Process for producing spiroketal-substituted cyclic ketoenols

Abstract

To provide new intermediates for use in new methods for producing cis-alkoxy substituted spirocyclic 1-H-pyrrolidine-2,4-dione derivatives.SOLUTION: For example, compounds of formula (V') and formula (IX') are illustrated. [R7 represents an optionally branched C2- to C8-alkyl; R8-R12 each represent H, methyl, ethyl, halogen or the like].SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to substituted cyclohexane amino acid esters and spiroketal-substituted cyclic keto- A novel process for producing enols, as well as the process according to the invention or novel intermediates or starting compounds used in the process. Amino acid esters are important intermediates for the synthesis of active insecticide, acaricide and herbicide ingredients. It is the body. [Background technology]

[0002] Certain spiroketal-substituted cyclic keto-enols have insecticidal, acaricidal or herbicidal activity It is already known that it has properties (WO99 / 16748; WO06 / 089633). One known synthesis of such a spiroketal-substituted cyclic keto-enol (A) (WO 2018 / 024659) corresponds to a spiroketal-substituted cyclohexasiloxane of general formula (I) This is the Bucherer-Bergs reaction In the reaction, the spiroketal-substituted hydantoin of general formula (II) By alkaline hydrolysis of these hydantoins, spirochetes of the general formula (III) are obtained. These amino acids are then reacted with methanol to give cyclohexane-substituted amino acids. and esterification with thionyl chloride to give compounds of the general formula (IV), (V) and (VI) ) to obtain a mixture of hydrochlorides of substituted cyclohexane amino acid methyl esters of the formula: These hydrochlorides can be used to obtain free cyclohexane compounds of the general formulae (IV), (V) and (VI) Amino acid methyl esters can then be obtained. It is acylated at nitrogen with phenylacetyl chloride of the general formula (VII) to obtain a mixture of compounds of the general formula ( VIII), (IX) and (X). Then, the compounds of the general formula (VIII) , (IX) and (X) are cyclized in the Dieckmann reaction by the action of a strong base such as potassium tert-butoxide or sodium meth oxide to obtain a mixture of substituted cyclic keto -enols of the general formula (XI), (XII) and (XIII). In the final step, these compounds are then converted to the compound of the general formula ( XI) by reaction with an α,π-diol of the general formula ( XIV). This process (A) is shown in Scheme 1. A major drawback of this method (A) is that when the amino acid of the general formula (II I) is esterified with methanol / thionyl chloride, methyl chloride is also formed . Due to its low boiling point (-24 °C), methyl chloride escapes with the exhaust gas. Its disposal (e.g., by combustion) can pose a major technical problem.

[0003] Scheme 1: Method A

Chemical Structure

[0004] In the general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VII ), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 8 、R 9 、R 10 、R 11 、R 12and n has the definitions shown below.

[0005] Therefore, the spiroketal-substituted cyclohexane amino acid ester of general formula (VIII) and the spiroketal-substituted cyclic keto-enol of general formula (XI) are still needed to be prepared under industrial conditions by a method with better performance.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] The synthesis of the spiroketal-substituted cyclohexane amino acid ester of general formula (VIII) and the general formula (XI) spiroketal-substituted cyclic keto-enol can be simplified by using higher-grade alcohols rather than methanol, and their corresponding alkyl chlorides can, due to their higher boiling points, be more easily removed from the waste gas stream by known technical methods in principle, or no longer occur therein. Surprisingly, it has now been found that in the reaction with alcohols higher than methanol, the formation of dialkyl acetals is clearly reduced. This simplifies the reaction sequence and shortens the last step of the process.

Means for Solving the Problems

[0008] A first embodiment of the process according to the invention (Process B) comprises the step of reacting a spiroketal of general formula (III) The substituted cyclohexane amino acid is represented by the general formula (XV) [ka]

[0009] [In the formula, R 7 is optionally branched C2-C8 alkyl. of alcohol and esterified by reaction with thionyl chloride to give a spiroketal of general formula (IV') -substituted cyclohexane amino acid esters, dialkyl ketal-substituted cyclohexane amino acid esters of the general formula (V') Cyclohexane amino acid esters and 4-cyclohexanone amino acid esters of general formula (VI') The method is characterized in that the hydrochloride salts of these esters are obtained by means of a base. The salts are used to prepare free spiroketal-substituted cyclohexane amino acid esters of general formula (IV'): esters, dialkyl ketal-substituted cyclohexane amino acid esters of general formula (V') and Then, the 4-cyclohexanone amino acid ester of the general formula (VI') can be obtained. These amino acid esters are converted into bases using phenylacetyl chloride of the general formula (VII). by acylation at the nitrogen in the presence of A mixture of compounds is obtained, which can then be reacted with potassium tert-butoxide or It is cyclized in the Dieckmann reaction by the action of a strong base such as sodium methoxide. This gives a mixture of compounds of general formula (XI), (XII') and (XIII). These compounds can be reacted with a compound of general formula (XIV) in the presence of an acid [ka]

[0010] [Wherein, R 1 to R 6 are independently hydrogen, methyl, ethyl or phenyl, and n is 0 or 1)] By reacting with the α,π-diol of a single spiroketal of general formula (XI)

[0011] Method (B) according to the present invention is shown in Scheme 2.

[0012] Scheme 2: Method B according to the present invention

Chemical formula

[0013] The second embodiment (Method C) of the method according to the present invention is a spiroketal of general formula (III)- substituted cyclohexane amino acid is of general formula (XV)

Chemical formula

[0014] [Wherein, R 7 is optionally branched C2-C8-alkyl] of the alcohol is esterified by reaction with thionyl chloride to give a mixture of a spiroketal-substituted cyclohexane amino acid ester of general formula (IV’), a dialkyl ketal-substituted cyclohexane amino acid ester of general formula (V’), and a hydrochloride of a 4-cyclohexanone amino acid ester of general formula (VI’). By means of a base, these hydrochloride salts are used to obtain the free spiroketal-substituted cyclohexane amino acid ester of general formula (IV’) ​​​Stell, a dialkyl ketal-substituted cyclohexane amino acid ester of general formula (V') and and a 4-cyclohexanone amino acid ester of general formula (VI') can be obtained. Next these amino acid esters are then acylated with phenylacetyl chloride of general formula (VII) in the presence of a base in nitrogen to obtain a mixture of compounds of general formulae (VIII'), (IX') and (X'). Next, these compounds are, in the presence of an acid, of general formula (XIV)

Chemical formula

[0015] 〔wherein, R 1 from R 6 are independently hydrogen, methyl, ethyl or phenyl, and n is 0 or 1〕 by reaction with an α,π-diol of general formula (XVI)

Chemical formula

[0016] 〔wherein, R 13 is optionally branched C2-C8-alkyl or -(CR 1 R 2 ) n -CR 3 R 4 -CR 5 R 6 -OH〕 is converted to a homogeneous spiroketal-substituted compound of general formula (XVI).

[0017] Finally, the compound of formula (XVI) is then cyclized in a Dieckmann reaction by the action of a strong base (e.g., potassium tert-but oxide or sodium methoxide) to obtain a compound of formula (XI). ​

[0018] The method (C) according to the present invention is shown in Scheme 3.

[0019] Scheme 3: Method C according to the present invention

Chemical formula

[0020] In general formulas (III), (IV’), (V’), (VI’), (VII), (VIII’), (IX ’), (X’), (XI), (XII’), (XIII), (XIV), (XV) and (XV I), R 1 ~R 6 are independently hydrogen, methyl, ethyl or phenyl, R 7 is optionally branched C2-C8-alkyl, R 8 ~R 12 are independently hydrogen, methyl, ethyl, fluoroalkyl having 1 or 2 carbon atoms and 1 to 5 fluorine atoms, halogen, methoxy, ethoxy, trifluoromethoxy, or phenyl which may be substituted with methyl, ethyl, methoxy or halogen, R 13 is optionally branched C2-C8-alkyl or -(CR 1 R 2 ) n -CR 3 R 4 -CR 5 R 6 -OH, n is 0 or 1.

[0021] Preferably, R 1 ~R 6 are independently hydrogen, methyl or ethyl, R 7is ethyl, n-propyl, i-propyl, n-butyl or n-hexyl, R 8 ~R 12 each independently is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, methoxy, ethoxy, trifluoromethoxy or phenyl optionally substituted with methyl-, ethyl-, methoxy-, ethoxy-, fluoro-, chloro- or bromo-; R 13 is ethyl, n-propyl, i-propyl, n-butyl, n-hexyl or -( CR 1 R 2 ) n -CR 3 R 4 -CR 5 R 6 -OH; n is 0 or 1.

[0022] More preferably, R 3 ~R 6 each independently is hydrogen or methyl; R 7 is ethyl, n-propyl, i-propyl, n-butyl or n-hexyl; R 8 ~R 12 each independently is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, methoxy, ethoxy or phenyl optionally substituted with methyl-, methoxy-, fluoro- or chloro-; R 13 is ethyl, n-propyl, i-propyl, n-butyl, n-hexyl or -( CR 1 R 2 ) n -CR 3 R 4 -CR 5 R 6 -OH; n is 0.

[0023] Most preferably, ​​R 3 is hydrogen, R 4 is hydrogen or methyl, R 5 is hydrogen, R 6 is hydrogen or methyl, R 7 is ethyl, n-propyl, i-propyl, n-butyl or n-hexyl, R 8 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, methyl, chlorine or bromine, R 11 is hydrogen, R 12 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine, R 13 is ethyl, n-propyl, i-propyl, n-butyl, n-hexyl or -( CR 1 R 2 ) n -CR 3 R 4 -CR 5 R 6 -OH, n is 0.

[0024] Particularly preferably, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is ethyl, n-propyl or n-butyl, R 8 is methyl, ethyl, chlorine or bromine, R 9 is hydrogen, R 10is hydrogen, chlorine or bromine, R 11 is hydrogen, R 12 is methyl, ethyl, chlorine or bromine, R 13 is ethyl, n-propyl, n-butyl or -(CR 1 R 2 ) n -CR 3 R 4 - CR 5 R 6 -OH, n is 0.

[0025] Very preferably, R 3 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is ethyl, n-propyl or n-butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen, R 12 is methyl, R 13 is ethyl, n-propyl, n-butyl or -(CR 1 R 2 ) n -CR 3 R 4 - CR 5 R 6 -OH, n is 0.

[0026] Similarly very preferably, R3 is hydrogen, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 is n-propyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen, R 12 is methyl, R 13 is n-propyl or -CH2CH2-OH, n is 0.

[0027] R 1 ~R 6 is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 is.

[0028] R 8 ~R 12 is R 8 , R 9 , R 10 , R 11 , R 12 is.

[0029] The method (B) according to the present invention will be described in detail below.

[0030] The first step (1) of method (B) according to the present invention : The reaction for obtaining the hydrochloride salts of the compounds of general formula (IV’), (V’) and (VI’) from the compound of general formula (III) and the alcohol of general formula (XV) and thionyl chloride is carried out without a diluent or optionally with an inert diluent such as toluene or N, chlorobenzene, 1,2 - dichlorobenzene, heptane, isooctane, methylcyclo hexane, anisole or acetonitrile. Preferably, it can be carried out in the absence of a diluent, which means that the alcohol used in the esterification is used in excess as a diluent.

