JPS63501720A - Synthesis method of cyclopentanecarboxylic acid derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Background of the invention of synthetic method for cyclopentanecarboxylic acid derivatives The present invention includes, for example, fragrances and aromatic compounds, fragrances and/or enhancers and Production of foods useful especially as components of synthetic sweeteners or as intermediates in their production. This invention relates to the synthesis of intermediates useful in the production of compounds.

In the field of synthetic sweeteners, some branched alkyl and alkylated cycloalkyls amines, alcohols and carboxylic acids, e.g. amides of L-aspartamide. When incorporated into components that bond to nitrogen atoms, 7'C imparts a strong sweetness to these molecules. It is known that the unique ability 'Iklj'. Such amines, alcohols Examples of acids include, for example, U.S. Pat. No. 4,399,163; No. 1464045 and European published patent specification 'f no. 0128654A2. It is white. In particular, 2,2,5,5-nato2methylcyclopentane-carboniS t is one mourner in this relation; W, D, puller, M, group Tudman (() 00 (Lman) and M, 8°7 el 2nd - (yerl anaer), J, Am, Chain, Boa, Vol. 107, p. 5821, 1985.

Existing preparations for the branched alkyl and alkylated cycloalkyl components of these sweeteners The manufacturing method is insufficient in the case of large quantities and requires improvement, e.g. simplification, sufficient yield, It requires mild conditions, few steps, and readily available starting materials.

Summary of the invention It is therefore an object of the present invention to obtain such an improved method.

It is a further object of the present invention to obtain the desired branching (cyclo) in which these steps are conveniently advantageous. The objective is to obtain useful individual steps in the process of producing alkyl components.

Another object of the present invention is to obtain a method comprising a combination of these steps. .

Another object of the invention is to obtain intermediates useful in the process of the invention.

Other objects and objectives of the invention may be realized by consideration of the specification and attached claims. The advantages and benefits will be apparent to those skilled in the art.

These objectives are to develop an overall cyclic method for synthesizing the desired cycloalkyl moieties. Achieved by gaining. This ring reduction results in the desired ring reduction of the cyclohexane derivative. Includes conversion to lopentane derivatives. Some of the steps included in the present invention are as follows: An advantageous embodiment of this overall synthetic system is outlined in the diagram below: is: formula: [In the formula, R4 * "2 e R3 and R4 are each independently H or or optionally substituted alkyl, aryl or aralkyl, and Each of Rs and R6 is independently H"11' or alkyl, aryl or aralkyl, or R, and R6 are To prepare a diketone of the formula: [wherein R7 and R8 are each independently alkyl] from Na0 to or in the presence of 0 to form the corresponding cyclic acyloin, and then The formation in situ requires oxidation with a fully effective oxidizing agent to form a total diketone. law; and formula: [In the formula, each of Rlt R2P R75 and R4 is independently H or or, in some cases, polysubstituted alkyl, aryl, aralkyl, parentheses, etc. Each of R5 and R6 is independently H, or in some cases, a polysubstituted atom. alkyl, aryl or aralkyl, or R5 and R6 together to form a fused ring], the corresponding diketo of the formula: pH 5 to 11 in the presence of an effective acid catalyst and preferably without any special Method of reacting with human 2D without H20 removal means: and formula: [In the formula, "l? R2e" Each of 3 and R4 is independently H or or, in some cases, fullkyl, aryl, and alkyl, and Each of R5 and R6 is independently H, or R5 is optionally a polysubstituted atom. Rukyl, aryl, and aryl are aralkyl, or R6 and R6 together cyclopentane carboxyl of a primary or secondary amine of To produce a compound, a competing diazoketone of the formula: can be reacted with an amine. and various combinations of these methods.

Preferred intermediates for use in these synthetic reactions are inter alia diketones 4 . This product is especially suitable for M, except for the production of new hydrazone 5.

In other embodiments, '! fc The present invention is based on the formula: [wherein, Rle R2t R3 and R, are each independently H or, as the case may be, alkyl R, aryl or t is aralkyl, and each of RIs and R6 is independently 9 alkyl, aryl or aral [R5 and R6 together form a fused ring] To make clopentane carboxylate, the formula: The corresponding diazoketone is reduced to a 6-membered diazoketone ring to form a cyclopentanka. A method comprising treating the carboxylic acid under conditions effective to form a five-membered ring, or and to produce cyclopentanecarboxylic acid of the same formula, the formula: 1 on the corresponding hydrazide with an oxidizing agent effective to convert the hydrazo group into an azo group. You can find a way to avoid vomiting.

detailed description Much of the following description is based on 2,2,5,5-tetramethylcyclopentanecarboxylic acid. (7) has been described because this compound is the whole of the present invention. This is because it is an advantageous product of synthetic systems. However, this is a matter of convenience. for the purpose of this invention, and is not intended to limit the scope of the present invention in any way. There isn't. This raw t7. The details marked with @ are the details of the method of the present invention as described below. In all areas of It can be applied to a single contact as customarily modified by a person skilled in the art according to the guidelines given above. .

In the description, suitable alkyl groups R1 to R4 typically have 1 to 8 carbon atoms, preferably cB has 1 to 4 molecules and is most preferably methyl or also ethyl. Ru. Other optional straight-chain or branched alkyl groups include n-propyl, 1-propyl, n-propyl, -ethyl, 1-ethyl, t-butyl, pentyl group, hexyl group, heptyl group or includes octyl groups. Advantageously, at least one of R1-R4 is alkyl. , and most preferably all four are alkyl groups.

-II has substituents R5 and R5, which can be used in order to carry out M-effects in various operational steps. There are no restrictions as long as they are reaction compatible and do not interfere with the underlying chemical reaction. .

Such interfering groups are readily discernible to those skilled in the art.

Suitable R5 and R6, if present, include alkyl groups of from μm to 8 carbon atoms. All of the above details for the OR1-R4 alkyl group apply here as well. . All of these alkyl groups Rx -R6'+7) may be the same, or all may be different. They may be the same, or they may be slightly different.

Suitable aryl groups as Rlt R2t R3* R4* R5 and R8 are: for example those with 121 to 6 C atoms, and hydrocarbons such as phenyl, 1-na Includes phthyl, 2-naphthyl and the like. The Peter ring is their counterpart, for example , IFJ contains 1 to 3 heteroatoms, such as O, N and/or 8T-, One or more fused rings, each typically consisting of 4 to 7 ring atoms ( Examples include 1 to 6), such as thiophenyl, furanyl, imidazolyl, These include indolyl and pyrrolyl. Other corresponding structures have R1/R6 generally may be a C atom or optionally 1 to 6 heteroatoms, e.g. 0. N or S etc., for example those forming a 4- to 6-membered fused ring, preferably 5,6-benzo. It is. In all cases, it is clear that the substituents R1% R, must be reaction compatible. , for example, all the rings are sufficiently Elec ingredients in minutes The number of C atoms in the kill group is from 1 to 8, such as the above-mentioned furkyl and aryl groups. Includes combinations of minutes. Aryl groups and fused rings are alkyl groups (for example, 1 to 8), carboxyl, hydroxy, alkoxy having 1 to 8 carbon atoms, alkyl Substitution with groups such as sulfonyl, amino, etc. is also possible. Also, alkyl group is substituted with a similar substituent to form the corresponding group. (singular or plural), and fc must be protected in accordance with customary law. No.

Generally, the esterifying components R7 and R8 are also alkyl groups having 1 to 8 carbon atoms, Decorate with a hook or branched chain. Again, with respect to these alkyl groups, per R1%R, This also applies if all of the details are correct.

