CH623330A5 - Process for the preparation of cephalosporin derivatives - Google Patents

Description

The present invention relates to a method for producing new compounds with the structure:

r - nh

Cf ^ S

C00H-

(I)

C ^ COOH

wherein R1 is acyl, an ester or a non-toxic pharmaceutically acceptable salt thereof.

The esters of the compounds of the formula I include, for example, those with the group of the formula in which, when W is hydrogen, Z has the meanings (lower rig) alkanoyl, benzoyl, naphthoyl, furoyl, thenoyl, nitrobenzoyl, methylbenzoyl, halobenzoyl, Phenylbenzoyl, N-phthalamido, N-succinimido, N-saccharino, n- (low) -al-alkylcarbamoyl, (low) alkoxy, (low) alkylthio, phenoxy, carbalkoxy, carbobenzoxy, carbamoyl, benzyloxy, chlorobenzyloxy, carbophenoxy, Has carbo-tert-butoxy or (lower) alkylsulfonyl and when W is carbalkoxy, Z is carbalkoxy and, when W is phenyl, Z is benzoyl or cyano, or where W and Z taken together represent a 2-oxocycloalkyl radical, which contains 4 to 8 carbon atoms inclusive. In the preferred embodiment of the invention, R2 represents hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, p-nitrobezyl, β, β, β-trichloroethyl, 3-phthalidyl or 5-indanyl.

The stereochemistry of the bicyclic nucleus is that found in cephalosporin C.

For example, acyl (R1) includes, but is not limited to, the groups with the structures:

(I) RuCnH2nCO—, where Ru is aryl (carbocyclic or heterocyclic, cycloalkyl, substituted aryl, substituted cycloalkyl or a non-aromatic or mesoionic heterocyclic group and where n represents an integer from 1 to 4. Examples of these Group includes phenylacetyl, substituted phenylacetyl, for example fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, ß- (o-aminomethylphenyl) propionyl, o-aminomethylphenylthioacetyl, o-, m- and p-guanidinophenylacetyl, o- and p-aminomethylphenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methylphenylacetyl or hydroxyphenylacetyl, N, N-bis (2-chloro-ethyl) aminophenyl-propionyl, thien-2- and -3-acetyl, 4-isoxa- zolyl- and substituted 4-isoxazolylacetyl, 1-cyclohexenyl-acetyl, 2-aminomethyl-1-cyclohexenylacetyl, 1,4-cyclo-hexadienylacetyl, 2-aminomethyl-1, 4-cyclohexadienylacetyl, pyridylacetyl, tetrazocyclo-acetyl (other hetero-grylacetylacetyl) Type are in the US patents 3,819,623 and 3,516,997) or a sydnone acetyl group as disclosed in U.S. Patents 3,681,328,3,530,123 and 3,563,983. The substituted 4-isoxazolyl group can be a 3-aryl-5-methyl-isoxazol-4-yl group, the aryl group being, for example, phenyl or halophenyl, for example chloro- or bromophenyl. An acyl group of this type is 3-o-chloro-5-phenyl-5-methylisoxazol-4-yl-acetyl and another is that in which isoxazole is replaced by isothiazole, as disclosed in U.S. Patent 3,551,440 . Other acyl groups of this type include cyanoacetyl (and similar compounds disclosed in U.S. Patent 3,719,673), 3,5,7-triaza-l-azonia-l-ada-30 mantyl-acetyl (as in US -PS 3,720,669), m-aminopyridinium acetyl (as disclosed in U.S. Patent 3,757,013), om- and p- (2'-aminoethoxy) phenylacetyl (as disclosed in U.S. Patent 3,759,905 ), 4,5-dimethoxycarbonyl-l, 2,3-triazol-l-yl-acetyl or 4-cyano-1,2,3-triazol-l-yl-acetyl (as in US Pat. No. 3,821,206 disclosed), imidazole (1) acetyl (as disclosed in U.S. Patent 3,632,810), p-aminomethylphenylacetyl (as disclosed in U.S. Patent 3,382,241), o-aminomethyl-p-hydroxy-phenylacetyl (as in U.S. Patent 3,823,141), β- (o-aminomethylphenyl) propionyl (as disclosed in U.S. Patent 3,813,391), a-amino-2,4,6-cycloheptatrienylacetyl (as in U.S. PS 3,539,562) and lower alkoxycarbonyl tyl (as disclosed in US Pat. No. 3,557,104);

(II) CnH2n + iCO-, where n is an integer from 1 to 7. The alkyl group can be straight or branched and can

45 if desired interrupted by an oxygen or a sulfur atom or substituted for example by a cyano group. Examples of such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl, butylthioacetyl and trifluoromethylthioacetyl;

50

(III) CnH2n-1 CO-, where n represents an integer from 2 to 7. The alkenyl group can be straight-chain or branched and, if desired, can be interrupted by an oxygen or sulfur atom. An example of this is allylthioacetyl;

55

Rev

I.

(IV) RuOC -CO-

60 I.

Rw in which Ru has the meaning defined under point (I) and can additionally also mean benzyl, and in which Rv and Rw, f.5, which may be the same or different, each represent hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybu-

623 330

tyryl, benzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p-cresoxyacetyl and p-methylthiophenoxyacetyl;

(V)

Rev

RUS-C -CO-

Rw in which Ru has the definition given under point (I) and can additionally stand for benzyl, and in which Rv and Rw have the meanings given under point (IV). Examples of such groups include S-phenylthioacetyl, S-chlorophenyltioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl, and o-aminomethylphenylthioacetyl, p-aminomethylphenylthioacetyl (as disclosed in U.S. Patent 3,663methylacetyl) like in the FR-PS

2,194,417), 4-pyridylthioacetyl (as described in U.S. Patent

3,503,967) and heterocyclylmercaptoacetyl (as disclosed in U.S. Patent 3,627,760);

(VI) RUZ (CH2) mCO-, in which Ru has the meanings given under point (I) and can additionally also represent benzyl, Z represents an oxygen or sulfur atom and m represents an integer from 2 to 5. An example of such a group is S-benzylthiopropionyl;

(VII) RuCO-, in which Ru has the meanings given under point (I). Examples of such groups include benzoyl, substituted benzoyl (e.g. amino-benzoyl), 4-isoxazolyl and substituted 4-isoxazolylcarbonyl, cyclopentane carbonyl, sydnoncarbonyl, naphthoyl and substituted naphthoyl (e.g. 2-ethoxynaphthoyl), quinoxalinylalylcarbonyl and substituted quinoxylcarbonyl 3-carboxy-2-quinoxalinylcarbonyl). Other possible substituents for benzoyl include alkyl, alkoxy, phenyl or phenyl, which is replaced by carboxy, alkylamido, cycloalkylamido, allylamido, phenyl (lower) alkylamido, morpholino-carbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydro-pyridino, furfurylamido or N-furylamido -N-anilino is substituted or derivatives thereof, and such substituents can be in the 2- or 2- and 6-positions. Examples of such substituted benzoyl groups include 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylaminobenzoyl and 2-carboxy-benzoyl. If the group Ru represents a substituted 4-isoxazolyl group, the substituents can be as indicated under point (I). Examples of such 4-isoxazole groups include 3-phenyl-5-methylisoxazol-4-ylcarbonyl, 3-o-chlorophenyl-5-methylisoxazol-4-ylcarbonyl and 3- (2,6-dichlorophenyl) -5- methylisoxazoI-4-yl-carbonyl;

(VIII) Ru-C H-CO- or Ru-C H-CH2CO-,

Tetrazolyl, cyano, halogen, acyloxy (for example formyloxy or lower alkanoyloxy) or an etherified hydroxy group. Examples of such acyl groups include a-aminophenylacetyl, a-carboxyphenylacetyl, 2,2-dime-5thyl-5-oxo-4-phenyl-l-imidazolidinyl, a-amino-p-hydr-oxyphenylacetyl, a-amino-p-acetoxyphenylacetyl , a-Hydr-oxyphenylacetyl and a-formyloxyphenylacetyl, or other acyl groups of this type, as disclosed for example in US Pat. Nos. 3,812,116 and 3,821,017, and a-amino-2- or io-3-thienylacetyl (cf. U.S. Patent 3,342,677) and a-Amino-3- or -4- or -5-isothiazole acetyl (see U.S. Patent 3,579,506) and other a-amino and a-hydroxy heterocyclic acetyl groups, such as in U.S. Patent No. 5,492,667 U.S. Patent 3,821,207;

(IX)

R *

Ry_C -CO-

R2

wherein Rx, Ry and Rz, which may be the same or different, may each represent lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is triphenylcarbonyl;

25 y

II

(X) Ru — NH-C -, Ru has the meanings given under point (I) and can also mean hydrogen, lower alkyl or lower alkyl substituted by halogen and in which Y represents oxygen or sulfur. An example of such a group is Cl (CH2) 2NHCO;

35

(XI)

(CH2) n

.CH,

LCH,

C-CO-I

X

X

X

wherein Ru has the meanings given under point (I) and X for hydrazino, guanidino, ureido, thioureido and substituted thioureido as disclosed in US Pat. No. 3,741,962, allophanamido (as disclosed in US Pat. No. 3,483,188), 3-gu-anyl-l-ureido (see U.S. Patent No. 3,579,501), cyanamino (see U.S. Patent No. 3,796,709), amino, substituted amino (e.g. acylamido or a group formed by reaction of the amino group and / or group (s) of the 7-side chain with an aldehyde or ketone, for example formaldehyde, acetaldehyde, butyraldehyde, acetylacetone, methylacetoacetamide, benzaldehyde, salicylic aldehyde, acetone, methyl ethyl ketone or ethyl acetoacetate, hydroxy, Carboxy (as disclosed in U.S. Patents 3,282,926 and 3,819,601), esterified carboxy (as disclosed, for example, in U.S. Patent 3,635,961), triazolyl,

wherein X has the meanings given under point (VIII) above and n represents an integer from 1 to 4. An example of such an acyl group is 1-aminocycIo-hexancarbonyl;

45 (XII) aminoacyl, for example RwCH (NH2) - (CH2) nCO-, where n is an integer from 1 to 10, or H2N-CnH2nAr (CH2) mCo, where m is zero or an integer from 1 to 10 and n represents zero, 1 or 2, Rw represents a hydrogen atom or an alkyl, aralkyl or carboxy group or something as defined for the group Ru and wherein Ar represents an arylene group, for example p-phenylene or 1,4-naphthylene, represents.

Examples of such groups are disclosed in GB-PS 551 054 806. One group of this type is the p-aminophenylacetyl group. Other acyl groups of this type include those, for example o-aminoadipoyl, derived from naturally occurring amino acids and derivatives thereof, for example N-benzoyl-o-aminoadipoyl; "I (XIII) Substituted glyoxyl groups of the formula Ry • CO ■ CO-, wherein Ry represents an aliphatic, araliphatic or aromatic group, for example a thienyl group, a phenyl group, or a mono-, di- or tri-substituted phenyl group, where the substituents are, for example, one or more halogen atoms (F, Cl, Br or J), methoxy groups, methyl groups or amino groups, or a fused benzene ring, such as disclosed in U.S. Patents 3,546,219 and 3,573,294;

9

623 330

O

(XIV) H02C-CH- (CH2) 3-C-I

NH

I.

c = o i

OR16

wherein R16 is (lower) alkyl or an aralkyl group of the formula where n is an integer from 0 to 6 and R17 and R18, which are the same or different, each represent H, Cl, Br, F, N02, (low) alkyl or (low) alkoxy;

O

(XVI)

HO, C-CH- (CH2) 3-C -I

NH

10th

R-

, 17th

wherein R20 is a-halogen or a, a-dihalo-C2-C4-alk-anoyl, or wherein R20 is N-isobornyloxycarbonyl, as disclosed in U.S. Patent 3,819,619, or wherein R20 is the group of the formulas

R

where n represents an integer from 1 to 6 and R17 and R18, which are the same or different, each represent H, Cl, Br, F, NO 2, (lower) alkyl or (lower) alkoxy;

-C-N

20 h

X

R21 R22

or

-C-O-R23 II

O

O

(XV)

H02C-CH- (CH2) 3-C -I

NH

I.

c = o

I.

NH

I.

r19

wherein R19 is (lower) alkyl or a group of the formula

»17th

where R21 and R22 are each hydrogen, lower alkyl, phenyl, halophenyl, tolyl, lower alkoxyphenyl 25 or naphthyl, X is oxygen or sulfur and R23 is lower alkyl as disclosed in U.S. Patent 3,819,621, or wherein R20 is hydrogen (as in cephalosporin C);

(XVII) Ru-CH-CO-

I.

NH

I.

Y = C

I.

H-N-C-Z

II

X

35

"(CH,)

R

R

18th

where Ru has the meanings given under point (I), X represents oxygen or imino, Y represents oxygen or Schwe-45 fei and Z has the meanings (lower) alkyl, cycloalkyl having 3,5,6 or 7 carbon atoms, monohalogen ( lower) alkyl, dichloromethyl, trichloromethyl, (lower) alkenyl with 2 to 6 carbon atoms,

^ g> - (ck2) n- k3-çh} - (ch2> „- rh | j)

'2n-CJL, tuX, "Ç3. Li.

