JPS6153358B2 - - Google Patents
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- Publication number
- JPS6153358B2 JPS6153358B2 JP52063900A JP6390077A JPS6153358B2 JP S6153358 B2 JPS6153358 B2 JP S6153358B2 JP 52063900 A JP52063900 A JP 52063900A JP 6390077 A JP6390077 A JP 6390077A JP S6153358 B2 JPS6153358 B2 JP S6153358B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- mixture
- general formula
- reaction mixture
- cooled
- 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.)
- Expired
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000010992 reflux Methods 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- -1 cyclic lactam Chemical class 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 4
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 8
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 235000019371 penicillin G benzathine Nutrition 0.000 description 5
- 229940056360 penicillin g Drugs 0.000 description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 239000005051 trimethylchlorosilane Substances 0.000 description 4
- LUBVCBITQHEVCJ-UHFFFAOYSA-N 1-trimethylsilylpyrrolidin-2-one Chemical compound C[Si](C)(C)N1CCCC1=O LUBVCBITQHEVCJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RPVBFFYNFVTCBX-UHFFFAOYSA-N 1-trimethylsilylazepan-2-one Chemical compound C[Si](C)(C)N1CCCCCC1=O RPVBFFYNFVTCBX-UHFFFAOYSA-N 0.000 description 2
- VIZXUYOIEGCSEJ-UHFFFAOYSA-N 3-trimethylsilylazepan-2-one Chemical compound C[Si](C)(C)C1C(=O)NCCCC1 VIZXUYOIEGCSEJ-UHFFFAOYSA-N 0.000 description 2
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- PMQNJTKTWDVUNY-UHFFFAOYSA-N Valero-1,5-lactam Chemical compound C[Si](C)(C)N1CCCCC1=O PMQNJTKTWDVUNY-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FCZNNHHXCFARDY-WQRUCBPWSA-N (2s,5r,6r)-3,3-dimethyl-4,7-dioxo-6-[(2-phenylacetyl)amino]-4$l^{4}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@H]1[C@@H]2N(C1=O)[C@H](C(S2=O)(C)C)C(O)=O)C(=O)CC1=CC=CC=C1 FCZNNHHXCFARDY-WQRUCBPWSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SLFUXNFVAANERW-UHFFFAOYSA-N ethyl hexanoate;potassium Chemical compound [K].CCCCCC(=O)OCC SLFUXNFVAANERW-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
- C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】
本発明は以下の一般式を有する7−アミノ−△
3−デスアセトキシセフアロスポラン酸誘導体の
製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides 7-amino-Δ having the following general formula
The present invention relates to a method for producing a 3 -desacetoxycephalosporanic acid derivative.
式中Rはフエニルもしくはフエノキシ基であ
り、R1は−Hまたはカルボキシル基の保護基で
ある。 In the formula, R is phenyl or phenoxy group, and R 1 is -H or a protecting group for carboxyl group.
上記()式の化合物自体は、例えばジヤーナ
ル、オブ、オーガニツク、ケミストリー36巻1259
頁(1971年)に記載されて公知であり、前述の文
献に記載されているように7−アミノデスアセト
キシセフアロスポラン酸(7ADCA)の製造に使
用される。 The compound of the above formula () itself can be used, for example, in Journal of Organic Chemistry Vol. 36, 1259.
(1971) and is used for the preparation of 7-aminodesacetoxycephalosporanic acid (7ADCA) as described in the aforementioned literature.
本発明の主な目的は上記式()の化合物を経
済的かつ高収率で得ることを可能とする方法を提
供することである。 The main object of the present invention is to provide a process which makes it possible to obtain compounds of the above formula () economically and in high yields.
