CN116589409A - Chemical synthesis method of chlorooxazoline amine - Google Patents
Chemical synthesis method of chlorooxazoline amine Download PDFInfo
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- CN116589409A CN116589409A CN202310553468.2A CN202310553468A CN116589409A CN 116589409 A CN116589409 A CN 116589409A CN 202310553468 A CN202310553468 A CN 202310553468A CN 116589409 A CN116589409 A CN 116589409A
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- -1 chlorooxazoline amine Chemical class 0.000 title claims abstract description 49
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 33
- WBPAOUHWPONFEQ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C(Cl)=C1 WBPAOUHWPONFEQ-UHFFFAOYSA-N 0.000 claims abstract description 26
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims abstract description 18
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000007857 hydrazones Chemical class 0.000 claims abstract description 7
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001412 amines Chemical class 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 239000003208 petroleum Substances 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 4
- 238000002360 preparation method Methods 0.000 abstract description 25
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- RLWRMIYXDPXIEX-UHFFFAOYSA-N muzolimine Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C)N1N=C(N)CC1=O RLWRMIYXDPXIEX-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002934 diuretic Substances 0.000 abstract description 3
- 230000001882 diuretic effect Effects 0.000 abstract description 3
- 229960001788 muzolimine Drugs 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000003999 initiator Substances 0.000 abstract 1
- 229960000964 phenelzine Drugs 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 28
- 239000000203 mixture Substances 0.000 description 15
- 238000000605 extraction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 206010030113 Oedema Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- IOPLHGOSNCJOOO-UHFFFAOYSA-N methyl 3,4-diaminobenzoate Chemical compound COC(=O)C1=CC=C(N)C(N)=C1 IOPLHGOSNCJOOO-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- OMBMILBFFMGAJD-UHFFFAOYSA-N (3,4-dichlorophenyl)methylhydrazine Chemical compound NNCC1=CC=C(Cl)C(Cl)=C1 OMBMILBFFMGAJD-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000009447 Cardiac Edema Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/52—Oxygen atom in position 3 and nitrogen atom in position 5, or vice versa
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a chemical synthesis preparation method of chlorooxazoline amine. The chloroxazoline amine is also called moxazol amine and Edrul, and is a diuretic. The invention adopts 3, 4-dichloro acetophenone as an initiator, and firstly reacts with hydrazine hydrate to obtain 3, 4-dichloro acetophenone hydrazine hydrazone; condensing 3, 4-dichloro acetophenone hydrazine hydrazone and cyanoacetic acid at room temperature under the catalysis of condensing agent EDC to obtain hydrazone cyanoacetamide, reducing hydrazone to obtain phenethyl hydrazine, heating in acid alcohol solution to form ring to obtain coarse chloroazolin amine product, and re-crystallizing to obtain white crystal. The synthetic method innovatively designs a synthetic route; the raw materials used in the synthesis process are cheap and easy to obtain, and the synthesis steps and methods are simple, safe and easy to operate; the overall process has short steps, relatively mild preparation conditions, easy product treatment and purification, and high target product yield, and is suitable for batch preparation.
Description
Technical Field
The invention belongs to the technical field of organic synthesis and pharmaceutical chemistry, and particularly relates to a chemical synthesis method of chlorooxazoline amine.
Background
Cloxazolinamine (CAS RN: 55294-15-0), also known as pyrazolone, moxazolamide, english alias: edrul, muzolimine, molecular formula: c (C) 11 H 11 Cl 2 N 3 O. The medicine is used for treating heart-derived edema, kidney-derived edema and liver-disease edema and hypertension, is a diuretic acting on the loops, has strong and durable effect, can inhibit reabsorption of the thick branch rising sections of the loops on sodium ions and chloride ions, and can increase excretion of potassium ions, calcium ions and magnesium ions. For the drug literature, bayer Inc. 1974, reported (DE 2319278) that a 3, 4-dichlorobenzyl hydrazine was needed as a starting material, which was not easy to prepare and could not be stored for a long time. In addition, the reported route has long steps, is not easy to operate and has low yield, which greatly limits the preparation and application of the medicine. The preparation method disclosed by the invention has the advantages of easily available raw materials, simple and convenient operation, high yield and easy purification, and is a cheap method suitable for mass preparation. Therefore, the invention has important research and practical value, and can greatly promote the preparation research of the medicaments.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a novel method for synthesizing chlorooxazoline amine, and the prepared chlorooxazoline amine has pharmacological activity, mild preparation reaction, easy product treatment and suitability for batch preparation.
