CN110894198A - Xanthine compound and preparation method and application thereof - Google Patents

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 invention relates to an important application of a new compound I, namely a method for synthesizing a compound III capable of treating type II diabetes by taking the compound I as a raw material, the 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

Xanthine compound and preparation method and application thereof

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 compound III is found to have low yield and low product purity when industrially synthesized by the method, and the purification effect is not ideal when column chromatography is adopted for purification, so that the production and the cost are not controlled easily.

Disclosure of Invention

We have studied and explored the synthetic route to compound III to develop a process for the preparation of compound III that can be applied to 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): 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, N, N-dimethylformamide or N-methylpyrrolidone; n, N-dimethylacetamide is preferred.

The preparation method of the compound I, disclosed by the invention, has the advantage 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, N, N-dimethylformamide or N-methylpyrrolidone; n, N-dimethylacetamide is preferred.

The preparation method of the compound I, disclosed by the invention, has the advantage 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 225 nm.

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) the compound I is used as an impurity reference substance in the linagliptin intermediate compound R3 during the related substance detection, so that the related substances in the linagliptin intermediate compound R3 can be effectively and conveniently monitored, the quality of the linagliptin intermediate compound R3 can be effectively controlled, and the quality control and stability analysis of linagliptin finished products are used as reference standards to ensure 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, special synthesis is not 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, and is 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 in lot number 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, carrying out 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 controls

Silica gel with 200-300 meshes is filled in the silica gel column, and the amount of the silica gel is controlled to be 30 times of the amount of the crude product of the compound I in wet column packing. 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) -ethyl acetate;

flow rate: 10 mL/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:¹H 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, heating to 75-85 ℃ for reaction, adding 3000mL of purified water after the reaction is finished, carrying out suction filtration, stirring and dissolving a filter cake with 900mL of dichloromethane, washing with 900mL of multiplied by 3 purified water, drying with anhydrous sodium sulfate, and carrying out suction filtration to obtain a dichloromethane solution of a compound II.

2) Preparation of Compound III

Adding the dichloromethane solution of the compound II obtained in the previous step into 199g of trifluoroacetic acid, stirring and reacting for 1.5h at room temperature, 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: 10), pulping, filtering and drying to obtain 48.3g of a compound III, wherein the yield is 51.1%, and the purity is 99.23%.

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, sodium carbonate 32g are added to 90mL N, N-dimethylformamide, heating to 75-85 ℃ for reaction, adding 300mL of purified water after the reaction is finished, carrying out suction filtration, stirring and dissolving a filter cake by 90mL of dichloromethane, washing by 90mL of multiplied by 3 purified water, drying by anhydrous sodium sulfate, and carrying out suction filtration to obtain a dichloromethane solution of a compound II.

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, evaporating the organic phase at 35-45 ℃ until the organic phase is dried, adding 90ml of ethanol/methyl tert-butyl ether (V/V is 1: 10), pulping, filtering and drying to obtain 4.6g of a compound III, wherein the yield is 48.5%, and the purity is 99.13%.

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 were added to 90mL of N-methylpyrrolidinone, heating to 75-85 ℃ for reaction, adding 360mL of purified water after the reaction is finished, carrying out suction filtration, stirring and dissolving a filter cake by using 100mL of dichloromethane, washing by using 100mL of multiplied by 3 purified water, drying by using anhydrous sodium sulfate, and carrying out suction filtration to obtain a dichloromethane solution of a compound II.

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, evaporating the organic phase at 35-45 ℃ until the organic phase is dried, adding 90ml of ethanol/methyl tert-butyl ether (V/V ═ 1: 10), pulping, filtering and drying to obtain 4.0g of the compound III, wherein the yield is 42.6%, and the purity is 98.90%.

Mass spectral data for compound III: 945.10(M + 1);

compound III hydrogen spectral data: 1H NMR (600MHz, DMSO): δ 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 to 1.65(d, 2H); 1.52(s, 3H).

Comparative example: preparation of Compound III according to the procedure 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) were 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 dissolved in methylene chloride, dried, reduced-pressure evaporated, 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 examples, compared with the method for preparing the compound III by using linagliptin in the comparative example, the method for preparing the compound III by using the compound I has the advantages that the conversion rate of ① is greatly improved, the method is more suitable for large-scale production, the reaction conversion rate is greatly improved and can reach 50% by using the compound I as an intermediate, the method in the comparative example 1 has the yield of only about 7.5% and is not suitable for large-scale production, the ② cost is low, the compound I serving as a material used in the method is easy to obtain and low in price, the linagliptin serving as a material in the comparative example 1 has high preparation difficulty and relatively high price, in addition, the cost is further reduced due to the high conversion rate of the method, the ③ purity is high, the compound III obtained in the method has the purity of up to 99%, and the compound III obtained in the comparative example 1 is only 97%, and further purification is needed for medicinal use.

Example 5: related substances of compound I used as impurity reference substance for determining linagliptin intermediate compound R3

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 225 nm.

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 0.1mg of the intermediate compound 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 the chromatogram of the 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 lot number 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 content table of related substances in compound R3

	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 (10)

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 tert-butoxycarbonyl (Boc), phthaloyl (Pht), benzyl (Bn) or benzyloxycarbonyl (Cbz), preferably tert-butoxycarbonyl;

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, 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.

3. A compound having the structure shown in formula I below:

4. a process for the preparation of compound I according to claim 3, comprising the steps of:

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:

preferably, the preparation method 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 using dichloromethane, washing with water, drying, and evaporating to obtain a compound I;

the method can also comprise the following steps:

3) separating the compound I obtained in the step 2) by silica gel column chromatography to obtain a purified compound I.

5. The process according to claim 2 or 4, wherein the acid scavenger is selected from potassium carbonate, sodium carbonate or sodium bicarbonate, preferably potassium carbonate.

6. The process according to claim 2 or 4, wherein the organic solvent is selected from N, N-dimethylacetamide, N, N-dimethylformamide or N-methylpyrrolidone; n, N-dimethylacetamide is preferred.

7. The method according to claim 2 or 4, wherein the heating temperature is 75 to 85 ℃.

8. Use of compound I according to claim 3 for the preparation of compound III having the formula:

9. use according to claim 8 for the preparation of compound III according to the process of any one of claims 1-2.

10. The use of a compound I according to claim 3 as a reference substance for the detection of compounds R3, compound R3 having the following structural formula:

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 225 nm.

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