CN111087412B - Pyrrolopyrimidine derivatives and synthetic method thereof - Google Patents
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Abstract
The invention discloses a pyrrolopyrimidine derivative which has a general formula with a structure shown in a formula (I):
Description
Technical Field
The disclosure relates to the technical field of pharmaceutical chemistry, in particular to pyrrolopyrimidine derivatives and a synthesis method thereof.
Background
Protein kinases are a group of enzymes that regulate the activity of their target proteins by adding phosphate groups to the protein substrate. Kinases play important roles in a number of physiological processes including cell division, differentiation, autoregulation of cells and signal transduction. Kinases can be subdivided into serine/threonine kinases and tyrosine kinases according to their targets. Tyrosine kinases are further subdivided into receptor tyrosine kinases and non-receptor tyrosine kinases. JAK (jus kinase) kinases, a class of non-receptor tyrosine protein kinases, four JAK family members have been described in the prior art: JAK1, JAK2, JAK3 and TYK 1. The substrates of JAKs are Signal Transducers and Activators of Transcription (STATs). STAT is phosphorylated by JAK, dimerizes, and then enters nucleus through nuclear membrane to regulate the expression of related genes, and the signal path is called JAK-STAT pathway, so that JAK plays an important role in the pathophysiological process of immune-mediated diseases and can be used for treating some autoimmune diseases such as atopic dermatitis, rheumatoid arthritis, psoriasis, ulcerative colitis and the like.
The WXFL10203614 compound is a new generation of JAK inhibitors for the treatment of rheumatoid arthritis, but the compound is poorly soluble, limiting its use. The structure of the WXFL10203614 compound is as follows:
disclosure of Invention
According to one aspect of the present disclosure, a class of pyrrolopyrimidine derivatives was devised, leading to the WXFL10203614 compound, which may address one or more of the above-mentioned problems. The pyrrolopyrimidine derivatives disclosed by the invention have a general formula with a structure shown in formula (I):
wherein R is selected from one of H, alkyl sulfonyl and aryl sulfonyl.
In certain embodiments, illustrative examples of alkylsulfonyl groups that can be used in the present disclosure include, but are not limited to, C1-6 alkylsulfonyl.
In certain embodiments, illustrative examples of C1-6 alkylsulfonyl groups that can be used in the present disclosure include, but are not limited to, methylsulfonyl or ethylsulfonyl.
In certain embodiments, illustrative examples of arylsulfonyl groups that can be used in the present disclosure include, but are not limited to, p-toluenesulfonyl.
The present disclosure also provides a method for synthesizing a compound of formula (i), comprising the steps of:
a) taking 7-amino-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester as a starting material to synthesize intermediates 1-6, wherein the specific synthetic route is as follows:
7-amino-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester →
b) The target compound shown in the formula (I) is obtained by taking 4-chloro-7H-pyrrole [2,3-D ] pyrimidine as a raw material through substitution reaction, amidation reaction and ring-closure reaction, and the specific synthetic route is as follows:
or the like, or, alternatively,
4-chloro-7H-pyrrole [2,3-D ] pyrimidine is used as a raw material to obtain a target compound shown in a formula (I) through amidation and ring closure reaction, and the synthetic route is as follows:
wherein R is selected from one of H, alkyl sulfonyl and aryl sulfonyl.
In certain embodiments, the substitution reaction in step b) is specifically performed by: dissolving 4-chloro-7H-pyrrole [2,3-D ] pyrimidine, alkyl sulfonyl chloride or aryl sulfonyl chloride in a mixed solution of dichloromethane and N, N-diisopropylethylamine, reacting at room temperature, adjusting the pH value to be neutral, washing with water, and drying to obtain the compound shown in the formula (II).
In certain embodiments, the particular steps of the amidation reaction in step b) are: dissolving the compound shown in the formula (II) in anhydrous tetrahydrofuran, adding triethylamine and formamide, carrying out reflux reaction, adding ice water, reducing pressure to remove tetrahydrofuran, extracting with dichloromethane, washing with water to neutrality, and carrying out silica gel column chromatography to obtain the compound shown in the formula (III).
