CN116023359A - Synthesis method of aminothiophene compound and aminothiophene compound - Google Patents

Synthesis method of aminothiophene compound and aminothiophene compound Download PDF

Info

Publication number
CN116023359A
CN116023359A CN202211703356.2A CN202211703356A CN116023359A CN 116023359 A CN116023359 A CN 116023359A CN 202211703356 A CN202211703356 A CN 202211703356A CN 116023359 A CN116023359 A CN 116023359A
Authority
CN
China
Prior art keywords
aminothiophene
compound
dioxane
general formula
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202211703356.2A
Other languages
Chinese (zh)
Inventor
谢应波
张庆
张华�
曹云
罗桂云
董斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHANGHAI TITAN TECHNOLOGY CO LTD
Original Assignee
SHANGHAI TITAN TECHNOLOGY CO LTD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SHANGHAI TITAN TECHNOLOGY CO LTD filed Critical SHANGHAI TITAN TECHNOLOGY CO LTD
Priority to CN202211703356.2A priority Critical patent/CN116023359A/en
Publication of CN116023359A publication Critical patent/CN116023359A/en
Pending legal-status Critical Current

Links

Landscapes

  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The application relates to the field of preparation of compounds, and particularly discloses a synthesis method of aminothiophene compounds and the aminothiophene compounds. The synthesis method of the aminothiophene compound comprises the following steps: the method comprises the steps of taking a compound shown in a general formula (I) and an ammoniation agent as raw materials and dioxane as a solvent, stirring and filtering under the conditions of catalysis of a catalyst and protection of nitrogen to obtain filtrate, and sequentially extracting, washing, concentrating, drying and purifying the obtained filtrate to obtain the aminothiophene compound; in the general formula (I): r is R 1 Selected from-CO 2 Me、‑COMe、‑CO 2 Me 3 or-CO 2 CH 2 Me；R 2 Selected from-H, -Me; wherein the feed ratio of the compound represented by the general formula (I), the ammoniating agent, the catalyst and the dioxane is 16mmol (100-120 ml) (5-10 mmol) (40-50 ml). The synthesis method has mild reaction conditions, is simple and feasible, and is convenient for large-scale preparationThe aminothiophene is prepared, and the yield of the prepared aminothiophene compound can meet the industrial production requirement.

