CN111910256A

CN111910256A - Single crystal preparation method of caffeine impurity II

Info

Publication number: CN111910256A
Application number: CN202010812714.8A
Authority: CN
Inventors: 张富强; 常森; 易晓清; 孙国春
Original assignee: Shandong Xinhua Pharmaceutical Co Ltd
Current assignee: Shandong Xinhua Pharmaceutical Co Ltd
Priority date: 2020-08-13
Filing date: 2020-08-13
Publication date: 2020-11-10

Abstract

The invention provides a single crystal preparation method of caffeine impurity II, and a single crystal preparation method of 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid, which comprises the following steps: firstly, dissolving caffeine impurity II, namely 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid, by using a solvent; then, volatilizing the solvent at a proper temperature until a crystal form capable of being detected on a computer is obtained; the invention provides a new research method for the research of the caffeine impurity spectrum.

Description

Single crystal preparation method of caffeine impurity II

Technical Field

The invention relates to a new impurity of caffeine, in particular to a single crystal preparation method of 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid (caffeine impurity II for short), belonging to the technical field of drug synthesis.

Background

Caffeine (Caffeine) is an alkaloid extracted from tea and coffee, has effects of relieving fatigue and exciting nerve, and can be used for treating neurasthenia and coma. However, a large dose or long-term use of the traditional Chinese medicine composition can cause damage to human bodies, particularly, the traditional Chinese medicine composition also has addiction, and various withdrawal symptoms such as mental retardation, fatigue and weakness can occur once the traditional Chinese medicine composition is stopped, although the addiction is weak, the withdrawal symptoms are not serious.

However, when the dosage is increased continuously due to the tolerance of the drug, the caffeine not only acts on cerebral cortex, but also can directly excite medulla oblongata, cause paroxysmal convulsion and skeleton tremor, damage important internal organs such as liver, stomach, kidney and the like, induce diseases such as respiratory inflammation, mastadenoma of women and the like, and even cause the next generation of low intelligence and limb deformity of a patient who takes food. And is therefore also included in the range of state-regulated psychopharmaceuticals. Caffeine abuse is also commonly available in both the form of ingestion and injection, and its excitatory stimulant action and toxic side effects, symptoms, and drug dependence are similar to those of amphetamines.

The common caffeine process includes neutralizing chloroacetic acid to obtain sodium chloroacetate, cyaniding with sodium cyanide to obtain sodium cyanoacetate, acidifying with hydrochloric acid to obtain sodium cyanoacetate, catalytic condensation with dimethyl urea under anhydrous condition to obtain dimethyl cyanoacetylurea, cyclizing dimethyl cyanoacetylurea under alkaline condition to obtain dimethyl 4AU, acid reacting with sodium nitrite to obtain dimethyl NAU, reducing reaction with Raney-Ni as catalyst and hydrogen to obtain dimethyl DAU, acylating reaction with formic acid to obtain dimethyl FAU, cyclizing under alkaline condition to obtain sodium theophylline, centrifuging to obtain solid sodium theophylline salt, methylating to obtain crude caffeine product, oxidizing and decolorizing with potassium permanganate, crystallizing, and filtering to obtain caffeine product, Centrifuging, drying, crushing and the like to finally obtain the finished caffeine.

When the company carries out the record work of the caffeine bulk drug, the company finds that an unknown impurity exists in a caffeine finished product, although the content of the unknown impurity is less than 0.1%, because the spectrum of the caffeine impurity needs to be researched, the unknown impurity in the finished product needs to be researched, because the spectrum of the unknown impurity cannot be positioned and analyzed with the known caffeine impurity on the market, the unknown impurity needs to be separated and purified, and then the company needs to explore the generation reason. However, the absolute structure of the solid impurities cannot be completely determined only by the methods of nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, related two-dimensional spectrum, high-resolution mass spectrum and the like, and for the solid impurities, the structure of the solid impurities can be completely determined only by obtaining single crystals of the solid impurities, then corresponding to a structure confirmation spectrogram according to the single crystal structure and completely matching the single crystal structure with the structure confirmation spectrogram. The invention discloses a single crystal preparation method of caffeine impurity 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid.