CH

3T

vn

Cr-

623 330

10th

(XVIII)

h3C

T

n

O

ch,

or Z-C -NH-CH.-CO-II

NH

wherein Ru has the meanings given under point (I) and Z has the meanings given under point (XVII) at-2o. Examples are disclosed in U.S. Patents 4,626,024 and 3,692,779;

Ru-C H-CO-I

S-C-R24 II

O

(XIX)

, n represents an integer from 0 to 3 inclusive and i5 each of the radicals R3 and R4 for hydrogen, nitro, di (low) al-kylamine, (low) alkanoylamine, (low) alkanoyloxy, (low-rig) alkyl ( including straight-chain and branched saturated. _,

Finally, aliphatic groups with 1 to 6 carbon atoms have the meanings given for Pu) ^ (J)), (lower) alkoxy, sulfamyl, chlorine, iodine, bromine, "0" and R "f nfd" sat Alky '' cycloalkyl, aryl or certain fluorine or trifluoromethyl. In preferred embodiments, examples are in the US "PS

Forms means Ru phenyl, p-hydroxyphenyl or 2- "° en art;

or 3-thienyl and Z represents 2-furyl or phenyl. Preferred according to the inventive method

Examples are compounds of the formula I, US Pat. Nos. 3,687,949 and 3,646,024, such as those in which R has the disclosed structure.

ch2nh2

-chgco-

ch2nh2

chgco-

ch2nh2

^ // s-chgco-

^, CH2NH2

o and chgchgco-ch - nh-

Further preferably prepared compounds of the formula I with the D configuration in the 7-side chain are those in which R1 has the following structures:

11

623 330

O-ç11-00-

n 'nh2

ch-

hch ^ C ^ -ÇH-

c1

co-

I?

H0 \ ÇHC0 ""

lîhg

I.

nh,

ko- ^ y — ch-co-

^ = ly ^ nh2

OCH-

hochg - / ^ y) —ch-co- ^ NHg b

- chco-NHg

. O

il / = \ ch ^ c-o-a a-chco-

\ '\ t1

L y — CHCO-

v-y K

cshjo-k y-chgçhco- ^ nh "

o nh,

ch_chco-

c. i nh,

(v — chco- ^ flHg

I.

chco-

NH.

or

Ol chco-

• s- ^ 2

Further preferably prepared compounds of the formula I with the D configuration in the 7-side chain are those in which R1 has the following structures:

y

H-CO-

I.

HC = 0

kjrr * - - ■ öj ch-co-I

Oh oh

623 330

12th

and wherein Y represents hydrogen, chlorine, bromine, fluorine, trifluorme. Further preferably prepared compounds of the formula I.

thyl, amino, nitro, hydroxyl, lower alkyl with 1 to 4 carbon atoms are those in which R1 has the following structures: lenstoffatomen or lower alkoxy with 1 to 4 carbon atoms.

CHgNHCH \\ // - evo-

• CHgNHCHj

"ch co ~ 2

CHgNHCHj

CHgCO-

^ PHgNHÇH ^

O

CH2C0-

CHgNHÇE ^ *

s-chgco-

chgnhçh.

A NlVCH2CH2C ° -

CHgNHQH ^

^^ - CHgCHgCO-

^ CKJmCE '—r "2 5

chgchgco-

O

CH, -NH-CH.

CT4? -

45

CH2CÙ- • (^ y-0-CHjTO-,

chgco-

J

, CI ^ C0-

chgco-cn n = .n '

/

N-CHgCO-

c0 or 0

NIL, o.

? @ ~ i

^ -CÎ ^ CO-n

13

623 330

o 0 chgnh-c-nh-c-z chgco-

0 o ayjH-Ü-NH-C-Z

HO

ö "s"

chgco-

0 • P

il n chjnh-c-nh-c-z 2

"s-chgco-

0 O chgnh-c-nh-c-z

-chgco-

0 o fl • Il ch2nh-c-nh-c-z

\ 3_CH2C0 "»

o 0

left 11

chgnh-c-nh-c-z

G-

CHgCHgCO-

O-

0 0 ii m chnh-c-nh-c-z

^ y - CHgCHgCO-

0 o chgnh-c-nh-c-z chgchgco-

or

0 0

1 If ciu-nh-c-nh-c-z where Z is for (lower) alkyl, cycloalkyl with 4,5,6 or 7 thyl, trichloromethyl, (lower) alkenyl with 2 to 6 carbon atoms

Carbon atoms, monohalogen (lower) alkyl, dichloro atoms,

45

gv) - (ch2) n-, (ch ^ n "'

'-o-,. &.

^, Cj. "'TJ.

623 330

14

fy

V'V.

! i!

CK "

K., • - ° H-

stands,

or

H ^ C

ay and each of the radicals R3 and R4 represent hydrogen, nitro, di (low forms Z represents phenyl, 2-thienyl, 3-thienyl, 2-fu-

rig) alkylamino, (lower) alkanoylamino, (lower) -alkanoyl-25 ryl or 5-nitro-2-furyl.

oxy, (lower) alkyl, (lower) alkoxy, sulfamyl, chlorine, iodine, further preferred compounds of formula I, with the

Bromine, fluorine or trifluoromethyl are available. In the most preferred D configuration in the 7-side chain are those in which R1 is the

Z is phenyl, 2-thienyl, 3-thienyl, has the following structures:

2-furyl or 5-nitro-2-furyl.

O-

"CH-CO-NH

i ii

0 = C-NH-C-Z

Ho / \ / V-CH-CO- ^ 'NH 0 "

i ii

0 = »C-NH-C-Z

CH-

in

0 = C-NH-C-Z

Cl

"07 / \\ _ CH-C0- H0-T_y-CH-C0 - \ = J KH 0 'NH o

I II <H

NH

0 = C-NH-C-Z

O-

—GH-CO-

¥ »0-C-NH-C-Z

CH-CO-

NH 0 '0-C-NH-C-Z

0

h / = \

CH ^ C-O-U /) - CH-CO-

^ NH 0

in

0 = C-NH-C-Z

O

-CH2CH-C0-

NH 0 I II 0 = C-NH-C-Z

15

ch2 ° ^ 5 "c

CHgCH-CO-NH O

i il

0 = C-NH-C-Z

O

—CH-CO-

or lîlH

i

• a

0 = C-NH-C-Z

where Z is (lower) alkyl, cycloalkyl having 4.5, 6 or 7 carbon atoms, monohalogen (lower) alkyl, dichloromethyl

O

\\ - cp-co-

NH 0 0 = i-NH-C-Z

• CH-CO-

t jj NH 0 I H 0 = C-NH-C-Z

623 330

thyl, trichloromethyl, (low) alkenyl with 2 to 6 carbon atoms,

- "5-q

R'— H- -tj— S-

* -0-, w-ÇX. ÇÎL.

ï

•H

CH,

0 ".

and each of the radicals R3 and R4 represents hydrogen, nitro, di (low) alkylamino, (low) alkanoylamino, (low) alk-anoyloxy, (low) alkyl, (low) alkoxy, sulfamyl, chlorine, iodine, bromine, Fluorine or trifluoromethyl. In the most preferred embodiments, Z represents phenyl, 2-thienyl, 3-thienyl, o? 2-FuryI or 5-nitro-2-furyl.

Further preferably prepared compounds of the formula I are those in which R1 is of the formula

H3c

1 ^ 3-

O

H02C-CH- (CH2) 3-C -

NH

c = o

OR "

623 330 16

in which R16 is (lower) alkyl or an aralkyl group, in which R19 is (lower) alkyl or a group pe of the formula of the formula r17, h17

10 r stands in which m represents an integer from 0 to 6 and in which R17 and R18, which are the same or different, each represent H, Cl,

Br, F, N02, (low) alkyl or (low) alkoxy.

Further preferably prepared compounds of the formula I are those in which m is an integer from 0 to 6 and Rn are those in which R1 of the formula is and R18, which are the same or different, in each case for H, CI, Br,

q F, N02, (low) alkyl or (low) alkoxy.

II

ho2c-ch- (ch2) 3-c-

nh 20

i c = o I

NH

| Further preferably prepared compounds of formula I.

r! 9 are such, where R1 has the following structures:

O-

ch-co-nh x y «= c-nh-fi-z ho-A ^ a- ch-co-

'nh x __ I II

y - c-nh-c-z ch-co-

nh x

• U y- c-nh-c-z

—Ch-co-nh x y =: c-nh-c-z

Cl ho-

V \

= i ch-co-

1 V

nh x Ii

-nh-c-z

!!

CH ^ C

vh h x

ii y »c-nh-c-z

ch-co-

W X y = c-nh-c-z

O-

choch-c0-

1 y

v ^ B y - c-nh-c-5

17th

623 330

CHjO

O

chgçh

-C0-

NH X r n Y = C-NH-C-Z

O

<jH-C0-

m x

Y ~ A-NH-C-Z

O-ÇH-C0-

or

NH *

^ 1 11

Y = C-NH-C-Z

U

-CH-CO-NH X

s <r i m

Y = C-NH-C-Z-

where X is oxygen or imino, Y is oxygen or iogen (low) alkyl, dichloromethyl, trichloromethyl, (low) -

Represents sulfur and Z has the meanings amino, (lower) alkenyl having 2 to 6 carbon atoms,

kyl, cycloalkyl with 4,5,6 or 7 carbon atoms, monoha-

r

(CH2) n-, K3 - ^ - (CH2) n- ^

«^ 0-. v-u-. u-.

O

CH-

0 "• q ~ -

or owns, and each of R3 and R4 is hydrogen, nitro, <>? Further preferably prepared compounds of the formula I di (lower) alkylamino, (lower) alkanoylamino, (lower) -alk- are those in which R1 on the alpha carbon atom is the D-configu-anoyloxy, (lower) alkyl, (lower) alkoxy, sulfamyl , Chlorine, ration and the formulas:

Bromine, iodine, fluorine or trifluoromethyl are available.

623 330

18th

W //

CH-CO-

t

NH

i

A

HO

Cl

HO

,. // \ N

OCH-

CH-CO-

i

NH

i

A

h0-o-

CHCO-

i

NH

i

A

- <Q> -ÇH-CO-,

NH

i

A

HIGHg- ^ n -CH-CO-NH

O

CHjC-O-

i

A

CHCO-

CHCO-

CHgCHCO-NH

CH3 ° A \

\\

CHgCHCO-NH

where A is for

S '

CL

O

CHCO-

t

NH

t

A

or

CHCO-

t

NH

i

A

in which Z is (lower) alkyl, cycloalkyl having 4,5,6 or 7 carbon atoms, monohalogen (lower) alkyl, dichloromethyl, trichloromethyl, (lower) alkenyl having 2 to 6 carbon atoms,

19th

623 330

o2n

~~ il fi il 1 1 fi "T 0J-> •

ch-

3 lì if n n

n n

f-ZA-

\\ // - J

n ch3

"3 ° [i and means n represents an integer from zero to 3 inclusive, and each of the radicals R3 and R4 represents hydrogen, nitro, di (lower) alkylamine, (lower) alkanoylamino, (lower) alk-anoyloxy, ( Lower) alkyl (including straight-chain and branched saturated aliphatic groups with 1 to 6 carbon atoms including), (lower) alkoxy, sulfamyl, chlorine, iodine, bromine, fluorine or trifluoromethyl.

Further preferably prepared compounds of formula I are those in which R1 is phenylacetyl, o-, m- and p-fluorophenylacetyl, o-, m- and p-nitrophenylacetyl, o-, m- and p-guanine-dinophenylacetyl, o -, m- and p-acetoxyphenylacetyl, o-, m- and p-methoxyphenylacetyl, o-, m- and p-methylphenylacetyl, o-, m- and p-hydroxyphenylacetyl, N, N'-bis- (2-chloroethyl ) -amino-phenylpropionyl, thien-2-acetyl, thien-3-acetyl, 4-is-oxazolylacetyl, 1-cyclohexenylacetyl, 1,4-cyclohexadienylacetyl, pyridylacetyl, sydnone acetyl, 3-o-chlorophenyl-5-methyl- isoxazol-4-yl-acetyl, cyanoacetyl, 3,5,7-triaza-l-azonia-l-ada-mantyl-acetyl, m-aminopyridiniumacetyl, o-, m- and p- (2'-aminoethoxy) phenylacetyl , 4,5-dimethoxycarbonyl-l, 2,3-triazol-l-yl-acetyl, 4-cyano-l, 2,3-triazol-l-yl-acetyl, imidazol- (l) -acetyl, m - And p-aminomethylphenylacetyl, a-amino-2,4,6-cycloheptatrienylacetyl, lower alkoxycarbonyl tyl, cyanoacetyl, hexanoyl, heptanoyl, octanoyl, butylthioacetyl, trifluoromethylthioacetyl, allylthioacet yl, phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybu-tyryl, benzyloxycarbonyl, 2-methyl-2-phenoxy-propionyl, p-cresoxyacetyl, p-methylthiophenoxyacetyl, S-phenylthioacetyl, S- Chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl, S-benzylthioacetyl, p-aminomethylphenyltioacetyl, cyanomethylthioacetyl, 4-pyridylthioacetyl, S-benzylthio-propionyl, benzoyl, isobyloyl carbonyl, benzobloyl carbonyl, aminobenzoyl Ethoxy-naphthoyl, quinoxalinylcarbonyl, 3-carboxy-2-quinoxalinylcarbonyl, 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methyl-

35 aminobenzoyl, 2-carboxybenzoyl, 3-phenyl-5-methylisoxazol-4-yl-carbonyl, 3-o-chlorophenyl-5-methylisoxazol-4-yl-carbonyl or 3,2 ', 6'-dichlorophenyl-5 -methylisoxazol-4-yl-carbonyl.

