Process for preparation of substituted aminothiophenes

Abstract

The present invention relates to a process for preparing 4-alkoxycarbonyl-3-aminothiophenes of formula (I) or an acid addition salt thereof of formula (I) ', comprising reacting the corresponding 3-oxotetrahydrothiophene compound of formula (II) with an acid addition salt of a hydroxylamine in the presence of a polar protic acidic solvent and a dehydration agent.

Description

Technical field:

[0001] The present invention relates to a process for preparing substituted 4-alkoxycarbonyl-3-aminothiophenes of formula (I) or acid addition salts thereof of formula (I)', which are known as intermediates for agricultural active ingredients, in particular for preparing herbicidally active thiencarbazone-methyl compounds. Background technology:

[0002] 4-Alkoxycarbonyl-3-aminothiophene can be used as an intermediate for preparing pharmaceutical and / or agricultural chemical compounds.

[0003] Baker, BR, et al., J. Org. Chem., 18, 138-152 (1953) describe a two-step process for preparing 3-amino-4-methoxycarbonylthiophene hydrochloride from 3-oxo-4-methoxycarbonylthiophene. The procedure involves isolating 3-oximino-4-methoxycarbonylthiophene and reacting it with hydrogen chloride in the presence of ether and methanol. It also involves reacting 3-oxo-4-methoxycarbonylthiophene with hydroxylamine, which is generated in situ from hydroxylamine hydrochloride and barium carbonate. The disadvantage of this reaction is that it is a two-step process and both steps in the process require long reaction times.

[0004] GB 1,587,084 discloses the reaction of 3-oxathetrahydrothiophene with an acid addition salt of hydroxylamine to produce 4-alkoxycarbonyl-3-aminothiophene. The resulting oxime can then be subjected to acid treatment or spontaneously converted to the corresponding amine hydrochloride. The disadvantages of this reaction are the appearance of the decarboxylated amine as an undesirable by-product, challenging purification, and the need to use a significant excess of the hydroxylamine acid addition salt.

[0005] US 4,317,915 patent discloses the conversion of 3-oxathetrahydrothiophene to produce 4-alkoxycarbonyl-3-aminothiophene in the presence of hydroxylamine hydrohalide and inert organic solvent. In addition, the reaction is carried out with an excess of nitrogenous base. The disadvantage of this reaction is the use of an excess of nitrogenous base.

[0006] EP 0,298,542 discloses the conversion of 3-oxatetrahydrothiophene with hydroxylamine hydrochloride and acetonitrile to produce 4-alkoxycarbonyl-3-aminothiophene. However, the yields achievable in this process are not completely satisfactory and it uses an excess of hydroxylamine hydrochloride in the reaction.

[0007] The methods described in the prior art have drawbacks such as long reaction times which make the method uneconomical; use of excess reagents which makes the method less efficient; use of expensive solvents which are difficult to recover. Therefore, there remains a need for a method which eliminates the drawbacks associated with the known methods.

[0008] Therefore, it is desirable to develop an effective method for preparing 4-alkoxycarbonyl-3-aminothiophene having formula (I) or its acid addition salt having formula (I)', which has higher yield and efficiency. Summary of the invention:

[0009] The present invention provides a method for preparing the following: 4-alkoxycarbonyl-3-aminothiophene having formula (I)

[0010]

[0011] or a hydrochloride having formula (I)'

[0012]

[0013] Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl;

[0014] The method comprises reacting the following in the presence of a polar protic solvent and a dehydrating agent: a compound having formula (II)

[0015]

[0016] Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl;

[0017] Acid addition salts with hydroxylamine, wherein the reaction is in the absence of a base.

[0018] In one aspect, the present invention provides compounds having formula (I) and formula (I)' wherein R 1 and R 2 , R 1 It is C 1 -C 4 -alkoxy, and R 2 is selected from the group consisting of methyl, ethyl, propyl or isopropyl, preferably R 1 is a methoxy group, and R 2 It's methyl.

[0019] In another aspect, the present invention provides compounds having formula (II) wherein R 1 and R 2 , R 1It is C 1 -C 4 -alkoxy, and R 2 is selected from the group consisting of methyl, ethyl, propyl or isopropyl, preferably R 1 is a methoxy group, and R 2 It's methyl.

[0020] In yet another aspect, the present invention provides an acid addition salt of hydroxylamine selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate or nitrate, preferably hydroxylamine hydrochloride.