[0031] The amount of thionyl chloride can be varied within a wide range. Typically, based on the compound of general formula (III), 0.5 - 5 molar equivalents of thionyl chloride are used. It is preferred to use 0.9 - 3 molar equivalents of thionyl chloride. It is particularly preferred to use 1.2 - 3

[0032] molar equivalents of thionyl chloride.

[0033] The reaction can, in principle, also be carried out under reduced pressure

[0034] or under high pressure. The work-up can be carried out, for example, by distilling off the alcohol and the excess thionyl chloride. In this way, the hydrochlorides of the compounds of general formula (IV’), (V’) and (VI’) are obtained, and

[0035] they can be used directly in the next step of the process (B) according to the invention. However, it is also possible to convert the hydrochlorides of the compounds of general formula (IV’), (V’) and (VI’) into the free amino ester

[0036] compounds of general formula (IV’), (V’) and (VI’) by the addition of a Lithium, potassium carbonate, potassium hydrogen carbonate, lithium hydroxide, sodium hydroxide, hydroxide Potassium, ammonia, triethylamine, tributylamine, pyridine or 2-methyl -5-ethylpyridine or a mixture of these bases may be used. It is preferable to use sodium carbonate. Similarly, it is preferable to use a mixture of sodium carbonate and sodium hydroxide.

[0037] The amount of the base is selected such that the proportion of hydrochloric acid (HCl) in the mixture of hydrochlorides of the compounds of general formulas (IV'), (V') and (VI') is neutralized.

[0038] The second step (2) of method (B) according to the present invention : The hydrochloride of the compound of general formulas (IV'), (V') and (VI' ) or the compound of general formulas (IV'), (V') and (VI') is reacted with an acid chloride of general formula (VII) in the presence of an inert diluent and a base to obtain the compounds of general formulas (VIII') , (IX') and (X').

[0039] Examples of the diluent used include dichloromethane, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, heptane, isooctane, methylcyclohexane, tetrahydro furan, ethyl acetate, acetonitrile, anisole or butyronitrile. Tetrahydrofuran (THF), anisole, toluene, xylene, chlorobenzene or acetonitrile is preferably used. Toluene, chlorobenzene or anisole is particularly preferably used.

[0040] The base used may be an inorganic or organic base. Examples here include sodium hydroxide ​​Thorium, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, carbonic acid Potassium hydrogen, triethylamine, tributylamine, morpholine, piperidine, pyridine 2 - methyl - 5 - ethylpyridine or a mixture of these bases can be mentioned. It is preferable to use sodium carbonate or potassium carbonate. It is particularly preferable to use sodium carbonate. It is also particularly preferable to use a mixture of sodium carbonate and sodium hydroxide similarly.

[0041] The amount of the base is derived depending on whether the hydrochloride salts of the compounds of general formulas (IV’), (V’) and (VI’) or the compounds of general formulas (IV’), (V’) and (VI’) are used. When the hydrochloride salts of the compounds of general formulas (IV’), (V’) and (VI’) are used, the hydrochloride salts are converted in situ to the free compounds of general formulas (IV’), (V’) and (VI’), and then at least 2 molar equivalents of the base are used for carrying out the acylation reaction . In contrast, when the free compounds of general formulas (IV’), (V’) and (VI’) are directly used , at least 1 molar equivalent of the base is used.

[0042] The acid chlorides of general formula (VII) can be used in any desired molar ratio based on the mixture of compounds (IV’), (V’) and (VI’). Typically, 0.9 to 2 molar equivalents of the acid chloride, preferably 0.95 to 1.3 molar equivalents of the acid chloride are used.

[0043] The reaction temperature is - 10 to 120 °C, preferably 0 to 100 °C.

[0044] In principle, the reaction can also be carried out under reduced pressure or high pressure.

[0045] The post-treatment is carried out by known methods in organic chemistry, for example by filtration or extraction.

[0046] The third step (3) of method (B) according to the present invention : Compounds of general formula (VIII’), (IX’) and (X’ ) are converted to compounds of general formula (XI), (XII’) and ( XIII) in the presence of an inert diluent and a strong base.

[0047] Examples of useful diluents include the following: toluene, ortho-xylene, meta-xylene or para-xylene, mesitylene, chlorobenzene, ortho-dichlorobenzene, anisole , acetonitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydro furan, cyclopentyl methyl ether, methyl tert-butyl ether, tert- amyl methyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, methanol, ethanol, 1-butanol , tert-butanol or mixtures of these solvents. Preferably, N,N-dimethylfor mamide, N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP ), methanol, tert-butanol, chlorobenzene, ortho-dichlorobenzene , anisole or mixtures of these solvents. DMAc, NMP, toluene, chloroben zene and anisole are particularly preferred.

[0048] The base used can be, for example, sodium hydroxide, potassium hydroxide, sodium methoxide , potassium methoxide, sodium ethoxide, potassium ethoxide, sodium ter t-butoxide or potassium tert-butoxide. Sodium methoxide and and potassium tert-butoxide are preferred. It is particularly preferred to use sodium methoxide.

[0049] The base is used in an amount of 0.9 to 4 molar equivalents based on the compounds of general formulas (VIII’), (IX’) and (X’). It is preferred to use 1 to 3.5 molar equivalents.

[0050] The temperature is 20 to 170 °C. It is preferred to work between 40 and 150 °C.

[0051] After the pH of the reaction mixture is adjusted to a value between 0 and 8, the compounds of general formulas (XI), (XII’) and (XIII) are isolated by known conventional methods in organic chemistry such as filtration, phase separation or extraction.

[0052] The fourth step (4) of method (B) according to the present invention : A mixture of the compounds of general formulas (XI), (XII’) and (XIII) is reacted with an α,π-diol of general formula (XIV) in the presence of an inert diluent and an acid to obtain the compound of general formula (XI).

[0053] Examples of useful diluents include the following: dichloromethane, toluene, ortho-, meta- or para-xylene, mesitylene, chlorobenzene, ortho-dichlorobenzene, acetonitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, methyl tert-butyl ether, tert-amyl methyl ether, 1,4-dioxane, anisole or mixtures of these solvents. Toluene, ortho-, meta- or para-xylene, chlorobenzene, acetonitrile, butyronitrile, 2-methyltetrahydrofuran, cyclopentylmethyl ether, methyl tert-butyl ether, 1,4-dioxane, anisole or mixtures of these solvents. Toluene, ortho-, meta- or para-xylene, chlorobenzene, acetonitrile, butyronitrile, 2-methyltetrahydrofuran, cyclopentylmethyl ether, methyl tert-butyl ether, 1,4-dioxane, anisole or mixtures of these solvents. Ruel ether, tert-amyl methyl ether, or a mixture of these solvents is preferred.

[0054] The α,π-diol of general formula (XIV) is used in an amount of at least 1 mole per mole of the compounds of general formulas (XII’) and (XIII). Also, it can be carried out with an excess of the α, π-diol of general formula (XIV), and thereby it can also be used as a solvent at the same time.

[0055] The fourth step of the method according to the present invention is carried out in the presence of a catalytic amount of an acid. Possible acids include, for example, the following: hydrogen chloride, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, para-toluenesulfonic acid, or an acidic ion exchange resin, for example, Amberlite. It is preferred to use sulfuric acid or para-toluenesulfonic acid. It is particularly preferred to use sulfuric acid.

[0056] The acid is used in an amount of 0.01 - 20% by weight based on the compounds of general formulas (XII’) and (XIII). 0.05 - 10% by weight is preferred.

[0057] The fourth step of the method according to the present invention is carried out at a temperature of 20 - 150°C, preferably 50 - 120°C.

[0058] To achieve the maximum conversion rate, it may be advantageous to remove the formed water of reaction, for example, by distillation.

[0059] The compound of general formula (XI) is isolated by known conventional methods in organic chemistry such as filtration, phase separation, or extraction.

[0060] Hereinafter, the method (C) according to the present invention will be described in detail.

[0061] ​​​​​​​​The first step (1) of method (C) according to the present invention : The reaction of the alcohol of general formula (XV) of the compound of general formula (III) with thionyl chloride to obtain the hydrochlorides of the compounds of general formulas (IV'), (V') and (VI') can be carried out without a diluent or, optionally, in the presence of an inert diluent such as toluene, chlorobenzene, 1,2-dichlorobenzene, heptane, isooctane, methylcyclohexane, anisole or acetonitrile. Preferably, it is carried out without a diluent, which means that the alcohol used for the esterification is used in excess as a diluent.

[0062] The amount of thionyl chloride can be varied within a wide range. Typically, based on the compound of general formula (III), 0.5 to 5 molar equivalents of thionyl chloride are used. It is preferred to use 0.9 to 3 molar equivalents of thionyl chloride. It is particularly preferred to use 1.2 to 3 molar equivalents of thionyl chloride.

[0063] The reaction temperature is -10 to 150 °C, preferably 0 to 120 °C.

[0064] The reaction can, in principle, also be carried out under reduced pressure or under high pressure.

[0065] The work-up can be carried out, for example, by distilling off the alcohol and the excess thionyl chloride. In this way, the hydrochlorides of the compounds of general formulas (IV'), (V') and (VI') are obtained, which can be used directly in the next step of process (C) according to the invention.

[0066] However, the hydrochlorides of the compounds of general formulas (IV'), (V') and (VI') can be treated with a base By the addition of, it is converted into the free amino acid compounds of general formulas (IV'), (V') and (VI'), and these can also be isolated by conventional post-treatment methods such as filtration or extraction.

[0067] The bases used may be inert inorganic and organic bases, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonia, triethylamine, tributylamine, pyridine or 2-methyl-5-ethylpyridine or a mixture of these bases. It is preferable to use sodium carbonate. Similarly, it is preferable to use a mixture of sodium carbonate and sodium hydroxide.

[0068] The amount of the base is selected so that the proportion of hydrochloric acid (HCl) in the mixture of the hydrochlorides of the compounds of general formulas (IV'), (V') and (VI') is neutralized.

[0069] The second step (2) of method (C) according to the present invention : The hydrochlorides of the compounds of general formulas (IV'), (V') and (VI') or the compounds of general formulas (IV'), (V') and (VI') are reacted with the acid chloride of general formula (VII) in the presence of an inert diluent and a base to obtain the compounds of general formulas (VIII'), (IX') and (X').

[0070] The diluents used may be, for example, dichloromethane, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, heptane, isooctane, methylcyclohexane, ethyl acetate, acetonitrile, anisole, tetrahydrofuran or butyronitrile. Tetrahydrofuran, anisole, toluene, xylene, chlorobenzene or acetonitrile ​​​​​​​​​​​​​​It is preferable to use lil. It is particularly preferable to use toluene, chlorobenzene or anisole. This is particularly preferred.

[0071] The base used may be an inorganic or organic base. Examples here include the following: sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, tributylamine, morpholine, piperidine, pyridine, 2-methyl-5-ethylpyridine. It is preferable to use sodium carbonate or potassium carbonate. It is particularly preferable to use sodium carbonate. It is also particularly preferable to use a mixture of sodium carbonate and sodium hydroxide.