上述の目的は、一般式
(式中Rはフエニルもしくはフエノキシ基であ
り、R1は−Hまたはカルボキシル基の保護基で
ある)を有するペニシリンスルホキシドを、無水
環境下で、ジオキサンまたはトルエン中におい
て、+60℃乃至+130℃の温度において、そして約
1乃至9時間、一般式
(式中nは3乃至5の整数)を有する環状ラクタ
ムよりなるシリル化剤を反応液中にアゼチジノン
誘導体よりなる中間体を生成するように反応せし
め、該反応液へピリジン臭化水素塩かまたはピリ
ジン/アセチルブロマイドよりなる環化剤を加
え、混合物を還流加熱し、その後ほぼ室温へ冷却
し、水を加え約2.5乃至0.5のPHへ酸性化し、0℃
乃至室温へ冷却し、そしてロ過して前記式()
の化合物より実質上なる沈澱を得る方法によつて
達成される。 The purpose of the above is to use the general formula (wherein R is a phenyl or phenoxy group and R 1 is -H or a protecting group for a carboxyl group) is prepared by adding penicillin sulfoxide having the formula: (R is a phenyl or phenoxy group, and R 1 is -H or a protecting group for a carboxyl group) in dioxane or toluene at a temperature of +60°C to +130°C in an anhydrous environment. and for about 1 to 9 hours, the general formula A silylating agent consisting of a cyclic lactam having the formula (n is an integer of 3 to 5) is reacted in a reaction solution to produce an intermediate consisting of an azetidinone derivative, and pyridine hydrobromide or A cyclizing agent consisting of pyridine/acetyl bromide is added and the mixture is heated to reflux, then cooled to about room temperature, acidified by addition of water to a pH of about 2.5 to 0.5 and 0°C.
Cool to room temperature and filter to obtain the formula ()
This is accomplished by a method that yields a precipitate that is substantially greater than that of the compound.
式()のペニシリンスルホキシド類は公知で
あり、そして例えばフリンの「セフアロスポリン
およびペニシリン」と題する書の第16章に記載さ
れている。 Penicillin sulfoxides of formula () are known and are described, for example, in Chapter 16 of the book entitled "Cephalosporins and Penicillins" by Flynn.
式()の環状ラクタム類自体も公知であり、
例えばルーマン等のANN.CHEM.686、226
(1965)に記載されている。 Cyclic lactams of formula () are also known per se,
For example, ANN.CHEM.686, 226 of Luhmann et al.
(1965).
式()および()の化合物のカルボキシル
基の保護基R1はペプチド化学およびセフアロス
ポラン誘導体の化学の分野では良く知られてお
り、例えば特開昭48−10077号公報にその例が開
示されている。 The carboxyl group protecting group R 1 of the compounds of formulas () and () is well known in the fields of peptide chemistry and cephalosporan derivative chemistry, and an example thereof is disclosed in JP-A-48-10077. .
式の化合物と式()の化合物との反応によ
つて生成するアゼチジノン誘導体は、次の一般式
を有している。 The azetidinone derivative produced by the reaction of the compound of formula and the compound of formula () has the following general formula.
式中R、R1およびnは前に定義したとおりで
ある。このような中間体は本発明者らによつては
じめて合成され、単離された新規化合物である。 where R, R 1 and n are as defined above. Such an intermediate is a novel compound synthesized and isolated for the first time by the present inventors.
式()の化合物を製造する操作は、連続的に
(すなわち中間体を単離することなく)実施する
こともでき、または該中間体を単離し、ジオキサ
ン、トルエンより選ばれた無水溶媒に前記環化剤
と反応させる前に溶解することもできる。 The operation for producing the compound of formula () can be carried out continuously (i.e. without isolating the intermediate) or by isolating the intermediate and adding the above to an anhydrous solvent selected from dioxane, toluene. It can also be dissolved before reacting with the cyclizing agent.
本発明をさらに明確に理解するために、以下に
実施例を記載する。 In order to understand the invention more clearly, examples are given below.
実施例 1
ベンゼン800ml中カプロラクタム180gとトリエ
チルアミン250mlとの混合物へトリメチルクロル
シラン226mlを加え、1時間で徐々に還流するま
で加熱し、さらに4時間還流した。反応混合物を
室温へ冷却し、ベンゼン400mlで洗つた。溶媒を
留去し、110乃至112℃で蒸留し、留分を集め、か
くしてN−トリメチルシリルカプロラクタム(一
般式)250gが得られた。Example 1 226 ml of trimethylchlorosilane was added to a mixture of 180 g of caprolactam and 250 ml of triethylamine in 800 ml of benzene, heated to gradual reflux over 1 hour, and further refluxed for 4 hours. The reaction mixture was cooled to room temperature and washed with 400 ml of benzene. The solvent was distilled off, distilled at 110-112°C, and the fractions were collected, thus obtaining 250 g of N-trimethylsilylcaprolactam (general formula).