Description

Synthesis method of aminothiophene compound and aminothiophene compound
Technical Field
The application relates to the technical field of organic synthesis, in particular to a synthesis method of an aminothiophene compound and the aminothiophene compound.
Background
The aminothiophene compound is an important pesticide and medical intermediate, and many derivatives thereof are special-effect medicines with remarkable efficacy and novel structure, and occupy very important positions in the aspects of molecular design and promotion of human health.
The aminothiophene compounds in the related art are mostly prepared by adopting an artificial synthesis method, and the classical strategy is to utilize substituted thiophene as a starting material, and synthesize the aminothiophene compounds through nitration and nitroreduction reactions.
Aiming at the related technology, the inventor discovers that the nitration sites of the nitration reaction are possibly not single, so that a plurality of byproducts are caused, and the reduction conditions of the nitration reaction and the nitro are harsh, so that the nitration reaction and the nitro have certain dangers and are not beneficial to the large-scale preparation of the aminothiophene compound. Therefore, there is an urgent need to provide a method for synthesizing aminothiophene compounds with mild reaction conditions.
Disclosure of Invention
In order to solve the problem that the aminothiophene compound is not easy to prepare in a large scale through nitration and nitroreduction reactions, the application provides a synthesis method of the aminothiophene compound and the aminothiophene compound.
In a first aspect, the present application provides a method for synthesizing an aminothiophene compound, which adopts the following technical scheme:
the synthesis process of aminothiophene compound includes stirring and filtering to obtain filtrate with compound shown in the general expression (I) and ammoniating agent as material and dioxane as solvent under the catalysis of catalyst and nitrogen protection, and the filtrate is first extracted, washed, concentrated, dried and purified to obtain aminothiophene compound;
Figure BDA0004025345080000021
in the general formula (I):
R 1 selected from-CO 2 Me、-C0Me、-C0 2 Me 3 or-CO 2 CH 2 Me；
R 2 Selected from-H, -Me;
wherein the feed ratio of the compound represented by the general formula (I), the ammoniating agent, the catalyst and the dioxane is 16mmol: (100-120 ml): (5-10) mmol: (40-50 ml).
According to the technical scheme, the compound in the general formula (I) and the ammoniating agent are used as reaction raw materials, dioxane is used as a reaction solvent, and in the process of synthesizing the aminothiophene compound through the ammoniation reaction under the catalysis of the catalyst, ammonia molecules are coordinated and complexed with the catalyst, and then the ammonia molecules and the compound represented by the general formula (I) are subjected to oxidation addition and reduction elimination, so that Br groups in the general formula (I) are efficiently substituted, and the aminothiophene compound is obtained.
Compared with the synthesis process of nitration and nitration reduction reactions, the method has the advantages of mild reaction conditions, convenience and easiness in preparation, and is suitable for preparing the aminothiophene compounds on a large scale. Meanwhile, the production of byproducts is reduced, the yield reaches more than 68 percent, the purity reaches more than 95 percent, and the method can be used for industrial production.
In addition, the synthesis method of the application uses dioxane as a solvent, compared with the yield of 40% when acetonitrile is used as the solvent, the yield can reach more than 68%, which shows that under the reaction condition of the application, the dioxane fully dissolves thiophene compounds and fully reacts with ammonia water, thereby reducing the generation of byproducts and ensuring the yield to be better.
Alternatively, the ammoniating agent is a dioxane solution of ammonia with a concentration of 3-5 mol/L.
By adopting the technical scheme, in the reaction route of the application, the dioxane solution of ammonia is preferably used as an ammoniation agent, so that the reaction yield reaches more than 68 percent, and can reach 80 percent at maximum, and the reaction yield is higher, thereby being suitable for industrialized mass production of aminothiophene compounds.
Alternatively, the-S group in formula (I) is in position 1, the-Br group is in position 3, 4 or 5.
By adopting the technical scheme, when the general formula (I) meeting the conditions is used as the raw material of the application, and the aminothiophene compound is prepared under milder reaction conditions, the yield is 68% at the minimum, and the requirement of industrial production is met.
Optionally, the-R2 group is in position 3, 4 or 5 and does not overlap with the-Br group.
Alternatively, the compound represented by the general formula (I) includes the following compounds:
Figure BDA0004025345080000031
/>
Figure BDA0004025345080000041
optionally, the catalyst is one of cuprous oxide, cuprous iodide and cuprous bromide.
Optionally, the stirring conditions are: stirring and reacting for 1-4h at 80-110 ℃.
In a second aspect, the present application provides an aminothiophene compound, which adopts the following technical scheme:
an aminothiophene compound prepared by the synthesis method of any one of the aminothiophene compounds.
By adopting the technical scheme, the yield is more than 68% under milder reaction conditions, the method can meet the requirement of industrialized production of the aminothiophene compound, the purity of the aminothiophene compound can reach more than 97%, the use value is high, and the aminothiophene compound can be prepared on a large scale.