[0072] The amount of the base is derived depending on whether the hydrochloride salts of the compounds of general formulas (IV'), (V') and (VI') or the compounds of general formulas (IV'), (V') and (VI') are used. When the hydrochloride salts of the compounds of general formulas (IV'), (V') and (VI') are used, the hydrochloride salts are converted in situ to the free compounds of general formulas (IV'), (V') and (VI'), and then at least 2 molar equivalents of the base are used for the silylation reaction. In contrast, when the free compounds of general formulas (IV'), (V') and (VI') are used directly, at least 1 molar equivalent of the base is used.

[0073] The acid chlorides of general formula (VII) can be used in any desired molar ratio based on the mixture of compounds (IV'), (V') and (VI'). Typically, 0.9 to 2 molar equivalents of the acid chloride, preferably 0.95 to 1.3 molar equivalents of the acid chloride are used.

[0074] ​The reaction temperature is -10 to 120°C, preferably 0 to 100°C.

[0075] The reaction can in principle also be carried out under reduced or elevated pressure.

[0076] The work-up is carried out by methods known in organic chemistry, for example by filtration or extraction.

[0077] The third step (3) of method (C) according to the present invention General formulas (VIII'), (IX') and (X α,π-dichlorobenzophenone-1, ... Reaction with ol gives a compound of general formula (XVI).

[0078] Examples of useful diluents include: dichloromethane, toluene, ortho-, meta- or para-xylene, mesitylene, chlorobenzene, ortho-dichlorobenzene, acetonitrile Nitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclohexyl penthyl methyl ether, methyl tert-butyl ether, tert-amyl methyl Ether, 1,4-dioxane, anisole or a mixture of these solvents. benzene, ortho-, meta- or para-xylene, chlorobenzene, acetonitrile, butyl tetrahydrofuran, cyclopentyl methyl ether, methyl t tert-butyl ether, tert-amyl methyl ether or a mixture of these solvents Particularly preferred are anisole, toluene and chlorobenzene.

[0079] The α,π-diol of general formula (XIV) is a diol of general formula (VIII'), (IX') and (X' ) is used in an amount of at least 0.5 moles based on 1 mole of the compound. It is possible to carry out in the α,π-diol of formula (XIV), whereby simultaneously It can also be used as a solvent.

[0080] The third stage of process (C) according to the invention is carried out in the presence of a catalytic amount of an acid. Possible acids include, for example, hydrogen chloride, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, para-toluenesulfonic acid or an acidic ion exchange resin, for example Amberlite. It is preferred to use sulfuric acid, hydrochloric acid or para-toluenesulfonic acid. It is particularly preferred to use hydrochloric acid or para-toluenesulfonic acid.

[0081] The acid is used in an amount of 0.01 to 2 0% by weight based on the compounds of general formula (VIII’), (IX’) and (X’). 0.05 to 10% by weight is preferred.

[0082] The third stage of process (C) according to the invention is carried out at a temperature of 20 to 150 °C, preferably 50 to 140 °C.

[0083] To achieve maximum conversion, it may be advantageous to remove the water of reaction formed, for example by distillation.

[0084] The compound of general formula (XVI) is isolated by customary methods known in organic chemistry such as filtration, phase separation or extraction.

[0085] The fourth step (4) of method (C) according to the present invention : The compound of general formula (XVI) is converted to the compound of general formula (XI) in the presence of an inert diluent and a strong base.

[0086] Examples of useful diluents include the following: toluene, ortho-, meta- or para-xylene ​​​Lenn, mesitylene, chlorobenzene, ortho-dichlorobenzene, acetonitrile, butyl ronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethy l ether, methyl tert-butyl ether, tert-amyl methyl ether, 1, 4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone, methanol, ethanol, 1-butanol, tert-butanol, anisole or a mixture of these solvents. Preferably, N,N-dimethylformamide, N ,N-dimethylacetamide, N-methylpyrrolidone, methanol, tert-butanol l, anisole, chlorobenzene, ortho-dichlorobenzene or a mixture of these solvents is. DMAc, NMP, xylene, toluene, chlorobenzene, anisole are particularly preferred . DMAc, toluene, chlorobenzene, anisole are very particularly preferred.

[0087] The base used is, for example, sodium methoxide, potassium methoxide, sodium eth oxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium lium tert-butoxide or potassium tert-butoxide. Preferred are sodium hydroxide, sodium methoxide and potassium tert-butoxide . It is particularly preferred to use sodium methoxide.

[0088] The base is used in an amount of 0.9 to 4 molar equivalents based on the compound of general formula (XVI) . It is preferred to use 1 to 3.5 molar equivalents.

[0089] The temperature is 20 to 170 °C. It is preferably carried out between 40 and 150 °C.

[0090] After the pH of the reaction mixture is adjusted to a value between 0 and 8, the compound of general formula (XI) is isolated by conventional methods known in organic chemistry such as filtration , phase separation or extraction.

[0091] In a preferred embodiment of the present invention, toluene is used as a solvent in the second, third and fourth steps of method C .

[0092] In a preferred embodiment of the present invention, toluene is used as a solvent in the second and third steps of method C, and DMAc is used as a solvent in the fourth step of method C .

[0093] In a preferred embodiment of the present invention, chlorobenzene is used as a solvent in the second, third and fourth steps of method C .

[0094] In a preferred embodiment of the present invention, chlorobenzene is used as a solvent in the second and third steps of method C, and DMAc is used as a solvent in the fourth step of method C .

[0095] In a preferred embodiment of the present invention, anisole is used as a solvent in the second, third and fourth steps of method C .

[0096] In a preferred embodiment of the present invention, chlorobenzene is used as a solvent in the first, second, third and fourth steps of method C .

[0097] The present invention also relates to the general formula (V') [Chemical formula]

[0098] [Group R 7is an optionally branched C2- to C8-alkyl, preferably, R 7 is ethyl, n-propyl, i-propyl, n-butyl or n-hex yl, more preferably, R 7 is ethyl, n-propyl or n-butyl, very preferably, R 7 is n-propyl or n-butyl〕 to provide a novel compound of.

[0099] The present invention also relates to the general formula (VI')[[]]

Chemical formula

[0100] 〔wherein, R 7 is an optionally branched C3- to C8-alkyl, preferably, R 7 is n-propyl, i-propyl, n-butyl or n-hexyl and, more preferably, R 7 is n-propyl or n-butyl〕 to provide a novel compound of.

[0101] The present invention also relates to the general formula (IX')[[]]

Chemical formula

[0102] 〔wherein, R 7 is an optionally branched C2- to C8-alkyl, and R 8 、R 9 、R 10 、R 11 and R 12 are independently hydrogen, methyl, ethyl, methyl - phenyl which may be substituted with ethyl, methoxy, ethoxy or halogen, being methoxy, ethoxy, fluorine, chlorine or bromine〕 to provide a novel compound of

[0103] Most preferably, R 7 is ethyl, n - propyl, i - propyl, n - butyl or n - hexyl, R 8 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, methyl, chlorine or bromine, R 11 is hydrogen, and R 12 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine.

[0104] Particularly preferably, R 7 is ethyl, n - propyl or n - butyl, R 8 is methyl, ethyl, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, chlorine or bromine, R 11 is hydrogen, and R 12 is methyl, ethyl, chlorine or bromine.

[0105] Very preferably, R 7 is ethyl, n - propyl or n - butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R11 is hydrogen, and R 12 is methyl.

[0106] Very exceptionally preferably, R 7 is n-propyl or n-butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen, and R 12 is methyl.

[0107] The present invention also provides a novel compound of general formula (X’)

Chemical formula

[0108] 〔wherein, R 7 is optionally branched C2-~C8-alkyl, and R 8 , R 9 , R 10 , R 11 and R 12 are independently hydrogen, methyl, ethyl, methyl -, ethyl-, methoxy-, ethoxy- or halogen-substituted phenyl, methoxy, ethoxy, fluorine, chlorine or bromine〕 is provided.

[0109] Most preferably, R 7 is ethyl, n-propyl, i-propyl, n-butyl or n-hexyl, R 8 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, methyl, chlorine or bromine, R 11 is hydrogen, and R 12 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine.

[0110] Particularly preferably, R 7 is ethyl, n-propyl or n-butyl, R 8 is methyl, ethyl, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, chlorine or bromine, R 11 is hydrogen, and R 12 is methyl, ethyl, chlorine or bromine.

[0111] Very preferably, R 7 is ethyl, n-propyl or n-butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen and R 12 is methyl.

[0112] Very exceptionally preferably, R 7 is n-propyl or n-butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen, and R 12 is methyl.

[0113] The present invention similarly provides a novel compound of general formula (XII’)

Chemical formula

[0114] 〔wherein, R 7 is an optionally branched C2-~C8-alkyl, and R 8 、R 9 、R 10 、R 11 and R 12 are independently hydrogen, methyl, ethyl, methyl -, ethyl-, methoxy-, ethoxy- or halogen-substituted phenyl which may be substituted, methoxy, ethoxy, fluorine, chlorine or bromine〕 is provided.

[0115] Most preferably, R 7 is ethyl, n-propyl, i-propyl, n-butyl or n-hexyl, R 8 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, methyl, chlorine or bromine, R 11 is hydrogen, and R 12 is hydrogen, methyl, ethyl, methoxy, ethoxy, chlorine or bromine.

[0116] Particularly preferably, R 7 is ethyl, n-propyl or n-butyl, R 8 is methyl, ethyl, chlorine or bromine, R 9 is hydrogen, R 10 is hydrogen, chlorine or bromine, R 11 is hydrogen, and R 12 is methyl, ethyl, chlorine or bromine.

[0117] Very preferably, R 7 is ethyl, n-propyl or n-butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen, and R 12 is methyl.

[0118] Very exceptionally preferably, R 7 is n-propyl or n-butyl, R 8 is methyl, R 9 is hydrogen, R 10 is chlorine, R 11 is hydrogen, and R 12 is methyl.

[0119] The definitions and explanations of the general groups listed above, or those listed in the preferred ranges, can be arbitrarily combined with each other. In other words, combinations between each range and the preferred ranges are included. They apply to both the final product and correspondingly the precursors and intermediates. are applied.

Example

[0120] The present invention will be described in detail by the following examples, but is not limited thereby. No.

