CN110551063A - Method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine - Google Patents
Method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine Download PDFInfo
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- CN110551063A CN110551063A CN201910988758.3A CN201910988758A CN110551063A CN 110551063 A CN110551063 A CN 110551063A CN 201910988758 A CN201910988758 A CN 201910988758A CN 110551063 A CN110551063 A CN 110551063A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 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 claims abstract description 30
- 239000012535 impurity Substances 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 20
- 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 claims abstract description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 229910017053 inorganic salt Inorganic materials 0.000 claims abstract description 10
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 8
- 238000011946 reduction process Methods 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 239000000047 product Substances 0.000 claims description 57
- 238000003756 stirring Methods 0.000 claims description 34
- 239000012074 organic phase Substances 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- 239000008213 purified water Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000001514 detection method Methods 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- 238000004321 preservation Methods 0.000 claims description 10
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 claims description 10
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 3
- 239000001099 ammonium carbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 230000014759 maintenance of location Effects 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- -1 amino compound Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine, belonging to the technical field of chemical synthesis. The technical scheme of the invention is as follows: firstly, carrying out substitution reaction on a compound I and a compound II to synthesize a compound III, and then reducing the compound III to obtain a product IV; the inorganic salt is added in the reduction process, so that the generation of azo impurity V can be effectively inhibited. The invention has the beneficial effects that: in the process of nitro reduction, the invention can effectively inhibit the generation of azo impurities by adding inorganic salts such as ammonium chloride, sodium bicarbonate and the like for reaction, thereby eliminating the impurities without refining in the subsequent treatment stage. The product quality is ensured, and the product yield is also ensured.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine.
Background
The reduction of nitro group to amino group is a common means for producing amino compound in chemical production, and Fe, Zn/HCl method, Pd/H method is generally adopted2Method, Na2s method, etc. Impurities of azo compounds can be generated simultaneously in the reduction process, so that the product quality is reduced; and the impurities are difficult to remove, generally requiringHigher purity can be achieved through multiple refinements, which results in increased production costs.
Disclosure of Invention
Aiming at the problem that azo compounds which are difficult to remove are easily generated in the nitro reduction process in the prior art, a synthesis method is provided
a method of 5- (N-BOC-piperazin-1-yl) pyridin-2-amine to solve the above problems. The inorganic salt is added in the reduction process, so that the generation of the azo compound can be effectively inhibited.
the synthetic route map of the invention is:
The technical scheme of the invention is as follows: firstly, carrying out substitution reaction on a compound I and a compound II to synthesize a compound III, and then reducing the compound III to obtain a product IV; the inorganic salt is added in the reduction process, so that the generation of azo impurity V can be effectively inhibited.
The specific synthetic steps of the invention are as follows:
(1) Synthesis of Compound III
Taking a compound II, adding 2.1-2.3 g/g of dimethyl sulfoxide into the compound II, stirring and dissolving the mixture to be clear, sequentially adding 0.21-0.23 g/g of lithium chloride, 1.06-1.15 g/g of compound I and 0.70-0.80 g/g of triethylamine, heating to 80-85 ℃, carrying out heat preservation and stirring reaction for 12 hours, cooling to 15-25 ℃ after HPLC detection reaction is completed, and carrying out stirring crystallization for 1-2 hours. Filtering, and drying the wet product at 50-55 ℃ to obtain a compound III.
(2) Synthesis of product IV
Adding the compound III into a reactor, adding 3.0-3.1g/g of purified water and 3.55-3.6g/g of methanol into the reactor, uniformly stirring, adding 1.95-2.03 g/g of sodium sulfide nonahydrate and 1.25-2.0 eq of inorganic salt, heating to 70-80 ℃, and carrying out heat preservation reaction for 2 hours. And after the HPLC detection reaction is completed, cooling to 20-30 ℃. And adding 6.5-7.0 g/g of dichloromethane into the reaction solution, stirring and extracting, standing and layering, and taking an organic phase. The organic phase was washed twice with 3g/g of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. And filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 3.4-4 g/g of n-heptane when the residual volume of the reaction solution is about 2ml/g, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 2ml/g, stirring for crystallizing for 1-2 h, filtering, and drying the wet product at 50-55 ℃ to obtain a product IV.
