 4
This example provides a method for synthesizing 16-hydroxycapsaicin, which starts from 6-heptenoic acid and synthesizes the target compound through amidation reaction and olefin metathesis reaction. The main difference between this example and the synthesis method provided in example 1 is that: the compound 3 in this example was synthesized by amidation reaction of 6-n-heptenoic acid and the compound 2. The specific synthesis method of the compound 3 in this example is: dissolving 3.80g of 6-heptenoic acid in 60mL of N, N-dimethylformamide, adding 9.70g of Diisopropylethylamine (DIPEA) and 13.7g of benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) at 0 ℃, stirring the reaction system at 0 ℃ for 30 minutes, then adding 6.80g of compound 2 in batches, and continuing to stir at room temperature for 2 hours; the reaction was quenched with 0.5M hydrochloric acid solution, extracted with ethyl acetate,the organic phase is dried over sodium sulfate and concentrated under reduced pressure, and the crude product is purified by chromatography to give 6.70g of compound 3 in 85% yield. Process for preparation of Compound 3 1 H NMR(400MHz,CDCl 3 ) δ 6.87-6.74 (m, 3H), 5.83-5.73 (m, 3H), 5.02-4.92 (m, 2H), 4.35 (d, J =5.7hz, 2h), 3.87 (s, 3H), 2.21 (t, J =7.6hz, 2h), 2.09-2.03 (m, 2H), 1.71-1.62 (m, 2H), 1.46-1.38 (m, 2H) ppm. The synthetic route of this step is as follows:
example 5
This example provides a method for synthesizing 16-hydroxy capsaicin, which is substantially the same as the method provided in example 4, but differs mainly in the conditions of the synthesis parameters of compound 3. Specifically, in this example, 5.10g of 6-heptenoic acid and 9.12g of Compound 2 were amidated at room temperature with 12.9g of DIPEA and 18.35g of HBTU to synthesize 8.68g of the compound 3 with a yield of 83%.
Example 6
This example provides a method of synthesis of a 16-hydroxy capsaicin marker that is essentially the same as that provided in example 1, except that this step essentially employs 6.68g of Compound d 3 -3 and 6.50g of Compound 4 are subjected to an olefin metathesis reaction to synthesize an isotopic label d of 5.35g of 16-hydroxycapsaicin 3 -16-hydroxycapsaicin in 63% yield and about 98.2% purity. The synthetic route of this step is as follows:
wherein d is 3 Method for producing (E) -16-hydroxy capsaicin 1 H NMR(400MHz,CDCl 3 )δ6.86(d,J＝8.0Hz,1H),6.80(d,J＝1.9Hz,1H),6.76(dd,J＝8.0,2.0Hz,1H),6.15–6.10(m,1H),5.72(br s,2H),5.66–5.58(m,1H),4.86(s,2H),4.35(d,J＝5.6Hz,2H),2.21(t,J＝7.6Hz,2H),2.15–2.09(m,2H),1.82(s,3H),1.73–1.64(m,2H),1.48–1.41(m,2H)ppm。
Example 7
This example provides a 16-hydroxy capsaicin labelSynthesis of a compound from 6-heptenoic acid and compound d 3 And 2, synthesizing the target compound by amidation reaction and olefin metathesis reaction. The main difference between this example and the synthesis method provided in example 1 is that: compound d in the present example 3 -3 is composed of 6-heptenoic acid and compound d 3 -2 is synthesized by amidation, essentially following the procedure for the synthesis of Compound 3 as provided in example 4, with the main difference that Compound d 3 The synthesis parameters of-3 are different. Specifically, in this example, under the action of 6.45g of DIPEA and 9.18g of HBTU, 2.55g of 6-heptenoic acid and 4.62g of compound d 3 -2 Synthesis of 4.63g of said Compound d by amidation at room temperature 3 -3, yield 88%. The synthetic route of the step is as follows:
finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.
