WO1984002703A1 - Process for preparing aminothiazolylacetic acid derivatives - Google Patents

Process for preparing aminothiazolylacetic acid derivatives Download PDF

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Publication number
WO1984002703A1
WO1984002703A1 PCT/JP1983/000003 JP8300003W WO8402703A1 WO 1984002703 A1 WO1984002703 A1 WO 1984002703A1 JP 8300003 W JP8300003 W JP 8300003W WO 8402703 A1 WO8402703 A1 WO 8402703A1
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WO
WIPO (PCT)
Prior art keywords
reaction
group
formula
compound
acid
Prior art date
Application number
PCT/JP1983/000003
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Kunio Takanohashi
Tsuneaki Yoshida
Shoichiro Fujii
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to PCT/JP1983/000003 priority Critical patent/WO1984002703A1/ja
Priority to EP84100069A priority patent/EP0115770B2/en
Priority to DE8484100069T priority patent/DE3464911D1/de
Priority to AT84100069T priority patent/ATE28455T1/de
Priority to US06/568,921 priority patent/US4695639A/en
Priority to KR1019840000044A priority patent/KR910000238B1/ko
Priority to JP59001241A priority patent/JPS59134784A/ja
Publication of WO1984002703A1 publication Critical patent/WO1984002703A1/ja

