TW434208B - Processes for the preparing of substituted 3-aminobenzonitriles and benzothiadiazole-7-carboxylic acid - Google Patents

Abstract

The invention relates to a process for the preparation of substituted 3-aminobenzonitriles of the formula I in which: R is hydrogen or C1-C12 alkyl, C3-C8 cycloalkyl, COR1, C1-C8 alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C8 aminoalkyl, C1-C8 alkyl-NH(C1-C4 alkyl), C1-C8 alkyl-N(C1-C4 alkyl)2 or substituted or unsubstituted benzyl; and R1 is C1-C8 alkyl, C3-C8 cycloalkyl or phenyl; and which comprises reacting a substituted 3-aminochlorobenzene of the formula II with a cyano-donating reagent Compounds of the formula I are important intermediates in the preparation of benzothiadiazole-7-carboxylic acid, which is obtained by diazotizing and hydrolysing the compounds of the formula I in any desired sequence.

Description

434208

A7 B7 V. Description of the invention (/) The present invention relates to a method for preparing a substituted 3-amino group of formula I

Where: R is hydrogen or (^ 1-(: 12alkyl · C3-C8cycloalkyl, C01, Ct-Csalkoxyalkyl1 Ci-Cshydroxyalkyl, Ci-C8aminoalkyl, ct-1 C8 alkyl-NH (Ci-C4 alkyl), (Ct-C8 alkyl_N (Ci-C4 alkyl) 2 'substituted or unsubstituted benzyl; and Ci-C8 alkyl , C3-C8 cycloalkyl or phenyl; it includes substituted 3-aminobenzene of formula II in a solvent above 30¾

II where R is as defined in Formula I and reacts with a cyano-supply test selected from K a) CuCN or cyano-potassium (II) (= K4 [Fe (CN) 6]) or Calcium cyanoferrate (11) (= Ca2 C Fe (CN) 6]), in the presence of the compounding agent; or -4- This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) I ~ Pack; Order '^ (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs 4342〇 &

V. Description of the invention (i) b) Any Cu (I) salt and Sickle gold tincture cyanide in the presence of complex ffl; or (Please read the notes on opening & then fill out this page) C) Alkali gold Use cyanide, HCN, Ni (CN) 2 or tetramethyl silane alkyl gas, or 嗣 HCN adduct or aldehyde HCN adduct, in the catalyst [C〇 + (CS) 4] 3-, or Pd . _u or prefer [一 辣 觞 MEDIA] Ni. In the presence of a Ln or a three-way mixture consisting of NiL2Hal2, a barbed LM, and a priming agent, M is a sickle contact, L is a ligand, and n is 2 to 4. The general proper nouns used above and under K * unless otherwise defined * have the following meanings: alkyl groups are linear or branched, depending on the number of carbon atoms, and are, for example, methyl, ethyl , N-propyl, isopropyl, η-butyl, sec-butyl, isobutyl, tert-butyl, sec-pentyl * tert-pentyl, 1-hexyl or 3-hexyl. Printed by the Central Laboratories of the Ministry of Economic Affairs and Consumer Cooperatives. Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl based on the size of the ring. The ligand is a phosphine group, where Q is C, -C8 alkyl, C3-C3 cycloalkane i • Unsubstituted aryl or Ci_C8 alkyl substituted aryl, Ci-C * hydroxyalkyl, Ci — C6 alkoxy, bis (Ci -C4 alkyl) amine (Ci mouth) This paper size is applicable to national standard CMS (CMS) A4 specification (210 × 297 mm) 4342 08 Ministry of Economic Affairs _ Central Standards Bureau employee consumption Cooperative printed A7 B7 V. Description of the invention (>) Alkyl, fluorine, S03, or N (Ci-C4 alkyl) 2; or the ligand is Q2 P- W- PQ2, where W is C 1 -Ca alkyl or unsubstituted ferrocenyl or ferrocenyl substituted with any of the free radicals mentioned in " aryl #. Preferred ferrocene ligands are unsubstituted ferrocene and substituted asymmetric species, such as 1-hydroxyethylferrocene and 1-dimethylaminoethyldiocene Alas. Preferred catalysts are those having the formula Ni ° -Ln, where L is triphenylphosphine and η is 2 to 4 * or having the formula Ni. One L2 • Among them, L is (1, bis-diphenylphosphine-L- (dimethylaminoethyl) diocene). Compounds of formula I are compounds of formula III and their acid derivatives * which have been exposed as plant immunizing agents and plant regulators (refer to EP-B-313 512), important intermediates in the preparation.

COOH

A method according to the present invention comprises reacting a substituted 3-limylazepine of formula II with a monocyanide to obtain a compound of formula I according to the present invention. a) and b) [For example CuCN / pyridine or 3-methylpyridine / 2 0 0 1C] This paper uses the Chinese National Standard (CNS) A4 specification (210X 297 mm): (^---^. ( (Please read the notes on the back before filling out this page) 4342C & A7 Β V / IV Instructions issued

S 2 Η (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs

c) [For example Ni (PPh3) 4 / KCN / 100t Ί The nitrogen group on the aromatic compound is passed through CuCN or M 合 metal cyanide • such as high cyano; potassium (II) iodate (= K4 C Fe (C8) 6)) or fluoro-based homophosphate (II) (= Ca2 [Fe (CN) 6]) Μ [The effect of substitution from S element plus W in the presence of pyridine is known (w Rosenaund-von Braun synthesis *; for example, Houben- Weyl * Methoden der organischen Chemie C Methods of Organic Cheaistry], V o1 VIII, p · 302-3; V o 1 · E5, p. 1463-5, 1985). It is also known that aromatic halogenated halides can be substituted with cyano groups and K through cyano-supplying compounds, such as _ (gold cyanide, HCN · Si (CN) 2 or tetramethylsilyl cyanide * Or CNHCN adducts or aldehydes HCN The paper scale is applicable to China National Standards (CNS) A4 specifications (210 × 297 mm) 434208 Printed by the Consumers ’Cooperative of the China Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention (<) Adducts in the presence of Co, Pd or Ni catalysts (eg * Homogeneous Catalysis 11Λ Adv · CheB · Ser * 132 ACS 1 97 4 p · 2 5 2; Coll · Czechoslovak (Cheam *