A large number of other corresponding compounds are applicable to the process of the invention as starting materials. , and most of the products are generally easily removable and commonly used for OH, amino components, etc. By substituting one or more substituents protected by the protecting group of The compound 'tJk included. Other equivalents are compatible substituents or structural advantages, e.g. For example, it contains unsaturation and is easily applicable to the process of the present invention by those skilled in the art. Includes compounds @ that are obvious.

Various substituents R~R8 may be used, for example, in Yoneka Patent Mei? 1ifi Survey No. 4399163 , UK Patent Specification No. 1434043 and European Patent Specification No. 0128654 No. 1, the disclosure of which is incorporated herein by reference.

Ring reduction of appropriately substituted cyclohexane derivatives to cyclobencune derivatives Said +! - By praying directly to the desired carboxylic acid group. 1 friend, this reaction is Related substances that can be advantageously converted into powder or other derivatives with minimal manipulation It is also possible to obtain quality. This process can be schematically illustrated as follows: The cyclohexane precursor is cyclopentane, which is also inexpensive and commercially applicable. It is readily available from a variety of sources.

Such reduction itself is known. For example, “Heamore” and C, David Gutche (DaVia Qut8he), 1 Calpoxycri tsu!・Ring Contraction Reactions” (Carboxyclia Please refer to Rlng cOntraCtiOn I (actions). Provides general guidance. See especially page 125 and the next page.

Seven details are available in Book E! It is perfectly matched by quoting it in the A detailed oath. this special A very special example of this lineage is Tetrahe 07-Letters. cLronLetzara) Volume 9, page 759 (1979), F, Casilan (Kaplan) and M.L.Mitchell (the Table 2 (760 negative), especially see compounds converted to tetramethyl); Cademia Scientea K Mu-7m Nikase K (Annalee Acaa emlae Seientiarum pennicae 3er,) 111 18.4-52 members (1962), D. Klenberg (1 (lenberg)) The report has been rejected, and its disclosure has been combined with citations in the Unspecified List.

The reactions described below are such that they convert R from a cyclohexane group to a cyclopentane group. It only relates to the disclosure of known technology in encompassing small and large movements. But long , described below +! : The reactions of the present invention often require unexpectedly advantageous reaction conditions. Underneath, and by the unexpected formation of @ (singular or plural in fc) itself, and/or other common reactions, including surprising reaction results, e.g. The on-site α method is surprisingly usable and yields surprisingly high yields. It turned out to be. Firstly, the most advantageous embodiment of the method of the invention will be described.

The conversion of adipate 3 to diketone 4 was subsequently obtained in the acyloin combination and the circular a Achieved by in-situ oxidation of sirloin to form the desired diketone. I can awn. The acyloin condensation itself is known) and, for example, the above-mentioned quotation Part 1: Annalea Academiae There are many wm-scripted texts, such as J, March, and 'Adver. Advanced Organic Chemistry'' (AdvancecL□rgan1c) chamistry) 3rd edition, 1985, 1116 Negative description.

In this case the reaction uses sodium or potassium metal, preferably sodium metal. It can be carried out in an inert solvent. The reaction temperature is set so that the reduction proceeds at an appropriate rate. t#+The temperature to be used is excessive. Typically, temperatures between 25 and 120°C Use makes me vomit. Typical reaction times are about 1-48 hours. Typically, 0.8-2. 0 Our alkali metals are no longer used.

Suitable solvents are known and include diethyl ether, tetrahydrofuran, and benzene. solvents such as toluene, toluene, xylene or other solvents compatible with sodium.

During preliminary experiments of this embodiment of the invention, it was determined that the diketone was a by-product of the acyloin combination. It was discovered that production would be delayed. Retirement@Surprisingly, it was discovered that diketone continues to be On-site oxidation By carrying out the procedure without isolating @, it can be obtained as the main product. @Is Rukoto. ■A useful oxidizing agent is chenyl chloride. However, other Numerous oxidizing agents include acid, oxygen, chlorine, sulfuryl chloride, and manganese dioxide. , iodobenzenediacetate, N-promsuccinimide, N-chlorsuccinimide chlorine imide, chlorine cyanuric acid, chlorinated amines, hypochlorite and hypochlorite Acid salts (including those consisting of t-butyl, sodium, calcium, etc.), persulfur sodium chloride, diphenyl disulfide, elemental sulfur, and the like.

Generally, the in-situ oxidation step is performed at a temperature of -10 to 140°C, using the same material used in the first step. It is carried out using about 1 to 8 equivalents of oxidizing agent in the same solvent. Representative oxidation E#rrJ Terrorism occurred from 1 to 24 o'clock r#rJ.

Advantageous conditions for the ring formation step are sodium in toluene ii at about 50°C for about 24 hours; Including the use of i equivalents.

Favorable oxidation conditions are obtained from the first step by cooling the reaction medium to 0°C and adding the oxidizing agent and after 7 hours heating to a reaction temperature of about 64°C for about 4 hours. .

The overall yield of ring formation/oxidation is very high, e.g. in the range of 90-100%, On the surface, the IF is 195%.

In another step of the uninvented process, from the hydrazone 5 or the diketone 4, this KP85-11 reacts with hydrazine in the presence of an acid catalyst. The stain is created. − of the reaction solution was found to be the criterion for achieving high yields. . (1) One advantageous range is 6-10, especially 8-10.

In another surprising embodiment of this reaction, it was discovered that water from the reaction This means that there is no need to carry out the process to achieve removal. Experience shows that this My friend was expecting it to be a mental image. Surprisingly, one reaction can be carried out at room temperature or at a lower temperature. Awning can not only be done, but also use hydrazine water as starting %J negative can be done. The reaction can therefore be carried out without heating, advantageously between 10 and 4 It is carried out within a temperature range of 0° C., most preferably at about room temperature. Expressly, It is still possible to carry out the reaction by continuously removing water at elevated temperatures. However, this is neither safe nor economical.

This reaction can be carried out using any of a number of weak and strong catalysts, typically PKIL values within the range of about 1 to 6. To! For example, benzoic acid, acetic acid, prodionic acid, trifluoroacetic acid, It can be carried out in the presence of fluoric acid and the like. - Dione is compatible with bath salts , typically aromatic hydrocarbon solvents such as benzene, toluene or fc in xylene. D. The presence of about 1 to 20 mole percent acid catalyst based on the amount of dione used. It is dissolved in Also, typical examples are alcohols, for example, carbon atoms of 1 to about 8 is fullcanol. Typical alcohol amounts are 0 to 50%. Typical hydra The amount of gin is about 1 to 10 equivalents, ie, generally in excess. Reaction time is generally 2~ I'll be back in 24 hours. In addition, the reaction yield of this step is high, for example about 90 to 100%. fJ is typically 95%.

Particularly advantageous conditions are hydrazine in toluene containing acetic acid and ethanol. Includes the use of 10 equivalents.

Another surprising thing about using excessive amounts of hydrazine is that monohydrazone is the main product. It is a product.

Monohydrazones are reported to be the products of the reaction between hydrazine and aryl ketones It's cold. Generally, in the reaction between hydrazine and furkyl ketone, unnecessary formation Do things ever fall apart? 7t is the residual NH, the group or the second group of the compound Azine is produced by combining with molecules, for example: Along with α-diketones, an additional expected by-product is osazone: In the present invention, no evidence of these side reactions or raw melon was found to be inappropriate. . J, March, “Advanced Organic Chemistry” -1 (Aavancea Organic (hemietry)) Above quotation m y=, see page 84.