Further preferably prepared compounds of formula I are those in which R1 is

45

o z-s-ch2-c -

0 is where Z is amino (lower) alkyl, N- (lower) alkylamino- (lower) alkyl or N, N-di (lower) alkylamino (lower) -alkyl, or wherein R1 is

O

z-s-ch2-c-

where Z is aminophenyl, aminophenyl (lower) alkyl, N- (lower) alkylaminophenyl, N, N-di (lower) alkylaminophenyl, N- (lower) alkylaminophenyl (lower) alkyl, N, N-di (low) rig) -alkylaminophenyl (lower) alkyl, phenylamino (lower) -65 alkyl, phenyl (lower) alkylamino (lower) alkyl, substituted phenylamino (lower) alkyl or substituted phenyl (lower) alkylamino (lower) alkyl, wherein the substituted Phenyl as a group of the formula

623 330

Y1

20th

means where R3 is (lower) alkyl, (lower) alkenyl or (lower) alkynyl, or wherein R1 is r6

O

'R5-N \ ^ r4_n ^

c-s-ch2-c-

in which the radicals R4, R5 and R6 are each (lower) alkyl,

is defined in which X1 and X2 are the same or different and are selected from hydrogen, fluorine, chlorine, bromine, (lower rig) alkyl, (lower) alkoxy, nitro, amino, trifluoro, methyl and phenyl, or in which R1 for

0 ^ -

/ 7 ~ \ h.

n v s-ch0 ~ c-

10 represent (lower) alkynyl, (lower) alkenyl or (lower) cycloalkyl and in which R5 can also denote hydrogen, or in which R1 represents s-chg-c-

or where R1 is y 1 n

0

(chol n> -s-c3î2-c-

H

in which n has the meanings 1 or 2, or in which R1 is

O

II

z-s-ch2-c-

where Z is a radical of the formulas

3 © r

or

\ ©

O-

25 is where X is fluorine or chlorine, or wherein R1 is

X O

II II

30 B-C -S-CH2-C -

is where X is oxygen or sulfur, B is di (lower) alkylamino, where the alkyl group may be the same or different, piperidino, methylpiperidino, di-35 methylpiperidino, pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino, methylmorpholino, dimethylmorpho -lino, N '- (lower) alkylpiperazino, N' - (lower) alkylamethylpiperazino, N '- (lower) alkyldimethylpiperazino, trimethylenimino no, hexamethyleneimino or a radical of the formula

Ar- (CH2) n -N-I

R7

is where n is zero, 1, 2 or 3, R7 is (lower) alkyl and Ar is a radical of the formulas

.8th

r

8th

53-.-0-

or r

8th

[> -

represents, wherein R8 and R9 are each hydrogen, fluorine, chlorine, further preferably prepared compounds of formula I.

Bromine, (low) alkyl or (low) alkoxy. are those in which R1 has the formulas

21st

623 330

y? -

o ch-S-

I.

oh f

£ 3 ~ f-

HC = 0

where R3 and R4 are each hydrogen, chlorine, bromine, fluorine, iodine, nitro, (low) alkyl, (low) alkoxy, (low) al-kylthio, di (low) aIkyIamino, (low) alkanoylamino, (low) rig) alkanoyl or (lower) alkylsulfonyl.

Further preferably prepared compounds of formula I are those in which R1 of the formula

O

II

Ar C -

\ c ^

ch2

i nh2

VCH,

where Ar is for

0-.G-

or r5

v "

i

CH ^

where R3 and R4 are each selected from hydrogen and (lower) alkyl, or where R1 is where R5 and R6 are each hydrogen, fluorine, chlorine, methoxy or methyl and R3 and R4 are each hydrogen, 45 means bromine or chlorine. hc

Further preferably prepared compounds of the formula I 11

are those in which R1 represents ch, ~ c-

3 Ii n,

0

ii c-ch0-c-

m d, N

or where r1 is r'O

o n

ch-c-

b4

n.

0

ii c-ch0c- | i 2

50

55

or where R1 is

0

ii ch2c-

O

'c'

i x

where X is selected from hydrogen and (lower) alkyl, or where R1 is

623 330

22

n l

n.

/

o ii c-ch2-c-

N-R12

"N '

or n

il n

R12

0

ii c-ch0-c-

II 2

n or

13 r -c-

i

= n 0. il

^ n-ch-c-

'N

where R12 is hydrogen or (lower) alkyl, R13 is hydrogen, chlorine, bromine, iodine, fluorine, trifluoromethyl, (lower rig) alkyl, (lower) alkoxy, (lower) alkylthio, carboxymethoxy, (lower) alkylsulfonyl, phenyl , Benzyl, phenoxy, benzyloxy and radicals of the formula

Rl

R6

: n-c "h:

2n or

13 r -c Ii n

0

ii n-ch2-c-

means in which R5 and R6 each represent hydrogen, (lower) alkyl, phenyl, benzyl, cycloalkyl having 3 to 7 carbon atoms inclusive and, when taken together with the> N—, form a heterocyclic ring which is selected from pyrrolidino, piperidino , Morpholino, 1,2,5,6-tetrahydropyridino, N- (lower) alkyIpiperazino and hexamethyleneimino, and in which n represents an integer from zero to 3 inclusive, or in which R1 for ii

(/ \ s ch-c-

r

8th

or p? iirn = n, in which R7, R8 and R9 are each selected from hydrogen, nitro, di (lower) alkylamino, (lower) alkanoylamino, (lower) alkanoyloxy, (lower) alkyl, (lower) alkoxy, sulfamyl, chlorine , Iodine, bromine, fluorine and trifluoromethyl, X and X ', which are the same or different, each represent hydrogen, or in which R1 is

11

^ N N NX1

i I

N = N

where X represents a divalent radical which is selected from

45

\/ and V

50 wherein R3 'and R4 are each selected from (lower) alkyl, chlorine, bromine and the rest of the formula h.

is, wherein R10 and R11 are each selected from hydrogen, chlorine, bromine, iodine and methyl.

Further preferably prepared compounds of formula I are those in which R 'is

5

r -c -

4 ii "j3 * r -c .c-ït ^ x ^

0 c-c-

ii wherein R6, R7 and R8 are each selected from hydrogen, fluorine, bromine and chlorine, and R5 is selected from hydrogen, (lower) alkyl and the rest of the formula

23

623 330

c 11

• 13th

Ra ;?

12th

v wherein R9, R1 (I and R11 are each selected from hydrogen, fluorine, bromine and chlorine, and when the radicals R4 and R5 are bonded together to form a benzo group each represent vinyl, or wherein R1 is

£ 3

n.Ii15

> = Q- ° -

12th

R

13

n-

al2

jlo- ^

R15

12

$ 0

'13

T *

r1> °

N

a15

13

1 H

il4

11

c-

12 r

623 330

24th

13

r -c left

C.

R15

o ii c-c-

w2

or where R12 and R13 are each selected from nitro, (lower) alkyl, (lower) alkoxy, (lower) alkanoylamino,

Chlorine, bromine, iodine, fluorine, hydroxy, (low) alkylthio, cyclo-hexyl, cyclopentyl, cycloheptyl, (low) alkoxycarbonyl, mer-capto, (low) alkylsulfonyl, (low) alkanoyl, (low) alk-anoyloxy and the three radicals of the formulas in which n is an integer from zero to 3 including 40 and R20, R21 and R22 are each selected from hydrogen, fluorine, bromine, chlorine, iodine, trifluoromethyl, (lower) alkyl, (lower rig) alkoxy, hydroxy, nitro and amino, R14 is selected from hydrogen, (lower) alkyl and the rest of the formula

55

wherein R2 ", R21 and R22 have the meanings given above, R1-" "is selected from hydrogen and (low) alkyl, R16 is selected from hydrogen and R12 with the above definition, R17 and R18 are each selected from (low) alkyl, (low) alkoxy, chlorine, bromine, iodine, fluorine, cyclohexyl, cyclopentyl, cycloheptyl and the two residues of the formulas

20th

21st

22

and

20th

- 0-

wherein n represents an integer from zero to 3 inclusive and where R20, R21 and R22 are the definitions given above

and wherein R19 is selected from hydrogen and R17 as defined above, or wherein R1 is

25 623 330

in which R2y, R30 and R31 represent hydrogen, chlorine, bromine, iodine, trifluoromethyl, fluorine, methylsulfonyl, nitro, (lower) alkyl or (lower) alkoxy and in which R32 represents (lower) alkyl, or in which R1 represents

u3

c-

.24

where R23 and R24 are each selected from (lower rig) alkyl, (lower) alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, styryl, phenylethyl, phenylpropyl, fu-ryl, thienyl, naphthyl and a radical of the formula

• 26

0-R

35

or

28

wherein R26, R27 and R28 are selected from hydrogen,

Fluorine, chlorine, bromine, iodine, trifluoromethyl, (lower) alkyl, (lower 30 rig) alkoxy, nitro, methylsulfonyl, cyano, di (lower) alkylamino and methyl mercapto, or wherein R1 for r

29

R

35, in which R33 and R34 each represent hydrogen, chlorine, bromine, iodine, (lower) alkyl, (lower) alkoxy or trifluoromethyl and R35 represents (lower) alkyl.

40 Further preferably prepared compounds of the formula I are those in which R1 has the following structures:

.CH ^ rCH- ^ / chgco-

623 330

26

chgn-ch ^ ~~ ^

V \ // - S-CH2C ° -

ch2n = chax / y

4>

ch2ch2co- or ch2-n = ch l jlch j-

.ch,

"1

\\ // - ch2ch2co-

d-

CH2N = CHA \ / y ch2ch2c0- or

25 where A is -H or -OH.

Further preferably prepared compounds of the formula r -ch c = 0

v "

h5c ch5

■ c-

I.

c

II

0

ch

I.

■ n ^

n ii n ii

.n ch2

^ C-CHg-S-C.

C * N

c — oh tü ^ ooh ii

8th

are those in which R1 has the following structures:

w //

ch,

ho

J \

Cl ho- ^

oh

h0ch2 - <\ /)

ho-

a

<ta-CH2-, CH30-q.CH, -, <^> -

1

27 623 330

Further compounds of the formula I which are preferably prepared are those in which R1 has the following structures:

CH-CO- HO ^> .- CO-

!AROUND

HO

chj-ch ch5-ch

CH- Cl a a

M XV-CH-C0- HO- \ '7-CH-CO-

II II

CH ^ -CH • CH, -CH

3 3

H0CH2 "^ ~ ^ ÇH-CO- _ HO - ^" ^ \ - ÇH-CO-

n> 'n ch5-ch ch5-ch

0 _

", <tVch-CO-

\ 'N N *

ch ^ -ch ch ^ -ch

CH ^ C-0 3

AA_CH-CH2-CO- ^ CH ^ O- ^ J ^ ÇH-

n if

CH ^ -CH CH ^ -CH

q. «-» -, p_

H N

CH, ~ CH Ii "

3 CHX-CH

3rd

CH2-CO-

ol ch-co-

'S

II

CH ^ -CH

623 330

Further preferably prepared compounds of formula I.

28

0 ii

Ar-CHC-

a *

r5o I II

Ar-X-C-C-

Â6

are those in which R1 corresponds to the following formulas:

0

II

Ar-C-

R

8th

0

ii c-9

0

•• 10

c — rough x ii

Ar-NH-C-

7? ~ 0

o »« z-c-c-

Federation

, I 0

0

Ch

V-C-OH

te- -

x

11 11

R -NH-C-

wherein R4 is selected from hydrogen, amino, carbobenzoxyoxy, phenyl, fluorine, chlorine, bromine, iodine, hydroxy, (low) alkanoyloxy and (low) alkoxy, X is selected from oxygen and sulfur, R5 and R6 are each selected from Hydrogen, phenyl, benzyl, phenethyl and (lower) alkyl, R7 is (lower) alkyl, Ra and R9 are each selected from (lower) alkyl, (lower) alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, Phenethyl, phenylpropyl, furyl, thienyl, naphthyl and Ar-, R10 is selected from (lower) alkylamino, di (lower) alkylamino, cycloalkylamino with 3 to 7 carbon atoms including, allylamino, diallylamino, phenyl (lower) alkylamino, morpholino, (Lower) alkylamino, pyrrolidino, (lower) alkyl-pyrrolidino, di (lower) alkylpyrrolidino, N, N-hexamethyleneimino, piperidino, (lower) alkylpiperidino, di (lower) alkylpiperidino, 1,2,5,6 -Tetrahydropyridino, N- (low) alkylpiper-azino, N-phenylpiperazino, N- (low) -alkyl (n lower) alkylpi-perazino, N- (lower) alkyl-di (lower) -alkylpiperazino, furfurylamino, tetrahydrofurfurylamino, N- (lower) alkyl-N-

furfurylamino, N-alkyl-N-anilino and (low) alkoxyanilino, Z1, Z2 and Z3 are each selected from (low) alkyl and Ar, R11 is selected from (low) alkyl, (low) cycloalkyl, 15 naphthyl, benzyl, Phenethyl and

O

Ar-C-

and where Ar represents a monovalent radical of the following formulas:

12

30th

"-O

-12

40

and i »

ö-

45 wherein R'2, R13 and R14 are each selected from hydrogen, chlorine, bromine, iodine, trifluoromethyl, phenyl, (lower) alkyl and (lower) alkoxy, but only one group R can be phenyl.

The process according to the invention for the preparation of the compounds of the formula I, in particular the abovementioned preferred compounds and their non-toxic, pharmaceutically acceptable salts, is characterized in that a compound of the formula ri-nh-c »

(III)

COOH

wherein R 'is acyl, or a salt or an easily hydrolyzable ester thereof with a compound of formula IV

29

623 330

N N

I.

CH2 COOH

implements.

The process according to the invention consists in displacing the 3-acetoxy group of a 7-acylaminocephalosporanic acid (produced, for example, by replacing the 7-aminocephalosporanic acid thiolated in 3-position with 7-aminocephalosporanic acid in the acylation procedures described here and also reported elsewhere) by a thiol of the formula ci ^ cooh:

Subsequently, the protective groups present, for example on an a-hydroxy or a-amino group or the like or on the carboxyl group, or both, are removed. Such a 3-acetoxy group can be displaced by such a thiol in solution, for example in water, or aqueous acetone at a temperature of at least room temperature and preferably within the range of about 50 to 100 ° C in the presence of a mild base such as sodium bicarbonate , for example in the vicinity of neutrality, for example at a pH of about 6. An excess of the thiol is preferably used. The reaction product is isolated by carefully acidifying the reaction mixture, followed by extraction with a water-immiscible solvent. In order to provide some specific examples, which are not intended to be limiting, substituted or unsubstituted D-mandelamidocephalosporanic acids are described by the general or specific in J. Med. Chem., 17 (1), 34-41 (1974) and those therein cited references, described procedures are produced. As previously noted, the preparation of many other 7-acylamidocephalosporanic acids is described in the patent and scientific literature, for example in US Patent Class 260-243C.

