CN117700369A - Preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester - Google Patents
Preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester Download PDFInfo
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- CN117700369A CN117700369A CN202311680368.2A CN202311680368A CN117700369A CN 117700369 A CN117700369 A CN 117700369A CN 202311680368 A CN202311680368 A CN 202311680368A CN 117700369 A CN117700369 A CN 117700369A
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- Prior art keywords
- acetic acid
- preparation
- compound
- ester
- chloropyrimidine
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 235000019439 ethyl acetate Nutrition 0.000 title claims abstract description 11
- QUXDHXIGIYSSPG-UHFFFAOYSA-N 2-(2-chloropyrimidin-5-yl)acetic acid Chemical compound OC(=O)CC1=CN=C(Cl)N=C1 QUXDHXIGIYSSPG-UHFFFAOYSA-N 0.000 title claims abstract description 10
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940125782 compound 2 Drugs 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910001923 silver oxide Inorganic materials 0.000 claims abstract description 9
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 6
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 claims abstract description 6
- DUCXUPKLVVSJKA-UHFFFAOYSA-N 2-chloropyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=C(Cl)N=C1 DUCXUPKLVVSJKA-UHFFFAOYSA-N 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- XWVPSJPQWOVRHJ-UHFFFAOYSA-N 2-(6-chloropyridin-3-yl)acetic acid Chemical compound OC(=O)CC1=CC=C(Cl)N=C1 XWVPSJPQWOVRHJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 4
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- UCRIJQVHAZNUGK-UHFFFAOYSA-N diazomethane;trimethylsilicon Chemical compound C=[N+]=[N-].C[Si](C)C UCRIJQVHAZNUGK-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 238000006462 rearrangement reaction Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 5
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 11
- 238000009509 drug development Methods 0.000 abstract description 6
- 239000012634 fragment Substances 0.000 abstract description 6
- -1 pyrimidine compound Chemical class 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000002547 new drug Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 10
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229940104302 cytosine Drugs 0.000 description 7
- 238000010907 mechanical stirring Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 230000008034 disappearance Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229940113082 thymine Drugs 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003230 pyrimidines Chemical class 0.000 description 4
- 229940035893 uracil Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012847 fine chemical Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XDQFBMPFEBUDIC-UHFFFAOYSA-N 1h-pyrimidine-2,4-dione Chemical compound O=C1C=CNC(=O)N1.O=C1C=CNC(=O)N1 XDQFBMPFEBUDIC-UHFFFAOYSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 229960004413 flucytosine Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- WRMCZHYLTVSDQU-UHFFFAOYSA-N pyrimidin-1-ium;acetate Chemical class CC(O)=O.C1=CN=CN=C1 WRMCZHYLTVSDQU-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester, and belongs to the technical field of drug synthesis. Firstly, reacting 2-chloropyrimidine-5-carboxylic acid with oxalyl chloride to generate corresponding acyl chloride, and then reacting the acyl chloride with trimethylsilyl diazomethane to generate a compound 2; and finally rearranging the compound 2 in alcohol or water under the action of silver oxide to obtain the 2-chloropyridine-5-acetic acid/ester. The reagents and the raw materials used in the invention are available in the market, so that the preparation method of the pyrimidine compound with the special structure is provided, the preparation cost is greatly reduced, and various structural fragments are provided for new drug development enterprises at present.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry production, in particular to a preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester.
Background
Pyrimidine is a basic nitrogen-containing heterocyclic organic compound, and its derivatives cytosine, uracil, thymine, etc. are important constituent components of nucleic acid. Three of the five bases forming DNA and RNA are pyrimidine derivatives: cytosine (Cytosine), thymine (Thymine), uracil (Uracil); the chemical structural formula is as follows:
where thymine can only be present in deoxyribonucleic acid, uracil can only be present in ribonucleic acid, and cytosine can be both.
Cytosine (Cytosine) is an important intermediate for fine chemical engineering, pesticides and medicines, is mainly used for synthesizing anti-AIDS medicines and anti-hepatitis B medicines lamivudine, anticancer medicines such as gemcitabine, enotabine, 5-fluorocytosine and the like in the field of medicines, and has very wide application. Both cytosine nucleosides and cytosine nucleotides can be used as drugs to raise leukocytes.
Thymine (Thymene) is a key intermediate for synthesizing anti-AIDS drugs AZT, DDT and related drugs. Thymidine is a biochemical reagent used in the preparation of biological media, such as HAT selective media.