In certain embodiments, the particular steps of the amidation reaction in step b) are: dissolving 4-chloro-7H-pyrrole [2,3-D ] pyrimidine in anhydrous tetrahydrofuran, adding triethylamine and formamide, carrying out reflux reaction, adding ice water, removing tetrahydrofuran under reduced pressure, extracting with dichloromethane, washing with water to neutrality, and carrying out silica gel column chromatography to obtain the compound shown in the formula (III).
In some embodiments, the ring closure reaction in step b) is specifically performed by: dissolving the compound shown in the formula (III) and the intermediate 6 in ethanol and water, carrying out reflux reaction, removing the solvent under reduced pressure, and carrying out silica gel column chromatography to obtain the compound shown in the formula (I).
In certain embodiments, the alkylsulfonyl group is selected from C1-6 alkylsulfonyl.
In certain embodiments, the C1-6 alkylsulfonyl group is selected from one of methylsulfonyl or ethylsulfonyl and the arylsulfonyl group is selected from p-toluenesulfonyl.
Compared with the prior art, the beneficial effect of this disclosure is: the pyrrolopyrimidine derivatives disclosed by the invention have good water solubility and are beneficial to clinical application of medicaments.
Detailed Description
The present disclosure is described in detail below with reference to various embodiments, but it should be understood that these embodiments are not intended to limit the present disclosure, and a person skilled in the art may make functional, methodological, or structural equivalent changes or substitutions based on these embodiments within the scope of the present disclosure.
Unless otherwise specified, the term "room temperature" in the examples of the present specification is specifically 25 ℃; the term "h" is in particular a time measurement unit: hours; the term "ml" is in particular a volume unit: ml; the term "g" is a unit of weight, i.e., grams.
The present disclosure provides a class of pyrrolopyrimidine derivatives having the general formula of formula (i):
wherein R is selected from one of H, alkyl sulfonyl and aryl sulfonyl.
In some embodiments, the alkylsulfonyl group is selected from C1-6 alkylsulfonyl.
In some embodiments, the C1-6 alkylsulfonyl group is selected from one of methylsulfonyl or ethylsulfonyl.
In some embodiments, the arylsulfonyl group is p-toluenesulfonyl.
The present disclosure also provides a method for synthesizing a compound represented by formula (i), comprising the following synthetic steps:
a) taking 7-amino-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester as a starting material to synthesize an intermediate 6, wherein the specific synthetic route is as follows:
7-amino-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester →
b) The target compound shown in the formula (I) is obtained by taking 4-chloro-7H-pyrrole [2,3-D ] pyrimidine as a raw material through substitution reaction, amidation reaction and ring-closure reaction, and the specific synthetic route is as follows:
or the like, or, alternatively,
4-chloro-7H-pyrrole [2,3-D ] pyrimidine is used as a raw material to obtain a target compound shown in a formula (I) through amidation and ring closure reaction, and the synthetic route is as follows:
the compound shown in the formula (II) mainly comprises an intermediate 8, an intermediate 10 and an intermediate 12, wherein the structures of the intermediate 8, the intermediate 10 and the intermediate 12 are as follows:
the compound shown in the formula (III) mainly comprises an intermediate 7, an intermediate 9, an intermediate 11 and an intermediate 13, wherein the structures of the intermediate 7, the intermediate 9, the intermediate 11 and the intermediate 13 are as follows:
the compound shown in the formula (I) mainly comprises a compound 1, a compound 2, a compound 3 and a compound 4, wherein the structures of the compound 1, the compound 2, the compound 3 and the compound 4 are as follows:
the preparation method of the intermediate 1-6 comprises the following steps:
preparation of intermediate 1
Dissolving 20.9g of 7-amino-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester in 100ml of tetrahydrofuran, slowly dropwise adding 200ml of 1M tetrahydrofuran solution of lithium aluminum hydride, reacting at room temperature for 8h after the dropwise adding process is finished, slowly dropwise adding ice water for quenching, performing suction filtration, extracting the filtrate for three times by using dichloromethane, washing an organic layer to be neutral, and drying by using anhydrous magnesium sulfate to obtain an intermediate 1, wherein the obtained intermediate 1 is directly used for the next reaction.
Preparation of intermediate 2
Dissolving 18.3g of intermediate 1 and 22.1g of manganese dioxide in a mixed solution of 120ml of dichloromethane and 120ml of methanol, heating to reflux, reacting for 24 hours, filtering to remove the manganese dioxide by suction, concentrating the filtrate to obtain an intermediate 2, and directly using the obtained intermediate 2 for the next reaction.