In a particularly advantageous embodiment of the invention, a diazoketone, for example 6, reacts with an amine. directly to form the corresponding amide of the corresponding cyclopentanecarzanoic acid. Ru. This reaction is particularly surprising because the effect of the amine in the ring chain is The reduction itself yields not only the desired ring-reduced ketone, but also disadvantageous side products. In consideration of the known knowledge that the corresponding α,β-unsaturated ketones are also formed, Because it could not have been predicted. Kashiran and Mitschel (Kδplan a) nd, the direct reaction of diazoketones with amines under ring reduction conditions leads to extremely high yields. Desired ring-reduced amine P12: and the corresponding amine having the above substituent Rx -R6 However, each of R, f, - and R1° independently O is kyl, aryl or aralkyl Amines suitable for use in this step of the invention include the first straddle of all comparability. 2 amines, such as ammonia, dimethylamine, methylamine, dibutylamine 6 Also, such amino acids include contains all naturally occurring amino acids and their optical isomers and racemates. Contains all important amino acids containing the body. Other amines are referred to herein. U.S. Pat. No. 1,439,163, incorporated herein by reference, Patent Specification No. 0128654, British Patent Specification No. 1434045, and others. It corresponds to the structure shown in relevant publications on synthetic sweeteners. Generally, amines and the R2 and R1o components in the new amide obtained are H and the above-mentioned or All alkyl, aryl, and alkyl components that can be described for the alkyl or aryl component. alkyl and alkaryl groups and their substituted and corresponding corresponding arrangements. Includes minutes. Also, many other possible amines will be readily apparent to those skilled in the art. As such, it is suitable for use in the present invention.

Typically, 1 to 2 equivalents of amine are used in the reaction with the diazoketone. Appropriate melting Agents include benzene, toluene, xylene, chlorobenzene, chloroform, and dichloromethane. Rumethane, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, Includes dimethoxyethane, acetonitrile, benzonitrile, etc. generally react is carried out at a temperature of 65-100° C. for a period of 2-4 hours. Amine reaction components are liberated unstable as a base or more preferably as an acid salt (e.g. hydrochloride) If applicable, the amine base is prepared in situ from its acid salt precursor by a tertiary amine (e.g. For example, triethylamine, like bicarbonate or alkaline earth metal oxides, It is acceptable to generate this using an inorganic base.

In the preparation of amide 12 and its progression from ketone 8 as described below, the starting atom The optical activity of amines, e.g. amines, is an optically active amino acid, e.g. It is maintained if the amino acid is Generally, maintenance of optical structural purity is desired. is important for maintaining end-use properties such as sweetness. maintain optical activity Determination of optimal reaction conditions is common and publicly available in the field of peptide bond formation, for example. It is knowledge. For example, the properties of the acid scavenger may be important in this connection, e.g. Often morpholine-based scavengers are combined with other commonly used reactants such as triethylamine. It is known to result in greater maintenance of optical activity than quality. diazoketone directly Another advantageous preparation of amide (12) from (6) results in an unacceptably high degree of racemization. If produced, carefully the ketone (8) is added below before adding the optically active amine. It can be manufactured as described. After that, the ketone (8) is can be converted to amide (12) under mild reaction conditions. This means that optical of chemically active compounds to the more reactive conditions used to produce ketones. , thereby reducing the possibility of racemization.

In another advantageous embodiment of the invention, the reaction of the amine and the diazoketone is In the reaction solution obtained after Drazone 5 was used to prepare diazoketone 6 will be carried out on-site. This indicates that the desired amide product can be obtained starting with a hydrazone. A very advantageous one-pot production of the product is obtained.

Hydrazone 5 is converted to diazoketone 6 by oxidation. This reaction is called hydra This can be carried out by stirring a solution of Zon in an inert solvent. Contains All common solvents that are compatible with the reactants of the present invention, such as toluene and The equivalents described elsewhere in the specification and known to a person skilled in the art may be used. can. Suitable oxidizing agents include manganese dioxide (■), silver oxide, and iodobenzenedia. Each set is different. Generally, the reaction takes place at a temperature of about 0 to 50°C and a time of about 1 to 24 hours. It is done. Typically, about 1 to 10 equivalents of oxidizing agent are used. In an advantageous embodiment This step involves adding hydrazone 5 in a toluene solution along with 2 The reaction is carried out at 5° C. with stirring for 2 hours together with 73 molar equivalents of activated mandioxide.

Also, the yields in this embodiment of the method are extremely high, e.g. 80-99% for the two reactions of hydrazone and amine, and the reaction of hydrazone and oxidizing agent. is within the range of 90-100%. Typically yields are about 95% with hydrazone oxidation. , and about 90% for the coupling of 6 with the amine.

In a particularly advantageous embodiment of the invention, the advantageous reactions mentioned are carried out sequentially, For example, diester 3 is used to make diketone 4, and then this diketone is Used in the production of hydrazone 5. Furthermore, this reaction sequence can be extended. , whereby hydrazone 5 is used in the production of diazoketone B. series can be started with diketone 4, which is used to make hydrazone 5. This in turn is used to prepare diazoketone 6. Obviously diazoketone series termination is most advantageously used, e.g., in direct preparation of amides of desired amines. It can be extended by reacting with nin methyl ester.

Regarding the other reactions in the above diagram, adipate (3) converts the corresponding acid (2) into alcohol. Esterification with alcohol and acid catalysts in such a way that the water formed during the reaction is removed It can be manufactured by This synthesis is sufficient to obtain esters. Suitable aliphatic alcohols include C1-C8 branched or straight hydrocarbon chains. It is represented by what you have. Acid catalysts such as sulfuric acid, toluenesulfonic acid Lylsulfonic acid, methanesulfonic acid, Nafion-H -HR). Generally, 1 temperature is 7 The temperature is 5-120°C and the reaction time is 4-24 hours. Typically, esterification is It is carried out in a hydrocarbon solvent that forms an azeotrope with water. An example is benzene, Includes toluene or xylene.

However, this does not mean that high boiling alcohols are used which form azeotropes with water. It is unnecessary if

One example is citanol. Advantageous conditions include combining the diacid (2) with sulfuric acid, ethanol and Dissolve and strain in the water mixture. It is clear to the person skilled in the art that all known literature The method for producing ester from carboxylic acid is compatible with the synthesis of (3) within the scope of the present invention. Is Rukoto.

Adipic acid (2) can be prepared by one of the various methods known from known publications. can be done. An advantageous method for the purposes of the present invention is the use of D, D, :l amine (Co ffman), G.L. Jenner and R.D. Rizos Lipscomb, J.

Am5r, Chem, Soc, ) Volume 80, page 2864 (1958) However, it includes methods to make significant improvements over that report. Contains.

Pivalic acid is oxidatively dimerized by mixing with water and sulfuric acid.

To this mixture, a solution of iron sulfate (It) in sulfuric acid and an aqueous solution of hydrogen peroxide were simultaneously added. added to. Generally, the temperature is 25-100°C and the reaction time is 1-10 hours. be. Typically, 1 to 10 mole equivalents each of hydrogen peroxide, ferrous sulfate, and sulfuric acid. amounts, most preferably 1 equivalent each of hydrogen peroxide and ferrous sulfate and 1.5 sulfuric acid. An equivalent amount of crab is used. A major invention revealed that a small amount (for example, pival Acid-based 0.1-0.5 wt/wt%), low acid content 100) added or raw The objective is to improve the properties of the formed precipitate. This precipitate is removed when the surface-active additive is omitted. When mixed, the reaction mixture exits with a sticky toffee-like consistency. This product has other points However, it is extremely difficult to process. Furthermore, according to the invention, for the removal of iron salts from the crude product, It has been found that the conventional ammonia treatment used in the processing of can be omitted.

