CN110845438B - Synthesis method of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide - Google Patents
Synthesis method of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide Download PDFInfo
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- CN110845438B CN110845438B CN201911129620.4A CN201911129620A CN110845438B CN 110845438 B CN110845438 B CN 110845438B CN 201911129620 A CN201911129620 A CN 201911129620A CN 110845438 B CN110845438 B CN 110845438B
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- FHTNNXCQKMDOJV-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-5-yl)-N-[4-(2-chloroethyl)phenyl]acetamide Chemical compound NC=1SC(=CN=1)CC(=O)NC1=CC=C(C=C1)CCCl FHTNNXCQKMDOJV-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000001308 synthesis method Methods 0.000 title description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- JMWPXJYTORPHOB-UHFFFAOYSA-N 2-(4-amino-1,3-thiazol-2-yl)acetic acid Chemical compound NC1=CSC(CC(O)=O)=N1 JMWPXJYTORPHOB-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- RFYZOXOYGVHVJX-UHFFFAOYSA-N C(C)(=O)Cl.NC=1SC=CN1 Chemical compound C(C)(=O)Cl.NC=1SC=CN1 RFYZOXOYGVHVJX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- DIDOBGBVBCPOEE-UHFFFAOYSA-N 4-(2-chloroethyl)aniline Chemical compound NC1=CC=C(CCCl)C=C1 DIDOBGBVBCPOEE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 5
- 239000012467 final product Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 description 4
- 229960001551 mirabegron Drugs 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000020629 overactive bladder Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a synthetic method of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, which comprises the following processing steps: s1, adding aminothiazole acetic acid into a solvent, and slowly dropwise adding thionyl chloride 35-40 for reaction to obtain aminothiazole acetyl chloride; s2, adding aminothiazole acetyl chloride and 4- (2 chloroethyl) aniline into dichloromethane, keeping the temperature at 10-25 ℃, slowly dropwise adding triethylamine, and reacting for 3 hours after dropwise adding; s3, after the reaction is finished, the reaction liquid is pumped into water, liquid separation is carried out, and dichloromethane is drawn out under reduced pressure, so that the off-white solid 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide is obtained. The method has the advantages of few reaction steps, high yield of the final product, good quality and suitability for large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide.
Background
Mirabegron, which is used for treating overactive bladder of adults. Clinical test data show that compared with the existing clinical treatment of overactive bladder of adults, the mirabegron has the characteristics of quick response, good tolerance, no sexual dysfunction to patients, small adverse reaction and the like. The chemical name of the compound is 2-amino-N- [4- [2- [ [ (2R) -2-hydroxy-2-phenylethyl ] amino ] ethyl ] phenyl ] -4-thiazole acetamide, and the chemical formula is as follows:
and 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide is an important intermediate for synthesizing mirabegron.
The prior art can not synthesize 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, which causes high cost of synthesizing mirabegron.
Disclosure of Invention
The invention aims to provide a synthesis method of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, which has the advantages of mild reaction, simple operation, high yield of final products and good quality.
In order to achieve the purpose, the invention adopts the technical scheme that: a method of synthesizing 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide comprising the following processing steps:
s1, adding aminothiazole acetic acid into a solvent, and slowly dropwise adding thionyl chloride 35-40 for reaction to obtain aminothiazole acetyl chloride;
s2, adding aminothiazole acetyl chloride and 4- (2 chloroethyl) aniline into dichloromethane, keeping the temperature at 10-25 ℃, slowly dropwise adding triethylamine, and reacting for 3 hours after dropwise adding;
s3, after the reaction is finished, the reaction liquid is pumped into water, liquid separation is carried out, and dichloromethane is drawn out under reduced pressure, so that the off-white solid 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide is obtained.
The technical scheme of further improvement in the technical scheme is as follows:
1. in the above scheme, the solvent in step S1 is one or more of dichloromethane, chloroform, acetone, butanone, and toluene.
2. In the scheme, the dosage of the solvent in the step S1 is 2-3 times of the mass of the aminothiazole acetic acid.
3. In the above scheme, the reaction time in the step S1 is 1-48 hours.
4. In the scheme, the molar ratio of the aminothiazole acetic acid to the thionyl chloride in the step S1 is 1: 1-20.
5. In the above scheme, the solubility of thionyl chloride in the solvent in step S1 is 20% to 28%, and the solubility of triethylamine in the solvent in step S2 is 30% to 70%.
6. In the scheme, the addition amount of the thionyl chloride is 0.9-1.2 times of the mass of the aminothiazole acetic acid, and the addition amount of the triethylamine is 0.7-1 time of the mass of the aminothiazole acetyl chloride.
7. In the scheme, the molar ratio of the aminothiazole acetyl chloride to the triethylamine in the step S2 is 1: 1-20.
8. In the scheme, the molar ratio of the aminothiazole acetyl chloride to the 4- (2 chloroethyl) aniline in the step S2 is 1: 1-20.
The chemical reaction formula of the synthetic method is as follows:
due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1. in the synthetic method, aminothiazole acetic acid and 4- (2 chloroethyl) aniline are used as starting materials, and the 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide is synthesized with a better yield, so that the reaction is mild and the operation is simple.
2. The synthesis method only uses dichloromethane with environmental protection as a solvent to prepare the 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, has few reaction steps, high yield of the final product and good quality, and is suitable for large-scale industrial production.
Drawings
FIG. 1 is a liquid chromatogram of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide prepared by the synthesis method of the present invention.
