CN115073382A - Preparation method of 2-chloro-pyrimidine-5-formaldehyde - Google Patents
Preparation method of 2-chloro-pyrimidine-5-formaldehyde Download PDFInfo
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- CN115073382A CN115073382A CN202210843487.4A CN202210843487A CN115073382A CN 115073382 A CN115073382 A CN 115073382A CN 202210843487 A CN202210843487 A CN 202210843487A CN 115073382 A CN115073382 A CN 115073382A
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- LJYQVOPFBNMTKJ-UHFFFAOYSA-N 2-chloropyrimidine-5-carbaldehyde Chemical compound ClC1=NC=C(C=O)C=N1 LJYQVOPFBNMTKJ-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000013067 intermediate product Substances 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000006482 condensation reaction Methods 0.000 claims abstract description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004202 carbamide Substances 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 90
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 239000011259 mixed solution Substances 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- -1 acetic acid compound Chemical class 0.000 claims description 13
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 13
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 13
- 229940106681 chloroacetic acid Drugs 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 238000006170 formylation reaction Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 12
- 239000000047 product Substances 0.000 abstract description 7
- 238000010923 batch production Methods 0.000 abstract description 3
- 125000000218 acetic acid group Chemical class C(C)(=O)* 0.000 abstract 1
- 229960000583 acetic acid Drugs 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- BUTTVUBNXIIXRH-UHFFFAOYSA-N 1-(cyclopropylmethyl)pyrazole-4-carbaldehyde Chemical compound C1=C(C=O)C=NN1CC1CC1 BUTTVUBNXIIXRH-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
- C07C273/1863—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety from urea
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 2-chloro-pyrimidine-5-formaldehyde, which comprises the following steps: step S1: formylating acetic acid compounds to obtain
Step S2: make it contain
Carrying out condensation reaction with a solution of urea to obtain
Step S3: to pair
Carrying out a ring closure reaction to obtain
Step S4: to pair
Carrying out chlorination reaction to obtain the 2-chloro-pyrimidine-5-formaldehyde. Based on the preparation process, the method has the advantages of lower raw material cost, higher utilization rate, better stability of intermediate products, more stable reaction process and higher product yield, is further more suitable for industrial batch production, and has better industrial application prospect.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of 2-chloro-pyrimidine-5-formaldehyde.
Background
Pyrimidine compounds, an aromatic chemical molecule having two nitrogen atoms at positions 1 and 3 of a six-membered ring, have been receiving extensive research attention because of their excellent biological activity. Pyrimidines have a variety of biological properties including antitubercular, antibiotic, antifungal, antiviral, anti-inflammatory, antimalarial, anticancer and antitumor effects and anti-HIV activity. Among them, 2-chloro-pyrimidine-5-formaldehyde is an important pharmaceutical intermediate, and the requirements for the preparation process of the 2-chloro-pyrimidine-5-formaldehyde intermediate, which is efficient, low-cost and environment-friendly, are increasing at home and abroad at present.
Regarding the synthesis technology of 2-chloro-pyrimidine-5-formaldehyde, few routes are currently available for research of synthesis, and in the prior art, for example, CN109369539A discloses a synthesis method of 2-chloro-pyrimidine-5-formaldehyde: the 2-chloropyrimidine-5-carbaldehyde is synthesized by the Grignard method, and the synthetic route is as follows:
however, the preparation method has high raw material cost and unstable properties, has high risk factors, increases the manufacturing cost and production risk, and is not suitable for large-scale industrial application.
In the prior art, for example, CN109928933A also discloses 2-chloropyrimidine-5-formaldehyde and a preparation method thereof, and reports that: the arnold salt was treated with chloroformamidine hydrochloride, the synthetic route of which is shown below:
however, this method has some safety problems such as strong hygroscopicity, corrosiveness to raw materials, high production cost and low yield.
In summary, the prior art methods for preparing 2-chloropyrimidine-5-formaldehyde all have the problems of expensive raw materials, difficult obtainment of raw materials, high reaction risk, poor environmental protection and the like, and therefore, there is a need to provide a new method for preparing 2-chloropyrimidine-5-formaldehyde to improve the above problems.