When the organic carboxylic acid contains a functional group such as amino or hydroxyl, it is often desirable to first block (or protect) the amino or hydroxyl group, then to carry out the coupling reaction and finally to subject the compound obtained to a chemical removal of the protective group, ie subjecting the obtained compound to an elimination reaction of the protecting group.

In the context of the present invention, particular mention should be made of the antibacterial agents which are prepared by the acylation process described above, using the organic monocarboxylic acids or their acid chlorides or other equivalents which have hitherto been used for the acylation of 6-aminopenicillanic acid, for example in U.S. Patents No. 2,941,995,

2 951 839.2 985 648.2 996 501.3 007 920.3 025 290.

3 028 379.3 035 047.3 040 033.3 041 332.3 041 333.3 043 831.3 053 831.3 071 575.3 071 576.3 079 305.

3 079 306.3 080 356, 3 082 204, 3 093 547.3 093 633, 3 116 285.3 117 119, 3 118 877.3 120 512, 3 120 513, 3 130 514, 3 127 394, 3 140 282, 3 040 032, 3 142 673, 3 147 247.3 174 964.3 180 863.3 198 804.3 202 653, 3 202 654, 3 202 655, 3 210 337, 3 157 639, 3 134 767, 3,132,136; in GB-PSen 874 414, 874 416, 876 516, 876 662, 877 120, 877 323, 877 531, 878 233, 880 042, 880 400, 882 335.888 110, 888 552, 889 066, 889 069, 889 070 , 889 168, 889 231, 890 201, 891 174, 891 279, 891 586, 891 777, 891 938, 893 518, 894 247, 894 457, 894 460, 896 072, 899 199, 900 666, 902 703, 903 785, 904 576.905 778.906 383.908 787.914 419.916 097, 916 204, 916 205, 916 488, 918 169, 920 176, 920 177, 920 300.921 513, 922 278.924 037, 925 281, 931 567, 932 644, 938 066, 938 321 , 939 708, 940 488, 943 608, 944 417; in numerous BE-PSe, for example 593 222, 595 171, 597 857, 602 494, 603 703, 609 039, 616 419, 617 187 and in the South African patent applications, for example 60/2882, 60/3057, 60 / 3748.61 / 1649, R61 / 2751, 62 / 54.62 / 4920.63 / 1612 and 63/2423.

The term lower alkyl used here means straight-chain and branched-chain aliphatic hydrocarbon radicals having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl, 2-ethylhexyl, heptyl, decyl, and the like. When the term “(low)” is used as part of the description of another group, for example “(low) aIkoxy”, it refers to the alkyl part of such a group, which therefore, as before, in connection with “(low) alkyl” is described.

In the case of the compounds having a substituted amino group in the 7-side chain, it is often desirable that the compound with an unsubstituted (free or primary) amino group be made first and then this product with the appropriate reagent to make the final products of the above the definitions of the acyl groups under the corresponding points Vili, XVII and XVIII type explained.

The above salts include the non-toxic carboxylic acid salts thereof, including non-toxic metal salts such as the sodium, potassium, calcium and aluminum salts, the ammonium salt and substituted ammonium salts, for example salts with non-toxic amines such as trialkylamines including triethylamine. Procaine, dibenzylamine, N-benzyl-beta-phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, dehydroabietylamine, N, N'-bis-dehydroabietylethylenediamine, N- (low) alkylpiperidines, e.g. N-ethylpiperidine and other amines for the preparation of salts with benzylpenicillin and the non-toxic acid addition salts thereof (ie the amine salts) including the mineral acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate and phosphate and the organic acid addition salts such as the maleate, acetate, Citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate, mandelate, ascorbate and the like.

Also to be mentioned are the compounds (which are used either as intermediates or as metabolic precursors) in which the amino group is “blocked” by substituents such as 2-iodoethoxycarbonyl (GB-PS 1 349 673), tert-butoxycarbonyl , Carbobenzyloxy, formyl, o-nitrophenylsulfyl, ß, ß, ß-trich! Orethoxycarbonyl, 4-oxo-2-pentenyl-2, l-carbomethoxy-l-propenyl-2 and the like. Such blocking groups include in particular the ketones (especially acetone) and aldehydes (especially formaldehyde and acetaldehyde), which are disclosed, for example, in US Pat. Nos. 3,198,804 and 3,347,851, and the β-keto esters and β-diketones, which are described, for example, in US Pat U.S. Patent 3,325,479, which are disclosed in Japanese Patent

5

10th

15

20th

25th

30th

35

40

45

50

55

fto

(■ <>

623 330

30th

Publication 71/24714 (Farmdoc 47,321S) disclosed β-keto-amides.

The preferred esters of the cephalosporins of the formula I are the pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters. They are all useful intermediates for the production of cephalosporin with a free carboxyl group, and the first three compounds are also of interest because, when administered orally, they create different absorption rates and amounts and different concentrations of the active antibacterial agent in the blood and tissues.

As indicated previously, these five esters of 7-amino-cephalosporanic acid are each made by known methods. An excellent method of operation is that of US Pat. No. 3,284,451, in which sodium cephalothin is esterified by reaction with the corresponding active chlorine or bromine compound (for example phenacyl bromide, chloroacetone, chloromethyl ether, pivaloyloxymethyl chloride (also called chloromethyl pivalate), acetoxymethyl chloride) and then in which the thienylacetic acid side chain is removed enzymatically as described in the same patent or chemically as in U.S. Patent 3,575,970 and in Journal of Antibiotics, XXIV (11), 767-773 (1971). In another good method, the triethylamine salt of 7-aminocephalosporanic acid is reacted directly with the active halogen compound; see. see GB-PS 1 229 453.

These esters of 7-aminocephalosporanic acid are then reacted with the nucleophile HSR2 in the same manner as explained here for 7-aminocephalosporanic acid as such. The thiolated ester of 7-aminocephalosporanic acid is then coupled with the organic carboxylic acid, for example D - (-) -2-phenylglycine, as before. Before or after the removal of any blocking group, for example on an amino or hydroxy group in the 7-side chain, the ester of cephalosporin thus obtained, if not used per se, is converted into its free acid, including its zwitterion (and if desired, in any salt) by removing the esterifying group, for example by aqueous or enzymatic hydrolysis (for example with human or animal serum) or acidic or alkaline hydrolysis or by treatment with sodium thiophene oxide as described in US Pat. No. 3,284,451 and the penicillin series of Sheehan et al., J. Org. Chem. 29 (7), 2006-2008, (1964).

The intermediates of the structure used in the process according to the invention:

N

ii

HS-C

N »

CH,

N

ii

N

.COOH

IV

can be prepared, for example, by using the lithium derivative of a thiol of the formula in an anhydrous solvent

N II

HS-C.

• N II

"N CH-

produces and this lithium derivative is reacted with carbon dioxide, forming a product which is then hydrolyzed, whereby the compound of the formula

N

ii

HS-C

N II N

CHgCOOH

receives.

One application of the process according to the invention is to use starting materials of the formula

N

ii hs-c

■ N

II

N

IV

I.

CHjÇOOH

25 which were prepared by reacting an isocyanate of the formula

O

so Rioo_0_c -CH, N = C = S

vi in which R100 is alkyl having 1 to 6 carbon atoms, phenyl, phenylalkyl or substituted phenyl or substituted phenylalkyl, with sodium azide, the thiol ester of formula 35 being obtained from VII.

40

KS

N *

■ N

II

(VII)

N

N I

CH

co2r100

and hydrolysis of the thiolester obtained. Here n

II

hs-c

N

II

n

55

n

I.

ch

—Co2r

100

m> formed, in which R100 has the above definition.

In the treatment of bacterial infections in humans, the compounds produced according to the invention are administered parenterally or orally in an amount of about 5 to 200 mg / kg / day and preferably of about 5 to 20 mg / kg / day in a divided dose, for example three or two administered four times a day. They are administered in dose units which contain, for example, 125, 250 or 500 mg of active ingredient together with suitable physiologically tolerable carriers or excipients,

31

623 330

contain. The dose units are in the form of liquid 6. Anhydrous carbon dioxide gas is quickly bubbled in

Preparations such as solutions or suspensions. vigorous stirring for 15 to 30 minutes at an approximate ambient temperature (0 to 10 ° C) that is not higher than + 20 ° C. Starting materials 7 j) the white precipitate that forms is suitably

A. l-Carboxymethyl-5-mercaptotetrazol s nete way by filtering in an area with less

Moisture collected. The precipitate is washed with approximately 75 ml of tetrahydrofuran.

II II 8. The precipitate is in 250 ml of water (pH 8.5 to 9.5)

hs ~ (x> -n dissolved. There may be a second layer of tetrahydrofuran.

N io This can be done in a vacuum rotary evaporator (bath 50 ° C).

I will be removed.

chgcooh 9. The aqueous solution is adjusted to pH 1.6 to 2.0 with concentrated hydrochloric acid.

a) recrystallization of 1-methyl-5-mercaptotetrazole. The acidic aqueous solution is washed twice with 250 ml of i? Portions of ethyl acetate extracted. Each of the 250 ml ethyl acetate procedures • extracts is again extracted with 100 ml portions of water.

1.110 g of 1-methyl-5-mercaptotetrazole are mixed in 350 ml. The water extracts are discarded. The ethyl acetate boiling chloroform slurried. An almost extract (which is free of any layer of water) is obtained. filtered and combined.

2. The hot solution (50 to 60 ° C.) is quickly evaporated to dryness. 604 paper that measures 0.645 cm (1/4 inch) to 0.847 cm (1/3 inch).

packed filter aid ("Supercel"). The filter bed is with ®'e crystals in the flask with 300 ml of chloroform

Washed 50 ml of chloroform at 50 to 60 ° C, which boiled to the filtrate for about 2 minutes. The hot slurry (50 to is added 25 ^ 0 ° Q through a heated Buchner funnel (11 cm, SS

3. The filtrate is cooled to approximately 0 to 6 ° C and 2 ^ r. ^ 04 ^ aP'er) ™ vacuum filtered. The crystals are kept at 0 to 6 ° C. for one hour. The crystals that formed formed about 75 ml of chloroform washed at 50 ° C. The crystals are collected by filtration at 0 to 6 ° C and washed with 60 ml of chloroform from 0 to 6 ° C at room temperature for about 3 hours is added. The crystals (fraction A) are placed in air 30 0.074 mm (100 to 200 mesh).

Dried at 37 to 45 ° C for 18 hours. 13-The crystals with a size of 0.148 to 0.074 mm are made with boiling chloroform in exactly the same way

4. The filtrate is treated on a vacuum rotary evaporator as described in step 12) (the hot chloroform (bath 60 ° C.) concentrated to approximately half the volume removes the bulk of the unreacted 1-methyl-5-mer-This slurry is on Chilled 0 to 6 ° C and 2 hours at 35 captotetrazols). Yield approximately 45 to 50 g of crystalline

Maintained 0 to 6 ° C. The crystals are filtered off with 0 l-carboxymethyl-5-mercaptotetrazole. These crystals can be collected up to 6 ° C, containing 40 ml chloroform from 0 to C q Q2 0.05 mol l-methyl-5-mercaptotetrazole,

washed, which is added to the filtrate. The crystals (Frak- u Die from level 13) are with 250 ml ethyl

tion B) are dried in air at 37 to 45 C for 18 hours. ether slurried at room temperature for 3 to 5 minutes. The crystal fractions A and B are combined, the mixture being filtered. The insoluble constituents (0.5 to a yield of approximately 65% by weight... 5%) can contain a contaminating, symmetrical mercapto-

5. The filtrate from fraction B in stage 4) can be worked up twice as described in m trazol ketone of the structure assumed below: stage 4), an additional 15% yield being obtained.

b) Preparation of the disodium salt of l-carboxymethyl-5- 45 _____ q - jj mercaptotetrazol I I * II I •

.n - ch - c - ch - n

Operation: Q c c>

1,500 ml essentially dry and pure tetrahydro- |

furan in a 2 liter. Three-necked flasks with a stirrer are cooled to approximately 10 ° C. in a 50 ml sh-salt-acetone-ice bath.

Dry nitrogen gas is blown onto the surface of the liquid.

2,500 ml, 15.06% (1.6 n) butyllithium in hexane (Foote caution: this compound explodes at approx. 205 to mineral co.) Over a period of 10 minutes under dry 21 ° C

Nitrogen and added to the tetrahydrofuran with stirring. 55 15. The ether filtrate from stage 14) is cooled on a vacuum rota. The almost dissolved mass is cooled to - 5 to - 10C. tion evaporator (bath 50 ° C) evaporated to dryness. Offered

3. Forty-six four tenths of a gram (46.4 g) of 1-methyl- approximates 42 to 4 g of crystalline i-carboxymethyl-5-mercaptote-5-mercaptotetrazole (recrystallized as described above) which is approximately 0.01 to 0.05 in trazole Mol 1-methyl-5-mercapto-den in 200 ml essentially pure and dry tetrahytetrazole is obtained.

solved drofuran. If the solution is cloudy, it is filtered and 60

then cooled to 5 to 10 ° C. 16. The crystals are dissolved in 420 ml of absolute ethanol

4. The chilled solution of stage 3) becomes 10 (approximately 100 mg / ml). The solution is heated to 50-60 ° C min with stirring and under dry nitrogen.