[0021] In another aspect, the present invention provides that the acid addition salt of hydroxylamine is used in an amount of 1 to 1.5 equivalents.

[0022] In one aspect, the present invention provides that the polar protic solvent is C 1 -C 4 Carboxylic acid, preferably acetic acid.

[0023] In another aspect, the present invention provides that the dehydrating agent is C 1 -C 4 Carboxylic anhydride, preferably acetic anhydride.

[0024] In yet another aspect, the present invention provides that the dehydrating agent is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 0.5 equivalents.

[0025] In another aspect, the present invention provides that the reaction is carried out at a temperature ranging from 60°C to 100°C, preferably from 80°C to 85°C.

[0026] In another aspect, the present invention provides a method for preparing thiocarbamide comprising preparing a compound having formula (I) and / or formula (I)' and further converting to thiocarbamide having formula (X).

[0027]

[0028] In a preferred aspect, the present invention provides a method for preparing 2-methyl-4-methoxycarbonyl-3-aminothiophene or 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride, which comprises reacting 2-methyl-4-methoxycarbonyl-3-oxotetrahydrothiophene with hydroxylamine hydrochloride in the presence of acetic acid and acetic anhydride. Specific implementation method:

[0029] For the sake of clarity, specific terms are used in describing embodiments of the present invention. However, it is not intended to limit the present invention to the specific terms selected, and it should be understood that each specific term includes all technical equivalents that operate in a similar manner to achieve a similar purpose.

[0030] It should be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. Unless the context clearly dictates otherwise, as used in this specification, the singular forms "a / an" and "the" include plural referents. Thus, for example, reference to "a compound" includes one or more such compounds.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although other methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, preferred materials and methods are described herein.

[0032] As used herein, the term "or" has both the meanings of "and" and "or". It will be further understood that the terms "comprises / comprising", "includes / including", or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition or method that includes a list of elements is not necessarily limited to only those elements, but may include other elements not expressly listed or inherent to such composition or method.

[0033] Throughout this application, descriptions of various embodiments use the term “comprising.” However, those skilled in the art will appreciate that, in some specific cases, the language “consisting essentially of” or “consisting of” may alternatively be used to describe the embodiments.

[0034] Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0035] Furthermore, the endpoints of all ranges referred to herein as the same component or property are inclusive of the endpoint, are independently combinable, and include all intermediate points and ranges.

[0036] The term "equivalent" refers to the amount of one substance that reacts with any amount (usually one mole) of another substance in a particular chemical reaction.

[0037] As used herein, the term "alkyl" refers to a straight or branched chain, saturated alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like.

[0038] As used herein, the term "alkoxy" refers to a saturated straight or branched chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and the like.

[0039] As used herein, the term "carboxylic acid" refers to a saturated straight or branched chain carboxylic acid group having 1 to 4 carbon atoms, such as formic acid, acetic acid, and the like.

[0040] As used herein, the term "carboxylic acid anhydride" refers to a saturated straight or branched chain carboxylic acid anhydride group having 1 to 4 carbon atoms, such as acetic anhydride, propionic anhydride, and the like.

[0041] As used herein, the term "dehydrating agent" refers to an agent that disconnects water molecules from a reactant and prevents side reactions. 1 -C 4 Carboxylic anhydrides, such as acetic anhydride, propionic anhydride, etc.

[0042] 4-Alkoxycarbonyl-3-aminothiophene can be used as an intermediate for preparing pharmaceutical and / or agricultural chemical compounds. For example, it is used as an intermediate for preparing herbicidal thiocarbazone sulfone compounds. US 4,428,963 patent discloses the use of certain 3-aminothiophenes in the preparation of thiophene derivatives, which can be used as lipid-lowering agents and weight-loss agents.

[0043] The present invention provides a method for preparing the following: 4-alkoxycarbonyl-3-aminothiophene having formula (I)

[0044]

[0045] or a hydrochloride having formula (I)'

[0046]

[0047] Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl;

[0048] The method comprises reacting the following in the presence of a polar protic solvent and a dehydrating agent: a compound having formula (II)

[0049]

[0050] Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl;

[0051] Acid addition salts with hydroxylamine, wherein the reaction is in the absence of a base.