In summary, the present application has the following beneficial effects:
1. according to the synthesis method, ammonia molecules are coordinated and complexed with a catalyst, and then are subjected to oxidation addition and reduction elimination with a compound represented by a general formula (I) to synthesize the aminothiophene compound, so that the reaction condition is mild and efficient, a target product is simple and easy to obtain, and the monotone large-scale synthesis of the aminothiophene compound is facilitated;
2. according to the method, the dioxane is adopted as a solvent, so that the thiophene compound is fully dissolved and fully reacts with ammonia water under the reaction condition of the method, the yield of the prepared aminothiophene compound is higher, and the industrial production requirement is met.
Detailed Description
The present application is described in further detail below with reference to examples.
Examples
Example 1
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000051
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000052
the specific steps of the synthesis reaction are as follows:
3.54g (16 mmol) of methyl 5-bromo-2-thiophenecarboxylate (formula I-1) are added to 40ml of dioxane, 0.713g (5 mmo 1) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 2 hours, wherein the rotating speed is 500r/min;
the preparation method of the dioxane solution of ammonia comprises the following steps: introducing ammonia gas into 100ml of dioxane solution, and reacting for 0.5h, wherein the flow rate of the ammonia gas is 1.8g/s, thus obtaining the catalyst.
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing a filter cake by 100ml of ethyl acetate to obtain filtrate;
collecting filtrate, standing for layering, extracting water phase with 50ml ethyl acetate twice, standing for layering, and combining organic phases to obtain ethyl acetate phase; adding 100ml of water into the ethyl acetate phase for washing to obtain a washed ethyl acetate phase;
drying the washed ethyl acetate phase by anhydrous sodium sulfate, and concentrating by a rotary evaporator to obtain a crude product of the aminothiophene compound;
adding 2.5g of the crude aminothiophene compound into 50ml of dichloromethane, adding 5g of 100-mesh silica gel, stirring and mixing, concentrating, and drying to obtain powdery crude product; subjecting the powdered crude product to 200 mesh silica gel column chromatography, eluting with petroleum ether/ethyl acetate mixed solvent at flow rate of 50mL/min to obtain 1.76g of methyl 5-amino-2-thiophenecarboxylate 1 H NMR(CDCl 3 400 MHz): delta 3.81 (3 h, s), 6.09 (1 h, d, j=3.9 Hz), 7.45 (1 h, d, j=3.9 Hz), in a yield of 70.0% and a purity of 97%.
Example 2
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000061
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000062
the specific steps of the synthesis reaction are as follows:
3.76g (16 mmoL) of ethyl 5-bromo-2-thiophenecarboxylate (formula I-2) are added to 40ml of dioxane, 0.713g (5 mmoL) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 2 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing filter cake by 100ml of ethyl acetate to obtain filtrate;
will be spentThe filtrate was subjected to extraction, washing, concentration, drying and purification in this order (the extraction, washing, concentration, drying and purification processes were the same as in example 1), to obtain 1.97g of ethyl 5-amino-2-thiophenecarboxylate [ 1 H NMR(CDCl 3 ，400MHz)：δ7.44(d，J＝4.OHz，1H)，6.08(d，J＝4.0Hz，1H)，4.32(s，2H)，4.27(q，J＝7.1Hz，2H)，1.33(t，J＝7.1Hz，3H)]The yield was 72.0% and the purity was 97%.
Example 3
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000071
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000072
the specific steps of the synthesis reaction are as follows:
3.28g (16 mmol) of 5-bromo-2-acetylthiophene (formula I-3) are added to 40ml of dioxane, 0.713g (5 mmo 1) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution with a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 2 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing a filter cake by 100ml of ethyl acetate to obtain filtrate;
the obtained filtrate was subjected to extraction, washing, concentration, drying and purification in this order (the processes of extraction, washing, concentration, drying and purification were the same as in example 1), to obtain 1.7g of 2-acetyl-5-aminothiophene [ 1 H NMR(CDCl 3 ，400MHz)：δ7.71(m，1H)，7.65-7.63(m，1H)，7.26(s，1H)，7.14
-7.12 (m, 1H), 2.58 (s, 3H) ], with a yield of 75.0% and a purity of 97%.
Example 4
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000081
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000082
the specific steps of the synthesis reaction are as follows:
3.28g (16 mmoL) of 2-acetyl-4-bromothiophene (formula I-4) was added to 40ml of dioxane, 0.713g (5 mmoL) of cuprous oxide as a catalyst and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L were added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 2 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing filter cake by 100ml of ethyl acetate to obtain filtrate;
the obtained filtrate was subjected to extraction, washing, concentration, drying and purification in this order (the processes of extraction, washing, concentration, drying and purification were the same as in example 1), to obtain 1.81g of 2-acetyl-4-aminothiophene [ 1 H NMR(CDCl 3 ，400MHz)：δ7.22(s，1H)，6.50(s，1H)，2.50(s，3H)]The yield was 80.0% and the purity was 97%.
Example 5
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000091
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000092
the specific steps of the synthesis reaction are as follows:
