GB2065658A

GB2065658A - Azetidinone derivatives

Info

Publication number: GB2065658A
Application number: GB8040697A
Authority: GB
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1977-11-18
Filing date: 1979-01-31
Publication date: 1981-07-01
Also published as: GB2012766B; GB2065658B; GB2012766A; JPS5476570A; BE869503A; DE2839646A1

Abstract

Compounds of the formula <IMAGE> useful as intermediates in the preparation of beta-lactam structures can be obtained by reacting a penicillin having the formula: <IMAGE> with a compound R3COOH in the presence of trimethyl phosphite, where R2 is hydrogen or a protected amino or amido group; COOA is a carboxylic group or an ester or salt thereof; and R3 is an alkyl or aryl radical or a heterocyclic residue, to give a compound of formula: <IMAGE> The latter compound can be converted a into the intended compound of formula IV by successive isomerisation of the olefinic bond, oxidative cleavage of the olefinic bond to give an oxamide and hydrolytic removal of the oxalyl group to give the compound of formula IV.

Description

1

GB 2 065 658 A

1

SPECIFICATION

Improvements in or relating to azetidinones

10

This invention relates to processes for preparing azetidinonesand to new azetidinones obtainable by those processes. In particular, the invention relates to a new process for preparing functionalized azetidinones which are useful intermediates for the synthesis of known and new |3-lactam structures. Among the latter clavulanic acid (I) (described and claimed in the German patent application DOS 2.517.316) and 1-oxa-1-diethiacephalosporins (II) (described and claimed in the German patent application DOS.2.355.209 and in the Belgian patent 832.174) have shown inhibition of |3-lactamases and, respectively, a remarkable antibiotic activity.

10

T5

20

h h

J—N —

(I)

oh h h

COOH

h h

RNH*4—

cooh

00

15

20

The starting materials of the present invention are azetidinones having the formula (III) below, which compounds are the subject of our copending Patent Application No. 79 03290 (publication number 25 2012766A) the disclosure of which is incorporated herein by reference.

25

30

35

h h r2.

3 4

O

0

ii i I'll OCRg

#1 V

COO A

35,45

cm)

30

35

where R2 is hydrogen or a protected amino or protected amido group; COOA is a carboxylic group or an 40 ester or salt thereof; and R3 is an alkyl oraryl radical or a heterocyclic residue. The protecting moiety of the protected amino group can be any of these suitable for use in protecting amino groups of penicillins, for example phthaloyl, phenoxyacetyl, trityl or carbobenzoxy.

The protected amino or amido group is conveniently a phthalimido, benzamido, phenylacetamido or phenoxyacetamido group; for example:

45

50

55

(%H5)3 CNH, CeH5CONH, C£H£CHpCONH, C6H50CH2C0NHor

®rN

R3 can be substituted or unsubstituted. Where it is alkyl it preferably has one to six carbon atoms, for example methyl or ethyl; where it is aryl it can be, for example, a phenyl radical. Phenyl radicals of special interest are those having halogen substituents, for example mono - or other chloro-substituted phenyl radicals. Treatment of compounds (III) with a weak base in an aprotic solvent affords the conjugated esters (VI) (eq.2). o t1 f »

jittlH OCR3

40

45

50

55

'rt,u»OCR3

/

■NnA

cooa cooa

(eg. 2)

35, 4S

Cm)

35, 4s

(m)

2

GB 2 065 658 A

2

10

The weak base used in the above process is conveniently a tertiary amine, for example triethylamine. An example of a suitable aprotic- solvent is methylene chloride.

The compounds of formula VI where R2, R3and - COOA have the meanings ascribed to them above are, with one exception, new compounds. The exception is the compound where R3 is CH3 and R2 is C6HsO-CH2-CO-NH which has been previously reported among the products formed in the reaction of penicillin esters with mercury {[(> acetate [R.J. Stoodley and N.R. Whitehouse, J.C.S. Perkin 1,1974,181 J.

Compounds (VI) can be transformed into the simpler azetidinones (IV) which are the subject of the present invention by known procedures which effect oxidative cleavage oftheolefinic bond followed by hydrolitic removal of theoxalyl group in the resulting oxamides (VII) (eq.3) [J.H.C. Nayleretal., J.C.S. Chem.Comm., 1972,229 and J.C.S. Perkin 1,1976,447; R.D.G. Cooper et al., J. Am. Chem. Soc., 94,1021 (1972)].

10

15

H

RZ»

H ? I '"OCR3 *2—

COOA

O

, If HH11OCR3

(EQ.3)

15

20

35,45

w

35.45 (3ZIT)

3S.4S

(W

20

25 The processes exemplified in eqs. 2 and 3 can be performed so as to give good yields with no loss of 25

stereochemistry.

