• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to novel cyclohexanecarboxylic acid and its derivatives represented by the general formula: <IMAGE> (wherein R1 is selected from the group consisting of hydrogen or methyl; R2 is selected from the group consisting of hydroxyl, lower alkoxy with 1-6 carbons or amino acid rest. In case R1 is hydrogen, however, R2 means amino acid rest, which of all the compounds of the present invention are entirely novel ones which have never been in any printed publications, possessing a high degree of pharmacological activities such as anti-allergic, anti-inflammatory, anti-ulcerative, antibacterial, anti-thrombotic and liver-function-improving activities, and therefore, these compounds are useful as medicines, and besides, these compounds are surface-active and, therefore, useful as additives for toothpaste and shampoo, as surface active agents for detergents, dispersing agents, emulsifying agents and cosmetics, as anticarious agents, and also in industrial fields the aforesaid compounds are useful as detergents for keeping textiles soft, as additives for lubricating oil, as anti-rust agents, additives for plastics and also as metal-capturing agent, ion-floating agents and emulsifying agents for other industrial purposes).
    公开号:SU797570A3
    申请号:SU782615705
    申请日:1978-04-29
    公开日:1981-01-15
    发明作者:Нода Кандзи；Накагава Акира；Ямагата Кендзи；Хачия Теруми；Идэ Хироюки；Кода Акихидэ
    申请人:Хизамицу Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING CYCLOGBXANKARBONIC ACID DERIVATIVES
    The invention relates to organic chemistry specifically to a process for the preparation of new derivatives of cyclohexanecarboxylic acid with the general formula 1 CH And - or CH3; R is an alkoxy group containing L6 carbon atoms or an amino acid residue. The compounds exhibit high pharmacological activity, such as anti-allergic, active inflammatory, anti-hypertensive, or anti-thrombotic. In addition, these compounds are surface-active substances and are suitable as additives for toothpaste and shampoos, as surface-active agents for detergents, emulsifiers, etc. A known method for producing carboxylic acid derivatives containing, instead of hydroxyl, an alkoxy group or amino acid residue by treating the carboxylic acid with a chlorine agent, followed by reacting the corresponding acid chloride with an alcohol or amine-containing compound 1. The purpose of the invention is to develop a method for producing new cyclohexanecarboxylic acid derivatives that are biologically active. as well as surfactants. This goal is achieved by the method of obtaining cyclohexanecarboxylic acid derivatives of the general formula T, where R is H or CH3. R is alkoxygroup, containing 1-6 carbon atoms or an amino acid residue. lots, by treating cocyeneni with the general formula T R of SOOH. where R is as defined above; a halogenating agent followed by the reaction of the corresponding acid chloride formed with an alcohol or amino acid. The reaction of the acid halide with a lower alcohol is carried out in the presence of organic solvent (e.g., tetraprofrofuran), which are not reactive in the presence of alkali (e.g. sodium triethylamine carbonate and potassium carbonate), at room temperature or when heated to 100 ° C. when dissolved in solvents such as water, alcohol, tetrahydrofuran, alkali and acid halide are added dropwise to the solution in an amount equal to or greater than the amino acid group in the presence of alkali (e.g. idroxide sodium). During the addition, the pH of the reaction mass should be kept in the range of 912, 5, and stirred while cooling or at room temperature (5-30 ° C) and, if necessary, following the addition, heat it with water at 40% 60 C. Compounds of general formula 1 exist as two stereogeometric isomers, namely cis-isomer and trans-isomer, which can be separated using differences in activity from functional groups and differences in their spatial configuration (for example, formed clathrate formulations, urea, thiourea and cyclodextrin or stability in hydrolytic reactions). Example 1. To a solution of 30 g of cis-4-isohexyl-1-methylcyclohexanecarboxylic acid in 150 ml of benzene was added 30 g