CN113754710A - Fenleramine 7-site metabolite and preparation and application thereof - Google Patents

Fenleramine 7-site metabolite and preparation and application thereof Download PDF

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CN113754710A
CN113754710A CN202010504554.0A CN202010504554A CN113754710A CN 113754710 A CN113754710 A CN 113754710A CN 202010504554 A CN202010504554 A CN 202010504554A CN 113754710 A CN113754710 A CN 113754710A
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methanol
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贾振华
吴相君
赵韶华
刘蕊
杨青瑞
李向军
王宏涛
汪磊
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Shijiazhuang Yiling Pharmaceutical Co Ltd
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Abstract

The invention provides a 7-site metabolite of phentermine and preparation and application thereof. The 7-bit metabolite of the fenle amine has good antioxidant activity, neuritis resistance and neuroprotective activity, and simultaneously, compared with the fenle amine, the 7-bit metabolite of the fenle amine is easier to penetrate through a blood brain barrier, so that the fenle amine can be used for preventing and treating the acute and chronic nephritisAnd has better targeting effect. Moreover, the 7-position metabolite of the phentermine is higher in human exposure than phentermine. The 7-position metabolite of the fenloramine is shown as the following formula (I):

Description

Fenleramine 7-site metabolite and preparation and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a 7-site metabolite of phentermine, and preparation and application thereof.
Background
Fenleramine (code: FLZ) is a derivative of annonaceous acetogenins, the structure of the compound is disclosed in Chinese patent CN1445211 (publication number), and the patent describes ' new annonaceous acetogenins derivative invented by the institute of medicine of Chinese academy of medical sciences ' and a preparation method, a pharmaceutical composition and an application thereof '.
The molecular structural formula of the fenloramine (chemical name: trans-2- (2, 5-dimethoxyphenyl) -3- (4-hydroxy-3-methoxyphenyl) -N- (4-hydroxyphenylethyl) acrylamide) is as follows:
Figure BDA0002526061850000011
the pharmacodynamic action of the phentermine for treating the Parkinson Disease (PD) is similar to that of the known positive medicine levodopa, and the activity is stronger than that of the levodopa. The inventive phentermine has novel action mechanism, can resist nerve cell apoptosis, and has neuroprotective effect. Preclinical studies show that phentermine is difficult to pass through the blood brain barrier, and the distribution of the blood in brain tissues is low after administration. Therefore, the research on the substitution of the phenamine is very important.
Disclosure of Invention
An object of the present invention is to provide a 7-position metabolite of phencyclamine;
another object of the invention is to provide a preparation method of the 7-position metabolite of the phentermine;
it is yet another object of the present invention to provide a pharmaceutical composition;
still another object of the present invention is to provide the use of the 7-position metabolite of phencyclamine.
To achieve the above objects, in one aspect, the present invention provides a 7-position metabolite of phentermine, wherein the 7-position metabolite of phentermine is represented by the following formula (I):
Figure BDA0002526061850000021
in another aspect, the invention also provides a preparation method of the 7-position metabolite of the phentermine, wherein the method comprises the step of preparing the 7-position metabolite of the phentermine shown in the formula (I) by taking the compound shown in the formula (7) as a raw material:
Figure BDA0002526061850000022
according to some embodiments of the invention, the method further comprises preparing a compound of formula (7) starting from a compound of formula (6):
Figure BDA0002526061850000023
according to some embodiments of the invention, the method further comprises preparing a compound of formula (6) starting from a compound of formula (4) and a compound of formula (5):
Figure BDA0002526061850000024
according to some embodiments of the invention, the method further comprises preparing a compound of formula (4) starting from a compound of formula (3):
Figure BDA0002526061850000031
according to some embodiments of the invention, the method further comprises preparing a compound of formula (3) starting from a compound of formula (1) and a compound of formula (2):
Figure BDA0002526061850000032
according to some embodiments of the invention, the method comprises the steps of:
Figure BDA0002526061850000033
according to some embodiments of the invention, the solvent of step 1 is selected from the group consisting of acetone, acetonitrile, DMF, DMSO, 1, 4-dioxane, tetrahydrofuran, and toluene.