Disclosure of Invention
The invention mainly aims to provide a preparation method of 2-chloro-pyrimidine-5-formaldehyde, which solves the problems of high cost, high risk, poor environmental protection and the like in the preparation of 2-chloro-pyrimidine-5-formaldehyde in the prior art.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a method for preparing 2-chloro-pyrimidine-5-carbaldehyde, comprising the steps of: step S1: performing formylation reaction on an acetic acid compound to obtain an intermediate product A; step S2: carrying out condensation reaction on a solution containing the intermediate product A and urea to obtain an intermediate product B; step S3: carrying out a ring-closing reaction on the intermediate product B to obtain an intermediate product C; step S4: carrying out chlorination reaction on the intermediate product C to obtain 2-chloro-pyrimidine-5-formaldehyde; wherein the acetic acid compound is
Intermediate A is
X represents Cl or Br; intermediate B is
Intermediate C is
Further, step S1 includes: mixing acetic acid compounds, N-N-dimethylformamide and phosphorus oxychloride to carry out formylation reaction; preferably, the molar ratio of the acetic acid compound, the N-N-dimethylformamide and the phosphorus oxychloride is 1 (12-14) to (8-9).
Further, when the acetic acid-based compound is bromoacetic acid, step S1 includes: under the inert gas atmosphere and at the temperature of 0-5 ℃, dropwise adding phosphorus oxychloride into N-N-dimethylformamide at a dropping speed of 0.05-0.1 mL/s, and then adding bromoacetic acid into the N-N-dimethylformamide every 5-15 min for 3-8 times to form a first mixed solution; stirring the first mixed solution at 85-95 ℃ for 5-10 h, and then sequentially dripping 35-45% by mass of aqueous hydrogen bromide solution and tetrahydrofuran at a dripping speed of 0.05-0.1 mL/s into the first mixed solution at 0-5 ℃ to form a second mixed solution; stirring the second mixed solution for 20-40 min at the temperature of 20-25 ℃ to obtain an intermediate product A; preferably, the amount of the hydrogen bromide is 1.0-1.2 times of the weight of the bromoacetic acid; the dosage of the tetrahydrofuran is 8-12 times of the weight of the bromoacetic acid.
Further, when the acetic acid-based compound is chloroacetic acid, step S1 includes: under the inert gas atmosphere and at the temperature of 0-5 ℃, chloroacetic acid is added into N-N-dimethylformamide, and then phosphorus oxychloride is dropwise added into the N-N-dimethylformamide at the dropping speed of 0.05-0.1 mL/s to form a fourth mixed solution; stirring the fourth mixed solution for 0.5-1.5 h at the temperature of 75-85 ℃, 0.5-1.5 h at the temperature of 90-100 ℃ and 0.5-1.5 h at the temperature of 100-110 ℃ in sequence, then, dropwise adding concentrated hydrochloric acid with the mass concentration of 30-36% and tetrahydrofuran in sequence at the dropping speed of 0.05-0.1 mL/s into the fourth mixed solution at the temperature of 20-25 ℃ and stirring for 20-40 min to obtain an intermediate product A; preferably, the dosage of the concentrated hydrochloric acid is 0.8-1.2 times of the weight of the chloroacetic acid; the dosage of the tetrahydrofuran is 8-12 times of the weight of the chloroacetic acid.
Further, step S2 includes: carrying out condensation reaction on the intermediate product A and urea in water; preferably, the molar ratio of the intermediate product A to the urea is 1 (1.9-2.2).
Further, the reaction temperature of the condensation reaction is 20-25 ℃, and the reaction time is 20-30 h.
Further, step S3 includes: and (3) mixing the intermediate product B with acetic acid, refluxing for 1-3 h at 105-115 ℃, removing the acetic acid in the system, adding toluene into the system, and continuously refluxing for 0.5-2 h to obtain an intermediate product C.
Furthermore, the molar ratio of the intermediate product B, acetic acid and toluene is 1 (20-30) to (10-15).