of phosphorus pentachloride, the mixture was kept at room temperature for 30 minutes, and then boiled for 1 hour. after completion of the reaction, the solvent was distilled off under reduced pressure, to obtain 33.5 g of cis-4-isohexyl-1-methylcyclohexanecarbonyl chloride. To a solution of 11 g of glycine in 100 ml of distilled water was added 11.7 g of sodium hydroxide and 21 ml of water while cooling and stirring, then the resulting mixture and the above acid chloride were alternately added dropwise to the solvent. During the addition, the pH of the medium is kept between 9-12.5. After the addition, the reaction mass is stirred at room temperature for 3 hours. After the reaction is complete, the pH is adjusted to 2 by adding dilute hydrochloric acid, and then the wire t extraction with ether. The ether is washed, dried and distilled, the residue thus obtained is recrystallized from petroleum ether. 37 g of N- (cis-4-isohexyl-l-methyl-cyclohexanecarbonyl)) - glycine are obtained in the form of colorless needles, melting at 90-93 ° C. Example 2. To a solution of 12.7 g of trans-4-isohexyl-1-methylcyclohexanecarboxylic acid in 50 ml of benzene was added 11.6 g of phosphorus pentachloride, the mixture was kept for 30 minutes at room temperature and then boiled for 1 hour After that, the solvent is distilled off from the mixture under reduced pressure. 13.2 g of trans-4-isohexyl-1-methylcyclohexanecarbonyl chloride are obtained. 4.5 g of sodium hydroxide in 10 ml of water are added to a solution of 4.3 g of glycine in 30 ml of distilled water with cooling and with stirring, and then the mixture and the above hydrochloride are alternately added in pairs to the solvent. During the addition, the pH of the medium is maintained between 9-12.5. After the addition is complete, the reaction mass is stirred at room temperature for 3 hours. After completion of the reaction, the pH of the medium was adjusted to 2 with dilute hydrochloric acid, and the mixture was extracted with ether. The ether layer is washed, dried and the solvent is distilled off. The residue thus obtained is recrystallized from a mixed solvent consisting of simple and petroleum ethers. 14.5 g of N- (trans-4-isohexyl-1-methylcyclohexanecarbonyl) -glycine are obtained in the form of colorless flakes melting at 108-111.5 ° C. Example 3. To a solution of 6.3 g of α-aminocaproic acid and 40 ml of distilled water was added 3.6 g of sodium hydroxide, dissolved in 8 ml of water, while cooling and stirring, the resulting mixture and 10.5 g of cis-4-isohexyl - 1-methylcyclohexanecarbonyl chloride is added alternately dropwise to the solvent. During the addition, the pH of the medium is maintained between 9-12.5. The mixture was kept at room temperature for 3 hours and then heated at 50 ° C for 15 minutes. After completion of the reaction, the pH was adjusted to 2 by addition of dilute hydrochloric acid, extracted with glacial acetic acid ethyl ester. The ether layer is washed and dried, the solvent is distilled off. The residue thus radiated is recrystallized from a mixed solvent of simple and petroleum ethers. 10.5 N- (cis-4-isohexyl-1-methylcyclohexanecarbonyl) -6. Aminocaproic acid is obtained in the form of colorless prisms having a melting point of 72-74 ° C.
    Example 4. To a solution of 4.6 g of o-methio. Niaa, 5 g of sodium carbonate and 40 ml of water are added 2.5 g of sodium hydroxide dissolved in 8 ml of water, with cooling, stirring, then the resulting mixture and 7.6 trans-4-isohexyl-1-methylcyclohexanecarbonyl chloride is added alternately dropwise to the solvent. During the addition, the pH of the medium is maintained between 9-12.5. After the addition, the reaction mass is kept for 3 hours at room temperature and then heated at 50 ° C for 15 minutes. After the reaction is complete, the pH is adjusted to 2 by adding dilute hydrochloric acid to the reaction mixture and then extracted with ether. The ether layer is washed, dried, the solvent is distilled off. The residue thus obtained was recrystallized from petroleum ether to obtain 8.8 g of M-1rais-4-isohexyl-1-methylcyclohexanecarbonyl-o-methionine in the form of colorless needles with a melting point of 102,104 ° C.