According to some embodiments of the invention, the solvent of step 2 is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, DMF, DMSO, 1, 4-dioxane, and tetrahydrofuran.
According to some embodiments of the invention, the solvent of step 3 is selected from one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether and diethyl ether.
According to some embodiments of the invention, the solvent of step 4 is selected from a mixture of one or more of methanol, ethanol and tetrahydrofuran.
According to some embodiments of the invention, the solvent of step 5 is selected from methanol, or one of the following mixed solvents: methanol/water, ethanol/water, acetonitrile/water, DMF/water, DMSO/water, tetrahydrofuran/water, and 1, 4-dioxane/water.
According to some embodiments of the present invention, step 1 is a step of preparing the compound of formula (3) by using the compound of formula (1) and the compound of formula (2) as raw materials in the presence of a basic substance.
According to some embodiments of the present invention, the basic substance in step 1 is selected from one or more of potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine and diisopropylethylamine.
According to some embodiments of the present invention, step 2 is to prepare the compound of formula (4) by using the compound of formula (3) as a starting material in the presence of a basic substance.
According to some embodiments of the present invention, the basic substance in step 2 is selected from one or more of sodium hydroxide, potassium carbonate, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide.
According to some embodiments of the present invention, step 3 is a step of preparing the compound of formula (6) by using the compound of formula (4) and the compound of formula (5) as raw materials in the presence of a catalyst.
According to some embodiments of the invention, wherein the catalyst of step 3 is an alkali metal catalyst or a lewis acid catalyst.
According to some embodiments of the invention, wherein the catalyst of step 3 is selected from BF3.Et2O、Ag2CO3And TMSOTf.
According to some embodiments of the present invention, step 4 is a step of preparing the compound of formula (7) by using the compound of formula (6) as a starting material in the presence of a catalyst and an acid.
According to some embodiments of the invention, the catalyst of step 4 is a palladium-containing catalyst.
According to some embodiments of the invention, the palladium-containing catalyst of step 4 is selected from one of the following catalysts: Pd/C, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, Pd (OAc)2And PdCl2。
According to some embodiments of the invention, the acid of step 4 is selected from the group consisting of p-toluenesulfonic acid, acetic acid and hydrochloric acid.
According to some embodiments of the present invention, wherein, in the step 5, when the solvent is selected from one of methanol/water, ethanol/water, acetonitrile/water, DMF/water, DMSO/water, tetrahydrofuran/water, and 1, 4-dioxane/water, the compound of formula (I) is prepared by using the compound of formula (7) as a raw material in the presence of a basic substance in the step 5.
According to some embodiments of the invention, wherein, in step 5, when the solvent is selected from methanol, step 5 is to prepare the compound of formula (I) starting from the compound of formula (7) in a methanol/sodium methoxide system.
According to some embodiments of the invention, the alkaline substance of step 5 is selected from the group consisting of sodium carbonate, potassium carbonate, a mixture of one or more of sodium hydroxide and potassium hydroxide.
According to some embodiments of the invention, wherein the molar ratio of the compound of formula (2) to the compound of formula (1) in step 1 is (1.0-2.0): 1.
according to some embodiments of the invention, the reaction temperature in step 1 is from room temperature to reflux temperature.
According to some embodiments of the invention, wherein the reaction temperature in step 2 is from 0 ℃ to 65 ℃.
According to some embodiments of the present invention, the alkaline substance in step 2 is added in the form of an aqueous solution of the alkaline substance, the concentration of the aqueous solution of the alkaline substance is 1 to 4mol/L, and the amount of the aqueous solution of the alkaline substance is 1 to 3 times the mass of the reaction substrate.
According to some embodiments of the invention, wherein the molar ratio of the compound of formula (5) to the compound of formula (4) in step 3 is (0.9-1.5): 1.
according to some embodiments of the invention, the reaction temperature in step 3 is from-30 ℃ to-10 ℃.
According to some embodiments of the present invention, step 3 further comprises preparing the compound of formula (6) by using the compound of formula (4) and the compound of formula (5) as raw materials in the presence of the 4A molecular sieve, wherein the amount of the 4A molecular sieve is 1-4 times of the mass of the reaction substrate.