Solution of the butyllithium added. The temperature should be at 17. For the hot solution of step 16) add 310 ml

- 5 ° C to a maximum of + 10 ° C. Fi5 41% solution of sodium 2-ethylhexanoate (SEH) can form in iso precipitates. propanol with very vigorous stirring over the course of 10 min.

5. The mixture is added under dry nitrogen at 0 ° C. A crystalline precipitate is formed. The mixture is stirred at + 10 ° C. for 2 hours. the mixture is slurried for 20 minutes at 50 to 60 ° C.

623 330

32

18. The mixture is filtered hot (50 to 60 ° C) through a heated Buchner funnel (11 cm, SS No. 604 paper). The crystals are washed with 75 ml of ethanol at 50 ° C.

19. The ethanol-moist crystals of stage 18) are slurried in 200 to 300 ml of ethanol. The slurry is passed through a sieve with a mesh size of 0.074 mm (200 mesh). The slurry is heated to 50 to 60 ° C. for 5 minutes with vigorous stirring (unconverted sodium l-methyl-5-mercaptotetrazole is very soluble in hot ethanol).

Improved procedure for the production of o- (2-amino-methyl-l, 4-cyclohexadienyl) acetic acid

CHgNHg

10th

^ —CHgCOgH

Li, tert. BuOH NH, -TEA • HCl '

20. The crystals are placed in a heated Buchner funnel on an 11 cm SS no. 604 paper collected at 50-60 ° C. The crystals are washed with 75 to 100 ml of ethanol and dried for 24 to 48 hours at 50 to 60 ° C. in vacuo. Yield: 40 to 48 g of disodium-l-carboxymethyl-5-mercaptotetrazole (according to the NMR spectrum free of l-methyl-5-mercaptotetrazole).

The other reagents used to prepare the compounds of Formula I are either synthesized as described in the prior art (e.g. in the aforementioned patents and publications) or are synthesized according to strictly analogous procedures. If, for example, a D - (-) -a-amino acid is used, it is used according to the procedures of US Pat. Nos. 3,198,804.3,342,677 or 3,634,418 or according to Friis et al., Acta Chem. Scand. 17, 2391-2396 (1966) or according to Neims et al., Biochemistry (Wash.) 5, 203 to 213 (1966) or in other publications on this subject. For the sake of simplicity and explanation, however, some specific examples of such syntheses for the production of carboxylic acids which contain a free amino group which is “blocked” with tert-butoxycarbonyl are described below.

Q-

ch2c02h + LiCI + (c2h5) 3n ch2nh2

20th

The Welch, Dolfini and Giarrusso designs are used in the c. 2- (tert-butoxycarbonylaminomethyl) -l, 4-cyclohexadien-nylacetic acid

A solution of 16.5 g (0.1 mole) of o-aminomethylphenyl acetic acid in 1.5 liters of liquid ammonia (which was treated with 50 mg of Li to remove a trace of moisture) is slowly tert with 500 ml of dry .-BuOH diluted. To the solution, 3.4 g (0.5 tom) of Li are added in small portions over the course of 4 hours, and the mixture is stirred for 16 hours at room temperature, the liquid ammonia being removed in a fume cupboard and finally evaporating below 40 ° c to dryness. The residue is dissolved in 500 ml of water and the solution is eluted on a column with IR-120 (H +, 700 ml) resin chromatographies and with 1% NH4OH solution. The ninhydrin-positive fractions of the eluate are pooled and evaporated to dryness. The residue is washed with four 50 ml portions of hot acetone and recrystallized from 500 ml of ethanol / water (1: 1), 11.2 g (67%) of colorless needles of o- (2-aminomethyl-l, 4- cycIohexadienyl) acetic acid with melting point 183 ° c.

IR spectrum: v ^ 1630.1520.1380.1356 cm "'.

NMR spectrum: j =

b D20 + K2C03 2.72 (4H, 2, H2C <^), 3.01 (2H,

s, CH2CO), 3.20 (2H, s, CH2-N), 5.78 (2H, s, H).

> =

Analysis C9H13HOt:

C "H N calc .: 64.65 7.84 8.38%

found: 64.77 8.06 8.44%

US Pat. No. 3,720,665 (Example 1) used method for the preparation of D-2-amino-2- (1,4-cyclohexadienyl) acetic acid. A solution of 830 ml of distilled liquid ammonia is dried with 40 mg of lithium under an argon atmosphere. 11.0 g (0.07 mol) of 2-amino-methylphenylacetic acid and 340 ml of tert-butyl alcohol are added to this stirred solution. A total of 1.6 g (0.225 mol) of lithium are added to the vigorously stirred solution over the course of 2 hours. The gray mixture is then treated with 35 g (0.215 mol) of triethylamine (TEA) 30 hydrochloride and stirred overnight at room temperature for 18 hours. The tert-butyl alcohol is removed at 40 ° C (15 mm), giving a white residue which is dried overnight over P205 in vacuo. The solid is dissolved in 30 ml 1: 1 methanol / water and with stirring 35 with 3.5 liters. 1: 1 chloroform / acetone at 5 ° C. The mixture is stirred for 20 minutes and the amino acid, a- (2-aminomethyl-l, 4-cyclohexadienyl) acetic acid, is collected and dried in vacuo over P2Os for 16 hours, 6.3 g (58%) being known Crystals with melting point 190 ° C (decomposition) 40 obtained. The IR and NMR spectra are consistent with the structure.

A solution of 19.31 g (0.135 mol) of tert-butoxycarbonyl azide in 152 ml of tetrahydrofuran (THF) becomes a stirred solution of 14.89 g (0.09 mol) of 2-aminomethyl-1,4-cyclo hexadienylacetic acid and 7.20 g (0.18 mol) sodium hydroxide in 281 ml water. The solution is stirred at 25 ° C. for 18 hours and then filtered through diatomaceous earth (Super-cel). The THF is removed at 40 ° C (15 mm) and the remaining solution is washed with twice 175 ml of ether and acidified with 6N hydrochloric acid (HCl). The mixture is then stirred in an ice bath, the precipitate is collected and dried in vacuo over P205 at 25 ° C. for 18 hours, 17.3 g (72.6%) of 2- (tert-butoxycaronylaminomethyl) -1.4 -cyclohexadienylacetic acid in the form of a white powder. The IR and NMR spectra are consistent with the structure.

D.D- (~) -p-Hydroxy ~ a-tert.butoxycarboxamidophenyleslacetic acid

5.65 g (0.14 mol) of magnesium oxide 60 and 11.7 (0.07 mol) of D - (-) - hydroxyphenylglycine are ground in a mortar and added to 177 ml of 50% dioxane. 20.0 g (0.14 mol) of tert-butoxycarbonyl azide are slowly added to the vigorously stirred mixture and the mixture is stirred at 45 to 50 ° C. for 20 hours.

Then the mixture is diluted with 710 ml of ice water and 177 ml of r> 5 ethyl acetate. The mixture is filtered and the filtrate is separated into two phases. The organic phase is washed three times with 50 ml of 3% sodium carbonate solution and three times with 50 ml of water. All water phases are combined, cooled

33

623 330

and with conc. Hydrochloric acid adjusted to pH 5.0. The NMR spectrum: ò ^ 11.58 (9H, s, t-butyl-H), 1.50-1.90 (4H,

The product is extracted with 3 X 125 ml of ethyl acetate. The m, -CH2-), 1.90-2.20 (4H, m, allylic methylene-H), 3.18

Ethyl acetate is washed with 2 X 50 ml of water, over Ma- (2H, s, CH2-CO), 3.78 (2H, d, 6 Hz, CH2-N), 5.00 (1H, br-s,

dried magnesium sulfate and then at 35 ° C / 15 mm to an NH), 8.98 (1H, br-s, COOH).

Evaporated oil. The oil is triturated with petroleum ether, 3

to D - (-) - p-Hydroxy-a-tert-butoxycarboxamidophenyles- Analysis C | 4Hi3N04:

Acetic acid in the form of a white solid. This product q H N

is collected and vacuumed over P205 at 25 ° C for 18 hours • 62.43 8.61 5.20%

dried, 13.5 g (72.2%) of whitish powder containing 62.12 8.77 5.37%

Receives melting point 102 ° C. The IR and NMR spectra are in agreement with the structure. G.2.tert.-Butoxycarbonylaminomethyl-4-hydroxyphenyles-

E. D - (-) - a-tert.-butoxycarboxamidophenylacetic acid acetic acid, for example according to US Pat. No. 3,823,141.

The procedure used is that of the departments previously used for the D - (-) - P-hydroxy-a-tert-butoxycarboxamido-H 0- (tert-butoxycarbonylaminomethyl) phenylthioacetic acid

phenylacetic acid used method. Two samples are obtained, for example according to US Pat. No. 3,657,232.

1, C 1; see. also U.S. Patent 3,813,390.

NMR spectra are consistent with structure L ß. / O-ftert.-ButoxycarbonylaminontethyO-phenylJ-pro-

f-2- (tert-Butoxycarbonylaminomethyl) -l, 2-cyclohexenylionic acid is, for example, according to US Pat. No. 3,813,391

acetic acid, also referred to as [2- (N-tert-butoxycarbonyl- f.

amino) methyl-l-cyclohexen-l-yl] acetic acid D - (-) - N-tert-butoxycarbonyl-2- (3'-methyl-4'-hydroxy-

a) a-il-itert.-Butoxycarbonylaminomethylj-IA-cyclohe- phenvl) elvein xadienyl] acetic acid (1), n "2- (3'-Meihyl-4'-hydroxyphenyl) -glycine

To a stirred solution of 8.0 g (0.048 mol) of a- (2- a solution of 59 02 (Q6 MoI) 75% i glyoxyic acid

^ Tr ^ y; ^ Cy ^^ eX uy) "eSSlgSaUTreU 3.8 g1 (n'f in 100 ml of water becomes a suspension of 54.6 g (0.5 mol) m 150 ml of water, a solution of 10 3 g 25 2. methyl henol and 140 ml concentrated ammonium hydroxide in

(0.072 mol) tert-butoxycarbonyl azide m 80 ml THF and stirred 400 ml of water added at room temperature. The tempera

Mix for 18 hours at room temperature. The tetrahydrofu- the mixture rises to 3r C. The mixture is stirred with ran (THF), removed under reduced pressure and the room temperature for 65 hours. The solution, which contains an initial solution, is washed with 2 × 100 ml of ether, with an R of 101 × is> acidified with 6N hydrochloric acid HC1 ^ and extracted with 3 × 100 ml of ether. The 30 adjusted to H 6 g> whereby the crystallization of the product combined extracts with water (2 x 100 ml) and is effected. The product is melted by stirring> washed with a saturated NaCl solution (100 ml), washed with Na2SO4 water and dried in vacuo over phosphorus pentoxide and evaporated to dryness. The oily back-dried, whereby 31.5 g (34.8%) of 2- (3'-methyl-4'hydro-stand is triturated with n-hexane, 10.5 g (82%) of xyphenyl) -glycine with melting point 196 to 199 ° C (decomposition)

n3 ° C6 'h "l Cr V ° n Compound (1) with melting point 35 obtained The infrared. and nuclear magnetic resonance spectra r a' are consistent with the desired product.

IR spectrum: v 3370.1715, 1640, 1530, 1280, 1160 cm "1. Literature: BE-PS 774 029 (Beecham Group Limited), 1972

(Farmdoc 27.122T); there a melting point of 205 to NMR spectrum is reported: ô ™ mcl '1.45 (9H, s, t-Bu-H), 2.73 (4H, s, 207 ° C).

-C = r 40

H2C ^), 3.16 (2H, s, CH2CO), 3.76 (2H, d, 6Hz, CH2N),

4.90 (1H, m, NH), 5.66 (2H, s, ^> C =), 10.6 (1H, br-s, analysis C9H „N03:

COOH).

45 members:

Analysis C14H21N04: found:

C H N found, correct

calc .: 62.90 7.92 5.24% yaw with respect to found: 63.13 8.21 5.26% 2.34% H20:

50

b) [2- (N-tert-butoxycarbonylamino) methyl-1-cyclohexene

1-ylj-acetic acid (2) D, L-N-chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) glycine

A solution of 1.33 g (5 mmol) of compound (1) [2- (N- A suspension of 20.2 g (0.112 mol) of D, L-2- (3'-methyl

tert-Butoxyarbonylamino) -methyl-l, 4-cyclohexadien-l-yl] -es- 4'-hydroxyphenyl) -glycine in 175 ml of water is mixed with 20% acetic acid in 10 ml of 3% ammonium hydroxide with palla; 5 Adjusted sodium hydroxide to pH 10.3, causing a solution of dium on activated carbon (10%, 0.2 g) at 2.81 kg / cm 2 (40 psi). The solution is cooled in an ice bath. One hydrates. In 3 hours the theoretical amount of hydrogen is added to 38.2 g (0.224 mol) of chloroacetic anhydride. The catalyst is removed and the filtrate and maintains the pH of the reaction mixture by adding acidified to pH 2 with dilute HCl and with 2 X 20% sodium hydroxide until no further change in pH

50 ml of ethyl acetate extracted. The combined extracts are determined w) at pH 10. The reaction mixture is stirred with 20 ml of water, dried with Na2SO4 and under a further 10 minutes in the cold. The reaction mixture is then evaporated under reduced pressure, acidifying 1.34 g of an oil with 6N hydrochloric acid to pH 2.0, which gives the mixture which solidifies on standing for several days. Recrystallizing the product is brought to crystallization. The solution is collected from n-hexane / ethyl acetate to give 1.2 g (90%) of compound product by filtration, washed with water and dried on (2) in the form of colorless prisms which are at 118 to 119 ° C. 5% of air. Recrystallization from 200 ml of hot water results in melting. 13.7 g (47.4%) D, L-N-chloroacetyI-2- (3'-methyl-4'-hydroxy-

phenyl) glycine. The infrared and nuclear magnetic resonance IR spectrum: v 3450.1730.1660.1510 errr '. spectra are in line with the desired product.

