CN109251162B - Tryptophan derivative and use thereof - Google Patents
Tryptophan derivative and use thereof Download PDFInfo
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- CN109251162B CN109251162B CN201711235472.5A CN201711235472A CN109251162B CN 109251162 B CN109251162 B CN 109251162B CN 201711235472 A CN201711235472 A CN 201711235472A CN 109251162 B CN109251162 B CN 109251162B
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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Abstract
The present disclosure relates to tryptophan derivatives and uses thereof. In particular to a compound shown in a formula I or a salt thereof, which can be used for detecting impurities in tryptophan or a preparation containing tryptophan and bisulfite, further used for controlling the quality of the tryptophan or the preparation containing tryptophan and bisulfite and ensuring the drug effect consistency of drugs,
Description
Technical Field
The present disclosure relates to tryptophan derivatives and uses thereof.
Background
Tryptophan (Tryptophan), the chemical name of which is L-2-amino-3 (β -indole) propionic acid, has the molecular formula: c11H12N2O2Belongs to amino acid drugs. Tryptophan is white to yellowish crystal or crystalline powder, has no odor, is slightly soluble in water, is slightly soluble in ethanol, is insoluble in chloroform, is soluble in formic acid, and is soluble in sodium hydroxide solution or dilute hydrochloric acid. Tryptophan is an important precursor for auxin biosynthesis in plants and is ubiquitous in higher plants.
Any substance that affects the purity of the drug is collectively referred to as an impurity. The research on impurities is an important content of drug development. The impurities are controlled within a safe and reasonable limit range, and the quality and the safety of the marketed medicine are directly related.
Impurities in the medicine are generally classified into three categories according to their physicochemical properties: organic impurities, inorganic impurities and residual solvents. Organic impurities, including process-induced impurities and degradation products, may be known or unknown, volatile or non-volatile, and are often referred to as related substances because the chemical structures of such impurities are generally similar or related to the active ingredient. The related substances are mainly starting materials, intermediates, polymers, side reaction products brought in during the production process, degradation products in the storage process and the like. Related substance research is one of key projects in medicine quality research, and the content of related substances is a direct index reflecting the purity of medicines.
For tryptophan or impurities in tryptophan preparations, 12 organic impurities are collectively collected in the European Pharmacopoeia (EP), and the nomenclature is from impurity a to impurity L in order.
Further studies are needed for tryptophan or impurities in tryptophan preparations, particularly related substances.
Disclosure of Invention
In the process of tryptophan quality research, the inventor finds a new impurity which is a tryptophan derivative. The tryptophan derivative can be used for detecting impurities in tryptophan or tryptophan preparations, and further used for quality control of tryptophan or tryptophan preparations and guarantee the drug effect consistency of medicines. The present disclosure has been completed based on the above findings.
The present disclosure relates to compounds of formula I or salts thereof,
in certain embodiments, the compound of formula I or salt thereof has the structure shown in formula II:
in certain embodiments, the compound of formula II or salt thereof is selected from:
or a salt thereof.
The disclosure also relates to a process for preparing a compound of formula I, comprising the steps of:
1) reacting bisulfite with tryptophan in a solvent;
2) optionally, the reaction solution obtained in step 1) is subjected to separation and purification.
In certain embodiments, the bisulfite is reacted with tryptophan under light conditions. Preferably, the illumination condition is natural light illumination, or near ultraviolet light and/or visible light illumination. The preferred light intensity is 4500. + -. 500 Lux. The light irradiation time is preferably 5 days or more, preferably 9 days or more, for example, 20 days or 30 days.
In certain embodiments, the reaction solution of both bisulfite and tryptophan is heated in a water bath. Preferably, the heating time in the water bath is 8-12 hours, such as 10 hours. Preferably, the water bath heating temperature is above 70 ℃, such as 80 ℃, 90 ℃ or 100 ℃.
