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WO1988001619A1 - Composes de 1'-methyl-beta-lactame et leur production - Google Patents

Composes de 1'-methyl-beta-lactame et leur production Download PDF

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Publication number
WO1988001619A1
WO1988001619A1 PCT/JP1987/000239 JP8700239W WO8801619A1 WO 1988001619 A1 WO1988001619 A1 WO 1988001619A1 JP 8700239 W JP8700239 W JP 8700239W WO 8801619 A1 WO8801619 A1 WO 8801619A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
formula
give
methyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1987/000239
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English (en)
Inventor
Shiro Terashima
Yoshikazu Kimura
Yoshio Ito
Takeo Kawabata
Kunikazu Sakai
Tamejiro Hiyama
Makoto Sunagawa
Akira Sasaki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sagami Chemical Research Institute
Sumitomo Pharma Co Ltd
Original Assignee
Sumitomo Pharmaceuticals Co Ltd
Sagami Chemical Research Institute
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
Priority claimed from JP61201576A external-priority patent/JPS62174048A/ja
Application filed by Sumitomo Pharmaceuticals Co Ltd, Sagami Chemical Research Institute filed Critical Sumitomo Pharmaceuticals Co Ltd
Publication of WO1988001619A1 publication Critical patent/WO1988001619A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel 1'-methyl-beta- lacta compounds and their production. More particularly, it relates to 1'-methyl-beta-lactam compounds useful as intermediates in the synthesis of beta-lactam compounds having a methyl group at the 1'3-position and their production.
  • the 1'-methyl-beta-lactam compounds of this invention are novel and can be represented by the formula:
  • R is an optionally substituted diarylmethyl group
  • R is a protective group for hydroxyl
  • aryl as he einabove and hereinbefore used alone or in combination with .any other group is intended to mean a ⁇ arbocyclic aromatic ring, preferably having not more than 20 carbon atoms, and its typical examples are phenyl, naphthyl, phenanthryl, etc., among which preferred is phenyl. 161 - 2 -, -
  • beta-Lactam compounds of the formula:
  • R is a protective group for hydroxyl
  • 1' -methyl- carbapenem compounds having a potential anti-microbial activity [D.H. Shin et al.: Heterocycles, 21 , 29 (1984)] and have heretofore been produced from the corresponding desmethyl compounds by drawing out the hydrogen atom at the l 1 -position in the acetic acid residue at the 4-position by the aid of a strong base and introducing a methyl group therein.
  • it is essential to use lithium diisopropylamide which can be handled with great difficulty in industry. Further, it is indispensable to perform the reaction at such a low temperature as -78°C.
  • 1'-Methyl-beta-lactam compounds (I) of the inven- tion have been found to be readily and advantageously converted into the beta-lactam compounds (II) without any drawback as seen in said conventional method for production of the beta-lactam compounds (II) .
  • conversion can be accomplished substantially by elimination of the amino- protective group at the 1-position, reduction of the car- bonyl group in the side chain at the 3-position to a hydroxymethylene group and oxidation of the hydro.xymethyl group in the side chain at the 4-position into a carboxyl group in an appropriate order.
  • R may be, for instance, an optionally substituted diarylmethyl group (e.g. diphenylmethyl, di-p-anisylmethyl) , a substi ⁇ tuted aryl group (e.g. p-methoxyphenyl, 2,4-dimethoxyphenyl, o-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 3,4,5-tri- methoxyphenyl group), or the like.
  • diarylmethyl group e.g. diphenylmethyl, di-p-anisylmethyl
  • a substi ⁇ tuted aryl group e.g. p-methoxyphenyl, 2,4-dimethoxyphenyl, o-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 3,4,5-tri- methoxyphenyl group
  • a substi ⁇ tuted aryl group e.g. p-methoxyphenyl, 2,
  • R 2 hydroxy-protective group (R ) are a straight or branched ,-C 5 alkyl group (e.g. t-butyl) , a C ⁇ -C fi alkenyl group
  • allyl e.g. allyl
  • C,-C 5 alkoxy(C,-C-.) alkyl group e.g. methoxy methyl- 1-ethoxyethyl, isopropoxymethyl, 1-methy1-1-methoxy- ethyl, t-butoxymethyl, 1-isopropoxyethyl
  • benzyl p-methoxybenzyl, 2,4-dimethoxy- benzyl, o-nitrobenzyl, p-nitrobenzyl) , an acyl group such as lower alkanoyl (e.g. acetyl) or benzoyl, etc.
  • lower alkanoyl e.g. acetyl
  • benzoyl etc.
  • the 1'-methyl-beta-lactam compound (I) can be produced, for instance, according to the following scheme:
  • R 1 and R2 are each as defined above.
  • the 1st step is concerned with the reaction between the aldehyde compound (III) and an a ine (IV) to give the i ine compound (V) .
  • the reaction may be carried out in the presence or absence of an inert solvent, if necessary, in the existence of a dehydrating agent (e.g. molecular sieve, anhydrous magnesium sulf te, anhydrous sodium sulfate, calcium chloride) .
  • a dehydrating agent e.g. molecular sieve, anhydrous magnesium sulf te, anhydrous sodium sulfate, calcium chloride
  • the inert solvent are aromatic hydrocarbons (e.g. benzene, toluene, xylene) , ethers (e.g. ether, tetrahydrofuran, dioxane, diglyme) , etc.
  • the reaction proceeds smoothly at a temper ⁇ ature of about 0 to 100°C.
  • the 2nd step relates to the reaction between the imine compound (V) and diketene in the presence of an imidazole compound, preferably in an inert solvent, to give the 1 '-methyl-beta-lactam compound (I) .
  • an imidazole compound there may be -exemplified imidazole, 2-methyi- imidazole, 4-methylimidazole, 2 ,4-dimethylimidazole, benz- imidazole, etc. Among them, preferred are imidazole and 4-methylimidazole.
  • the amount of the imidazole compound is usually from 0.1 to 2.0 equivalents to the imine compound (V) .
  • Example of the inert solvent are aromatic hydrocarbons (e.g.
  • benzene, toluene, xylene) ethers (e.g. ether, tetra ⁇ hydrofuran, dioxane) , halogenated hydrocarbons (e.g. di ⁇ chloromethane, chloroform, carbon tetrachloride) , aliphatic hydrocarbons (e.g. hexa ⁇ e, heptane, pen ane, cyclohexane) , polar solvents (e.g. acetonitrile, dimethylformamide, dimethylsulfoxide) , their mixtures, etc.