Preparation of intermediate 3
15g of intermediate 2 and 5.5g of hydroxylamine hydrochloride were dissolved in 150ml of ethanol, 40ml of an aqueous solution containing 3.6g of sodium acetate was added, the mixture was heated to reflux, reacted for 8 hours, the solvent was removed under reduced pressure, methylene chloride was dissolved and then washed with ice water, dried over anhydrous magnesium sulfate, and concentrated to give 13.5g of intermediate 3, which was a white solid, as intermediate 3.
Preparation of intermediate 4
Dissolving 25g of intermediate 3 in 120ml of acetic anhydride, heating to reflux, reacting overnight, concentrating the reaction solution, and performing silica gel column chromatography, wherein an eluent is a mixed solution of ethyl acetate and cyclohexane, and the volume ratio of the ethyl acetate to the cyclohexane is 2: 1 to yield 16.2g of intermediate 4, intermediate 4 as a white solid.
Preparation of intermediate 5
Dissolving 19.2g of the intermediate 4 in 100ml of ethanol, dropwise adding 2ml of concentrated sulfuric acid, stirring at room temperature until the intermediate 4 is dissolved, continuously adding 12.4ml of hydrazine hydrate, refluxing for overnight reaction, adding 20ml of ice water, removing ethanol under reduced pressure, extracting with ethyl acetate for three times, combining organic layers, washing with water until the organic layers are neutral, drying with anhydrous magnesium sulfate, and concentrating to remove the solvent to obtain an intermediate 5.
Preparation of intermediate 6
Reacting 22.4g of intermediate 5 with 90g of formamide at 90 ℃ overnight, adding 120ml of ice water, extracting with methyl tert-butyl ether three times, combining the organic layers and washing with ice water twice, drying over anhydrous magnesium sulfate, concentrating to remove methyl tert-butyl ether, and recrystallizing the residue with a mixed solution of acetone and water at a volume ratio of 5: 1 to yield 17.9g of intermediate 6, intermediate 6 as a white solid.
Example 1
The preparation of compound 1 comprises the following two steps:
(1) preparation of intermediate 7
Dissolving 30.1g of 4-chloro-7H-pyrrolo [2,3-D ] pyrimidine in 124ml of anhydrous tetrahydrofuran, adding 2.8ml of triethylamine and 9g of formamide, carrying out reflux reaction for 8 hours, adding 30ml of ice water, removing tetrahydrofuran under reduced pressure, extracting with dichloromethane three times, combining organic layers, washing with water until the organic layers are neutral, and carrying out silica gel column chromatography on residues, wherein an eluent is a mixed solution of ethyl acetate and cyclohexane, and the volume ratio of the ethyl acetate to the cyclohexane is 3:1, so that 26.1g of intermediate 7 is obtained, and the intermediate 7 is a white solid.
(2) Dissolving 32g of intermediate 6 and 25.1g of intermediate 7 in 75m l ethanol and 75ml of water, heating and refluxing for 24h, removing the solvent under reduced pressure, and subjecting the residue to silica gel column chromatography to obtain a mixed solution of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is 50: 1, 41.9g of Compound 1 are obtained, Compound 1 being a white solid. MS (ESI) calculation C for Compound 1 prepared in this example16H13N9[M+H]+331, measured value 331.
Example 2
The preparation of the compound 2 comprises the following three steps:
(1) preparation of intermediate 8
15.6g of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and 19g of p-toluenesulfonyl chloride were dissolved in a mixed solution of 200ml of dichloromethane and 12.1ml of N, N-diisopropylethylamine, and stirred at room temperature for 4 hours, the reaction solution was adjusted to neutral pH with dilute hydrochloric acid, washed with ice water, dried over anhydrous magnesium sulfate, and spin-dried to obtain 23.5g of intermediate 8, which was a white solid.
(2) Preparation of intermediate 9
Dissolving 30.7g of intermediate 8 in 124ml of anhydrous tetrahydrofuran, adding 2.8ml of triethylamine and 9g of formamide, carrying out reflux reaction for 8 hours, adding 30ml of ice water, removing the tetrahydrofuran under reduced pressure, extracting with dichloromethane for three times, combining organic layers, washing with water until the mixture is neutral, carrying out silica gel column chromatography on the residue, wherein an eluent is a mixed solution of ethyl acetate and cyclohexane, the volume ratio of the ethyl acetate to the cyclohexane is 3:1, and obtaining 22.4g of intermediate 9 which is a white solid.