Further, step S4 includes: after dissolving the intermediate product C in acetonitrile, sequentially dropwise adding N, N-diisopropylethylamine and phosphorus oxychloride into the system at a dropping speed of 0.02-0.05 mL/s at a temperature of 0-5 ℃ to form a fifth mixed solution; stirring the fifth mixed solution for 4-8 h at the temperature of 75-85 ℃, and regulating the pH value of the system to 6.5-7.5 at the temperature of 20-25 ℃ to obtain the 2-chloro-pyrimidine-5-formaldehyde.
Furthermore, the molar ratio of the intermediate product C, N, N-diisopropylethylamine and phosphorus oxychloride is 1 (1.1-1.2) to 1.4-1.6.
The invention takes a specific acetic acid compound as a reaction raw material, and has the advantage of lower raw material cost compared with the 2-methoxy-5-aldehyde pyrimidine in the prior art. And the stability of the intermediate product involved in each reaction process is better, for example, the intermediate product A in the process is an Arnold salt with good stability, and is convenient for long-term storage and transportation. Meanwhile, the method avoids using highly corrosive formamidine hydrochloride in the preparation process, and has better environmental protection property. In particular, the reaction process is simpler to operate, simpler in flow and higher in reaction safety. Therefore, based on the preparation process, the preparation method has the advantages of lower raw material cost, higher utilization rate, better stability of intermediate products, more stable reaction process and higher product yield, is further more suitable for industrial batch production, and has better industrial application prospect.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 shows a nuclear magnetic hydrogen spectrum of an intermediate compound A prepared in example 1 of the present invention;
FIG. 2 shows a nuclear magnetic hydrogen spectrum of intermediate compound B prepared in example 1 of the present invention;
FIG. 3 shows a nuclear magnetic hydrogen spectrum of intermediate compound C prepared in example 1 of the present invention;
FIG. 4 shows a nuclear magnetic hydrogen spectrum of 2-chloropyrimidine-5-carbaldehyde prepared in example 1 of the present invention;
FIG. 5 shows a GC-MS spectrum of 2-chloropyrimidine-5-carbaldehyde prepared in example 1 of the present invention.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
As described in the background of the invention section, the prior art has problems of high cost, high risk, low product yield and the like when preparing 2-chloro-pyrimidine-5-formaldehyde. In order to solve the problem, the invention provides a preparation method of 2-chloro-pyrimidine-5-formaldehyde, which comprises the following steps: step S1: performing formylation reaction on an acetic acid compound to obtain an intermediate product A; step S2: carrying out condensation reaction on a solution containing the intermediate product A and urea to obtain an intermediate product B; step S3: carrying out a ring closure reaction on the intermediate product B to obtain an intermediate product C; step S4: centering is carried outPerforming chlorination reaction on the intermediate product C to obtain 2-chloro-pyrimidine-5-formaldehyde; wherein the acetic acid compound is
Intermediate A is
X represents Cl or Br; intermediate B is
Intermediate C is
The synthetic route of the preparation method of the invention is as follows:
based on the above, the invention takes the specific acetic acid compound as the reaction raw material, and has the advantage of lower raw material cost compared with the prior art of 2-methoxy-5-aldehyde pyrimidine. And the stability of the intermediate product involved in each reaction process is better, for example, the intermediate product A in the process is an Arnold salt with good stability, and is convenient for long-term storage and transportation. Meanwhile, the method avoids using highly corrosive formamidine hydrochloride in the preparation process, and has better environmental protection property. In particular, the reaction process is simpler to operate, simpler in flow and higher in reaction safety. Therefore, based on the preparation process, the preparation method has the advantages of lower raw material cost, higher utilization rate, better stability of intermediate products, more stable reaction process and higher product yield, is further more suitable for industrial batch production, and has better industrial application prospect.
In a preferred embodiment, step S1 includes: mixing acetic acid compound, N-N-dimethylformamide and phosphorus oxychloride to perform formylation reaction. Preferably, the molar ratio of the acetic acid compound, the N-N-dimethylformamide and the phosphorus oxychloride is 1 (12-14) to (8-9). Based on this, the reaction process of the formylation reaction is more stable, the operation process is safer, the utilization rate of the acetic acid compound is higher, and the yield of the intermediate product A is higher.
