CN112679505A - Synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine - Google Patents
Synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine Download PDFInfo
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- CN112679505A CN112679505A CN202011564838.5A CN202011564838A CN112679505A CN 112679505 A CN112679505 A CN 112679505A CN 202011564838 A CN202011564838 A CN 202011564838A CN 112679505 A CN112679505 A CN 112679505A
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- QWIAHMVNMONKCU-UHFFFAOYSA-N 4-methyl-7h-pyrrolo[2,3-d]pyrimidine Chemical compound CC1=NC=NC2=C1C=CN2 QWIAHMVNMONKCU-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 35
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 21
- -1 methyl Grignard reagent Chemical class 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 106
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 238000001914 filtration Methods 0.000 claims description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 53
- 238000001035 drying Methods 0.000 claims description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- CDVAIHNNWWJFJW-UHFFFAOYSA-N 3,5-diethoxycarbonyl-1,4-dihydrocollidine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C CDVAIHNNWWJFJW-UHFFFAOYSA-N 0.000 claims description 10
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 7
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 7
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- SHWZFQPXYGHRKT-FDGPNNRMSA-N (z)-4-hydroxypent-3-en-2-one;nickel Chemical compound [Ni].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O SHWZFQPXYGHRKT-FDGPNNRMSA-N 0.000 claims description 4
- 238000006298 dechlorination reaction Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 1
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 230000000382 dechlorinating effect Effects 0.000 abstract description 2
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 50
- 239000000243 solution Substances 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 19
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 2
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
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Abstract
The invention provides a synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which comprises the following steps: (a) reacting a substance shown in a formula (I) with a methyl Grignard reagent under the action of a catalyst to obtain a compound shown in a formula (II); (b) and (3) dechlorinating the compound shown in the formula (II) under the action of a reducing agent to obtain the compound shown in the formula (III). The preparation method provided by the invention has the advantages that the initial raw materials, the process route and the post-treatment process are different, the raw materials are simple and easy to obtain, the cost is low, and the preparation method is suitable for small-scale preparation in a laboratory and industrial production.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine.
Background
4-methyl-7H-pyrrolo [2,3-d ] pyrimidine is an important medical intermediate, and can be used for synthesizing TrK enzyme inhibitors and JAK enzyme inhibitors and E1 activating enzyme inhibitors (WO2011133637A2, WO2015083028, WO2007092213 and the like). However, few reports have been made to date on the preparation of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine (WO 2007092213). In view of the above, a new synthesis method is needed.
The invention content is as follows:
the invention provides a synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which is different from the initial raw materials, process routes and post-treatment processes, and has the advantages of simple and easily obtained raw materials, low cost and simple operation.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine comprises the following steps:
the synthesis method comprises the following steps:
(a) dissolving a compound shown in a formula (I) in a first solvent, cooling, adding a catalyst, reacting with a methyl Grignard reagent, and carrying out aftertreatment to obtain a compound shown in a formula (II);
(b) the compound shown in the formula (II) is dechlorinated in a second solvent under the catalysis of a reduction catalyst, and then the compound shown in the formula (III) is obtained after post-treatment;
wherein, the compound shown in the formula (I):
a compound represented by the formula (II):
a compound represented by the formula (III):
as a preferred technical scheme, the specific steps are as follows:
(a) dissolving the substance shown in the formula (I) in tetrahydrofuran, adding ferric acetylacetonate at the temperature of-10 ℃, dropwise adding a tetrahydrofuran solution of a methyl magnesium chloride Grignard reagent, and keeping the temperature and stirring for 1 hour after dropwise adding.
The post-treatment process of the step (a) comprises the following steps: and (3) extracting the compound shown in the formula (II) obtained by the reaction with tetrahydrofuran, drying, filtering, desolventizing, and recrystallizing with a solvent to obtain the compound shown in the formula (II).
(b) Dissolving the compound shown in the formula (II) in methanol, adding a reduction catalyst, dechlorinating, keeping the temperature at 50-60 ℃, stirring for 3 hours, reacting, and carrying out post-treatment to obtain the compound shown in the formula (III).
The post-treatment process of the step (b) comprises the following steps: filtering the compound shown in the formula (III) obtained by the reaction, removing the solvent, and recrystallizing with the solvent to obtain the compound.