C.

H

N

h2o

59.66

6.13

7.73

%

57.68

6.23

7.47

2.34%

59.06

6.12

7.67

%

623 330

34

Analysis CiIHI2N04C1H, 0:

C H N

calc .: 47.92 5.118 5.081%

found: 48.11 5.16 5.15%

D - (-) -N-chloroacetyl-2- (3 'methyl-4' hydroxyphenyl) glycine

5.0 g (0.0194 mol) of D, LN-chloroacetyl-2- (3'-methyl-4'-hydroxy-phenyl) glycine and 6.1 g (0.0213 mol) of L-ephenaminace-tat dissolved in 50 ml of isopropyl alcohol by heating on a steam bath. 50 ml of water are added and the L-ephenamine salt crystallizes on cooling. The salt is collected by filtration and air dried.

The salt is suspended in 30 ml of water and 50 ml of methylene chloride and the mixture is adjusted to pH 10.0 with 20% sodium hydroxide. The phases are separated and the aqueous phase is extracted twice more with methylene chloride.

Then the aqueous solution is adjusted to pH 2.0 with 6N hydrochloric acid, causing the product to crystallize. The product is collected by filtration and dried in vacuo over phosphorus pentoxide, 0.9 g (36.1%) of D - (-) - N-chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) - glycine with melting point 170 to 172 ° C, [a] ^ =

185.9 ° (C 1; 95% EtOH). The infrared and nuclear magnetic resonance spectra are consistent with the desired product.

Analysis CnHi2N04CI:

C H N

calc .: 51.27 4.696 5.436%

found: 51.21 4.77 5.29%

1,2-diphenyl-2-methylaminoethanol, which is generally referred to as ephenamine (see Federai Register, June 7, 1951) has the structure:

NH

I.

CH.

The compound is also referred to as N-methyl-1,2-diphenyl-2-hydroxyethylamine or a, β-diphenyl-β-hydroxy-N-methyl-ethylamine or 1,2-diphenyl-2-methylamino-1-ethanol.

The present invention uses only the levo-erythro isomer. Processes for its preparation and reaction with penicillin G are described in U.S. Patents 2,645,638 and 2,768,081. The latter patent provides an overview of the previous literature, as W.B. Wheatley et al., J. Org. Chem. 18 (11), 1564-1571 (1953). It was developed by Sheehan et al., J. Am. Chem. Soc. 8JL, 3089-3094 (1959), cf. in particular page 3091, used for the separation of racemic phenoxymethylpenicillin.

D - (-) -2- (3-Methyl-4'-hydroxyphenyl) glycine

11.1 g (0.0431 mol) of D - (-) -N-chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) -glycine are combined with 100 ml of 2N hydrochloric acid and the mixture is held for 1.5 Hours at reflux. The solution is cooled and the pH is adjusted to 5.0 with 20% sodium hydroxide, causing the product to crystallize. The product is collected by filtration, washed with water and dried over in vacuo

Phosphorus pentoxide, 7.4 g (94.7%) of D - (-) -2- (3'-methyl-4'-hydroxyphenyl) glycine with a melting point of 205 to

209 ° C (decomposition), [et] ^ = - 152.6 ° (Cl; In HCl).

s The infrared and nuclear magnetic resonance spectra are consistent with the desired product.

Analysis CgH, iN03:

C H N H, 0 io calc .: 59.66 6.13 7.73%

found: 58.62 5.49 7.78 1.46%

found, correct 59.48 5.41 7.84%

regarding 1.13% H20:

15

D - (-) -N-tert. -Butoxycarbonyl-2- (3'-methyl-4'-hydroxyphenyl) glycine

To a slurry of 7.2 g (0.0397 mol) of D - (-) -2- (3'-methyl-4'-hydroxyphenyl) glycine and 3.2 g (0.08 mol) of powdered magnesium oxide, which stirred in 100 ml of 50% dioxane at room temperature, 9.7 g (0.068 mol) of tert-butoxycarbonyl azide are added dropwise. The reaction mixture is then heated to 42-45 ° C for 19 hours under a nitrogen atmosphere. Then the mixture is diluted with 25100 ml of ice water. The solution is overlaid with ethyl acetate and filtered to remove any insoluble material that has separated. The aqueous phase of the filtrate is separated off and extracted twice more with ethyl acetate. The aqueous solution is then adjusted to pH 30 5.0 with 42% phosphoric acid and extracted five times with ethyl acetate. The combined organic extracts are washed three times with water, dried over sodium sulfate and the solvent is removed under reduced pressure, leaving an oil. The oil is dried in vacuo over phosphorus pentoxide, 35.6 10.6 g (95%) of D - (-) -N-tert-butoxycarbonyl-2- (3'-methyl-4'-hydroxyphenyl) glycine receives. The infrared spectrum is in conflict with the desired structure.

K. D - (-) - N-tert-Butoxycarbonyl-2- (3 '-methoxy-4'-hydroxyphenyl) -glycine 40 2- (3'-methoxy-4'-hydroxyphenyl) -glycine

A solution of 59.2 g (0.6 mol) of 75% glyoxylic acid in 100 ml of water is added to a suspension of 62.07 g (0.5 mol) of 2-methoxyphenol and 140 ml of conc. Ammonium hydroxide in 400 ml of water added at room temperature. The temperature of the mixture rises to 35 ° C. The mixture is stirred at room temperature for 65 hours. The product which has crystallized is collected by filtration, washed with water, then with acetone and dried in vacuo over phosphorus pentoxide, 57.4 g (58.2%) of 2- (3'-methoxy-4'-hydr -5ooxyphenyl) glycine with melting point 218 to 220 ° C (decomposition) (literature: 240 ° C). The infrared and nuclear magnetic resonance spectra are consistent with the desired product.

55 Analysis C9H,, N04:

C.

54.82 53.77 54.38

H

5.62 5.91 5.85

N H2Ö

7.10%

6.97 1.13%

7.05%

calc .:

found:

found, corrected for 1.46% H2ö:

Literature: B. Block, Z. Physiol. Chem., 98, 226 (1917).

Separation of 2- (3'-methoxy-4'-hydroxyphenyl) glycine h5 A. Methyl 2- (3'-methoxy-4'-hydroxyphenylj-glycinate) A chilled suspension of 94 g (0.476 mol) 2- (3 '-Methoxy-4'-hydroxyphenyI) -glycine in 500 ml of absolute methanol is at high speed with HCl for 20 min

35

623 330

fumigated. First a clear solution is obtained and then the crystalline product is separated quantitatively. After 20 hours the methyl ester hydrochloride is filtered and washed extensively with methanol; 99.6 g of product are obtained after drying in air. A cooled solution of the hydrochloride in 800 ml of water is adjusted to pH 8 (NaOH), a crystalline precipitate of the free ester base being obtained; 81.3 g of product are obtained. The IR and NMR spectra are consistent.

Analysis CU1H13N04:

C H N H20 calc .: 56.88 6.20 6.63%

found: 56.46 6.28 6.55 0.59%

crystalline amino acid HCl salt collected by filtration. The salt is recrystallized from 75 ml in HCl, dissolved in 500 ml of water by heating, the solution is subjected to clear filtration and adjusted to pH 4.5 (NaOH), where-5 is caused by the crystallization of the zwitterion. The mixture is heated to boiling, filtered and stored in the cold to precipitate the crystalline product, L - (+) - 2- (3'-methoxy-4'-hydroxyphenyl) glycine. The product is collected by filtration, washed moderately with water and methanol, and dried at 40 ° C .; 9.6 g of product are obtained;

Wd4 ° = + 127.2 ° (Cl; In HCl).

The IR and NMR spectra are in unison with each other.

B. D - (-) -2- (3 '- Methoxy-4' hydroxyphenyl) glycine

A mixture of 50 g (0.237 mol) of methyl 2- (3'-meth-oxy-4'-hydroxyphenyl) glycinate, 19 ml (0.333 mol) of acetic acid and 1 liter of Iso-PrOH (isopropyl alcohol) are heated to the boil , giving a partial solution. 89.2 g (0.237 mol) of dibenzoyl-tartaric acid monohydrate are added with thorough stirring and the mixture is then kept at reflux. The salt will soon crystallize. Turn off the heat and let the flask cool slowly to room temperature. After cooling in an ice bath, the precipitate is collected by filtration. Concentrate the filtrate to about a third of its initial volume, giving a small second crop of salt; Total yield of both fractions 54.1 g after drying in air (solid A; see below).

The filtrate is concentrated until it is free of solvent. The viscous residue is combined with 300 ml in HCl and the mixture is extracted with 400 ml CHC13. The CHC13 phase is extracted twice with 100 ml portions in HCl. The combined HCl extracts are briefly concentrated to remove remaining CHC13 and are refluxed for 1 hour. The solution is concentrated to a small volume, causing the amino acid HCl salt to crystallize. The product is collected by filtration and recrystallized from 50 ml in HCl. A solution of the product in 200 ml of water is adjusted to pH 4.5 (NaOH). The mixture is heated almost to the boil and allowed to cool to precipitate the D - (-) -2- (3'-methoxy-4'-hydroxyphenyl) glycine as fluffy, needle-like crystals. After cooling overnight, the product is collected by filtration, washed moderately with water and methanol and at

40 ° C dried; 8.7 g [a] = -136.5 ° (Cl;

In HCl). The IR and NMR spectra are consistent.

Analysis C9HnN04 ■ H20:

C H N

calc .: 50.23 6.09 6.51

20 found: 50.53 6.06 6.62

h2o

8.37% 7.46%

Analysis C9H]] N04 • H20:

C H N

calc .: 50.23 6.09 6.51

found: 50.43 6.23 6.51

h2o

8.37% 9.95%

C. L - (+) - 2- (3'-methoxy-4'-hydroxyphenyl) glycine 54.1 g of the above solid A are suspended in 300 ml of HCl and 500 ml of CHCI3 with good stirring. In this system the salt does not dissolve immediately and therefore the CHC13 is separated as well as possible and 300 ml MIBK (methyl isobutyl ketone) are added with good stirring. The MIBK phase is extracted with a further 200 ml in HCl in three portions. The combined and filtered HCl extracts are briefly concentrated to remove remaining solvents and heated to reflux for 1 hour to hydrolyze the ester. The reaction mixture is concentrated to a small volume. After cooling in an ice bath, it will

D - (-) -N- (tert -butoxycarbonyl) -2- (3'-methoxy-4'-hydroxyphenyl) glycine

A mixture of 8.6 g (0.04 mol) of D - (-) -2- (3'-meth-25 oxy-4'-hydroxyphenyI) glycine, 3.2 g (0.08 mol) of magnesium oxide, 9.7 g (0.068 mol) of tert-butoxycarbonyl azide and 240 ml of 1: 1 dioxane / water are stirred and heated to 45 to 50 ° C. under a nitrogen atmosphere for 20 hours. The cooled reaction mixture is diluted with 240 ml of ice water, filtered and extracted once with ethyl acetate. The acidified (pH 2) aqueous phase is extracted five times with ethyl acetate. The combined and dried (Na2S04) ethyl acetate extracts are concentrated to remove solvents under reduced pressure, the product being obtained in the form of a viscous oil; Yield 6.3 g.

L. D - (-) -N-tert-butoxycarbonyl-2- (4-acetoxyphenyl) glycine

This compound is prepared by adding the D - (-) -2- (3'-methyl-4'-hy-40-hydroxyphenyl) -glycine used in the above procedure through an equimolar amount by weight of D - (-) -2- (4-Acetoxyphenyl) glycine, which is prepared in the following manner.

Preparation of D - (-) -2-Amino-2- (4-acetoxyphenyl) acetic acid-45 acid

Method A (in acetic acid as solvent)

203.5 g (1 mol) of D - (-) -p-hydroxyphenylglycine chloride, 800 ml of acetic acid and 314 g (4 mol) of acetyl chloride are stirred for 48 hours at room temperature. The solid is collected, 50 washed three times with acetone (3 X 250 ml) and twice with ethanol (2 X 250 ml) and dried at 40 ° C. The yield is 210 g (85.4%). This hydrochloride is dissolved in 3.0 liters of water, the solution is cooled to +5 to 10 ° C. and the pH is adjusted to 4.5 with 20% NH4OH. The suspension is stirred for 1 hour at 55 ° C., the solid is collected, washed twice with water and twice with acetone and dried at 40 ° C. The yield is 133 g (64%, starting from D - (-) -p-hydroxyphenylglycine).

cxD (1% HCl N / I0) = - 104.5.

60

Method B (in methylene chloride)

4.07 g (0.02 mol) of D - (-) -p-hydroxyphenylglycine hydrochloride, 30 ml of methylene chloride and 6.28 g (0.08 mol) of ace-65 tyl chloride are stirred for 48 hours at room temperature. The solid is collected, washed twice with acetone and twice with ethanol. The yield is 4.17 g (84.5%). Analysis: cl = 14.8% (calculated 14.4%).

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36

Method C (in trifluoroacetic acid)

1.67 g (0.01 mol) of D - (-) -p-hydroxyphenylglycine are added with stirring to 10 ml of trifluoroacetic acid at room temperature. After dissolution, 1.57 g (0.02 mol) of acetyl chloride are added. A solid appears after a slightly exothermic reaction. The suspension is stirred for 1 hour at room temperature and the trifluoroacetic acid is then removed in vacuo. The remaining solid is collected, washed with methylene chloride and with ethanol. The D - (-) -2-amino-2- (4-acetoxyphenyl) acetic acid is identical to the compound prepared by methods A or B. Yield: 1.9 g (75%).

