JPH0441489A - Elimination of allyl group - Google Patents
Elimination of allyl groupInfo
- Publication number
- JPH0441489A JPH0441489A JP2146495A JP14649590A JPH0441489A JP H0441489 A JPH0441489 A JP H0441489A JP 2146495 A JP2146495 A JP 2146495A JP 14649590 A JP14649590 A JP 14649590A JP H0441489 A JPH0441489 A JP H0441489A
- Authority
- JP
- Japan
- Prior art keywords
- alkali metal
- carboxylic acid
- salt
- acid
- allyl
- 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.)
- Granted
Links
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 title claims abstract description 18
- 230000008030 elimination Effects 0.000 title 1
- 238000003379 elimination reaction Methods 0.000 title 1
- -1 allyl ester Chemical class 0.000 claims abstract description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 6
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 6
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims abstract description 4
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims abstract description 4
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 150000001735 carboxylic acids Chemical class 0.000 abstract description 4
- 238000007275 deallylation reaction Methods 0.000 abstract description 3
- 239000011541 reaction mixture Substances 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 description 26
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000370 acceptor Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 3
- 239000004324 sodium propionate Substances 0.000 description 3
- 235000010334 sodium propionate Nutrition 0.000 description 3
- 229960003212 sodium propionate Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 description 2
- WCASXYBKJHWFMY-UHFFFAOYSA-N crotyl alcohol Chemical compound CC=CCO WCASXYBKJHWFMY-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000004686 pentahydrates Chemical class 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- AYRVGWHSXIMRAB-UHFFFAOYSA-M sodium acetate trihydrate Chemical compound O.O.O.[Na+].CC([O-])=O AYRVGWHSXIMRAB-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- MNVCCKVPSGWSCN-RXMQYKEDSA-N (5r)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound S1C(C)=C(C(O)=O)N2C(=O)C[C@H]21 MNVCCKVPSGWSCN-RXMQYKEDSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- WCASXYBKJHWFMY-NSCUHMNNSA-N 2-Buten-1-ol Chemical compound C\C=C\CO WCASXYBKJHWFMY-NSCUHMNNSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910000083 tin tetrahydride Inorganic materials 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、β−ラクタム系抗生物質を合成する際に、カ
ルボキシル基等の保護基として頻繁に利用されているア
リル基を脱離する方法に関する。[Detailed Description of the Invention] [Field of Industrial Application] The present invention provides a method for eliminating allyl groups, which are frequently used as protective groups such as carboxyl groups, when synthesizing β-lactam antibiotics. Regarding.
β−ラクタム系抗生物質を合成する際に、カルボキシル
基等の保護基としてアリル基を使用する方法が有用であ
ることは、Ｓ、 Ｗ、 ＭｃＣｏｍｂｉｅら（Ｊ。S., W., McCombie et al. (J.
Ｏｒｇ、 Ｃｈｅｍ、、 ４７．５８７（１９８２））
により、あるいは特開昭５５−９４３２１号、特開昭６
２−６１９８４号等に既に報告されている。Org, Chem, 47.587 (1982))
or JP-A No. 55-94321, JP-A No. 6
It has already been reported in No. 2-61984.
しかしながら、その結果得られるアリルエステル化合物
は、合成の何れかの段階でこのアリル基を除去しなけれ
ばならない。However, the resulting allyl ester compound must have this allyl group removed at some stage of the synthesis.
このアリル基を除去する方法としては、■アリル基受容
体として炭素数５〜８のカルボン酸アルカリ金属塩（例
えば２−エステルヘキサン酸ナトリウム）を、触媒とし
てテトラキス（トリフェニルホスフィン）パラジウム（
０）及びトリフェニルホスフィンを用い、室温で反応さ
せる方法［Ｊ。As a method for removing this allyl group, 1) an alkali metal salt of a carboxylic acid having 5 to 8 carbon atoms (for example, sodium 2-ester hexanoate) is used as an allyl group acceptor, and tetrakis(triphenylphosphine)palladium (
0) and triphenylphosphine at room temperature [J.
Ｏｒｇ、 Ｃｈｅｍ、、 ４７．５８７（１９８２）あ
るいは特開昭５５−９４３２１号〕、■テトラキス（ト
リフェニルホスフィン）パラジウム（０）及びトリブチ
ル錫ヒドリドと反応させる方法（特開昭６０−７２８９
３号）、■テトラキス（トリフェニルホスフィン）パラ
ジウム（０）の存在下、アセチルアセトンまたはジメド
ンと反応させる方法（特開昭６２−６１９８４号）等が
知られている。Org, Chem, 47.587 (1982) or JP-A No. 55-94321], ■ Method of reacting with tetrakis(triphenylphosphine) palladium (0) and tributyltin hydride (JP-A No. 60-7289)
3), (2) A method of reacting with acetylacetone or dimedone in the presence of tetrakis(triphenylphosphine)palladium (0) (Japanese Patent Application Laid-Open No. 62-61984), and the like are known.