ConiDun * Vo I · 48 (1 9 8 3) p · 1 7 6 5) 〇 The conversion of acetochloroanilines with special 1,2,3 arrangements to the desired nitriles is novel. This amazing aspect is that the reaction proceeds with good selectivity and high yields without substantial cleavage of carbon-sulfur bonds. What's more, this reaction has not been expected to work well in a system rich in tritium (the sulfur and amine groups on the benzene ring are both electron-donating substituents). What is even more surprising is that even large groups * such as tert-butylsulfide · isopropylsulfide M and cyclohexylsulfide * are located adjacent to the reaction center and do not hinder the reaction to a considerable degree. Reactions a) and b) are performed in the presence of a complexing agent. This coupler on the one hand causes an increase in the Cl / CN replacement reaction, and on the other hand, suppresses the cleavage of S-R—. The compounding agent is a nitrogen-containing compound, such as pyridine, quinoline or isoquinoline, which is unsubstituted or via a Ci-C4 alkyl group, a Ci_C4 alkane group, an amine group, and a Ci-C4 alkane. Amino group or (Ci-C4 alkyl) 2 amino group is substituted by single to three times. Particularly suitable as a compounding agent is -8 This paper has been repeatedly used in China National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling this page) —Packing --- 434206 A7 B7 5 2. Description of the invention (G) atpyridine, which is unsubstituted or substituted by methyl or quinoline in a single or triple manner; very particular are pyridine M and 3-methylpyridine. In a specific specific fact, the following is used to perform reaction a) and the like (based on II) of the amount of CuCN or potassium cyanophosphate (ΙΠ (-[Fe (CN) 6]) or cyanochlorine Calcium (II) acid (= Ca2 [Fe (CN) 6]), in pyridine, methylpyridine, dimethylpyridine, trimethylpyridine, quinoline, dimethylaniline. Ethyl film, DMSO * benzonitrile , In the presence of DMF or tetramethylurea; or b) any Cu (I) salt with at least equal moles or more (based on hi) of sickle gold cyanide Methylpyridine, trimethylpyridine, quinoline, dimethylaniline, acetonitrile > in the presence of DMSO, benzonitrile, DMF or tetramethylurea; or c) at least equal to the mole (based on II) amount Metal cyanide, HCN, Ni (CN) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) 2 or tetramethylsilyl cyanide, or ketone HCN adduct Or aldehyde HCN adduct, in catalyst M3 [Co + (CN) 4] 3- * S Pd ° -Ln or, preferably, Ni °-Ln, or fjiL2Hal2, the excess of L and a rhenium agent Three-way mixture exists Next, Μ as sickle metal, L is a ligand of the seat and η 2-4. Easy-to-use solvents are polar solvents that are inert to protons, such as dioxolan, dimethylformamide, dimethylacetamide, ff-methylpyrrolidine®, dimethyl ®, acetonitrile, benzonitrile, tetramethylurea, hexamethylphosphonium triamine. In a preferred specific fact, at least wait for Moore ’s best 1-* &v; v -9- This paper wave scale is applicable to China National Standard (CNS) A4 specification (210X297 mm) 434208 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative A7 B7 V. Description of the invention (1) The mixture is based on Cu or Fe and is directly used as a solvent; pyridine and 3 ~ methylpyridine are particularly fake, and 3-methylpyridine is a non-preferred one. , Because of its high boiling point allows the method to be carried out at atmospheric pressure, even at high temperatures. The response is to pickle between 50 and 35QTC, with a preference between 150 and 25QX :. Usually the response is performed at atmospheric pressure or a slightly elevated scraping force (20 bar), with preference for atmospheric pressures up to 10 bar. After a reaction time of about 3 to 18 hours, the yield of the compound of formula I is as high as 75% of the theoretical value, and the reaction rate is 80%. This is equivalent to more than 90% of the yield based on the reactive vitamins. Reaction a) Accompanying the use of CuCN is preferred. The reaction is completed by, for example, the following: tfa2 S or NaCN · If desired, it is added to the reaction mixture in the form of an aqueous solution * and then the mixture is diluted with a solvent such as ethyl acetate or methyl ethyl copper ( MEK) M makes filtration easier, the salts are separated by encounters | peroxide is volatilized * and the residue is purified by distillation or crystallization. When (JaCiJ) is used, CuCN can be directly used to obtain reusable CuCN. In reaction C) * M gas is used to replace cyano group in the presence of rhenium. -1 0- This paper size applies Chinese National Standard (CNS) Α4 size (2 丨 〇 × 297mm) (Please read the precautions on the back before filling in this purchase) Packing 434208 A7 B7 V. Description of the invention (Service) This reaction can be performed in nitriles (acetone, benzoate), hydrocarbides, especially aromatic. • In addition, ketones * alcohol (acetic acid), water, 醢Performed in amines (dimethylformamide = DMF), ethers or mixtures of these | Preference in DMF. The reaction temperature is between 30 and 150TC, with a preference of 40 to 100 t :. This catalytic reaction can be modified by the appropriate regeneration of the catalyst during the reaction. This regeneration can be achieved either chemically by the mold or by the addition of Kantar. In this change the yield can even be less than 90% * and the crude mixture can be further reacted directly to obtain benzodiazol-7-carboxylic acid III without isolating the intermediates. The catalysts are prepared by adding M with known methods, such as EP-3 8 4 3 9 2, 〃 Hom gege ou s C ata 1 ysis 11 n Adv · Cheai · Ser * 132 ACS 1 9 7 4 b · 2 5 2; J ·