The crude precipitate from the reaction mixture can be easily crystallized from methanol. . Needless to say, this reduces the amount of wastewater produced by the process. It greatly simplifies and shortens the process and saves costs. In addition, ionic surfactants , including anionic and cationic ones, can be used. like this Non-limiting examples of surfactants include dialkyl sulfosuccinates, such as dioctylsulfosuccinates. Rusulfosuccinate, long chain alcoholic rubenzene sulfonate, e.g. sodium Includes dodecylbenzene sulfonate and the like.

If the aforementioned advantageous methods are not applicable (for example, if R5/R, ), a number of selections include diacids with various substituents R1 to R6 as specified above. (2) and the corresponding diester (3). for example , many members of this class of compounds are suitable diols, dienes, dihalides, etc. Or, if hydrocarbons are available, the customary Koch-half reaction Haaf reaction) [1 unit] - Synthesis with Carbon Monoxide” (Naw 5ynth eses with Car-bon Monoxides), J, 7 Albe (Falbe), Ed, Siniprin - Fellag Publishers (Sp-ringer-Vsrlag Publishsrs), 1980 , see Chapter 5]. Many members are derived from enolizable esters or nitriles. It can be produced by alkylating the derived anion. this The method detects the alpha position for the ester functionality from slightly substituted to It is also useful in producing highly substituted diesters. The above description should be understood by those skilled in the art. It serves as an example of a reaction type that is commonly used. Many others are described herein. This is possible when producing compounds (2) and/or (3) listed in . starting material (2) For all reactions listed herein to produce t- The essential starting materials are either conventional per se or known or easily producible. They can be conventionally prepared from standard starting materials using conventional reactions.

Simple addition of a solution of diazoketone (6) in a substantially anhydrous, non-hydroxyl solvent. The heat induces a thermal rearrangement with the evolution of nitrogen and the final use of this compound is the acid (7 ) forms a ketone (8) which can be regarded as a functional counterpart of (8). This dislocation Suitable solvents for It has a boiling point and is also reaction compatible. A solution that satisfies the group M in this reaction Some examples of agents are tetrahydrofuran, dioxane, benzene, to name a few These are toluene, xylene, diglolethane and chlorobenzene. ketone formation The actual temperature range is 60° to 140°C. Typically, reaction times are 1 to 7 hours. It is. Advantageous conditions are the use of toluene as solvent at 90°C. Excellent yield for example 90-100%, typically about 95%. The advantage of this method is The solution of the prepared ketone can be used directly as an acylating agent.

In this regard, ketones, due to their remarkable reactivity, have very mild reactions. Allows the use of adaptive conditions. Specifically, ketone (8) is hydrolyzed to acid (7). or react with amines such as those already mentioned above a, -20 °C to 2 Amide (12)t: may be formed at a temperature within the range of 5°C.

Obviously, higher temperatures are also effective. Other reaction parameters are diazoketone (6 ) is the same as that described for similar rearrangements starting with ). Other advantages of this method The amine to be acylated is optically active and does not undergo racemization as described above. Obtained if it is easy to receive.

This function (high reactivity) is due to the acid (7)'f! : Manufacture and isolation and then this can only be achieved selectively by converting it to the activated state in a separate step. stomach.

Carbon f again! ! 2(7) can be produced from (6). For example this The diazoketone (6) was dissolved in an aqueous alkaline medium containing an organic co-solvent. , and subsequently this homogeneous solution at a temperature sufficient to cause rearrangement and hydrolysis. This can be achieved by heating to . Typical temperature is 65-100℃, and reaction time is 2 to 8 hours. Compatibility auxiliary solvents include lower alcohols, Tylene glycol, acetonitrile, tetrahydrofuran, dioxane, dimethylene It exhibits considerable water solubility, such as rusulfoxide.

Suitable aqueous alkaline solutions are sodium or potassium hydroxide solutions. selectively , the solvent which is practically immiscible with water is, as is known, tetra-n-butylammon used in combination with phase transfer catalysts such as nium ions, 18-crown-6 fathoms be able to. Equivalents of these reactants and conditions will be apparent to those skilled in the art. example For example, a reaction occurs in the absence of an alkaline reagent (for example,

(albeit more slowly). Favorable conditions for this reaction with ethanol’e as co-solvent and 18.75 (w/w)% sodium hydroxide. It is used by mixing it with a solution of 3:1. This reaction mixture is used to obtain (7) Reflux for 2 hours. Obviously, the reaction from (6) to (7) is also that from (5) to (6) The reaction(s) used to produce the reaction may be carried out on site. can. For example, see Example 10 below.

Another method for obtaining rR (7) from dione (4) is to reduce the dione metal ring. The droxy acid (9) is also converted into the acid ester (10). This reaction is (4) Water or alcohol solution with t-sodium hydroxide or alkoxide This can be achieved by treatment in an agent. This reaction takes place in a nitrogen atmosphere. The heating process is continued for 1 to 18 hours at 65 to 100°C. Alcohol is useful in this process. The alcohol/alkoxide combination contains 1 to 8 carbon atoms in each component. It is something to do. If the acid (9) is prepared, this is converted in a separate step to the ester, e.g. For example, it may be converted into a C7-8 alkyl ester. (10) T-take as a representative example These esters are used to prepare the acyl hydrazides (11). child This means that the ester (1-0), along with an excess of hydrazine, is added to the reaction mixture. Heat at 90-140°C for 6-48 hours in the presence of a solubilizer to make a completely homogeneous solution. It can be implemented by

More particularly, 1 to 10 equivalents of hydrazine are equal to the volume of hydrazine used. It can be used in a volume of high boiling alcohol. This kind of alcohol Examples are butanol, ethylene glycol and their congeners, or above 100℃ is another alcohol with a boiling point of Advantageous conditions are (10) and 4 equivalents of hydrogen. This includes heating at 105° C. for 20 hours in radin and in-butanol.

The acid hydrazide produced by this method is used for the synthesis of acid (7) by the oxidation method. can be done. In this method, hydrazide converts the hydrazo component into an azo component. exposed to reactants that can be converted to minutes. Most surprisingly, this reaction This is done at the same time as the withdrawal, and as a result acid (7) is produced. be. A number of common oxidizing agents known in the art can be used. . It can be used stoichiometrically or in excess. These limitations Non-active examples include halogens such as chlorine or bromine, silver or mercury oxides, and mercury dioxide. Manganese 4t-includes.

The conditions used depend on the oxidizing agent used.

Descriptions indicating those characteristics that are generally practical are as follows: the reaction is between 0 and 0. carried out in water or organic solvents or mixtures of the two within a temperature range of 100°C be done. Acceptable organic solvents include alcohols, such as C1-C4 alcohols, recalls, such as ethylene glycol or propylene glycol, ethers, Examples include evaporated tetrahydrofuran, 1,2-dimethoxyethane and dioxane. do. Other useful solvents are acetonitrile and dimethylformamide.

An advantageous embodiment of this reaction involves converting a solution of sodium hypochlorite into hydrazide (11 ) at a temperature of 0°0 and subsequently heated to 25°C for 1 hour. It consists of many things. Nitrogen gas is released and compound (7) is obtained.