[0052] In one embodiment, the present invention provides that in the compounds of formula (I) and formula (I)', R 1 and R 2 , R 1 It is C 1 -C 4 -alkoxy, and R 2 is selected from the group consisting of methyl, ethyl, propyl or isopropyl, preferably R 1 is a methoxy group, and R 2 It's methyl.

[0053] In another embodiment, the present invention provides that in the compound having formula (II) R 1 and R 2 , R 1 It is C 1 -C 4 -alkoxy, and R 2 is selected from the group consisting of methyl, ethyl, propyl or isopropyl, preferably R 1 is a methoxy group, and R 2 It's methyl.

[0054] The aforementioned reaction is carried out using an acid addition salt of hydroxylamine in the presence of a polar protic solvent and a dehydrating agent.

[0055] The acid addition salt of hydroxylamine is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate or nitrate, preferably hydroxylamine hydrochloride. The polar protic solvent is C 1 -C 4 Carboxylic acid, such as formic acid, acetic acid, etc., preferably acetic acid. The dehydrating agent is C 1 -C 4 Carboxylic anhydride, such as acetic anhydride, propionic anhydride, etc., preferably acetic anhydride.

[0056] In one embodiment, the present method provides that the acid addition salt of hydroxylamine is used in an amount of 1 to 1.5 equivalents. In another embodiment, the acid addition salt of hydroxylamine is used in an amount of 1 to 1.4 equivalents. In yet another embodiment, the acid addition salt of hydroxylamine is used in an amount of 1.1 to 1.4 equivalents. In a preferred embodiment, the acid addition salt of hydroxylamine is used in an amount of 1.2 equivalents.

[0057] In one embodiment, the present invention makes the process more efficient and has the ability to reduce the excess hydroxylamine hydrochloride to zero.

[0058] In one embodiment, the method of the present invention provides a molar ratio between the acid addition salt of hydroxylamine and the compound of formula (I) or formula (I') of about 1:1 to 1.5:1. In another embodiment, the molar ratio between the acid addition salt of hydroxylamine and the compound of formula (I) or formula (I') is about 1.1:1 to 1.5:1. In yet another embodiment, the molar ratio between the acid addition salt of hydroxylamine and the compound of formula (I) is about 1.1:1 to 1.4:1. In a preferred embodiment, the molar ratio between the acid addition salt of hydroxylamine and the compound of formula (I) or formula (I') is about 1.2:1.

[0059] In another embodiment, the method of the present invention provides that the dehydrating agent is used in an amount of 0.1 to 10 equivalents. In another embodiment, the dehydrating agent is used in an amount of 0.2 to 8 equivalents. In another embodiment, the dehydrating agent is used in an amount of 0.2 to 5 equivalents. In yet another embodiment, the dehydrating agent is used in an amount of 0.2 to 3 equivalents. In another embodiment, the dehydrating agent is used in an amount of 0.2 to 1 equivalent. In a preferred embodiment, the dehydrating agent is used in an amount of 0.2 to 0.5 equivalents.

[0060] In one embodiment, the reaction of forming a compound of formula (I) from a compound of formula (II) is carried out at a temperature of about 60° C. to about 100° C., preferably about 65° C. to about 95° C., more preferably about 70° C. to about 90° C. In a preferred embodiment, the reaction is carried out at a temperature ranging from about 75° C. to about 85° C.

[0061] In preferred embodiments, the reaction is carried out at a temperature ranging from about 80°C to about 85°C.

[0062] The method according to the present invention is usually carried out at atmospheric pressure. However, it is also possible to carry out the method according to the present invention under an increased or reduced pressure. In one embodiment, the method for preparing a 4-alkoxycarbonyl-3-aminothiophene with formula (I) or its acid addition salt with formula (I) 'can be carried out at a pressure of about 1 bar to about 10 bars. In another embodiment, the method can be carried out at a pressure of about 1 bar to about 5 bars. In another embodiment, the method for preparing a 4-alkoxycarbonyl-3-aminothiophene with formula (I) or its acid addition salt with formula (I) 'can be carried out at atmospheric pressure. In another embodiment, the method can be carried out at about 10 bars. In certain embodiments, it may be preferred that the method is carried out at a pressure less than atmospheric pressure. For example, the method can be carried out at 0.7 bar, 0.75 bar, 0.8 bar, 0.9 bar or 0.95 bar.