According to some embodiments of the invention, the reaction temperature in step 4 is from 20 ℃ to reflux.
According to some embodiments of the invention, the molar amount of the catalyst used in step 4 is 0.2 to 0.5 of the molar amount of the reaction substrate.
According to some embodiments of the invention, the acid is used in an amount of 0 to 1 equivalent in step 4.
According to some embodiments of the present invention, step 5 further comprises a step of adjusting the pH of the reaction solution to 4.0 to 8.0 after the completion of the reaction.
In yet another aspect, the present invention also provides a pharmaceutical composition comprising the 7-position metabolite of phencyclamine according to the present invention, and one or more pharmaceutically acceptable carriers and/or excipients.
In another aspect, the invention also provides application of the 7-position metabolite of the fenhydramine in preparing anti-oxidation drugs, anti-neuritis drugs and neuroprotection drugs.
The invention also provides application of the 7-bit metabolite of the phentermine in preparing medicines for preventing and treating Parkinson's disease, improving learning and memory disorder and treating hypomnesis and Alzheimer's disease.
In conclusion, the invention provides a 7-position metabolite of phentermine, and preparation and application thereof. The 7-position metabolite of the fenle amine has the following advantages:
the 7-bit metabolite of the fenle amine has good antioxidant activity, neuritis resistance and neuroprotective activity, and simultaneously, compared with the fenle amine, the 7-bit metabolite of the fenle amine is easier to penetrate through a blood brain barrier, so that the 7-bit metabolite of the fenle amine has better targeting effect. Moreover, the 7-position metabolite of the phentermine is higher in human exposure than phentermine.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
Example 1
Step 1:
compound 1(7.00g, 14.3mmol), anhydrous acetone (potassium carbonate bubble, 150mL), potassium carbonate (2.95g,21.4mmol), allyl bromide (2.05g, 17.1mmol) were heated under reflux in a single vial for 7 hours, LCMS was used to monitor completion of the reaction, filtration was carried out, the solvent was evaporated, and silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1-4:1) gave crude compound 3(3.5 g, yield 46%).
1HNMR CDCl3δ:7.80(s,1H),6.98-6.96(d,2H),6.94-6.87(m,3H),6.80-6.77(0,3H),6.63-6.58(dd,2H,J1＝15.6Hz,J2＝1.6Hz),6.12-6.02(m,1H),5.63-5.60(t,1H),5.45-5.41(dd,1H,J1＝17.2Hz,J2＝1.65Hz),5.32-5.30(m,1H),4.52-4.51(d,2H,J＝5.2Hz),3.77-3.75(d,3H),3.71-3.69(d,3H),3.55-3.50(m,2H),3.45(s,3H),2.74-2.70(t,2H),2.28(s,3H)。
LC-MS:m/z＝532.2(M+1)。
Step 2:
compound 3(3.50g, 6.59mmol) and methanol (40mL) were added to a single-neck flask, a 4N NaOH (10mL) solution was added under ice bath, the mixture was stirred at room temperature for 2 hours, after completion of the TLC monitoring reaction, the solvent was evaporated under reduced pressure, 1N hydrochloric acid was used to adjust the pH to acidic, ethyl acetate was extracted three times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and silica gel column chromatography (petroleum ether: ethyl acetate: 7:1) was performed to obtain compound 4(2.3g, yield 72%).
1HNMR CDCl3δ:7.78(s,1H),6.98-6.93(m,4H),6.80-6.73(m,4H),6.65-6.64(t,1H),6.46(s,1H),6.12-6.02(m,1H),5.80(s,1H),5.60-5.57(t,1H),5.46-5.40(m,1H),5.32-5.29(m,1H),4.53-4.51(m,2H),3.82(s,3H),3.79-3.77(t,3H),3.73-3.50(m,5H),2.74-2.70(t,2H)。
LC-MS:m/z＝490.2(M+1)。
And step 3:
a three-necked flask was charged with compound 4(2.00g, 4.08mmol), compound 5(3.90g, 8.18mmol), 4A molecular sieve (8.00g), and anhydrous dichloromethane (50mL), and BF was added dropwise under nitrogen protection at-20 deg.C3.Et2O (1.16g, 8.18mmol), after stirring for 2 hours at-20 ℃ TLC showed complete reaction and 1 drop triethylamine was added to stop the reaction. Filtering, washing with dichloromethane, mixing organic phases, washing with water and saturated salt solution sequentiallyDried over sodium sulfate, filtered, evaporated to remove the solvent, and chromatographed on silica gel (petroleum ether: ethyl acetate: 5:1) to give the title compound 6(1.73g, 52% yield).