[0121] Examples Example 1 Methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate, methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate and methyl 1- amino-4-oxocyclohexanecarboxylate

Chemical formula

[0122] 29.1 g [0.145 mol] of 8-amino-1,4-dioxaspiro[4.5]de cane-8-carboxylic acid forms the initial charge in 160 g of methanol. At 0 - 5 °C , while cooling, 34.4 g [0.289 mol] of thionyl chloride is metered in. The mixture is left to warm to 20 °C and stirred at 20 °C for 16 hours, then further stirred for 4 hours under reflux (64 °C). Methanol and thionyl chloride are distilled off under reduced pressure. The residue is adjusted to pH 8 with sodium hydroxide solution (32%), and extracted twice with 100 ml each of methyl tert-butyl ether (M TBE). The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure . 19.5 g of residue is obtained, which consists of 1 H and 13 by 1H and 13C NMR analysis,

[0123] Quantification 1 Composition by 1H NMR: 61% methyl 8-amino-1,4-dioxaspiro[4 .5] Decane-8-carboxylate; 9% methyl 1-amino-4,4-dimethoxycyclo hexanecarboxylate; 21% methyl 1-amino-4-oxocyclohexanecar boxylate Methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate : 13 C-NMR (150 MHz, d-DMSO): δ = 30.2 (CH2), 32.5 (CH2), 51.8 ( Me -OCO), 55.9 ( C (NH2)COOMe), 63.7 (O- C H2-C), 63.8 (O- C H2-C), 107.8 ( C -OCCO-), 177.6 ( C (=O)OMe) p pm. Methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate: 13 C-NMR (1 50 MHz, d-DMSO): δ = 27.7 (CH2), 31.5 (CH2), 47.0 ( Me O-C(OMe)), 47.1 ( Me O-C(OMe )), 51.8 ( Me -OCO), 56.2 ( C (NH2)COOMe), 99.2 ( C (OMe)2), 177.6 ( C (=O)OMe) ppm. Methyl 1-amino-4-oxocyclohexanecarboxylate: 13 C-NMR (150 MHz, d-DMSO): δ = 34.1 (CH2), 36.6 (CH2), 52.0 ( Me -OCO), 55.7 ( C (NH2)COOMe), 177.1 ( C(=O)OMe), 210.1 (C- C (=O)-C) ppm. Example 2 Ethyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and ethyl 1-amino-4-oxocyclohexanecarboxylate [Chemical formula]

[0124] The procedure is the same as in Example 1, except that ethanol is used instead of methanol. A 29 g mixture is obtained, which 1 by H and 13 C NMR analysis consists of two title compounds.

[0125] Quantification 1 Composition by H NMR: 83.6% ethyl 8-amino-1,4-dioxaspiro [4.5]decane-8-carboxylate; 16.7% ethyl 1-amino-4-oxo cyclohexanecarboxylate.

[0126] Ethyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate : 13 C-NMR (150 MHz, d-DMSO): δ = 14.2 ( C H3-CH2O(CO)), 30.3 (CH2), 32.5 (CH2), 5 5.9 ( C (NH2)COOMe), 60.3 (CH3- C H2O(CO)), 63.8 (O- C H2-C), 107.8 ( C -OCCO-), 177.1 ( C (=O)OMe) ppm. Ethyl 1-amino-4-oxocyclohexanecarboxylate:13 C-NMR (150 MHz, d-DMSO): δ = 14.2 ( C H3-CH2O(CO)), 34.2 (CH2), 36.6 (CH2), 55.6 ( C (NH2)COOMe), 6 0.5 (CH3- C H2O(CO)), 176.6 ( C (=O)OMe), 210.2 ((C- C (=O)-C) ppm. Example 3 n-propyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxy rate

Chemical formula

[0127] The procedure is the same as in Example 1 except that 1-propanol is used instead of methanol to obtain 29.5 g of the title compound

[0128] Quantification 1 Purity by 1H NMR: 90% n-propyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxy rate: 13 C-NMR (150 MHz, d-DMSO): δ = 10.4 ( C H3-CH2CH2O(CO)), 21.7 (CH3- C H2CH2 O(CO)), 30.3 (CH2), 32.5 (CH2), 56.0 ( C (NH2)COOMe), 63.8 (O- C H2-C), 65.7 (CH3CH2 - C H2O(CO)), 107.8 ( C -OCCO-), 177.1 ( C (=O)OMe) ppm Example 4 n-Propyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate n-Propyl 1-amino-4,4-dipropoxycyclohexanecarboxylate and n-Propyl 1-amino-4-oxocyclohexanecarboxylate

Chemical formula

[0129] 99 g [0.492 mol] of 8-amino-1,4-dioxaspiro[4.5]decane -8-carboxylic acid is initially charged into 200 g of 1-propanol. While cooling at 0-5 °C, 76.1 g [0.64 mol] of thionyl chloride is metered in within 1 hour. The mixture is left to warm up to 20 °C and stirred at 20 °C for 16 hours, then further stirred under reflux for 6 hours Propanol and thionyl chloride are distilled off under reduced pressure. The residue is adjusted to pH 8 with sodium carbonate solution and extracted twice with 150 ml of methyl tert-butyl ether (MTBE) each time The combined organic phases are washed with 50 ml of water, dried over sodium sulfate, and concentrated under reduced pressure 100 g of residue is obtained, which consists of 1 H and 13 by 13C NMR analysis, of the three title compounds

[0130] Quantification 1 1H NMR: 69% n-Propyl 8-amino-1,4-dioxaspiro[4.5 decane-8-carboxylate; 16% n-Propyl 1-amino-4,4-dipropoxy cyclohexanecarboxylate; 10% n-Propyl 1-amino-4-oxocyclo hexanecarboxylate ​​n-Propyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxy Rate: 13 C-NMR (150 MHz, d6-DMSO): δ = 10.4 ( C H3-CH2CH2O(CO)), 21.7 (CH3- C H2CH 2O(CO)), 30.3 (CH2), 32.5 (CH2), 56.0 ( C (NH2)COOMe), 63.8 (O- C H2-C), 65.7 (CH3CH 2- C H2O(CO)), 107.8 ( C -OCCO-), 177.1 ( C (=O)OMe) ppm n-amino-4-propyl 1-amino-4-dipropoxycyclohexanecarboxylate Rate: 13 C-NMR (150 MHz, d6-DMSO): δ = 10.5 ( C H3-CH2CH2O(CO)), 11.0 / 11.1 (C(OCH2 CH2 C H3)2), 21.7 (CH3- C H2CH2O(CO)), 23.0 (2xCH2), 30.3 (2xCH2), 32.6 (2xCH2), 56. 0 ( C (NH2)COOPr), 60.7 / 60.8 (C(O C H2CH2CH3)2), 65.7 (CH3CH2- C H2O(CO)), 98.9 ( C (OCH 2CH2CH3)2), 177.2 (C- C O-OPr) ppm n-Propyl 1-amino-4-oxo-cyclohexanecarboxylate: 13 C-NMR (1 50 MHz, d6-DMSO): δ = 10.4 ( CH3-CH2CH2O(CO)), 21.5 (CH3- C H2CH2O(CO)), 29.6 (2x CH2), 35.8 (2xCH2), 57.3 ( C (NH2)COOPr), 67.9 (CH3CH2- C H2O(CO)), 170.9 (C- C O-OPr) , 207.8 (C-( C =O)-C) ppm Example 5 n-butyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and n-butyl 1-amino-4,4-dibutoxycyclohexanecarboxylate

Chemical formula

[0131] The procedure was the same as in Example 1 except that 1-butanol was used instead of methanol and 39 g of a mixture was obtained, which was 1 H and 13 by 1H and consisted of the two title compounds

[0132] Quantification 1 Composition by 1H NMR: 69% n-butyl 8-amino-1,4-dioxaspiro [4.5]decane-8-carboxylate and 23% n-butyl 1-amino-4,4 -dibutoxycyclohexanecarboxylate n-butyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate: 13 C-NMR (150 MHz, d6-DMSO): δ = 13.7 ( C H3-CH2CH2CH2O(CO)), 18.8 (CH3- C H2C ​H2CH2O(CO)), 30.4 (CH3-CH2 C H2CH2O(CO)), 30.4 ( C H2), 32.6 (CH2), 56.0 ( C (NH2)COOM e), 63.7 (O- C H2-C), 63.9 (CH3CH2CH2- C H2O(CO)), 107.8 ( C -OCCO-), 177.1 ( C (=O)OMe) ppm n-butyl 1-amino-4,4-dibutoxycyclohexanecarboxylate: 13 C-NM R (150 MHz, d6-DMSO): δ = 13.7 ( C H3-CH2CH2CH2O(CO)), 14.0 ( C H3CH2CH2CH2O-C(OBu) , 18.8 (CH3- C H2CH2CH2O(CO)), 19.3 (CH3 C H2CH2CH2O-C(OBu), 28.7 ( C H2), 30.4 (CH3-C H2 C H2CH2O(CO)), 31.6 ( C H2), 31.9 (CH3CH2 C H2CH2O-C(OBu), 56.2 ( C (NH2)COOBu), 58.8 (CH3CH2CH2 C H2O-C(OBu), 63.8 (CH3-CH2CH2 C H2O(CO)), 98.9 ( C (OBu)2), 177.2 ( C (=O)O Bu) ppm Example 6 n-propyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1 ,4-Dioxaspiro[4.5]decane-8-carboxylate [Chemical formula]

[0133] 27 g [0.111 mol] of n-propyl 8-amino-1,4-dioxaspiro[4 .5]decane-8-carboxylate (compound from Example 3) forms the initial charge in 70 g of 20% aqueous sodium hydrogen carbonate. At about 5 °C, 24.1 g [0.111 mol] of (4-chloro-2,6-dimethylphenyl)acetyl chloride in 20.3 g of toluene is metered in within about 2 hours. During this metered addition, 35 g of water and 50 g of toluene are added to the reaction mixture. After the metered addition is complete, stirring is continued at 20 °C for a further 1 hour, and the solid is suction filtered, washed with water, and dried. This gives 29.5 g of the title compound.

[0134] Quantification 1 Purity by 1H NMR: 92% 13 13C-NMR (150 MHz, d6-DMSO): δ = 10.4 ( C H3-CH2CH2O(CO)), 19.9 ( C H3-Ar), 21.7 (CH 3- C H2CH2O(CO)), 29.9 (CH2), 30.2 (CH2), 35.2 (N-CO- C H2-Ar), 57.5 ( C (NHCO)COOPr), 63.8 (O- C H2 C H2O), 65.9 (CH3CH2- C H2O(CO)), 107.3 ( C (OCH2CH2O)), 127.1 ( C Ar -H), 1​ 30.4 ( C Ar -Cl), 133.0 (COCH2- C Ar ), 139.6 ( C Ar -Me), 169.6 (N- C O-CH2), 173.7 (C- C O- OPr) ppm Reprecipitation: n-propyl 1-[2-(4-chloro-2,6-diethylphenyl)acetamido]- 4-oxocyclohexanecarboxylate

Chemical formula

[0135] n-propyl 1-[2-(4-chloro-2,6-diethylphenyl)acetamido]- 4-oxocyclohexanecarboxylate: 13 C-NMR (150 MHz, d6-DMSO): δ = 10.4 (C H3-CH2CH2O(CO)), 19.9 (CH3-Ar), 21.7 (CH3-CH2CH2O(CO)), 31.5 (CH2), 35.2 (N-CO-C H2-Ar), 36.4 (CH2), 57.2 (C(NHCO)COOPr), 66.2 (CH3CH2-CH2O(CO)), 127.0 (C Ar -H), 130.4 (C Ar -Cl), 132.9 (COCH2-C Ar ), 139.7 (C Ar -Me), 170.0 (N-CO-CH2), 173.1 (C-CO -OPr), 209.1 (C-CO-C) ppm n-propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]ami no]-4,4-dipropoxycyclohexanecarboxylate [Chemical formula]