(3) Dissolving 32g of intermediate 6 and 30.5g of intermediate 9 in 75ml of ethanol and 75ml of water, heating and refluxing for 24h, removing the solvent under reduced pressure, and carrying out silica gel column chromatography on the residue, wherein an eluent is a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 50: 1, 48.9g of compound 2 are obtained, compound 2 being a white solid. Calculated value C of MS (ESI) for Compound 2 prepared in this example23H19N9O2S[M+H]+485.5, measurement 485.5.
Example 3
The preparation of the compound 3 comprises the following three steps:
(1) preparation of intermediate 10
15.6g of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and 6.2g of methanesulfonyl chloride were dissolved in a mixed solution of 200ml of dichloromethane and 12.1ml of N, N-diisopropylethylamine, and stirred at room temperature for 4 hours, the reaction solution was adjusted to neutral pH with dilute hydrochloric acid, washed with ice water, dried over anhydrous magnesium sulfate, and spin-dried to obtain 16.2g of intermediate 10, which was a white solid.
(2) Preparation of intermediate 11
Dissolving 23g of intermediate 10 in 124ml of anhydrous tetrahydrofuran, adding 2.8ml of triethylamine and 9g of formamide, carrying out reflux reaction for 8 hours, adding 30ml of ice water, removing the tetrahydrofuran under reduced pressure, extracting with dichloromethane for three times, combining organic layers, washing with water to be neutral, carrying out silica gel column chromatography on residues, and using a mixed solution of ethyl acetate and cyclohexane as an eluent, wherein the volume ratio of the ethyl acetate to the cyclohexane is 3:1, so as to obtain 17.2g of intermediate 11, and the intermediate 11 is a white solid.
(3) Dissolving 32g of intermediate 6 and 24g of intermediate 11 in 75ml of ethanol and 75ml of water, heating and refluxing for 24h, removing the solvent under reduced pressure, and carrying out silica gel column chromatography on the residue, wherein an eluent is a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 50: 1, 45.3g of compound 3 are obtained, compound 3 being a white solid. Calculated value C of MS (ESI) of Compound 3 prepared in this example17H15N9O2S[M+H]+409.4, found 409.4.
Example 4:
the preparation of the compound 4 comprises the following three steps:
(1) preparation of intermediate 12
15.6g of 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine and 6.8g of ethanesulfonyl chloride were dissolved in 200ml of dichloromethane and 12.1ml of N, N-diisopropylethylamine, and the mixture was stirred at room temperature for 4 hours, the reaction solution was adjusted to neutral pH with dilute hydrochloric acid, washed with ice water, dried over anhydrous magnesium sulfate, and spin-dried to give 15.7g of intermediate 12, which was a white solid.
(2) Preparation of intermediate 13
Dissolving the intermediate 12 in 124ml of anhydrous tetrahydrofuran, adding 2.8ml of triethylamine and 9g of formamide, carrying out reflux reaction for 8h, adding 30ml of ice water, removing the tetrahydrofuran under reduced pressure, extracting with dichloromethane for three times, combining organic layers, washing with water to be neutral, carrying out silica gel column chromatography on residues, wherein an eluent is a mixed solution of ethyl acetate and cyclohexane, the volume ratio of the ethyl acetate to the cyclohexane is 3:1, and obtaining 17.9g of intermediate 13, and the intermediate 13 is a white solid.
(3) Dissolving 32g of intermediate 6 and 25.5g of intermediate 13 in 75ml of ethanol and 75ml of water, heating and refluxing, reacting for 24h, removing the solvent under reduced pressure, and passing the residue through a silica gel columnAnd (3) performing chromatography, wherein an eluent is a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 50: 1, 38.9g of compound 4 are obtained, compound 4 being a white solid. MS (ESI) calculation C for Compound 4 prepared in this example18H17N9O2S[M+H]+413.2, found 413.2.
In the above examples, 4-chloro-7H-pyrrolo [2,3-D ] pyrimidine is a commercially available product having CAS No. 3680-69-1.