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a method for producing a novel aminothiazo-enzymatic acid derivative which is useful in the synthesis of -pactam-based products.
  • the chemical properties of the carboxyl group in the amino-substituted part of the conductor and the carboxylic group of the permeated part are similar, so that the reactivity of acid halides, acid anhydrides, active amides, etc. ⁇ ⁇
  • a protecting group that can be removed by a chemical reaction such as ⁇ - --to- ⁇ -pene S ⁇ , is used, but it is difficult to protect the compound after the oxidation reaction.
  • a tert-butyl group which is considered to be removable in the above process, is also used, but in the second production method of the aminothiazo-conductor described above, in which the carboxyl group in the perturbed portion is mainly converted into an ethyl group.
  • the tert-butyl group is also removed at the same time as the S-I-Nation reaction before leading to the reactive derivative. Therefore, an industrially advantageous method for producing an aminothiazo->> acid derivative in which the amino group and the carboxyl group of acetic acid ⁇ ⁇ are not protected and only the carboxy group in the a-position is protected is not yet available.
  • the present inventors have studied the use of an aminothiazo- »acid derivative as an intermediate for ⁇ - ⁇ -type antibiotics « I-type intermediates>. Knowing that the step of protection can be omitted, the power of the amino group and the hydroxyl group in the urine is not protected and the ⁇ group is not protected.
  • OMPI Power of the displacing unit Aminothiazo-based key conductor with a protected boxoxy group is industrially advantageous. * Production method Various inspections were conducted. As a result, among the possible combinations of various processes, diketin and hagen are reacted, and then reacted with ⁇ -grade aki or phospho-thiacco, and then oxidized with nitrous acid. However, after the reaction with thiourea, the reaction of the kimchi is advantageously prevented, and the W group of the carboxyl group in the peroxidized portion of the resulting compound is selectively and easily removed.
  • X ′ is halogen and the others are as defined above.
  • H 2 are the same or different and represent hydrogen or a B-rank group.
  • B 2 are, for example, methyl, ethyl, isobutyl, isobutyl, iso-butyl, sec-butyl A ⁇ tert-butyl. Group is used.
  • B 2 is preferably a hydrogen atom or a methyl group, or one of them is hydrogen and the image is a methyl group.
  • B is ®
  • a ft Kyua key group represented by B includes, for example, described in B a; Gotoki ⁇ prime t of 3 ⁇ 4 to 4 ® Kyua year group 3 ⁇ 4 etc. is use.
  • Examples of the preferred B are: ⁇ , ⁇ , which is represented by ⁇ , ⁇ , ⁇ ⁇ ⁇ ⁇ , and ⁇ .
  • X may be the same, or may represent different * ⁇ -gens. The halogens commonly used as X and ⁇ 'are * element and autum.
  • diketin and a halogen are first reacted to give a 4-halogenoacetic acid halide.
  • This production method is carried out by dissolving ⁇ ketin in a solvent and cooling it.
  • 3 ⁇ 4 MU * C is for example as planted methylene, ⁇ ⁇ Stenoles such as halogenated hydrocarbons, acetic acid, and ethers such as ether and dioxane are used The reaction is usually performed under cooling at ⁇ 70 * to 10 ⁇ : Reaction time Is short and short-lived.
  • the 4-halogenoatoacetic halide to be masked can be isolated and purified by known means, for example, (1) solvent extraction, liquid conversion, sugar A, chromatography, etc. It is advantageous to use it as a raw material for the next process
  • OMPI , N, dioxane, di-thieth, etc. are preferred (used ⁇ also the presence of the soil group "R reaction"
  • the «dose of the lump group is a 3 — class [2] ⁇
  • the compound [I] is generally reacted with nitrous acid in an approximately equivalent amount, but it may be used in a slightly different manner.
  • the nitrous acid may be used as it is, but may be used as, for example, aluminum metal such as sodium and potassium.
  • the reaction is carried out in a water-cooled medium-cooled insulator room ( ⁇ 50 ⁇ 50X: preferably 110 ⁇ 40c).
  • Examples of 11 used include, for example, ethyl ufurans, dioxane, ethiues of jetiate, fatty acids such as glazed acid, or a mixture thereof.
  • the water to be added to these may be arbitrarily added.
  • the ⁇ reaction which can add water to the reaction system, varies depending on the amount of the raw material, the solvent, etc., but usually progresses quickly in W (20 minutes to 3 hours).
  • the body [] can be purified by known means S, for example, steaming, solvent extraction, concentration, reconstitution, etc., but it is necessary to purify it in the end.
  • the compound of formula [V] can be obtained by reacting the oxime compound [W] with thiourea.
  • one thiourea is reacted with one compound [nr], but it is eaten with the use of urine which has no adverse effect on the reaction.
  • This reaction is usually carried out in a solvent.
  • Water and a port medium mixed with water such as alcohols such as methanol and ethanol, ketones such as acetone and jetiketone, and citrahydroplan , Di;
  • Ethanes such as xane and thietate; ⁇ , If-dimethy ⁇ formamide; acid amides such as N, K-dimethyacetoamide; and organic amides such as ir-methibiberidone.
  • ⁇ Bag aliphatic power plants include sodium vinegar, sodium acetate, potassium acetate, barium acid, barium citrate, potassium nut, sodium provinate, sodium hexane, and hexane potassium.
  • Lower aliphatic carboxylic acids of the formulas 1 to 6 for example, sodium diacid, potassium, and any other organic group; for example, trimethylene Triamine, triXthiamin, triptiamine, etc., which are tri-substituted amines having a low alkyl number of 1 to 4 and, for example, a-methylidine, H-ethylamine P-Resin, If-Metibidurazine, Kotibiperazine * 5 to 8 cyclic amines with 1 to 2 carbon atoms each having 1 to 2 carbon atoms.
  • the ir, H-dimethylformamide, ir, ir-dimethylacetamide, u-methide When using dong as a solvent, it is necessary to add the basic substance described above *.