    Example 5. To a solution of 4.1 g of D, L norleucine, 5 g of sodium carbonate and 40 ml of water are added 2.5 g of sodium hydroxide, dissolved in 8 ml of water with cooling and stirring, and then the resulting mixture and 7.6 g of trans-4-isohexyl-1-methyl CEC of l-hexanecarbonyl chloride is added dropwise alternately to the solvent. During the addition, the pH of the medium is maintained between 9-12.5. After the addition was complete, the reaction mass was kept at room temperature for 3 hours and then heated at 50 ° C for 15 minutes. After completion of the reaction, the medium was adjusted to pH 2 by adding dilute hydrochloric acid and then extracted with ether. The ether layer is washed and dried, and then the solvent is distilled off. The residue thus obtained was recrystallized from petroleum ether. 9.4 g of M- (trais4-isohexyl-1-methylcyclohexanecarboiyl) -0 are obtained, inorulation in the form of colorless needles with a melting point of 109-111 ° C.
    Example 6. To a solution of 3.4 g of sarcozyme, 6 g of sodium carbonate and 40 ml of water were added 3.2 g of sodium hydroxide dissolved in 8 ml of water with cooling and stirring, and then the resulting mixture and 8.7 g of trans-4 -isohexylcyclohexanecarbonyl chloride
    add alternately dropwise to the solvent.
    The time of addition of the RP medium is maintained within the range of 9-12.5. After the addition, the reaction mass is maintained at room temperature for 3 hours and then heated for 15 minutes at 50 ° C. After the completion of the reaction, the pH of the medium is adjusted to 2 by adding dilute hydrochloric acid to the reaction mixture and then extracted with ether. The ether layer is washed and dried, the solvent is distilled off. The residue thus obtained is recrystallized from a mixed solvent, simple and petroleum ethers, which gives 9.5 g of N- (trans-4-isohexylcyclohexanecarbonyl) -sarcosine as colorless needles with a melting point of 131-132 ° C.
    Example 7. To a solution of 20 g of glycine ethyl ether, 15 g of triethylamine and 100 ml of tetrahydrofuran was slowly added dropwise 23.4 g of cis-4-isohexyl-1-methylcyclohexanecarbonyl chloride at ice temperature. After adding dropwise the reaction mass is stirred at room temperature for 3 hours. After completion of the reaction, the triethylamine hydrochloric acid salt is filtered off. The solvent was distilled off under reduced pressure to give a residue, to which ice water was added. The precipitated crude crystals are collected by filtration and dried. . Recrystallization of the crystals from acetonitrile will yield 30 g of M- (yis-4-isohexyl-b-methyl-cyclohexanecarbonyl) -substituted glycine tylyl ether as colorless needles with a temperature of 86-89 C.
    Example 8. To a solution of 4.6 g of glycine and 70 ml of water was added 10 g of cis-4-isohexyl-1-methylcyclohexanecarbonyl chloride with cooling and stirring, and then 13 g of triethylamine were added dropwise at room temperature. After the addition, the mixture is stirred for 1 hour and left at 50 ° C for 30 minutes. After the reaction is complete, the pH is adjusted to 2 by adding diluted hydrochloric acid to the reaction mixture and then extracted with ether. The ether layer is washed and dried, and then the ether is distilled off.
    The residue thus obtained is recrystallized from petroleum ether, which gives also g of N- (cis-4-isohexyl-1-methylcyclohexanecarbonyl) -glycine as colorless needles with a melting point of 90-93 ° C.