3.99g (16 mmoL) of ethyl 5-bromo-3-methyl-2-thiophenecarboxylate (formula I-5) are added to 40ml of dioxane, 0.713g (5 mmoL) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 2 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing filter cake by 100ml of ethyl acetate to obtain filtrate dissolved with the product;
the filtrate was sequentially subjected to extraction, washing, concentration, drying and purification (the processes of extraction, washing, concentration, drying and purification were the same as those of example 1) to obtain 2.19g of ethyl 5-amino-3-methyl-2-thiophenecarboxylate [ 1 H NMR(CDCl 3 ，400MHz)：δ5.95(s，1H)，4.25(q，J＝7.1Hz，2H)，2.41(s，3H)，1.32(t，J＝7.1Hz，3H)]The yield was 74.0% and the purity was 97%.
Example 6
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000101
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000102
the specific steps of the synthesis reaction are as follows:
3.54g (16 mmoL) of methyl 4-bromo-2-thiophenecarboxylate (formula I-6) are added to 40ml of dioxane, 0.713g (5 mmoL) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 2 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing filter cake by 100ml of ethyl acetate to obtain filtrate;
the obtained filtrate was sequentially subjected to extraction, washing, concentration, drying and purification (the processes of extraction, washing, concentration, drying and purification were the same as those of example 1) to obtain 1.96g of methyl 4-amino-2-thiophenecarboxylate [ 1 H NMR(CDCl 3 ，400MHz)：δ7.31(d，J＝1.6Hz，1H)，6.40(d，J＝1.6Hz，1H)，3.85(s，3H)，3.63(brs，2H)]The yield was 78.0% and the purity was 97%.
Example 7
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000103
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000111
the specific steps of the synthesis reaction are as follows:
3.54g (16 mmoL) of methyl 3-bromo-2-thiophenecarboxylate (formula I-7) are added to 40ml of dioxane, 0.713g (5 mmo 1) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 100 ℃, stirring and reacting for 1h, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing filter cake by 100ml of ethyl acetate to obtain filtrate dissolved with the product;
the obtained filtrate was subjected to extraction, washing, concentration, drying and purification in this order (the processes of extraction, washing, concentration, drying and purification were the same as in example 1), to obtain 1.76g of methyl 3-amino-2-thiophenecarboxylate [ 1 H NMR(CDCl 3 ，400MHz)：δ7.25(d，J＝8.0Hz，1H)，6.52(d，J＝8.0Hz，1H)，5.26
(m, 2H), 3.81 (s, 3H), the yield was 70.0% and the purity was 97%.
Example 8
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000112
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000113
the specific steps of the synthesis reaction are as follows:
3.76g (16 mmoL) of methyl 3-bromo-5-methyl-2-thiophenecarboxylate (formula I-8) are added to 40ml of dioxane, 0.713g (5 mmoL) of cuprous oxide are added as catalyst, and 100ml of ammonia solution of 0.4mol/L in dioxane are added dropwise. Under the protection of nitrogen, controlling the temperature to be 90 ℃, stirring and reacting for 3 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing a filter cake by 100ml of ethyl acetate to obtain filtrate;
the obtained filtrate was subjected to extraction, washing, concentration, drying and purification in this order (the extraction, washing, concentration, drying and purification process were the same as in example 1), to obtain 1.86g of methyl 3-amino-5-methyl-2-thiophenecarboxylate [ 1 HNMR(CDCl 3 ，400MHz)：δ6.25(s，1H)，5.30(bs，2H)，3.81(s，3H)，2.37(s，3H)]The yield was 68.0% and the purity was 97%.
Example 9
An aminothiophene compound with the structural formula:
Figure BDA0004025345080000121
the synthesis reaction equation of the aminothiophene compound is as follows:
Figure BDA0004025345080000122
the specific steps of the synthesis reaction are as follows:
4.21g (16 mmoL) of tert-butyl 5-bromo-2-thiophenecarboxylate (formula I-9) are added to 40ml of dioxane, 0.713g (5 mmoL) of cuprous oxide are added as catalyst, and 100ml of ammonia dioxane solution at a concentration of 0.4mol/L are added dropwise. Under the protection of nitrogen, controlling the temperature to be 80 ℃, stirring and reacting for 4 hours, wherein the rotating speed is 500r/min;
TLC monitoring (developing agent is mixed solution of petroleum ether and ethyl acetate according to the weight ratio of 2:1), adding 100ml of ethyl acetate for quenching reaction, adsorbing and filtering by 200-300 meshes of silica gel, and washing a filter cake by 100ml of ethyl acetate to obtain filtrate;
the obtained filtrate was subjected to extraction, washing, concentration, drying and purification in this order (the processes of extraction, washing, concentration, drying and purification were the same as in example 1), to obtain 2.39g of tert-butyl 5-amino-2-thiophenecarboxylate [ 1 H NMR]δ1.42 (9 h, s), 6.10 (1 h, d, j=3.9 Hz), 7.41 (1 h, d, j=3.9 Hz), yield 75.0% and purity 97%.
Comparative example 1
The aminothiophene compound is prepared from 2-thiophenecarboxylic acid serving as a raw material through nitration and nitroreduction reactions, and the synthetic reaction equation is as follows:
Figure BDA0004025345080000131
the specific steps of the synthesis reaction are as follows:
25.6g (200 mmol) of 2-thiophenecarboxylic acid are added to 30ml of acetic anhydride, the ice bath is cooled to-10℃and 48ml of fuming nitric acid and acetic anhydride are added dropwise under stirring in a weight ratio of 3:5, the dripping time is 3 hours, and the temperature is controlled not to be higher than 0 ℃ in the dripping process. Continuously stirring at-5-0deg.C for 10h, extracting with diethyl ether, washing the organic phase with distilled water for 3 times, washing with saturated sodium chloride water solution for 2 times, and drying to obtain 32.6g of mixture of 5-nitro-2-thiophenecarboxylic acid and 4-nitro-2-thiophenecarboxylic acid;