M. D - (-) -N-tert-butoxycarbonyl-2- (l'-cyclohexenyl) glycine

This compound is prepared by operating the D - (-) -2- (3'-methyl-4'-hydroxyphenyl) glycine with an equimolar amount by weight of D - (-) -2- (1 '-Cyclohexenyl) glycine, produced according to BE-PS 773 773 (Farmdoc 25.515T) or according to US Pat. No. 3,824,237.

N. D - (-) -N-tert-butoxycarbonyl-2- (3'-chloro-4'-hydroxy-phenyl) -glycine is prepared, for example, as disclosed in U.S. Patent 3,489,751.

O. D - (-) -N-tert-butoxycarbonyl-2- (l ', 4'-cyclohexadienyl) glycine

This compound is prepared by operating the D - (-) -2- (3'-methyl-4'-hydroxyphenyl) glycine in the above procedure with an equimolar amount by weight of D - (-) -2- (l ', 4'-Cyclohexadienyl) glycine (also referred to as D-2-amino-2- (1,4-cyclohe-xadienyl) acetic acid), prepared according to US Pat. No. 3,485,819, was replaced.

P. D - (-) -2-tert-Butoxycarboxamido-3- (l ', 4'-cyclohexadienyl) propionic acid

This compound is prepared by operating the D - (-) -2- (3'-methyl-4'-hydroxyphenyl) glycine in the above procedure with an equimolar amount by weight of D-2-amino-3- (l , 4-cyclohexadienyl) propionic acid, prepared according to US Pat. No. 3,485,819, is replaced.

Q. D - (-) -2-tert-Butoxycarboxamido-3- (4'-methoxy-1 ', 4'-cyclohexadienyl) propionic acid

This compound is prepared by operating the D - (-) -2- (3'-methyl-4'-hydroxyphenyl) -gly-cin in the above procedure with an equimolar amount by weight of D-2-amino-3- (4th '-methoxy-l, 4-cyclohexadienyl) propionic acid, prepared according to US Pat. No. 3,485,819, is replaced.

R. 2-tert. -Butoxycarbonylaminomethylphenylacetic acid is produced, for example, according to US Pat. No. 3,766,175.

S. N-tert. -Butoxycarbonyl-1-aminocyclohexane carboxylic acid This compound is prepared by replacing the D - (-) -2- (3'-methyl-4'-hydroxyphenyl) glycine in the above procedure with an equimolar amount by weight of 1-aminocyclohexane carboxylic acid .

T. D - (-) -a-tert-butoxycarboxamido-3-thienylacetic acid is prepared, for example, in accordance with US Pat. Nos. 3,634,418 and 3,198,804 and in accordance with the corresponding literature references mentioned therein.

U. D - (-) -a-tert-butoxycarboxamido-2-thienylacetic acid is prepared, for example, in accordance with US Pat. Nos. 3,634,418 and 3,198,804 and the corresponding literature references mentioned therein.

V. \\ - (2-tert-Butoxycarbonylaminomethyl-l, 4-cyclohe-xadienyl) propionic acid a) $ - (2-aminomethyl-l, 4-cyclohexadienyl) propionic acid A solution of 10.74 g (60 mmol ) ß- (o-Aminomethyl-phenyl) propionic acid in 1000 ml of liquid ammonia (previously treated with approximately 50 mg of lithium to remove a trace of water), is carefully with 300 ml of dry tert-BuOH

diluted. 2.08 g (0.3 tom) of lithium are added to the solution in portions over the course of 3 hours, and the mixture is stirred overnight to remove the liquid ammonia and evaporated to dryness. The residue is dissolved in 200 ml of water. 5 The solution is chromatographed on a column with IR-120 (H + form, 500 ml) and eluted continuously with 2000 ml of water and approx. 2000 ml of 5% ammonium hydroxide. The ninhydrin-positive fractions are combined, evaporated to dryness and the residue is crystallized from 90% ethanol to give colorless needles. The yield of ß- (2-aminomethyl-1,4-cyclohexadienyl) propionic acid is 9.68 g (89%); Melting point = 228 to 229 C.

IR spectrum: v 2130.1540.1300 cm-1.

15

NMR spectrum: ô ^ ° 2.68 (4H, s, CH2CH2CO), 2.74 (4H, s, ring methylene), 3.68 (2H, s, CH2N), 5.79 (2H, s, ring vinyl) H). . Analysis C10H15NO2:

c

H

N

calc .:

66.27

8.34

7.73%

found:

66.25

8.35

7.61%

25th

66.31

8.52

7.71%

b) fi- (2-tert-butoxy carbonylaminomethyl-1,4-cyclohe-xadienyl) propionic acid

To a mixture of 1.40 g (7.7 mmol) of β- (2-aminome-30 ethyl-1, 4-cyclohexadienyl) propionic acid and 2.02 g (20 mmol) of triethylamine in 20 ml of 50% aqueous THF a solution of 1.43 g (10 mmol) of tert-butyl azidoformate in 5 ml of THF is added and the reaction mixture is stirred overnight at room temperature. The mixture is washed with 2 × 20 ml of ether 35 and the aqueous layer is acidified to pH 2 with dilute hydrochloric acid. The mixture is extracted with 4 × 30 ml of chloroform and the combined extracts are washed with water and dried. Evaporation of the extracts under reduced pressure gives ß- (2-tert.-butoxycarbonylaminomethyl-40 l, 4-cyclohexadienyl) propionic acid in the form of a colorless oil; Yield 2.10 g (97%).

IR spectrum: v [$, x 1700.1510, 1240, 1160 cm "1.

45 NMR spectrum: Ô ™ cl <1.47 (9H, s, t-Bu-H), 2.45 (4H,

s, CH2CH2), 2.69 (4H, s, ring methylene), 3.80 (2H, d, 5 Hz, CH2N), 5.70 (2H, s, ring vinyl-H).

W. ß- (2-tert-Butoxycarbonylaminomethyl-l-cyclohexe-50 nyl) propionic acid

0.92 g (3.2 mmol) of β- (2-tert-butoxycarbonylaminomethyl-l, 4-cyclohexadienyl) propionic acid are dissolved in 20 ml of 3% aqueous ammonium hydroxide and mixed with 0.1 g of 10% palladium Hydrogenated on activated carbon at 2.11 kg / cm 2 (30 psi) in 55 Parr apparatus for 3 hours. The mixture is filtered and the filtrate is acidified to pH 2 with dilute hydrochloric acid and extracted with 3 × 30 ml of ethyl acetate. The combined extracts are washed with a small amount of water and dried. Removal of the solvent w, under reduced pressure, gives the ß- (2-tert-butoxycarbonylaminomethyl-l-cyclohexenyl) propionic acid in the form of an oil; Yield 0.84 g (91%).

'IR spectrum: v ^, 3350 (NH), 3200-2400 (COOH), 1750 NMR spectrum: ô 1.48 (9H, s, t-Bu), 1.5-1.8 (4H, m ,

37

623 330

(CH2CH2), 1.8-2.2 (4H, m, allyl-CH2), 2.4 (4H, CH2CH2CO), 3.72 (2H, s, N-CH2).

X. D - (-) -N-tert-butoxycarbonyl-2- (4'-hydroxymethylphenyl) glycine

This compound, which is also referred to as D - (-) -N-tert-butoxycar-bonyl-p-hydroxymethylphenylglycine, is prepared in accordance with South African patent specification 73/4055; for the sake of simplicity, the relevant disclosure is given below.

To a solution of 50.0 g (0.373 mol) of 1,4-benzenedicar boxaldehyde in 200 ml of dry tetrahydrofuran (THF), 104.0 g (0.410 mol) of lithium tri- (tert. -butoxy) aluminum hydride, dissolved in 500 ml of dry tetrahydrofuran. After stirring for 1/2 hour in an ice bath, the reaction mixture is poured into 2 liters of ice-cold 2N hydrochloric acid. The aqueous solution is extracted with four 800 ml portions of ether. The combined ether layers are washed with 500 ml of ice-cold 5% sodium bicarbonate solution and then with 500 ml of saturated sodium chloride solution. After drying, the ether is removed under reduced pressure to give 46 g of crude p-hydroxymethylbenzaldehyde. The crude product is chromatographed over 1 kg of neutral aluminum oxide and the fractions are eluted with ether and concentrated. On cooling, 17.0 g (yield 35%) of p-hydroxymethylbenzaldehyde with a melting point of 44.5 to 46 ° C. crystallize out.

To a stirred mixture of 10.0 g (0.0735 mol) of p-hydroxymethylbenzaldehyde and 17.1 g (0.15 mol) of ammonium carbonate in 110 ml of 60% ethanol, which is heated to 50 ° C., is added dropwise 4.0 g (0.081 mol) of sodium cyanide, dissolved in 10 ml of water. The mixture is stirred and heated to 55-60 ° C for 3 hours and then the temperature is raised to 85 ° C for 1 hour. After cooling in an ice bath, the pH of the solution is increased by adding conc. Hydrochloric acid brought to 6. After cooling overnight, the precipitated solid is filtered, washed with cold water and dried. The 5- (p-hydroxymethylphenyl) hydantoin (11.0 g, yield 72%) with a melting point of 189 to 196 ° C. (decomposition) is used without further purification to prepare the amino acid.

A mixture of 10.9 g (0.053 mol) of 5- (p-hydroxymethylphenyl) hydantoin and 25.5 g (0.081 mol) of barium hydroxide (• 8 H20) in 125 ml of water is stirred and kept under reflux for 18 hours . After cooling in an ice bath, the reaction mixture is diluted with 125 ml of water. The solution is with conc. Acidified sulfuric acid to pH 1, the barium sulfate is filtered and the pH of the filtrate is adjusted to 6 with lead carbonate. After filtering the lead sulfate, the filtrate is saturated with hydrogen sulfide and the lead sulfide is filtered off. Then the aqueous solution is concentrated to 100 ml by azeotroping with ethanol under reduced pressure. After cooling, 5.2 g (yield 54%) of p-hydroxymethylphenylglycine with a melting point of 228 to 229 ° C. (decomposition) precipitated. After recrystallization from ethanol / water, the compound has a melting point of 230 to 231 ° C (decomposition).

The reaction mixture is washed twice with 200 ml portions of ether overnight at room temperature. The aqueous layer is covered with ether and acidified to pH 3-3.5 in an ice bath with 3N hydrochloric acid. The acidic solution is extracted three times with 200 ml portions of ether. The combined ether layers are washed with saturated sodium chloride solution, dried and the ether is evaporated under reduced pressure. The oil obtained is triturated with chloroform / hexane and the solid is filtered off, 7.74 g (yield 63%) of dl-N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine having a melting point of 139 to 141.5 ° C. (decomposition ) receives.

Analysis of C14H19NOs:

i5 C H N

calc .: 59.78 6.81 4.98%

found: 59.67 6.76 4.69%

7.560 g (0.0269 mol) of dl-N-tert-butoxycarbonyl-p-hydr-2o oxymethylphenylglycine and 10.199 g (0.0269 mol) of quinine are mixed and dissolved in 110 ml of boiling ethanol. The solution is allowed to cool to room temperature and crystallized overnight. The salt is filtered off and the crystallization is repeated three times.

25 The salt (17.76 g; melting point 198 to 201 ° C (decomposition), [a + jj - 149.8, (C = 1; CH3OH) gives the separated salt after three recrystallizations (4.6 g, melting point 205 to 206 ° C (decomposition), [a] - 163.4, (C = 1; CH3OH)).

30 Further recrystallization does not increase the optical rotation.

The (-) quinine salt of (-) -N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine is suspended in 75 ml of water and 175 ml of 35 ether in an ice bath and 3N hydrochloric acid is added to pH 2.5. The ether layer is removed and the aqueous layer is extracted twice with 100 ml portions of ether. The combined ether layers are washed with 100 ml of saturated sodium chloride, dried and the 4N ether is removed under reduced pressure. The residue is triturated with chloroform / hexane and filtered, giving 1.68 g (98% recovery) of D - (-) -N-tert.-butoxycarbonyl-p-hydroxymethylphenylglycine with a melting point of 111 to 113.5 ° C. ( Decomposition).

45

W d = - 136.5 (C = 1; CH3OH).

Analysis G, H | in O,:

C H N

calc .: 59.66 6.12 7.73%

found: 59.46 6.24 7.93%

6.95 g (0.049 mol) of tert-butoxycarbonyl azide, dissolved in 120 ml, are added to a solution of 8.0 g (0.044 mol) of p-hydroxymethylphenylglycine and 8.8 g (0.087 mol) of triethylamine in 160 ml of water Tetrahydrofuran. After stirring over

The use of an "en-anim" blocking group with a future 7-side chain containing a free amine group prior to acylation of a nucleus such as that of Formula II is known from U.S. Patents 3,223,141,3,813,390,3 813 391, 3 823 141 and BE-PS 773 773 are well known. For the sake of simplicity, some specific examples follow.

Sodium 2- [N- (l-carbäthoxypropen-2-yl) aminomethyl] -1, 4-cyclohexadienyl acetate (4)

3.34 g (0.02 mol) of 2-aminomethyl-l, 4-cyclohexadienylacetic acid and 3.1 g are added to a stirred solution of 460 mg (0.02 mol) of metallic sodium in 100 ml of absolute EtOH (0.024 mol) of ethyl acetoacetate and the mixture is heated to reflux with stirring for 4 hours. The hot reaction mixture is filtered and the filtrate is left in the cold overnight to give 2.0 g of colorless needles of compound (4) which melt at 264 ° C. 3.3 g of additional product are obtained by concentrating The total yield is 5.3 g (88%).