[0136] 13 C-NMR (150 MHz, d6-DMSO): δ = 10.4 ( C H3-CH2CH2O(CO)), 11.0 (2x C(OCH2CH2 C H3)2 ), 20.1 (2x Aryl- C H3), 21.6 (CH3- C H2CH2O(CO)), 22.9 / 23.0 (2xCH2), 28.6 (2xCH2), 28.9 (2xCH2), 35.2 (Aryl- C H2-(CO)N), 57.8 ( C (NH2)COOPr), 60.8 / 60.9 (C(O C H2CH2CH3 )2), 65.8 (CH3CH2- C H2O(CO)), 98.5 ( C (OCH2CH2CH3)2), 126.6 (2x C Ar -H), 128.8 ( C Ar -Cl), 136.3 (COCH2- C Ar ), 138.9 (2x C Ar -Me), 169.4 (N- C O-CH2), 173.7 (C- C O-OPr) p pm Example 7 Methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate [Chemical formula]

[0137] 2748 g [11.56 mol] of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid hydrochloride was initially charged in 50 liters of methanol, and then 2050 g [17.23 mol] of thionyl chloride was metered in within 1 hour at 5-10 °C. The mixture was stirred at 40-45 °C for 48 hours, then cooled to 5 °C, the mixture was filtered, and the solid was washed with 3 liters of methanol. The filtrate was concentrated under reduced pressure. The obtained residue was stirred in a solution of 1900 g of potassium carbonate in 8 liters of water, and extracted 5 times with 8 l of methylene chloride each time. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. The mixture was stirred at 40-45 °C for 48 hours, then cooled to 5 °C, the mixture was filtered, and the solid was washed with 3 liters of methanol. The filtrate was concentrated under reduced pressure. The obtained residue was stirred in a solution of 1900 g of potassium carbonate in 8 liters of water, and extracted 5 times with 8 l of methylene chloride each time. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. The mixture was stirred at 40-45 °C for 48 hours, then cooled to 5 °C, the mixture was filtered, and the solid was washed with 3 liters of methanol. The filtrate was concentrated under reduced pressure. The obtained residue was stirred in a solution of 1900 g of potassium carbonate in 8 liters of water, and extracted 5 times with 8 l of methylene chloride each time. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. The mixture was stirred at 40-45 °C for 48 hours, then cooled to 5 °C, the mixture was filtered, and the solid was washed with 3 liters of methanol. The filtrate was concentrated under reduced pressure. The obtained residue was stirred in a solution of 1900 g of potassium carbonate in 8 liters of water, and extracted 5 times with 8 l of methylene chloride each time. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. The mixture was stirred at 40-45 °C for 48 hours, then cooled to 5 °C, the mixture was filtered, and the solid was washed with 3 liters of methanol. The filtrate was concentrated under reduced pressure. The obtained residue was stirred in a solution of 1900 g of potassium carbonate in 8 liters of water, and extracted 5 times with 8 l of methylene chloride each time. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. The mixture was stirred at 40-45 °C for 48 hours, then cooled to 5 °C, the mixture was filtered, and the solid was washed with 3 liters of methanol. The filtrate was concentrated under reduced pressure. The obtained residue was stirred in a solution of 1900 g of potassium carbonate in 8 liters of water, and extracted 5 times with 8 l of methylene chloride each time. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained. Thereby, 2240 g of an oil containing 65.4% of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate and 31.1% of methyl 1-amino-4,4-dimethoxycyclohexanecarboxylate was obtained.

[0138] Example 8 Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate, methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4,4-dimethoxycyclohexanecarboxylate and methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxocyclohexanecarboxylate Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate, methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4,4-dimethoxycyclohexanecarboxylate and methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxocyclohexanecarboxylate Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate, methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4,4-dimethoxycyclohexanecarboxylate and methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxocyclohexanecarboxylate Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate, methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4,4-dimethoxycyclohexanecarboxylate and methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxocyclohexanecarboxylate Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate, methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4,4-dimethoxycyclohexanecarboxylate and methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxocyclohexanecarboxylate

Chemical Structure

[0139] 67.5% methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carbo xylate [0.313 mol], 30.1% methyl 1-amino-4,4-dimethoxysy clohexanecarboxylate [0.138 mol] and 0.5% methyl 1-amino-4 -oxocyclohexanecarboxylate [0.003 mol] in a mixture of 100 g is dissolved in ace tonitrile 1.44 l. While stirring, 121 g of potassium carbonate is added, and then about 90 ml of wet acetonitrile is distilled off for azeotropic drying. Then, the mixture is cooled to 5 °C, and a solution of 95.5 g [0.44 mol] of (4-chloro-2,6-dimethylpheny l)acetyl chloride is added dropwise within 2 hours. Next, the mixture is stirred at 5 °C for a further 2 hou rs and at 20 °C for 16 hours, then the reaction mixture is stirred into 6.6 liters of water, filtered , the solid is washed with 0.7 liter of water and dried. The result is 165 g of a white solid, which by GC-MS analysis is 69.2% methyl 8-[2-(4-chloro-2,6- dimethylphenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-car boxylate, 20.1% methyl 1-[2-(4-chloro-2,6-dimethylphenyl )acetamido]-4,4-dimethoxycyclohexanecarboxylate and 7.8% of methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxo cyclohexanecarboxylate.

[0140] Example 9 Methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-1,4- dioxaspiro[4.5]decane-8-carboxylate, methyl 1-[2-(4-chloro Ro-2,6-dimethylphenyl)acetamide]-4,4-dimethoxycyclohexaneca Ruboxylate and methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acet Amide]-4-oxocyclohexanecarboxylate

Chemical formula

[0141] To an initial charge of 4.23 g (11.1 mmol) of 8-[2-(4-chloro-2,6- Dimethylphenyl)acetamide]-1,4-dioxaspiro[4.5]decane-8-carboxylic acid in 50 ml of methanol, 0.11 g of concentrated sulfuric acid was added and the mixture was heated to reflux for 16 h. Subsequently, the reaction mixture was concentrated under reduced pressure. Thereby, by GC-MS analysis, a residue of 57.6% of methyl 8-[2-(4-chloro-2,6-dimethylphenyl)acetamide]-1,4-dioxaspiro [4.5]decane-8-carboxylate and 35.2% of methyl 1-[2-(4-chloro-2,6-dimethylphenyl )acetamide]-4,4-dimethoxycyclohexanecarboxylate, 5 .5 g was obtained.

[0142] Example 10 11-(4-chloro-2,6-dimethylphenyl)-12-hydroxy-1,4-dioxa Sa-9-azadispiro[4.2.48.25]tetradec-11-en-10-one, 3 -(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8,8-dimethoxy- 1-azaspiro[4.5]dec-3-en-2-one and 3-(4-chloro-2,6-di Methylphenyl)-4-hydroxy-1-azaspiro[4.5]dec-3-en-2,8 -dione [Chem.]

[0143] 5491 g [48.934 mol] of KOtBu was dissolved in 31 liters of dimethylformamide (DMF), and then 6550 g of a mixture of 68.3% methyl 8-[2-(4-chloro-2,6-dimethyl phenyl)acetamido]-1,4-dioxaspiro[4.5]decane-8-carboxylate, 16.8% methyl 1-[2-(4-chloro-2,6-dimethylphenyl)a cetamido]-4,4-dimethoxycyclohexanecarboxylate, and 12.1% methyl 1-[2-(4-chloro-2,6-dimethylphenyl)acetamido]-4-oxocyclohexanecarboxylate was added little by little within 2 hours, and the reaction mixture was warmed to 40 °C during this process. The mixture was stirred at 40 °C for an additional 3 hours, stirred overnight at room temperature, 26 liters of DMF was distilled off under reduced pressure, 75 liters of ice water was added to the residue, 4 liters of glacial acetic acid was added thereto, and the mixture was stirred at 15 °C overnight. The precipitated solid was suction filtered, washed three times with 5 liters of water each time, and dried. The result was 5720 g of the following composition by HPLC analysis: 71.8% 11-(4-chloro-2,6-dimethylphenyl)-12-hydroxy-1 71.8% 11-(4-chloro-2,6-dimethylphenyl)-12-hydroxy-1 <Pyrrolo[4.5]deca-3-ene-2,8-dione Example 11 11-(4-Chloro-2,6-dimethylphenyl)-12-hydroxy-1,4-dioxaspiro[4.2.4.8.2.5]tetradec-11-ene-10-one 9-Azadispiro[4.2.4.8.2.5]tetradec-11-ene-10-one

Chem.

[0144] 5720 g of the product mixture from Example 10 is suspended in 27 liters of ethylene glycol , and 95 g of para-toluenesulfonic acid is added. The mixture is heated to about 130 °C (bath temperature 155 °C) for 2 hours while stirring. Subsequently, at the same bath temperature, 4 liters of acetonitrile is metered in, as a result of which the internal temperature drops to about 111 °C. The mixture is stirred at the same bath temperature for 3 hours , and the acetonitrile is first distilled off at standard pressure, and then the pressure is reduced to about 200 mbar and distilled off until the internal temperature rises to about 130 °C again . The mixture is stirred at 130 °C overnight , then cooled to room temperature, the solid is suction filtered, stirred in 30 liters of water for 1 hour, suction filtered again , washed with 10 l of water, and dried. This gives 5080 g of a light beige solid which, according to HPLC analysis, consists of the title compound to about 99.3% .

[0145] Example 12

Chem.

[0146] An initial charge of 60 g [0.296 mol] of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (99%) in 154 g of 1-propanol is heated to 80 - 85 °C Heat to ℃ and meter and supply 24.8 g of thionyl chloride at 0.5 ml / min. After the metering addition is completed, stir the mixture at 90 °C for an additional 3 hours and then cool to 40 - 45 °C. At about 3 0 mbar, remove 89 g of the distillate, then break the vacuum and cool the mixture to 5 - 10 °C . Next, meter and supply 9.3 g of NaOH and 61.9 g of Na2CO3 dissolved in 300 g of water at a rate such that the internal temperature is always kept below 10 °C. Next, meter 128 .6 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride in THF (42. 2% solution) into the reaction mixture at 2.5 ml / min. Add 200 g of THF and then adjust the mixture to pH 7 - 8 with dilute HCl. Remove the organic phase and concentrate it on a rotary evaporator . This gives 125 g of a mixture of n-propyl 8-[[2-(4-chloro-2,6-dimethyl phenyl)acetyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate (65%) / n-propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino no]-4,4-dipropoxycyclohexanecarboxylate (8%) / n-propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino no]-4-oxocyclohexanecarboxylate (13%). Yield: 86%

[0147] Yield: 86% Example 13

Chemical formula

[0148] 20 g [0.041 mol] of the crude product isolated from Example 12, 60 g of xylene, In 3.9 g of ethanediol and 0.3 g of para-toluenesulfonic acid, at 130 °C for 4 hours Stir, and further add 0.9 g of para-toluenesulfonic acid and 3.9 g of ethanediol, Reflux the mixture for an additional 8 hours. Next, distill off xylene using a rotary evaporator, Take up the residue in 80 g of DMAc. First, distill DMAc and remove 25 g of the distillate. Then, Add 8 g of sodium methoxide (30% solution in methanol) at an internal temperature of 110 °C . Repeat incipient distillation at 250 mbar and an internal temperature of about 100 - 110 °C, then cool the mixture to 80 °C, add 50 g of water, and then 10 g of acetic acid . After cooling to room temperature, filter the suspension by suction and wash with 30 g of water. 2 -(4-Chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxa- 4-azadispiro[4.2.48.25]tetradec-1-en-3-one 9.5 g is obtained in a yield of 64% and a purity of 97%.