無水ジオキサン400ml中のベンジルペニシリン
42gを室温でN−トリメチルシリルカプロラクタ
ム155gへ加えた。混合物を6時間還流加熱し、
減圧下濃縮し溶媒を留去した。残渣を希塩酸でPH
1.5に処理した。混合物を10℃に加熱し、ロ過
し、そして得られた生成物を酢酸エチルへ溶解
し、溶媒を水洗し、シリカゲルカラム上で精製し
た。生成物を硫酸ナトリウム上で脱水し、蒸発し
て固形残渣とし、石油エーテルと混練すると1−
(1−カルボキシ−2−メチルプロペン−2−イ
ル)−3−フエニルアセタミド−4−(2−ケトヘ
キサメチレンイミノ)チオアゼチジン−2−オン
(一般式)19gが得られた。 Benzylpenicillin in 400ml of anhydrous dioxane
42 g was added to 155 g of N-trimethylsilylcaprolactam at room temperature. The mixture was heated to reflux for 6 hours,
It was concentrated under reduced pressure and the solvent was distilled off. PH the residue with dilute hydrochloric acid
Processed to 1.5. The mixture was heated to 10° C., filtered and the resulting product was dissolved in ethyl acetate, the solvent was washed with water and purified on a silica gel column. The product was dried over sodium sulfate, evaporated to a solid residue, and kneaded with petroleum ether to give 1-
19 g of (1-carboxy-2-methylpropen-2-yl)-3-phenylacetamido-4-(2-ketohexamethyleneimino)thioazetidin-2-one (general formula) was obtained.
無水ジオキサン200ml中15gの1−(1−カルボ
キシ−2−メチルプロペン−2−イル)−3−フ
エニルアセタミド−4−(2−ケトヘキサメチレ
ンイミノ)チオアゼチジン−2−オンへ、N・O
−ビス−トリメチルシリルアセタミド36.2mlを加
えた。混合物を60℃で1時間加熱し、ピリジン
2.4mlついでアセチルブロミド2.3mlを加え、3時
間還流加熱した。室温へ冷却した後、水250mlを
加え、塩酸でPH1.5とし、10℃へ冷却し、ロ過
し、イソブチルメチルケトン30mlを加えると、7
−フエニルアセタミド−△3−デスアセトキシセ
フアロスポラン酸9.8gが得られた。 To 15 g of 1-(1-carboxy-2-methylpropen-2-yl)-3-phenylacetamido-4-(2-ketohexamethyleneimino)thioazetidin-2-one in 200 ml of anhydrous dioxane, N. O
36.2 ml of -bis-trimethylsilylacetamide was added. Heat the mixture at 60°C for 1 hour and add pyridine
Next, 2.3 ml of acetyl bromide was added to the mixture, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, add 250 ml of water, adjust the pH to 1.5 with hydrochloric acid, cool to 10°C, filter, and add 30 ml of isobutyl methyl ketone.
-Phenylacetamide- Δ3 -Desacetoxycephalosporanic acid (9.8 g) was obtained.
実施例 2
2−ピロリドン85gおよびトリエチルアミン
165mlとのベンゼン600ml中の混合物へ、かきまぜ
ながらトリメチルクロルシラン150mlを加え、3
時間半還流加熱した。混合物を室温へ冷却し、ロ
過し、ベンゼン200mlで洗い、ロ液を減圧留去
し、残渣(18mmHg)を蒸留し98−100℃の留分を
集め、N−トリメチルシリルピロリジン−2−オ
ン(一般式)118gを得た。Example 2 85g 2-pyrrolidone and triethylamine
Add 150 ml of trimethylchlorosilane while stirring to a mixture of 165 ml and 600 ml of benzene,
Heated at reflux for half an hour. The mixture was cooled to room temperature, filtered, washed with 200 ml of benzene, the filtrate was distilled off under reduced pressure, the residue (18 mmHg) was distilled, the fractions at 98-100°C were collected, and N-trimethylsilylpyrrolidin-2-one ( General formula) 118g was obtained.