As a preferred technical solution, in the step a), the catalyst comprises iron acetylacetonate or nickel acetylacetonate; the first solvent is tetrahydrofuran, and the methyl Grignard reagent is methyl magnesium chloride Grignard reagent.
As a preferable technical solution, in the step b), the second solvent includes methanol or tetrahydrofuran, and the reduction catalyst includes one of a mixture of zinc powder and acetic acid, raney nickel, and 5% palladium on carbon.
Preferably, the molar ratio of the substance represented by the formula (I), the methyl Grignard reagent and the iron acetylacetonate is 1: 2.0: 0.05.
as a preferable technical scheme, 20g of the substance shown in the formula (I) is added into every 100mL of tetrahydrofuran, and the molar concentration of the methyl Grignard reagent tetrahydrofuran solution is 3.0M.
As a preferable technical scheme, when the reduction catalyst is a mixture of zinc powder and acetic acid, the molar ratio of the compound shown in the formula (ii) to the zinc powder and the acetic acid is 1: 3.0-5.0: 3.0 to 5.0;
when the reduction catalyst is Raney nickel, hydrogen is added during dechlorination, the hydrogen pressure is 0.05Mpa, and the mass ratio of the compound shown in the formula (II) to the Raney nickel is 1: 0.10 to 0.30;
when the reduction catalyst is 5% palladium carbon, hydrogen is added during dechlorination, the hydrogen pressure is 0.05Mpa, and the mass ratio of the compound shown in the formula (II) to the 5% palladium carbon is 1: 0.05 to 0.2.
As a preferred embodiment, 8.3g of the substance represented by the formula (II) is added to 100mL of methanol.
As a preferred technical solution, the recrystallization solvent in the post-treatment process of step (b) is tetrahydrofuran; the mass ratio of the compound represented by the formula (II) to the recrystallization solvent is 1: 5.4.
advantageous effects
The preparation method provided by the invention has the advantages that the initial raw materials, the process route and the post-treatment process are different, the raw materials are simple and easy to obtain, the cost is low, and the operation is simple.
The post-treatment of the invention does not need to use column chromatography to purify and separate products, because the selection of the raw materials and the process route of the invention ensures that the post-treatment is simpler and more convenient, the purification is easy, the use of column chromatography purification is avoided, the production cost is saved, meanwhile, the time is greatly shortened, and the invention is suitable for industrialized mass production and is also suitable for small-scale preparation in laboratories.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive exercise.
FIG. 1 is a process scheme of the present invention;
FIG. 2 is 4-methyl-7H-pyrrolo [2,3-d ] prepared according to the method of example 1]Process for preparing pyrimidines1HNMR atlas.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.1g of a compound II.
Adding the compound II (20.1g) into methanol (240mL), replacing once with nitrogen and three times with hydrogen at the hydrogen pressure of 0.05mpa, heating to 50-60 ℃, preserving heat, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 hour, filtering and drying to obtain 13.5g of compound III.
FIG. 2 shows 4-methyl-7H-pyrrolo [2,3-d ] prepared in this example]Process for preparing pyrimidines1HNMR atlas.
1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 2
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (10.5g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.3g of a compound II.
Adding a compound II (20.3g) into methanol (240mL), replacing the mixture once with nitrogen, adding 5% palladium-carbon (1.0g), replacing the mixture three times with hydrogen, keeping the hydrogen pressure at 0.05mpa, heating to 50-60 ℃, keeping the temperature, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 hour, filtering and drying to obtain 13.4g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 3
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (100mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 15.1g of a compound II.
Adding a compound II (15.1g) into methanol (240mL), replacing once with nitrogen, adding 5% palladium carbon (1.0g), replacing three times with hydrogen, keeping the hydrogen pressure at 0.05mpa, heating to 50-60 ℃, keeping the temperature, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL),adjusting pH to 8-9 with concentrated ammonia water, layering, drying with anhydrous sodium sulfate (50g), filtering, removing solvent to 95mL, heating to dissolve, slowly cooling to-10-0 deg.C, stirring for 0.5 hr, filtering, and oven drying to obtain 10.3g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 4
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (166mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.2g of a compound II.