  • the reaction proceeds smoothly at a temperature of about -50 to 50°C.
  • the product may be recovered from the reaction mixture by a per se conven ⁇ tional procedure for post-treatment.
  • the starting aldehyde compound (III) in the 1st step is obtainable, for instance, from methyl 3-hydroxy-2- methylpropionate by a known method.
  • the use of the starting material in an optically active form can afford ultimately the product, i.e. the 1'-methyl-beta-lactam compound (I) in an optically active form.
  • the conversion of the 1'-methyl-beta-lactam compound (I) into the beta-lactam compound (II) can be accomplished substantially by elimination of the amino- protective group at the 1-position, reduction of the carbonyl group in the side chain at the 3-position to a hydroxymethylene group and oxidation of a hydroxymeth l group in the side chain at the 4-position to a carboxyl group. Said elimination, reduction and oxidation may be carried out in an appropriate order. During any of those reactions, any group which should not receive any influence from the reaction is protected by a per se conventional procedure. Among various procedures for the conversion, typical examples are as follows:
  • the step A is the conversion of a carbonyl group into a hydroxymethylene group, which may be carried out, for instance, by reduction with a metal hydride complex (e.g. sodium borohydride, potassium serectride, diborane-amine complex) .
  • a metal hydride complex e.g. sodium borohydride, potassium serectride, diborane-amine complex
  • reduction with potassium serectride or reduction with diborane-amine complex Japanese Patent Publication (unexamined). No. 215667/85) .
  • the step B is the protection of a hydroxyl group. It s particularly preferred that the protective group R 3 to be used at this stage is the one which can be eliminated by a method different from the method to be employed for
  • the step C is the removal of the protective group
  • R which may be carried out, for instance, by oxidative treatment with cerium (IV) ammonium nitrate or treatment with trifluoroacetic acid.
  • the step D is the elimination of the protective
  • the step E is the conversion of a hydroxymethyl group into a carboxyl group, which may be achieved, for instance, by treatment with chromium trioxide-sulfuric acid (Jones' reagent) or treatment with pyridinium dichromate.
  • imine compound (4.5 mM) was dissolved in toluene (25 ml) and cooled to -30°C, followed by addition of imidazole (0.37 g; 5.4 mM) thereto.
  • a solution of diketene (1.12 g; 13.3 mM) in toluene (10 ml) was further added thereto, followed by stirring for 22 hours.
  • the reaction mixture was diluted with ethyl acetate, washed with 0.IN hydrochloric acid, a saturated sodium bicarbonate solution and a saturated sodium chloride solution in order and dried over anhydrous magnesium sulfate.
  • the production ratio of the (1"R,3S,4R) form and the (1"R,3R,4S) form was ascertained to be 6.1 : 1 by NMR spectrum.
  • the optical purity of the (1"R,3S,4R) form was determined to be more than 91 % ee by the use of a chiral type shifting agent, i.e. tris [3- (heptafluoropropylhydroxy- methylene) -d-camphorite] europium (III) .
  • the stereoisomer was further recrystallized from isopropyl ether to give colorless crystals, of which the optical purity was more than 95 % ee when determined in the same manner as above.
  • the reaction mixture was subjected to post treatment in the same manner as in Example 1-(1) to give a mixture of (1"R,3S,4R)- and (1"R,3R,4S)- 1-(di-p-anisylmethyl)-3-acetyl-4-[1"-(benzyloxymethyl)- ethyl]azetidin-2-one (1.40 g, 52 % yield) as a colorless solid.
  • the production ratio of the (1"R,3S ⁇ 4R) form and the (1"R,3R,4S) form was ascertained to be 11 : 1 by NMR spectrum.
  • IR (neat) ⁇ 2980, 1755, 1715, 1610, 1515, 1250, 1180, 1035 cm -1 ;
  • imine compound 1.0 mM was dissolved in tetrahydrofuran (3 ml) and, after addition of imidazole (85 mg; 1.2 mM) , cooled to -30°C.
  • a solution of diketene (260 mg; 3.'0 mM) in tetra ⁇ hydrofuran (1 ml) was further added thereto, followed by stirring for 10 hours.
  • reaction mixture was diluted with ethyl acetate, washed successively with IN hydrochloric acid, a saturated sodium bicarbonate solution and a satu ⁇ rated sodium chloride .solution and dried over anhydrous magnesium sulfate.
  • Methyl (S)-(+)-2-methyl-3-methoxyethoxymethyloxy- propionate (2.06 g; 10 mM) was dissolved in dry ether (60 ml) , followed by cooling to -70°C under argon stream.
  • a IM hexane solution of diisobutylaluminium hydride (DIBAL) (12.5 ml; 12.5 mM) was dropwise added thereto in 15 minutes, and the resultant mixture was stirred at the same temperature for 45 minutes.
  • DIBAL diisobutylaluminium hydride
  • Methanol (10 ml) was added to the reaction mixture, which was then heated to room temperature. Water (10 ml) was added thereto, followed by stirring to produce turbidity.
  • the reac ⁇ tion mixture was diluted with ethyl acetate and washed successively with water, a saturated sodium bicarbonate solution and a saturated sodium sulfite solution, a satu ⁇ rated sodium bicarbonate solution and a saturated sodium chloride solution.
  • this invention provides the 1'-methyl-beta-lactam compounds (I), which can be readily converted into the beta-lactam compounds (II) , which are known as the intermediates in the synthesis of 1 t -methylcarbapenem compounds having a potential anti-microbial activity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Composé de 1'-méthyl-bêta-lactame de formule (I), dans laquelle R1 est un groupe diarylméthyl éventuellement substitué ou un groupe aryle éventuellement substitué et R2 est un groupe protecteur de l'hydroxyle. Ce composé est utile en tant que produit intermédiaire dans la synthèse d'agents antimicrobiens.
PCT/JP1987/000239 1986-08-29 1987-04-15 Composes de 1'-methyl-beta-lactame et leur production Ceased WO1988001619A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP61/201576 1986-08-29
JP61201576A JPS62174048A (ja) 1985-10-16 1986-08-29 １′−メチル−β−ラクタム誘導体