To further increase the efficiency of the formylation reaction and thus the product yield, in a preferred embodiment, when the acetic acid-based compound is bromoacetic acid, step S1 comprises: under the inert gas atmosphere and at the temperature of 0-5 ℃, dropwise adding phosphorus oxychloride into N-N-dimethylformamide at a dropping speed of 0.05-0.1 mL/s, and then adding bromoacetic acid into the N-N-dimethylformamide every 5-15 min for 3-8 times to form a first mixed solution; stirring the first mixed solution at 85-95 ℃ for 5-10 h, and then sequentially dripping 35-45% by mass of aqueous hydrogen bromide solution and tetrahydrofuran at a dripping speed of 0.05-0.1 mL/s into the first mixed solution at 0-5 ℃ to form a second mixed solution; and stirring the second mixed solution for 20-40 min at the temperature of 20-25 ℃ to obtain an intermediate product A. Preferably, the dosage of the aqueous hydrogen bromide is 1.0-1.2 times of the weight of the bromoacetic acid; the dosage of the tetrahydrofuran is 8-12 times of the weight of the bromoacetic acid. In the dropping process of the hydrogen bromide water solution and the tetrahydrofuran, solid matters are separated out, the reacted feed liquid is filtered under the protection of nitrogen, and filter cakes are leached by acetic acid and acetonitrile in sequence. Drying the leached solid in a 1L single-mouth bottle at 60 ℃ under reduced pressure for 1h, and drying in a vacuum drying oven at 60 ℃ under reduced pressure for 6h to obtain an intermediate product A
To further increase the efficiency of the formylation reaction and thus the product yield, in a preferred embodiment, when the acetic acid-based compound is chloroacetic acid, step S1 comprises: under the inert gas atmosphere and at the temperature of 0-5 ℃, chloroacetic acid is added into N-N-dimethylformamide, and then phosphorus oxychloride is dropwise added into the N-N-dimethylformamide at the dropping speed of 0.05-0.1 mL/s to form a fourth mixed solution; and stirring the fourth mixed solution for 0.5-1.5 h at the temperature of 75-85 ℃, 0.5-1.5 h at the temperature of 90-100 ℃ and 0.5-1.5 h at the temperature of 100-110 ℃ in sequence, then, dropwise adding concentrated hydrochloric acid with the mass concentration of 30-36% and tetrahydrofuran in sequence at the dropping speed of 0.05-0.1 mL/s into the fourth mixed solution at the temperature of 20-25 ℃ and stirring for 20-40 min to obtain an intermediate product A. Preferably, the dosage of the concentrated hydrochloric acid is 0.8-1.2 times of the weight of the chloroacetic acid; the dosage of the tetrahydrofuran is 8-12 times of the weight of the chloroacetic acid. In the dropwise addition of the concentrated hydrochloric acid and tetrahydrofuran, a solid was precipitated. Filtering the reacted feed liquid, washing the filter cake with THF, and vacuum drying in a vacuum drying oven at 60 deg.C for 6h to obtain intermediate product A
In a preferred embodiment, step S2 includes: mixing the intermediate product A, urea and water to perform condensation reaction; preferably, the molar ratio of the intermediate product A to the urea is 1 (1.9-2.2). Based on the method, the reaction process of the condensation reaction is more stable, the operation process is safer, and the yield of the intermediate product B is higher. In order to further balance the efficiency and stability of the condensation reaction, in a preferred embodiment, the reaction temperature of the condensation reaction is 20 to 25 ℃ and the reaction time is 20 to 30 hours. After the condensation reaction is finished, the reaction solution is changed from yellow to transparent, the material liquid after the reaction is filtered, and the filter cake is dried in an air-blast drying oven for 6 hours at 50 ℃ after being washed by water to obtain white powder, namely the intermediate product B.