Adding the compound II (20.2g) into methanol (240mL), replacing once with nitrogen, adding 5% palladium carbon (1.0g), replacing three times with hydrogen under the pressure of 0.05mpa, heating to 50-60 ℃, preserving heat, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 hour, filtering and drying to obtain 13.5g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 5
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.0g of a compound II.
Adding a compound II (20.0g) into methanol (240mL), adding 5% palladium carbon (2.0g), replacing once with nitrogen and three times with hydrogen, keeping the hydrogen pressure at 0.05mpa, heating to 50-60 ℃, keeping the temperature, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 hour, filtering and drying to obtain 13.4g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 6
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Nickel acetylacetonate (2.57g) was added thereto, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly dropped into the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 18.0g of a compound II.
Compound II (18.0g) was added to methanol (240mL), and 5% palladium on carbon (1)0g), replacing once with nitrogen, replacing three times with hydrogen, keeping the hydrogen pressure at 0.05mpa, heating to 50-60 ℃, keeping the temperature, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 h, filtering and drying to obtain 12.1g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 7
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Nickel acetylacetonate (7.71g) was added thereto, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly dropped into the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.0g of a compound II.
Adding a compound II (20.0g) into methanol (240mL), adding 5% palladium carbon (1.0g), replacing once with nitrogen and three times with hydrogen, keeping the hydrogen pressure at 0.05mpa, heating to 50-60 ℃, keeping the temperature, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 hour, filtering and drying to obtain 13.2g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 8
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.3g of a compound II.
Adding the compound II (20.3g) into methanol (240mL), adding Raney nickel (4.0g), replacing once with nitrogen and three times with hydrogen, keeping the hydrogen pressure at 0.05mpa, heating to 50-60 ℃, keeping the temperature, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, desolventizing to 95mL, heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 hour, filtering and drying to obtain 9.4g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 9
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.3g of a compound II.
Adding the compound II (20.3g) into tetrahydrofuran (100mL), adding acetic acid (29.0g), adding (31.4) zinc powder, replacing with nitrogen once, heating to 50-60 ℃, and carrying out reflux stirring for 5 hours. Cooling, removing solvent, adding methanol (100mL), filtering, removing solvent, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, filtering, layering, drying with anhydrous sodium sulfate (50g), filtering, removing dryness, and purifying with silica gel column to obtain 2.4g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
Example 10
Referring to FIG. 1, this example provides a method for the synthesis of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine:
under the protection of nitrogen, compound I (37.6g,200mmol) is dissolved in tetrahydrofuran (188mL), and the reaction solution is cooled to-10 ℃. Ferric acetylacetonate (3.53g) was added, and a 3.0M solution of methylmagnesium chloride Grignard reagent in tetrahydrofuran (133mL) was slowly added dropwise to the reaction solution while controlling the reaction temperature at-10 to 10 ℃. After the dropping, the reaction was continued for 1 hour under heat. Dropwise adding the reaction solution into a saturated ammonium chloride aqueous solution (188mL), stirring for 30 minutes, demixing, extracting the water phase once with tetrahydrofuran (113mL), combining the organic phases, washing once with saturated saline (114mL), drying with anhydrous sodium sulfate (50g), filtering, removing to be thick, stirring for 0.5 hour at-10-0 ℃, filtering, and drying a filter cake to obtain 20.1g of a compound II.
Adding the compound II (20.1g) into methanol (240mL), replacing once with nitrogen and three times with hydrogen at the hydrogen pressure of 0.05mpa, heating to 50-60 ℃, preserving heat, stirring and stirring for 3 hours. Cooling, filtering, drying, adding tetrahydrofuran (200mL), adjusting pH to 8-9 with concentrated ammonia water, demixing, drying with anhydrous sodium sulfate (50g), filtering, drying, adding ethanol (63mL), heating to dissolve, slowly cooling to-10-0 ℃, stirring for 0.5 h, filtering and drying to obtain 12.3g of compound III.1H-NMR(500MHz，DMSO-d6)δ(ppm)：11.98(s,1H),8.60(d,J＝10.5Hz,1H),7.47(s,1H),6.63(s,1H),2.64-2.66(m,3H)。
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (10)
1. A method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine, which is characterized by comprising the following steps:
(a) dissolving a compound shown in a formula (I) in a first solvent, cooling, adding a catalyst, reacting with a methyl Grignard reagent, and carrying out aftertreatment to obtain a compound shown in a formula (II);
(b) the compound shown in the formula (II) is dechlorinated in a second solvent under the catalysis of a reduction catalyst, and then the compound shown in the formula (III) is obtained after post-treatment;
wherein, the compound shown in the formula (I):
a compound represented by the formula (II):
a compound represented by the formula (III):
2. the method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 1, wherein in the step a), the catalyst comprises ferric acetylacetonate or nickel acetylacetonate; the first solvent is tetrahydrofuran, and the methyl Grignard reagent is methyl magnesium chloride Grignard reagent.
