IE913297A1 - Process for the preparation of carbapenem compounds - Google Patents

Abstract

Compound I is obtained by reacting compound IV with compound V in a suitable organic solvent at temperatures from 50 to 180 DEG C.

Description

- laHOECHST AKTIENGESELLSCHAFT HOE 90/F 283K Dr. VF/AP Process for the preparation of carbapenem compounds The invention relates to a process for the preparation of carbapenem compounds.

Carbapenem derivatives of the formula I are valuable compounds having antibiotic properties. Synthesis methods known from the literature make use of the intermediates of the compounds of the formulae II and III, whose preparation is time-consuming: COOS(4) A further process variant consists in the cyclization of the precursor IV (oxalimide cyclization): In the literature, the cyclization reagent which is used exclusively is trimethyl phosphite or triethyl phosphite.

The disadvantage is that the yields are often very low because of the high reaction temperatures and long reaction times which are necessary.

Surprisingly, it has now been found that these disadvantages can be avoided when the precursor IV is cyclized using dialkyl alkylphosphonites. Compared with alkylphosphites, these novel reagents lead to a cyclization under considerably milder reaction conditions and therefore to considerably higher yields of end product I.

The invention therefore relates to a process for the preparation of carbapenem derivatives of the formula I in which: R(l) and R(2) are hydrogen, (Cj-C*)alkyl, (Cj-CJalkenyl, (Cj-CJ alkoxy, (C4-C7)cycloalkyl or (C3-C6)spirocyclyl, R(3) is hydrogen, (Cx-C,,) alkyl, (Cj-C^)alkylthio [where the alkyl groups are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, (Ci-CJalkoxy, (Cx-CJalkyloxycarbonyl, (Cx-CJacyloxy, amino, (Cx-CJ alkylamino, (Cx-CJacylamino, thiol, (Ci-CJalkylthio or heterocyclylthio, for example thiazolyl, thiadiazolyl, pyridylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio [where the phenyl and heterocyclyl rings are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, carboxyl, (Cx-CJalkoxycarbonyl, allyloxy10 carbonyl, aminocarbonyl, (Ci-C4)alkylaminocarbonyl, cyano, F, Cl, Br], (C3-Ce) cycloalkyl, (C3-C6)cycloalkylthio, (C5-Ce) oxacycloalkyl [saturated, mono- or diunsaturated], (C3-C6) oxocycloalkyl, (C3-C6)[ 1,1-bis- (Cx-Ca)alkyloxy]cycloalkyl, (C3-Ce) -[ (Cx-C3) 15 alkylimino]cycloalkyl,(C3-C6)-[phenylimino]cycloalkyl, (C3-C6)-(hydroxyimino)cycloalkyl, (C3-C6)[ (Ci-C3)alkyloxyimino]cycloalkyl, in which radicals the cycloalkyl radical is unsubstituted or mono- or disubstituted by (Cx-C3) alkyl, preferably methyl, by (Cj-Ca)alkoxy, preferably methoxy, by halogen such as F, Cl, Br, preferably chlorine, or by methylene, and is saturated or can contain one or two double bonds, R(4) is hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R(5) is hydrogen or a customary alcohol protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically.

The following are examples of particularly preferred substituents: R(l) and (R(2) are hydrogen, (Cj-C^)alkyl, (Cx-C4)alkenyl, (Cx-C J alkoxy, (C4-C7) cycloalkyl or (C3-C6)spirocyclyl, R (3) is hydrogen, (Cx-C4) alkyl (for example methyl, ethyl, hydroxymethyl and aminomethyl), (Cx-C4)hydroxyalkyl, (Cx-C3)alkylthio (for example methylthio, ethylthio and propylthio, methoxycarbonylmethylthio), phenyl (for example 4-carboxamidophenyl, protected 3,4-dihydroxyphenyl, 4-fluorophenyl or 4-cyanophenyl), heterocyclyl, for example pyridyl, phenylthio, saturated or unsaturated (C5-C6)oxacycloalkyl (for example tetrahydrofuryl or furyl), (CA-C6)oxocycloalkyl (for example l-oxocyclobut-3-yl), 3-hydroxy5 iminocyclobutyl, 3-methoxyiminocyclobutyl and 3,3-dimethoxycyclobutyl, R(4) is a carboxyl protective group such as allyl, p-nitrobenzyl or trimethylsilylethyl, R(5) is hydrogen or an alcohol protective group such as trimethylsilyl, dimethyl-tert.-butylsilyl, diphenyltert.-butylsilyl, allyloxycarbonyl, trichloroethyloxycarbonyl or 4-nitrobenzyloxycarbonyl.