the mixture of 5-nitro-2-thiophenecarboxylic acid and 4-nitro-2-thiophenecarboxylic acid obtained above was mixed with 550ml of water, and barium hydroxide was added at 80℃to adjust the pH to 10, followed by cooling, precipitation and filtration to obtain a filtrate. While stirring, adding concentrated hydrochloric acid dropwise to adjust pH to 1, cooling, suction filtering, drying filter cake to obtain 6.6g of 5-nitro-2-thiophenecarboxylic acid 1 H NMR(CDCl)：δppm：7.82(d，1H，J＝4Hz，thiophene4-H)，7.93(d，1H，J＝4Hz，thiophene 3-H)，11.12(s，1H，C00H)]The yield was 19.3%;
2.9g (16.7 mmoL) of the 5-nitro-2-thiophenecarboxylic acid obtained above was added to 47ml of methanol under ice bath cooling, 10ml (36 mmoL) of thionyl chloride was added dropwise, the mixture was refluxed for 8 hours, and the solvent was evaporated to dryness to give 2.9g of methyl 5-nitrothiophene-2-carboxylate [ 1 H NMR(CDC1 3 )：δppm：3.98(s，3H，C00CH 3 )，7.71(d，1H，J＝4Hz，thiophene3-H)]；
Adding 15.3g (274.4 mmoL) of iron powder into 120 glacial acetic acid, stirring, adding 15.3g (274.4 mmoL) of the obtained 5-nitrothiophene-2-methyl formate, stirring at 50 ℃ for reaction for 5 hours, distilling under reduced pressure, adding 350ml of dichloromethane, filtering to obtain filtrate, extracting 3 times with 600ml of saturated sodium bicarbonate, washing 2 times with distilled water, washing 1 time with saturated sodium chloride, adding anhydrous sodium sulfate, drying and distilling to obtain a crude product, and passing the crude product through a flash column to obtain 5-aminothiophene-2-methyl formate [ 1 H NMR(CDCl 3 )：δppm：3.75(s，3H，C00CH 3 )，4.28(s，2H，NH 2 )，6.21(d，1H, J=4Hz, thiophene 4-H), 7.49 (d, 1H, J=4Hz, thiophene 3-H)]The yield thereof was found to be 71.8%.
Comparative example 2
An aminothiophene compound has the following synthetic reaction equation:
Figure BDA0004025345080000141
the specific steps of the synthesis reaction are as follows:
36.9g (179 mmoL) of 3-bromothiophene-2-boric acid and 125.3g (0.895 mole L) of ammonia water with the concentration of 25wt percent are taken as raw materials, 2.5g (18 mmoL) of cuprous oxide is taken as a catalyst, 200mL of methanol is taken as a solvent, and the mixture is stirred and reacted for 24 hours at the temperature of 25 ℃, filtered, concentrated and distilled under reduced pressure to obtain 22.7g of 3-bromothiophene-2-aminothiophene [ 1 H NMR(CDCl 3 ，400HMz)：6.72(d，1H)，6.34(d，1H)，4.82(bs，2H)]The yield was 71.2% and the purity was 98.5%.
Comparative example 3
An aminothiophene compound, which is different from comparative example 2 in that acetonitrile was used as a solvent instead of methanol in an equivalent amount, and was stirred at 25 ℃ for 36 hours to obtain;
the hydrogen spectrum data of the obtained 3-bromothiophene-2-aminothiophene was found to be identical to comparative example 2, and the yield was 64.5% and the purity was 98.0%.
Comparative example 4
An aminothiophene compound was different from example 1 in that tetrahydrofuran was used as a solvent instead of dioxane in an equivalent amount;
the hydrogen spectrum data of the obtained methyl 5-amino-2-thiophenecarboxylate were found to be identical to those of example 1, the mass was 754mg, the yield was 30% and the purity was 97%.
Comparative example 5
An aminothiophene compound was different from example 1 in that acetonitrile was used as a solvent instead of dioxane in an equivalent amount;
the hydrogen spectrum data of the obtained 5-amino-2-thiophenecarboxylic acid methyl ester were found to be the same as in example 1, and the mass was 1g, the yield was 40%, and the purity was 97%.
Example 10
An aminothiophene compound was different from example 1 in that the compound represented by the general formula (I-1), a dioxane solution of ammonia, a monovalent copper salt and dioxane were fed in a ratio of 16mmol:110 ml:7.5 mmol:45ml;
the hydrogen spectrum data of the obtained methyl 5-amino-2-thiophenecarboxylate were found to be identical to those of example 1, with a mass of 1.74g, a yield of 69.2% and a purity of 97%.
Example 11
An aminothiophene compound was different from example 1 in that the compound represented by the general formula (I-1), a dioxane solution of ammonia, a monovalent copper salt and dioxane were fed in a ratio of 16mmol:120 ml:10 mmol:50 ml;
the hydrogen spectrum data of the obtained methyl 5-amino-2-thiophenecarboxylate were found to be identical to those of example 1, with a mass of 1.71g, a yield of 68% and a purity of 97%.
Comparative example 6
An aminothiophene compound was different from example 1 in that the compound represented by the general formula (I-1), a dioxane solution of ammonia, a monovalent copper salt and dioxane were fed in a ratio of 16 mmol:90 ml:4.5 mmol:35 ml;
the hydrogen spectrum data of the obtained methyl 5-amino-2-thiophenecarboxylate were found to be identical to those of example 1, with a mass of 1.43g, a yield of 57% and a purity of 97%.
Comparative example 7
An aminothiophene compound was different from example 1 in that the compound represented by the general formula (I-1), a dioxane solution of ammonia, a monovalent copper salt and dioxane were fed in a ratio of 16mmol:125 ml: 11mmol:55ml;
the hydrogen spectrum data of the obtained 5-amino-2-thiophenecarboxylic acid methyl ester were found to be the same as in example 1, and the mass was 1.2g, the yield was 47.7%, and the purity was 97%.
Example 12
An aminothiophene compound was different from example 1 in that an equivalent amount of cuprous iodide was used instead of cuprous oxide as a catalyst;
the hydrogen spectrum data of the obtained methyl 5-amino-2-thiophenecarboxylate were found to be identical to those of example 1, with a mass of 1.70g, a yield of 67% and a purity of 97%.
Example 13
An aminothiophene compound was different from example 1 in that an equivalent amount of cuprous bromide was used instead of cuprous oxide as a catalyst;