3. The method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 1, wherein the temperature is kept between-10 ℃ and 10 ℃ when the methyl format reagent is added in the step a).
4. The process of claim 1, wherein in step b), the second solvent comprises methanol or tetrahydrofuran, and the reduction catalyst comprises one of zinc powder and acetic acid mixture, raney nickel, and 5% palladium on carbon.
5. The method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 1, wherein the reaction temperature in the step b) is 50-60 ℃.
6. The method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 1, wherein in the step a), the molar ratio of the compound shown as the formula (I), the methyl Grignard reagent and the catalyst is 1: 1.5-2.5: 0.05 to 0.15.
7. The process of claim 4, wherein when the reduction catalyst is a mixture of zinc powder and acetic acid, the molar ratio of the compound of formula (II) to the zinc powder and acetic acid is 1: 3.0-5.0: 3.0 to 5.0;
when the reduction catalyst is Raney nickel, hydrogen is added during dechlorination, the hydrogen pressure is 0.05Mpa, and the mass ratio of the compound shown in the formula (II) to the Raney nickel is 1: 0.10 to 0.30;
when the reduction catalyst is 5% palladium carbon, hydrogen is added during dechlorination, the hydrogen pressure is 0.05Mpa, and the mass ratio of the compound shown in the formula (II) to the 5% palladium carbon is 1: 0.05 to 0.2.
8. The synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 1, wherein the post-treatment process of the step (a) is as follows: and (3) quenching the compound shown in the formula (II) obtained by the reaction by using an ammonium chloride aqueous solution, extracting by using tetrahydrofuran, drying, filtering, desolventizing, and recrystallizing by using a solvent to obtain the compound.
9. The synthesis method of 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 1, wherein the post-treatment process of the step (b) is as follows: filtering the compound shown in the formula (III) obtained by the reaction, removing the solvent, and recrystallizing with the solvent to obtain the compound.
10. The method for synthesizing 4-methyl-7H-pyrrolo [2,3-d ] pyrimidine according to claim 9, wherein the recrystallization solvent in the post-treatment process of the step (b) comprises methanol, ethanol or tetrahydrofuran; the mass ratio of the compound represented by the formula (II) to the recrystallization solvent is 1: 2.4 to 5.4.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007092213A2 (en) * | 2006-02-02 | 2007-08-16 | Millennium Pharmaceuticals, Inc. | Inhibitors of e1 activating enzyme |
| CN104341422A (en) * | 2013-07-26 | 2015-02-11 | 重庆医药工业研究院有限责任公司 | Tofacitinib intermediate and preparation method thereof |
| CN105102446A (en) * | 2013-02-11 | 2015-11-25 | 星座制药公司 | Modulators of methyl-modifying enzymes, compositions and uses thereof |
| CN107278205A (en) * | 2015-02-24 | 2017-10-20 | 辉瑞大药厂 | Substituted nucleoside derivates as anticarcinogen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007092213A2 (en) * | 2006-02-02 | 2007-08-16 | Millennium Pharmaceuticals, Inc. | Inhibitors of e1 activating enzyme |
| CN101379061B (en) * | 2006-02-02 | 2016-06-15 | 千禧药品公司 | E1 activating enzyme inhibitors |
| CN105102446A (en) * | 2013-02-11 | 2015-11-25 | 星座制药公司 | Modulators of methyl-modifying enzymes, compositions and uses thereof |
| CN104341422A (en) * | 2013-07-26 | 2015-02-11 | 重庆医药工业研究院有限责任公司 | Tofacitinib intermediate and preparation method thereof |
| CN107278205A (en) * | 2015-02-24 | 2017-10-20 | 辉瑞大药厂 | Substituted nucleoside derivates as anticarcinogen |
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