    Example 9. To a solution of 8.0 g of cis-4-isohexyl-1-methylcyclohexanecarboxylic acid and 30 ml of benzene was added 12.7 g of thionyl chloride and the mixture was heated under reflux for 3 hours at 80 ° C. After 7
    sepiJajejflH reactions G1 used during the reaction, the solvent is distilled off the mixture under reduced pressure Sh1 to obtain 8.6 g of 1C1c-4-isohexyl-1-methi-cyclohexanecarboxylic acid chloride. To a solution of 9.6 g of n-hexyl stripe and 30 ml of tetrahydrofuran, 1P) 1-st acid chloride was added dropwise. A 15 g ml of grigilamine was added and the mixture was dried for 1 hour at 55 ° C. After completion of the reaction, the solvent was distilled off under reduced pressure. Some ice water is added and the residue is extracted with diethyl ether, and diethyl ether is distilled off after washing and drying the ether layer.
    The residue is distilled in vacuo to obtain 6.8 g of n-hexyl ester of is-4-isohexyl-1-methylcyclohexanecarboxylic acid in the form of a colorless oil, boiling at 120122 ° C at a pressure of 0.7 mm pr. Art.
    Analysis results; calculated for Ci HjgOj: C, 76.45%, and 12.83%. Found: C, 76.42%, - H, 12.79%.
    Example 10. To a solution of 7.2 g of n-propyl alcohol and 35 ml of tetrahydrofuran was added dropwise 10.0 tons of 1CHS-4-isohexyl-1-methylcyclohexanecarboxylic acid chloride. When the addition is complete, 16 ml of triethylamine are added dropwise and the mixture is stirred for 1 hour at 50-60 ° C. After completion of the reaction, the solvent is distilled off under reduced pressure. Some ice water is added and the resulting residue is extracted with diethyl ether. The ether is distilled off after washing and dehydrating the ether solution. The residue was distilled under vacuum to obtain 7.2 g of cis-4-isohexyl-1-methylcyclohexanecarboxylic acid n-propyl ester in the form of a colorless oil, boiling at 158-160 ° C at a pressure of 30 mm. Hg
    Analysis results: calculated for C17H3A: C, 76.06%, H, 12.02%. Found: From 75.98%, H 12.03%.
    Example 11. To a solution of 4.6 g of trans-4-isohexyl-1-methylcyclohexanecarboxylic acid and 20 ml of benzene was added 7.3 g of thionyl chloride and the mixture was heated under reflux at 80 ° C for 3 hours. Upon completion of the reaction, the solvent distilled from the mixture under reduced pressure to obtain 5.0 g of trans-4-isohexyl-1-methylcyclohexanecarboxylic acid chlo ride. To a solution of 3.1 g of ethyl alcohol and 30 ml of tetrahydrofuran is added dropwise indicated hydrochloric acid hydrochloride. Upon completion of the dropwise addition, 12 ml of triethylamine is added and the mixture is stirred for 2 hours at 50 ° C. After completion of the reaction, the solvent is distilled off from the mixture under reduced pressure.
    708
    pressure. Some ice water is added and the resulting residue is extracted with diethyl ether. The ether is distilled off after washing and dehydrating the ether layer. The residue is distilled in vacuo to obtain 3.8 g of ethyl trans-4-iheohexyl-1-methyl diclohexanecarboxylic acid in the form of a colorless oil, boiling at 157-159 ° C at a pressure of 30 mm Hg
    Analysis results: calculated for QeHsoOa: C 75.53; H 11.89%. Found: C 75.68%, H 11.74%.
    Examples 12-15. The compounds listed in the table below. 1 can be obtained by a method similar to that described in examples 9-11.
    In accordance with the proposed method, compounds of the general formula are obtained.
    COR
    Presented in table. 2
    30 Basic compounds of the invention of the general formula
    trance
    are presented in table. 3
    Basic compounds of the invention of the general formula
    Soybean
    cis
    Uh
    are presented in table. four.