The product (7) formed by any of the above methods produces a number of useful compounds. can be used directly in a number of known reactions to produce selectively this The acid can be completely converted into any of its known functional equivalents, such as any acid chloride. can be generally converted. The acid products of the present invention can be used to produce desired known products. It is quite common to use it to Fuller, Gutsud Goodman and Fell 5eries), edited by Saul Patai ( 8aul Patai Editor), “De chemistry osi de cal Zaxil Group” (Ths Chemistry of the Car boxyl Group, ), Wiley Interscience (Wiley I terscience-ce), 1966.

Without further elaboration, one skilled in the art can, using the foregoing description, comprehend the present invention to its fullest extent. It seems that it can be used again.

Accordingly, the following advantageous specific embodiments are to be construed as illustrative only; There is no restriction on other disclosures. In the above specification and the following examples All temperatures are expressed in degrees Celsius without correction.1. and all parts and percentages By weight unless otherwise specified.

Example 1 5,0t 6-necked baffle equipped with stirrer, thermometer and 2 dropping funnels 2282 mj of water in the flask.

28.51 J of sulfuric acid and 195.0 g (1.91 mol) of bivaric acid are charged.

(Conco) 100 (0,25d) and with vigorous stirring , 6.67 molar solution of hydrogen peroxide 2951 and F12SO4105m 1432 mj of a 1.33 molar solution of ferrous sulfate (previously purged with nitrogen for 30 minutes) ) are added simultaneously via a graduated dropping funnel. This reaction mixture is Maintain at 65-40°C during the 15 minute addition time using a water bath. At the end of the addition time, A mixture of pivalic acid and water 11001dt-distilled from the reaction flask. frass Cool the contents to t-20°C and collect the crude 2.2.5.5-tetramethylazide. Isolated by filtration on pin a1, washed with water and dried double weight 73.0 &. 73.0 g of this double was crystallized from methanol 731, and 2.2.5.5 - Tetramethyladipic acid 4 a, o g is obtained, melting point 181-184°C, Neutralization equivalent: 101; theoretical value: 101.1° Example 2 Diethyl-2,2,5,5-tetramethyladipate 2.2.5.5-tetramethyl Thiladipic acid 186.0g (0.92mol), toluene 135Qd, ethanol The total amount of 45ON and E2SO44,751!7 (0-09 mol) was added to the pot. A thermometer, a vapor thermometer, a stirring device, and a Vigrsux column. column) and Dean-Stark tube (Dean-8tark tube) q) Place into a 3.Ot flask fitted with a condenser with f. Hula Heat sco to mild reflux and wet out at 74.2-75℃, ethanol, toluene. and water azeotrope is collected. Expected ft:, FhO3!1.111 vs 1. Total amount of exudate containing H40359' 545*lf: Collected. temperature The solution (ETOEi-) toluene) 40017 is distilled off.

Cool the solution to 5-10℃ and add 16-7% Na2CO3 solution 60.0 Gradually add g. Separate the organic layers and add 1001 parts of saturated NaE (Cod Wash three times with S solution.

Dry the toluene layer over Na2SO4. After distilling off toluene under atmospheric pressure, Ethyl-2,2,5,5-tetramethyl azobate was purified by vacuum distillation, boiling point 9. 5-98°02) via a short Vigreux column. The yield is 196. 0 g, 82.7% of the theoretical amount.

Example 3 2-Hydroxy-3,3,6,6-titramethylcyclosodium beads 41. D g (1,78 mol) in a stirred solution of dry toluene 1761 maintained under dry nitrogen. Add diethyl 2,2,5.5-tetramethyl adipate 81.0.9 (0, 314 mol) in toluene 229d at 25-30°C over 45 minutes. Add to.

A slight exotherm occurs during ester addition. The reaction mixture was maintained at 45-50°C for 20 hours. do. The gelatinous mass was cooled to 5-10 °C under N2 and heated to 35% H2SO. Carefully add the 4250 cod. Separate the layers and dry the organic layer over Na2SO4 do. The toluene is distilled off and the product is vacuum distilled. The yield is 2-hydroxy- 3,3,6,6-tetramethylcyclohexane 34.0 g, boiling point at 8-10 torr 82-85°C; 66.4% of theory: melting point 29-31°C.

Example 4 3.3,6.6-tetramethylcyclohexane-1゜2-hydroxy-3,3, 6,6-tetramethylcyclohexane 68.09 (0,397 mol), dry pipe 67% of lysine and 520% of dry toluene at 0-5°C under N2 atmosphere. Chenyl chloride 2401Lt (3.3M) was added to the cooled stirring solution at a temperature of 10 Add gradually while maintaining temperature at or below °C. After adding 5ocz@, the reaction The mixture is heated gently at 60-65°C for 12 hours. Cool the reaction mixture to 20°C , and then slowly added to the stirred mixture of crushed ice and water (1250 m/).

These ii were separated and the toluene layer was mixed with saturated NaCl 500 M-1,500 Wash twice with 1 volume of saturated NaEICO3 and finally with saturated NaNaC15O0 do. The toluene solution was dried over Na2SO4 and rotary evaporated. Concentrate and dry. Add 1001 portions of cyclohexane to the yellow solid residue. Living Product t-Collected by filtration and washed with cyclohexane 1011117 do. Yield: 3.3.6.6-tetramethylcyclohexane-1,2-dione 5 4.0 g, yellow crystals, melting point 112-113°C, 81.0% of theory.

Manufacturing of Diethyl 2.2.5.5-tetramethyl adipate (25.8 g, 0.10 mol )i, Sodium beads (9,2,9,0-40 mol) in toluene under nitrogen atmosphere Add to the vigorously stirred suspension at 25° C. under air. After the addition is complete, reduce the temperature to 5. 0°C and maintained for 24 hours. Then soak the thick, gelatinous mixture in a water bath. Cool in a vacuum and feed in chenyl chloride. Maintain cooling, but if the temperature The temperature rose to 65°C. Maintain this for 30 minutes. After that, an excessive amount of chenilcro Recover the lido and toluene by distillation and slurry the residue twice with hexane. and remove the diester. This residue (13,1y, (1,078 mol) is almost It consists of almost pure dione and shows a yield of 78%.

Example 6 Production of tetramethylcyclohexane-1,2-dione (4) The method of Example 5 is followed exactly up to the addition of chenyl chloride. At this point, the anti- Cool the reaction flask in a dry ice-acetone bath. Internal temperature reaches 110℃ In this case, chenyl chloride r was gradually dissolved as a 50% (vol/vol) solution in toluene. be introduced separately. If the temperature during addition exceeds 4°C, no condensation occurs. When the addition is complete, The internal temperature is brought to below 65°C and maintained at this temperature for 12 hours. After that, Allow the mixture to cool to room temperature. Then add this twice with water and saturated carbonate. Extract twice with sodium hydrogen solution. Toluene phase over anhydrous magnesium sulfate Dry, filter and concentrate to obtain solid dione, 15.8 JF, 94% yield. , melting point 106-108°C.

Example 7 3. Monohydrazo of 3,6,6-tetramethylcyclohexane-1°2-dione Preparation of (5) Hydrazine (14.0 g, 0.44 mol) was azeotropically removed from water. 3, 3, 6, 6-teeth in a flask equipped with a Dean-Stark apparatus. tramethylcyclohexane-1,2-dione (6,73 g, 0,04 mol), Add slowly to a stirred solution consisting of 251 u of ethanol and 50 u of benzene ( fever). After the hydrazine addition is complete (indicating a 15°C temperature increase), acetic acid is added. water is added and the mixture is refluxed while continuously removing water. Theoretical quantity (0,811 1j) is obtained in 8 hours. The reaction mixture is allowed to cool to room temperature. After that, 1 Extract 3 times with 0.01 minute amount of water, and then 2 times with saturated NδCt solution of 5Qd amount.