Organomet Che®. 1 7 3 (1 9 7 9) p * 3 3 5 »J *

Organomet-Chea · 243 (1 9 8 3) p * 95; Coll ·

Czechos loval Chenn > Cosaun * Vo 1 · 48 (1 9 8 3) p · 1765. The preferred triphenylphosphine nickels are prepared from hydrated nickel nickel, triphenylphosphine K, and a phosphonium agent. The suitable agents used are gold tinctures, such as Mϋ · Zη * Mg or A1 in the form of shavings or powder; hydrides, such as shed sodium hydride, lithium aluminum hydride or sodium hydride, or other rhenium chemical methods. The vehicle can be added to the reaction mixture, but it is preferred to prepare it in situ. A further advantage of methods a, b or c is that, after further reaction to produce a benzothiadiazole-7-carboxylic acid of formula III, the non-reflected androgen II is converted to the relative 7-benzophenazine Azoles. The atmospheric benzo-11- This paper is suitable for national standards (CMS) A4 specifications (210X297 mm) of different countries ----: ------------------------ Order,- ------ ^ (Please read the notes on the back before filling this page) 434208

V. Description of the invention () The oxadiazoles can be easily removed from the warm compounds by a simple phase separation method (water / organic solvent) using a compound of formula 111. The present invention is also compatible with the use of a compound of formula I for obtaining a compound of formula I I I. Therefore, these compounds can be prepared from 2,3-dichloronitrobenzene (which is a known compound), such as the following chemical formula 1, plus M: (Please read the notes on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Bureau Employee Consumer Cooperative Prints Chemical Equation 1

-12-

III This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 434208 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, Type IV 2-3 Dinitronitrobenzene and compound HS — R · Where R is as defined above, and the reaction under sickle conditions produces a radical R_S in the 2-position which is specifically replaced by an aromatic atom K to obtain a compound of formula V; nitro-refining becomes amine hydrazone production formula Compound of II. The reduction is performed by a method known per se, such as by the Bechaep burial method, which uses truncated / aerated hydrogen, catalytic argonization (Pd or Raney nickel), or the Naz S kanbara method. . The resulting compound of formula II can be converted to one of the compounds of formula I via the method of M C1 replacing CN as described above for K. In the next step, the compound of formula I is diazotized and cyclized to produce a compound of formula VII 'via * 1 3-The paper scale applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) — 11 1Ί H ^ n H 1 寐 (Please read the precautions on the back before filling this page) 434208 Α7 Β7 Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (U) Hydrolyzing cyano groups to form carboxyl groups can be obtained from formula III Compounds, or related carbenamines can be obtained from partial hydrolysis. Alternatively, when the sequence is retained, the hydrolysis of the cyano group in the compound of formula I will give the carboxylic acid of formula VI or, if desired, the carbaminides. Compounds can be obtained therefrom via diazotization ΠΙ. Diazotization is performed by conventional methods plus M, such as using nitrous acid (= HO NO) or using inorganic or hydrating nitrite. Examples that may be mentioned are NaN02 or alkyl nitrite having up to 8 carbon atoms. The acid or hydrazone hydrolysis of the nitrile group in compound I or VII is also performed by conventional methods, such as using concentrated sulfuric acid, hydrochloric acid or βββ gold 羼 oxides, gold 羼 hydroxides, alkaline earth gold. Samarium oxides or Samarium hydroxides, for example using NaOH or KOH. Due to peptides, the present invention also provides for the preparation of benzodiazol-7-carboxylates from compounds of formula II via 3-amine benzobenzonitrile. Method for Acid III | It obtains the 3-aminobenzonitrile of formula I by a) replacing ClK with M Cl as described above, and further bl) hydrogenation of the cyano group M to obtain the compound of formula VI. Then using nitric acid or Nitrite causes the amine group to undergo diazotization and cyclization to obtain a compound of formula III; or b2) Use nitric acid or nitrite to cause the amine group to undergo diazotization. The compound of formula V 11 is obtained, followed by hydrolysis of the cyano group to obtain the compound of formula [11]. ------------ Installation ---- J--Order ------ line (please read the precautions on the back before filling this page) This paper size applies to Chinese National Standards (CNS ) A4 specification (210X 297 mm) 434208 Α7 B7 V. Description of the invention (丨 X) This method prefers to use R-secondary-C3_c6 alkyl, tertiary C4-Cs alkyl or c5_CS cycloalkyl Compounds are administered with M, with particular preference for isopropyl > tert-butyl or cyclohexyl. Cyclization to be benzothiadiazole • According to Chemical Equation 2, it can be performed at the cyanide level (I) · carboglycine level (IA) or carboxylic acid level (VI) plus K. Chemical Equation 2 (Please read the notes on the back before filling out this page) Printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

VII ΥΠΑ ΠΙ Method for preparing compound of formula XI This paper size applies to Chinese national standard (CNS > Α4 size (210 '× 29 · 7mm) 4342 08 Α7 Β7

XI V. Description of the Invention (α)

X where Z is CN, CO-NH2 or COOH, including the diazotization of compounds of formula X, where 2 and R are as defined above, which uses nitric acid or nitrite and then cyclizes the product, and is therefore also possible by the present invention Provide it —, ------- ^ —— (Please read the notes on the back before filling out this page) Order _ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This method is preferred to use where R is Zhongyi C3— Ce alkyl, tert-C 4 -C 6 alkyl or Cs-Cs alkyl groups are added plus M, with particular preference for isopropyl, tert-butyl or cyclohexyl. According to the chemical formula 3, the compound of formula IV is converted into the compound of formula Vi and its primordial effect. The compound of formula II is obtained. The chemical formula 3-16 is known in principle. This paper uses China National Standards (CNS) A4. Specifications (210X297 mm) 434208 Α7 Β7 Staff Consumer Cooperative Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China Imprint 5. Invention Description (if)