1HNMR CDCl3δ:7.78(s,1H),6.98-6.90(m,5H),6.78-6.70(m,3H),6.62-6.61(m,1H),6.52-6.51(d,1H,J＝2.0Hz),6.12-6.04(m,1H),,5.60-5.57(t,1H),5.46-5.40(m,1H),5.34-5.23(m,4H),5.00-4.98(d,1H,J＝7.2Hz),4.53-4.51(m,2H),4.09-4.07(m,1H),3.76-3.71(m,6H),3.63(s,3H),3.54-3.49(m,2H),3.16(s,3H),2.74-2.71(t,2H),2.25-2.17(m,9H)。
LC-MS:m/z＝805.6(M+1)。
And 4, step 4:
compound 6(7.00g, 8.69mmol), anhydrous methanol (150mL), Pd/C (700mg), TsOH (0.74g, 4.34mmol) were added to a single-neck flask, heated to reflux, TLC monitored for reaction completion, filtered, and the solvent was evaporated under reduced pressure to give crude compound 7(6g, crude).
And 5:
compound 7(6g, 7.83mol) was dissolved in methanol/water (135mL, v/v ═ 2:1) and Na was added2CO3(13.1g, 125mmol) and stirred at room temperature overnight. LCMS monitor reaction completion. The reaction solution was spin-dried, dissolved in water, the pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid, filtered, and the filter cake was crude, which was purified by prep-HPLC to give compound T2 (phencyclamine 7-position metabolite) (1.1g, yield 22%).
1HNMR CD3ODδ:7.57(s,1H),7.05-7.07(d,1H),6.98-7.02(m,2H),6.93-6.95(d,2H),6.79-6.81(d,1H),6.66-6.69(d,3H),6.61-6.62(d,1H),6.54-6.55(d,1H),4.95-4.97(d,1H),3.93-3.96(d,1H),3.71(s,3H),3.67(s,3H),3.58-3.63(m,1H),3.48-3.52(t,2H),3.42-3.45(m,5H),2.67-2.71(t,2H)。
LC-MS:m/z＝626(M+1)。
Test example 1
This test example evaluates and compares the antioxidant, anti-neuritic and neuroprotective activity of phentermine (FLZ) and its inventive phentermine metabolite at the 7-position in vitro.
1. Experimental methods
1.1 determination of the content of Malondialdehyde (MDA) which is a product of lipid peroxidation
Preparing liver microsomes: rat liver tissue was weighed and 10% homogenate was prepared in Tris-HC1 buffer and liver microsomes were isolated by differential centrifugation.
The experiment is provided with a blank group, a model group, an FLZ group and an FLZ 7-bit metabolite group, and each group is provided with 3 multiple wells. PBS buffer, liver microsomes, cysteine and test drug solution were added to each tube. FLZ or FLZ 7 metabolite is added into each tube of the test drug group, and the final concentration is 1 × 10-4、1×10-5And 1X 10-6M, blank group, model group each tube added with the same volume of DMSO. Shaking in 37 deg.C water bath for 15min, adding 1 × 10 for each tube for model group and dosing group-2M FeSO4The solution and blank group were added with PBS buffer of the same volume and further shaken in a water bath at 37 ℃ for 15 min. Then adding TCA solution and TBA solution into each tube, and carrying out water bath at 100 ℃ for 10 min. Centrifuge at 8000rpm for 10 min. The supernatant was taken and absorbance (OD) was measured at 532 nm.