The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the mole as a yellow solid. 7.19 g of nohydrazi are obtained, melting point 87.5-89.5°C. NMR and I R data is consistent with the expected product.

Example 8 In a 100 WLt round bottom flask equipped with a magnetic stirring bar, add 1.68 g of dione (4). (0.01 mol); 12.5 liters of ethanol: 7.5 d of ethanol and vinegar Charge 2.5117 ml of acid.

While stirring at room temperature, add 5.50 g of a 64 (wt/wt)% aqueous solution of hydrazine. (0,11 mol) t-add. get it The resulting mixture was stirred at room temperature. The progress of the reaction was monitored by thin layer chromatography (silica Gel: V monitored with 1% ethyl acetate in dichloromethane as eluent).

After 2.5 hours, the dione (4) is completely converted to the hydrazone (5). two phase mixture Separate the compound. The upper phase containing the hydrazone was dissolved in a new volume of water (5M each). ) and then dried over anhydrous sodium sulfate. Filter the dry solution , followed by evaporation of the solvent, leaving 1.819 ft of substantially pure hydrazone. . The yield is 99%. This material was crystallized from an ethanol-water mixture and produced yellow needles. A melting point of 93.2-94.5°C is obtained. Furthermore, this crystalline hydrazone is Identification by the following spectral characteristics: NMR-60MHz, CC1, downfield ppm from solution TMS : 1.10, s; 1.13.8 (12H); 1.68, s (4Fl) ; 9.1, br, s ('IH) I R-CC1, solution (selected band) cm-”: 3480.3210.2960.2930.2860.1670 ．． 1530.1465.1450.1378.1655.1097.1007゜ A solution of hydrazone (5) (0.6 g, 3.29 mmol) in benzene 8, MnO4 (0,99 g, 11-39 mmol) and Mg5O4 over 30 min (1-65g) in 8.5μ of benzene at room temperature. TLC analysis The hydrazone was completely consumed in 2 hours and was contaminated with extremely small amounts of impurities. It was shown to produce diazoketones. The reaction mixture was allowed to stand overnight. the Later, it was filtered off and the filtrate was concentrated to obtain a yellow oily residue weighing 0.57 g. It was. This oil is identified by NMR and IR spectra. chromatog Roughly homogeneous product obtained by flash chromatography, 0 ．． 28 g (yield 46%).

Example 10 3.3,6,6-titramethylcyclobentane-1,2-dione (26,10 g, 0.14 mol) in benzene (23,499) was Slurry with manganese (3.10 g, o, 9 moles of a) and let the product cool at room temperature. Stir for 2 hours. The solids are filtered off and the filtrate is concentrated to give an oily residue. this was dissolved in ethanol 41, and this solution was added to an aqueous sodium hydroxide solution at 25°C. Add while stirring. This mixture is biphasic and therefore additional ethanol 2- is added to obtain homogeneity. At this point, the solution was heated to reflux for 2 hours (75 (no obvious gas emissions at ℃). After cooling to 25°C, the ethanol is removed in vacuo.

The aqueous residue is acidified and extracted with ether. Afterwards, the ethereal extract is removed. Water Mg80. dried over water, filtered off and concentrated to give tetramethylcyclopentane-1 - The carboxylic acid is obtained as an off-white solid (23.49 g, 0.137 molar), melting point 125.5-128°C. The yield from hydrazone is 96%. Before The NMR spectrum of the product shows that it is pure TMCP-CO2]11 Show that.

Example 11 25% solution (9.41M) of IJium hydroxide) using a thermometer, reflux condenser, etc. and a magnetic stir bar. all equipment Purge and maintain under N2 atmosphere. With vigorous stirring, the diazoketone (6) Solution of (0,275 g, 1.5 mmol) in ethylene glycol (31) feed-batch. The mixture was heated to reflux for 2 hours.

The resulting yellow solution is cooled to room temperature and extracted six times with ether. then this was acidified and extracted six times with 20,117 parts of ether which were combined again and extracted with water. Extract twice with IJum (2 times and saturated chloride). This ethereal solution t-M After drying over g5O, filtering off and concentrating, 0.238 g of crude product is obtained.

This weight corresponds to 91% of the expected theoretical yield. of this substance NMR analysis showed that 50% of it was the desired acid, giving an overall yield of 45%. Ru. A crystalline sample is isolated from a petroleum ether solution of the crude product. This thing is Identical in all respects to the authentic sample of this acid.

Example 12 CL)-Methyl-N-(2,2,5,5-tetramethyldiazoketone (6) ( 1.8g, 10mmol) of toluene 5r! The solution in Lt was diluted with L-alanine methyl ether. Stelhydrochloride (1,39g, 101u) and triethylamine (1- Add to a stirred suspension of 59 ttls (10 mmol) in 5 WLl of toluene.

Thereafter, the reaction mixture obtained is heated at 90° C. for 3 hours. After cooling to room temperature, This mixture was mixed once with 5% aqueous hydrochloric acid, once with water and saturated with sodium bicarbonate. Wash once with aqueous solution. After that, this toluene solution was mixed with anhydrous magnesium sulfate. (L)-Methyl-N-(2,2,5,5-te). Solid residue of tramethylcyclopentane-1-carbonyl)alaninate i11.7 4g is obtained.

The resulting cassillating product is approximately 90% pure.

Carboxylic acid amide Following the method of Example 12, instead of L-alanine ester hydrochloride? Use Followed: Methylmine hydrochloride, dimethylamine, aniline, di-n -Butylamine and phenylpropaturamine hydrochloride. This person again The method was carried out using 3 equivalents of each of the amine reactants and triethyl amine in the case of methylamine. The method was changed to use amine: and dimethylamine was added as a 22% aqueous solution. , that is, a two-phase reaction was induced. If using the amine itself, triethylamine was not used. The following amyls were obtained respectively (yield%; melting point ('O)) : N-methyl-2,2,5,5-tetramethylcyclopentane-1-carboxami (84%: 170-173.5) NMR: Down feed ppm from TMS 1-13 s 5 (12E1 ); 1.58, m (4R); 1.85.8 (IE); 2.8, (1 (3H) ; 5.66 brs (IE) and l (selected band, steel-1) = 3475 ．． 3360.2990.2950.2870.1665.15o5.1460. 1410.1385.1367.76゜(br　) N,N-dimethyl-2,2,5,5-tetramethylcyclopentane-1-carbo Xamide (67%: oil) NMR: Downfield ppm from TMS : 1.05, d(12B); 1.05, d(12F(); 1.58, m( 4a); 1.85.8 (IB): 3.0, d (6B) IR (Selected Ban cm-1): 2960.2880°1650.1460.1415.139 2.1388.1370.1132 N-phenyl-2,2,5,5-tetramethylcyclopentane-1-carboxa Mid (86%: 115.5-117.5’) NMR: Dow 7 fee/’)’ppm from TMS = 1.15, d(12 B); 1.6, m (4B); 2-0% a (I Fl); 7.3, m (6E) “　”　　　　　　　　　d　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　cm-”　　　　　　　3　d’l　Os　29 5052870.1685.1598.15o7.1460°1432.138 5.1365.13o2.1150゜1140.760 (br) N,N-di-n-butyl-2,2,5,5-tetramethylcyclopentane-1- Carzaxamide (76%, oil) NMR: Downfield ppm from TMS: 1.07, m (221: 1.55, m (Ba); 1.86.8 (IH): 3.21, m (4F) ■(Selected band, cm-’): 2960, 2880° 1650.1460, 1415.1392.1388.1370.1132 N-(1-hydroxyl-1-phenyl-zolo7'-2-yl)-2,2,5, 5-tetramethylcyclopentane-1-carboxamide (76%, 122-12 2.8) NMR: Downfield ppm of TMS: 1.1, m(1 5H): 1.55, m (41; L8.8 (IB); 1.63, quart (1111); 4-27, m (11; 4.75, a (IH); 5. 65, m (IH); 7-3, s (5E) Once (selected band, cm-1): 3 A 35.3380 (br), 29 45.2860, 1650, 1490, 1455.1383.1364.750 (br) Example 14 A solution of hydrazone (5) (L82 g, 10.0 mmol) in benzene arl was 0 minutes, M: 1102 (3, OI s 34-62 m mol) k. and Mg”’Oa (5-0211) f) Stirred suspension in 8.5 d of benzene at room temperature. Add with TLC analysis showed that the hydrazone was completely consumed in 2 hours, and very late. Next, filter this and add the diazoketone solution in parentheses to alanine methyl ester. rrochloride (1,39Ji', 10 mmol) and triethylamine (1,3 9M, 10 mmol) in toluene.