The asymmetric centers C-l, C-5, C-6 and C-8 can exist both in the R configuration and in the S configuration.

The compounds of the formula I are prepared by the process according to the invention by reacting a compound of the formula IV in which X is oxygen or sulfur and R(l), R(2), R(3), R(4) and R(5) are as defined above with a trivalent organic phosphorus compound of the formula V in which: R(6) and R(7) are (Cj-C4)alkyl, allyl, benzyl or phenyl which can be substituted by (Cj-Ca) alkyl or (Ci-Ca) alkoxy, and R(6) and R(7) can be identical or different, and R(8) is (Cj-CJalkyl, for example methyl, ethyl or tri5 fluoromethyl, phenyl which can be substituted by (Ci-Ca)alkyl or (C!-C3)alkoxy.

The reaction between a compound IV and a compound V can be carried out in a suitable organic solvent, for example in tetrahydrofuran, ethyl acetate, an aromatic hydro10 carbon such as benzene, toluene, xylene or mesitylene, or in a halogenated hydrocarbon such as dichloromethane, trichloromethane or 1,1,2-trichloroethane.

The reaction temperature can vary between 50 and 180°C, preferably between 70 and 165C.

The concentration of the compound IV to be cyclized is between 1 mmol/1 and 150 mmol/1, preferably between 2 mmol/1 and 50 mmol/1.

The amount of the compound V can be between 2 and 8 mol equivalents, preferably between 2 and 6 mol equivalents, relative to IV.

The dialkyl alkylphosphonates and dialkyl alkylthiophosphonates which are formed as separate products can be separated off in simple fashion.

The compounds of the formulae IV and V are known or can be prepared by methods known from the literature.

The examples which follow are intended to further illustrate the invention. •Ε 913297 - e Example 1 Allyl (IR,5S,6S)-6-[(IR)-tert.-butyldimethylsilyloxyethyl)-2-(methoxycarbonylmethylthio)-1-methylcarbapen2-em-3-carboxylate A solution of 1.0 g (2 mmol) of (3S,4S)-l-allyloxycarbonylcarbonyl-3-[(IR)-tert-butyldimethylsilyloxyethyl )-4-[(2R)-1-methoxycarbonylmethy1thio-1-oxopropyl]azetidin-2-one in 50 ml of dry xylene is heated to the boil, and 1.36 g (10 mmol) of diethyl methylphosphonite are added. After 15 minutes, the mixture is cooled, the solution is concentrated in vacuo, and the residue is chromatographed over silica gel (deactivated with 10% of water) using toluene:ethyl acetate (10:1). After the product fractions have been concentrated, a colorless, crystalline solid is obtained. Yield: 740 mg (78% of theory).

The compounds I listed in Table 1 were obtained analogously from the starting substances IV listed in Table 2 under the reaction conditions listed in Table 3. n iH u Q U M s O rCN <0 Table tert.-butyldimethylsilyl, Me = methyl - 8 3 £ (X Ο Γ(Ν ιη βΓ CN X I X) T3 * χΐ 8 Ο CO $ ίι -& <Ο <0 η - Τ I -Ο -ίο X Τ“ 05 £1 *” Ο Ν* co X X co «3* X CJ V ® Ξ . C <- co <· ° I Ο Ο ♦ σ> Ο ? § « ~ ω Ο CD ο CSI cn hCD CM CO o> LU c ο •Η •Μ <0 C •Η μ C Ο υ φ ι—ί Λ <Β Ε-< φ •Η IX ι χ •ο C C0 ό q.

X ο ω X CJ w χ X Ε ν· ιη r> ο αχ •Ο Ό c c co re co < < ιι s *-5 X o XI o ο ιη ιη X q s-z • o £ 3 iD I s N 9 X X in 00 CQ 1 o » m CQ “0 x‘ ··. < T3 co z—s < n N X n CM $ X II CM V CJ N 1 £ CD W c re CO CJ I CO m I » I E, X » N X rΌ Ό e re '« X oo •o c re ί T U X Ή o s • g X 2 re ε δ ι » εΐ 8 ί £ ί s * « 3 έ £ 9 x (0 <0 _ I x‘ CD JO o tn O P ο ΙΛ s X *· c -> L·. m wt· C T ΊΓ £ 5 m' i ?? i.

X- £ cj m X ο ιι X ο Μ X ο I <ν ο ζ I W X <0 Ο ό. '<Μ Ο ο CJ X ο ω □r o II X q X o X q X q g w -C.H, -CH,CH=CH, -TBDMS 0.10 (s, 6H, -SHOW; 0.90 (s, 9H.

-SiC(CH,W; 1.27 (d, J - 8 Hz, 3H, ω CJ co O r> CM OS X z os I CM Λ I c 0 •H p 10 _ C M P c 0 u at ι rσ> CM co V Λ Em Φ fM (X X Cd σ> Ul r\ ό·’ I m Ί- IO x •o co τ’ φ Ο X ±1 ι 9 CO u c E- co X . E i * CM T. W E r> CM 8 in .. ώ T in Q J ι C? CM o ri £ o' < Ξ· θ S .η Ο Ύ Ϊμ 9 g x ® - £ o O P . p v u o- m π X to 5S *ο si r a a? ® w o © 05 °> xl « · * * m X _ o ,_ ® 2 £5 42. o 5 9 c co »“ *« X a x‘ o CO S5 < r- *M X 9 co xl co 1 o 1 o CO x' w a £ o • X 8 υ χ' CM, co W £ h- X ο Ρ CO x‘ in fp ώ ί O δ1 I X5 C (0 in 42. s o' X o I 3< Ϊ 8 o co x‘ CO 1 x‘ ω im’ co X X 00 IM X ·> X I*.

R £ «0 c co © 5, ί ? CM, 7. CM 2 ? 9 «Μ J - 7and10 Hz, 1H, H-1); 4.22-4.45 (m, 2H, -CH-CH,); 4.52-4.70 (m, 2H, -ΟΟ,ΟΗ,-); 5.1-5.3 (m, 2H, -CHJ; 5.62-5.89 (m, 1H, -CH»); 7.3-7.4 (rn, 5H, aromatic H). ω Σ O EC ιw Σ o co H £ si X o X o in □r o II X X o ID §. Ν £ Ο r· (Ν X —Η ιη « t Is.

O) CN CO > UJ X σ> νί ιη οο ό <> χ ο ω χ co X W, ιη ο ο •ο C Q 1 X P TT - 5 in T3 C x' co x‘ 7 CM Ό a o co N co s. § ui X 00 N X o V CM 1» X II -} 00 II CO 11 43 ”3 £ TJ in “5 xiΞ s x* o p x“ σ> ο in · Ζ' £ a -. ο φ τ m Ρ ω Τ. £ <Ρ ιη X « Ν 2 χ cm Ε 8 ί κ Q CQ V) CO S ιη *=Κ « g * 8 J ο 3= cf y ο 3 CM 00 V ο> ο δ5 « χ CM Ο U (0 m _r < X S. in Ο Ι» (0 -ό W -ft □Γ ϋ ρ S ,09 (Ο £ Ν X r* η ω a CD Cl I CM X w φ (0 φ H 0. w o ffi H □f P II X P M X P X O* I 3f P co •ο C α CM Μ CM Η Λ -, ιη I X co ίο I X Ν X E* .. X* CM Λ-s X s-** ft υ 8 X E, •rl 4-> τ CM CO E O 5 X fsZ L. v CM11 in (0 -¾ £ o x' CO X P I in T E* XI in s X * 9 9 w l> x‘ in X* ώ b·’ £ i* £ Λ^ p X 3· CD r 1 co 2 8 1 b; •H 4J x“ O CM in u co -CH, -CH, -C,H, -CH2CH2SiMe, -TBDMS -0.05 (s, 9H, Si(CH,),); 0.11 (s, 6H.

-Si(CH,W; 0.78-0.87 (m. 2H, -CHjCHj-SKCH,),); 0.90 (s. 6H, -C(CH,)^; Oi g, (X O t— cm - N T XJ CM w ι· cj “3 3* o I X o i X* CJ N X rII -j d co rv cj a ID « I CM hσ> CM cn φ uj φ X) <0 Φ a ΓΟΟ .. ci X . - CM Ii X K 5 £ S r- * ό ii £ *** » -i CM X 11 X -J >(J * Ή X x § ε ε CO ° I ® έ CJ I— X g . 9. ~ E 1 X o 5 xi il 6 9 9” X CJ X χ OJ 6 £, N Ϊ O a ?S • TX* -¾ CO ~ 42- Q CM O O > V) Σ o H X o II X 9. x o .2? si S> ' ci X £ S < X 5i r* ¢4 -o ** « ii w δ ί CJ ·|S. —· sr •O UJ s ΐ ·ε ι J « ΙΛ co X .- E ο -τ» g ί! * S ~ £ £ ~ (D i 9 CJ CM ii 7. Si φ 9 X- Ο ί co B o u CO X‘ CJ r— £ z . CJ .«>N Ϊ o X xj ϋ S5 $ 42- o £ θ x S5 ω Σ o H □r o II X O N X o LL « X o Φ-CH-CHj); 3.08-3.3 (m, 3H, H-1andH-6); 4.20-4.33 (m, 2H, -CH-CH.andH-5); 4.58-4.79 (m, 2H, -COj-CH,-); 5.17-5.37 (m, 2H, -CHJ; X cw 5C u co ε o L ro CJ Q CJ O ΓCN CN X I h* σ> CM co Ο) LU c Ή P «0 C •H P c o υ u XI rt Φ i—l οr> X ό ™ ε ϊ ί > . in X Π •c- h~ 8 in υ •rt CD tn 3? O © d 1 © co ε o υ 1 $ CD m' o u b— o ω I ο d w o m CM X o II X o cw X o U_ w X φ ό cw .. Ύ Ο) ί tn. ό ν' X fN a •ο S ο CD ι X cw CD tN CD 4έ ο ο Ο Σ 05 X o II X q, X o z o I w X o* ώ. 9. J 8 ” c ώ ρ «ο τ, £· ιο ιη d _ _ 0 «Μ Ο y § h a X o 1 X 35 T- O _ ·γ1 C .fc. CO E o L CO in *. 5 in . - ® ?2 « x cw co X CW ό ω Ο CD 0.95 (2 χ S, 2 χ 9Η, 2 χ SJC(CH,),); 1.28 (d, J - 7 Hz, 3H, -CH-CH,); 3.10-3.40 (m, 3H, X. Ο I ο. w χ ο t ω Ο a X ο 0> LLJ 99999999999999 9 rσ> CM co LXJ rs CM Q) rH Λ fl Eh n Ό C a u O' a •H Ή fl cn S nf fill oc 999110999 IXII X Illi - xx^ a E fl X ω »-non mic ® σ> £! η v 5£ tert.-butyldimethyl silyl, Me = methyl I I I B ί 1 ι m I E4 I fN σι aupj-.o IT <£ Ca O OOOOOOOOOOOOOO J= ?????????????? U -0 TJ U U U Ό-0 ΤΪ ΊΟ-0 U U-σ Ό 33333333333333 ί Φ » Φ » Φ ΓΙω au ω ωοιο wuiu ο u σιυισι Η· ΗΦ ft α οι ο ΓΟ§ ΰο^§“ο^8οθ8ο | η ο Ο Tabelle 3 Reaktionsbedingungen fur die Zyklisierungsreaktion >5 3 3 3 3 Η 3 * 3 3 3 * I I I I V I I I I Η'χΗΧΜςΜ^ΜΜΗΗ'μ'}3 I—ί |—ι |—ι |—ι X· I—ι 3 Η Η Η 3 3 3 Φ Φ φ Φ Φ φΦφφφΦΦΦ 3333 3 222 φ φ φ φ Φ φ φ fB Μ Μ >< Μ CO ο Η· Φ r+ 83383883838888 α ί ΙΌ OOOOO ΑΟΟΦΟΟΟΟΟ 8&δί888^88&3&5ί 2? φ ο> ο Γ+ Η· Ο «oesaaasBississta —» *< <#> Η· — Φ - ST IE 913297 HOE 90/F 283K

Claims (6)

1. Patent Claims:

1. A process for preparing a carbapenem compound I in which: 5 R( 1) and R(

2. ) are hydrogen, (Cx-C 4 )alkyl, (Cj-C*)alkenyl, (Cj-CJ alkoxy, (C 4 -C 7 ) cyc loalkyl or (C 3 -C 6 )spirocyclyl, R(3) is hydrogen, (Cx-C 4 ) alkyl, (0χ-0χ 2 )alkylthio [where the alkyl groups are unsubstituted or mono- or disubstituted by hydroxyl, protected hydroxyl, 10 (Cx-C 4 ) alkoxy, (Ci-C 4 )alkyloxycarbonyl, (Cx-C 4 ) acyloxy, amino, (Cx-C 4 ) alkylamino, (Cx-C 4 )acylamino, thiol, (Cx-C 4 )alkylthio or heterocyclylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio [where the phenyl and heterocyclyl rings are unsubstituted 15 or mono- or disubstituted by hydroxyl, protected hydroxyl, carboxyl, (Cx-C 4 ) alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (Cx-C 4 )alkylaminocarbonyl, cyano, F, Cl, Br], (C 3 -C 6 ) cyc loalkyl, (C 3 -C 6 )cycloalkylthio, (C 5 -C e )oxacycloalkyl [saturated, mono- or 20 diunsaturated], (C 3 -C 6 ) oxocycloalkyl, (C 3 -C 6 )[ 1,1-bis- (Cx-C 3 ) alkyloxy]cycloalkyl, (C 3 -C 6 ) - [ (Cx-C 3 ) alkyl imino ] cyc loalkyl, (C 3 -C 6 ) - [ phenyl imino ] cycloalkyl, (C 3 -C 6 )-(hydroxyimino) cycloalkyl, (C 3 -C 6 )[ (C x -C 3 )alkyloxyimino]cycloalkyl, in which radicals 25 the cycloalkyl radical is unsubstituted or mono- or disubstituted by (Cx-C 3 )alkyl, by (Cj-Cj) alkoxy, by halogen or by methylene, and is saturated or can contain one or two double bonds, R(4) is hydrogen or a customary carboxyl protective group 30 which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R(5) is hydrogen or an alcohol protective group, which comprises reacting a compound of the formula IV *<3) IV in which X is oxygen or sulfur and R(l), R(2), R(3), R(4) and R(5) are as defined above with a trivalent organic phosphorus compound of the formula V R(8) in which R(6) and R(7) are (Cj-CJalkyl, allyl, benzyl or phenyl 10 which can be substituted by (Cj-C 3 ) alkyl or (Ci—C 3 )alkoxy, and R(6) and R(7) can be identical or different, and R(8) is (Ci-C*) alkyl, phenyl which can be substituted by (Cj-C 3 )alkyl or (C 3 -C 3 )alkoxy. 15 2. The process as claimed in claim 1/ wherein the compound IV is reacted with V in an organic solvent. 3. The process as claimed in claim 1, wherein the reaction is carried out between +50’C and +180’C. 4. The process as claimed in claim 1, wherein R(l) and R(2) are hydrogen, (Cj-CJalkyl, (Cx-CJalkenyl, (Ci-CJ alkoxy, (C 4 -C 7 ) cycloalkyl or (C 3 -C 6 )spirocyclyl, R(3) is hydrogen, (C 1 -C 4 )alky1, hydroxy (Cx-C 4 ) alkyl, 5 (Cx-Cg)alkylthio, phenyl, heterocyclyl, phenylthio, saturated or unsaturated (C s -C 6 )oxacycloalkyl, (C 4 -C 6 ) oxocycloalkyl, 3-hydroxyiminocyclobutyl,

3. - methoxyiminocyclobutyl and 3,3-dimethoxycyclobutyl, 10 R(4) is a carboxyl protective group selected from the group comprising allyl, p-nitrobenzyl and trimethylsilylethyl, R(5) is hydrogen or an alcohol protective group selected from the group comprising trimethylsilyl, dimethyl15 tert.-butylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxycarbonyl or

4. - nitrobenzyloxycarbonyl. - 19

5. A process as 1 claimed in claim 1, substantially as hereinbefore described and exemplified.

6. A carbapenem compound of the formula I given and defined in claim 1, whenever prepared by a process claimed in a preceding claim.