[0063] In another embodiment, the present invention provides that the resulting compound of formula (I) or formula (I') is present in a purity of at least 60%, at least 80%, at least 85%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0064] In yet another embodiment, the present invention provides a compound having formula (I) or formula (I')' for use in preparing a thiathionsulfuron compound.

[0065] In a preferred embodiment, the present invention provides a method for preparing 2-methyl-4-methoxycarbonyl-3-aminothiophene or 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride, which comprises reacting 2-methyl-4-methoxycarbonyl-3-oxotetrahydrothiophene with hydroxylamine hydrochloride in the presence of acetic acid and acetic anhydride.

[0066]

[0067] The method of the present invention is advantageous because it is highly efficient, provides shorter reaction times and less effluent. The resulting compound of formula (II) is then reacted with an acid addition salt of hydroxylamine in the presence of acetic acid and acetic anhydride as a dehydrating agent, which removes water at each equilibrium step. The reduction in water concentration in the reaction mass not only shifts the equilibrium but also prevents side reactions. It also provides high conversion and selectivity and higher final product yields.

[0068] One-pot method for preparing 4-alkoxycarbonyl-3-aminothiophene having formula (I)

[0069]

[0070] or a hydrochloride having formula (I)

[0071]

[0072] Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl;

[0073] The method comprises reacting the following in the presence of a polar protic solvent and a dehydrating agent: a compound having formula (II)

[0074]

[0075] Where R1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl;

[0076] With hydroxylamine acid addition salt, wherein the reaction is in the absence of base. In a preferred embodiment, R 1 is a methoxy group, and R 2 is methyl. In another embodiment, the acid addition salt of hydroxylamine is hydroxylamine hydrochloride. In another embodiment, the polar protic solvent is acetic acid, and the dehydrating agent is acetic anhydride. The one-pot process of the present invention reduces production costs, simplifies post-processing, and minimizes any effluent disposal issues.

[0077] According to embodiments, the resulting product comprises a compound of formula (I) or formula (I') having a purity of at least 60%, at least 80%, at least 85%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0078] The progress of the synthesis reaction of (I) / (I)' can be monitored using any suitable method, which may include, for example, chromatographic methods, such as, for example, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), etc. In yet another embodiment, the compound of formula (I) or formula (I') can be separated from the reaction mixture by any conventional technique well known in the art. Such separation techniques may be selected from, but not limited to, the group consisting of: extraction, crystallization, or precipitation by concentration, cooling or anti-solvent addition; filtration; centrifugation, and combinations thereof, followed by drying.

[0079] In yet another embodiment, the compound of formula (I) or formula (I') can be optionally purified by any conventional technique well known in the art. Such purification techniques can be selected from, but not limited to, the group consisting of: precipitation, crystallization, extraction, slurrying, washing in a suitable solvent, filtering through a packed bed column, dissolving in an appropriate solvent, reprecipitating by adding a second solvent in which the compound is insoluble, and combinations thereof.

[0080] In another embodiment, the present invention provides a method for preparing thiocarbamide having formula (X), which comprises preparing the above-mentioned compound having formula (I) or formula (I)' and further converting it into thiocarbamide having formula (X). The compound having formula (I) or formula (I)' can be converted into formula (X) as described in the art, for example, in PCT application number WO 2001 / 005788.

[0081]

[0082] The following examples illustrate the practice of the present invention in some embodiments thereof but should not be construed as limiting the scope of the present invention. Other embodiments will be apparent to those skilled in the art from consideration of the specification and examples. It is contemplated that the specification (including examples) is considered to be exemplary only, and does not limit the scope and spirit of the present invention.

[0083] An exemplary experimental procedure for the production of 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride is described below:

[0084] Example 1:

[0085] Acetic acid (834g) and hydroxylamine hydrochloride (135.5g, 1.95mol, 1.02 equivalents) are placed in a four-necked flask. The reaction mixture is heated to 80°C to 85°C. During 1h, a mixture of acetic anhydride (93.8g, 0.92mol, 0.48 equivalents) and 2-methyl-4-methoxycarbonyl-3-oxo-tetrahydrothiophene (333.8g, 1.92mol, 1 equivalent) is added dropwise at 80°C to 85°C. The reaction mixture is kept at 80°C to 85°C for 2h and the reaction progress is monitored by HPLC. The reaction mixture is cooled to 5°C to 10°C and kept for 1.5h. The suspension is filtered, and the product is dried in a vacuum to obtain 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride. The yield of 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride is 83%.