The compounds of formulae VII and IV where R2, R3 and A have the meanings ascribed in them above are,

with one exception, new compounds. The exception is the compound of formula IV where R2 is C6H50-CH2-C0-NH and R3 is CH3-.

3q Clavulanic acid structurally related racemic novel 1-oxa-1-dethia penam derivatives have been prepared 30 from the optically active (3S, 4S)-4-acetoxy-3-phenoxy acetamidoazetidin-2-one of structure (IV) (R2=C6H5—O—CH2—CO—NH, R3=CH3) [R.G. Alexander and R. Southgate, J.C.S. Chem. Comm. 7377,405]

and from racemic 4-acetoxy-azetidin-2-one of structure (IV) (R2=H, R3=CH3) [Belgian Patent No. 844.533; A.G. Brown, D.F. Corbett and T. Trefor Howarth, J.C.S. Chem. Comm., 1977,359].

35 Racemic 4-acetoxy-azetidin-2-one of structure (IV) (R2=H, R3=CH3) has been also used forthe synthesis of 35 known -lactam antibiotics [H.W. Schnabel, D. Grimmond, H. Jensen: Liebigs Ann. Chem. 1974,477; G.

Schmid, K.K. Prasad, T. Petrilzka; Helv. Chim. Acta, 59,2294 (1976)].

The following examples illustrate the preparation of compounds of formula IV in accordance with the invention (Examples 10-14) and compounds formed as intermediates during such preparation, the starting 4q compounds being the subject of the previously mentioned copending patent application No. 79 03290 to 40 which reference should be made for further details.

EXAMPLE 1

(3S,4Sj-1-( 1-methoxycarbonyl-2-methytprap-1-enyl)-4-acetoxy-3 (phthalimido}azetidin-2-one

45

50

55

COOMe cooMe

45

50

55

A solution of (3S,4S)-1-(1 °c-methoxycarbonyl-2-methylprop-2-enyl)-4- acetoxy-3 (phthalimido)azetidin-2-one (3.36 g, 8.7 mmole) dissolved in methylene chloride (80 ml) was treated with few drops of triethylamine.

3

GB 2 065 658 A

3

After standing overnight, the solvent was evaporated in vacuo to yield the title compound quantitatively as a colorless oil.

P.M.R. (CDCI3,8):

I.R. (CHCI3, cm-1) 10 M.S. (m/e):

CH,

2.12 (s,CH3—CO); 2.12 and 2.29 (s.

CH 3/

,C=C); 3.85 (s, COOCH3);

5.35 and 6.52 (d, J = 1.5, p- lactam protons); 7.82 (br, aromatic protons). 1780,1730.

386,344,326,231,189.

10

EXAMPLE 2

(3S,4S)-1-( 1-methoxycarbonyl-2-methylprop- 1-eny/)-4-acetoxy-3 (phenoxyacetamidojazetidin-2-one

15

20

11 H H H

0 u

11 H

H"

1—N

f'

COOMe u COOMe

25 The title compound was obtained with a procedure similar to that given in Example 9.

15

20

25

P.M.R. (CDCI3,5):

30

CH

2.02 and 2.25 (s, CH3-C=C); 2.11 (s, CH3CO); 3.77 (s, COOCH3);

4.56 (s, O-CH2-CO); 5.10 (dd, J = 8 and J = 1.5 cps, C-3 p-lactam proton); 6.23 30

(d, J = 1.5 cps, C-4 |3-lactam proton); 6.85 - 7.45 (m, N-H and aromatic protons).

EXAMPLE 3

35 (3S,4S)- 1-(1-methoxycarbonyl-2-methylprop- 1-enyl)-4-(2-chloro)benzoyloxy-3 (phenoxyacetamido)azetidin- 35 2-one

40

45

50

o o 9'- 0 0 9^~

UNI>

O f o

COOMe COOMe

The title compound was obtained with a procedure similar to that given in Example 9.

H3C

40

45

50

P.M.R. (CDCI3r 6): 55 I.R. (CHCI3, cm-1):

2.00 and 2.20 (s, CH3 -C=C); 3.72 (s, COOCH3); 4.50 (s, 0-CH2-C0);

5.18 (dd, J = 8 and J = 1.5 cps, C-3 fi-lactam proton); 6.53 (d, J = 1.5 cps, C-4 (B-lactam proton); 6.85 - 8.00 (m, N-H and aromatic protons).

3410,1785,1725,1700 55

4

GB 2 065 658 A

4

EXAMPLE 4

(3S, 4SJ-1-( 1-methoxycarbonyl-2-methyIprop- 1-enyl)-4(4-chforo)benzoyfoxy-3 (phthalimido)azetidin-2-one

10

15

0 >-nsA

O 1

cooMe

CL

COOMe

The title compound was obtained with a procedure similarto that given in Example 9.

H3C

20 P.M.R. (CDCI3,6):

I.R. (CHCI3, cm-1):

2.09 and 2.23 (s, CH3 -C=C); 3.74 (s, COOCH3); 5.46 and 6.67

(d, J = 1.5 cps, p-lactam protons); 7.15 - 7.90 (m, aromatic protons).

1790,1780,1725.

EXAMPLE 5

25 (3S, 4SJ- 1-methyloxafyl-4-acetoxy-3 (phthalimido)azetidin-2-one

10

15

20

25

30

35

30

35

(3S, 4S)-1-(1-methoxycarbonyl-2-methylprop-1-enyl)-4-acetoxy-3 (phthalimido) azetidin-2-one (1.93 g, 5 40 mmole) dissolved in methylene chloride (300 ml) was cooled down to -78°C and treated with a stream of 03 40 till saturation of the solvent occurred. An excess of sodium metabisulphite was added and the stirred mixture was allowed to reach room temperature naturally. Enough water to dissolve the salt was added, the organic layer was separated, washed with saturated NaCI solution (3 x 100 ml) and dried (Na2S04). The solvent was evaporated in vacuo to give the title compound as white crystals (Et20) in quantitative yield. 45 45'

P.M.R. (CDCI3,5): 2.16 (s, CH3CO); 3.94 (s, COOCH3); 5.48 and 6.72 (d,J = 2 cps, p-lactam protons); 7.82 (br, aromatic protons).

EXAMPLE 6

50 (3S,4Sj- 7-methyloxa/y/-4-acetoxy-3(phenoxyacetamido)azetidin-2-one 50

5

GB 2 065 658 A

5

The title compound was obtained as white crystals (Et20) with a procedure similar to that given in Example 5.

P.M.R. (CDCI3,5):

I.R. (CHCI3, cm"1): M.S. (m/e):

m.p.:

2.13 (s, CH3-CO); 3.93 (s, COOCH3); 4,58 (s, 0-CH2-C0); 4.77 (dd, J = 8 and J

= 2 cps, C-3 p-lactam proton); 6.69 (d, J = 2 cps, C-4 p-lactam proton); 6.80 - 5

7.60 (m, N-H and aromatic protons).

3440,1840,1770,1730,1700.

364,304,245,235,211.

121-3°C.

10

EXAMPLE 8

(3S, 4S)-1-methyloxalyl-4-(4-ch/oro)benzoyloxy-3(phenoxyacetamido)azetidin-2-one

"15

20

On On

^^-O-CH^-C-N H H P-ChQ)-CL Q-0-CHj-C-B.S I P"^"^3"CL

cooMe

"nY°

0 COOMe

10

15

20

25 The title compound was obtained with a procedure similar to that given in Example 5.

I.R. (CHCI3, cm-1): mp.:

3440,1830,1755,1730,1700. 53-5°C.

30 EXAMPLE 8

(3S,4S)-1-methyloxa/yl-4-(2-chloro)benzoyloxy-3 (phenoxyacetamido)azetidin-2-one

25

30

35

40

Fhhh f hhh g0-C^C-NHjlp-C{} <C>°-CH2"C-\M/"C0

0 X

coc

COOMe COOMe

The title compound was obtained with a procedure similar to that given in Example 5. ■45 P.M.R. (CDCI3, 6):

I.R. (CHCI3, cm

-1\.

50 EXAMPLE 9

(3S,4S)-1-methyloxalyl-4-(4-chloro)benzoyloxy-3 (phtalimidojazetidin-2-one

35

40

3.84 (s, COOCH3); 4.48 (s, 0-CH2-C0); 4.98 (dd, J = 8 and J = 2 cps, C-3 45 P-lactam proton); 6.78 (d, J = 2 cps, C-4 p-lactam proton); 6.80 - 7.90 (m, N-H and aromatic protons).

3430,1830,1755,1720,1700.

50

COOMe cooMe

6

GB 2 065 658 A

6

The title compounds was obtained with a procedure similarto that given in Example 5.

