CN110894198B - Xanthine compound and preparation method and application thereof - Google Patents
Xanthine compound and preparation method and application thereof Download PDFInfo
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- CN110894198B CN110894198B CN201811066925.0A CN201811066925A CN110894198B CN 110894198 B CN110894198 B CN 110894198B CN 201811066925 A CN201811066925 A CN 201811066925A CN 110894198 B CN110894198 B CN 110894198B
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- C07D—HETEROCYCLIC COMPOUNDS
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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
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel compound I (shown as a formula I), and a preparation method and application thereof. The present invention relates to novel compoundsThe method has the advantages of high conversion rate, simple process and mild reaction conditions, and provides an economic and environment-friendly route for preparing the compound III; compared with the method for preparing the compound III by linagliptin in the prior art, the method has the advantages that: higher yield, better purity, simple operation and lower cost, and is suitable for industrial production. The compound I is solid and easy to store and purify, and the preparation route of the compound I has mild reaction conditions and simple operation.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel intermediate compound of a compound III with pharmaceutical activity for treating type II diabetes, namely a xanthine compound I, and a preparation method and application thereof. One of the important uses of compound I is in the preparation of compound III.
Background
WO-2013010964 discloses a novel, potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor having the following structure:
this patent document discloses a method for synthesizing compound III from linagliptin, the synthetic route being shown in the following figure:
the specific route is as follows: linagliptin was suspended in aqueous hydrochloric acid and stirred at room temperature overnight. Then aqueous sodium hydroxide solution was added. The precipitate was separated and dissolved in dichloromethane. The organic phase was dried and the solvent was removed, then the remaining residue was purified by silica gel column chromatography and the fractions were combined.
In the research, the yield of the compound III is not high when the route is adopted for industrial synthesis, the product purity can not meet the requirement, and the purification effect is not ideal when column chromatography is adopted for purification, so that the production and the cost control are not facilitated.
Disclosure of Invention
The synthetic route of compound III was studied and explored to develop a preparation method of compound III that could be suitable for industrial production.
In the process of researching and developing the preparation process of the compound III, the compound III is prepared by taking the newly found compound I as the starting raw material, and compared with the process for preparing the compound III by using linagliptin in the prior art, the preparation method for preparing the compound III has the advantages of higher yield, better purity and lower cost, and is suitable for industrial production.
The invention provides a novel compound I (structural formula is shown in formula I), a preparation method thereof, a method for preparing a compound III by using the compound I, application of the compound I in preparing the compound III, and application of the compound I as an impurity reference substance of a linagliptin intermediate compound R3.
The chemical name of the compound I of the invention is: 8-bromo-1- [ [4- [ [2- [ [ 8-bromo-7- (2-butynyl) -2,3,6,7-tetrahydro-3-methyl-2,6-dioxo-1H-purin-1-yl ] methyl ] -1,4-dihydro-4 methyl-4-quinazolinyl ] methyl ] -2-quinazolinyl ] methyl ] -7- (2-butynyl) -3,7-dihydro-3-methyl-1H-purine-2,6-dione.
In the invention, the compound R3 is an intermediate compound of linagliptin; compound III is a known compound distinct from linagliptin having pharmaceutical activity for treating type II diabetes.
The structural formulas of the compound I, the compound III and the compound R3 in the invention are respectively as follows:
the invention firstly provides a novel compound I, the structural formula of which is shown in formula I (all the compounds I and impurities I in the invention refer to compounds with the structure shown in the formula I):
the preparation method of the compound I comprises the following steps (compounds with structural formulas shown as R1, R2 and R3, which are respectively referred to as the compound R1, the compound R2 and the compound R3 in short): adding a compound R1, a compound R2 and an acid-binding agent into an organic solvent together for reaction to obtain a compound R3 and a compound I, wherein the reaction formula is as follows:
preferably, the preparation method of the compound I comprises the following steps:
1) Adding a compound R1, a compound R2 and an acid-binding agent into an organic solvent together, heating to 60-100 ℃ for reaction, adding into purified water after the reaction is finished, performing suction filtration, and drying a filter cake to obtain a compound R3;
2) Extracting the filtrate obtained in the step 1) by suction filtration with dichloromethane, washing with water, drying, and evaporating to obtain a compound I.
More preferably, the preparation method of the compound I of the present invention further comprises the following refining steps:
3) Separating the compound I obtained in the step 2) by silica gel column chromatography to obtain a purified compound I.
The preparation method of the compound I of the invention is characterized in that the acid-binding agent is selected from potassium carbonate, sodium carbonate or sodium bicarbonate, preferably potassium carbonate.