Thereafter, the resulting reaction mixture is heated at 90'C for 3 hours. After cooling to room temperature , this mixture was diluted once with 5% aqueous hydrochloric acid, once with water and saturated sodium bicarbonate. Wash once with water solution. After that, this toluene solution was mixed with anhydrous magnesium sulfate. (L)-Methyl-N-(2,2,5t5-te Solid residue of tramethylcyclopentane-1-carvinyl)-alaninate 1.7 4g is obtained. The resulting coupled product is 90% pure.

Example 15 A solution of diazoketone (6) (1.80 g, 10 mmol) in 1 Qd of dry toluene was prepared. , whose presence can no longer be detected by thin layer chromatography Heat to 90°C. This takes 3-4 hours. Cool the resulting solution to room temperature. After cooling, it can be used directly to acylate the primary and secondary amines or is hydrolyzed to acid (7).

Example 16 1-Hydroxy-2,2,5,5-tetramethylcyclopentanecarboxylic acid (9 ) 3.3,6.6-titramethylcyclobexane-1,2-dione 16.8 g ( 2.0.1 mol). Add to 788ml of 4N NaOH in a sake-resistant bottle. Add. By saturating this solution with N2 and heating the stirred solution, Maintain the reaction mixture at 110 °C for 24 hours at a pressure of 5p81 at 25 °C. and extract this alkaline solution twice with 100 d portions of methylene chloride. do. The extracted solution is acidified with concentrated EC1285-. This acidified solution t-10 Extract 3 times with 0.011j volumes of methylene chloride. Combined CH2Ct2 extract Dry over Na2SO4 and evaporate to dryness. Yield 12.0 F; 1-hydro xy-2,2,5,5-tetramethylcyclopentane-1-carboxylic acid, melting point 7 4-76°C, off-white crystals, 64% of theory.

Hydroxy acid (9) (0.37 g, 2.0 mmol) was added to a tube equipped with a magnetic stirrer. Pour into a 5Q+j round bottom flask (ground joint). Total amount of ether 5d 1 and started stirring the resulting solution. Ether solution of diazomethane , Ald-richemica Acta! N-methyl-N by the method described in Volume 16, (1), page 3 (1983) -nitrone-p-) luenesulfonamide. Diazometa formed The solution, as it is formed, is distilled directly into the acid solution of the hydroxy acid. child This is continued until the reaction solution exhibits a persistent yellow color. At this point the solution was Boil in a stream of plain air until the color fades. Concentrate the remaining solution until an oily residue is obtained. , pure ester (10) 0.49 g.

Ester (10)t-1 identified by its NMR and IR spectral properties: First ppm: 0-92.5 (6B); 1.1.8 (6B); 1.75, b r, s (4F3); 3-37, ε (IH): 3.8.8 (3E1 ) IR: CCt, solution (selected band) cWL-1: 3630.3540.30 00.2970.2890.1755.1725.1475.1390.123 0.1162. Example 18 1-Hydroxy-2,2,5,5-tetramethylcyclopentanecarboxylic acid hydride Production of radide (11) Methyl ester (10) (2.0 g, 10 mmol), none Water hydrazine (1,2811Ij, 40mmol) and n-sitanol (1,O a! The mixture of j) was heated in a reflux condenser at 100 to 105°C with stirring in a nitrogen atmosphere. Heat under a heat sink for 20 hours. The mixture is then allowed to cool to room temperature and filtered. Excess hydrazine and sitanol are removed under vacuum. product, i.e. viscous The oil is partitioned between water and diazomethane. Separate these phases and Concentrate under vacuum until an oily residue is obtained. This substance is replaced with sodium hypochlorite. used directly in the oxidation process. When hydrazir is present in this substance, its NMR and downfield identified by IR spectral characteristics; 1.1, br, s (12H); 1.75, br, m (4H); 4.8, s, ex ckx.

IR: CHCL3 acid solution (0, I Ji+/cc), cm-1: 334 0.3080, 3000-2900br, 2860, 2800-2400br, 2350, 1700-1500br.

1455, 1375, 1 335, 1 1 5.0.1075゜This is an example It can be isolated and purified by conventional methods, for example using chromatography techniques. Ru.

Example 19 2.2.5. Production of 5-tetramethylcyclopentanecarzanoic acid (7) 2.2,5.5-tetramethyl-1-hydroxycyclopentanecarboxylic acid hydride Radide (11) (0,035 y, o, 1 sm mol) was added with a magnetic stirring bar. Place in a 5D round bottom flask. Total amount of water 100mC2t-added, and the milky white color The solution is cooled by immersing the flask in an ice water bath. Stir this solution. At the same time, an aqueous solution of sodium hypochlorite (8.37 wt/wt%) (157 mcz, 0.176 mmol). Shows intense gas generation and deposits Formed. hypochlorous acid After complete addition of salt, the mixture was allowed to warm to ≦room temperature. Add this to 100 mc of water and the product (pH 7) was extracted twice with ether. aqueous phase, chlorinated water The pH was acidified to below 1.0 using basic acid. Clarified after ether extraction and before acidification. The clear solution takes on a milky appearance again.

This was extracted twice with ether, and the organic extract was concentrated to dryness, leaving a residue of 5.4 leave. The presence of acid (7) was determined from the authentic sample by thin layer chromatography. Detected by comparison.

The foregoing examples may be used to describe the invention in general or specific terms, as opposed to those used in the foregoing examples. Similar advantages can be obtained by applying the reactants and/or operating conditions described in Can be repeated.