It has now been found that compounds of formula II can be prepared with a yield and purity of M g plus M, when a) '2,3-diazanitrobenzene of formula IV, K and R therein are the compounds as defined above HS-R In aqueous », 30 to 1201, a reaction K is carried out in the presence of a phase transfer catalyst to obtain a compound of formula V; after this reaction, the product is extracted by washing with a polar solvent, such as alcohol, such as isopropyl or butan. And then use a dilute acid, such as hydrogen acid, to wash to pH 5 to 7 * and b) the nitrogen effect of nitropyrene and hydrogen / Raney nickel is performed in alcohol or water or a mixture of these . When the compound of formula V is used, it has been prepared and purified as described in a). The nitro group and Raney nickel ’s orthorhombic effect proceeds surprisingly quickly and requires only a small amount of ; This can eliminate the dangerous accumulation of readily degradable hydroxylamines. * From the point of view of safety, it is a considerable improvement. Therefore, the present invention also provides the method described on K as a compound of formula IV from the compound of formula IV, a compound of formula II from the compound of formula V * M and a two-step method as a compound of formula IV via a compound of formula V, wherein R is a compound of formula II as defined above. -17- The size of this paper applies to Chinese National Standard (CNS) Α4 specification (2ίΟΧ 297 mm)-^ ------ ^ I pack ----- ^-order ------ ice ( Please read the notes on the back before filling out this page) 434208 A7 B7 V. Description of the invention (New and also provided by the present invention is the compound of formula I

Where hydrazone is hydrogen, Ci- "2-alkyl, C3-C8 cycloalkyl, COR I > Ci-Cs alkoxyfluorenyl, Ci-Cs fluorenylfluorenyl, Cj-C β aminoalkyl, Ci -C8 alkyl-NHiCi-C * alkyl), Ci-C8 alkyl-fMCi_c4 alkyl) 2 or buried or unsubstituted benzyl, R! Is Ci_C8 alkyl · C3-u ring Alkyl or phenyl. Preferred compounds of formula I are those in which R is a secondary C3-C6 alkyl, tertiary C4-C6 alkyl, or Cs-Cs cycloalkyl, with particular preference for isopropyl, tert-butyl or cyclo Hexyl. What is new and also provided by the present invention is the compound of formula V (please read the precautions on the back before filling this page) • installed · -f Printed by the Central Consumers' Bureau of the Ministry of Economic Affairs and Consumer Cooperatives

V where R is as defined in Formula I, except for hydrogen, methyl and substituted or unsubstituted benzyl; R prefers secondary C3-C6 alkyl, tertiary c + -cs alkyl or C5- (: 6-cycloalkyl * particularly preferred isopropyl, -18- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 434208 A7 B7 5. Description of the invention (丨 ㈧ tert-butyl or cyclic Hexyl. What is novel and also provided by the present invention is compound C1 of formula II

Where R is as defined in Formula I. Except for hydrogen * methyl, ethyl, and substituted or unsubstituted benzyl M; R prefers secondary-c3-c6 alkyl, tertiary-C4-c6 alkyl Or c5 to c6 cycloalkyl, with particular preference for isopropyl, tert-butyl or cyclohexyl. Novel and also provided by the present invention are compounds of formula IA (please read the precautions on the back before filling this page) CO-NH,

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs where R is as defined by Formula I; R prefers a secondary C3_CS alkyl or tertiary -C4 -Cs alkyl or C5 cycloalkyl, with particular preference for isopropyl Base or cyclohexyl. What is novel and also provided by the present invention is the compound of formula VI -1 9- This paper size is applicable to Chinese National Standard (CNS) A4 (2 丨 OX29? Mm) 434208 A7 B7

COOH

Alkyl or C cyclohexyl. 5. Description of the invention (

VI NH. Where R is as defined in Formula I | except for substituted or unsubstituted nodal groups; R prefers secondary _C3 — Cs complex or tertiary * ~ C4 _Cs c6 cycloalkyl * particularly preferred isopropyl Base, tert-butyl or preparation examples (please read the notes on the back before filling this page)

124-4 grams of potassium carbonate and 144 grams of 2-dioxan-3-nitrobenzene were incorporated into 400 grams of dimethylacetamide and the mixture was heated at 77¾. At this temperature, 72.2 grams of tributyltellurol was added dropwise over a period of 1 hour. The mixture was then stirred under ιοου for 2 hours. The reaction mixture was concentrated under 75t: slight vacuum * and added with 500ml of water, and the final product was then separated at 80¾. This gave 185.5 g of a product having a melting point of 50 ν (yield> 35%). -2 0-This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 4342 08 A7 B7 V. Description of the invention (丨 name) Example H-2: Preparation

CI

Method of printing by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs a): The previous technique method is as described in Example H-1. • Except the use of 81 g of isopropyl mercaptan instead of tert-butyl mercaptan In addition, 175 g of a product with a melting point of 6 6 7 t were obtained (yield> 35%). Method b): According to the method of the present invention, 80 · 1 g of isopropylthiol is metered in at 65 to 195.5 g of 2,3-dinitronitrobenzene, 3.2 A of bromo-tetrabutyl Ammonium, a mixture of 157.3 grams of a 30% sodium hydroxide solution and 12G grams of water. Immediately stir at 65 to 7 (3t: hold the pan for 1 hour, 100 g of isopropion is added to the reaction mixture, and the bottom aqueous phase is carved out. The organic phase can be added with a diluted aqueous solution of hydrogen acid. Wash to pH 5 to 7 and cool to Ot: · The crystallized product is separated by filtration and washed with about 40 g of isopropanol. This gives 225 g of product, melting point 65 to 67¾ (yield 95%) Theoretical value). Practical example H-3: Preparation-2 1- ------ * --- * ----- J--Order (Please read the precautions on the back before filling this page) This Paper size adopts Chinese National Standard (CNS) A4 specification UIOX297 mm) 434208 A7 B7 V. Description of the invention (q)