In a preferred embodiment, step S3 includes: after dissolving the intermediate product B in acetic acid, refluxing for 1-3 h at 105-115 ℃, removing the acetic acid in the system, adding toluene into the system, and continuously refluxing for 0.5-2 h to obtain an intermediate product C. Based on the method, the reaction process of the ring-closing reaction is more stable, the operation process is safer, and the yield of the intermediate product C is higher. In order to further balance the efficiency and stability of the condensation reaction, in a preferred embodiment, the molar ratio of the intermediate product B, acetic acid and toluene is 1 (20-30) to (10-15). And adding toluene, continuously refluxing for 0.5-2 h, cooling the feed liquid to room temperature, filtering, and leaching a filter cake with toluene to obtain an intermediate product C.
To further increase the product yield, in a preferred embodiment, step S4 comprises: after dissolving the intermediate product C in acetonitrile, sequentially dropwise adding N, N-diisopropylethylamine and phosphorus oxychloride into the system at a dropping speed of 0.02-0.05 mL/s at a temperature of 0-5 ℃ to form a fifth mixed solution; stirring the fifth mixed solution for 4-8 h at the temperature of 75-85 ℃, and regulating the pH value of the system to 6.5-7.5 at the temperature of 20-25 ℃ to obtain the 2-chloro-pyrimidine-5-formaldehyde. Wherein, the reaction process can be monitored by TLC, after TLC shows that no raw material remains, the feed liquid after the reaction is cooled to room temperature, sodium carbonate aqueous solution is dripped to adjust the pH value to the range, ethyl acetate is added for extraction, and the extracted organic phase is washed by water and then is dried by spinning. And adding the rotary-dried crude product into feed liquid of MTBE (methyl tert-butyl ether) and n-heptane (1: 2), stirring for 30min, and filtering the feed liquid to obtain a solid, namely 2-chloro-pyrimidine-5-formaldehyde. Preferably, the molar ratio of the intermediate C, N, N-diisopropylethylamine and phosphorus oxychloride is 1 (1.1-1.2) to 1.4-1.6.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1
(1) Preparation of intermediate A
DMF (315.6g, 4.32mol) was added to a 2L round bottom four-necked flask and replaced with nitrogen three times. Cooling to 0 ℃ in ice water bath. Controlling the temperature to be 0-5 ℃ under the protection of nitrogen and dripping POCl 3 (441.3g, 2.88mol), about 30 min. Bromoacetic acid (50g, 0.36mol) was added to the reaction in 5 portions with a nitrogen blanket, each 10 min apart.
The reaction was transferred to an oil bath and heated to 90 ℃ and stirred for 6h under nitrogen protection. Attention is paid to acid tail gas absorption. The reaction changed from colorless to transparent to a red liquid. The reaction was cooled to 0 deg.C and 40% HBr (58.2g, 0.72mol) was added dropwise under nitrogen followed by THF (500 mL). The reaction was stirred at room temperature for 30min and a solid precipitated. Filtration was carried out under nitrogen, and the filter cake was rinsed successively with acetic acid (360mL) and acetonitrile (250 mL). The solid was dried under reduced pressure in a 1L single-necked flask at 60 ℃ for 1 hour and then dried under reduced pressure in a vacuum oven at 60 ℃ for 6 hours. 73.2g of a white hygroscopic solid was obtained with a yield of 48%.
The HNMR assay is shown in fig. 1, with the following results:
1 H-NMR(400MHz,[d 6 ]-DMSO):δ＝8.82(s,3H,CH),3.58(s,9H,CH3),3.47(s,9H,CH3)ppm.
(2) preparation of intermediate B
Intermediate A (10g, 36.77mmol) was added to a 250mL three-necked flask. Urea (4.41g, 73.47mmol) was dissolved in 20mL of water and added to the reaction flask. 70mL of water was added and the mixture was stirred at room temperature for 24 hours.
The reaction solution changed from yellow to transparent and was washed out with a white solid. The filter cake was rinsed with 20mL of water and dried in an air-blown dry oven at 50 ℃ for 6 h. 4.3g of a white powder was obtained in a yield of 82.4%.