The preparation method of the compound I of the invention is characterized in that the organic solvent is selected from N, N-dimethylacetamide or N, N-dimethylformamide or N-methylpyrrolidone; preferably N, N-dimethylacetamide.
The preparation method of the compound I of the invention is characterized in that the heating temperature is preferably 75-85 ℃.
The compound I is solid, is easy to store and purify, and has mild reaction conditions and simple operation in each preparation route.
The present invention also provides a process for the preparation of a compound of formula III (herein referred to simply as compound III) by the preparation of compound I of the present invention as a starting material/intermediate. Namely: one of the important uses of the compounds I according to the invention is as starting material/intermediate for the preparation of compounds III, namely: compound I has the use of preparing a pharmaceutical composition suitable for the treatment of type II diabetes.
A process for the preparation of compound III comprising the steps of:
1) Reacting compound I with (R) -3-Ak-aminopiperidine to give compound II, wherein Ak is selected from tert-butoxycarbonyl (Boc), phthaloyl (Pht), benzyl (Bn) or benzyloxycarbonyl (Cbz), preferably tert-butoxycarbonyl;
2) Deprotecting compound II to give compound III:
preferably, the preparation method of the compound III comprises the following steps:
1) Adding a compound I, (R) -3-Ak-aminopiperidine and an acid-binding agent into an organic solvent, heating to 60-100 ℃ for reaction, adding into purified water after the reaction is finished, carrying out suction filtration, stirring and dissolving a filter cake by using dichloromethane, washing by using purified water, and drying by using anhydrous sodium sulfate to obtain a dichloromethane solution of a compound II;
2) Adding a deprotection agent into the dichloromethane solution of the compound II obtained in the step 1), stirring and reacting for 1.5h, extracting, returning alkali, washing, drying, filtering, evaporating the filtrate to dryness to obtain a compound III,
preferably, the deprotecting agent in step 2) is selected from trifluoroacetic acid, concentrated sulfuric acid, concentrated hydrochloric acid, hydrobromic acid or hydrogen chloride;
more preferably, the deprotecting agent in step 2) is trifluoroacetic acid.
The preparation method of the compound I of the invention is characterized in that the acid-binding agent is selected from potassium carbonate, sodium carbonate or sodium bicarbonate, preferably potassium carbonate.
The preparation method of the compound I of the invention is characterized in that the organic solvent is selected from N, N-dimethylacetamide or N, N-dimethylformamide or N-methylpyrrolidone; preferably N, N-dimethylacetamide.
The preparation method of the compound I of the invention is characterized in that the heating temperature is preferably 75-85 ℃.
The present invention also provides the use of a compound I as described above for the preparation of compound III, having the structural formula:
the use of the above-mentioned compound I of the present invention means that the compound III can be prepared according to the aforementioned method using the compound I as a starting material/intermediate.
The present invention also provides another use of compound I, namely: the compound I can be used as a reference substance for detecting related substances of the compound R3, and the structural formula of the compound R3 is as follows:
preferably, the related substances are detected by an HPLC method, and the chromatographic conditions are as follows: the filler is octadecylsilane chemically bonded silica; the mobile phase A is phosphate buffer solution, and the mobile phase B is methanol-acetonitrile (55: 45); the column temperature was 55 ℃; the detection wavelength was 225nm.
The invention has the technical effects that:
(1) The invention discloses a new compound I, a preparation method and application thereof; one important application is that the compound I is used as a starting material/intermediate to synthesize the compound III for treating the type II diabetes, the whole process is simple, the reaction condition is mild, and an economic and environment-friendly synthetic route is provided for the synthesis of the compound III;
(2) When the compound I is used as an impurity reference substance in the linagliptin intermediate compound R3 during the detection of related substances, the related substances in the linagliptin intermediate compound R3 can be effectively and conveniently monitored so as to effectively control the quality of the linagliptin intermediate compound R3, thereby serving the quality control and stability analysis of a linagliptin finished product as reference standards and ensuring the safety and effectiveness of linagliptin and preparations thereof in clinical use;
(3) Compared with the method for preparing the compound III by linagliptin in the prior art, the preparation method of the compound III disclosed by the invention has the following advantages: because the preparation of the compound I adopts the reaction mother liquor of the compound R3, no special synthesis is needed, the process is more environment-friendly, the compound I is easier to purify than the compound III, the compound I is easier to separate and has higher purity, and the compound III prepared by the compound I has higher yield, better purity and lower cost, thereby being suitable for industrial production.