Preferably, the inorganic salt in step (2) is one or more of ammonium chloride, sodium bicarbonate, potassium bicarbonate and ammonium bicarbonate.
Preferably, the charging ratio of the inorganic salt in the step (2) is 1.8eq based on the compound III.
Preferably, the dosage of the compound I in the step (1) is 1.1g/g based on the compound II.
preferably, the charging amount of lithium chloride in the step (1) is 0.21g/g based on the compound II.
Preferably, the charging amount of triethylamine in the step (1) is 0.75g/g based on the compound II.
preferably, the input amount of the sodium sulfide nonahydrate in the step (2) is 2.00g/g based on the compound II.
The invention has the beneficial effects that:
In the process of nitro reduction, the invention can effectively inhibit the generation of azo impurities by adding inorganic salts such as ammonium chloride, sodium bicarbonate and the like for reaction, thereby eliminating the impurities without refining in the subsequent treatment stage. The product quality is ensured, and the product yield is also ensured.
Drawings
in order to more clearly illustrate the embodiments or technical solutions in the prior art of the present invention, the drawings used in the description of the embodiments or prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained based on these drawings without creative efforts.
FIG. 1 is the MS spectrum of the impurity in the product of example 2;
FIG. 2 shows impurities in the product of example 21An H-NMR spectrum;
FIG. 3 is an HPLC chromatogram of the product of example 2;
FIG. 4 is an HPLC chromatogram of the product of example 3;
FIG. 5 is an HPLC chromatogram of the product of example 4;
FIG. 6 is an HPLC chromatogram of the product of example 5;
FIG. 7 is an HPLC chromatogram of the product of example 6;
FIG. 8 is an HPLC chromatogram of the product of example 7.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the technical solution in the embodiment of the present invention will be clearly and completely described below with reference to the drawings in the embodiment of the present invention, and it is obvious that the described embodiment is only a part of the embodiment 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
Synthesis of Compound III
Taking 120.0g of the compound II, adding 263.9g of dimethyl sulfoxide, stirring, dissolving, sequentially adding 25.5g of lithium chloride, 131.9g of the compound I and 89.9g of triethylamine, heating to 80-85 ℃, keeping the temperature, stirring, reacting for 12 hours, detecting the reaction is complete, cooling to 15-25 ℃, stirring, and crystallizing for 1.5 hours. Filtering, and drying the wet product at 50-55 ℃ to obtain 177.9g of a compound III, wherein the yield is as follows: 97.6 percent.
Example 2
synthesis of product IV
adding 50.0g of the compound III synthesized in the example 1 into a reactor, calculated by the compound III, then adding 150g of purified water and 180g of methanol, stirring uniformly, adding 100.0g of sodium sulfide nonahydrate, heating to 70-80 ℃, and reacting for 2 hours under the condition of heat preservation. And after the detection reaction is completed, cooling to 20-30 ℃. 330g of dichloromethane is added into the reaction solution, stirred and extracted, and is kept stand for layering, and an organic phase is taken out. The organic phase was washed twice with 150g of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. Filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 170g of n-heptane when the residual volume of the reaction solution is about 100ml, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 100ml, stirring for crystallization for 1.5h, filtering, and drying a wet product at 50-55 ℃ to obtain a product IV 43.2g, wherein the yield is as follows: 95.8 percent.
The HPLC test results of the synthesized product of example 2 are shown in the following Table 1:
| peak number | Retention time (min) | area (mAU s) | Height (mAU) | Width (min) | Purity (%) |
| 1 | 5.586 | 3886.80127 | 927.16119 | 0.0649 | 99.4938 |
| 2 | 8.063 | 19.77433 | 2.88527 | 0.0940 | 0.5062 |
| Total of | —— | 3906.57560 | 930.04647 | —— | 100 |
After purifying the impurity with retention time of 8.063min in the product synthesized in example 2, MS detection was performed, and the detection result was M + H of 553.3, molecular weight of azo impurity V: 552.68.