the hydrogen spectrum data of the obtained 5-amino-2-thiophenecarboxylic acid methyl ester were found to be the same as in example 1, and the mass was 1.66g, the yield was 66% and the purity was 97%.
Comparative example 8
An aminothiophene compound was different from example 1 in that copper acetylacetonate was used as a catalyst in place of cuprous oxide in an equivalent amount;
the hydrogen spectrum data of the obtained methyl 5-amino-2-thiophenecarboxylate were found to be consistent with example 1, yield was 35% and purity was 97%.
The yields and purities of the products obtained in examples 1 to 13 and comparative examples 1 to 8 were examined, and the examination data are shown in Table 1:
TABLE 1 yields and purities of the target products in examples 1-13 and comparative examples 1-8
Figure BDA0004025345080000171
/>
Figure BDA0004025345080000181
The following analysis was performed on aminothiophene compounds synthesized using the synthetic method of the present application in combination with examples 1 to 13 and comparative examples 1 to 8, and the corresponding data in table 1.
In examples 1-9, the synthesis method is used, and the synthesis method of the ammonification molecular oxidation addition and reduction elimination is used for synthesizing the aminothiophene, so that compared with the synthesis method of nitration and nitroreduction, the synthesis method has mild reaction conditions, is simple and feasible, is convenient for industrialized large-scale preparation of the aminothiophene, and has wide application prospect.
In comparative example 1, the by-product 4-nitro-2-thiophenecarboxylic acid was produced by nitration due to the non-uniformity of the nitration site, but the yield in synthesizing 5-nitro-2-thiophenecarboxylic acid from 4-nitro-2-thiophenecarboxylic acid was extremely low, namely 19.3%, thus decreasing the yield of 5-aminothiophene-2-carboxylic acid methyl ester as the final product prepared from raw material 2-thiophenecarboxylic acid; the yield of the target product in the examples 1-9 reaches 68% or more, the highest yield can reach 80%, the purity is 97%, and the highest yield is superior to that of the comparative example 1, so that the synthesis method can prepare the aminothiophene compound with higher purity under milder reaction conditions, and the reaction yield can meet the requirement of industrial mass production.
Comparative example 2 differs from example 1 in that the solvent is different, the raw materials are different, the reaction time is 24 hours, and the industrial production efficiency is low; comparative example 3 is different from comparative example 2 in that acetonitrile is used as a solvent, which has a longer reaction time of up to 36 hours and lower industrial production efficiency, so that both methanol and acetonitrile are not suitable for industrial mass production when the solvent is used.
Whereas the reaction time of the present application required only 2 hours, the efficiency was significantly higher than that of comparative examples 2 and 3, and the yield in the process of the present application was mostly better than 71.2% in comparative example 2, 64.5% in comparative example 3. Therefore, the synthesis method has the advantages of extremely high efficiency, convenience for industrial production and better yield on the basis of mild reaction conditions, can be used for preparing the aminothiophene compounds on a large scale, and has wide application prospect.
Comparative example 4 differs from example 1 in that tetrahydrofuran was used as the solvent, the yield thereof was only 30%; comparative example 5 differs from example 1 in that acetonitrile was used as a solvent, and the yield thereof was only 40%;
and both comparative example 3 and comparative example 5 used acetonitrile as a solvent, but the yield of comparative example 3 (different from the reaction conditions of example 1) was higher than that of comparative example 5 (same as the reaction conditions of example 1). Therefore, under the reaction condition of the application, the yield of other solvents such as acetonitrile is lower, and dioxane is used, so that the yield of the synthesized product is improved from 40% to about 70%, the yield of the target product is greatly improved, and the industrial production requirement is met. The reason for this analysis may be that dioxane sufficiently dissolves aminothiophene compounds, and under the reaction conditions of the present application, it is sufficiently reacted with ammonia dioxane solution, reducing the formation of byproducts, and improving the yield.
Examples 10 and 11 and comparative examples 6 and 7 differ from example 1 in that the feed ratio of the compound represented by the general formula (I-1), ammonia dioxane solution, monovalent copper salt and dioxane differs, and the yields in examples 10 and 11 are 68% or more, whereas those in comparative examples 6 and 7 are only 47.7 to 57%, and the yields are low; it follows that when the feed ratio is at 16mmol: (100-120 ml): (5-10) mmol: in the range of (40-50) ml, the ratio of the compound represented by the general formula (I-1), ammonia dioxane solution, monovalent copper salt and dioxane is suitable, and the yield of the target product is high.
Examples 12, 13 and comparative example 8 differ from example 1 in the use of the catalyst, and in examples 1, 12 and 13, cuprous oxide, cuprous iodide and cuprous bromide were used as catalysts, respectively, to minimize the product yield to 66%, to provide a good catalytic effect and a small amount of by-products, and to enable industrial mass production, whereas in comparative example 8, copper acetylacetonate was used as catalyst, to provide a yield of only 35% and a low target product yield.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.