The HNMR assay is shown in fig. 2, with the following results:
1 H-NMR(400MHz,[d 6 ]-DMSO):δ＝11.26(d,J＝3.3Hz；1H,NH),9.84(d,J＝3.4Hz；1H,CHO),9.53(s,1H,CHO),8.28(dd,J＝12.9Hz,J＝3.2Hz；1H,CH),7.83(S,1H,NH2),7.53(s,1H,NH2)ppm.
(3) preparation of intermediate C:
a100 mL round bottom flask was charged with intermediate B (4.5g, 31.7mmol), dissolved in 50mL glacial acetic acid, and refluxed at 110 ℃ for 2h to give a light brown crude product. And (3) performing dry ice acetic acid rotation, adding 50mL of toluene, refluxing for 1h at 110 ℃, reacting, cooling to room temperature, filtering, and leaching a filter cake with 10mL of toluene to obtain a pale yellow solid, wherein the yield is 96.7%.
The HNMR assay is shown in fig. 3, with the following results:
1 H-NMR(400MHz,[d 6 ]-DMSO):δ＝12.67(s,1H,OH),9.65(s,2H,CH),8.81(s,1H,CHO)ppm.
(4) preparation of 2-chloro-pyrimidine-5-carbaldehyde:
intermediate C (5g, 40.29mmol) was added to a 250mL three-necked flask. Add 50mL acetonitrile to dissolve. The reaction was cooled to 0 ℃ and N, N-diisopropylethylamine (6.25g, 48.35mmol) and phosphorus oxychloride (9.27g, 60.44mmol) were added dropwise, the reaction was heated to 80 ℃ and stirred for 6 h. TLC showed no starting material remaining. The reaction is cooled to room temperature, sodium carbonate aqueous solution is added dropwise to adjust the pH value to be neutral, and 20ml of ethyl acetate is added for extraction. The organic phase is washed with 20ml of water and then spin-dried to give a brown-yellow crude product. The crude product was stirred for 30min after addition of MTBE ═ heptane 1:2, and filtered to give 4.8g of a pale yellow solid in 83.5% yield.
The HNMR assay is shown in fig. 4, with the following results:
1 H-NMR(400MHz,CDCl 3 ):δ＝10.2(s,1H,CHO),9.2(s,2H,CH)ppm.
FIG. 5 shows a GC-MS spectrum of 2-chloropyrimidine-5-carbaldehyde prepared in example 1 of the present invention.
Example 2
(1) Preparation of intermediate A
2-Chloroacetic acid (10.00g, 0.11mol) was dissolved in DMF (92.82g, 1.27mmol), and the solution was charged into a 1-L round-bottomed four-necked flask and replaced with nitrogen 3 times. Cooling to 0 deg.C in ice-water bath, and dripping POCl 3 (129.8g, 0.85 mol). After the dripping is finished, the reaction is heated to 80 ℃ and stirred for 1 h. The temperature is increased to 95 ℃ and the mixture is stirred for 1 h. The temperature is increased to 105 ℃ and stirring is carried out for 1 h. The reaction was cooled to room temperature, concentrated hydrochloric acid (7.72g, 0.22mol) was added dropwise followed by THF (200mL) and stirring for 30 min. Solid precipitated. The mixture was filtered, and the filter cake was rinsed with THF (40mL) and dried in a vacuum oven at 60 ℃ for 6 h. 21.10g of a white solid was obtained with a yield of 68.8%.
The results of HNMR were as follows:
1 H-NMR(400MHz,D 2 O):δ＝8.30(s,3H,CH),3.57(s,9H,CH3),3.40(s,9H,CH3)ppm.
(2) preparation of intermediate B
Intermediate A (10g, 36.77mmol) was added to a 250mL three-necked flask. Urea (4.41g, 73.47mmol) was dissolved in 20mL of water and added to the reaction flask. 70mL of water was added and the mixture was stirred at room temperature for 24 hours.
The reaction solution changed from yellow to transparent and was washed out with a white solid. The filter cake was rinsed with 20mL of water and dried in an air-blown dry oven at 50 ℃ for 6 h. 4.4g of a white powder was obtained in 84.3% yield.