In order to solve the technical problems, the invention adopts the following technical scheme:
the structural formula of the chlorooxazoline amine is
。
The synthesis method of the chlorooxazoline amine comprises the following steps:
(1) 3, 4-dichloro acetophenone 1 is taken as a starting material, and reacts with hydrazine hydrate in ethanol at 80-90 ℃ for 2-3 hours to obtain 3, 4-dichloro acetophenone hydrazine hydrazone 2;
(2) Dissolving 3, 4-dichloro acetophenone hydrazine hydrazone in dichloromethane, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), adding cyanoacetic acid, reacting for 2-4 hours at room temperature, washing with water, drying, and concentrating to obtain a compound 3;
(3) Dissolving the compound 3 in methanol, adding sodium borohydride, reacting for 8-10 hours at 80-85 ℃ after adding, decompressing and removing the solvent, and extracting with ethyl acetate to obtain a compound 4;
(4) Dissolving the compound 4 in ethanol, adding concentrated hydrochloric acid, reacting at 80-90 ℃ for 6-8 hours, decompressing and removing the solution, adjusting the pH to 10, extracting with ethyl acetate to obtain a crude product of the chloroazolin amine, and recrystallizing with ethyl acetate and petroleum ether to obtain a white solid 5;
the specific preparation reaction route is as follows:
。
the starting material used in the invention is 3, 4-dichloro acetophenone and hydrazine hydrate.
Further, in the step (1), the molar ratio of the 3, 4-dichloroacetophenone to the hydrazine hydrate is 1:1-1:2.
Further, in the step (2), the molar ratio of 3, 4-dichloro acetophenone hydrazone, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) to cyanoacetic acid is 1:1.5:1-1:3:1.2.
Further, in the step (3), the molar ratio of the compound 3 to the sodium borohydride is 1:2-1:3.
Further, in the step (4), the molar ratio of the compound 4 to the hydrochloric acid is 1:5-1:10.
Further, the volume ratio of the recrystallized petroleum ether to the ethyl acetate in the step (4) is 1:1.
The invention has the beneficial effects that: the chloroxazoline amine is used for treating cardiac edema, renal edema, hepatic edema and hypertension, and is a diuretic acting on a loop. There was only a 1974 bayer corporation report on this report (DE 2319278). The preparation method disclosed by the invention has the advantages of easily available raw materials, simple and convenient operation, relatively mild reaction, high yield, easy treatment and purification of products and suitability for batch preparation, so that the preparation method of the cloxazoline amine has important application value.
Drawings
FIG. 1 is a LC-MS spectrum of the chloroazolin amine prepared in example 1.
FIG. 2 is a schematic diagram of H for preparing chlorooxazoline amine from example 1 1 -NMR spectrum.
Detailed Description
The invention will be further illustrated with reference to specific examples. The following examples are intended to be illustrative of the present invention and are not intended to limit the scope of the invention, as numerous insubstantial modifications and adaptations can be made by those skilled in the art in light of the above disclosure.
Example 1
The chemical synthesis method of the chlorooxazoline amine comprises the following steps:
(1) Synthesis of 3, 4-dichloro acetophenone hydrazone (2)
11.34g (0.06 mol) of 3, 4-dichloroacetophenone was added to a 500ml single-necked flask, and 300ml of ethanol was added thereto to dissolve the mixture under stirring, followed by dropwise addition of 5.4g (0.108 mol) of hydrazine hydrate, followed by stirring at 90℃for 3 hours after completion of the dropwise addition. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted, dried and concentrated to give 11.4g of methyl 3, 4-diaminobenzoate (2) in 94.1% yield.
(2) Preparation of Compound (3)
6.06g (0.03 mol) of 3, 4-dichloro acetophenone hydrazone (2) was added to a 500ml single-necked flask, and 200ml of methylene chloride was added thereto and dissolved with stirring, followed by 17.25g (0.09 mol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and then 5.04g (0.06 mol) of cyanoacetic acid was slowly added thereto to react for 4 hours. After the reaction was completed, the product was washed with water, dried, and concentrated to give 7.41g of compound (3) in 91.5% yield.
(3) Preparation of Compound (4)
5.4g (0.02 mol) of Compound (3) was added to a 500ml single-necked flask, 150ml of methanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 1.9g (0.05 mol) of sodium borohydride thereto, and stirring was continued for 10 hours at 85 ℃. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate, and ethyl acetate was removed by evaporation under reduced pressure to give 5.07g of Compound (4) in 93.2% yield.
(4) Preparation of chloroazolin amine (5)
5.44g (0.02 mol) of Compound (4) was added to a 500ml single-necked flask, 250ml of ethanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 13.33ml of concentrated hydrochloric acid (containing 0.16mol of hydrogen chloride) thereto, and stirring was carried out at 90℃for 8 hours. After the reaction is finished, the solvent is distilled off under reduced pressure, the pH is regulated to 10, ethyl acetate is used for extraction, the concentration is carried out to obtain a crude product of the chlorooxazoline amine, and then mixed solvent of ethyl acetate and petroleum ether in a ratio of 1:1 is used for recrystallization to obtain 5.08g of white solid chlorooxazoline amine (5), and the yield is 93.4%.