345 grams of sodium sulfide hydrate in 500 liters of water were added to 401.3 grams of 560 liters of isopropion at a temperature of 8 [) to 82¾ in 2 hours. 1-dish-2 -cyclohexylsulfur 3 -nitrate Benzene. After stirring the mixture at 8210 for 3 hours, it was cooled to 2Q to 25t 'and the aqueous phase was separated. The organic phase was washed with 2 GQ ml of a 2 5% sodium chloride solution. The organic phase was then condensed and steamed at 18D1C / 0.2 Torr. Yield: 278.4 g (77%) of a yellow oil. Example Η— 4: Preparation ----: --------- Equipment, _ Order- (Please read the precautions on the back before filling in this education) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ,

335. Grams of 1 gas_2-isopropylpyrene 3-nitrobenzene (obtained from Example Η-2) in 900 grams of formic acid, 35 to 40 t: / 5 bar, 27.5 grams of Raney (Raney ) Sulfurization in the presence of nickel (as a small aqueous solution). After the absorption of hydrogen, the mixture was cooled to room temperature. Raney-22- The standard for the paper was tens of national standards (CNS) A4 (210X297 mm) 434208 Employees' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs printed A7 B7 5. Description of the invention (π) (Raney) Nickel is separated by filtration, and the solvent is separated by adding M on a rotary dry mill. The residue (crude product) was applied directly in the next step or distilled at 90 to 100 000 / 0.05 bar. Yield: 272 g (95%). Reaction time: a) For according to Free matter prepared by the prior art: Example VII-2, Method a): 3-5 hours. b) For a sickle prepared by adding K according to the method of the present invention: pickling example H_2, method b): 0.5 hours. „Example H-5: Preparation

CN \ human XCH3 νη2 3 Η- 5 (1): 60. 5 grams of 3-gas-2 isopropylamidoaniline (obtained from Example Η — 4 >, 26.9 grams of cyanide network (I) K and 26-1 grams of pyridine is heated for 7 hours at 190 C. 100 ml of acetonitrile is added dropwise with «evaporative cooling» and then 7 liters of water are added in small portions at a time and then 21 > 5 grams of Sodium sulfide. After the mixture was stirred at 80 t for 4 hours, it was cooled and filtered, and the condensate was concentrated. After 70 to 1 2 Q t: / 0. 5 Torr steaming -23- This paper uses the Chinese National Standard (CNS) A4 (210X 297 mm). ^ — «1 · m -I — ^ ni I Jut« ^ —Β— ^^^^ 1 It, Ze-4 (Please read the notes on the back before filling this page) 43420 Α7 Β7 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (//) After distillation, 200 ml of hexane was added to the mixture for filtration Yield: 22.7 g (40%) of 3-amino-isopropyl benzobenzonitrile, melting point 82 t. B-5 (2): 202 g of 3-gas-2-isopropyl Thioaniline From Example H-4), 134 g of gadolinium (I) K and 140 g of 3-methylpyridine were heated at 19Qt for 9 hours. Then 200 g of methyl ethyl ketone was added. 60 g of gadolinium M and 10 grams of water, the mixture is stirred, the salts are decanted, and the dehydrated matter is irrigated. The residue * which contains the product and free matter, is carried out at 70 to 12〇υ / 0 * 05 巴Distillation • The distillate is crystallized from methylcyclohexane. This gives 125 g of product (65¾ of theoretical value); free matter (20% of theoretical value) remains in the mother liquor and can be recycled. Implementation Example H-6: Preparation of catalyst Ni ° (PPh3) 4 47.5 g of nickel cyanide hexahydrate was incorporated into 1,000 g of dimethylformamide and the mixture was vigorously stirred. Immediately incorporated 2 09 · 8 grams of triphenylphosphine. 150 grams of DHF was steamed and separated, and 22 grams of manganese powder was added under an inert nitrogen gas environment (nitrogen). The adduct was fed at 50t: 1 '5 During this period, the color of the dissolved spines changed from dark green to reddish brown through green. At this moment, the catalyst does not need to be separated and can be used. -2 4-—I. „ I ί 1-, decoration ~ I nf (Please read the precautions on the back before filling in this page) This paper size adopts Chinese National Standard (CNS) A4 specification (2 丨 0 乂 297mm) 43420η Bulletin Α7 Β7 V. Description of the invention ()-Example Η-7: Preparation of Junki-2 —isopropylcypronitrile 5 ml of DMF in inert gas using Si (PPh3) 2 Cl2 + 2PPh3 as the catalyst M The mixture was stirred at ambient temperature to 327 mg of nickel bistriphenylphosphine, 82 mg of manganese powder and 2S2 mg of tribenzylphosphine and the mixture was stirred at 50 ° C for 45 minutes. One gram of 3-aerobic 2-isopropylthioaniline and 3 5 grams of potassium nitride were then added. The mixture was stirred at 50Γ for hours. After 15 ml of toluene and iQ ml of water were added, the mixture was clarified by filtration. One hundred milliliters of toluene was added to the manganese compound and washed with 30 milliliters of water. The organic phase was used for filtration and the residue was subjected to chromatography on silica gel (hexane / ethyl acetate = 4: 1). This gave 0 * 72 g of colorless crystals (yield: 76%). ○ Implemented 洌 Η — 3: The catalyst prepared as described in Example Η-6 was used to prepare 3-amino-2-isopropyl Thiobenzoic acid 201 * 5 g of 3-chloro-2-isopropylthioaniline was added to the catalyst mixture obtained in Gongshi Example VII-6. 5 1,5 g of sodium cyanide was added at 50 ° C with vigorous searching. Check the reaction every 3 hours. After the maximum of 24 hours, the reaction is over. The reaction mixing shuttle 1 was concentrated under vacuum. The residue M was treated with 1 liter of methyl ethyl ketone and 1 liter of water 5D, stirred vigorously and subjected to mashing. The solvent was left to stand to allow each phase to be separated. -25- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the unintentional matter on the back before filling this page) ^ --- -----: Order -------- Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 434208 A7 B7 V. Description of Invention (> 彳) Open. The separated phase was concentrated and the residue K 8 0 Q liters of cyclohexane was treated with M at 50 υ. After the solid is dissolved, it is cooled to ot: and seeded. 117 g (61¾) of white crystals were obtained. Example Η— Preparation of 3: 3 -Amino-2—isopropylphosphinobenzoate 6 liters of dimethylmethylose limbs were added to 50 grams of gasified nickel dihydrate • BPPPA (1,1 -bisdiphenylphosphine 1- (dimethylaminoethyl) diocene box) K and 49 g of manganese powder, and the mixture was stirred for 2 hours under 50 P · inert gas atmosphere. A brown suspension formed. 1,2 (JQ grams of 3-gas-2-isopropyl aniline and 430 grams of KCH were added to the suspension and the mixture was stirred at 50 ° C for 16 hours. After completion, the white crystals with a melting point of 8210 were about 90% of the yield. The rate is obtained by adding M. Example Η_ 10: Preparation (Please read the notes on the back before filling in this 贳) Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs

COOH

2 δ. 8 grams of 3-amino-2-isopropylfluorenebenzonitrile was added to a mixture of 30.6 grams of 96% oleic acid and 8.6 grams of water at 12 0 t. The mixture is heated at 12Qt for 2 hours and further added at 149¾-2 6-This paper size applies the Chinese national standard icNS) A4 size (2 丨 0X297 mm) 494208 A7 B7 V. Description of the invention (> f) After 2 hours, 3-amino-2-isopropyl benzoic acid was obtained in the form of acetic acid for almost quantitative yield. When cooling, the suspension was treated with 150 ml of water and 80 ml of isopropanol plus M. The mixture was cooled to () ¾ and 20 * 8 grams of sodium nitrite solution in 48.6 grams of water was added dropwise over a period of 4 hours. Further at Ot; after 1 hour, the mixture was used in 20 liters of water 10 * 6 grams of acetamide plus K treatment and «. Yield: 23.4 grams of white crystals (87%). Example Η-11: Preparation (Please read the precautions on the back before filling this page)

CN

9.6 grams of 3-amino-2-isopropylacrylonitrile printed in 20 liters of Ding Ye in the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs was added dropwise to 7 at 15C over a 3-hour period. Grams of amyl nitrite, 4 (3 liters of butyl ferment and 1.1 gram of concentrated cyanic acid. After the mixture was further stirred for 3 hours, fl'6 grams of etheramine and 10Q liters of water were added. There are «phases separated and subjected to hydration under vacuum. This gives 8.3 g of 7-cyanobenzothiadiazole in white crystalline form (yield: >97%); melt adhesion 114 to 117TC. Example H_ 12: Preparation -27- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 434208 Α7 Β7 V. Description of the invention (/)

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8'1 g of 7-cyanobenzoxadiazole in 8Q g of dimer was treated with 16.8 g of a 5% potassium hydroxide solution and treated with M and the mixture was heated for 3 hours at a lower temperature. During the 3-hour period, the 7-carbon glycosamine monobenzosotriazole precipitated out and was later redissolved to form the acid. After the mixture had cooled to 40 to 50, 200 liters of water was added and the phases were separated. The aqueous phase was acidified with hydrochloric acid plus M and subjected to dehydration. Yield: .8 g of benzosadiazol-7-fluorenic acid, 230 g (88%) of melt-adhesive. Examples

^^^ 1 —Bn 1 · 0 —— ^ — 1 ^ 1 ^ 1 fn ^^^^ 1 ^^^^ 1 ^^^^ 1 TJ J 0¾-? {Please read the precautions on the back first (Fill in this page) Printed in 80 liters of water and 14.3 grams of 32% hydroxamic acid by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs * 9'6 grams in the form of a suspension 3 ~ amino- 2 -isopropyl The benzobenzonitrile was treated with 3.45 g of sodium nitrite solution in 20 liters of water over 15 hours. After the mixture has been read at 15C for 2 hours • Add 1.5 g of ethyl »amine, and the precipitated product is separated by pumping with Mβ» • Wash with water and M and perform suspicion. Yield: 7.7 grams (33%) of -28- This paper size applies to Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) 4342 A7 B7 V. Description of the invention (yt?) White crystal, melting point 11 6 to 11 died. Example E-14: Preparation

Employees of the Central Bureau of Procurement, Ministry of Economic Affairs, Consumer Cooperation Du printed 20.2 grams of 3_chloro-isopropylamidineaniline, 1Q.8 grams of europium cyanide (1), 〇 ♦ 7 grams of hydrazone (II) κ, and 3 ' 2 grams of pyridine was heated at 160.0 for 22 hours. After this time * 50 liters of Ding Yeast and 11.2 grams of K0Η were added and the mixture was heated at 110C for 6 hours. 4 liters of water were then added and the mixture was further stirred at 11QC for 18 hours. When cooling, the mixture was treated with 1QQ liters of water, filtered, and each liquid phase was washed with 50 liters of methyl isobutyl ketone and 50 liters of water. 2Q grams of concentrated chloroacid Perform acidification. After the phases were separated, the aqueous lithium was dissolved with 30% sodium hydroxide to give sickle properties, and the precipitate was extracted with methyl isobutyl ketone plus K. The methyl isobutyl hydrazone phase was passed through and shrunk to obtain a brown oil which was solidified later; melt-bonded 93 to 97C 〇 Example 15: --29- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) tut -111 ί ^^^ 1 ^ ϋ— m 4 ^ kz, i In ^^^ 1 m · ^ J. 凄-, T. (Please read the precautions on the back before filling this page ) 434208 A7 B7 five