Uracil (Uracil) is a drug, such as anti-anemia of giant red blood cells, treating liver; cerebral blood vessels; cardiovascular diseases, and the like, are also diseases in which fluorouracil (S-FC) is produced; deoxynucleosides; iodides (IDUR); bromoglycoside (BUDR); fluoroglycoside (FUDR) and other medicines.
Pyrimidine rings are therefore a ubiquitous building block in natural products, and synthetic analogues thereof also possess a broader range of physiological activities.
In the drug development stage, new drug development companies are interested in pyrimidine derivatives, and usually perform activity screening on pyrimidine rings and pyrimidine acetic acid derivatives, so as to try to find more effective active fragments. CHUGAI PHARMACEUTICAL CO LTD [ JP ] in the development of vitamin D compounds, a number of pyrimidine ring derivative containing structures have been prepared and screened, and these active molecules have been patented and protected, typically as follows:
ECCOGENE SHANGHAI CO LTD [ CN ] [ WO2022199661A1 ] the derivative screening of fragment 1 was also performed when GLP-1 receptor agonists and predatory drugs were developed to produce anti-HBV drugs. The synthesis of fragments is reported in patent EP18949111, but the required raw materials are not readily available and are costly.
In conclusion, pyrimidine derivatives are important components which are not negligible in modern drug development, have potential application values, but the preparation cost is high because of one more methylene, and the fragment 1 is a good investigation point for drug development from the aspects of activity investigation and structural diversity.
Disclosure of Invention
The invention aims to solve the problems that: by optimizing the synthesis route, the preparation cost of the target molecule TM is greatly reduced.
The synthetic route of the invention adopts a reaction equation as follows:
the first step: chlorination and substitution reactions
Firstly, reacting 2-chloropyrimidine-5-carboxylic acid with oxalyl chloride to generate corresponding acyl chloride, and then reacting the acyl chloride with trimethylsilyl diazomethane to generate a compound 2;
second, rearrangement reaction
Rearranging the compound 2 in alcohol or water under the action of silver oxide to obtain 2-chloropyridine-5-acetic acid/ester TM.
Further, in the above technical scheme, in the first step of the chlorination reaction, the reaction is performed in a chlorinated solvent, such as dichloromethane and dichloroethane; the nucleophilic substitution solvent is acetonitrile and tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran solvent.
Further, in the technical scheme, the molar ratio of the 2-chloropyrimidine-5-carboxylic acid, oxalyl chloride and trimethyl silicon diazomethane in the first step is 1:1.5-5:1-1.5.
Further, in the above technical scheme, the alcohol in the second step is selected from methanol, ethanol or benzyl alcohol.
Further, in the above technical scheme, the molar ratio of the compound 2 to the silver oxide in the second step is 1:0.01-0.20.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the invention provides a preparation method of pyrimidine compounds with special structures, which greatly reduces the preparation cost and provides new diversity structural fragments for new drug development enterprises.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1 preparation of Compound 2
In a 3L three-necked flask, mechanical stirring was provided, starting material 1 (100 g,0.631 mol) and 1.5L of anhydrous dichloromethane were added, and mechanical stirring was started under nitrogen. Then cooling to 0 ℃, dropwise adding oxalyl chloride (110 mL,1.3 mol), wherein the internal temperature is lower than 10 ℃, adding 1mL of DMF after the dropwise adding, then reacting for 4 hours at 25 ℃ (the solid basically disappears to become a solution), and stopping the reaction when TLC detects the disappearance of the raw material. The low boiling point material was removed by concentrating under reduced pressure, 300mL of anhydrous methylene chloride was distilled off to obtain an acid chloride intermediate.
The acid chloride intermediate was dissolved in 500mL tetrahydrofuran and 500mL acetonitrile and cooled to 0deg.C, and 2M TMSCHN was added dropwise 2 N-hexane solution (380 mL,0.76 mol) was added, and the mixture was allowed to warm to room temperature for 2 hours. TLC detection, starting material disappeared, stopping the reaction. Cooling to 0deg.C, adding 100mL of acetic acid and 500mL of water, quenching, and extracting with ethyl acetate (500 mL) twice; the organic phases were combined, washed with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 2 (110 g) which was used directly in the next step. TLC: PE: EA=4:1, R f ＝0.23,254nm. 1 HNMR(400MHz,CDCl 3 )8.96(s,2H),5.94(s,1H).