I.R. (CHCI3, cm'1): 1830,1780,1750,1725

5 EXAMPLE 10

(3S,4S)-4-acetoxy-3-(phthalimido}azetidin-2-one

10

15

10

15

COOMe

20 (3S,4S)-1-methyl oxalyl-4-acetoxy-3 (phthalimido)azetidin-2-one (1.8 g, 5 mmole) dissolved in methanol (40 ml) was treated with a catalytic amount of sodium methoxide. After few hours the resulting precipitate was filtered off, the filtrate was evaporated in vacuo and the residue triturated with Et20 and MeOH to afford more crystals. The combined precipitates were washed with cold ether and dried. The title compound was obtained in quantitative yield.

25

P.M.R. (CDCI3,6): 2.12 (s, CH2-CO); 5.37 and 6.12 (d, J = 1.5, p-lactam protons); 6.74 (br, N-H);

7.75 (br, aromatic protons).

I.R. (CHCI3, cm-1): 3430,1805,1785,1745,1730.

[a]D = -57.1° (CHCI3)

30 m.p.: 185-7°C

EXAMPLE 11

(3S,4S)-4-(4-chloro)benzoyloxy-3(phthalimido)azetidin-2-one

35

40

45

,°"0\=/'CL

C00Me

20

25

30

35

40

45

The title compound was obtained with a procedure similar to that given in Example 10. 50 P.M.R. (CDCI3,5):

I.R. (CHCI3, cm-1):

5.55 and 6.43 (d, J = 1.5 cps, p-lactam protons); 7.20-8.10 (m, N-H and aromatic protons).

3420,1800,1725

EXAMPLE 12

55 (3S, 4S)-4-acetoxy-3(phenoxyacetamido)azetidin-2-one

50

55

V O OO

^^O-CHr-C-N W « O-C-CH3 <Q^O-CH2-(!:-K J HpJ_CH£

COOMe

7

GB 2 065 658 A

7

The title compound was obtained as white crystals with a procedure similar to that given in Example 10.

P.M.R. (CDCIg, 6): 2.09 (s, CH3-CO); 4.47 (s, 0-CH2-C0); 4.86 (dd, J=8 and J=1.5, C-3

p-lactam proton); 5.87 (d, J = 1.5 cps, C-4 p-lactam proton); 6.70 - 7.63 (m, N-H and aromatic protons).

3420,1795,1745,1690.

LR. (CHCI3, cm"1):

10

15

EXAMPLE 13

(3S, 4S)-4-(4-chloro)benzoyloxy-3(phenoxyacetamido)azetidin-2-one

<£>'V-NO-CCL

"Ny0

cooMe cf

-KIH

10

15

20 The title compound was obtained as white crystals with a procedure similar to that given in Example 10. P.M.R. (CDCI3,5):

4.54 (s, 0—CH2-CO); 4.89 (dd, J = 8 and J = 1.5 cps, C-3 p-lactam proton); 6.05 (d, J = 1.5 cps, C-4 p-lactam proton); 6.70-7.90 (dd and m, N-H and aromatic protons).

25

30

35

EXAMPLE 14

(3S,4S)-4-(2-ch/oro) benzoyloxy-3(phenoxyacetamido)azetidin-2-one

O O CL O O CL

<Q)-0-CHp-C-K ^ H fife <^-°-CHp-C-S ^ y

|«N \*~ i»v

NH

20

25

30

35

40

I.R. (CHCI3, cm"1):

Claims

45 1. A compound of the formula: 50

3420,1785,1750,1690.

H H ' || k3-4 |^0cr3

cf

•NH

40

45

50

55

3S, 4-S

Civ)

55
2. A compound according to Claim 1, in which R2 is hydrogen or a protected amino group or a protected amido group and R2 is an alkyl or aryl radical or a heterocyclic residue but excluding those compounds in

60 which R3 is methyl and R2 is C6H50 - CH2-CO-NH and in which R3 is methyl and R2 is hydrogen. 60
3. A compound according to Claim 1, in which R2 is phenoxyacetamido.'
4. A compound according to Claim 1,2, or 3 in which R3 is methyl.
5. A compound according to Claim 1,2 or 3 in which R3 is a phenyl radical.
6. A compound according to Claim 5, in which R3 is a chloro-substituted phenyl radical.

65
7. A compound according to Claim 6, in which R3 is an o-chlorophenyl orp-chlorophenyl radical. 65

8

GB 2 065 658 A

8
8. The compound named in the title of any oneof Examples 10 to 14.
9. A process for preparing a compound as claimed in Claim ^substantially as described herein.
10. A process for preparing a compound as claimed in Claim 1, substantially as described in any oneof Examples 10 to 14.

5
11. A compound of formula IV obtained by the process of Claim 9 or 10.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1981. Published by The Patent Office, 25 Southampton Buildings, London, WC2A1AY, from which copies may be obtained.