[0086] Example 2:

[0087] Acetic acid (980g) and hydroxylamine hydrochloride (160.1g, 2.30mol, 1.2 equivalents) are placed in a four-necked flask. The reaction mixture is heated to 80°C to 85°C. During 1h, a mixture of acetic anhydride (195.8g, 1.92mol, 1 equivalent) and 2-methyl-4-methoxycarbonyl-3-oxo-tetrahydrothiophene (333.8g, 1.92mol, 1 equivalent) is added dropwise at 80°C to 85°C. The reaction mixture is kept at 80°C to 85°C for 4h and the reaction progress is monitored by HPLC. The reaction mixture is cooled to 5°C to 10°C and kept for 1.5h. The suspension is filtered, and the product is dried in a vacuum to obtain 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride. The yield of 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride is 84%.

[0088] Comparative example:

[0089] Acetic acid (834g) and hydroxylamine hydrochloride (126.8g, 1.82mol, 0.95 equivalent) are placed in a four-necked flask. The reaction mixture is heated to 80°C to 85°C. During 1h, a mixture of acetic anhydride (93.8g, 092mol, 0.48 equivalent) and 2-methyl-4-methoxycarbonyl-3-oxo-tetrahydrothiophene (333.8g, 1.92mol, 1 equivalent) is added dropwise at 80°C to 85°C. The reaction mixture is kept at 80°C to 85°C for 3h and the reaction progress is monitored by HPLC. The reaction mixture is cooled to 5°C to 10°C and kept for 1.5h. The suspension is filtered, and the product is dried in a vacuum to obtain 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride. The yield of 2-methyl-4-methoxycarbonyl-3-aminothiophene hydrochloride is 76%.

Claims

1. A method for preparing a 4-alkoxycarbonyl-3-aminothiophene having formula (I) or a hydrochloride having formula (I)' Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl; The method comprises reacting the following in the presence of a polar protic solvent and a dehydrating agent: a compound having formula (II) Where R 1 It is C 1 -C 4 -alkoxy, and R 2 It is C 1 -C 4 alkyl; Acid addition salts with hydroxylamine, wherein the reaction is in the absence of a base.

2. The method according to claim 1, in, The compounds of formula (I) and formula (I)', wherein R 1 is methoxy, ethoxy, propoxy or butoxy; R 2 Selected from the group consisting of methyl, ethyl, propyl or isopropyl.

3. The method according to claim 2, in, The compounds of formula (I) and formula (I)', wherein R 1 is a methoxy group, and R 2 It's methyl.

4. The method according to claim 1, in, The compound having formula (II), wherein R 1 is methoxy, ethoxy, propoxy or butoxy; R 2 Selected from the group consisting of methyl, ethyl, propyl or isopropyl.

5. The method according to claim 4, in, The compound of formula (II), wherein R 1 is a methoxy group, and R 2 It's methyl.

6. The method according to claim 1, in, The acid addition salt of hydroxylamine is used in an amount of 1 to 1.5 equivalents.

7. The method according to claim 1, in, The acid addition salt of hydroxylamine is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate or nitrate.

8. The method according to claim 1, in, The polar protic solvent is C 1 -C 4 carboxylic acid.

9. The method according to claim 8, in, C 1 -C 4 The carboxylic acid is acetic acid.

10. The method according to claim 1, in, The dehydrating agent is C 1 -C 4 Carboxylic anhydride.

11. The method according to claim 10, in, The C 1 -C 4 The carboxylic anhydride is acetic anhydride.

12. The method of claim 1, in, The dehydrating agent is used in an amount of 0.1 to 10 equivalents.

13. The method according to claim 12, in, The dehydrating agent is used in an amount of 0.2 to 0.5 equivalents.

14. The method of claim 1, in, The reaction is carried out at a temperature of 60°C to 100°C.

15. The method of claim 14, in, The reaction is carried out at a temperature of 80°C to 85°C.

16. The method of claim 1, in, The compound having formula (II) is reacted with hydroxylamine hydrochloride in the presence of acetic acid and acetic anhydride.

17. The method of claim 1, in, The compound of formula (I) is further converted into thiathionsulfuron-methyl of formula (X).

18. A method for preparing a thiocarbamide compound, the method comprising preparing a compound having formula (I) as claimed in claim 1 and further converting it into a thiocarbamide having formula (X).

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