Example 2 preparation of Compound TM (R=Me)
In a 3L three-necked flask, mechanical stirring was provided, and Compound 2 (110 g,0.602 mol), silver oxide (7.5 g,0.033 mol) and 1.5L of anhydrous methanol were added and refluxed under nitrogen for 16 hours. TLC detects the disappearance of starting material and stops the reaction. Cooled to room temperature, filtered, and the filtrate was concentrated and purified (PE: ea=6:1 to 5:1) to give 100g of the target product TM as a colorless liquid. The yield of the two steps is 85%. TLC: PE: ea=4:1, rf=0.25, 254nm. 1 HNMR(400MHz,CDCl 3 )8.58(s,2H),3.77(s,3H),3.65(s,2H).
Example 3 preparation of Compound TM (R=H)
In a 500mL three-necked flask, mechanical stirring was provided, and compound 2 (10 g,0.055 mol), silver oxide (2.5 g,11 mmol) and 100mL water were added and refluxed under nitrogen for 16 hours. TLC detects the disappearance of starting material and stops the reaction. Cooled to room temperature, filtered, and concentrated to give 5.2g of the desired product TM (r=h). The yield of the two steps is 48%.
Example 4 preparation of Compound TM (R=Et)
In a 500mL three-necked flask, mechanical stirring was provided, and compound 2 (10 g,0.055 mol), silver oxide (0.6 g,2.6 mmol) and 100mL absolute ethanol were added and refluxed under nitrogen for 16 hours. TLC detects the disappearance of starting material and stops the reaction. Cooled to room temperature, filtered, and the filtrate was concentrated and purified (PE: ea=6:1 to 5:1) to give 10.5g of the target product TM as a colorless liquid. The yield of the two steps is 76%.
Example 5 preparation of Compound TM (R=Bn)
In a 500mL three-necked flask, compound 2 (10 g,0.055 mol), silver oxide (1 g,4.3 mmol), benzyl alcohol (15 g,0.139 mol) and 100mL absolute ethanol were added with mechanical stirring and refluxed under nitrogen for 16 hours. TLC detects the disappearance of starting material and stops the reaction. Cooled to room temperature, filtered, and concentrated to give 11g of the desired product TM as pale yellow solid (r=bn). The yield of the two steps is 60%.
The foregoing description is only illustrative of the preferred embodiments of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.
Claims (6)
1. A method for preparing 2- (2-chloropyrimidine-5-yl) acetic acid/ester, which is characterized by comprising the following steps:
the first step: chlorination and substitution reactions
Firstly, reacting 2-chloropyrimidine-5-carboxylic acid with oxalyl chloride to generate corresponding acyl chloride, and then reacting the acyl chloride with trimethylsilyl diazomethane to generate a compound 2;
second, rearrangement reaction
Rearranging the compound 2 in alcohol or water under the action of silver oxide to obtain 2-chloropyridine-5-acetic acid/ester TM.
2. The process for the preparation of 2- (2-chloropyrimidin-5-yl) acetic acid/ester according to claim 1, wherein: in the first step, the chlorination reaction is carried out in a chlorinated solvent; the nucleophilic substitution solvent is acetonitrile and tetrahydrofuran, acetonitrile and 2-methyltetrahydrofuran solvent.
3. The process for preparing 2- (2-chloropyrimidin-5-yl) acetic acid/ester according to claim 2, wherein: the chlorinated solvent is selected from dichloromethane and dichloroethane.
4. The process for the preparation of 2- (2-chloropyrimidin-5-yl) acetic acid/ester according to claim 1, wherein: the molar ratio of the 2-chloropyrimidine-5-carboxylic acid, oxalyl chloride and the trimethyl silicon diazomethane in the first step is 1:2-5:1-1.5.
5. The process for the preparation of 2- (2-chloropyrimidin-5-yl) acetic acid/ester according to claim 1, wherein: the alcohol in the second step is selected from methanol, ethanol or benzyl alcohol.
6. The process for the preparation of 2- (2-chloropyrimidin-5-yl) acetic acid/ester according to claim 1, wherein: the molar ratio of the compound 2 to the silver oxide in the second step is 1:0.05-0.20.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202311680368.2A CN117700369A (en) | 2023-12-08 | 2023-12-08 | Preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester |
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| CN202311680368.2A CN117700369A (en) | 2023-12-08 | 2023-12-08 | Preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester |
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| CN117700369A true CN117700369A (en) | 2024-03-15 |
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| CN202311680368.2A Pending CN117700369A (en) | 2023-12-08 | 2023-12-08 | Preparation method of 2- (2-chloropyrimidine-5-yl) acetic acid/ester |
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| Country | Link |
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| CN (1) | CN117700369A (en) |
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2023
- 2023-12-08 CN CN202311680368.2A patent/CN117700369A/en active Pending
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