  • the amount of the basic substance to be added is 0.5 to 1.3 * for the compound [W] and the molybdenum, depending on the raw material, the type of the solvent, and the like.
  • the reaction is usually performed at 0 to 4 O x:, but depending on the * U cooling or heating that does not hinder the reaction! You can also adjust the reaction speed. ⁇ Generally
  • the reaction is completed in 10 minutes to 4 hours.
  • the compound of the formula [V] thus obtained can be purified by a known method such as steam S, liquid conversion, crystallization, and re-transfer ft. When the anti-isomer is mixed, it can be separated according to a known method. Also, since compound [V] has a basic amino group at the 2-position of the thiazo ring, it is possible to use an organic acid, such as »jun, tartaric acid, methanol, etc., in accordance with a conventional method. It can also be isolated and purified as inorganic acids such as hydrogen acid, acetic acid, phosphoric acid, agin, asparagine kin, glutamic acid and other perfect amino.
  • the compound [V] a compound in which an amino group is left free or a compound formed with a spear as described above is used as a raw material.
  • the compound [VI] of molybdenum may be reacted, but usually the compound [V] or the compound [VI] of 1.5 to 2.0 ⁇ with respect to 1 mol thereof is used.
  • the reaction is performed in a solvent.
  • solvent used examples include, for example, acetone, methetic; u ketone, such as ketones, and acetate tri, fi-. Solvents are commonly used in similar reactions, but the disadvantages of using amides such as ⁇ , ⁇ -dimethylformamide, etc. are rather improved. Is done. $ *
  • a 3 ⁇ 4 group may be added to the reaction system in order to deviate the reaction by an advantageous tC.
  • the 3 ⁇ 4 group used is a special ⁇ group that can promote the reaction. However, it is preferable to use * acids such as sodium acid carbonate, sodium carbonate, and sodium hydrogen carbonate (organic organic groups may cause a side reaction and the yield may decrease). . 3 ⁇ 4The amount of group used is urine compound
  • the ratio is preferably 5 to 10 times, preferably 1.5 to 5 times. Further, in order to favor this reaction, it is preferable to add water to the reaction system, especially to the solvent, and the amount of water to be added is ⁇ 0 J Jt * 2 Jt volume for the solvent to be used. It is 1.5% volume, and if it is out of this range, the reaction will be extended and one prolonged decomposed product will be generated. * The reaction is between 0 and 60. 20 to 50 c is preferable. ⁇ ⁇ Under the conditions, the reaction quantitatively escapes, and the raw materials disappear * in 0.5 to 3 hours. Therefore, the reaction can be terminated at this point. After completion of the reaction, the target isomer [VI] can be isolated and purified by a known means such as extraction, liquid conversion, crystallization, distillation, chromatography and the like.
  • Compound [W] is a compound
  • [W] ⁇ p ⁇ tiC total; ⁇ solution occurs.
  • the hydrophilic solvent for example, alcohols such as mono- and eno-, ketones such as acetone, and birds such as a-to-tri may be used. It is better to use 0.5 to 10 times as much water as the port medium. The degree of hydrolysis is
  • the base used may be any one having a pH of about 3 to 12; for example, organic amines such as carbon dioxide lime, carbon dioxide lime, carbon lime, triethylamine, isopropylamine, etc.
  • the amount of the group to be used may be more than about 5 times, and the hydrolysis is usually completed in about 30 minutes or 2 hours. It can be isolated and purified by known means such as:
  • the target compound [I] is a 2-amino group of the thiazo ring, which can be isolated as an acid of the same dicarboxylic acid as described in the compounds [V] and [3 ⁇ 4], and has a carboxyl group *.
  • sodium metal, potassium and other metals, metals, magnesium, etc. can also be separated from the metal in the soil.
  • WMH Svetat was measured with a Varian T60 (60 MHz) and expressed in ppm with reference to citrahmethy silane. Also, 7ts is the gritlet d is doublet, 7 is triblet, -3 ⁇ 4 is force test, m is machiblet, J is integration constant, DS0 is dimethyl Vhod, br is g t »-de, arom means aromatic.
  • reaction solution is poured into water and extracted with a water heater.
  • Arigami layer After water »Reduced to dryness and solidified vinegar sorbet Isoprobech (t: 5) Obtained from i ⁇ * A from greed.
  • the oily substance with (3) was dissolved in an aqueous solution of tr ethano- ⁇ 8.3 and water 0.43.
  • Methyl square 2- (2-aminothiazol-1-41) obtained in Example 3 and 2-hydroxyimino vinegar (ester) 0 / are added to acetate-tori 20. t-butyl 7.7 fir was added. Further powder Fushimi anhydrous Sumi ⁇ potassium adding water 1.2 W, 8 ⁇ 85 f 3 ⁇ 4 , it reacted in the last three click of diisocyanato Li um 5. room added S f conc. After the reaction was completed, the precipitate was removed by filtration. Water 30 was added to the filtrate, and potassium carbonate solution 40 was maintained at pH 1 10.5 and hydrolyzed by dropwise addition.
  • aminothiazo-firewood derivative [I] is used as an advantageous synthetic intermediate for synthesizing ⁇ -pectam antibiotics having excellent antibacterial activity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/JP1983/000003 1983-01-07 1983-01-07 Process for preparing aminothiazolylacetic acid derivatives WO1984002703A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
PCT/JP1983/000003 WO1984002703A1 (en) 1983-01-07 1983-01-07 Process for preparing aminothiazolylacetic acid derivatives
EP84100069A EP0115770B2 (en) 1983-01-07 1984-01-05 Thiazole Derivatives
DE8484100069T DE3464911D1 (en) 1983-01-07 1984-01-05 Thiazole derivatives
AT84100069T ATE28455T1 (de) 1983-01-07 1984-01-05 Thiazolderivate.
US06/568,921 US4695639A (en) 1983-01-07 1984-01-06 Thiazole derivatives
KR1019840000044A KR910000238B1 (ko) 1983-01-07 1984-01-07 티아졸 유도체의 제조방법
JP59001241A JPS59134784A (ja) 1983-01-07 1984-01-07 アミノチアゾ−ル酢酸誘導体及びその製造法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1983/000003 WO1984002703A1 (en) 1983-01-07 1983-01-07 Process for preparing aminothiazolylacetic acid derivatives