N 2 · 1 g of 3-amino-2-isopropylammonium benzamidine (obtained from Example H-11) * 20 l of water M and 5.7 g of ammonium hydroxide at 1〇 ^ 45 During a minute, 0.7 g of NaGa K nitrite treatment in 4 ml of water was used. After 10 hours, 1 gram of aminosulfonic acid was added, and the mixture was then imparted with sodium hydroxide solution. After filtering and washing with water, the mixture was dried. Yield: 1.2 g of crystalline (67%) melting point > 3 0 0 C. Example Η — .16: Preparation (Please read the precautions on the back before filling this page)

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140 grams of sodium nitrite aqueous solution printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, up to 0 to 5 1 C, up to 192 grams of 3-amino-isopropylbenzene at 110 grams of sparse acid and 500 grams of water Eye suspension. After this reaction, the mixture was extracted with toluene, and the ammonium phase was stirred with 360 g of a 30% sodium argon oxide solution at 60 t for 4 hours. The toluene phase (which contains the second product) is separated • The aqueous phase is acidified with hydrogen S acid | and the product crystallized during this process is separated by filtration. Yield: 171 g (9 5% of theory). -30- Chinese paper standard (CNS) A4 is standard for this paper (210X297 mm)

Claims (1)

434208 A8 B8 C8 | D8, τ. Patent Application Fan Qi Bulletin Form Employees' Cooperative Cooperative Printing Policy of the Central Bureau of Standards of the Ministry of Economic Affairs 1 · One method: Preparation of a substituted 3-aminobenzonitrile for formula I Where: R is hydrogen or Ci 2 alkyl, cyclohexyl; it includes, in a solvent above 30 ° C, a substituted 3-aminoaminobenzene of formula II Where ϋ is as defined in formula I and reacts with a fluoro-supply reagent selected from K a) CuCN in the presence of a complexing agent selected from the group consisting of pyridine and 3-methylpyridine; Or b) an alkali metal cyanide in the presence of a compound selected from the group consisting of pyridine and 3-methylpyridine; or c) an alkali metal cyanide * HCN, Mi (CN) 2 or tetramethyl Silane atmosphere * or ketone HCN adduct or aldehyde HCN adduct | Using formula Ni ° This paper is fully applicable to the Chinese National Standard (CNS) A # see the grid (21 OX297 mm)-; ----- --t .------ iT ------ 0 m (Please read the precautions on the back before filling this page) 434206 A8 B8 C8 D8 Yin Dongliu 、 Application of patent scope _Ln catalyst plus K, where L is triphenylphosphine and η is 2 to 4 * or use the formula-L2 catalyst, which is (1, plant one bisdiphenylphosphine 1 Mono (dimethylaminoethyl) dimethylene). Γ · The method according to item 1 of the scope of patent application, wherein the reaction is performed at 5!] To 3 5 ο υ. 3. The method according to item 1 of the scope of patent application *, wherein the reaction a) or b) is performed at 150 to 25x; 4. The method according to item 1 of the scope of patent application, wherein reaction C) is performed at 30 to 150 ¾. 5-The method according to item 1 of the scope of patent application, wherein * in reaction a), at least an equal molar amount of a Cu or Fe-based complexing agent is used as a solvent. 6. · A compound for formula II, in which R is the method for preparing benzothiadiazole-7-carboxylic acid of formula III as described in item 1 of the scope of patent application-2-This paper applies Chinese national standards (CNS) A4 specifications (2 [0X297 mm) --------- ^ ------ 1T ------ i • * (Please read the '^' on the back first; ^ items then (Fill in this page) 4342C〇A8 BS C8 D8 Patent scope Cl COOH CN COOH III VII (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, which includes a) Substituting a cyano group with a substituted atom in 3-aminochlorobenzene of formula II K can be based on 3-aminobenzonitrile of formula I according to item 1 of the scope of the patent application, and further ii) hydrogenation of the cyano group to obtain a compound of formula VI, and then use nitric acid or nitrite to make the amine group proceed Diazotization, accompanied by ring-3- This paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 434208 ABCD 6. Applying for patent scope, M will obtain the compound of formula 11 I; or b2) use Nitric acid or nitrite causes the amine group to undergo diazotization, with cyclization, to obtain a compound of formula VII * followed by hydrolysis of a cyano group to obtain a compound of formula II I. 7-The method according to item 6 of the scope of application for patents, wherein R is a secondary -C 3 -Cs courtyard or tertiary -C4-Cs courtyard or cyclohexyl. 