Figure BDA0002526061850000081
Figure BDA0002526061850000082
1.2, anti-neuritis administration and detection of Nitric Oxide (NO) content
BV2The cells were cultured in DMEM medium containing 10% fetal bovine serum at 37 deg.C with 5% CO2Cultured in an incubator. Cells in logarithmic growth phase are selected to be divided into a blank group, a model group, an FLZ group and an FLZ 7-position metabolite group, and each group is provided with 3 multiple wells. Adding FLZ or FLZ 7 site metabolite at different concentrations (final concentration 1 × 10)-5，1×10-6，1×10-7M), adding DMSO with the same volume into a blank group and a model group, adding 500ng/mLLPS into the model group and a dosing group after 1h, and incubating for 24h, and adding PBS buffer with the same volume into the blank group. Sucking 100 μ L of culture medium per well, adding prepared Griess reagent, and standing at room temperature for 20 min. The absorbance (OD) of each group was measured at 540 nm. The absorbance was converted to NO concentration value using a standard curve and calculated by substituting the formula.
NO inhibitionRate ═ 1- (C)Test compound-CBlank space)/(CModel (model)-CBlank space]×100％
1.3 neuroprotective drug delivery and cell viability assay
SH-SY5Y nerve cells are cultured in DMEM medium containing 10% fetal calf serum and placed at 37 ℃ and containing 5% CO2Cultured in an incubator. Cells in logarithmic growth phase were selected for the experiments. SH-SY5Y cells were divided into blank, model, FLZ and FLZ 7 metabolite groups, each group being 3 duplicate wells. Adding FLZ or FLZ 7 site metabolite at different concentrations (final concentration 1 × 10)-5，1×10-6，1×10-7M), 1h post-model group and dosing group 8mM MPP was added+Incubate for 24h and add the same volume of PBS buffer to the blank. The supernatant was aspirated off, 100. mu.L of MTT (0.5mg/mL) was added to each well, incubation was continued for 4h, and absorbance (OD value) was measured on a microplate reader at a wavelength of 570 nm.
Effective rate%Test compound-ODModel (model))/(ODBlank space-ODModel (model))×100％
2. Results of the experiment
2.1 Effect of FLZ and FLZ glucuronic acid conjugates on lipid peroxidation
In an in vitro liver microsome lipid antioxidant experiment, FLZ and FLZ 7 site metabolite T2 have certain inhibition effects on MDA generation and a certain dose effect relationship, and the antioxidant efficacy of T2 is higher than that of FLZ (Table 1).
TABLE 1 results of antioxidant Activity of FLZ 7-site metabolites in vitro
Figure BDA0002526061850000091
Figure BDA0002526061850000092
2.2 Effect of FLZ and its metabolites at position 7 of FLZ on NO Release
After BV2 microglia is stimulated by LPS, the level of NO in the culture medium is obviously increased, FLZ and FLZ 7-site metabolite T2 have certain inhibition effect on NO release of BV2 cells, and T2 has stronger inhibition effect on NO release than FLZ (Table 2).
TABLE 2 results of in vitro anti-neuritic Activity of FLZ and its glucuronic acid conjugate
Figure BDA0002526061850000093
Figure BDA0002526061850000101
2.3 Effect of FLZ 7-position metabolites on cell survival
Addition of MPP to SH-SY5Y cells+The survival rate of the later cells is obviously reduced, and the FLZ 7 metabolite T2 has a certain protective effect on cell injury and has a dose-effect relationship (Table 3).
TABLE 3 in vitro neuroprotective Activity results for FLZ 7 metabolites
Figure BDA0002526061850000102
Figure BDA0002526061850000103
3. Conclusion
The FLZ 7 metabolite has certain antioxidant, anti-neuritis and neuroprotective activity, wherein the high concentration effect is better, and the dose dependence is realized. The drug effect of the FLZ 7 site metabolite on the anti-neuritis and neuroprotection activity is higher than that of FLZ.