Claims (8)

1. A synthesis method of aminothiophene compounds is characterized in that a compound represented by a general formula (I) and an ammoniation agent are taken as raw materials, dioxane is taken as a solvent, and under the conditions of catalysis of a catalyst and nitrogen protection, stirring and filtering are carried out to obtain filtrate, and the obtained filtrate is sequentially extracted, washed, concentrated, dried and purified to obtain the aminothiophene compounds;
Figure FDA0004025345070000011
in the general formula (I):
R 1 selected from-CO 2 Me、-COMe、-CO 2 Me 3 or-CO 2 CH 2 Me；
R 2 Selected from-H, -Me;
wherein the feed ratio of the compound represented by the general formula (I), the ammoniating agent, the catalyst and the dioxane is 16mmol (100-120 ml) (5-10 mmol) (40-50 ml).
2. The method for synthesizing aminothiophene compound according to claim 1, wherein the ammoniating agent is a dioxane solution of ammonia with a concentration of 3-5 mol/L.
3. The method for synthesizing aminothiophene compounds as claimed in claim 1, wherein the-S group in the general formula (I) is located at the 1-position, the-Br group is located at the 3-position, the 4-position or the 5-position.
4. The method for synthesizing aminothiophene compound according to claim 3, wherein-R 2 The group is in position 3, 4 or 5 and does not overlap with the-Br group.
5. The method for synthesizing aminothiophene compounds as claimed in claim 4, wherein the compound represented by the general formula (i) comprises the following compounds:
Figure FDA0004025345070000012
/>
Figure FDA0004025345070000021
6. the method for synthesizing aminothiazole compounds according to claim 1, wherein the catalyst is one of cuprous oxide, cuprous iodide and cuprous bromide.
7. The method for synthesizing aminothiazole compound according to claim 1, wherein the stirring conditions are as follows: stirring and reacting for 1-4h at 80-110 ℃.
8. An aminothiophene compound, which is prepared by the synthesis method of the aminothiophene compound according to any one of claims 1 to 7.
CN202211703356.2A 2022-12-29 2022-12-29 Synthesis method of aminothiophene compound and aminothiophene compound Pending CN116023359A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211703356.2A CN116023359A (en) 2022-12-29 2022-12-29 Synthesis method of aminothiophene compound and aminothiophene compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211703356.2A CN116023359A (en) 2022-12-29 2022-12-29 Synthesis method of aminothiophene compound and aminothiophene compound