In certain embodiments, the solvent in step 1) of the present disclosure is water or a polar organic solvent; water is preferred.
In certain preferred embodiments, the bisulfite salt is sodium bisulfite.
The disclosure also relates to another method for preparing the compound shown in the formula I, which takes a preparation containing tryptophan and bisulfite as raw materials and comprises the following steps:
1) irradiating the preparation with visible or natural light for more than 1 day, preferably for more than 2 days, such as 5 days, 8 days, 9 days or 10 days; or
Heating the formulation in a water bath; the preferable time for heating in the water bath is 8-12 hours, such as 10 hours; the preferred water bath heating temperature is 70 ℃ or above, e.g., 80 ℃, 90 ℃ or 100 ℃;
2) optionally, the solution obtained in step 1) is subjected to separation and purification.
In certain embodiments, the separation and purification is performed by chromatography in both methods of preparation described in the present disclosure; preferably, the chromatography is selected from normal phase chromatography, reverse phase chromatography and gel chromatography.
In certain embodiments, the separation and purification in both methods of preparation described in the present disclosure is preferably performed using high performance liquid chromatography. Preferred chromatographic conditions are one or more of the following items 1) to 5):
1) the chromatographic column is a preparative octadecylsilane bonded silica gel column, and the preferred chromatographic column is waters XBridge C18,150 × 19mm, 5 μm;
2) the mobile phase is an aqueous solution of organic solvent-volatile acid or base, the organic solvent can be acetonitrile or methanol, preferably methanol; the aqueous solution of the volatile acid or base may be an aqueous solution of formic acid, acetic acid, trifluoroacetic acid, ammonium acetate, etc., preferably an aqueous solution of formic acid, more preferably an aqueous solution of formic acid at ph 2.7. The preferred volume ratio of methanol to aqueous formic acid solution, pH2.7, is (80-90): 20-10), e.g. 85: 15;
3) detection wavelength 200nm-360nm, preferably 220nm, 275nm or 316 nm;
4) the flow rate is 5-15 ml/min, preferably 8-12 ml/min, such as 10 ml/min;
5) collecting the target compound according to the liquid phase ultraviolet chromatogram and/or the molecular weight.
In certain embodiments, of the two methods of preparation described in the present disclosure, the separation and purification is preferably performed by high performance liquid chromatography. Preferred chromatographic conditions are one or more of the following items 1) to 5):
1) the chromatographic column is a preparative octadecylsilane bonded silica gel column, and the preferred chromatographic column is waters XBridge C18,150 × 19mm, 5 μm;
2) the mobile phase is acetonitrile-pH2.7 formic acid aqueous solution, and the preferable volume ratio of the acetonitrile to the pH2.7 formic acid aqueous solution is (80-90): 20-10), such as 85: 15;
3) detection wavelength is 200nm-360nm, preferably 220nm, 275nm and 316 nm;
4) the flow rate is 5-15 ml/min, preferably 8-12 ml/min, such as 10 ml/min;
5) and (4) sampling according to a liquid phase ultraviolet chromatogram and/or a molecular weight.
In certain preferred embodiments, the bisulfite salt is sodium sulfite.
The disclosure also relates to the use of a compound of formula I or a salt thereof as an impurity control in tryptophan or a formulation containing tryptophan and bisulfite. In certain preferred embodiments, the bisulfite salt is sodium sulfite.
The disclosure also relates to the use of a compound of formula I or a salt thereof for detecting the level of impurities in tryptophan or a formulation containing tryptophan and bisulfite. In certain embodiments, the impurity is a related substance. In certain embodiments, the impurity is a related substance or active ingredient. In certain preferred embodiments, the bisulfite salt is sodium sulfite.
The disclosure also relates to the use of a compound of formula I or a salt thereof for quality control in the production of tryptophan or a formulation containing tryptophan and bisulfite. In certain preferred embodiments, the bisulfite salt is sodium sulfite.