しかしながら、■の方法では、生成物が収率よく結晶と
して析出しない限り、目的化合物を反応混合物から分離
精製することが困難であり、■の方法は、高価でかつ取
扱いに注意を必要とするトリブチル錫ヒドリドを使用し
ているため、大量合成あるいは実用的な合成には不適で
あり、また■の方法は、目的化合物を塩として得ようと
した場合、塩基による処理を必要とする等の種々の問題
点があった。そしてまた、これら公知の方法では通常、
更にカラム分離した後、凍結乾燥等により目的物を得な
ければならないため工業的製法としては好ましいもので
はなかった。However, in the method (2), it is difficult to separate and purify the target compound from the reaction mixture unless the product is precipitated as crystals in good yield, and the method (2) uses tributyl, which is expensive and requires careful handling. Because it uses tin hydride, it is unsuitable for large-scale synthesis or practical synthesis, and method (2) has various problems such as the need for treatment with a base when trying to obtain the target compound as a salt. There was a problem. Furthermore, these known methods usually
Furthermore, after column separation, the desired product had to be obtained by freeze-drying or the like, which was not suitable as an industrial production method.
かかる実情において、本発明者らは上記欠点を解決せん
と鋭意研究を行った結果、ペナム化合物のアリルエステ
ルを、触媒量のパラジウム錯体の存在下、炭素数１〜４
のカルボン酸のアルカリ金属塩、またはアルカリ金属塩
及び炭素数１〜４のカルボン酸とを反応させる際、水を
加えることにより、高収率かつ一工程で脱アリル化と塩
形成が行われること、並びに該塩がより結晶性のよい水
和物を形成し、単離が容易になることを見い出し、本発
明を完成するに至った。Under these circumstances, the present inventors conducted intensive research to solve the above-mentioned drawbacks, and as a result, the allyl ester of the penum compound was converted into a compound having 1 to 4 carbon atoms in the presence of a catalytic amount of a palladium complex.
When reacting an alkali metal salt of a carboxylic acid, or an alkali metal salt and a carboxylic acid having 1 to 4 carbon atoms, by adding water, deallylation and salt formation can be carried out in high yield and in one step. , and that the salt forms a hydrate with better crystallinity, making it easier to isolate, leading to the completion of the present invention.
すなわち、本発明は、一般式〔Ｉ〕
ｎ
（式中、ｍは０または１を、Ｒ’は置換されてもよいア
リル基を示す）
で表わされるペネム化合物のアリルエステルを、触媒量
のパラジウム錯体及び水の存在下、炭素数１〜４のカル
ボン酸のアルカリ金属塩または炭素数１〜４のカルボン
酸及びアルカリ金属塩とを反応せしめて一般式［Ｕ］
（式中、Ｒ２はアルカリ金属を示し、ｍは前記と同じも
のを示す）
で表わされるペネム化合物とすることを特徴とするアリ
ル基の脱離方法を提供するものである。That is, the present invention provides an allyl ester of a penem compound represented by the general formula [I] n (wherein m is 0 or 1, and R' is an optionally substituted allyl group), in which a catalytic amount of palladium is added. In the presence of the complex and water, an alkali metal salt of a carboxylic acid having 1 to 4 carbon atoms or a carboxylic acid having 1 to 4 carbon atoms and an alkali metal salt are reacted to form the general formula [U] (wherein, R2 is an alkali metal and m is the same as defined above).
本発明のペネム化合物のアリルエステル（以下、アリル
エステル化合物と称する）〔■〕のＲ’で示される置換
されていてもよいアリル基としては、例エバアリルアル
コール、ハロアリルアルコール、メチルアリルアルコー
ル、クロチルアルコール、これらの低級アルコキシ酸誘
導体、シンナミルアルコール、シンナミルアルコールの
活性エステルから誘導される基などが挙げられる。Examples of the optionally substituted allyl group represented by R' in the allyl ester of the penem compound of the present invention (hereinafter referred to as an allyl ester compound) [■] include evalyl alcohol, haloallyl alcohol, methylallyl alcohol, Examples include crotyl alcohol, lower alkoxy acid derivatives thereof, cinnamyl alcohol, and groups derived from active esters of cinnamyl alcohol.
アリル基受容体として用いる炭素数１〜４のカルボン酸
のアルカリ金属塩としては、例えば酢酸、プロピオン酸
、酪酸、イソ酪酸またはシュウ酸、マロン酸もしくはそ
のモノアルキルエステルのナトリウム塩またはカリウム
塩が挙げられる。Examples of the alkali metal salts of carboxylic acids having 1 to 4 carbon atoms used as allyl group acceptors include acetic acid, propionic acid, butyric acid, isobutyric acid or oxalic acid, malonic acid or the sodium salt or potassium salt of its monoalkyl ester. It will be done.
また、アリル基の受容体として、炭素数１〜４のカルボ
ン酸及びアルカリ金属塩を用いる場合のカルボン酸とし
ては、上に例示したものと同様のカルボン酸が、アルカ
リ金属塩としては該カルボン酸と金属塩を形成するもの
、例えば炭酸水素ナトリウムもしくはカリウム、炭酸ナ
トリウムもしくはカリウム等が例示できる。In addition, when a carboxylic acid having 1 to 4 carbon atoms and an alkali metal salt are used as an allyl group acceptor, the carboxylic acid may be the same as those exemplified above, and the alkali metal salt may be the carboxylic acid. Examples include those that form metal salts with, for example, sodium or potassium hydrogen carbonate, and sodium or potassium carbonate.