[0149] Example 14

Chemical formula

[0150] First, charge 550 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate (~78% purity) into 724 g of water at room temperature. Gradually add 20% HCl to the mixture until the pH reaches 5 - 6. Filter the suspension by suction, wash the filter cake with 212.6 g of water, and then dry it .

[0151] Yield: 356.7 g (92%) of 8-amino-1,4-dioxaspiro[4.5]decane ​​​-8-carboxylic acid, purity 94 mass% NMR 1 H-NMR (600 MHz, d-D2O + 1 drop of NaOD): δ = 1.55-1.60 (m, 2H), 1.69-1.73 (m, 2H), 1.77-1.82 (m, 2H), 2.00-2.04 (m, 2H), 4.021 (s, 4H) ppm Example 15

Chemical formula

[0152] Initial charge of 370.7 g [0.296 mol] of 8-amino- 1,4-dioxaspiro[4.5]decane-8-carboxylic acid (96.7%) in 1178 g of 1-propanol is heated to 80-85 °C, and 233 g of thionyl chloride is metered in within 2 hours. After the metered addition is complete, the mixture is stirred at 90 °C for an additional 3 hours to give a 22-25% (w / w) solution for use in the subsequent reaction.

[0153] Example 16

Chemical formula

[0154] 235.3 g of the solution prepared as in Example 15 is initially distilled at an internal temperature of 25-30 °C and 25 m bar. After removing 128.9 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. After cooling to 0-5 °C, 43.8 g of Na 2CO3 dissolved in 400 g of water is metered in slowly enough to keep the temperature constantly below 5 °C. After the metered addition is complete 121.9 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride​ (39.5% in toluene, 0.85 eq) is added within 1 hour at a rate such that the internal temperature does not exceed 5 °C. The mixture is stirred at 0 - 5 °C for an additional 1 hour and then heated to 73 °C. The organic phase is removed and concentrated on a rotary evaporator. Thereby, 98.8 g of a pale yellow solid consisting of propyl 8 - [2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxo spiro[4.5]decane-8-carboxylate (84%) / propyl 1-[[2-( 4-chloro-2,6-dimethylphenyl)acetyl]amino]-4,4-dipropoxysicy clohexanecarboxylate (7%) / propyl 1-[[2-(4-chloro-2,6- dimethylphenyl)acetyl]amino]-4-oxocyclohexanecarboxylate ( 7%) is obtained. The yield is quantitative.

[0155] Example 17

Chemical formula

[0156] A 232.4 g solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 25 - 30 °C and 25 mbar. After removing 126.8 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. After cooling to 0 - 5 °C, 43.7 g of Na2 CO3 dissolved in 400 g of water is slowly metered in at a rate sufficient to keep the temperature always below 5 °C. After the metered addition is complete then 133.6 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride (39.5% in toluene) is added within 1 hour at a rate such that the internal temperature does not exceed 5 °C. The mixture is stirred at 0 - 5 °C for an additional 3 hours and then heated to 75 °C. The organic phase is removed Remove and concentrate with a rotary evaporator. Thereby, propyl 8-[[2-(4- chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxaspiro[4 .5]decane-8-carboxylate (79%) / propyl 1-[[2-(4-chloro- 2,6-dimethylphenyl)acetyl]amino]-4,4-dipropoxycyclohexane carboxylate (8%) / propyl 1-[[2-(4-chloro-2,6-dimethylphen yl)acetyl]amino]-4-oxocyclohexanecarboxylate (7%) consisting of 103.5 g of a pale yellow solid is obtained. The yield is 97%.

[0157] Example 18

Chemical formula

[0158] 233.2 g of the solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 25 to 30 °C and 25 m bar. After removing 130.6 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. After cooling to 0 to 10 °C, 43.8 g of Na2CO3 dissolved in 381.7 g of water and 32.6 g of 32% sodium hydroxide solution are metered in slowly enough to keep the temperature below 5 °C at all times. After the metering addition is complete, then 121.9 g of 2-(4-ch loro-2,6-dimethylphenyl)acetyl chloride (39.5% in toluene) is added within 1 hour at a rate such that the internal temperature does not exceed 5 °C. The mixture is stirred at 0 to 5 °C for a further 30 minutes and then heated to 72 °C. The organic phase is removed and concentrated with a rotary evaporator. Thereby, propyl 8-[[2-(4-chloro-2,6-dimethylphen yl)acetyl]amino]-1,4-dioxaspiro[4 .5]decane-8-carboxylate (79%) / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4,4-dipropoxycyclohexane 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate -ate (78%) / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acety l]amino]-4,4-dipropoxycyclohexanecarboxylate (8%) consisting of 97.1 g of a pale yellow solid is obtained. The yield is 89%.

[0159] Example 19

Chemical formula

[0160] The initial charge of 227.8 g of the solution described in Example 15 is heated to 40 °C, 400 g of toluene is added, and an initial distillation is carried out under reduced pressure to 25 mbar. After removing 126.1 g of the distillate 400 g of toluene is added, and a further 265.8 g of the distillate is removed at 54 - 70 mbar The vacuum is broken with nitrogen and the mixture is brought to standard pressure. The mixture is cooled to 0 - 5 °C, and a solution of 41.7 g of Na2CO3 in 208 g of water is metered in within 40 minutes, and 128.5 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride (39.9% in toluene) is metered into the white suspension obtained at 0 - 5 °C within 2 hours. After the metered addition is complete the mixture is heated to 77.4 °C, the phases are separated from each other, and the organic phase is concentrated on a rotary evaporator This gives propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acety l]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate (87%) / propyl 1-[(2-(4-chloro-2,6-dimethylphenyl)acety l]amino]-4,4-dipropoxycyclohexanecarboxylate (1%) / pro pyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate (87%) / propyl 1-[(2-(4-chloro-2,6-dimethylphenyl)acety Ropilyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4 -oxocyclohexanecarboxylate (9%) mixture 100.6 g is obtained. The yield is 99%.

[0161] Example 20

Chemical formula

[0162] 225.4 g of a solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 25 to 30 °C and 25 m bar. After removing 119.8 g of the distillate, the vacuum is broken with nitrogen and the mixture is returned to standard pressure. 400 g of toluene is added and the initial distillation is repeated at 50 to 80 mbar . The toluene is continuously replenished during the distillation. In this way, a further 279.9 g of distillate is obtained and a total of 250 g of toluene is replenished. Next, the mixture is aerated to standard pressure and cooled to 15 to 20 °C. At this temperature, 41.4 g of Na2C O3 in 208.6 g of water is first metered in within 30 minutes, followed by 128.5 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride (39.5% in toluene) is added dropwise within 90 minutes at such a rate that the temperature does not exceed 20 °C . The mixture is stirred at 20 °C for a further 1 hour and then heated to 78 °C. The organic phase is removed and concentrated on a rotary evaporator. Thereby propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino -1,4-dioxaspiro[4.5]decane-8-carboxylate (87%) / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4, ​4-Dipropoxycyclohexanecarboxylate (2%) / propyl 1-[[2-(4 -Chloro-2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexane carboxylate (9%) to give 98.1 g of a pale yellow solid. The yield is 98%.

[0163] Example 21

Chemical formula

[0164] 225.6 g of the solution prepared in the same manner as in Example 15 was initially distilled at an internal temperature of 30 - 40 °C and 25 mb ar. After removing 120.5 g of the distillate, the vacuum was broken with nitrogen and the mixture was returned to standard pressure. 400 g of toluene was added and the initial distillation was repeated at 50 - 80 mbar with the toluene being continuously replenished during the distillation. In this way, a further 191.5 g of distillate was obtained and a total of 189 g of toluene was replenished. The mixture was aerated to standard pressure and heated to 40 °C. At this temperature, 41.4 g of Na2CO3 in 208.6 g of water was first metered in within 20 minutes, followed by 12 8.16 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride (39.5% in toluene) being added dropwise within 90 minutes at a rate such that the temperature did not exceed 40 °C . The mixture was stirred at 40 °C for a further 15 minutes and then heated to 77 °C. The organic phase was removed and concentrated on a rotary evaporator. Thereby, propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1,4 -dioxaspiro[4.5]decane-8-carboxylate (88%) / propyl 1- [2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4,4-diprop yl 1,4-dioxaspiro[4.5]decane-8-carboxylate (12%) yl 1,4-dioxaspiro[4.5]decane-8-carboxylate (12%) (7%) carboxypoxycyclohexane / propyl 1-[[2-(4-chloro- 2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexanecarboxy (3%) to obtain 101.92 g of a pale yellow solid. The yield is 99%.

[0165] Example 22

Chemical formula

[0166] 223.5 g of the solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 30 to 40 °C and 25 mbar ar. After removing 123.7 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. 400 g of toluene is added and the initial distillation is repeated at 50 to 80 mbar . Toluene is continuously replenished during the distillation. In this way, an additional 231.75 g of distillate is obtained and a total of 200 g of toluene is replenished. Next, the mixture is aerated to standard pressure and heated to 40 °C. At this temperature, 41.4 g of Na2CO3 in 208.6 g of water is first metered in within 20 minutes, and then 133.65 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride (39.5% in toluene) is added dropwise within 90 minutes at a rate such that the temperature does not exceed 40 °C. The mixture is stirred at 40 °C for an additional 15 minutes and then heated to 77 °C. The organic phase is removed and concentrated on a rotary evaporator. Thereby , propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino] -1,4-dioxaspiro[4.5]decane-8-carboxylate (87%) / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4,4 ​ -Dipropoxycyclohexanecarboxylate (1%) / propyl 1-[[2-(4- Chloro-2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexanecar boxylate (8%) to obtain 103.4 g of a pale yellow solid. The yield is 98%.

[0167] Example 22a

Chemical formula

[0168] 183.22 g of a solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 30-40 °C and 25 m bar. After removing 102.13 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. 330 g of toluene is added, the mixture is heated to 60 °C, and 100-300 mbar and distilled initially again. Toluene is continuously replenished during the distillation. In this way a further 127.5 g of distillate is obtained and a total of 107.6 g of toluene is replenished. Next, the mixture is aerated to standard pressure and, at 60 °C, 33.5 g of Na2CO3 in 171.3 g of water is first metered in within 20 minutes, followed by 133.65 g of 2-(4-chloro-2,6-dimethyl phenyl)acetyl chloride (39.5% in toluene) being added dropwise at a rate not exceeding 6 0 °C within 90 minutes. The mixture is stirred at 40 °C for a further 15 minutes and then heated to 77 °C The organic phase is removed and concentrated on a rotary evaporator. Thereby, pro pyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-1, 4-dioxaspiro[4.5]decane-8-carboxylate (89%) / propyl 1- [[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4,4-dip ropoxycyclohexanecarboxylate (0%) / propyl 1-[[2-(4-chloro -2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexanecarbox ylate (7%) consisting of 84.5 g of a yellow solid is obtained. Yield 97%.