8-The method according to item 7 of the scope of patent application, wherein R is isopropyl, tert-butyl or cyclohexyl. --------- ^ ------ ΐτ ------ 0 (Please read the precautions on the back > ',, 4 to write this page). * Central Bureau of Standards, Ministry of Economic Affairs The paper size printed by the employee consumer cooperative is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) Application date: 84 1 10 0 7 ft., Category is% continued 1 (the above are filled out by this bureau) A4 C4 434208 Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China Yin Yunling Patent Specification Invention 1 'υ Name New Chinese-made 竜 泾 Substituted 3-aminobenzone and benzothiadiazole-7-carboxylic acid Method English PROCESSES PCR 5REPARESG SOBSTITUIED 3-AMINOBE > I2CNITRILES AND BEH2miaDIAZQLE-7-CaRBOXYLIC SOD ^ Invention I. Creation of the name of the country Borisia Blaise (2) Banno. Lisboa (3) Adriano .Indore⑷Felena.Li Xin⑴Germany⑵⑶⑷Swiss residence and residence⑴Switzerland 4 142Minsingstein.9 Essing Street⑵Switzerland 4142Minsingstein.16 Mizuya Road ⑶Switzerland 3 Lin. Sarinen St. 198 No. 198 Uken. Kember St. 5G28, Switzerland _ Name (Name) Novartis Nationality Switzerland III. Applicant's Residence and Residence (Office) 4058 Barvale, Switzerland • Black Forest Avenue Name of Representative No. 215 1. Cheng Na · Wadek 2. Watlow. Fogle-1-iir -------- 0-, ------ This paper uses the Chinese country Standard (CNS) A4 now (210X 297 mm) installed 434208 V. Description of the invention () The oxadiazoles can be easily removed from the warm compounds by a simple phase separation method (water / organic solvent) using a compound of formula 111. The present invention is also compatible with the use of a compound of formula I for obtaining a compound of formula I I I. Therefore, these compounds can be prepared from 2,3-dichloronitrobenzene (which is a known compound), such as the following chemical formula 1, plus M: (Please read the notes on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Bureau Employee Consumer Cooperative Prints Chemical Equation 1 -12- III This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 43420η Bulletin A7 B7 V. Description of the invention ()-Example 使用 7: Use of Si (PPh3) ) 2 Cl2 + 2PPh3 as the catalyst M to prepare Junji-2 — isopropyl cyanoboronitrile 5 ml of DMF was immersed in an inert gas environment to 327 mg of aerated bistriphenylphosphine nickel, 82 mg of manganese powder And 2S2 mg of tribenzylphosphine and the mixture was stirred at 50 ° F for 45 minutes. One gram of 3-aerobic 2-isopropylthioaniline and 3 5 grams of potassium nitride were then added. The mixture was stirred at 50Γ for hours. After 15 ml of toluene and iQ ml of water were added, the mixture was clarified by filtration. One hundred milliliters of toluene was added to the manganese compound and washed with 30 milliliters of water. The organic phase was used for filtration and the residue was subjected to chromatography on silica gel (hexane / ethyl acetate = 4: 1). This gave 0 * 72 g of colorless crystals (yield: 76%). ○ Implemented 洌 Η — 3: The catalyst prepared as described in Example Η-6 was used to prepare 3-amino-2-isopropyl Thiobenzoic acid 201 * 5 g of 3-chloro-2-isopropylthioaniline was added to the catalyst mixture obtained in Gongshi Example VII-6. 5 1,5 g of sodium cyanide was added at 50 ° C with vigorous searching. Check the reaction every 3 hours. After the maximum of 24 hours, the reaction is over. The reaction mixing shuttle 1 was concentrated under vacuum. The residue M was treated with 1 liter of methyl ethyl ketone and 1 liter of water 5D, stirred vigorously and subjected to mashing. The solvent was left to stand to allow each phase to be separated. -25- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the unintentional matter on the back before filling this page) ^ --- -----: Order -------- Member of the Intellectual Property Bureau of the Ministry of Economics and Consumer Cooperatives printed 434208 Bulletin A5 B5 丨 · Amendment IV. Chinese Invention Abstract (Name of the invention: — System replaced by The present invention relates to a process for the preparation of substituted 3-aminobenzone of formula I. 3-Aminobenzonitrile and benzothiadiazole-7-carboxylic acid I where: R is hydrogen or Ci—Cl2 alkyl, C3_Cs cycloalkyl, Cori, Ci—Cs alkoxyalkyl, Ci—Cs hydroxyalkyl, Ci—Cs aminoalkyl, Ci—C: 3 Fluorenyl-SH (Ci — C4 tracer) '(Ci —Cs alkyl — N (Ci — c4 alkyl) 2 or substituted or unsubstituted ^^^^ 1 ^^^^ 1 nn 11— ^ ^^^ 1 t I ^^^^ 1 ^^^^ 1 (Please read the notes on the back before filling in the columns on this page) English Abstract of the Invention (Name of the Invention :) Absrract The invention relates to a process for the preparation of subsrimeed 3-aminobenzoniixiles of chc formula I Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs in which: R is hydrogen or CrC12alkylt C3-C3cycloaikyi, CORLi CrC3alkoxyaLkyl, CrC6hydroxyaikyl, CrC8aminoaikyl, CVCsalkyl-NHCCL-Qtaiicyt), C ^ CgaJJcyl-NiCpQalicyi) CotCircyl or unsubcncyyl or unsub or phenyl; and which include reacting a subsucuced. 3-aminochIorobcazene of che formula Π The size of the paper is applicable to the Chinese National Standard (CNS) A4 gauge (21〇X297 mm) 434208 A8 B8 C8 | D8, τ. Bulletin Board Policy of Employees' Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs1. A method of preparing: a method for preparing a substituted 3-aminobenzonitrile of formula I Where: R is hydrogen or Ci 2 alkyl, cyclohexyl; it includes, in a solvent above 30 ° C, a substituted 3-aminoaminobenzene of formula II Where ϋ is as defined in formula I and reacts with a fluoro-supply reagent selected from K a) CuCN in the presence of a complexing agent selected from the group consisting of pyridine and 3-methylpyridine; Or b) an alkali metal cyanide in the presence of a compound selected from the group consisting of pyridine and 3-methylpyridine; or c) an alkali metal cyanide * HCN, Mi (CN) 2 or tetramethyl Silane atmosphere * or ketone HCN adduct or aldehyde HCN adduct | Using formula Ni ° This paper is fully applicable to the Chinese National Standard (CNS) A # see the grid (21 OX297 mm)-; ----- --t .------ iT ------ 0 m (Please read the notes on the back before filling this page)