無水ジオキサン400ml中31.5gのベンジルペニ
シリンスルホキシドへ、N−トリメチルシリルピ
ロリジン−2−オン95gを加え、5時間加熱還流
した。混合物を室温へ冷却し、500mlの水を加
え、希塩酸でPH1.7とした。 95 g of N-trimethylsilylpyrrolidin-2-one was added to 31.5 g of benzylpenicillin sulfoxide in 400 ml of anhydrous dioxane, and the mixture was heated under reflux for 5 hours. The mixture was cooled to room temperature, 500 ml of water was added, and the pH was adjusted to 1.7 with dilute hydrochloric acid.
ロ過後、沈澱物を水600mlへ懸濁し、トリエチ
ルアミンでPH7.2にして溶解した。生成物をロ過
し、酢酸エチル200mlで洗い、水層を400mlの酢酸
エチルで処理し、塩酸でPH2とした。有機相を硫
酸ナトリウムで脱水し、蒸発乾固し、石油エーテ
ルで処理し、1−(1−カルボキシ−2−メチル
プロペン−2−イル)−3−フエニルアセタミド
−4−(N−ピロリジン−2−オン)チオアゼチ
ジン−2−オン(一般式)12gを得た。 After filtration, the precipitate was suspended in 600 ml of water and dissolved at pH 7.2 with triethylamine. The product was filtered and washed with 200 ml of ethyl acetate, the aqueous layer was treated with 400 ml of ethyl acetate and the pH was brought to 2 with hydrochloric acid. The organic phase was dried over sodium sulfate, evaporated to dryness and treated with petroleum ether to give 1-(1-carboxy-2-methylpropen-2-yl)-3-phenylacetamide-4-(N- 12 g of thioazetidin-2-one (pyrrolidin-2-one) (general formula) was obtained.
1−(1−カルボキシ−2−メチルプロペン−
2−イル)−3−フエニルアセタミド−4−(N−
ピロリジン−2−オン)チオアゼチジン−2−オ
ン9gの無水トルエン20mlに懸濁した。混合物へ
ヘキサンメチルジシクロキサン12.6mlおよびトリ
メチルクロルシラン16.5mlを加えた。混合物を50
℃〜1時間加熱し、ピリジン臭化水素酸塩3.2g
を加え、2時間還流加熱した。混合物を室温へ冷
却し、メタノール35mlを注加した。生成物を10%
アンモニア水溶液100mlで2回抽出して水層へ移
行し、水性抽出液を合し、アセトン50mlを加え、
3N塩酸でPH0.8へ酸性化した。沈澱物を口取し、
洗浄して7−フエニルアセタミド−△3−デスア
セトキシセフアロスポラン酸5.6gを得た。 1-(1-carboxy-2-methylpropene-
2-yl)-3-phenylacetamide-4-(N-
9 g of thioazetidin-2-one (pyrrolidin-2-one) were suspended in 20 ml of anhydrous toluene. 12.6 ml of hexanemethyldicycloxane and 16.5 ml of trimethylchlorosilane were added to the mixture. 50 mixture
3.2 g of pyridine hydrobromide by heating for 1 hour at °C.
was added and heated under reflux for 2 hours. The mixture was cooled to room temperature and 35 ml of methanol was added. 10% product
Extract twice with 100 ml of ammonia aqueous solution, transfer to the aqueous layer, combine the aqueous extracts, add 50 ml of acetone,
Acidified to pH 0.8 with 3N hydrochloric acid. Take the sediment,
After washing, 5.6 g of 7-phenylacetamide- Δ3 -desacetoxycephalosporanic acid was obtained.
実施例 3
トルエン600ml中δ−バレロラクタム105gとト
リエチルアミン180mlとの混合物へ、トリメチル
クロルシラン165mlを加え、4時間半還流加熱し
た。混合物を冷却し、そしてロ過し、トルエン
200mlで洗い、溶媒を留去し、残渣を蒸留し79−
80℃(12mmHg)の留分としてN−トリメチルシ
リルピペリジン−2−オン158gを得た。Example 3 165 ml of trimethylchlorosilane was added to a mixture of 105 g of δ-valerolactam and 180 ml of triethylamine in 600 ml of toluene, and the mixture was heated under reflux for 4 and a half hours. The mixture was cooled and filtered with toluene.
Wash with 200 ml, distill off the solvent, and distill the residue.
158 g of N-trimethylsilylpiperidin-2-one was obtained as a fraction at 80°C (12 mmHg).
無水ジオキサン500ml中35gのベンジルペニシ
リンスルホキシドへ、N−トリメチルシリルピペ
リジン−2−オン120gを加え、6時間還流加熱
した。混合物を室温へ冷却し、水600mlを加え、
希塩酸でPHを1.8とした。生成物をロ過し、沈澱
物を酢酸エチルに溶解し、水酸化カリウムの希水
溶液で処理し、PH7.2で抽出した。水相を塩基性
アルミナカラムを通し、溶出液を酢酸エチルで洗
い、希塩酸々性とした。残渣を石油エーテルで洗
つた後、有機相を蒸発乾固して1−(1−カルボ
キシ−2−メチルプロペン−2−イソ)−3−フ
エニルアセタミド−4−(N−ピペリジン−2−
オン)チオアゼチジン−2−オン13.9gを得た。 120 g of N-trimethylsilylpiperidin-2-one was added to 35 g of benzylpenicillin sulfoxide in 500 ml of anhydrous dioxane and heated under reflux for 6 hours. Cool the mixture to room temperature, add 600 ml of water,
The pH was adjusted to 1.8 with dilute hydrochloric acid. The product was filtered and the precipitate was dissolved in ethyl acetate, treated with a dilute aqueous solution of potassium hydroxide and extracted with PH7.2. The aqueous phase was passed through a basic alumina column, and the eluate was washed with ethyl acetate and made acidic with dilute hydrochloric acid. After washing the residue with petroleum ether, the organic phase was evaporated to dryness to give 1-(1-carboxy-2-methylpropene-2-iso)-3-phenylacetamide-4-(N-piperidine-2 −
13.9 g of thioazetidin-2-one (13.9 g) were obtained.
無水ジオキサン200ml中1−(1−カルボキシ−
2−メチルプロペン−2−イル)−3−フエニル
アセタミド−4−(N−ピペリジン−2−オン)
チオアゼチジン−2−オン11gおよびN−トリメ
チルシリルピロリジン−2−オン22.9gを45分間
60℃へ加熱し、ピリジン1.55mlおよびアセチルブ
ロミド1.5mlを加え、2時間加熱還流した。混合
物を室温で冷却し、水300mlを加え、希塩酸でPH
1.7とし、沈澱物をPH7.2に希水酸化ナトリウム水
溶液で溶解し、酢酸エチルで洗つた。有機層を2
−エチルヘキサン酸カリウムで処理し、7−フエ
ニルアセタミド−△3−デスアセトキシセフアロ
スポラン酸カリウム塩5.6gを得た。 1-(1-carboxy-
2-methylpropen-2-yl)-3-phenylacetamide-4-(N-piperidin-2-one)
11 g of thioazetidin-2-one and 22.9 g of N-trimethylsilylpyrrolidin-2-one for 45 minutes
The mixture was heated to 60°C, 1.55 ml of pyridine and 1.5 ml of acetyl bromide were added, and the mixture was heated under reflux for 2 hours. Cool the mixture to room temperature, add 300 ml of water and adjust the pH with dilute hydrochloric acid.
1.7, and the precipitate was dissolved at pH 7.2 with dilute aqueous sodium hydroxide solution and washed with ethyl acetate. 2 organic layers
Treatment with potassium -ethylhexanoate gave 5.6 g of 7-phenylacetamide- Δ3 -desacetoxycephalosporanic acid potassium salt.
実施例 4
ベンジルペニシリンスルホキシド35gを無水ジ
オキサン350ml中トリメチルシリルカプロラクタ
ム120gで処理した。混合物を55℃へ1時間加熱
し、ピリジン1.8mlおよびアセチルブロミド4.5ml
を加え、6時間還流加熱した。混合物を室温へ冷
却し、水450mlを加え、希塩酸でPH1.7とし、そし
て混合物を10℃へ冷却しロ過した。得られた生成
物をイソブチルメチルケトン50mlと練り、そして
再びロ過して7−フエニルアセタミド−△3−デ
スアセトキシセフアロスポラン酸25.8gを得た。Example 4 35 g of benzylpenicillin sulfoxide were treated with 120 g of trimethylsilylcaprolactam in 350 ml of anhydrous dioxane. Heat the mixture to 55°C for 1 hour, add 1.8 ml of pyridine and 4.5 ml of acetyl bromide.
was added and heated under reflux for 6 hours. The mixture was cooled to room temperature, 450 ml of water was added, the pH was brought to 1.7 with dilute hydrochloric acid, and the mixture was cooled to 10° C. and filtered. The resulting product was triturated with 50 ml of isobutyl methyl ketone and filtered again to obtain 25.8 g of 7-phenylacetamide- Δ3 -desacetoxycephalosporanic acid.
実施例 5
ベンジルペニシリン50gを無水トルエン400ml
へ懸濁した。室温で混合物へトリメチルシリルカ
プロラクタム171.5gを加え、60℃で45分間加熱
して溶解した。次にピリジン臭化水素酸塩9gを
加え、混合物を還流した。110℃の温度を2時間
保ち、混合物を65℃へ冷却し、メチルイソブチル
ケトン65mlを加えた。60℃へ予熱した水375mlを
溶液中へ注いだ。混合物を30℃へ冷却し、20%希
硫酸を加えPH1.2とした。混合物を室温で1時間
かきまぜ、ロ過し、水200ml、トルエル150mlおよ
びメチルイソブチルケトン75mlで順次洗つた。生
成物は50℃でオーブン乾燥し、7−フエニルアセ
タミド−△3−デスアセトキシセフアロスポラン
酸34.7gを得た。Example 5 50g of benzylpenicillin and 400ml of anhydrous toluene
suspended in. 171.5 g of trimethylsilylcaprolactam was added to the mixture at room temperature and dissolved by heating at 60° C. for 45 minutes. Then 9 g of pyridine hydrobromide were added and the mixture was refluxed. The temperature of 110°C was maintained for 2 hours, the mixture was cooled to 65°C and 65ml of methyl isobutyl ketone was added. 375 ml of water preheated to 60°C was poured into the solution. The mixture was cooled to 30°C, and 20% dilute sulfuric acid was added to adjust the pH to 1.2. The mixture was stirred at room temperature for 1 hour, filtered and washed successively with 200 ml water, 150 ml toluene and 75 ml methyl isobutyl ketone. The product was oven dried at 50°C to obtain 34.7 g of 7-phenylacetamide- Δ3 -desacetoxycephalosporanic acid.
Claims (1)
Hまたはカルボキシル基の保護基である)を有
するペニシリンスルホキシドを、無水環境下、
ジオキサンまたはトルエン中、+60℃ないし+
130℃の温度で、約1ないし9時間、一般式 (式中nは3ないし5の整数)を有する環状ラ
クタムシリル化剤とを反応させることにより、
一般式 (式中符号は前記に同じ)を有するアゼチジノ
ン誘導体を反応混合物中に生成させ、次いで B 前記式()のアゼチジノン誘導体を反応混
合物から単離した後ジオキサンまたはトルエン
へ溶解した液かもしくは前記反応混合物そのま
まを、ピリジン臭化水素酸塩かまたはピリジ
ン/アセチルブロマイドよりなる環化剤と還流
加熱し、反応混合物を冷却後約2.5ないし0.5の
PHへ酸性化し、冷却して一般式 (式中符号は前記に同じ)を有する化合物より
実質的になる沈澱をロ過して採取することを特
徴とする7−アミノ−△3−デスアセトキシセ
フアロスポラン酸誘導体の製法。 2 前記カルボキシル基の保護基R1がトリメチ
ルシリル基である特許請求の範囲第1項の方法。[Claims] 1 A General formula (In the formula, R is a phenyl or phenoxy group, R 1 is H or a protecting group for a carboxyl group) in an anhydrous environment,
+60°C to + in dioxane or toluene
At a temperature of 130℃ for about 1 to 9 hours, the general formula (wherein n is an integer of 3 to 5) by reacting with a cyclic lactam silylating agent,
general formula (The symbols in the formula are the same as above) are produced in the reaction mixture, and then the azetidinone derivative of the formula (B) is isolated from the reaction mixture and then dissolved in dioxane or toluene, or the reaction mixture is The as-is is heated to reflux with a cyclizing agent consisting of pyridine hydrobromide or pyridine/acetyl bromide, and the reaction mixture is cooled to a concentration of about 2.5 to 0.5.