[0169] Example 23

Chemical formula

[0170] 180.4 g of the solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 30 to 40 °C and 25 mbar ar. After removing 94.5 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. 330 g of toluene is added, the mixture is heated to 70 to 80 °C, and then first distilled again at 300 to 400 mbar. Toluene is continuously replenished during the distillation. In this way, an additional 100 g of distillate is obtained and a total of 69.9 g of toluene is replenished to it. Then, the mixture is aerated to standard pressure, and at 60 to 80 °C, 33.5 g of Na2 CO3 in 171.3 g of water is first metered in within 20 minutes, followed by 107.9 g of 2-(4-chloro-2,6- dimethylphenyl)acetyl chloride (39.5% in toluene) is added dropwise within 90 minutes at a rate not exceeding 80 °C . The mixture is stirred at 80 °C for an additional 15 minutes and then heated to 77 °C . The organic phase is removed and concentrated on a rotary evaporator. As a result , propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino -1,4-dioxaspiro[4.5]decane-8-carboxylate (88%) / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4, 4-Dipropoxycyclohexanecarboxylate (0%) / propyl 1-[[2-(4 -Chloro-2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexane carboxylate (6%) to give 81.9 g of a yellow solid. The yield is 93%.

[0171] Example 24

Chemical formula

[0172] 184.4 g of the solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 30 - 40 °C and 25 mbar ar. After removing 99.2 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. 330 g of chlorobenzene is added, the mixture is heated to 40 °C and again initially distilled to 35 mbar. Chlorobenzene is continuously replenished during the distillation. In this way a further 193.2 g of distillate is obtained and a total of 200 g of chlorobenzene is replenished . Then the mixture is vented to standard pressure and, at 40 °C, 33.7 g of Na2 CO3 in 171.3 g of water is first metered in within 20 minutes, followed by 109.6 g of 2-(4-chloro-2,6- dimethylphenyl)acetyl chloride (39.8% in toluene) being added dropwise at a rate not exceeding 40 °C within 90 minutes. The mixture is stirred at 40 °C for a further 30 minutes and then heated to 75 °C. The organic phase is removed and concentrated on a rotary evaporator. Thereby propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino -1,4-dioxaspiro[4.5]decane-8-carboxylate (86%) / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4, 4-Dipropoxycyclohexanecarboxylate (3%) / propyl 1-[[2-(4 -Chloro-2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexane carboxylate (5%) consisting of 81.4 g of a yellow solid is obtained. The yield is 90% .

[0173] Example 25

Chemical formula

[0174] 184.4 g of the solution prepared in the same manner as in Example 15 is initially distilled at an internal temperature of 30 to 40 °C and 25 mbar ar. After removing 99.5 g of the distillate, the vacuum is broken with nitrogen and the mixture is brought to standard pressure. 330 g of chlorobenzene is added, the mixture is heated to 40 °C, and then again to 35 mbar for initial distillation. Chlorobenzene is continuously replenished during the distillation. In this way a further 122 g of distillate is obtained and a total of 120 g of chlorobenzene is replenished . Next, the mixture is vented to standard pressure and at 40 °C, 33.7 g of Na2CO3 in 171.3 g of water is first metered in within 20 minutes, followed by 111.9 g of 2-(4-chloro-2,6-dimethylphenyl)acetyl chloride (39.1% in chlorobenzene) being added dropwise at a rate not exceeding 40 °C within 90 minutes. The mixture is stirred at 40 °C for a further 30 minutes and then heated to 7 5 °C. The organic phase is removed and concentrated on a rotary evaporator. Thereby propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]- 1,4-dioxaspiro[4.5]decane-8-carboxylate (82%) / propyl ​​1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4,4- Dipropoxycyclohexanecarboxylate (7%) / Propyl 1-[[2-(4-chloro- (2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexanecal 86.7 g of a yellow solid consisting of carboxylate (4%) are obtained, the yield being 95%.

[0175] Example 26 [ka]

[0176] 60 g of 8-amino-1,4-dioxaspiro[4. 5) Heat the initial charge of decane-8-carboxylic acid to 70-80°C. g of thionyl chloride is added dropwise to the mixture. The gas formed contains sodium hydroxide solution. The mixture is stirred at 80-90°C for a further 4 hours. The mixture is cooled to 45°C and incipiently distilled under reduced pressure, yielding 120g of distillate. 455 g of toluene was added to the bottom of the distillation column, and an additional 164 g of distillate was removed. Cool to 5°C and measure in 50g of sodium carbonate dissolved in 274g of water within 40 minutes Then, 152.8 g of 2-(4-chloro-2,6-dimethylphenyl)acetamide chloride was added. Chill (40% in toluene) is metered in at a rate such that the temperature does not exceed 5°C. The suspension was heated to 70-80°C, the lower aqueous phase was removed, and the upper organic phase was dissolved in 70 g of water at 80°C. Wash once. Add 9 g of ethanediol and 2.8 g of 7% hydrochloric acid to the organic phase and add 102-110 After 3 hours, the toluene was distilled off and the residue was diluted with 123 g of DMAc. Take it and perform an initial distillation again at about 100 °C under reduced pressure. 101.4 g of 30% sodium meth oxide solution is added to the remaining reaction mixture within 1 hour. Under slightly reduced pressure, continuously obtain the methanol and propanol that are distilled off. Stir the mixture for an additional 4 hours, then add 352 g of water and stir the mixture at 95 °C for an additional 1 hour. Cool the solution to 80 °C, and meter in 56 g of 37% hydrochloric acid. Cool the mixture to room temperature within 2 hours, and filter the formed suspension liquid, wash the filter cake with 2 × 120 g of water, and dry it at 50 °C under reduced pressure. This yields 96 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy-9 ,12-dioxa-4-azadispiro[4.2.4 8 .2 5 tetradec-1-en-3 -one (purity 94%). The yield is 88%.

[0177] Example 27

Chemical formula

[0178] 100 g of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid forms the initial charge in , 319 g of 1-propanol. At 70 - 85 °C, meter in 63.2 g of thionyl chloride within 1 hour, then stir the mixture at 80 - 90 °C for an additional 1 hour . Cool the mixture to 30 °C and perform an initial distillation at 30 - 50 mbar under reduced pressure. This yields 130 g of distillate. Add 470 g of toluene and remove an additional 333 g of distillate by performing an initial distillation again. Cool the bottom product of the column to -5 to 5 °C and dissolve it in 435 g of water containing 87 Weigh and supply 109 g of Na2CO3 within 1 hour, and then weigh and supply 265 g of 2-(4-chloro-2, 6-dimethylphenyl)acetyl chloride as a 39.6% toluene solution within 40 minutes. Stir the mixture at room temperature for an additional 1 hour and heat it to 80 °C. Remove the lower aqueous phase, and then wash the remaining organic phase with 50 g of water. Then, add 9.2 g of para-toluenesulfonic acid and 30 g of ethanediol, reflux the mixture, and separate water for 3 hours. Next, perform an initial distillation of the reaction mixture (308 g of distillate), and add 100 g of DMAc. Perform an initial distillation of the mixture again and remove 15 g of distillate. Weigh and supply 135 g of sodium methoxide (30% solution in methanol) to the remaining mixture at 110 °C within 30 minutes, and distill off the methanol and 1-propanol obtained under slightly reduced pressure for 3 hours. Add 235 g of water, and stir the mixture at 90 - 100 °C for 1 hour. Then, cool the mixture to 80 °C, add 46.4 g of acetic acid within 30 minutes, cool the mixture to room temperature within 3 hours, and filter off the formed suspension. Wash the filter cake with 2 × 150 g of water. Thus, 165 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy -9,12-dioxa-4-azadispiro[4.2.4 8 .2 5 tetradec-1-en 8 -3-one (purity 87%) is obtained. The yield is 82%.

[0179] Example 28

Chemical Structure

[0180] 109 g of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ( 96.9%) is used to form the initial charge in 357 g of 1-propanol. At 70 - 80 °C 71 g of thionyl chloride is metered in within 50 minutes. After the metered addition is complete, the mixture is stirred for about 4 more hours. The initial distillation is carried out up to a maximum jacket temperature of 45 °C and a vacuum of 23 mbar until 178 g of distillate is removed. Then 830 g of toluene is added, and another 462 g of distillate is removed, and the mixture is cooled to -5 - 5 °C. 91 g of Na2CO3 in 500 g of water is added within 1 hour, and subsequently 280 g of 2-(4-chloro-2,6-dimethylphenyl) acetyl chloride (40% in toluene) is added within 1 hour in the same way. The mixture is heated to 80 - 90 °C to remove the aqueous phase, and the organic phase is mixed with 9 g of para-toluenesulfonic acid and 32 g of ethanediol . With a water separator attached, the mixture is refluxed at standard pressure for 5 hours . Toluene is distilled off, and the residue is taken up in 224 g of DMAc. The mixture is first distilled to a small amount , and 185 g of sodium methoxide (30% solution in methanol) is metered in at 100 - 120 °C . Methanol and 1-propanol are distilled off at 100 - 120 °C under slightly reduced pressure over 2 hours. 600 g of water is added to the mixture, and this is stirred at 85 - 100 °C for an additional 1 hour. The mixture is cooled to 80 °C, and 97 g of acetic acid is added within 30 minutes. Then, the mixture is cooled to room temperature, the suspension is suction filtered, and the filter cake is washed with 2 × 180 g of water . After drying under reduced pressure, 171.5 g of 2-(4-chloro-2,6-dimethylphenyl)-1- hydroxy-9,12-dioxa-4-azadispiro[4.2.4 8 .2 5 tetradeca -1-en-3-one is obtained with a purity of 94% and a yield of 86%.

[0181] Example 29

Chem.

[0182] 60 g of 8-amino- in 130 g of 1-propanol and 140 g of chlorobenzene The initial charge of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid is heated to 70 - 80 °C. 70 g of thionyl chloride is added dropwise to this mixture within 30 minutes. The gas formed is removed through a scrubber containing sodium hydroxide solution. The mixture is stirred at 80 - 9 0 °C for an additional 12 hours. The mixture is cooled to 45 °C and initially distilled under reduced pressure. This yields 160 g of distillate. 50 g of sodium carbonate dissolved in 274 g of water is metered in within 40 minutes. Then, 152.8 g of 2-(4-chloro-2,6-dimethyl phenyl)acetyl chloride (40% in toluene) is metered in. The resulting suspension is heated to 7 0 - 80 °C, the lower aqueous phase is removed, and the upper organic phase is washed once with 150 g of water at 80 °C and purified. 9 g of ethanediol and 2.8 g of para-toluenesulfonic acid are added to the organic phase, and while slightly reducing the pressure, water is separated from the mixture at 100 - 110 °C. After 2 hours, an additional 9 g of eth anediol is added, and water is separated for an additional 4 hours. Then, at 110 °C, 105 g of 3 0% sodium methoxide solution is added within 1 hour. While slightly under reduced pressure, the continuously obtained methanol and propanol are distilled off. The mixture is stirred for an additional 4 hours, then 3 25 g of water is added, and the mixture is stirred at 95 °C for an additional 1 hour. The solution is cooled to 80 °C, 43 g of acetic acid is metered in. The mixture is cooled to room temperature over several hours, and the resulting suspension is Filter, wash the filter cake with 2 × 60 g of water, and dry it under reduced pressure at 50 °C. Thereby , 87 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12 -dioxo-4-azadispiro[4.2.4 8 .2 5 tetradeca-1-en-3-one (purity 89%) is obtained. The yield is 77%.