反応は、まずアリル基受容体とアリルエステル化合物Ｃ
Ｉ＋を有機溶剤中で混合し、水を添加する。水の添加量
はアリルエステル化合物〔１１１モルに対し、２．５モ
ル以上であればよいが、あまり水の量が多いと後処理で
生成物が水に溶解し、収率が低下するため、２．５〜１
０モル程度が好ましい。また、炭素数１〜４のカルボン
酸のアルカリ金属塩として酢酸ナトリウム（３水塩）等
の水和物を使用する場合にはトータルの水の量が２．５
〜１０モルとなるように添加するのが好ましい。The reaction begins with the allyl group acceptor and allyl ester compound C.
Mix I+ in organic solvent and add water. The amount of water added should be at least 2.5 moles per 111 moles of the allyl ester compound, but if the amount of water is too large, the product will dissolve in water during post-treatment and the yield will decrease. 2.5-1
About 0 mol is preferable. In addition, when using a hydrate such as sodium acetate (trihydrate) as an alkali metal salt of a carboxylic acid having 1 to 4 carbon atoms, the total amount of water is 2.5
It is preferable to add it so that it becomes 10 mol.
アリル基受容体とアリルエステル化合物［Ｉ）との好ま
しい割合は後者１当量に対し、前者１〜１．５当量であ
る。A preferred ratio of the allyl group acceptor to the allyl ester compound [I] is 1 to 1.5 equivalents of the former to 1 equivalent of the latter.
このようにして調製された溶液に触媒量のパラジウム錯
体を添加し、１０〜４０℃で反応させる。A catalytic amount of palladium complex is added to the solution thus prepared and reacted at 10-40°C.
パラジウム錯体としては配位ホスフィン配位子を有する
ものが用いられ、配位ホスフィン配位子としてはトリフ
ェニルホスフィンのようなトリアリールホスフィンが好
ましい。最も好ましい錯体はテトラキス（トリフェニル
ホスフィン）パラジウム（０）であるが、ビス（トリフ
ェニルホスフィン）パラジウム（ｎ）ジクロリド、ジク
ロロージ〔ベンゾニトリル〕パラジウム（■）、二酢酸
パラジウムと数隻量のトリフェニルホスフィンの併用（
Ｆｉｅｓｅｒ及びＦｉｅｓｅｒ、 Ｒｅａｇｅｎｔ ｆ
ｏｒ ＯｒｇａｎｉｃＳｙｎｔｈｅｓｉｓ、 Ｖｏｌ
、 Ｖ、 ４８７頁、５０３頁、５０４頁）等の溶
剤可溶性パラジウム錯体を用いてもよい。As the palladium complex, one having a coordinating phosphine ligand is used, and the coordinating phosphine ligand is preferably triarylphosphine such as triphenylphosphine. The most preferred complex is tetrakis(triphenylphosphine)palladium(0), but also bis(triphenylphosphine)palladium(n) dichloride, dichlorodi[benzonitrile]palladium(■), palladium diacetate and several amounts of triphenyl Concomitant use of phosphine (
Fieser and Fieser, Reagent f
or OrganicSynthesis, Vol.
, V, pp. 487, 503, 504) may also be used.
パラジウム錯体の使用量は、例えば、テトラキス（トリ
フェニルホスフィン）パラジウム（０）を用いる場合、
アリルエステル化合物［Ｉ］に対して０．５モル％〜２
．５モル％が好ましいが、更に増量して反応時間を短縮
させることもできる。また、トリフェニルホスフィンを
反応時間を短縮するため、あるいはテトラキス（トリフ
ェニルホスフィン）パラジウム（０）の使用量を減らす
等の目的で使用することも可能である。The amount of palladium complex used is, for example, when using tetrakis(triphenylphosphine)palladium(0),
0.5 mol% to 2 based on allyl ester compound [I]
．． Although 5 mol% is preferable, the amount can be further increased to shorten the reaction time. It is also possible to use triphenylphosphine for the purpose of shortening the reaction time or reducing the amount of tetrakis(triphenylphosphine)palladium(0) used.
有機溶媒としてはアリルエステル化合物〔Ｉ〕及び触媒
のパラジウム錯体を溶解できるものであれば特に限定さ
れないが、例えば、ジクロロメタン、クロロホルム等の
ようなハロゲン化アルキル類；酢酸メチル、酢酸エチル
等のようなエステル類；ジエチルエーテノペエチレング
リコールジメチルエーテル、テトラヒドロフラン、１．
４−ジオキサン等のようなエーテル類；メタノール、エ
タノール等のアルコール類；アセトニトリル、プロピオ
ニトリル等のようなニトリル類；アセトン、メチルエチ
ルケトンのようなケトン類；またはベンゼン、トルエン
、キシレン等のような芳香族炭化水素類が挙げられる。The organic solvent is not particularly limited as long as it can dissolve the allyl ester compound [I] and the palladium complex of the catalyst, but examples include alkyl halides such as dichloromethane, chloroform, etc.; methyl acetate, ethyl acetate, etc. Esters; diethyl etherene ethylene glycol dimethyl ether, tetrahydrofuran, 1.
Ethers such as 4-dioxane; alcohols such as methanol and ethanol; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl ethyl ketone; or aromatics such as benzene, toluene, xylene, etc. Examples include group hydrocarbons.