Acidified to PH, cooled and general formula A method for producing a 7-amino- Δ3 -desacetoxycephalosporanic acid derivative, which comprises filtering and collecting a precipitate substantially consisting of a compound having the same formula as above. 2. The method according to claim 1, wherein the carboxyl group protecting group R 1 is a trimethylsilyl group.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT23825/76A IT1063088B (en) | 1976-06-01 | 1976-06-01 | AZETIDINONIC DERIVATIVES AND PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINE |
KR7701295A KR810000859B1 (en) | 1976-06-01 | 1977-06-01 | Method for preparing derivatives of 7-amino- 3-desacetoxy cephalosporanic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5323989A JPS5323989A (en) | 1978-03-06 |
JPS6153358B2 true JPS6153358B2 (en) | 1986-11-17 |
Family
ID=26328424
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6390077A Granted JPS5323989A (en) | 1976-06-01 | 1977-05-30 | Production of 77aminoodelta 33 desacetoxycephalosporanic acid derivative |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS5323989A (en) |
KR (1) | KR810000859B1 (en) |
CH (1) | CH626369A5 (en) |
DE (1) | DE2724286A1 (en) |
FR (1) | FR2353558A1 (en) |
GB (1) | GB1542049A (en) |
IT (1) | IT1063088B (en) |
YU (1) | YU136477A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102617602A (en) * | 2012-03-15 | 2012-08-01 | 江苏九九久科技股份有限公司 | Method for synthesizing 7-phenylacetylaminodeacetoxycephalo G acid |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA695612B (en) * | 1968-08-23 | 1971-03-31 | Lilly Co Eli | Preparation of cephalosporin compounds |
FR2037858A5 (en) * | 1969-03-11 | 1970-12-31 | Glaxo Lab Ltd | |
BE787618A (en) * | 1971-08-17 | 1973-02-16 | Gist Brocades Nv | PROCESS FOR PREPARING HETEROCYCLIC COMPOUNDS |
GB1465893A (en) * | 1973-02-09 | 1977-03-02 | Gist Brocades Nv | I-carboxypropenyl-4-iminothio-azetidine-2-one derivatives methods for their preparation and use |
-
1976
- 1976-06-01 IT IT23825/76A patent/IT1063088B/en active
-
1977
- 1977-05-28 DE DE19772724286 patent/DE2724286A1/en not_active Ceased
- 1977-05-30 JP JP6390077A patent/JPS5323989A/en active Granted
- 1977-05-30 GB GB7722686A patent/GB1542049A/en not_active Expired
- 1977-05-31 CH CH663377A patent/CH626369A5/en not_active IP Right Cessation
- 1977-06-01 KR KR7701295A patent/KR810000859B1/en active
- 1977-06-01 YU YU01364/77A patent/YU136477A/en unknown
- 1977-06-01 FR FR7717607A patent/FR2353558A1/en active Granted
Also Published As
Publication number | Publication date |
---|---|
CH626369A5 (en) | 1981-11-13 |
JPS5323989A (en) | 1978-03-06 |
IT1063088B (en) | 1985-02-11 |
DE2724286A1 (en) | 1977-12-15 |
KR810000859B1 (en) | 1981-08-10 |
GB1542049A (en) | 1979-03-14 |
FR2353558A1 (en) | 1977-12-30 |
YU136477A (en) | 1982-10-31 |
FR2353558B1 (en) | 1983-12-16 |
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