[0183] The following examples proceed from a product mixture of propyl 8-[[2-(4-chloro-2,6-dimethylphenyl)acety l]amino]-1,4-dioxaspiro[4.5]decane-8-carboxylate / propyl 1-[[2-(4-chloro-2,6-dimethylphenyl)acetyl]amino]-4 ,4-dipropyloxycyclohexanecarboxylate / propyl 1-[[2-(4- chloro-2,6-dimethylphenyl)acetyl]amino]-4-oxocyclohexanecarboxylate, but, as in Examples 26-29, without isolation of any intermediate starting from 8-amino -1,4-dioxaspiro[4.5]decane-8-carboxylic acid or their corresponding sodium or potassium salts, it can be carried out similarly. -1,4-dioxaspiro[4.5]decane-8-carboxylic acid or their corresponding sodium or potassium salts, it can be carried out similarly without isolation of any intermediate starting from 8-amino -1,4-dioxaspiro[4.5]decane-8-carboxylic acid or their corresponding sodium

[0184] Example 30

Chemical formula

[0185] To 50 g of the mixture prepared as in Examples 15-25 in 116.7 g of chlorobenzene , add 1.5 g of 37% hydrochloric acid and 3.8 g of ethanediol, heat the mixture to reflux, after 4 hours, add an additional 1.5 g of hydrochloric acid, and stir the mixture under reflux for an additional 3 hours. The mixture Cool the compound to 115 °C and meteredly feed 42.8 g of sodium methoxide (30% solution in methanol) within 30 minutes under slightly reduced pressure. Continuously distill off the resulting methanol and 1-propanol for 2 hours. Add 118 g of water to the mixture and stir it at 90 - 100 °C for 1 hour. Cool the mixture to 80 °C and meteredly feed 23.2 g of 37% hydrochloric acid within 30 minutes . Cool the mixture to room temperature over several hours, add another 50 g of water to the formed suspension to obtain stirrability, then filter. Wash the filter cake with 3 × 60 g of water. Thus, 33.9 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy -9,12-dioxa-4-azadispiro[4.2.4 .2 8 .2 5 tetradec-1-en -3-one is obtained with a purity of 95%. The yield is 87% based on the mixture used.

[0186] Example 31

Chemical Structure

[0187] To 50 g of the mixture prepared in the same manner as in Examples 15 - 25 in 116.7 g of chlorobenzene, add 1.5 g of 37% hydrochloric acid and 3.8 g of ethanediol, and stir the mixture under reflux for 3 hours with a water separator attached. Initially distill off a small amount of chlorobenzene, add 100 g of DMAc, and distill off chlorobenzene under reduced pressure at a jacket temperature of 130 °C. At 94 °C, add 2.8 g of sodium methoxide to the mixture within 30 minutes, and distill off 1-propanol and methanol under slightly reduced pressure for 2 hours. Then, add 118 g of water to the mixture and... , stir this at 90 - 100 °C for an additional 1 hour. Cool the mixture to 80 °C and add 23.2 g of 37% hydrochloric acid within 30 minutes. Cool the mixture to 10 °C and filter. Wash the filter cake with 60 g of water and dry it under reduced pressure at 50 °C. Thereby, 39.2 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxa-4-azadispiro[4.2.4]tetradec-1-en-3-one (purity 90%) is obtained. The yield is 95% based on the mixture used. To 50 g of the mixture prepared in the same manner as in Examples 15 - 25 in 116.7 g of anisole, add 5.3 g of p-toluenesulfonic acid and 6.5 g of ethanediol, and stir the mixture under reflux for 3 hours. Cool the mixture to 115 °C and meteredly supply 42.8 g of sodium methoxide (30% solution in methanol) under slightly reduced pressure within 30 minutes. Continuously distill off the obtained methanol and 1-propanol for 2 hours. Add 118 g of water to the mixture and stir this at 90 - 100 °C for 1 hour. Cool the mixture to 80 °C and meteredly supply 20.8 g of acetic acid within 30 minutes. Cool the mixture to room temperature over several hours and filter the formed suspension. Wash the filter cake with 2 × 60 g of water. Thereby, 35 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxa-4-azadispiro[4.2.4]tetradec-1-en-3-one is obtained. 8 .2 5

[0188] Example 32

Chemical Structure

[0189] 8 .2 5 ​​​​​​​​​​​​​​Tetradec-1-en-3-one (purity 87%) is obtained. The yield is 80% based on the mixture used. Example 33

Chemical formula

[0190] To 40 g of the mixture prepared in the same manner as in Examples 15 to 25 and 115 g of toluene, 1.5 g of para-toluenesulfonic acid and 5.4 g of ethanediol are added, and the mixture is heated to reflux. Most of the toluene is distilled off after 2 hours, and 40 g of DMAc is added to the bottom product. ~8 g of the distillate is removed from the mixture, which is cooled to 115 °C, and 28.1 g of sodium methoxide (30% solution in methanol) is metered in under slightly reduced pressure within 30 minutes. The resulting methanol and 1-propanol are continuously distilled off for 3 hours. 95 g of water is added to the mixture, and this is stirred at 9 0 - 100 °C for 1 hour. The mixture is cooled to 80 °C, and 19 g of acetic acid is metered in within 30 minutes . The mixture is cooled to 10 °C over 3 hours, and then the formed suspension is filtered. The filter cake is washed with 2 × 50 g of water. Thereby, 31.5 g of 2-( (4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxa-4- azaspiro[4.2.4 (4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxa-4-azaspiro[4.2.4 .2 8 .2 5 tetradec-1-en-3-one (purity 97%) is obtained. The yield is 91% based on the mixture used.

[0191] Example 34

Chemical formula

[0192] 50 g of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid in 59 g of 1-propanol and 100 g of toluene The initial charge is heated to 80 °C, and 29 g of thionyl chloride is metered into the mixture within 1 hour. After 5 hours, a check of the conversion still shows 20% of the reactant.

[0193] Example 35

Chemical formula

[0194] 60 g of 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylic acid in 86 g of 1-propanol and 120 g of chlorobenzene The initial charge is heated to 80 °C , and a sample is taken from the mixture: the conversion check shows a reactant content of ~25%. 39 g of thionyl chloride is metered into the mixture within 1 hour. After 5 hours at 80 - 90 °C, the conversion check shows ~11% w / w of the reactant. A further 15 g of thionyl chloride is added, and the mixture is stirred at 80 - 90 °C for a further 5 hours. Another conversion check shows 3.8% w / w of the reactant . A further 0.5 equivalent of thionyl chloride is added, and the mixture is stirred at 80 - 90 °C for a further 4 hours. The conversion check shows 0.3% w / w of the reactant in the reaction mixture.

[0195] Example 36

Chemical formula

[0196] 8-amino-1,4-dioxaspiro[4.5]decane in 101 g of 1-propanol Charge initially 51 g of -8-carboxylic acid and heat to 80 °C. Take samples from the mixture: Conversion check shows a reactant content of 23% w / w. Meter 28.9 g of thionyl chloride into the mixture within 1 hour. After 5 hours at 80 - 90 °C, the conversion check shows 1.4% reactant in the reaction mixture. The conversion rate check shows a reactant content of 23% w / w. Meter 28.9 g of thionyl chloride into the mixture within 1 hour. After 5 hours at 80 - 90 °C, the conversion rate check shows 1.4% reactant in the reaction mixture.

[0197] Example 37

Chem.

[0198] Charge initially 50 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate in 130 g of 1-propanol and heat to 80 - 90 °C. Take samples from the mixture: The conversion check shows ~23% w / w reactant. Meter 46.9 g of thionyl chloride into the mixture within 1 hour. After 5 hours at 80 - 90 °C, the conversion rate check shows 1.5% reactant in the reaction mixture. Charge initially 50 g of sodium 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate in 130 g of 1-propanol and heat to 80 - 90 °C. Take samples from the mixture: The conversion check shows ~23% w / w reactant. Meter 46.9 g of thionyl chloride into the mixture within 1 hour. After 5 hours at 80 - 90 °C, the conversion rate check shows 1.5% reactant in the reaction mixture.

[0199] Example 38

Chem.

[0200] To 50 g of a mixture (about 0.081 mmol) prepared as in Examples 15 - 25 in 94 g of toluene, add 1 g of 96% sulfuric acid and 5.9 g of ethanediol. Heat the mixture to reflux with a water separator attached. After 5 hours, distill off most of the toluene and add 50 g of DMAc. After further initial distillation of the mixture, meter 34 g of sodium methoxide (30% solution in methanol) under slightly reduced pressure within 30 minutes at 115 °C. To 50 g of a mixture (about 0.081 mmol) prepared as in Examples 15 - 25 in 94 g of toluene, add 1 g of 96% sulfuric acid and 5.9 g of ethanediol. Heat the mixture to reflux with a water separator attached. After 5 hours, distill off most of the toluene and add 50 g of DMAc. After further initial distillation of the mixture, meter 34 g of sodium methoxide (30% solution in methanol) under slightly reduced pressure within 30 minutes at 115 °C. ​​​​ The obtained methanol and 1-propanol are continuously distilled off for 2 hours. 95 g of water is added to the mixture, and the mixture is stirred at 90 to 100 °C for 1 hour. The mixture is cooled to 80 °C, and 11.3 g of acetic acid is metered and supplied within 30 minutes. The mixture is cooled to room temperature over several hours, and then the formed suspension is filtered. The filter cake is washed with 2 × 50 g of water. As a result, 28.5 g of 2-(4-chloro-2,6-dimethylphenyl)-1-hydroxy-9,12-dioxo-4-azadispiro[4.2.48.25]tetradec-1-en-3-one is obtained with a purity of 94%. The yield is 90% based on the mixture used. In the formula image, the abbreviation "Pr" represents n-propyl.

[0201]

[0202] In the formula image, the abbreviation "Bu" represents n-butyl.

Claims

1. Formula (V') 【Chemical 1】 〔wherein, R ７ is n-propyl) compound.

2. Formula (IX') [Chemical Formula 2] 〔wherein, R ７ is n-propyl, R ８ is methyl, and R9 is hydrogen, R10 is chlorine, R11 is hydrogen, and R12 is methyl〕 compound.

3. Formula (X') 【Chemical Formula 3】 〔wherein, R ７ is n-propyl, R ８ is methyl, and R9 is hydrogen, R10 is chlorine, R11 is hydrogen, and R12 is methyl〕 compound.

4. Formula (XII') 【Chemical 4】 〔wherein, R ７ is n-propyl, R ８ is methyl, and R9 is hydrogen, R10 is chlorine, R11 is hydrogen, and R12 is methyl〕 compound.

5. Formula (VI') 【Chemical Formula 5】 [wherein, R ７ is n-propyl] compound.

Images