1 H NMR (300 MHz, CDCl 3 ): δ 7.41-7.35(d，1H)，7.11-7.08（dd，1H），5.15-5.12 (m，1H)，5.00（s，1 H），3.52(s，2H)，1.81(d，3H)
LC-MS，m/z（%）：[M+1]+:272.1,274.0。
Example 2
The chemical synthesis method of the chlorooxazoline amine comprises the following steps:
(1) Synthesis of 3, 4-dichloro acetophenone hydrazone (2)
11.34g (0.06 mol) of 3, 4-dichloro acetophenone was added to a 500ml single-port bottle, and 300ml of ethanol was added thereto, followed by stirring for dissolution, and then 2.94g (0.06 mol) of hydrazine hydrate was added dropwise thereto, followed by stirring at 80℃for 2 hours after completion of the addition. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted, dried and concentrated to give 10.38g of methyl 3, 4-diaminobenzoate (2) in a yield of 85.2%.
(2) Preparation of Compound (3)
6.06g (0.03 mol) of 3, 4-dichloro acetophenone hydrazone (2) was added to a 500ml single-necked flask, and 200ml of methylene chloride was added thereto and dissolved with stirring, followed by 14.38g (0.075 mol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and then 3.78g (0.45 mol) of cyanoacetic acid was slowly added thereto. The reaction was carried out for 3 hours. After the reaction, the product was washed with water, dried and concentrated to give 6.92g of compound (3) in 85.4% yield.
(3) Preparation of Compound (4)
5.4g (0.02 mol) of Compound (3) was added to a 500ml single-necked flask, 150ml of methanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 1.51g (0.04 mol) of sodium borohydride thereto, and stirring was carried out at 85℃for 8 hours. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate, and ethyl acetate was removed by evaporation under reduced pressure to give 4.87g of Compound (4) in 89% yield.
(4) Preparation of chloroazolin amine (5)
5.44g (0.02 mol) of Compound (4) was added to a 500ml single-necked flask, 250ml of ethanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 16.67ml of concentrated hydrochloric acid (containing 0.2mol of hydrogen chloride) thereto, and stirring was carried out at 85℃for 7 hours. After the reaction is finished, the solvent is distilled off under reduced pressure, the pH is regulated to 10, ethyl acetate is used for extraction, the concentration is carried out to obtain a crude product of the chlorooxazoline amine, and then the mixed solvent of ethyl acetate and petroleum ether according to the volume ratio of 1:1 is used for recrystallization to obtain 5.01g of white solid chlorooxazoline amine (5), and the yield is 92.1%.
Example 3
The chemical synthesis method of the chlorooxazoline amine comprises the following steps:
(1) Synthesis of 3, 4-dichloro acetophenone hydrazone (2)
11.34g (0.06 mol) of 3, 4-dichloroacetophenone was added to a 500ml single-necked flask, and 300ml of ethanol was added thereto to dissolve the mixture under stirring, and then 5.89g (0.12 mol) of hydrazine hydrate was added dropwise thereto, followed by stirring at 90℃for 3 hours after completion of the addition. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted, dried and concentrated to give 11.3g of methyl 3, 4-diaminobenzoate (2) in a yield of 92.8%.
(2) Preparation of Compound (3)
6.06g (0.03 mol) of 3, 4-dichloro acetophenone hydrazone (2) was added to a 500ml single-necked flask, and 200ml of methylene chloride was added thereto and dissolved with stirring, followed by 8.63g (0.045 mol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and then 2.52g (0.03 mol) of cyanoacetic acid was slowly added thereto for reaction for 2 hours. After the reaction was completed, the product was washed with water, dried, and concentrated to give 6.59g of compound (3) in a yield of 81.3%.
(3) Preparation of Compound (4)
5.4g (0.02 mol) of Compound (3) was added to a 500ml single-necked flask, 150ml of methanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 2.27g (0.06 mol) of sodium borohydride thereto, and stirring was continued for 10 hours at 85 ℃. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate, and ethyl acetate was removed by evaporation under reduced pressure to give 5.02g of Compound (4) in 92.3% yield.
(4) Preparation of chloroazolin amine (5)
5.44g (0.02 mol) of Compound (4) was added to a 500ml single-necked flask, 250ml of ethanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 8.33ml of concentrated hydrochloric acid (containing 0.1mol of hydrogen chloride) thereto, and stirring was carried out at 80℃for 8 hours. After the reaction is finished, the solvent is distilled off under reduced pressure, the pH is regulated to 10, ethyl acetate is used for extraction, the concentration is carried out to obtain a crude product of the chlorooxazoline amine, and then the mixed solvent of ethyl acetate and petroleum ether according to the volume ratio of 1:1 is used for recrystallization to obtain 4.76g of white solid chlorooxazoline amine (5), and the yield is 87.5%.