これらは単独でまたは必要に応じて二種以上混合して用
いられる。These may be used alone or in combination of two or more if necessary.
反応により生成する一般式［ｎ］で表わされるペネム化
合物は通常、水和物の形で存在し、使用した溶剤に難溶
な場合は、一般に生成物が結晶として析出するので、こ
れを濾過することにより目的物を単離することができる
。また、目的物が反応混合物から結晶として析出し難い
場合は、反応に用いた溶剤とよく混和し、がっ目的物が
難溶性の溶剤を添加することにより目的物の結晶を析出
させることもできる。The penem compound represented by the general formula [n] produced by the reaction usually exists in the form of a hydrate, and if it is poorly soluble in the solvent used, the product will generally precipitate as crystals, so this should be filtered. By this, the target product can be isolated. In addition, if the target product is difficult to precipitate as crystals from the reaction mixture, crystals of the target product can be precipitated by adding a solvent that is well miscible with the solvent used in the reaction and in which the target product is poorly soluble. .
このようにして得られた、目的物の結晶は、必要に応じ
て、再結晶等の操作で更に精製することもできる。The crystals of the target product thus obtained can be further purified by operations such as recrystallization, if necessary.
以下に実施例を示して本発明を更に具体的に説明するが
、これらが本発明を限定するものでないことは言うまで
もない。The present invention will be explained in more detail with reference to Examples below, but it goes without saying that these are not intended to limit the present invention.
実施例１
（１’ Ｒ，５Ｒ，６Ｓ）−６−（１’ −ヒドロキシ
エチル）−２−（３’−テトラヒドロフラニル）メチル
ペネム−３−カルボン酸アリルエステル８．４９ｇ （
２５ｍ ｍｏｌ）にテトラヒトｏ ７５ ”／ ２５ｍ
１ヲ加え溶解した後、水２．２５ｇ （１２５ｍ ｍｏ
ｌ）、プロピオン酸ナトリウム３．１２ｇ （３２，５
ｍ ｍｏｌ）、トリフエニルホスフィンＤＪ３ｇ （１
，２５ｍ ｍａｔ）、及びテトラキス（トリフェニルホ
スフィン）パラジウム（０）０．２９ｇ （０，２５ｍ
ｍｏｌ）加え、２５℃で４時間攪拌した。Example 1 8.49 g of (1'R,5R,6S)-6-(1'-hydroxyethyl)-2-(3'-tetrahydrofuranyl)methylpenem-3-carboxylic acid allyl ester (
25 m mol) to 75 ”/25 m
After adding and dissolving 1, add 2.25g of water (125m mo
l), sodium propionate 3.12g (32,5
m mol), triphenylphosphine DJ3g (1
,25m mat), and tetrakis(triphenylphosphine)palladium(0) 0.29g (0,25m
mol) and stirred at 25°C for 4 hours.
反応終了後、２℃迄冷却し析出してきた結晶を濾過した
。After the reaction was completed, the mixture was cooled to 2° C. and the precipitated crystals were filtered.
得られた結晶を乾燥することにより（１’Ｒ。By drying the obtained crystals (1'R.
５Ｒ，６Ｓ） −６−（１’ −とドロキシエチル）−
２−（３’−テトラヒドロフラニル）メチルペネム−３
−カルボン酸ナトリウム塩の２．５永和物の微黄色結晶
７．７９ｇを得た。ＨＰＬＣで分析したところ純度は９
８％であった（収率８３％）。5R,6S) -6-(1'- and droxyethyl)-
2-(3'-tetrahydrofuranyl)methylpenem-3
- 7.79 g of pale yellow crystals of 2.5-eternal salt of carboxylic acid sodium salt were obtained. When analyzed by HPLC, the purity was 9.
8% (yield 83%).
この結晶に水２０．１ｇを加え加温溶解したのち、アセ
トン６２ｍ１を加え０℃迄冷却後、濾過し乾燥すること
により （１’ Ｒ，５Ｒ，６Ｓ）−６−（１′−ヒド
ロキシエチル）−２−（３’−テトラヒドロフラニル）
メチルペネム−３−カルボン酸す） ＩＪウム塩の２．
５水和物の白色結晶６．８８ｇを得た。ＨＰＬＣで分析
したところ純度は１００％であった（収率７５％）。After adding 20.1 g of water to the crystals and dissolving them by heating, 62 ml of acetone was added and cooled to 0°C, filtered and dried to obtain (1' R, 5 R, 6 S)-6- (1'-hydroxyethyl). -2-(3'-tetrahydrofuranyl)
2. Methylpenem-3-carboxylic acid) IJium salt.
6.88 g of white crystals of pentahydrate were obtained. HPLC analysis showed that the purity was 100% (yield 75%).
得られた化合物の物性を下記に示す。The physical properties of the obtained compound are shown below.
ＭＭＲスペクトル： （０２０，δｐｐｍ）１．１６
．１．１７（各々３／２）１． ｄ、 Ｊ＝６）１ｚ）
、 １．４１−１．６２（ＬＨ，ｍ）、 １．８８−
２．０４（１８，ｍ）、 ２．２８−２．４６（Ｉｆ
（。MMR spectrum: (020, δppm) 1.16
．． 1.17 (3/2 each)1. d, J=6)1z)
, 1.41-1.62 (LH, m), 1.88-
2.04 (18, m), 2.28-2.46 (If
(.
ｍ）、 ２．４６−３．００（１１（、ｍ）、 ３
．２６−３．４０（ＬＨ，ｍ）。m), 2.46-3.00 (11(, m), 3
．． 26-3.40 (LH, m).
３．５８−３．８２（４Ｈ，ｍ）、 ４．０４−４．
１７（１８，ｍ）、 ５．４７（ＩＨ，ｄ、 Ｊ＝
２Ｈｚ）
ＩＲスペクトル： （ＫＢｒ、 ｃｒｌｌ−’） ３４
００． １７５５［α〕二’ ： ＋１２１ ” （Ｈ
２Ｏ，ｃｍ０．２６９．脱水物換算）実施例２
（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒ
ドロキシエチル）−２−（２’−テトラヒドロフラニル
）ペネム−３−カルボン酸アリルエステル２４．０ｇ
（７３，８ｍ ｍｏｌ）、水６．６４ｇ （３６９ｍ
ｍｏｌ）、プロピオン酸ナトリウム９．２２ｇ （９６
，０ｍ田ｏｆ）及びトリフェニルホスフィン０．９７ｇ
（３，７ｍ ｍｏｌ）のテトラヒドロフラン７４ｒｎ
１の溶液にテトラキス（トリフェニルホスフィン）パラ
ジウム（０） ０．８５ ｇ （０，７４ｍｍｏｌ）を
加え、２５℃で２．５時間、攪拌した。反応終了後、０
℃まで冷却し、濾過した。3.58-3.82 (4H, m), 4.04-4.
17 (18, m), 5.47 (IH, d, J=
2Hz) IR spectrum: (KBr, crll-') 34
00. 1755[α]2': +121'' (H
2O, cm0.269. Example 2 (1'R,2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid allyl ester (in terms of dehydrate) 24. 0g
(73.8m mol), water 6.64g (369m
mol), sodium propionate 9.22g (96
,0m field) and triphenylphosphine 0.97g
(3,7m mol) of tetrahydrofuran 74rn
0.85 g (0.74 mmol) of tetrakis(triphenylphosphine)palladium(0) was added to the solution of 1, and the mixture was stirred at 25° C. for 2.5 hours. After the reaction is completed, 0
Cooled to °C and filtered.
得られた結晶を乾燥することにより（１’ Ｒ。By drying the obtained crystals (1'R.
２’ Ｒ，５Ｒ，６Ｓ）−６−（１’ −ヒドロキシエ
チル’）−２−（２’−テトラヒドロフラニル）ペネム
−３−カルボン酸のナトリウム塩の２．５水和物の白色
結晶を２４．９ｇ得た。ＨＰＬＣで分析したところ純度
は、９９．０％であった。（収率９５％）。2'R,5R,6S)-6-(1'-hydroxyethyl')-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid sodium salt hexahydrate white crystals .9g was obtained. When analyzed by HPLC, the purity was 99.0%. (Yield 95%).
得られた化合物の物性を以下に示す。The physical properties of the obtained compound are shown below.
元素分析値： Ｃ＋Ｊ＋ａＮＮａＯｓＳ ” ２．５Ｈ
２０（分子量 ３５２．３４３）
計算値（Ｃ，Ｈ，Ｎ） ： ４０．９１．５．４４．３
．９８測定値（Ｃ，Ｉｔ、Ｎ） ： ４０．７Ｂ、 ５
．４４．３．９３ＭＭＲスペクトル： （ＣＤＣＩ、
、δｐｐｍ、 ７ＭＳ標準）１．７１（３Ｎ、 ｄ、
Ｊ＝６Ｈｚ）、 １．７３−２．０３（３）１． ｍ）
。Elemental analysis value: C+J+aNNaOsS” 2.5H
20 (molecular weight 352.343) Calculated value (C, H, N): 40.91.5.44.3
．． 98 measurement value (C, It, N): 40.7B, 5
．． 44.3.93 MMR spectrum: (CDCI,
, δppm, 7MS standard) 1.71 (3N, d,
J=6Hz), 1.73-2.03(3)1. m)
.
２．１８−２．３５（ＬＨ，ｍ）、 ３．６７−３．９
２（３Ｈ，ｍ）。2.18-2.35 (LH, m), 3.67-3.9
2 (3H, m).
４．０５−４．１９（１Ｍ、 ｍ）、 ５Ｊ８（１）１
． ｄ、 ｄ、 Ｊ＝７ｆ（ｚ）。4.05-4.19 (1M, m), 5J8(1)1
．． d, d, J=7f(z).
５、４６ （ＬＨ，５）
ＩＨ７，ベクトル： （ＫＢｒ、ｃｍ−’） ３２８
０． １７５２［α］：’ ： １３２．６（Ｈ２Ｏ
，ｃｍ０．９９）Ｘ線回折
〔測定条件〕 Ｘ線電力 ５０ＫＶ ２００ｍＡ照射源
Ｃｕ、グラファイトモノク
ロメータ−
０、３Ｘ Ｏ，３Ｘ ０．５ｍｍ
斜方晶系
Ｐ２．２．２
〔結晶データ〕 大きさ
結晶差
、空間群
格子定数
ａ ９．２０７８ ｂ ３２．４５３８ ｃ ５．４９
５１α９０．０ β９０．Ｏｒ ９０．０実施例３
（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒ
ドロキシエチル）−２−（２’−テトラヒドロフラニル
）ペネム−３−カルボン酸アリルエステル６．５１ｇ
（２０ｍｍｏｌ）、水３．６ｇ （２００ｍ ｍｏｌ）
、プロピオン酸ナトリウム２．５ｇ （２６ｍ ｍｏｌ
）及びトリフェニルホスフィン０．２６ （１ｍ ｍｏ
ｌ）のアセトン２０ｄの溶液にテトラキス（トリフェニ
ルホスフィン）パラジウム（０）０．４６ｇ （０，０
４ｍ ｍｏｌ）を加えて、２５℃で、４．５時間攪拌し
た。反応終了後、０℃迄冷却し濾過した。5, 46 (LH, 5) IH7, vector: (KBr, cm-') 328
0. 1752[α]:' : 132.6(H2O
, cm0.99) X-ray diffraction [Measurement conditions] X-ray power 50KV 200mA Irradiation source Cu, graphite Monochromator 0, 3X O, 3X 0.5mm Orthorhombic system P2.2.2 [Crystal data] Size crystal difference, space group lattice constant a 9.2078 b 32.4538 c 5.49
51α90.0 β90. Or 90.0 Example 3 (1'R,2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid allyl ester6. 51g
(20mmol), water 3.6g (200mmol)
, sodium propionate 2.5g (26m mol
) and triphenylphosphine 0.26 (1 m mo
0.46 g of tetrakis(triphenylphosphine)palladium(0) (0,0
4 mmol) was added thereto, and the mixture was stirred at 25°C for 4.5 hours. After the reaction was completed, it was cooled to 0°C and filtered.
得られた結晶を乾燥し、（１’ Ｒ，２’ Ｒ，５Ｒ，
６Ｓ）−６−（１’ −ヒドロキシエチル）２− （２
’−テトラヒドロフラニル）ペネム−３−カルボン酸の
ナトリウム塩の２，５水和物の白色結晶を６．６２ｇ得
た。ＨＰＬＣで分析したところ純度は、９９％であった
（収率９３％）。The obtained crystals were dried and (1' R, 2' R, 5R,
6S)-6-(1'-hydroxyethyl)2-(2
6.62 g of white crystals of the di,pentahydrate sodium salt of penem-3-carboxylic acid ('-tetrahydrofuranyl) were obtained. When analyzed by HPLC, the purity was 99% (yield 93%).
実施例４
（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒ
ドロキシエチル’）−２−（２’−テトラヒドロフラニ
ル）ペネム−３−カルボン酸アリルエステル６．５１ｇ
（２０ｍ ｍｏｌ）、水０．４ （２２，２ｍ ｍｏ
ｌ）、酢酸ナトリウム（３水塩） ３．５４ｇ （２６
ｒｒＩｍｏｌ）及びトリフェニルホスフィン０゜２６ｇ
（１ｍ ｍｏｌ）のテトラヒドロフラン２０ｍＺの溶
液にテトラキス（トリフェニルホスフィン）パラジウム
（０）０．４６ｇ （０，４ａｌｆｆｌｏ１）を加え、
２０℃で４．５時間攪拌した。反応終了後、０℃まで冷
却し、濾過した。Example 4 (1'R,2'R,5R,6S)-6-(1'-hydroxyethyl')-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid allyl ester 6.51 g
(20m mol), water 0.4 (22,2m mol)
l), sodium acetate (trihydrate) 3.54g (26
rrImol) and triphenylphosphine 0°26g
Add 0.46 g (0,4alfflo1) of tetrakis(triphenylphosphine)palladium(0) to a solution of (1 mmol) in 20 mZ of tetrahydrofuran,
The mixture was stirred at 20°C for 4.5 hours. After the reaction was completed, it was cooled to 0°C and filtered.
得られた結晶を乾燥することにより（１’ Ｒ。By drying the obtained crystals (1'R.
２’ Ｒ，５Ｒ，６３）−６−（１’ −ヒドロキシエ
チル）−２−（２’−テトラヒドロフラニル）ペネム−
３−カルボン酸のナトリウム塩の２．５水和物の白色結
晶を６．７８ｇを得た。ＨＰＬＣで分析したところ純度
は、９４．４％であった（収率９７％）。2'R,5R,63)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-
6.78 g of white crystals of 2.5 hydrate of sodium salt of 3-carboxylic acid were obtained. When analyzed by HPLC, the purity was 94.4% (yield 97%).
この結晶に水１６．５ｇを加え加温溶解したのちアセト
ン５５ｒｎ１を加え、０℃まで冷却後、濾過、乾燥する
ことにより、（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ） −
６−（１’−ヒドロキシエチル）−２−（２′−テトラ
ヒドロフラニル）ペネム−３−カルボン酸のす） ＩＪ
ウム塩の２．５水和物の白色結晶５．７ｇを得た。ＨＰ
ＬＣで分析したところ純度は、１００％であった（収率
８１％）。After adding 16.5 g of water to the crystals and dissolving them by heating, adding 55rn1 of acetone, cooling to 0°C, filtering and drying, (1' R, 2' R, 5R, 6S) -
6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid) IJ
5.7 g of white crystals of 2.5 hydrate of um salt were obtained. HP
When analyzed by LC, the purity was 100% (yield 81%).
実施例５
（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒ
ドロキシエチル）−２−（２’−テトラヒドロフラニル
）ペネム−３−カルボン酸アリルエステル６．５１ｇ
（２０ｍ ｍｏｌ）、水１．８ｇ （１００ａ＋ ｍｏ
ｌ）及び酪酸ナトリウム３．０８ｇ （２８ｍ ｍｏｌ
）のテトラヒドロフラン４０ｍ１！の溶液にトリフェニ
ルホスフィン０．２６ｇ （１ｒｎ ｍｏｌ）、テトラ
キス（トリフェニルホスフィン）パラジウム（０）０．
２３ｇ （０，２ｍ ｍｏｌ）を加えて、２５℃で２．
０時間攪拌した。反応終了後、０℃まで冷却し、濾過し
た。Example 5 (1'R,2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid allyl ester 6.51 g
(20m mol), water 1.8g (100a+ mo
l) and sodium butyrate 3.08g (28m mol
) of tetrahydrofuran 40ml! In a solution of 0.26 g (1 rn mol) of triphenylphosphine and 0.26 g (1 rn mol) of tetrakis(triphenylphosphine)palladium(0).
Add 23g (0.2m mol) and heat at 25°C for 2.
Stirred for 0 hours. After the reaction was completed, it was cooled to 0°C and filtered.
得られた結晶を乾燥することにより（１’ Ｒ。By drying the obtained crystals (1'R.
２’ Ｒ，５Ｒ，６Ｓ）−６−（１’ −ヒドロキシエ
チル）−２−（２’−テトラヒドロフラニル）ペネム−
３−カルボン酸のナトリウム塩の２．５水和物の白色結
晶６．５９ｇを得た。ＨＰＬＣで分析したところ純度は
、９６．３％であった（収率９ｏ％）。2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-
6.59 g of white crystals of 2.5 hydrate of sodium salt of 3-carboxylic acid were obtained. When analyzed by HPLC, the purity was 96.3% (yield: 90%).
この結晶に水１５．６ｇを加え加温溶解したのち、アセ
トン５１ｍｆを加え０１まで冷却後、濾過、乾燥するこ
とにより（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（
１’−ヒドロキシエチル）−２−（２’−テトラヒドロ
フラニル）ペネム−３−カルホン酸のナトリウム塩の２
．５水和物の白色結晶５．７８ｇを得た。ＨＰＬＣで分
析したところ純度は、１００％であった（収率８２％）
。After adding 15.6 g of water to the crystals and dissolving them by heating, 51 mf of acetone was added and cooled to 01, filtered and dried to obtain (1' R, 2' R, 5R, 6S) -6-(
2 of the sodium salt of 1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carphonic acid
．． 5.78 g of white crystals of pentahydrate were obtained. When analyzed by HPLC, the purity was 100% (yield 82%)
.
実施例６〜１０
実施例２と同様の手順で第１表に示す条件で、アリル受
容体の種類を変えて反応を行った結果、得られた（１’
Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（１′−ヒドロキ
シエチル）−２−（２’−テトラヒドロフラニル）ペネ
ム−３−カルボン酸ナトリウム塩の２．５永和物の純度
及び収率は以下の表−１の通りであった。Examples 6 to 10 Reactions were carried out in the same manner as in Example 2 under the conditions shown in Table 1, with different types of allyl receptors, resulting in (1'
The purity and yield of the 2.5-eternal product of R,2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid sodium salt are It was as shown in Table 1 below.
以下余白
実施例１１
（１’ Ｒ，２’ Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒ
ドロキシエチル）−２−（２’−テトラヒドロフラニル
）ペネム−３−カルボン酸アリルエステル６．５１ｇ
（２０ｍ ｍｏｌ）及びプロピオン酸３．０ｇ（２６ｍ
ｍｏｌ）のテトラヒドロフラン４０ｍ１！の溶液に、
炭酸水素カリウム、２．６ｇ （２６ｍ ［００１）、
水１．８ｇ（１００ａ＋ ｍｏｌ）を加え更に、トリフ
ェニルホスフィン０．２６ｇ （１ｍ ｍｏｌ）、テト
ラキス（トリフェニルホスフィン）パラジウム（０）０
．２３ｇ （０，２ｍ ｍｏｌ）を加え、２５℃で２時
間攪拌した。反応終了後、０℃まで冷却し、濾過した。Below is the blank space Example 11 (1'R,2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid allyl ester 6.51g
(20 m mol) and propionic acid 3.0 g (26 m mol)
mol) of tetrahydrofuran 40ml! In a solution of
Potassium bicarbonate, 2.6g (26m [001),
Add 1.8 g (100a+ mol) of water, and add 0.26 g (1 m mol) of triphenylphosphine and 0.0
．． 23 g (0.2 mmol) was added and stirred at 25°C for 2 hours. After the reaction was completed, it was cooled to 0°C and filtered.
得られた結晶を乾燥することにより（１’ Ｒ。By drying the obtained crystals (1'R.