After purifying the impurity with retention time of 8.063min in the product synthesized in example 2, performing nuclear magnetic detection, wherein the detection result is as follows:1H-NMR(CDCl3,400MHz)：1.49(s，18H)，3.37(t，8H)，3.63(t，8H)，7.28(m，2H)，7.98(d，2H)，8.36(d，2H)。
And confirming and detecting the structure of the impurity to determine that the generated impurity is the azo compound V.
Example 3
Synthesis of product IV
adding 50.0g of the compound III synthesized in the example 1 into a reactor, adding 150g of purified water and 180g of methanol, uniformly stirring, adding 100.0g of sodium sulfide nonahydrate, adding 15.6g of ammonium chloride, heating to 70-80 ℃, and carrying out heat preservation reaction for 2 hours. And after the detection reaction is completed, cooling to 20-30 ℃. 330g of dichloromethane is added into the reaction solution, stirred and extracted, and is kept stand for layering, and an organic phase is taken out. The organic phase was washed twice with 150g of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. Filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 170g of n-heptane when the residual volume of the reaction solution is about 100ml, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 100ml, stirring for crystallization for 1.5h, filtering, and drying a wet product at 50-55 ℃ to obtain a product IV 43.4g, wherein the yield is as follows: 96.2 percent.
The HPLC test results of the synthesized product of example 3 are shown in the following Table 2:
| Peak number | Retention time (min) | Area (mAU s) | Height (mAU) | Width (min) | Purity (%) |
| 1 | 5.176 | 5.02311 | 1.01935 | 0.0706 | 0.0693 |
| 2 | 5.477 | 7242.56543 | 1523.79395 | 0.0744 | 99.9307 |
| Total of | —— | 7247.58854 | 1524.81329 | —— | 100 |
Example 4
Synthesis of product IV
Adding 25.0g of the compound III synthesized in the example 1 into a reactor, adding 75g of purified water and 90g of methanol, uniformly stirring, adding 50.0g of sodium sulfide nonahydrate, adding 12.3g of sodium bicarbonate, heating to 70-80 ℃, and carrying out heat preservation reaction for 2 hours. And after the detection reaction is completed, cooling to 20-30 ℃. 165g of dichloromethane was added to the reaction solution, followed by stirring, extraction, standing, and separation to obtain an organic phase. The organic phase was washed twice with 75g of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. Filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 85g of n-heptane when the residual volume of the reaction solution is about 50ml, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 50ml, stirring for crystallization for 1.5h, filtering, and drying a wet product at 50-55 ℃ to obtain 21.6g of a product IV, wherein the yield is as follows: 95.6 percent.
The HPLC test results of the synthesized product of example 4 are shown in the following Table 3:
| Peak number | Retention time (min) | Area (mAU s) | Height (mAU) | Width (min) | Purity of(％) |
| 1 | 5.460 | 2893.98950 | 719.34375 | 0.0615 | 99.9131 |
| 2 | 7.278 | 2.51747 | 0.688339 | 0.0558 | 0.0869 |
| total of | —— | 2896.50697 | 720.03209 | —— | 100 |
Example 5
Synthesis of product IV
adding 25.0g of the compound III synthesized in the example 1 into a reactor, adding 75g of purified water and 90g of methanol, uniformly stirring, adding 50.0g of sodium sulfide nonahydrate, adding 14.6g of potassium bicarbonate, heating to 70-80 ℃, and carrying out heat preservation reaction for 2 hours. And after the detection reaction is completed, cooling to 20-30 ℃. 165g of dichloromethane was added to the reaction solution, followed by stirring, extraction, standing, and separation to obtain an organic phase. The organic phase was washed twice with 75g of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. Filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 85g of n-heptane when the residual volume of the reaction solution is about 50ml, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 50ml, stirring for crystallization for 1.5h, filtering, and drying a wet product at 50-55 ℃ to obtain 21.5g of a product IV, wherein the yield is as follows: 95.1 percent.