Publications (1)

Publication Number Publication Date
CN116023359A true CN116023359A (en) 2023-04-28

Family

ID=86078811

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211703356.2A Pending CN116023359A (en) 2022-12-29 2022-12-29 Synthesis method of aminothiophene compound and aminothiophene compound

Country Status (1)

Country Link
CN (1) CN116023359A (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1552709A (en) * 2003-06-04 2004-12-08 鲁南制药股份有限公司 Preparation of Leiliqusai
CN102146008A (en) * 2011-01-18 2011-08-10 陕西师范大学 Organic solvent-free synthesis method of aromatic amine compounds
CN105218560A (en) * 2015-11-04 2016-01-06 上海泰坦科技股份有限公司 The synthesis technique of 7-bromo-4-diuril phenol also [3,2-D] pyrimidine
CN107616976A (en) * 2017-09-11 2018-01-23 南京正大天晴制药有限公司 A kind of pharmaceutical composition of Raltitrexed and preparation method thereof
CN114436991A (en) * 2021-12-25 2022-05-06 上海泰坦科技股份有限公司 Synthetic method of 2-aminothiazole compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1552709A (en) * 2003-06-04 2004-12-08 鲁南制药股份有限公司 Preparation of Leiliqusai
CN102146008A (en) * 2011-01-18 2011-08-10 陕西师范大学 Organic solvent-free synthesis method of aromatic amine compounds
CN105218560A (en) * 2015-11-04 2016-01-06 上海泰坦科技股份有限公司 The synthesis technique of 7-bromo-4-diuril phenol also [3,2-D] pyrimidine
CN107616976A (en) * 2017-09-11 2018-01-23 南京正大天晴制药有限公司 A kind of pharmaceutical composition of Raltitrexed and preparation method thereof
CN114436991A (en) * 2021-12-25 2022-05-06 上海泰坦科技股份有限公司 Synthetic method of 2-aminothiazole compound

Similar Documents

Publication Publication Date Title
JP5202635B2 (en) Processes and intermediates for the preparation of integrase inhibitors
CN111592507A (en) Novel green and simple method for preparing polysubstituted furan
EA036663B1 (en) Method for preparing azoxystrobin
CN116023359A (en) Synthesis method of aminothiophene compound and aminothiophene compound
CN108689874B (en) Method for preparing 2-aryl malonamide and application thereof
CN113511986B (en) Preparation method of aryl acetonitrile derivative
CN104774183B (en) A kind of auspicious relax of formoxyl cuts down the preparation method of spit of fland calcium intermediate
CN111072450B (en) Synthesis method of allyl alcohol derivative
CN110028448B (en) Preparation method of 3-hydroxy-2,3-dihydroisoquinoline-1, 4-diketone compound
CN108929251B (en) Method for direct trifluoromethylation of C (sp3) -H
CN108558974B (en) Preparation and application of sugar-derived nickel pyridine triazole catalyst
CN108250008B (en) Chiral resolution method of 3,3,3',3' -tetramethyl-1, 1 '-spiroindane-6, 6' -diol derivative
CN113372281A (en) Synthetic method of metronidazole
JP2010513472A (en) Method for producing taxane derivative and intermediate used therefor
CN115304557B (en) Enamine derivative and preparation method thereof
CN109574866B (en) Preparation method of 2, 6-dimethylaniline long-chain compound
CN110746337B (en) Synthesis method of 1-methyl-2-cyano-3-aliphatic substituted azole compound
CN110746336B (en) Green preparation method of N-methyl-2-cyano-3-arylpyrrole compound
CN111320579B (en) Preparation method of 8-amide-5-halogenated quinoline derivative
CN113912526B (en) Preparation method of N-acetyl tellurium carbamic acid ester compound
CN107629039A (en) The preparation method and intermediate of deuterated acrylamide
KR100763770B1 (en) Process for preparing chiral intermediates useful in synthesis of atorvastatin
CN116082214A (en) 2-aryl-3-tert-butylindole compound, preparation method and application thereof
KR100502833B1 (en) Improved preparation method of simvastatin and their intermediates
KR100225534B1 (en) Stereospecific process for preparing (2r,3s)-beta--phenylisoserine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination