Method of producing 6-(1-oxyethyl)anhydropenicillin in the form of 5,6-trans isomer

专利摘要:
A novel stereocontrolled process is disclosed for converting 6-aminopenicillanic acid to an optically active azetidinone of the formula <IMAGE> wherein R'' is a hydroxy-protecting group by use of a 6,6-dihaloanhydropenicillin or 6,6-bis(phenylselenyl)anhydropenicillin intermediate.
公开号:SU1435154A3
申请号:SU864027635
申请日:1986-06-13
公开日:1988-10-30
发明作者:Мартель Алаин；Дарис Жан-Поль
申请人:Бристоль-Мейерз Компани (Фирма)；
IPC主号:

专利说明:

 CM
114
This invention relates to a process for the preparation of a novel compound 6- (1-oxo-ethyl) anhydropenicillin, which is an activity in the synthesis of penem and carbapenem antibiotics.
The aim of the invention is to obtain a new intermediate product, which allows, on its basis, to stereospecific synthesis of antibiotics of the penem and carbopenem series.
Example 1. A. Obtaining an-hydro-6 5 6-dibrompenitsitshina


® Br- | -f N,
0
;
 target compound: m.p. 102-103 C (CHjOH), 16.1 g (47.2 mmol), yield 85%.
Spectrum of the NDP (CDCl ,, 80 MHz) S: 5.80 (1H, s, H-5); 2.2G (3N, s, SI,) and 2.15 ppm (ZN, s, CH ,.
IR spectrum () „ks 1800 (s, p-lactam), 1708 (s, lactone) and 1640 cm (W, olefin). ; (06) + 88.9 ° (s, 0.144, CH, OH).
Found X, C From 28.08; H 1.98; N 4.06.
SBr4
Calculated,%: C 28,17i H 2.07 {
N 4,10.
B. Preparation of 6 oi-bromo-6 / - (1 K) Rxyethyl Zanhydropenicillin:
20.00 g (55.56 mmol) of 6 6-dibromopenicillonic acid, dissolved in 200 ml of methylene chloride, cooled in an ice-methanol bath, are treated and 58.4 mmol (B ml) of triethylamine are added dropwise and stirred for 15 minutes. 8.40 ml (61.2 mmol) of trifluoroacetic acid is added dropwise to the solution. The mixture was stirred for 30 minutes, then 4.8 ml (61.2 mmol) of pyridine was added dropwise. The mixture is stirred for 30 minutes at and then for 18 hours at. The mixture is successively washed with tH. Aqueous hydrochloric acid, water, 1 M aqueous NaHCOj and brine, dried over magnesium sulfate. The residue obtained by evaporation of the solvent is again dissolved in ethyl acetate (EtOAC). And treated with activated carbon to obtain
II 2) CHjCHO
-zo c
pHBr
ABOUT
g
Reagents: Anhydropenicillin 5
five
THF
- 10.23 g (0.03 mol) 12.21 ml
(.0.0348 mol, J6% excess, 2.85 M solution in the air, Aldrich)
0 TROUBLE 6.6, 4 ml
(0.15 mol, d 0.788, Aldrich) 150 ml (dried over molecular sieves; Tami).
To a solution of 10.23 g of anhydro-6,6-dibromopenicillin in 150 ml of dry THF, cooled to -20 s, was added dropwise 12.21 ml of methylmagnesium bromide over 10 yins, while the temperature was kept at (-15) - (- 20) p. The resulting solution was stirred at -20 ° C for 10 minutes and then at 5
0
five
0
five
First, 8.4 ml of acetaldehyde is added dropwise over 5 minutes, maintaining the temperature at (-15) - (-20) ° C. To the reaction mixture were added 10 ml of a saturated solution of ammonium chloride, then 80 ml of water. The mixture is extracted with 150 ml and 50 ml of ethyl acetate. The ethyl acetate extract is washed twice with 100 ml of brine, dried over anhydrous sodium sulfate and concentrated to give 8.9 g of oil (97%). According to high performance liquid chromatography, there is 92% cis, no trans isomer, 8% impurities.
Column / i Porasil (Waters) Solvent 3% CH, CN / CHjClj | Flow rate 90 mp / h UV Detection 275 nm Dilution 0.2
C. Preparation of anhydro-6 pt. And (1 K) -oxyethyl penicillin
ONVR
-% V °
he
WV °
 A solution of 4.20 g (13.7 mmol) of anhydro-66-bromo-60-U K) -oxyethyl penicillin in 40 ml of methanol and 4.2 g of iin / Ag is prepared, which is cooled in an ice-methanol bath, and is stirred for 15 minutes. Another 1.1 g of Zn / Ag is added and the mixture is stirred for 10 minutes. The cold suspension is filtered through Celite into a cold concentrated aqueous solution of ammonium chloride. The solid is washed with ether and the two phases are separated. The aqueous phase is extracted with 2 times 20 ml of ether. The ether extracts are combined and washed sequentially with 1N. aqueous hydrochloric acid, water, 1 M aqueous NaHCO, and brine, then dried. The residue after evaporation of the solvent was thoroughly triturated with a cold mixture of petroleum ether / ether 9: 1, 1.3 g (5.7 mmol) were obtained, yield 42% as a white solid, mp. 173-4 0 (CH С12 / ether 2/8).
PMR spectrum (CDC1,): 5.28, C1H, d, L 1.7, H-5), 4.35 (1H, quintet, J 6.2, H-1); 3.57 (1H, dd,, 2,, 7, H-6); 2.19 (ZN, s, CH), 2, 11 (ZN, s, CH,); 1.72 (1H, broad singleton OH) and 1.40 ppm (3N, d, 3, CH,).
IR spectrum (.СН2С1г): 9mo | ks-3500 (N, III); 1775 (s, / -pactam), 1695 (s, lactone) and 1635 (m, olefin).
Found,%: C 52.86; H 5.72j N 6.08.
CioH ,, NO, S
Calculated,%: C, 52.84; H, 5.76; N 6.16.
The cold ether / / petroleum ether 1: 9 is evaporated and the pure 6-isomer is isolated using preparative ones (2% CH 3 CH / CH 2 C).
PMR spectrum (CDC1,) 5: 5.40, (1H, d, 6, H-5); 4.36 (1I, double quartet,, 1,, 0 H-1), 3.74 (1H, dd,, 0,, 6, H-6); 2.19 (3N, s, CHj); 2.25-1.90 (1H, wide singlet, OH); 2.09 (3N, s, CH,) and 1.27 ppm (ZN, d,, 0, SI,;.
IR spectrum (.CH.Cl,)
Max
: 3580
(W, OH); 1770 (s, r-lactam), 1700 (s, lactone) and 1640 (m
olefin). The reaction conditions are not optimized. A 56.6% bob isomer yield was obtained by repeating at -50 ° C. Example 2. Preparation of 6oi-bromo-5p- (. 1 R-hydroxyethanol anhydropenicillin.
BP
Br-1-fSv O-it-
About cH, Mgci
2) DETACHABLE
THF -45 ° C
ONVG
0
Reagents: Anhydropenicillin CH, MgCl
ATTACHMENT
THF
five
34.1 g (and 1 mol) 39.6 MP (0.116 mol), 16% excess, 2.9 M solution in THF 28 ml-22 g (0.5 mol, do, 788) 350 ml (dried over molecular citites)
The technique.
A solution of 34.1 g of anhydrous, 6-dibromopenicillin in 350 ml of dry THF is cooled down and 39.6 ml of methyl magnesium chloride are added dropwise, maintaining the temperature below -40 ° C. The resulting solution is stirred for 10 minutes at (-45) - ( -40) C and 28 ml of acetaldehyde are added dropwise first over 5 minutes, maintaining the temperature below -30 ° C. The solution is stirred for 15 minutes at
-40 ° C. To the reaction mixture was added 35 ml of the high-grade ammonium chloride solution, then 400 ml of water. The mixture is extracted with 350 ml and 150 ml of toluene. The toluene extract is washed with 2 times 300 ml of brine, dried over anhydrous magnesium sulphate and concentrated to a volume of 100 ml. 300 ml of toluene was added to the concentrated solution, then continued 5 1A351
concentration to approximately 300 np.
The high performance liquid chrome graphic shows 92% purity.
 trans isomer.
 ColumnPorasil (Boters)
Solvent% CH, CN / CH Cl, j
Flow rate 90 ml / h
UV detection 275
Dilution0,2
TLC: silica gel, ether-petroleum-ether 1: 1, 1 j.
F
formula from. bratis
and;
The method of obtaining 6- (1-hydroxyethyl) and hydropericone in the form of a 5,6-transomer of formula 1
%
distinguished by the fact that 6-dibromanganhydropenicillin II
W H N
Bp-uj-s o
Q -1T-V
is reacted with methylmagnesium Yoride in an anhydrous inert organic solvent at a temperature of (-45) to (-15) ° C, the resulting product is reacted with acetaldehyde under the same conditions to form 6-monobromo-substituted anhydropenicillin as a cis isomer of the formula III
20
he
-N-4H
o- ni-y
25
is reduced in an inert solvent using a zinc-silver pair as a reducing agent and the desired product is isolated as a 5,6-trans-isomer.

权利要求:
Claims (1)
[1]
Claim
Porassil (Waters) 3% Sn ₅ sy / Sn _g C1 ₂ 90 ml / h UV 275 nm
The method of obtaining 6- (1-hydroxyethyl) anhydropenicillin as 5,6-trans-isomer of formula I 2.1
characterized in that,
6,6-dibromanhydropenicillin · formula II
W H N
is reacted with methylmagnesium Toride in an anhydrous inert organic solvent at a temperature of (-45) to (-15) ° C, and the resulting product is reacted with acetaldehyde under the same conditions as 6-monobromide anhydropenicillin as the cis isomer of the formula III
20
ONWLOW
xM - py **
reduced in an inert solvent using a pair of zinc-silver in
25 as a reducing agent and isolate the desired product as
5,6 trans-isomer.

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1435154A3|1988-10-30|Method of producing 6-|anhydropenicillin in the form of 5,6-trans isomer

---

Chida et al.1991|Synthesis of optically active substituted cyclohexenones from carbohydrates by catalytic Ferrier rearrangement

---

DE3428049C2|1989-09-28|

---

DE3109086C2|1991-05-02|

---

JPH06329624A|1994-11-29|Production of azetidinone derivative

---

Hiyama et al.1987|Synthesis of 4-Amino-2 |-furanones through Intra-and Intermolecular Nitrile Addition of Ester Enolates. Construction of Carbon Framework of an Antitumor Antibiotic Basidalin

---

JP3479720B2|2003-12-15|Method for producing carbapenems

---

Torii et al.1990|Palladium-catalyzed tandem assembly of norbornene, vinylic halides, and cyanide nucleophile leading to cis-exo-2, 3-disubstituted norbornanes

---

JP2575781B2|1997-01-29|2,3-diacyloxy-4-hydroxy-topenanal and method for producing the same

---

FR2518098A1|1983-06-17|PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE PENEM DERIVATIVES

---

CA1339123C|1997-07-29|Penem derivatives, production and use thereof

---

JP2958834B2|1999-10-06|Azetidin-2-one derivatives

---

US4789740A|1988-12-06|Halogenation process for preparing 2-|-3-chloromethyl-3-butenoate

---

US4847266A|1989-07-11|Method for preparing 6-β-halopenicillanic acids

---

TANAKA et al.1983|Synthetic studies on a picrotoxane sesquiterpene, coriamyrtin. II. An effective stereocontrolled synthesis of the picrotoxane skeleton except for a C1 unit at the C9 position and functionalization of the five-membered ring

---

JP2958835B2|1999-10-06|Method for producing 4- | azetidin-2-one derivative

---

KR100543172B1|2006-01-20|A Process for Preparing Terrein Compounds

---

Altamura et al.1988|Oxidation of A 4-Benzoyl-2-Azetidinone by Potassium Peroxomonosulfate

---

US4499292A|1985-02-12|7-Oxabicycloheptane prostaglandin intermediates and method for preparing same

---

CA1252471A|1989-04-11|Process for the preparation of azetidinones

---

US4769478A|1988-09-06|Preparation of | 6,6-dimethyl-4-hydroxy-3-oxabicyclo | hexan-2-one and its ethers

---

JP3532224B2|2004-05-31|Method for removing silyl group from silyl ether compound

---

US5220034A|1993-06-15|Protected derivatives of the enone of spectinomycin

---

EP0229384B1|1994-08-10|Beta-lactam compounds and their production

---

JP2669970B2|1997-10-29|Azetidinone derivative

同族专利:

---

公开号 | 公开日

---

AT388556B|1989-07-25|

---

BE902133A|1985-10-07|

---

HUT40442A|1986-12-28|

---

AR241139A1|1991-11-29|

---

HU193959B|1987-12-28|

---

FI851324A0|1985-04-02|

---

SE9000790L|1991-09-07|

---

NZ211457A|1989-03-29|

---

CS253724B2|1987-12-17|

---

SE8501679L|1985-10-07|

---

ES541866A0|1987-01-01|

---

JPH032157B2|1991-01-14|

---

JPS6117586A|1986-01-25|

---

SE9000791L|1991-09-07|

---

KR850007585A|1985-12-07|

---

YU134487A|1988-02-29|

---

NO166132B|1991-02-25|

---

HUT38349A|1986-05-28|

---

YU134587A|1988-02-29|

---

GB2156814B|1987-12-31|

---

IE58409B1|1993-09-22|

---

ATA104285A|1988-12-15|

---

FR2562541A1|1985-10-11|

---

IT1190351B|1988-02-16|

---

US4596677A|1986-06-24|

---

FR2562541B1|1986-12-26|

---

JPS61171485A|1986-08-02|

---

GB8508847D0|1985-05-09|

---

GB2156814A|1985-10-16|

---

YU46059B|1992-12-21|

---

SE8501679D0|1985-04-03|

---

NL8500986A|1985-11-01|

---

US4639335A|1987-01-27|

---

NO164902C|1990-11-28|

---

ES8702422A1|1987-01-01|

---

AU4086485A|1985-10-10|

---

KR920006919B1|1992-08-22|

---

FI86852B|1992-07-15|

---

YU46060B|1992-12-21|

---

PT80235A|1985-05-01|

---

DE3512250A1|1985-10-17|

---

GR850879B|1985-11-25|

---

CA1261318A|1989-09-26|

---

JPH0312072B2|1991-02-19|

---

NO166132C|1991-06-05|

---

SG91090G|1991-01-18|

---

SE9000791D0|1990-03-06|

---

ZA852237B|1985-11-27|

---

SU1400504A3|1988-05-30|

---

YU45918B|1992-09-07|

---

ZW5585A1|1985-11-06|

---

NO164902B|1990-08-20|

---

IE850867L|1985-10-06|

---

FI851324L|1985-10-07|

---

DK156085A|1985-10-07|

---

SE9000790D0|1990-03-06|

---

IL74799D0|1985-07-31|

---

CH665420A5|1988-05-13|

---

IL74799A|1988-11-15|

---

PT80235B|1987-10-20|

---

CY1572A|1991-12-20|

---

IT8520246D0|1985-04-05|

---

OA07984A|1987-01-31|

---

LU85841A1|1985-12-16|

---

AR241139A2|1991-11-29|

---

FI86852C|1992-10-26|

---

SE466201B|1992-01-13|

---

DK156085D0|1985-04-03|

---

AU580043B2|1988-12-22|

---

HK106090A|1990-12-21|

---

NO860326L|1985-10-07|

---

DD232132A5|1986-01-15|

---

HU194250B|1988-01-28|

---

YU57185A|1988-02-29|

---

NO851310L|1985-10-07|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3311638A|1961-08-16|1967-03-28|Bristol Myers Co|Anhydropenicillins|

---

US3950352A|1972-04-10|1976-04-13|Queen's University|2,2-Dimethyl-3R-carboxy-6S-phenylacetamido-1-oxa-4-aza-5R-bicyclo[3,2,0]heptan-7-one and processes for their production|

---

SE449103B|1979-03-05|1987-04-06|Pfizer|SET TO PENICILLANIC ACID-1,1-DIOXIDE AND ESSERS THEREOF|

---

US4356120A|1979-07-23|1982-10-26|Merck & Co., Inc.|3--4--azetidin-2-one and derivatives|

---

US4468351A|1983-06-06|1984-08-28|Pfizer Inc.|Process for debromination of dibromopenicillanic acid and derivatives|AU601180B2|1986-04-30|1990-09-06|Kanegafuchi Kagaku Kogyo Kabushiki Kaisha|Process for preparing 4-acetoxy-3-hydroxyethylazetidin -2- one derivatives|

---

US4876338A|1986-07-21|1989-10-24|Schering Corporation|Synthesis of azetidinones using CuCl|

---

US5053502A|1986-07-21|1991-10-01|Schering Corporation|Anhydro penicillin derivatives|

---

US4767853A|1986-07-21|1988-08-30|Schering Corporation|Synthesis of 1--methyl-3--4-beta-naphthoxythiocarbonylthio-2-azetidinones and hydroxy protected analogs thereof|

---

US5075438A|1986-07-21|1991-12-24|Schering Corporation|Synthesis of azetidinones|

---

US4948885A|1986-07-21|1990-08-14|Schering-Plough Corp.|Synthesis of azetidinones|

---

US5274188A|1987-05-04|1993-12-28|Ciba-Geigy Corporation|Process for the manufacture of 4-acyloxy-3-hydroxyethyl-azetidinones|

---

EP0290385B1|1987-05-04|1992-10-21|Ciba-Geigy Ag|Process for preparing 4-acyloxy-3-hydroxyethyl-azetidinones|

---

US4876365A|1988-12-05|1989-10-24|Schering Corporation|Intermediate compounds for preparing penems and carbapenems|

---

ES2336677T3|2003-09-03|2010-04-15|Otsuka Chemical Co., Ltd.|PRODUCTION PROCESS OF PENICILANIC ACID COMPOUNDS.|

---

US8293893B2|2007-03-09|2012-10-23|Otsuka Chemical Co., Ltd.|Method for producing 6-hydroxyethylpenam compound|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US06/597,765|US4596677A|1984-04-06|1984-04-06|Anhydropenicillin intermediates|

---