Description of the drawings:
FIG. 1 is an HPLC chromatogram of the detected level of the substance of interest in Compound R3 from run No. 1801001.
Detailed Description
The foregoing and other aspects of the present invention are achieved by the following detailed description, which should not be construed to limit the claimed subject matter in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods.
Example 1: preparation of Compound I
1) Preparation of crude Compound I
Adding 224g of 8-bromo-7- (2-butynyl) -3-methylxanthine (compound R1), 154g of 2-chloromethyl-4-methylquinazoline (compound R2) and 208g of potassium carbonate into 2240mL of N, N-dimethylacetamide, heating to 75-85 ℃ for reaction, adding 6600mL of purified water after the reaction is finished, performing suction filtration, and drying a filter cake to obtain 8-bromo-7- (2-butynyl) -3,7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2,6-dione (compound R3); the filtrate was extracted with 1000mL × 3 dichloromethane, the combined organic phases were washed with 1000mL × 3 purified water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness to give 15g of crude compound I.
2) Purification/refinement of Compound I reference
Silica gel with 200-300 meshes is filled in the silica gel column, and the dosage of the silica gel in the wet column packing is controlled to be 30 times of the crude product of the compound I. Dissolving a crude product of the compound I in dichloromethane, adding the crude product solution into a silica gel column, and performing column chromatography separation;
mobile phase: ethyl acetate/n-heptane (1:1) to ethyl acetate;
flow rate: 10mL/min;
TLC developing agent: ethyl acetate;
collecting chromatographic solution with Rf value of 0.3-0.4, and vacuum concentrating at vacuum degree of 0.1 and temperature of 40 deg.C to obtain 2.0g of compound I control.
Mass spectral data for compound I: 906.30 (M + 1);
compound I hydrogen spectra data: 1 H NMR(300MHz,DMSO):δ＝8.29～8.31(t,2H)；7.90～8.01(m,4H)；7.71～7.77(t,2H)；5.77(s,4H)；5.17～5.18(d,4H)；3.33～3.40(d,6H)；2.93(s,6H)；1.75～1.76(s,6H)。
example 2: preparation of Compound III
1) Preparation of Compound II
8-bromo-1- [ [4- [ [2- [ [ 8-bromo-7- (2-butynyl) -2,3,6,7-tetrahydro-3-methyl-2,6-dioxo-1H-purin-1-yl ] methyl ] -1,4-dihydro-4 methyl-4-quinazolinyl ] methyl ] -2-quinazolinyl ] methyl ] -7- (2-butynyl) -3,7-dihydro-3-methyl-1H-purine-2,6-dione (compound I) 90.6g, (R) -3-Boc-aminopiperidine 30.0g, potassium carbonate 41.5g are added to 900mL of N, N-dimethylacetamide, heated to 75-85 ℃ for reaction, after the reaction is completed, 3000mL of purified water is added, the filter cake is filtered, after the filter cake is dissolved by stirring with 900mL of dichloromethane, the solution is washed with 900mL of purified sodium sulfate × 3, dried over anhydrous sodium sulfate, and a solution of compound II is obtained by suction filtration.
2) Preparation of Compound III
Adding the dichloromethane solution of the compound II obtained in the previous step into 199g of trifluoroacetic acid, stirring at room temperature for reaction for 1.5h, extracting, returning alkali, washing, drying an organic phase, evaporating the organic phase at 35-45 ℃ until the organic phase is dried, adding 900ml of ethanol/methyl tert-butyl ether (V/V = 1.
Example 3: preparation of Compound III
1) Preparation of Compound II
8-bromo-1- [ [4- [ [2- [ [ 8-bromo-7- (2-butynyl) -2,3,6,7-tetrahydro-3-methyl-2,6-dioxo-1H-purin-1-yl ] methyl ] -1,4-dihydro-4 methyl-4-quinazolinyl ] methyl ] -2-quinazolinyl ] methyl ] -7- (2-butynyl) -3,7-dihydro-3-methyl-1H-purine-2,6-dione (compound I) 9.1g, (R) -3-Boc-aminopiperidine 3.0g, and sodium carbonate 32g are added to 90mL of N, N-dimethylformamide, heated to 75-85 ℃ for reaction, and after the reaction is completed, 300mL of purified water is added, and filtered, the filter cake is stirred and dissolved with 90mL of dichloromethane, washed with 90mL of purified water of 3 × sodium sulfate, dried without water, and a dichloromethane solution of compound II is obtained.