Claims (10)
1. A method for synthesizing 16-hydroxy capsaicin comprises the step of synthesizing the 16-hydroxy capsaicin by olefin metathesis reaction by taking a compound 3 and a compound 4 as raw materials, wherein the structural formula of the compound 3 is shown in the specification
The compound 4 has the structural formula of->
2. The synthesis method according to claim 1, characterized in that it comprises: under the action of Grubbs secondary catalyst in nitrogen atmosphere, the compound 3 and the compound 4 undergo olefin metathesis at 25-50 ℃ to synthesize the 16-hydroxy capsaicin.
3. The method of claim 2, comprising, after said olefin metathesis synthesis of 16-hydroxycapsaicin, vacuum concentration and column chromatography to produce pure 16-hydroxycapsaicin.
4. The method of synthesis according to claim 1, 2 or 3, characterized in that the method of synthesis of compound 3 comprises: taking 6-heptenoic acid and a compound 2 as raw materials to carry out amidation reaction to synthesize the compound 3, wherein the structural formula of the compound 2 is shown in the specification
5. The method of synthesis according to claim 4, wherein the method of synthesis of compound 3 comprises: 6-heptenoic acid and the compound 2 are subjected to amidation reaction at 0-30 ℃ under the action of diisopropylethylamine and benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate to synthesize the compound 3.
6. A method for synthesizing a 16-hydroxy capsaicin marker, which comprises the following steps: with a compound d 3 -3 and compound 4 as raw materials to perform olefin metathesis reaction to synthesize d 3 -16-hydroxycapsaicin, wherein the compound d 3 -3 has the structural formula
The structural formula of the compound 4 is as follows: />
d 3 The structural formula of the (E) -16-hydroxy capsaicin is shown in the specification
7. The synthesis method according to claim 6, characterized in that it comprises: under the action of Grubbs secondary catalyst in nitrogen atmosphere, the compound d 3 -3 and 4 at 25 ℃ to 50 ℃ for the synthesis of d by olefin metathesis 3 -16-hydroxycapsaicin, and said compound d 3 -3, grubbs' second generation catalyst and compound 4 in a molar ratio of 1: (0.01-0.05): (2.0-4.0).
8. The synthesis process according to claim 7, characterized in that it comprises carrying out the olefin metathesis synthesis d 3 After-16-hydroxy capsaicin, the product is purified by vacuum concentration and column chromatography to obtain d 3 -pure 16-hydroxy capsaicin.
9. The method of synthesis according to claim 6 or 7 or 8, wherein the compound d is 3 The synthesis method of the-3 comprises the following steps: with 6-n-heptenoic acid and compound d 3 -2 is used as a raw material to carry out amidation reaction to synthesize the compound d 3 -3, wherein the compound d 3 The structural formula of-2 is
10. The method of synthesis according to claim 9, wherein compound d is 3 The synthesis method of the-3 comprises the following steps: under the action of diisopropylethylamine and benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate, 6-heptenoic acid and compound d 3 -2 amidation reaction at 0-30 ℃ to synthesize the compound 3; and 6-heptenoic acid, diisopropylethylamine, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate and compound d 3 -2 in a molar ratio of 1: (2.0-3.0): (1.0-1.5): (1.0-1.5).
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| CN109364998A (en) * | 2018-10-15 | 2019-02-22 | 天津科技大学 | A kind of catalyst and its methods for making and using same for olefin metathesis reaction |
| CN109692709A (en) * | 2018-12-10 | 2019-04-30 | 天津科技大学 | A kind of catalyst and its methods for making and using same of olefin metathesis reaction |
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| CN109364998A (en) * | 2018-10-15 | 2019-02-22 | 天津科技大学 | A kind of catalyst and its methods for making and using same for olefin metathesis reaction |
| CN109692709A (en) * | 2018-12-10 | 2019-04-30 | 天津科技大学 | A kind of catalyst and its methods for making and using same of olefin metathesis reaction |
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