Disclosure of Invention

The invention provides a single crystal preparation method of caffeine impurity II, namely 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid, which comprises the following steps:

(1) firstly, dissolving a 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid sample by using a solvent;

(2) and then, naturally volatilizing the solvent at a proper temperature until a crystal form capable of being detected on a computer is obtained.

The solvent is one of pyridine, methanol, a pyridine-water mixed solvent, a methanol-water mixed solvent, a pyridine-methanol-water mixed solvent, ethanol, acetonitrile, tetrahydrofuran, an ethanol-water mixed solvent, an acetonitrile-water mixed solvent and a tetrahydrofuran-water mixed solvent;

the solvent is a mixed solvent of pyridine, methanol and water;

the volume ratio of the mixed solvent of pyridine, methanol and water is 1:1:0.5, 2:1:1, 2:0.5: 1;

the volume ratio of the mixed solvent of pyridine, methanol and water is 2:1: 1;

the growth temperature of the single crystal is one of 20 ℃, 25 ℃ and 30 ℃;

the single crystal growth temperature is 25 ℃.

(3) Single crystal

(3.1) the single crystal diagram is shown in figure 1 in the attached drawing of the specification;

(3.2) Single Crystal data

Table 1 Crystal data and structure refinement for a_0m_sq.

Table 2 Fractional Atomic Coordinates(×10⁴)and Equivalent Isotropic Displacement Parameters

for a_0m_sq.U_eq is defined as 1/3 of of the trace of the orthogonalised U_IJ tensor.

Table 3 Anisotropic Displacement Parameters

for a_0m_sq.The Anisotropic displacement factor exponent takes the form:-2π²[h²a*²U₁₁+2hka*b*U₁₂+…].

Table 4 Bond Lengths for a_0m_sq.

Table 5 Bond Angles for a_0m_sq.

Table 6 Hydrogen Atom Coordinates

and Isotropic Displacement Parameters

for a_0m_sq.

Table 7 Solvent masks information for a_0m_sq.

(3.3) analysis of Single Crystal

From the single crystal plot, we can determine that the caffeine impurity structure is:

at the same time, it can be seen that in the single crystal diagram there areThe metal complex, because the impurity itself has a carboxyl group, obtains a metal complex of potassium ions at a hydroxyl position by reacting with potassium carbonate in the caffeine production process, and is very difficult to obtain a proper on-machine crystal form in the preparation of single crystals due to the existence of the complex. By combining nuclear magnetic and mass spectrometry, the compound contains 11 hydrogens and 10 carbons, wherein the primary carbons are 3 and the quaternary carbons are 7; the mass spectrum positive ion mode shows the molecular ion peak [ M + H ] of the compound]⁺The mass-to-charge ratio of the peak is 266.0885, which are consistent with the structure, and the impurity structure is determined to be the above structure.

Drawings

FIG. 1 is a single crystal diagram of 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid.

Detailed Description

The following examples are intended to further illustrate the invention, but not to limit it.

Example 1

5mg of pure impurities were weighed out and 10ml of pyridine was added and stirred to dissolve them completely. Then naturally volatilizing at 20 ℃, and finally obtaining filamentous crystals which do not meet the upper computer condition.

Example 2

When 5mg of pure impurities were weighed out and 10ml of methanol was added, it was found to be very insoluble and hardly dissolved even when the amount of methanol was increased to 100ml, so that the intended single crystal could not be obtained by dissolving methanol.

Example 3

5mg of pure impurities were weighed out and then 10ml of a 5:1 volume ratio aqueous pyridine mixture was added and stirred to dissolve all impurities. Then naturally volatilize at 25 ℃, finally obtain filamentous crystals, and do not meet the upper computer condition.

Example 4

Weighing 5mg of pure impurities, and then adding 10ml of methanol-water mixture with the volume ratio of 5:1, although the solubility is improved compared with that of methanol used as a solvent, the pure impurities are still difficult to completely dissolve, so that the target single crystal cannot be obtained, and the upper machine condition is also not met.