2) Preparation of Compound III
Adding the dichloromethane solution of the compound II obtained in the previous step into 25.6g of hydrogen chloride/methanol solution (4N), stirring and reacting at room temperature for 1.5h, extracting, returning alkali, washing, drying an organic phase, reducing and steaming the organic phase at 35-45 ℃ to dryness, adding 90ml of ethanol/methyl tert-butyl ether (V/V = 1.
Example 4: preparation of Compound III
1) Preparation of Compound II
8-bromo-1- [ [4- [ [2- [ [ 8-bromo-7- (2-butynyl) -2,3,6,7-tetrahydro-3-methyl-2,6-dioxo-1H-purin-1-yl ] methyl ] -1,4-dihydro-4 methyl-4-quinazolinyl ] methyl ] -2-quinazolinyl ] methyl ] -7- (2-butynyl) -3,7-dihydro-3-methyl-1H-purine-2,6-dione (compound I) 9.0g, (R) -3-Boc-aminopiperidine 3.0g, sodium bicarbonate 5.1g are added to 90mL of N-methyl pyrrolidone, heated to 75-85 ℃ for reaction, 360mL of purified water is added after the reaction is completed, suction filtration is performed, the filter cake is dissolved with 100mL of dichloromethane with stirring, washed with 100mL of purified water, dried over anhydrous sodium sulfate, and a dichloromethane solution of compound II is obtained.
2) Preparation of Compound III
Adding the dichloromethane solution of the compound II obtained in the previous step into 25g of concentrated hydrochloric acid, stirring and reacting at room temperature for 1.5h, extracting, returning alkali, washing, drying an organic phase, reducing and steaming the organic phase at 35-45 ℃ to dryness, adding 90ml of ethanol/methyl tert-butyl ether (V/V = 1.
Mass spectral data for compound III: 945.10 (M + 1);
compound III hydrogen spectral data: 1H NMR (600MHz, DMSO): delta =7.79 to 7.87 (m, 3H); 7.49 (s, 1H); 6.98-7.00 (t, 1H); 6.83 (d, 1H); 6.74 (d, 2H); 5.25 to 5.39 (m, 2H); 4.85-4.91 (m, 4H); 4.34 (d, 1H); 3.64-3.68 (t, 3H); 3.53 to 3.60 (m, 7H); 3.41 (s, 5H); 3.17 (s, 2H); 2.99-3.04 (t, 2H); 2.83-3.04 (m, 6H); 1.90 (d, 2H); 1.80-1.82 (m, 3H); 1.74-1.75 (t, 6H); 1.63-1.65 (d, 2H); 1.52 (s, 3H).
Comparative example: preparation of Compound III as described in WO-2013010964
10.0g of 8- [ (3R) -3-amino-1-piperidinyl ] -7- (2-butyn-1-yl) -3,7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2,6-dione (linagliptin) was suspended in 30mL of aqueous hydrochloric acid (4N) and stirred at room temperature overnight. The precipitate was separated by adding 30mL of an aqueous sodium hydroxide solution (4N), and the precipitate was dissolved in dichloromethane, dried, evaporated under reduced pressure, and subjected to silica gel column chromatography to give 1.5g of compound III, yield: 7.5% and 97.0% purity (literature yield 25%).
As can be seen from the above examples 1-4 and comparative example, the method for preparing compound III by using compound I of the present invention has advantages over the method for preparing compound III by using linagliptin in the comparative example in that: (1) the conversion rate is greatly improved, and the method is more suitable for large-scale production: by adopting the compound I as an intermediate, the reaction conversion rate is greatly improved and can reach 50 percent, while the yield of the method in the comparative example 1 is only about 7.5 percent, and the method is not suitable for large-scale production; (2) the cost is low: the compound I used as the material is easy to obtain and low in price, while the linagliptin used in the comparative example 1 is high in preparation difficulty and relatively high in price, and in addition, the conversion rate is high, so that the cost is further reduced; (3) the purity is high: the purity of the compound III obtained by the invention is up to 99 percent, while the purity of the compound III obtained in the comparative example 1 is only 97 percent, and the compound III can be used pharmaceutically only by further purification.
Example 5: related substances for determining linagliptin intermediate compound R3 by using compound I as impurity reference substance
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; phosphate buffer solution is used as a mobile phase A, and methanol-acetonitrile (55: 45) is used as a mobile phase B; the column temperature was 55 ℃; the detection wavelength was 225nm.
Test solution: taking a proper amount of the linagliptin intermediate compound R3, precisely weighing, placing into a proper brown measuring flask, adding a diluent to dissolve and dilute into a solution containing about 0.1mg per 1ml, and using the solution as a test solution.