２’ Ｒ，５Ｒ，６Ｓ） −６−（１’ −ヒドロキシ
エチル）−２−（２’−テトラヒドロフラニル）ペネム
−３−カルボン酸カリウム塩の２．５永和物の白色結晶
６．９２ｇを得た。ＨＰＬＣで分析したところ純度は、
９９％であった（収率９３％）。2'R,5R,6S)-6-(1'-hydroxyethyl)-2-(2'-tetrahydrofuranyl)penem-3-carboxylic acid potassium salt 2.5-eternal product 6.92g of white crystals were obtained. Ta. As analyzed by HPLC, the purity was
The yield was 99% (yield 93%).
叙上の如く、本発明によれば簡単な操作にて高収率でベ
ナム化合物のアリルエステルのアリル基を脱離すること
ができ、しかもアリル基の脱離と同時に塩、更には結晶
性のよいその水和物を形成して単離を容易にすることが
できるという利点を有する。As described above, according to the present invention, the allyl group of the allyl ester of the benam compound can be removed in high yield with simple operations, and at the same time, the allyl group can be removed and the salt, furthermore, crystalline It has the advantage of being able to form a good hydrate thereof to facilitate isolation.
以 上that's all
Claims (5)
アリル基を示す） で表わされるペネム化合物のアリルエステルを、触媒量
のパラジウム錯体及び水の存在下、炭素数１〜４のカル
ボン酸のアルカリ金属塩または炭素数１〜４のカルボン
酸及びアルカリ金属塩とを反応せしめて一般式〔II〕 ▲数式、化学式、表等があります▼〔II〕 （式中、Ｒ＾２はアルカリ金属を示し、ｍは前記と同じ
ものを示す） で表わされるペネム化合物とすることを特徴とするアリ
ル基の脱離方法。(1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, m is 0 or 1, and R^1 represents an optionally substituted allyl group.) The allyl ester of the compound is reacted with an alkali metal salt of a carboxylic acid having 1 to 4 carbon atoms or a carboxylic acid and an alkali metal salt having 1 to 4 carbon atoms in the presence of a catalytic amount of a palladium complex and water to form the general formula [ II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II] (In the formula, R^2 represents an alkali metal, and m represents the same as above) Allyl characterized by being a penem compound represented by Method for removing groups.
ル基、クロチル基またはシンナミル基である請求項１記
載の方法。(2) The method according to claim 1, wherein R^1 is an allyl group, a haloallyl group, a methylallyl group, a crotyl group, or a cinnamyl group.
酪酸またはシュウ酸、マロン酸もしくはそのモノアルキ
ルエステルである請求項１記載の方法。(3) The method according to claim 1, wherein the carboxylic acid is acetic acid, propionic acid, butyric acid, isobutyric acid, oxalic acid, malonic acid, or a monoalkyl ester thereof.
たはカリウム塩である請求項１記載の方法。(4) The method according to claim 1, wherein the alkali metal salt of carboxylic acid is a sodium salt or a potassium salt.
カリウム、または炭素ナトリウムもしくはカリウムであ
る請求項１記載の方法。(5) The method according to claim 1, wherein the alkali metal salt is sodium or potassium hydrogen carbonate, or sodium or potassium carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2146495A JP2949363B2 (en) | 1990-06-05 | 1990-06-05 | Allyl group elimination method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2146495A JP2949363B2 (en) | 1990-06-05 | 1990-06-05 | Allyl group elimination method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0441489A true JPH0441489A (en) | 1992-02-12 |
| JP2949363B2 JP2949363B2 (en) | 1999-09-13 |
Family
ID=15408920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2146495A Expired - Lifetime JP2949363B2 (en) | 1990-06-05 | 1990-06-05 | Allyl group elimination method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2949363B2 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5587474A (en) * | 1992-06-18 | 1996-12-24 | Tanabe Seiyaku Co., Ltd. | Method for removing the protecting group for carboxyl group |
| US5621084A (en) * | 1994-04-05 | 1997-04-15 | Pfizer Inc. | Process for removal of allyl group or allyloxycarbonyl group |
| WO2001009135A1 (en) * | 1999-07-30 | 2001-02-08 | Eisai Co., Ltd. | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
| CN1314689C (en) * | 2005-08-22 | 2007-05-09 | 鲁南制药集团股份有限公司 | Faropenem sodium synthesis method from reaction by-product |
| US7977475B2 (en) | 2005-10-05 | 2011-07-12 | Ranbaxy Laboratories Limited | Process for the preparation of faropenem |
-
1990
- 1990-06-05 JP JP2146495A patent/JP2949363B2/en not_active Expired - Lifetime
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5587474A (en) * | 1992-06-18 | 1996-12-24 | Tanabe Seiyaku Co., Ltd. | Method for removing the protecting group for carboxyl group |
| US5621084A (en) * | 1994-04-05 | 1997-04-15 | Pfizer Inc. | Process for removal of allyl group or allyloxycarbonyl group |
| WO2001009135A1 (en) * | 1999-07-30 | 2001-02-08 | Eisai Co., Ltd. | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
| US6642377B1 (en) | 1999-07-30 | 2003-11-04 | Eisai Co., Ltd. | Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates |
| CN1314689C (en) * | 2005-08-22 | 2007-05-09 | 鲁南制药集团股份有限公司 | Faropenem sodium synthesis method from reaction by-product |
| US7977475B2 (en) | 2005-10-05 | 2011-07-12 | Ranbaxy Laboratories Limited | Process for the preparation of faropenem |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2949363B2 (en) | 1999-09-13 |
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