Water solubility test
Water solubility experiments were performed using test methods known in the art, and the results were as follows:
| name (R) | Water solubility (mg/L) |
| WXFL10203614 | 0.12 |
| Compound 1 | 1.45 |
| Compound 2 | 2.87 |
| Compound 3 | 1.01 |
| Compound 4 | 2.55 |
From the above test results, it is clear that the water solubility of compounds 1 to 4 in the present disclosure is significantly higher than that of WXFL10203614 compound, and the water solubility of compound 2 is significantly higher than that of compounds 1, 3 and 4.
What has been described above is merely some embodiments of the present disclosure. It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the inventive concept of the present disclosure, which falls within the scope of the disclosure.
Claims (2)
1. A pyrrolopyrimidine derivative having the general formula of formula (i):
wherein R is selected from H, methylsulfonyl, ethylsulfonyl or p-toluenesulfonyl.
2. A method for synthesizing a compound of formula (i), comprising the steps of:
a) taking 7-amino-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-2-carboxylic acid ethyl ester as a starting material to synthesize intermediates 1-6, wherein the specific synthetic route is as follows:
b) the target compound shown in the formula (I) is obtained by taking 4-chloro-7H-pyrrole [2,3-D ] pyrimidine as a raw material through substitution reaction, amidation reaction and ring-closure reaction, and the specific synthetic route is as follows:
or the like, or, alternatively,
4-chloro-7H-pyrrole [2,3-D ] pyrimidine is used as a raw material to obtain a target compound shown in a formula (I) through amidation and ring closure reaction, and the synthetic route is as follows:
wherein R is selected from H, methylsulfonyl, ethylsulfonyl or p-toluenesulfonyl;
b) the substitution reaction in the step (A) is specifically as follows: dissolving 4-chloro-7H-pyrrole [2,3-D ] pyrimidine, alkyl sulfonyl chloride or aryl sulfonyl chloride in a mixed solution of dichloromethane and N, N-diisopropylethylamine, reacting at room temperature, adjusting the pH value to be neutral, washing with water, and drying to obtain a compound shown in a formula (II); wherein, the alkyl sulfonyl chloride is methyl sulfonyl chloride or ethyl sulfonyl chloride, and the aryl sulfonyl chloride is p-toluene sulfonyl chloride;
b) the amidation reaction in the step (a) is specifically as follows: dissolving the compound shown in the formula (II) in anhydrous tetrahydrofuran, adding triethylamine and formamide, performing reflux reaction, adding ice water, removing the tetrahydrofuran under reduced pressure, extracting with dichloromethane, washing with water to neutrality, and performing silica gel column chromatography to obtain a compound shown in the formula (III); or, the amidation reaction in the step b) is specifically carried out by: dissolving 4-chloro-7H-pyrrole [2,3-D ] pyrimidine in anhydrous tetrahydrofuran, adding triethylamine and formamide, performing reflux reaction, adding ice water, removing tetrahydrofuran under reduced pressure, extracting with dichloromethane, washing with water to neutrality, and performing silica gel column chromatography to obtain a compound shown in a formula (III);
b) the ring closure reaction in the step is specifically as follows: dissolving the compound shown in the formula (III) and the intermediate 6 in ethanol and water, carrying out reflux reaction, removing the solvent under reduced pressure, and carrying out silica gel column chromatography to obtain the compound shown in the formula (I).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016192563A1 (en) * | 2015-05-29 | 2016-12-08 | 南京明德新药研发股份有限公司 | Janus kinase inhibitor |
| WO2017035366A1 (en) * | 2015-08-26 | 2017-03-02 | Incyte Corporation | Pyrrolopyrimidine derivatives as tam inhibitors |
| CN109369654A (en) * | 2018-11-20 | 2019-02-22 | 山东大学 | 1,3- bis- substituted-4-amino Pyrazolopyrimidines and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016192563A1 (en) * | 2015-05-29 | 2016-12-08 | 南京明德新药研发股份有限公司 | Janus kinase inhibitor |
| WO2017035366A1 (en) * | 2015-08-26 | 2017-03-02 | Incyte Corporation | Pyrrolopyrimidine derivatives as tam inhibitors |
| CN109369654A (en) * | 2018-11-20 | 2019-02-22 | 山东大学 | 1,3- bis- substituted-4-amino Pyrazolopyrimidines and its preparation method and application |
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