Impurity control solution: taking a proper amount of impurity reference substance compound I, precisely weighing, placing in a proper brown measuring flask, adding a diluent to dissolve and dilute to obtain a solution containing 0.1mg of impurity reference substance per 1ml, and using the solution as an impurity reference substance solution.
The determination method comprises the following steps: precisely measuring 10 μ l of each of the sample solution and the impurity reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram. If an impurity peak exists in a chromatogram of a test solution, the impurity-containing compound I in the compound R3 is not more than 1.5 percent according to the external standard method by calculating the peak area.
The compound I is used as an impurity reference substance for detecting related substances of the linagliptin intermediate compound R3, and the results are as follows:
| batch number | 171208-1 | 171208-2 | 1801001 |
| Impurity I (Compound I) | 0.29％ | 0.27％ | 0.55％ |
| Purity of R3 | 98.64％ | 98.57％ | 98.28％ |
Wherein, in the batch No. 1801001, the HPLC chromatogram of the detection level of the related substance in the compound R3 is shown in FIG. 1; the specific content of the related substances in the compound R3 is shown in Table 1.
TABLE 1 TABLE OF THE CONTENT OF THE COMPOUND R3 IN THE TABLE
| Peak Name | Retention Time | Area | ％Area | Height | Int Type | |
| 1 | Compound R1 | 4.775 | 5020 | 0.03 | 179 | BB |
| 2 | 6.242 | 5921 | 0.03 | 277 | BB | |
| 3 | 7.479 | 6084 | 0.03 | 352 | BB | |
| 4 | Compound R2 | 8.341 | 74699 | 0.43 | 5633 | BB |
| 5 | Compound I | 14.152 | 95573 | 0.55 | 11625 | BV |
| 6 | 14.602 | 23762 | 0.14 | 3013 | VB | |
| 7 | Compound R3 | 15.109 | 17147692 | 98.28 | 2185239 | BV |
| 8 | 15.703 | 8015 | 0.05 | 745 | VB | |
| 9 | 16.604 | 18390 | 0.11 | 2696 | BV | |
| 10 | 18.162 | 10380 | 0.06 | 1446 | VV | |
| 11 | 18.324 | 8789 | 0.05 | 889 | VV | |
| 12 | 18.940 | 8830 | 0.05 | 1199 | VB | |
| 13 | 19.789 | 7145 | 0.04 | 667 | VV | |
| 14 | 21.270 | 6075 | 0.03 | 947 | BV | |
| 15 | 21.598 | 7628 | 0.04 | 836 | VV | |
| 16 | 22.145 | 6279 | 0.04 | 926 | VB | |
| 17 | 23.186 | 7762 | 0.04 | 1046 | BV |
Claims (4)
1. A process for the preparation of compound III, comprising the steps of:
1) Reacting compound I with (R) -3-Ak-aminopiperidine to give compound II, wherein Ak is selected from t-butoxycarbonyl (Boc), phthaloyl (Pht), benzyl (Bn) or benzyloxycarbonyl (Cbz);
2) Deprotecting compound II to give compound III:
2. the method of claim 1, comprising the steps of:
1) Adding a compound I, (R) -3-Ak-aminopiperidine and an acid-binding agent into an organic solvent, heating to 60-100 ℃ for reaction, adding into purified water after the reaction is finished, carrying out suction filtration, stirring and dissolving a filter cake by using dichloromethane, washing by using purified water, and drying by using anhydrous sodium sulfate to obtain a dichloromethane solution of a compound II;
2) Adding a deprotection agent into the dichloromethane solution of the compound II obtained in the step 1), stirring and reacting for 1.5h, extracting, returning alkali, washing, drying, filtering, and evaporating the filtrate to dryness to obtain a compound III, wherein the deprotection agent is selected from trifluoroacetic acid, concentrated sulfuric acid, concentrated hydrochloric acid, hydrobromic acid or hydrogen chloride.
3. The use of compound I for the preparation of compound III, compound I, compound III having the formula:
4. use according to claim 3 for the preparation of compound III according to the process of any one of claims 1-2.
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| US9056112B2 (en) * | 2011-12-28 | 2015-06-16 | Dr. Reddy's Laboratories Limited | Process for preparation of pure linagliptin |
| CN103709163B (en) * | 2012-09-29 | 2016-12-21 | 齐鲁制药有限公司 | Xanthine derivative, Preparation Method And The Use |
| CN105503872B (en) * | 2015-12-01 | 2017-06-27 | 北京普德康利医药科技发展有限公司 | A kind of Li Gelieting impurity and its preparation method and application |
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