Example 5

5mg of pure impurities are weighed, 10ml of pyridine methanol water mixture with the volume ratio of 1:1:0.5 is added, and the mixture is stirred and dissolved. Then naturally volatilizes at 20 ℃. Finally, the fine rod-shaped crystals are obtained, but the data collection is not good, and the crystal form is not large enough, so that the preparation is failed finally.

Example 6

5mg of pure impurities are weighed, 10ml of pyridine methanol water mixture with the volume ratio of 2:1:1 is added, and the mixture is stirred and dissolved. Then naturally volatilizes at 25 ℃. Finally, granular crystals are obtained, data collection is good, and the target single crystal is finally obtained.

Example 7

5mg of pure impurities are weighed, 10ml of pyridine methanol water mixture with the volume ratio of 2:0.5:1 is added, and the mixture is stirred and dissolved. Then naturally volatilizes at 30 ℃. Because the temperature is higher and the volatilization is faster, no crystal is obtained at last, and the preparation of the single crystal fails.

Example 8

5mg of pure impurities were weighed out and 10ml of ethanol was added, and even if the amount was increased to 100ml, the impurities were hardly dissolved by stirring, so that single crystal production could not be carried out.

Example 9

When 5mg of pure impurities were weighed out and 10ml of acetonitrile was added, the impurities were hardly dissolved by stirring even when the amount was increased to 100ml, and thus, single crystal production was impossible.

Example 10

When 5mg of pure impurities were weighed out and 10ml of tetrahydrofuran was added, the impurities were hardly dissolved by stirring even when the amount was increased to 100ml, and thus, single crystal production was impossible.

Example 11

5mg of pure impurities are weighed and then 10ml of ethanol-water mixed solvent with the volume ratio of 5:1 is added, and even if the volume is increased to 100ml, the impurities are difficult to dissolve by stirring, so that the single crystal preparation cannot be carried out.

Example 12

When 5mg of pure impurities were weighed out and 10ml of a 5:1 by volume acetonitrile/water mixed solvent was added, the mixture was hardly dissolved by stirring even when the volume was increased to 100ml, and thus, single crystal production was impossible.

Example 13

After 5mg of pure impurities were weighed out and 10ml of a tetrahydrofuran water mixed solvent at a volume ratio of 5:1 was added, the mixture was not dissolved easily by stirring even when the volume was increased to 100ml, and thus, single crystal production was impossible.

Claims

1. A single crystal preparation method of caffeine impurity II is characterized by comprising the following steps:

(1) firstly, dissolving a caffeine impurity II, namely a 1, 3-dimethyl-7- (methylamino) -2, 4-dicarbonyl-1, 2,3, 4-tetrahydropteridine-6-carboxylic acid sample by using a solvent;

(2) and then volatilizing the solvent at a proper temperature until the crystal form which can be detected on a machine is obtained.

2. The method of claim 1, wherein the solvent is one of pyridine, methanol, pyridine-water mixed solvent, methanol-water mixed solvent, pyridine-methanol-water mixed solvent, ethanol, acetonitrile, tetrahydrofuran, ethanol-water mixed solvent, acetonitrile-water mixed solvent, and tetrahydrofuran-water mixed solvent.

3. The method of producing a single crystal of caffeine impurity II according to claim 1, wherein the solvent is a mixed solvent of pyridine, methanol and water.

4. The method of producing a single crystal of caffeine impurity II according to claim 1, wherein the volume ratio of the mixed solvent of pyridine, methanol and water is one of 1:1:0.5, 2:1:1, 2:0.5: 1.

5. The method of producing a single crystal of caffeine impurity II according to claim 1, wherein the volume ratio of the mixed solvent of pyridine and methanol in water is 2:1: 1.

6. The method of preparing a single crystal of caffeine impurity II according to claim 1, wherein the single crystal growth temperature is one of 20 ℃, 25 ℃, 30 ℃.

7. The method of preparing a single crystal of caffeine impurity II according to claim 1, wherein the single crystal growth temperature is 25 ℃.