The disclosure also relates to the use of a compound of formula I or a salt thereof for detecting the purity of tryptophan or a preparation containing tryptophan and bisulfite. In certain preferred embodiments, the bisulfite salt is sodium sulfite.
In the present disclosure, the tryptophan or the preparation containing tryptophan and bisulfite is a preparation in general guidelines of chinese pharmacopoeia, such as an injection, an ophthalmic preparation, a nasal preparation, an inhalation preparation, an aerosol, a gel, a syrup, a liniment, a tincture, an oral solution, an oral suspension, an oral emulsion, an otic preparation, a lotion, a rinse, an enema, a mixture, a decoction, a wine, a lotion, a tea, a fluid extract, an extract, a tablet, a capsule, or a granule. In certain preferred embodiments, the bisulfite salt is sodium sulfite.
The disclosure also relates to a method for detecting impurities in tryptophan or a formulation containing tryptophan and bisulfite, using the compound of claim 1 or a salt thereof as an impurity control.
In certain embodiments, the methods of detecting impurities in tryptophan or a formulation containing tryptophan and bisulfite as described in the present disclosure, comprise the steps of:
1) providing a compound of claim 1 or a salt thereof as an impurity control;
2) the impurity content in tryptophan or a preparation containing tryptophan and bisulfite is detected.
In certain preferred embodiments, the bisulfite salt is sodium sulfite.
The tryptophan described in the present disclosure may be L-tryptophan, D-tryptophan or a racemate thereof, as necessary.
Drawings
FIG. 1 is a chromatogram of a formulation containing tryptophan and sodium bisulfite photodisrupting the relevant substances in a sample.
FIG. 2 is an extracted ion flow diagram, an ultraviolet chromatogram and an extracted ion flow diagram of tryptophan of a target impurity.
FIG. 3 is a chromatogram of a photodisrupted sample of a formulation containing tryptophan and sodium bisulfite measured using an external standard method for 2-bisulfite tryptophan.
Detailed Description
Embodiments of the present disclosure will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present disclosure and should not be construed as limiting the scope of the present disclosure. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Tryptophan used in the following examples is L-tryptophan; and the tryptophan and the preparation containing the tryptophan and the sodium bisulfite are both recorded in Chinese pharmacopoeia and are available on the market.
In the following examples, in addition to example 8, the tryptophan related substance or 2-bisulfite tryptophan content in the sample was measured by the following high performance liquid chromatography. The specific method is as follows:
1) the samples to be tested were: preparation containing tryptophan and sodium bisulfite or self-made tryptophan water solution, and control solution is 1% tryptophan solution.
2) The stationary phase is octadecylsilane chemically bonded silica (phenomenex Gemini 5U C18110A), the column temperature is 40 ℃, the detection wavelength is 220nm, and the flow rate is 0.7 ml/min. The elution was carried out by using acetonitrile-pH 2.3 buffer (10:990V/V) as mobile phase A and acetonitrile-pH 2.3 buffer (350:650V/V) as mobile phase B in the following manner. Sample introduction amount: 20 μ l.
preparation of a buffer solution with pH 2.3: about 700ml of a 2.9g/L phosphoric acid solution was taken, 3.90g of potassium dihydrogen phosphate was added thereto for dissolution, and the pH was adjusted to 2.3 with concentrated phosphoric acid.
EXAMPLE 1 determination of Tryptophan-related substances in a formulation containing Tryptophan and sodium bisulfite
Detecting tryptophan related substances in the preparation containing tryptophan and sodium bisulfite by high performance liquid chromatography, finding out that there is an unknown tryptophan impurity in chromatogram, peaking at 32min (see figure 1), and calculating its content to be 0.2% by area normalization.