the HPLC test results of the synthesized product of example 5 are shown in the following Table 4:
| Peak number | retention time (min) | Area (mAU s) | Height (mAU) | Width (min) | Purity (%) |
| 1 | 5.459 | 2449.11694 | 620.42255 | 0.0606 | 100.0000 |
| Total of | —— | 2449.11694 | 620.42255 | —— | 100.0000 |
Example 6
Synthesis of product IV
Adding 25.0g of the compound III synthesized in the example 1 into a reactor, adding 75g of purified water and 90g of methanol, uniformly stirring, adding 50.0g of sodium sulfide nonahydrate, adding 11.5g of ammonium bicarbonate, heating to 70-80 ℃, and carrying out heat preservation reaction for 2 hours. And after the detection reaction is completed, cooling to 20-30 ℃. 165g of dichloromethane was added to the reaction solution, followed by stirring, extraction, standing, and separation to obtain an organic phase. The organic phase was washed twice with 75g of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. Filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 85g of n-heptane when the residual volume of the reaction solution is about 50ml, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 50ml, stirring for crystallization for 1.5h, filtering, and drying a wet product at 50-55 ℃ to obtain 21.7g of a product IV, wherein the yield is as follows: 96.0 percent.
The HPLC test results of the synthesized product of example 6 are shown in the following Table 5:
| peak number | Retention time (min) | Area (mAU s) | Height (mAU) | Width (min) | Purity (%) |
| 1 | 5.452 | 3340.34131 | 818.28870 | 0.0622 | 100.0000 |
| Total of | —— | 3340.34131 | 818.28870 | —— | 100.0000 |
from the analysis of the product test results of example 2, example 3, example 4, example 5 and example 6, it can be seen that the content of azo impurities is substantially about 0.5% without adding inorganic salts such as ammonium chloride in example 2, azo impurities are not generated after adding inorganic salts such as ammonium chloride in example 3, example 4, example 5 and example 6, and the yield of the product is not affected after adding the inorganic salts. Therefore, the generation of azo impurities can be effectively suppressed after adding sodium bicarbonate in the process of reducing the nitro group.
Example 7
The invention also carries out a batch of large-scale production, and the specific synthesis steps are as follows:
(1) Synthesis of Compound III
taking 240kg of the compound II, adding 528kg of dimethyl sulfoxide into 240kg of the compound II, stirring and dissolving, sequentially adding 50.4kg of lithium chloride, 264kg of the compound I and 180kg of triethylamine, heating to 80-85 ℃, keeping the temperature, stirring and reacting for 12 hours, cooling to 15-25 ℃ after complete reaction detection, and stirring and crystallizing for 1.5 hours. Filtering, and drying the wet product at 50-55 ℃ to obtain the compound III349.5kg with the yield: 95.9 percent.
(2) Synthesis of product IV
adding 349.5kg of compound III, 1050kg of purified water and 1250kg of methanol into a reactor according to the compound III, uniformly stirring, adding 699kg of sodium sulfide nonahydrate and 109.1kg of ammonium chloride, heating to 70-80 ℃, and reacting for 2 hours under the condition of heat preservation. And after the detection reaction is completed, cooling to 20-30 ℃. 2440kg of methylene chloride was added to the reaction solution, followed by stirring, extraction, standing, and separation to obtain an organic phase. The organic phase was washed twice with 1050kg of purified water each time, and the washed organic phase was dried over anhydrous sodium sulfate. Filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 1200kg of n-heptane when the residual volume of the reaction solution is about 700L by steaming, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 700L by steaming, stirring for crystallization for 1.5h, filtering, and drying a wet product at 50-55 ℃ to obtain 301.3kg of a product IV, wherein the yield is as follows: 95.5 percent.