Publications (1)

Publication Number Publication Date
WO1984002703A1 true WO1984002703A1 (en) 1984-07-19

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Application Number Title Priority Date Filing Date
PCT/JP1983/000003 WO1984002703A1 (en) 1983-01-07 1983-01-07 Process for preparing aminothiazolylacetic acid derivatives

Country Status (3)

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JP (1) JPS59134784A (enrdf_load_stackoverflow)
DE (1) DE3464911D1 (enrdf_load_stackoverflow)
WO (1) WO1984002703A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101362732B (zh) * 2008-09-16 2012-07-25 山东金城医药化工股份有限公司 一种头孢克肟侧链酸的制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61143379A (ja) * 1984-12-14 1986-07-01 Tanabe Seiyaku Co Ltd チアゾ−ル酢酸誘導体の製法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5598189A (en) * 1976-04-12 1980-07-25 Fujisawa Pharmaceut Co Ltd Syn-isomer of 3, 7-di-substituted-3-cephem-4-carboxylic acid compound, its salt, and their preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5598189A (en) * 1976-04-12 1980-07-25 Fujisawa Pharmaceut Co Ltd Syn-isomer of 3, 7-di-substituted-3-cephem-4-carboxylic acid compound, its salt, and their preparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Journal of Chemical Society, No. 97 (1910) F. Chick et al: "The Polymerisation of Keten. Cyclobutan - 1 : 3 - dione ("Acetylketen") P. 1978-2000 *
Journal of Pharmaceutical Science, Vol. 59, No. 1 (January, 1970) (U.S.A.) A. Kapoor: "Recent Trends in the Synthesis of Linear Peptides" P. 1-27 *
Miklos Bodanszky et al: "Peptide Synthesis" second edition (1976) John Wiley and sons Inc., (U.S.A.) P. 54-56 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101362732B (zh) * 2008-09-16 2012-07-25 山东金城医药化工股份有限公司 一种头孢克肟侧链酸的制备方法

Also Published As

Publication number Publication date
JPS59134784A (ja) 1984-08-02
JPH0513949B2 (enrdf_load_stackoverflow) 1993-02-23
DE3464911D1 (en) 1987-08-27

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