Detailed Description
In the description of this patent, it is noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the present invention; the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance; furthermore, unless expressly stated or limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, as they may be fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The meaning of the above terms in this patent may be specifically understood by those of ordinary skill in the art.
The invention is further described below with reference to the following examples:
example 1:
under the condition of room temperature, 300ml of dichloromethane and 158 g of aminothiazole acetic acid are added into a reaction bottle, the temperature is reduced to 0-10 ℃, 119g of thionyl chloride is slowly dripped, the temperature of the mixed solution is increased to 35-40 ℃ after the dripping is finished, and the mixed solution is stirred and refluxed for 3 hours.
Cooling to 10-15 ℃, adding 155g of 4- (2-chloroethyl) aniline into the reaction solution, slowly dropwise adding 111g of triethylamine, reacting for 3h at 10-25 ℃, adding 200g of water, stirring for 1h, separating, cooling to-10 ℃, and filtering to obtain 290g of off-white solid 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, wherein the yield is 98.3%, and the purity is 99.81%.
Example 2:
under the condition of room temperature, 300ml of toluene and 158 g of aminothiazole acetic acid are added into a reaction bottle, the temperature is reduced to 0-10 ℃, 119g of thionyl chloride is slowly dripped, the temperature of the mixed solution is increased to 35-40 ℃ after the dripping is finished, and the mixed solution is stirred and refluxed for 3 hours.
Cooling to 10-15 ℃, adding 155g of 4- (2-chloroethyl) aniline into the reaction solution, slowly dropwise adding 111g of triethylamine, reacting for 3h at 10-25 ℃, adding 200g of water, stirring for 1h, separating, cooling to-10 ℃, and filtering to obtain 280g of off-white solid 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, wherein the yield is 95% and the purity is 99.71%.
Example 3:
under the condition of room temperature, 300ml of toluene and 158 g of aminothiazole acetic acid are added into a reaction bottle, the temperature is reduced to 0-10 ℃, 121g of thionyl chloride is slowly dripped, the temperature of the mixed solution is raised to 35-40 ℃ after the dripping is finished, and the mixed solution is stirred and refluxed for 3 hours.
Cooling to 10-15 ℃, adding 165g of 4- (2-chloroethyl) aniline into the reaction solution, slowly dropwise adding 131g of triethylamine, reacting for 3h at 10-25 ℃, adding 100g of water, stirring for 1h, separating, cooling to-10 ℃, and filtering to obtain 267g of off-white solid 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide, wherein the yield is 90.5% and the purity is 99.21%.
Subsequently, a sample of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide prepared by the method of synthetic example 1 of the present invention was sampled and detected by liquid chromatography.
Detection conditions are as follows: the instrument comprises the following steps: agilent 1100 hplc;
a chromatographic column: luna C18,4.6mm × 250mm,5 μm;
column temperature: 25 ℃;
flow rate: 1.0 ml/min;
detection wavelength: 235 nm;
sample introduction volume: 5 ul;
mobile phase: acetonitrile: 0.1% aqueous phosphoric acid 60:40 (v/v);
operating time: and (3) 30 min.
The liquid chromatogram of the detected sample is shown in FIG. 1; the analysis results are shown in table 1.
Table 1: chromatographic analysis results of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide samples prepared by the synthetic method of the invention case 1
As can be seen from fig. 1 and table 1: the purity of 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide prepared by the synthetic method of the invention case 1 is higher and reaches 99.8 percent.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A method for synthesizing 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide is characterized by comprising the following steps: the method comprises the following processing steps:
s1, adding aminothiazole acetic acid into a solvent, and slowly dropwise adding thionyl chloride 35-40 for reaction to obtain aminothiazole acetyl chloride;
s2, adding aminothiazole acetyl chloride and 4- (2 chloroethyl) aniline into dichloromethane, keeping the temperature at 10-25 ℃, slowly dropwise adding triethylamine, and reacting for 3 hours after dropwise adding;
s3, after the reaction is finished, the reaction liquid is pumped into water, liquid separation is carried out, and dichloromethane is drawn out under reduced pressure, so that the off-white solid 2- (2-aminothiazole-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide is obtained.
2. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: and the solvent in the step S1 is one or more of dichloromethane, trichloromethane, acetone, butanone and toluene.
3. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the dosage of the solvent in the step S1 is 2-3 times of the mass of the aminothiazole acetic acid.
4. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the reaction time in the step S1 is 1-48 hours.
5. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the molar ratio of the aminothiazole acetic acid to the thionyl chloride in the step S1 is 1: 1-20.
6. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the solubility of the thionyl chloride in the solvent in the step S1 is 20% -28%, and the solubility of the triethylamine in the solvent in the step S2 is 30% -70%.
7. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the addition amount of the thionyl chloride is 0.9-1.2 times of the mass of the aminothiazole acetic acid, and the addition amount of the triethylamine is 0.7-1 time of the mass of the aminothiazole acetyl chloride.
8. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the molar ratio of the aminothiazole acetyl chloride to the triethylamine in the step S2 is 1: 1-20.
9. The process for the synthesis of 2- (2-aminothiazol-5-yl) -N- [4- (2-chloro-ethyl) -phenyl ] -acetamide according to claim 1, characterized in that: the molar ratio of the aminothiazole acetyl chloride to the 4- (2-chloroethyl) aniline in the step S2 is 1: 1-20.
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