EXAMPLE 2 measurement of Tryptophan-related substances in a sample photo-disrupted by a formulation containing Tryptophan and sodium bisulfite
The preparation containing tryptophan and sodium bisulfite was exposed to light box (from MMM, CLC-E/CL 707, Germany) for 2 days to obtain sample 1, and the tryptophan related substances were detected, and it was also found that the chromatogram had an identical unknown tryptophan impurity, the content of which was increased to 3.7%.
EXAMPLE 3 preparation containing Tryptophan and sodium bisulfite measurement of Tryptophan-related substances in photo-disrupted samples
The preparation containing tryptophan and sodium bisulfite is placed in a light box for 9 days to obtain a sample 2, and then related substances of tryptophan are detected, and the obtained chromatogram is shown in figure 1, and the chromatogram is also found to contain the same unknown tryptophan impurity, wherein the content of the unknown tryptophan impurity is obviously increased to 10%.
EXAMPLE 4 preparation of crude target impurity
Weighing 4g of sodium bisulfite, placing the sodium bisulfite in a conical flask, adding purified water, stirring to dissolve, adding 1g of tryptophan, performing ultrasonic treatment, fully stirring to dissolve, and placing the conical flask in sunlight for 30 days to obtain a sample 3, wherein the content of the same unknown impurities can reach more than 10%, or placing the conical flask in a water bath, heating overnight to obtain a sample 4, and the content of the same unknown impurities can reach more than 10%.
EXAMPLE 5 preparation of crude target impurity
Weighing 4g of sodium bisulfite, placing the sodium bisulfite in a conical flask, adding purified water, stirring to dissolve, adding 1g of tryptophan, performing ultrasonic treatment, fully stirring to dissolve, placing the conical flask in an illumination box, respectively illuminating for 9 days and 30 days, taking out to obtain a sample 5 and a sample 6, and respectively measuring the content of the unknown impurities, wherein the content is respectively 10% and 23%.
Example 6 isolation and purification of the target impurity:
the separation method comprises the following steps: the used equipment, water preparative high performance liquid chromatography-Mass spectrometer (water e 2545-2767-. The sample receiving method is shown in fig. 2, wherein gray and white column parts are the received sample parts, the upper part of fig. 2 shows an extracted ion flow diagram (EIC diagram) of the unknown impurity, the middle part shows an ultraviolet chromatogram, and the lower part is an EIC diagram of tryptophan. Placing the sample solution in 500ml eggplant-shaped bottle, concentrating and drying under reduced pressure, controlling the temperature below 40 ℃, analyzing the content in the drying process, and performing secondary separation on the concentrated solution with the content of less than 90%. Finally, drying the vacuum concentrated solution to obtain white powder. The purity of the product is 95% by analysis.
Example 7 structural characterization of the target impurity
The pure compound obtained in example 6 was subjected to ultraviolet, mass spectrometry, and nuclear magnetic resonance measurement. UV characteristic absorption was 275 nm. The molecular weight of the unknown tryptophan impurity is (M/z, [ M + H ] identified by high resolution mass spectrometry Q-TOF-MS (Agilent 6230TOF LC/MS)]+)285.0536, given the formula C11H12N2O5And S. Measured by mass spectrometry (QSTAR Elite LC/MS/MS System (CADM-YQ-014)) and nuclear magnetic resonance (BRUKER AVANCEIII-400 type)1HNMR(400MHz,CD3OD) and13CNMR(400MHz,CD3OD), the data is shown in Table 1, the structural formula is shown in formula II-1, and the chemical name is: 2-Bisulfite tryptophane (2-bisulfate tryptophan).
TABLE 1 preparation of compounds represented by formula II-11HNMR and13chemical Shift value of CNMR
(delta. solvent is CD)3OD)
Example 8 measurement of the content of 2-bisulfite Tryptophan in a photodisrupted sample of a preparation containing Tryptophan and sodium bisulfite by high performance liquid chromatography using an external standard method
1. A sample to be tested:
test solution: the preparation containing tryptophan and sodium bisulfite is placed in a light box and irradiated for 9 days to obtain a test solution.
Control solution: an appropriate amount of the 2-hydroxytryptophan sulfite prepared in example 6 was weighed out precisely, dissolved in water, and the volume was determined to a scale, to obtain a solution containing 12 μ g of 2-hydroxytryptophan per ml.
2. Chromatographic conditions are as follows:
high performance liquid chromatograph: waters 2998-;
a chromatographic column: the stationary phase was octadecylsilane chemically bonded silica (Waters Atlantics T3C18, 250 mm. times.4.6 mm, 5 μm);
mobile phase:
a: acetonitrile-phosphate buffer solution (1:99v/v) is prepared by mixing 1000ml of sodium dihydrogen phosphate dihydrate solution with the concentration of 3.9g/L and 700ml of phosphoric acid solution with the concentration of 2.9g/L uniformly;
b: acetonitrile-phosphate buffer (35: 65);
precisely sucking 20ul of each of the test solution and the reference solution, injecting into a liquid chromatograph, performing gradient elution according to the method shown in the following table, and recording the liquid chromatogram.
Detection wavelength: 220 nm; column temperature: 50 ℃; flow rate: 1.0 ml/min; sample introduction amount: 20 μ l.
The chromatogram is shown in FIG. 3. The peak time of 2-tryptophan bisulfite was 28.6 min.
The content of the 2-tryptophan bisulfite in the test solution is calculated to be 10 percent by an external standard method.
Claims (11)
1. A compound of the formula I, wherein,
2. the compound of claim 1, selected from the group consisting of:
3. use of a compound according to claim 1 or 2 as a control for impurities in formulations containing tryptophan and bisulfite.
4. Use of a compound according to claim 1 or 2 for detecting the content of impurities in a formulation containing tryptophan and bisulfite.
5. The use of claim 4, wherein the impurity is a related substance.
6. Use of a compound according to claim 1 or 2 for checking the product purity of a formulation containing tryptophan and bisulfite.
7. The use according to claim 3, wherein the formulation containing tryptophan and bisulfite is an injection, an ophthalmic formulation, a nasal formulation, an inhalation formulation, an aerosol, a gel, a syrup, a liniment, a tincture, an oral solution, an oral suspension, an oral emulsion, an otic formulation, a lotion, a rinse, an enema, a mixture, a decoction, a wine, a lotion, a tea, a fluid extract, an extract, a tablet, a capsule or a granule.
8. The use according to claim 4, wherein the formulation containing tryptophan and bisulfite is an injection, an ophthalmic formulation, a nasal formulation, an inhalation formulation, an aerosol, a gel, a syrup, a liniment, a tincture, an oral solution, an oral suspension, an oral emulsion, an otic formulation, a lotion, a rinse, an enema, a mixture, a decoction, a wine, a lotion, a tea, a fluid extract, an extract, a tablet, a capsule or a granule.
9. The use according to claim 6, wherein the formulation containing tryptophan and bisulfite is an injection, an ophthalmic formulation, a nasal formulation, an inhalation formulation, an aerosol, a gel, a syrup, a liniment, a tincture, an oral solution, an oral suspension, an oral emulsion, an otic formulation, a lotion, a rinse, an enema, a mixture, a decoction, a wine, a lotion, a tea, a fluid extract, an extract, a tablet, a capsule or a granule.
10. A method for detecting impurities in a formulation containing tryptophan and bisulfite using a compound of claim 1 as an impurity control.
11. The method of claim 10, comprising the steps of:
1) providing a compound of claim 1 as an impurity control;
2) the impurity levels in formulations containing tryptophan and bisulfite were tested.
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| Separation and isolation of trace impurities in Ltryptophan by high-performance liquid chromatography;Mary W.Trucksess;《Journal of Chromatography》;19931231;第630卷;147-150 * |
| 结晶氨基酸输液研制概述;仲肇明等;《氨基酸通讯》;19810702;第53-59页 * |
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