1H-NMR(400MHz,[d6]-DMSO):＝11.26(d,J＝3.3Hz；1H,NH),9.84(d,J＝3.4Hz；1H,CHO),9.53(s,1H,CHO),8.28(dd,J＝12.9Hz,J＝3.2Hz；1H,CH),7.83(S,1H,NH2),7.53(s,1H,NH2)ppm.
(3) Preparation of intermediate C:
a100 mL round bottom flask was charged with intermediate B (4.5g, 31.7mmol), dissolved in 50mL glacial acetic acid, and refluxed at 110 ℃ for 2h to give a light brown crude product. And (3) performing dry ice acetic acid spinning, adding 50mL of toluene, refluxing for 1h at 110 ℃, reacting, cooling to room temperature, filtering, and leaching a filter cake with 10mL of toluene to obtain a pale yellow solid, wherein the yield is 99.1%.
1H-NMR(400MHz,[d6]-DMSO):＝12.67(s,1H,OH),9.65(s,2H,CH),8.81(s,1H,CHO)ppm.
(4) Preparation of 2-chloro-pyrimidine-5-carbaldehyde:
intermediate C (5g, 40.29mmol) was added to a 250mL three-necked flask. Add 50mL acetonitrile to dissolve. The reaction was cooled to 0 ℃ and N, N-diisopropylethylamine (6.25g, 48.35mmol) and phosphorus oxychloride (9.27g, 60.44mmol) were added dropwise, the reaction was heated to 80 ℃ and stirred for 6 h. TLC showed no starting material remaining. The reaction is cooled to room temperature, sodium carbonate aqueous solution is added dropwise to adjust the pH value to be neutral, and 20ml of ethyl acetate is added for extraction. The organic phase is washed with 20ml of water and then spin-dried to give a brown-yellow crude product. The crude product was stirred for 30min after addition of MTBE ═ heptane 1:2, and filtered to give 4.7g of a pale yellow solid in 81.7% yield.
1 H-NMR(400MHz,CDCl 3 ):δ＝10.2(s,1H,CHO),9.2(s,2H,CH)ppm.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of 2-chloro-pyrimidine-5-formaldehyde is characterized by comprising the following steps:
step S1: performing formylation reaction on an acetic acid compound to obtain an intermediate product A;
step S2: carrying out condensation reaction on the solution containing the intermediate product A and urea to obtain an intermediate product B;
step S3: carrying out a ring-closing reaction on the intermediate product B to obtain an intermediate product C;
step S4: performing chlorination reaction on the intermediate product C to obtain the 2-chloro-pyrimidine-5-formaldehyde;
wherein the acetic acid compound is
The intermediate product A is
X represents Cl or Br; the intermediate product B is
The intermediate product C is
2. The process for producing 2-chloro-pyrimidine-5-carbaldehyde according to claim 1, wherein the step S1 includes: mixing the acetic acid-based compound, N-N-dimethylformamide and phosphorus oxychloride to perform the formylation reaction;
preferably, the molar ratio of the acetic acid compound, the N-N-dimethylformamide and the phosphorus oxychloride is 1 (12-14) to (8-9).
3. The process for producing 2-chloro-pyrimidine-5-carbaldehyde according to claim 1 or 2, wherein when the acetic acid-based compound is bromoacetic acid, the step S1 includes: under the inert gas atmosphere, the reaction kettle is filled with a gas,
dropping phosphorus oxychloride into N-N-dimethylformamide at a dropping speed of 0.05-0.1 mL/s at the temperature of 0-5 ℃, and then adding bromoacetic acid into the N-N-dimethylformamide every 5-15 min for 3-8 times to form a first mixed solution;
stirring the first mixed solution at 85-95 ℃ for 5-10 h, and then sequentially dripping 35-45% by mass of aqueous hydrogen bromide solution and tetrahydrofuran at a dripping speed of 0.05-0.1 mL/s into the first mixed solution at 0-5 ℃ to form a second mixed solution;
stirring the second mixed solution for 20-40 min at the temperature of 20-25 ℃ to obtain an intermediate product A;
preferably, the amount of the hydrogen bromide is 1.0-1.2 times of the weight of the bromoacetic acid; the amount of the tetrahydrofuran is 8-12 times of the weight of the bromoacetic acid.