Publications (1)

Publication Number Publication Date
WO1988001619A1 true WO1988001619A1 (fr) 1988-03-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0684230B1 (fr) * 1993-03-12 2002-07-03 Takasago International Corporation Dérivés de 4-(R)-1'-formyléthyl-azetidin-2-one

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0010317A1 (fr) * 1978-10-24 1980-04-30 Merck & Co. Inc. Acides 1-carbapen-2-em-3-carboxyliques 6-, 1- et 2-substitués, procédés pour leur préparation et compositions pharmaceutiques les contenant
US4348320A (en) * 1976-11-19 1982-09-07 Merck & Co., Inc. Substituted azetidiones
EP0188816A1 (fr) * 1984-12-27 1986-07-30 Sumitomo Pharmaceuticals Company, Limited Bêta-lactames et leur préparation
EP0192171A1 (fr) * 1985-02-19 1986-08-27 Merck & Co. Inc. Procédé pour la synthèse chirale d'intermédiaires de 1-bêta-méthyl-carbapénème

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4348320A (en) * 1976-11-19 1982-09-07 Merck & Co., Inc. Substituted azetidiones
EP0010317A1 (fr) * 1978-10-24 1980-04-30 Merck & Co. Inc. Acides 1-carbapen-2-em-3-carboxyliques 6-, 1- et 2-substitués, procédés pour leur préparation et compositions pharmaceutiques les contenant
EP0188816A1 (fr) * 1984-12-27 1986-07-30 Sumitomo Pharmaceuticals Company, Limited Bêta-lactames et leur préparation
EP0192171A1 (fr) * 1985-02-19 1986-08-27 Merck & Co. Inc. Procédé pour la synthèse chirale d'intermédiaires de 1-bêta-méthyl-carbapénème

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0684230B1 (fr) * 1993-03-12 2002-07-03 Takasago International Corporation Dérivés de 4-(R)-1'-formyléthyl-azetidin-2-one

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