    9797570
    Basic compounds of the invention of the general formula
    COR
    I TpQHcJ
     CKj are presented in Table. 5. Compounds obtained using the proposed method, have acute toxicity, 15 antiallergic and surface properties. Some compounds have been found to show10
    I a o l and c a 1
    12 Iis-4-isohexyl-methyl methyloxy cyclohexanecarboxylic acid 154-155 / 30
    10 13 cis-4isohexyl-1-methylcyclohex116-117 / 07 sulcarboxylic acid isopentyl ester 14 cis-4-isohexyl-1-methylcyclohexanecarboxylic acid n-butyl ester 100-101 / 07 n-propyloxy-4-isohexyl-1-methylcycloherohecananeacanacroacanacanacanacanacanacanacanacroacchannecarboxylicacidic acid; -106 / 0.7
     - COOH
    eleven
    -NHCH2CHjCH2COOH
    SL2CH2S01 H2
    -1HSSNSOZON (L form) SNGSNgSoon
    -1QHCHCOOH (L form
    Hj - UNP
    CHzCH SCHj
    -tw un dream {L form)
    CHjSH -YU1SYASON {L form)
    soon (-1IH -sn - CH2 3) 2 (-L form}
    Compound
    -NHCHjCOOH
     S sn J - ITEMS (1 Forep
    SNaSngSNgSNz --1 "nsn: soon (Di form)
    sns
    - Nz
    -TQHCHCOOH (L form)
    -NHCHjCHjCOOH
    SNS:
    I SNS-Innsoon (L form)
    Continuation of table 2
    Ether, Petroleum Colorless
    112 needle ether
    Colorless
    109 needles
    Acetonitrile
    Colorless 131 needles
    Colorless
    135 needles 82
    Colorless scales
    136
    Colorless prism
    Colorless tr oil
    82
    Colorless
    Acetonitrile needles
    T a b l and c a 3
    Appearance
    Melting Point Solvent, ° C
    111.5 Colorless
    Ether, petroleum ether flakes
    104
    Colorless
    Petroleum ether needles
    111
    Petroleum ether
    Colorless
    Ether,
    132. isopropyl ether needles
    115
    Isopropyl
    Blessed ether flakes
    - 114
    Colorless scales
    86
    Colorless
    Lethone polygrin prism
    -NHCHjCHjCOOH
    SN
    , five
    -UNSONS (L form)
    mon, I
    -BSP;, COOH
    CH2, CHjCOOH:
    -Innson (L form)
    36
    37 -NHCHjCHjCHjCHjCHjCOOH
    Continued table. 3
    105 - 110 White needles
    132- 135 White needles Isopropyl.
    ether
    Petroleum
    105 - 110 ether
    165 - 168 White prisms Ethanol, isopropyl ether
    121 - 124 White needles Ethyl acetate,
    权利要求:
    Claims (1)
    [1]
    isopropyl ester. Formula of the invention. A method for preparing cyclohexanecarboxylic acid derivatives of the formula TH- or Sie; an alkoxy group containing 1-6 carbon atoms or an amino acid residue, 25-30 characterized in that the compound of the general formula: P CHj where R - is as defined above; treated with a halogenating agent followed by reaction of the resulting acid chloride with an alcohol or amino acid. Sources of information taken into account during the examination 1. Fizer L. and Fnzer M. Organic Chemistry, M., Chemistry, 1969, V. 1, p. 447-449
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    同族专利:
    公开号 | 公开日
    ES469314A1|1980-01-01|
    AU519919B2|1982-01-07|
    CH633251A5|1982-11-30|
    NL7804192A|1978-12-19|
    AR222304A1|1981-05-15|
    AT358006B|1980-08-11|
    AT358007B|1980-08-11|
    ZA782228B|1979-04-25|
    AR223317A1|1981-08-14|
    AU3500378A|1979-10-18|
    ATA311678A|1980-01-15|
    GB1593469A|1981-07-15|
    FR2394514A1|1979-01-12|
    ES469313A1|1979-10-01|
    SU704452A3|1979-12-15|
    CA1125304A|1982-06-08|
    IT7849127D0|1978-04-28|
    CA1111862A|1981-11-03|
    MX5006E|1983-02-09|
    US4228304A|1980-10-14|
    SE7806433L|1978-12-17|
    ATA311778A|1980-01-15|
    JPS545949A|1979-01-17|
    DE2818879A1|1979-01-18|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
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