From the foregoing description, a person skilled in the art can ascertain the actual features of the invention and understand its The invention may be adapted to various uses and conditions without departing from the spirit and scope of the invention. Various changes and modifications can be made to achieve this.

international search report international search report 11-^-, +mN@, PCT/EP 861006711-1-^-mmm -, PCT/EP 86100678 *am+1IIIalm Il#klj bll*IILPC? /EP861006711ANNEX To T)! E INTERNATIONAL 5EARCHREPORT 0NZNTERNA TIONAL APPL CATION No. PCT/EP 861006 7B (Sk 15330) υS-8-to 3151986 None

Claims (36)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, each of R1, R2, R3 and R4 is independently H or alkyl, aryl or aralkyl substituted by combination, and R5 or and R6 are each independently B, or optionally substituted alkyl , aryl or aralkyl, or R5 and R6 taken together Forming a fused ring] Formula: ▲Mathematical formula, chemical formula, table, etc. I'm here▼ Corresponding compounds of [wherein each of R7 and R8 is independently alkyl] in the presence of Na° or K° to form the corresponding cyclic acyloin, and oxidizing said product in situ with a favorable oxidizing agent to form diketone as the main product. A method for producing diketones, comprising the steps of: 2. The first step is Na°, R5=R6=H, and R1=R2=R3=R4= 2. The method of claim 1, carried out in the presence of CH3. 3. The corresponding process uses 0.8-2.0 equivalents of Na° and is compatible at 25-120°C. carried out in a solvent, and the oxidation is carried out in a compatible solvent at -10 to 140 °C, The method according to claim 2. 4. Oxidizing agents include thienyl chloride, chlorine, sulfuryl chloride, oxygen, and macer dioxide. Claim 3, which is ganganic acid, sodium persulfate or chloroisocyanuric acid. The method described in section. 5. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, each of R1, R2, R3 and R4 is independently H or alkyl, aryl or aralkyl substituted by combination, and R5 or and R6 are each independently H or optionally substituted alkyl , aryl or aralkyl, or R5 and R6 taken together Forming a fused ring] Formula: ▲Mathematical formula, chemical formula, table, etc. I'm here▼ of the corresponding diketone with hydrazine at pH 5-11 in the presence of an effective acid catalyst. hydrazone, thereby obtaining hydrazone as the main product. manufacturing method. 6. Claims R5=R6=H and R1=R2=R3=R4=CH3 The method described in Section 5. 7. The acid catalyst has a pka of about 1 to 6 and is used in an amount of 1 to 20 mol% and is reaction is carried out in the presence of alcohol and a compatible solvent, and the amount of hydrazine 7. The method according to claim 6, wherein is 1 to 10 equivalents. 8. 6. The method according to claim 5, which is carried out without heating. 9. The proposed method is carried out without any special means of carrying out H2O removal from the reaction. The method described in item 5 of the scope of the request. 10. carried out without any special means of carrying out H2O removal from the reaction, The method according to claim 6. 11. 11. The method of claim 10, wherein the method is carried out at about room temperature. 12. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, each of R1, R2, R3 and R4 is independently H or alkyl, aryl or aralkyl substituted by combination, and R5 or and each of R6 is independently H or optionally substituted alkyl , aryl or aralkyl, or R5 and R6 taken together Forming a fused ring] Formula: ▲Mathematical formula, chemical formula, table, etc. I'm here▼ The corresponding diazoketone of is reacted with an amine, thereby forming a cyclopentane carbo Cyclopenes of primary or secondary amines, consisting of obtaining xamide as main product Method for producing tancarboxamide. 13. The claims where R5=R6=H and R1=R2=R3=R4=CH3 The method described in item 12. 14. diazoketone in the presence of triethylamine or N-ethylmorpholine 14. The process according to claim 13, wherein the amine is reacted with the amine as a hydrochloride salt. . 15. Claim 12, wherein the amine is L-alanine or a derivative thereof. the method of. 16. Claim 13, wherein the amine is L-alanine or a derivative thereof. the method of. 17. Claim 14, wherein the amine is L-alanine or a derivative thereof. the method of. 18. The reaction is carried out by oxidizing the corresponding hydrazone with a compatible oxidizing agent. The claimed invention is carried out in situ in the reaction mixture obtained from the production of said diazoketone. The method according to scope item 12. 19. Further diazoketone, formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ oxidation of the corresponding hydrazone with a compatible oxidizing agent and subsequent oxidation of the diazoketone and produced by carrying out the reaction of amines and amines or amine hydrochlorides in situ. 13. The method of claim 12, comprising: 20. Further, the diketone has the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Corresponding compounds of [wherein each of R7 and R8 is independently alkyl] in the presence of Na° or K° to form the corresponding cyclic acyloin, The product is subsequently oxidized in situ with an effective oxidizing agent to form a diketone. 6. The method according to claim 5, comprising: 21. Furthermore, the hydrazine is combined with the corresponding diketone in the presence of an effective acid catalyst. prepared by reacting with hydrazine at pH 5 to 11, and the diketone , the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ Corresponding compounds of [wherein each of R7 and R8 is independently alkyl] in the presence of Na° or K° to form the corresponding cyclic acyloin, and subsequently oxidizing said product in situ with an effective oxidizing agent to form a diketone. 20. The method according to claim 19, comprising: 22. Furthermore, the hydrazone is combined with the corresponding diketone and hydrazine using an effective acid catalyst. produced by reaction at pH 5 to 11 in the presence of a medium, The method according to claim 19. 23. In the formula, R5=R6=H and R1=R2=R3=R4=methyl, The method according to item 20. 24. In the formula, R5=R6=H and R1=R2=R3=R4=methyl, The method according to item 21. 25. Claim 24, wherein the amine is L-alanine or a derivative thereof. the method of. 26. Claims where R5=R6=H and R1=R2=R3=R4=methyl The method according to paragraph 22. 27. Claim 26, wherein the amine is L-alanine or a derivative thereof. the method of. 28. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, each of R1, R2, R3 and R4 is independently H or alkyl, aryl or aralkyl substituted by combination, and R5 and R each of 6 is independently H or optionally substituted alkyl, ali or aralkyl, or R6 and R6 taken together form a fused ring. In preparing a compound of the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ of the corresponding diazoketone under conditions effective to reduce the 6-membered diazoketone ring. A cyclopetrope obtained by treating the cyclopentane carboxylic acid to form a 5-membered ring. A method for producing carboxylic acid. 29. The claims where R5=R6=H and R1=R2=R3=R4=CH3 The method according to paragraph 28. 30. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In producing the compound of the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ of the corresponding hydrazide with an oxidizing agent effective in converting the hydrazo group to an azo group. A method for producing cyclopentanecarboxylic acid, which comprises reacting. 31. The claims where R5=R6=H and R1=R2=R3=R4=CH3 The method according to paragraph 30. 32. adipic acid or its alkyl or aryl derivative with the corresponding pival The acid compound is dimerized by a fermentation method, thereby forming the adipic acid or its derivative. In the method of producing a compound by forming it as a precipitate, dimerization in the presence of an effective amount of a surfactant to increase the degree of separation of the products from the reaction medium. Adipic acid or its alkyl or aryl derivatives, characterized in that How the body is manufactured. 33.3,3,6,6-tetramethylcyclohexan-1-one-2-hydrazo hmm. 34. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, each of R9 and R10 is independently H, C1-8 alkyl, C6-1 0 aryl or C6-10-al-C1-8 alkyl, or NR9 A compound in which R10 is a naturally occurring amino acid residue. 35. N-methyl-2,2,5,5-tetramethylcyclopentane-1-carbo Xamide, N,N-dimethyl-2,2,5,5-tetramethylcyclopentane- 1-carboxamide, N-phenyl-2,2,5,5-tetramethylcyclopene Tan-1-carboxamide, N,N-di-n-butyl-2,2,5,5-tetra Methylcyclopentane-1-carboxamide, or N-(1-hydroxy-1 -phenyl-prop-2-yl)-2,2,5,5-tetramethylcyclopenta 35. A compound according to claim 34, which is a carbon-1-carboxamide. 36. Methyl-1-hydroxy-2,2,5,5-tetramethylcyclopentane -1-carboxylate; or 1-hydroxy-2,2,5,5-tetramethylate cyclopentanecarboxylic acid hydrazide.