4. The process for producing 2-chloro-pyrimidine-5-carbaldehyde according to claim 1 or 2, wherein when the acetic acid-based compound is chloroacetic acid, the step S1 includes: under the inert gas atmosphere, the reaction kettle is filled with a gas,
under the condition of the temperature of 0-5 ℃, firstly adding chloroacetic acid into N-N-dimethylformamide, and then dropwise adding phosphorus oxychloride into the N-N-dimethylformamide at the dropping speed of 0.05-0.1 mL/s to form a fourth mixed solution;
stirring the fourth mixed solution for 0.5-1.5 h at the temperature of 75-85 ℃, 0.5-1.5 h at the temperature of 90-100 ℃, 0.5-1.5 h at the temperature of 100-110 ℃ and 0.5-1.5 h at the temperature of 20-25 ℃, then sequentially dripping concentrated hydrochloric acid with the mass concentration of 30-36% and tetrahydrofuran into the fourth mixed solution at the dripping speed of 0.05-0.1 mL/s and stirring for 20-40 min at the temperature of 20-25 ℃ to obtain an intermediate product A;
preferably, the dosage of the concentrated hydrochloric acid is 0.8-1.2 times of the weight of the chloroacetic acid; the dosage of the tetrahydrofuran is 8-12 times of the weight of the chloroacetic acid.
5. The process for producing 2-chloro-pyrimidine-5-carbaldehyde according to any one of claims 1 to 4, wherein the step S2 includes: carrying out the condensation reaction on the intermediate product A and urea in water;
preferably, the molar ratio of the intermediate product A to the urea is 1 (1.9-2.2).
6. The method for preparing 2-chloro-pyrimidine-5-carbaldehyde according to claim 5, wherein the condensation reaction is carried out at a temperature of 20 to 25 ℃ for 20 to 30 hours.
7. The process for producing 2-chloro-pyrimidine-5-carbaldehyde according to any one of claims 1 to 6, wherein the step S3 includes: and after mixing the intermediate product B with acetic acid, refluxing for 1-3 h at 105-115 ℃, removing the acetic acid in the system, adding toluene into the system, and continuously refluxing for 0.5-2 h to obtain an intermediate product C.
8. The method for preparing 2-chloro-pyrimidine-5-carbaldehyde according to claim 7, wherein the molar ratio of the intermediate product B, acetic acid and toluene is 1 (20-30) to (10-15).
9. The process for producing 2-chloro-pyrimidine-5-carbaldehyde according to any one of claims 1 to 6, wherein the step S4 includes:
after dissolving the intermediate product C in acetonitrile, sequentially dropwise adding N, N-diisopropylethylamine and phosphorus oxychloride into the system at a dropping speed of 0.02-0.05 mL/s at a temperature of 0-5 ℃ to form a fifth mixed solution;
and stirring the fifth mixed solution for 4-8 hours at the temperature of 75-85 ℃, and regulating and controlling the pH value of the system to be 6.5-7.5 at the temperature of 20-25 ℃ to obtain the 2-chloro-pyrimidine-5-formaldehyde.
10. The method for preparing 2-chloro-pyrimidine-5-carbaldehyde according to claim 9, wherein the molar ratio of the intermediate product C, N, N-diisopropylethylamine and phosphorus oxychloride is 1 (1.1-1.2) to 1.4-1.6.
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| CN109475565A (en) * | 2016-04-05 | 2019-03-15 | 免疫传感器公司 | CGAS agonist compounds |
| CN109369539A (en) * | 2018-11-19 | 2019-02-22 | 华东师范大学 | A kind of preparation method of the chloro- 5- aldehyde radical pyrimidine of 2- |
| CN109928933A (en) * | 2019-01-10 | 2019-06-25 | 安徽昊帆生物有限公司 | Chloro- 5- aldehyde radical pyrimidine of 2- and preparation method thereof |
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