The HPLC test results of the synthesized product of example 7 are shown in the following Table 6:
| peak number | Retention time (min) | Area (mAU s) | Height (mAU) | Width (min) | Purity (%) |
| 1 | 5.565 | 629.33069 | 178.99858 | 0.0556 | 100 |
| Total of | —— | 629.33069 | 178.99858 | —— | 100 |
As is clear from the results of the examination of the product of example 7, no azo impurity V was detected in the product IV produced on a scale of 300 kg. Therefore, the preparation method of the invention has stable process and product quality after scale-up.
Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (9)
1. A method for synthesizing 5- (N-BOC-piperazine-1-yl) pyridine-2-amine is characterized in that a compound I and a compound II are subjected to substitution reaction to synthesize a compound III, and the compound III is reduced to obtain a product IV; adding inorganic salt in the reduction process of the compound III, wherein the specific structure of the compound is as follows:
A compound I:compound II:Compound III:
And (3) a product IV:Impurity V:
2. The process of claim 1 for the synthesis of 5- (N-BOC-piperazin-1-yl) pyridin-2-amine, wherein product IV is synthesized by the following steps:
adding the compound III into a reactor, adding 3.0-3.1g/g of purified water and 3.55-3.6g/g of methanol into the reactor, uniformly stirring, adding 1.95-2.03 g/g of sodium sulfide nonahydrate and 1.25-2.0 eq of inorganic salt, heating to 70-80 ℃, and carrying out heat preservation reaction for 2 hours; after the detection reaction is completed, cooling to 20-30 ℃; adding 6.5-7.0 g/g of dichloromethane into the reaction solution, stirring and extracting, standing and layering, and taking an organic phase; washing the organic phase twice with purified water, wherein the consumption of the purified water is 3g/g each time, and drying the washed organic phase with anhydrous sodium sulfate; and filtering the dried organic phase, distilling the filtrate at 40-50 ℃ under reduced pressure, adding 3.4-4 g/g of n-heptane when the residual volume of the reaction solution is about 2ml/g, continuing distilling at 40-50 ℃ under reduced pressure, cooling to 5-10 ℃ when the residual volume of the reaction solution is about 2ml/g, stirring for crystallizing for 1-2 h, filtering, and drying the wet product at 50-55 ℃ to obtain a product IV.
3. The process of claim 1 for the synthesis of 5- (N-BOC-piperazin-1-yl) pyridin-2-amine, characterized by the following steps for the synthesis of compound III:
Taking a compound II, adding 2.1-2.3 g/g of dimethyl sulfoxide into the compound II, stirring and dissolving the mixture to be clear, sequentially adding 0.21-0.23 g/g of lithium chloride, 1.06-1.15 g/g of compound I and 0.70-0.80 g/g of triethylamine, heating to 80-85 ℃, carrying out heat preservation stirring reaction for 12 hours, cooling to 15-25 ℃ after complete detection reaction, stirring and crystallizing for 1-2 hours; filtering, and drying the wet product at 50-55 ℃ to obtain a compound III.
4. The process of claim 2, wherein the inorganic salt is one or more of ammonium chloride, sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate.
5. The process for the synthesis of 5- (N-BOC-piperazin-1-yl) pyridin-2-amine according to claim 2, wherein the inorganic salt is fed in a ratio of 1.8eq, based on compound III, in the step of synthesis of product IV.
6. The process for the synthesis of 5- (N-BOC-piperazin-1-yl) pyridin-2-amine according to claim 3, wherein in the step of synthesis of compound III, the charge of compound I is 1.1g/g based on compound II.
7. the process according to claim 3, wherein the amount of lithium chloride used in the step of synthesizing compound III is 0.21g/g based on compound II.
8. the method for synthesizing 5- (N-BOC-piperazin-1-yl) pyridin-2-amine according to claim 3, wherein in the step of synthesizing compound III, the amount of triethylamine charged is 0.75g/g based on compound II.
9. The process according to claim 2, wherein the amount of sodium sulfide nonahydrate fed in the step of synthesizing the product IV is 2.00g/g based on the compound II.
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