Test example 2
Bioavailability of FLZ metabolite at position 7 (T2) and studies crossing blood brain barrier
1. Instrument and animal
1.1 Main instrument (see Table 4)
TABLE 4
Figure BDA0002526061850000104
1.2 animals
Species and strains: beagle dog;
grade of experimental animals: beagle dog;
the source of the test animal is as follows: marts biotechnology (gu' an) ltd;
number and sex of animals: 16, each half of male and female;
2. dosage and mode of administration (see Table 5)
TABLE 5
Figure BDA0002526061850000111
3. Sampling method
3.1 blood sampling method: approximately 1mL of blood was taken from the vein. The whole blood taken out is immediately transferred to a heparin sodium anticoagulated blood collection tube (stored in crushed ice before use), is manually inverted for a plurality of times and is uniformly mixed, and is stored in the crushed ice. Centrifuging at 3000g and 4 deg.C for 10min for 1 hr to separate plasma, subpackaging the centrifuged plasma into new labeled centrifuge tubes, and rapidly transferring to-70 deg.C for storage.
3.2 brain tissue harvesting: after the blood taking of the animals in the intravenous injection group is finished, isoflurane anaesthetizes abdominal aorta to exsanguinate and euthanasia, the brain tissue is obtained, the brain tissue is washed for 2-3 times by using normal saline, and surface liquid is sucked by filter paper. Then immediately taking tissues with proper sizes, placing the tissues into a homogenization tube weighed in advance, adding a proper volume of sodium chloride injection after weighing again, and enabling the ratio of the volume of the finally added solution to the mass of the tissues to be 4:1 (mL: g). 4-6 magnetic beads are placed in each homogenizing tube, homogenized on a homogenizer, and the homogenate is stored below-70 ℃ for analysis. The detailed weighed homogenate record was saved in the raw material.
4. Description of the test:
the test was carried out with 16 animals divided into 2 groups of 8 animals each, each half of which was male and female. The first group of animals was placebo. The second group of animals was gavaged with 1000mg/kg of test article (phenxamine tablets). Plasma and brain tissue samples were collected 2h after dosing.
The content of the fenramine in the blood plasma is determined by adopting a verified LC-MS/MS method, and the lower limit of the quantification of the method is 0.5 ng/mL; the content of FLZ 7 metabolite (T2) in plasma is measured by an LC-MS/MS method, and the lower limit of the quantification of the method is 1 ng/mL. The content of FLZ 7-bit metabolite in the brain tissue homogenate is measured by adopting an LC-MS/MS method, and the lower limit of the quantification of the method is 1 ng/mL.
Kinetic parameter calculations were performed using a non-compartmental model (NCA) method, and pharmacokinetic parameters of fenhydramine and its phase ii metabolites in plasma are shown in table 6 below:
TABLE 6
Figure BDA0002526061850000121
5. Results
From the data in table 6 above, it can be seen that:
1. the research on canine brain tissue distribution proves that the 7-position metabolite T2 of the phentolamine can cross the blood brain barrier to reach the brain tissue to exert pharmacodynamic activity.
2. The concentration of the 7-position metabolite T2 of the phenamine in brain tissue is far higher than that of the phenamine prototype, and the prediction is the main drug effect substance basis.
3. The cerebral blood ratio (drug concentration in brain tissue/blood plasma) of the 7-site metabolite T2 of the fenle amine is obviously higher than that of a fenle amine proto-drug; the 7-position metabolite is easier to cross blood brain barrier than the phencyclamine, and the drug effect is exerted.