Example 4
The chemical synthesis method of the chlorooxazoline amine comprises the following steps:
(1) Synthesis of 3, 4-dichloro acetophenone hydrazone (2)
11.34g (0.06 mol) of 3, 4-dichloroacetophenone was added to a 500ml single-necked flask, and 300ml of ethanol was added thereto to dissolve the mixture under stirring, followed by dropwise addition of 4.41g (0.09 mol) of hydrazine hydrate, followed by stirring at 85℃for 2.5 hours after completion of the dropwise addition. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted, dried and concentrated to give 11.4g of methyl 3, 4-diaminobenzoate (2) in 93.6% yield.
(2) Preparation of Compound (3)
6.06g (0.03 mol) of 3, 4-dichloro acetophenone hydrazone (2) was added to a 500ml single-necked flask, and 200ml of methylene chloride was added thereto and dissolved with stirring, followed by 14.38g (0.075 mol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and then 5.04g (0.06 mol) of cyanoacetic acid was slowly added thereto for reaction for 2 hours. After the reaction, the product was washed with water, dried and concentrated to give 7.29g of compound (3) in a yield of 90%.
(3) Preparation of Compound (4)
5.4g (0.02 mol) of Compound (3) was added to a 500ml single-necked flask, 150ml of methanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 1.9g (0.05 mol) of sodium borohydride thereto, and stirring was carried out at 80℃for 9 hours. After the reaction was completed, methanol was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate, and ethyl acetate was removed by evaporation under reduced pressure to give 5.05g of Compound (4) in 92.8% yield.
(4) Preparation of chloroazolin amine (5)
5.44g (0.02 mol) of Compound (4) was added to a 500ml single-necked flask, 250ml of ethanol was added thereto, and the mixture was dissolved by stirring, followed by slowly adding 16.67ml of concentrated hydrochloric acid (containing 0.2mol of hydrogen chloride) thereto, and stirring was carried out at 85℃for 6 hours. After the reaction is finished, the solvent is distilled off under reduced pressure, the pH value is regulated to 10, ethyl acetate is used for extraction, the concentration is carried out to obtain a crude product of the chlorooxazoline amine, and then the mixed solvent of ethyl acetate and petroleum ether according to the volume ratio of 1:1 is used for recrystallization to obtain 4.94g of white solid chlorooxazoline amine (5), and the yield is 90.8%.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. The chemical synthesis method of the chlorooxazoline amine is characterized by comprising the following steps of:
(1) 3, 4-dichloro acetophenone 1 is taken as an initial raw material, and reacts with hydrazine hydrate in ethanol to obtain 3, 4-dichloro acetophenone hydrazine hydrazone 2;
(2) Dissolving 3, 4-dichloro acetophenone hydrazone 2 in dichloromethane, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), adding cyanoacetic acid for reaction, washing with water after the reaction is finished, drying, and concentrating to obtain a compound 3;
(3) Dissolving the compound 3 in methanol, adding sodium borohydride for reaction, removing the solvent under reduced pressure after the reaction is finished, and extracting with ethyl acetate to obtain a compound 4;
(4) Dissolving a compound 4 in ethanol, adding concentrated hydrochloric acid for reaction, evaporating a solvent under reduced pressure after the reaction is finished, adjusting the pH to 10, extracting with ethyl acetate to obtain a crude product of the chlorozoline amine, and recrystallizing with ethyl acetate and petroleum ether to obtain a white solid 5 which is the chlorozoline amine;
the specific synthetic route is as follows:
。
2. the chemical synthesis method of chloroazolin amine according to claim 1, wherein: in the step (1), the molar ratio of the 3, 4-dichloro acetophenone to the hydrazine hydrate is 1:1-1:2.
3. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: the reaction temperature in the step (1) is 80-90 ℃ and the reaction time is 2-3 hours.
4. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: in the step (2), the molar ratio of 3, 4-dichloro acetophenone hydrazone to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) to cyanoacetic acid is 1:1.5:1-1:3:1.2.
5. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: the reaction temperature in the step (2) is room temperature, and the reaction time is 2-4 hours.
6. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: and (3) in the step (3), the molar ratio of the compound 3 to the sodium borohydride is 1:2-1:3.
7. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: the reaction temperature in the step (3) is 80-85 ℃ and the reaction time is 8-10 hours.
8. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: and (3) in the step (4), the molar ratio of the compound 4 to the hydrochloric acid is 1:5-1:10.
9. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: the reaction temperature in the step (4) is 80-90 ℃ and the reaction time is 6-8 hours.
10. The chemical synthesis method of chloroazolin amine according to claim 1, wherein: the volume ratio of petroleum ether to ethyl acetate adopted in the recrystallization in the step (4) is 1:1.
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