Claims (12)

1. A phencyclamine 7-position metabolite, wherein the phencyclamine 7-position metabolite is represented by the following formula (I):
Figure FDA0002526061840000011
2. the method for producing a 7-position metabolite of phentolamine according to claim 1, wherein the method comprises producing the 7-position metabolite of phentolamine represented by formula (I) using a compound of formula (7):
Figure FDA0002526061840000012
3. the process of claim 2, further comprising preparing a compound of formula (7) starting from a compound of formula (6):
Figure FDA0002526061840000013
4. the process of claim 3, further comprising preparing a compound of formula (6) starting from a compound of formula (4) and a compound of formula (5):
Figure FDA0002526061840000014
5. the process according to claim 4, further comprising preparing a compound of formula (4) starting from the compound of formula (3):
Figure FDA0002526061840000021
6. the process of claim 5, further comprising preparing a compound of formula (3) starting from a compound of formula (1) and a compound of formula (2):
Figure FDA0002526061840000022
7. the method of manufacturing according to claim 2, wherein the method comprises the steps of:
Figure FDA0002526061840000023
Figure FDA0002526061840000031
8. the production method according to claim 7, wherein:
the solvent in the step 1 is selected from one or a mixture of more of acetone, acetonitrile, DMF, DMSO, 1, 4-dioxane, tetrahydrofuran and toluene;
the solvent in the step 2 is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, DMF, DMSO, 1, 4-dioxane and tetrahydrofuran;
the solvent in the step 3 is one or more of dichloromethane, tetrahydrofuran, 1, 4-dioxane, methyl tert-butyl ether and diethyl ether;
the solvent in the step 4 is one or more selected from methanol, ethanol and tetrahydrofuran;
the solvent of the step 5 is selected from methanol or one of the following mixed solvents: methanol/water, ethanol/water, acetonitrile/water, DMF/water, tetrahydrofuran/water, DMSO/water, and 1, 4-dioxane/water.
9. The production method according to claim 7 or 8, wherein:
step 1, preparing a compound shown in a formula (3) by taking a compound shown in a formula (1) and a compound shown in a formula (2) as raw materials in the presence of an alkaline substance; preferably, the alkaline substance in step 1 is selected from one or more of potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine and diisopropylethylamine;
step 2, in the presence of alkaline substances, taking the compound of the formula (3) as a raw material to prepare a compound of a formula (4); preferably, the alkaline substance in step 2 is selected from one or more of sodium hydroxide, potassium carbonate, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide;
step 3, preparing a compound shown in a formula (6) by taking a compound shown in a formula (4) and a compound shown in a formula (5) as raw materials in the presence of a catalyst; preferably, the catalyst of step 3 is an alkali metal catalyst or a lewis acid catalyst; more preferably, the catalyst of step 3 is selected from BF3.Et2O、Ag2CO3And TMSOTf;
step 4, preparing a compound of formula (7) by using a compound of formula (6) as a raw material in the presence of a catalyst and an acid; preferably, the catalyst of step 4 is a palladium-containing catalyst; more preferably, the palladium-containing catalyst of step 4 is selected from one of the following catalysts: Pd/C, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, Pd (OAc)2And PdCl2(ii) a Preferably the acid is selected from one or more of p-toluenesulfonic acid, acetic acid and hydrochloric acid;
step 5 when the solvent is selected from one of methanol/water, ethanol/water, acetonitrile/water, DMF/water, DMSO/water, tetrahydrofuran/water and 1, 4-dioxane/water, the step 5 is to prepare the compound of the formula (I) by taking the compound of the formula (7) as a raw material in the presence of an alkaline substance; or, when the solvent is selected from methanol, the step 5 is to prepare the compound shown in the formula (I) by taking the compound shown in the formula (7) as a raw material in a methanol/sodium methoxide system or a sodium tert-butoxide/methanol system; preferably, the alkaline substance of step 5 is selected from a mixture of one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
10. The production method according to any one of claims 7 to 9,
the molar ratio of the compound of formula (2) to the compound of formula (1) in step 1 is (1.0-2.0): 1; the reaction temperature is from room temperature to reflux temperature;
the reaction temperature in the step 2 is 0-65 ℃;
the molar ratio of the compound of formula (5) to the compound of formula (4) in step 3 is (0.9-1.5): 1; the reaction temperature is-30 ℃ to-10 ℃;
the reaction temperature in step 4 is from 20 ℃ to reflux temperature.
11. A pharmaceutical composition comprising the phentermine 7-position metabolite of claim 1, and one or more pharmaceutically acceptable carriers and/or excipients.
12. Use of the 7-position metabolite of phentermine as claimed in claim 1 for the preparation of anti-oxidant, anti-neuritic and neuroprotective drugs; preferably, the application is the application of the 7-bit metabolite of the phentermine in preparing the medicines for preventing and treating Parkinson's disease, improving learning and memory disorder and treating hypomnesis and Alzheimer's disease.
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Citations (1)

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