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38

IR spectrum: 3300, 1635, 1600, 1570, 1300, 1275, 11 170, 1090 cm "1.

NMR spectrum: ô 1.23 (3H, t, 7Hz, CH2CH3), 1.96 and

2.25 (3H, s, C = C-CH3, eis and trans), 2.70 (4H, s, H2C / =), 3.04 (2H, s, CH2CO), 3.66 and 3.95 (2H, s, CH2-N, eis and trans), 4.07 (2H, q, 7Hz, CH2CH3), 4.45 and 4.56

(lH, s, = "" H, eis and trans), 5.76 (2H, s, -) 1

^ r

Analysis C15H2oN04Na:

C H N

calc .: 59.79 6.69 4.64%

found: 59.69 6.76 4.75%

Sodium D-N- (2-methoxycarbonyl-l-methylvinyl) -a-amino-a- (3'-methyl-4'-hydroxyphenyl) acetate

To a stirred solution of 3.02 g (0.078 mol) of NaOH in 320 ml of methanol is added 0.08 mol of D - (-) -2- (3 '~ methyl-4'-hydroxyphenyl) glycine and the mixture obtained is heated to reflux while adding a solution of 9.6 ml (0.088 mol) of methyl acetoacetate in 80 ml of methanol over 30 minutes. After refluxing for a further 30 minutes, the methanol is distilled off, while methanol is added at the same rate in order to keep the internal volume approximately the same. When the internal temperature reaches 100 ° C, the suspension is cooled in ice water for 4 hours, filtered, washed well with toluene, air-dried and dried to a constant weight over P205 in vacuo, solid sodium-DN- (2- methoxycarbonyl-l-methylvinyl) -a-amino-a- (3'-methyl-4'-hydroxyphenyl) acetate is obtained.

Sodium D-N- (2-methoxycarbonyl-l-methylvinyl) -a-ammo-a- (3'-methoxy-4'-hydroxyphenyl) acetate

To a stirred solution of 3.02 g (0.078 mol) of NaOH in 320 ml of methanol is added 0.08 mol of D - (-) -2- (3 '-methoxy-4'-hydroxyphenyl) -glycine and the mixture obtained is heated to reflux while adding a solution of 9.6 ml (0.088 mol) of methyl acetoacetate in 80 ml of methanol over 30 minutes. After refluxing for a further 30 minutes, the methanol is distilled off while toluene is added at the same rate in order to keep the internal volume approximately the same. When the internal temperature reaches 100 ° C, the suspension is cooled in ice water for 4 hours, filtered, washed well with toluene, air-dried and dried in vacuo over P205 to constant weight, with solid sodium DN- (2- methoxycarbonyl-l-methylvinyl) -a-amino-a- (3'-methoxy-4'-hydroxyphenyl) acetate is obtained.

The same use of a proton as a protecting group, such as in an acid chloride hydrochloride, is also well known and can be explained as follows.

Filter D - (-) -2- (3'-methoxy-4'-hydroxyphenyl) glycyl chloride hydrochloride to collect the product. The filter cake is washed with dioxane and methylene chloride and then dried in a vacuum desiccator over P2Os, giving 5 about 7 g of D - (-) -2- (3'-methoxy-4'-hydroxyphenyl) glycyl chloride hydrochloride.

Preparation of D - (-) - 2-Amino-2- (4-acetoxyphenylacetylchloride hydrochloride) Ul 83.6 g (0.40 mol) D - (-) -2-Amino-2- (4- acetoxyphenyl) acetic acid with 1.25 liters of anhydrous methylene chloride are cooled with stirring to -5 ° C. 152 g of phosphorus pentachloride are then slowly added, followed by 4 ml of dimethylformamide, and the mixture is stirred for 4 hours at 0 ° C. Collect the solid, wash with anhydrous methylene chloride and dry in vacuo at room temperature, yield 61 g (57.5%).

Analysis: total chlorine = 27.2% (theory 26.9%).

2 »Production of D-mandelic carboxyanhydride.

COCl2

25th

30th

C6H, -C H-COOH

i

OH

c6h5 "

Y

0

2nd

D-mandelic carboxy anhydride (2)

Phosgene is bubbled through a solution of 2.0 g (0.013 mol) of D - (-) -mandelic acid (1) in dry tetrahydro-, 5 furan for 30 min. The solution is left to stand overnight and after this time it is heated to reflux for 10 minutes. Evaporation of the solvent under reduced pressure gives an oily residue, which is solidified by trituration with 20 ml of n-hexane. The product is collected by filtration and dried over KOH in a vacuum. The yield is 2.3 g of D-mandelic acid carboxyanhydride.

IR spectrum: v 1895, 1875, 1780, cm "1.

Among the most active compounds according to the invention, those with the D configuration at the a carbon atom in 45 of the 7-side chain, i.e. the compounds prepared from D-2-phenylglycine or D-mandelic acid or a monosubstituted D-2-phenylglycine or D-mandelic acid, as will be explained here. In addition, the configuration at the two optically active asymmetric centers in the β-Lac-50 tamkern corresponds to that of the cephalosporin C produced by fermentation and that of the 7-aminocephalosporan derived therefrom

acid.

D - (-) -2- (3'-methoxy-4'-hydroxyphenylj-glycylchloride-hydrochloride is produced with high purity and very effectively according to the following procedure:

Approximately 0.06 mol of D - (-) -2- (3'-methoxy-4'-hydroxyphenyl) glycine is slurried in 100 ml of dioxane. The slurry is stirred and COCl2 (phosgene) is bubbled in while maintaining the temperature of the slurry at 50 to 58 ° C (W). The COCl2 is introduced for a total of 3.5 hours. A yellow solution is obtained. The solution is flushed with nitrogen to drive off excess COCl2. HCl gas is bubbled through the solution for 2.5 hours. The solution is stirred and a small amount is mixed with a little ether ,, 5

diluted to obtain some crystals which are added to the batch as seed crystals. The solution is stirred for 16 hours at 20 to 25 ° C. The resulting slurry of crystalline

The following examples serve to explain the present invention. All temperatures are given in ° C. 7-aminocephalosporanic acid is abbreviated as 7-ACA; -ACA- means the unity of the structure:

c - cho -

cooh

39

623 330

O

and thus 7-ACA can be represented as H-ACA-O-C -CH3. Methyl isobutyl ketone is called MIBK. "Skel-Iysolve B" is a petroleum ether fraction with a boiling point of 60 to 68 ° C, which consists essentially of n-hexane.

LA-1 resin is a mixture of secondary amines, wherein each secondary amine of the formula

R1

CH, (CH2) 10CH2NHC -R2 I

R3

15

in which each of R1, R2 and R3 is a monovalent aliphatic hydrocarbon radical and in which R1, R2 and R3 contain a total of 11 to 14 carbon atoms. This special mixture of secondary amines, which is sometimes referred to in the examples as “liquid amine mixture No. II”, is a clear, amber-colored liquid with the following physical characteristics:

Viscosity at 25 ° C: 70 cpd;

specific gravity at 20 ° C: 0.826;

Refractive index at 25 ° C = 1.4554; 25th

Distillation range at 10 mm: up to 170 ° C 0.5%;

170 to 220 ° C 3%; 220 to 230 ° C 90%; and above 230 ° C

6.5%.

IR-120 is called Amberlite IR-120 and is a strong cation exchange resin that contains sulfonic acid residues. 30 Amberlite IR-120 is a commercially available polystyrene sulfonic acid type cation exchange resin; it is thus a core sulfonated polystyrene resin that is crosslinked with divinylbenzene and is obtained according to the procedure of Kunin, Ion Exchange Resins, 2nd edition (1958), John Wiley and Sond, Inc.

Vergi, there for example pp. 84 and 87.

Sodium 7-cyanoacetamidocephalosporanate,

Sodium 7- (1-tetrazolylacetamido) cephalosporanate, sodium 7-trifluoromethylthioacetamidocephalosporanate, sodium 7- (a-azidophenylacetamido) cephalosporanate, sodium 7-sydnon-3-acetamidocephalosporanate, sodium 7-nano-chloroate. Sodium 7-bromoacetamidocephalosporanate,

how to get:

7-phenylacetamido-3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (2-thienylacetamido) -3- (l-carboxymethyltetrazol-5-yl-thio-methyl) -3-cephem-4-carboxylic acid,

7- (3-thienylacetamido) -3- (l-carboxymethyltetrazol-5-yl-thio-methyl) -3-cephem-4-carboxylic acid,

7- (4-pyridylthioacetamido) -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid, 7-cyanoacetamido-3- (l-carboxymethyltetrazol-5-yl-thiomethyl) - 3-cephem-4-carboxylic acid,

7 - (1-tetrazolylacetamido) -3- (1-carboxymethyltetrazole-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7-trifluoromethylthioacetamido-3- (l-carboxymethyltetrazole-5-

yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (a-azidophenylacetamido) -3- (l-carboxymethyltetrazole-5-

yl-thiomethyl) -3-cephem-4-carboxylic acid,

7-sydnon-3-acetamido-3- (l-carboxymethyltetrazol-5-yl-thio-

methyl) -3-cephem-4-carboxylic acid,

7-chloroacetamido-3- (1-carboxymethyltetrazole-5-yl-thiomethyl) -3-cephem-4-carboxylic acid or 7-bromoacetamido-3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3 -cephem-4-carboxylic acid.

example 1

7-phenoxyacetamido-3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid by thiolating 7-phenoxyacetamidocephalosporanic acid

0.27 mol of sodium 7-phenoxyacetamido cephalosporanate is suspended in 1000 ml of 0.1 M phosphate buffer of pH 6.4, to which 0.31 mol of disodium l-carboxymethyl-5-mercaptote-trazole is added. The solution is heated to 55 ° C for 5 hours under a nitrogen atmosphere. After 1 hour the pH is adjusted to 6.4 by adding a small amount of 40% H3P04. At the end of the 5 hour heating period, the solution is cooled to 23 ° C and the pH is adjusted to 2 by adding 3N HCl under a layer of ethyl acetate. The product is extracted into ethyl acetate and stirred for 15 minutes at 23 ° C. with 2 g of decolorizing activated carbon (“Darco KB”). Then, filter through a bed of diatomaceous earth ("Celite") and remove the ethyl acetate under vacuum, leaving an oil which is triturated to a solid with diethyl ether, collected by filtration and dried over P2Ö5 under vacuum, giving solid 7-phenoxyacetamido -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid is obtained.

Example 2

If, in the procedure of Example 1, the sodium 7-phenoxyacetamidocephalosporanate is replaced by an equal amount of:

Sodium 7-phenylacetamidocephalosporanate, sodium 7- (2-thienylacetamido) cephalosporanate, sodium 7- (3-thienylacetamido) cephalosporanate, sodium 7- (4-pyridylthioacetamido) cephalosporanate,

Example 3

7- [Da-amino-a- (p-hydroxyphenyl) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid 35 by thiolating 7- [Da- tert-Butoxycarbonylamino-a- (p-hydroxyphenyl) acetamido] cephalosporanic acid, followed by unblocking.

A. 7- [a-4-Hydroxyphenyl) -a-D- (tert-butoxycarbonylamino) acetamido] -3 - (1-carboxymethyltetrazole-5-yl-thiome-

40 thyl) -3-cephem-4-carboxylic acid

0.27 mol of sodium 7- [a- (4-hydroxyphe-nyl) - <xD- (tert-butoxycarbonylamino) -acetamido] -cephalosporanate is suspended in 1000 ml of 0.1 ml of phosphate buffer of pH 6.4 , to which are added 0.31 mol of disodium l-carboxymethyl I-5-mercaptotetrazole 45. The solution is heated to 55 ° C for 5 hours under a nitrogen atmosphere. After 1 hour the pH is adjusted to 6.4 by adding a small amount of 40% H3P04. At the end of the 5 hour heating period, the solution is cooled to 23 ° C and the pH is adjusted to 2 by adding 3N HCl under such a layer of ethyl acetate. The product is extracted into ethyl acetate and stirred for 15 minutes at 23 ° C. with 2 g of decolorizing activated carbon (“Darco KB”). Then it is filtered through a bed of diatomaceous earth ("Celite") and the ethyl acetate is removed under vacuum, leaving an oil which has been triturated to a solid with 55 ethyl ether, collected by filtration and dried over P2Ö5 in vacuo, giving solid 7- [a- (4-Hydroxyphenyl) -aD- (tert-butoxycarbonylamino) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid.

60

B. 7- [D-a-Amino-a- (p-hydroxyphenyl) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid

0.1 mol of 7- [a- (4-hydroxyphenyl) -aD- (tert-butoxycar-65bonylamino) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid are dissolved in 30 ml of trifluoroacetic acid at 5 ° C. The mixture is allowed to come to 23 ° C. and stirred for a further 30 min. This solution is slowly added with vigor

623 330

like to pour stirring in 1000 ml of anhydrous ethyl ether. The precipitate is collected by filtration, washed with 100 ml of ethyl ether and dried in vacuo over P205. Then it is dissolved in 75 ml of H20 and, after stirring for 30 minutes at 23 ° C., the solids are filtered off. 2 g of decolorizing activated carbon (“Darco KB”) are added to the filtrate and, after stirring for 10 minutes at 23 ° C., the slurry is filtered through a “Celite” bed. The pH of the filtrate is adjusted to 4 by adding triethylamine and the solids are filtered off. The filtrate is evaporated to an oil under high vacuum and triturated with acetonitrile. The product, 7- [Da-amino-a- (p-hydroxyphenyl) acetamido] -3- (l-carboxymethyltetrazole-5-yl-thiomethyl) -3-cephem-4-carboxylic acid is collected by filtration and collected air dried.

Example 4

In the procedure of Example 3, the sodium 7- [a- (4-hydroxyphenyl) -aD- (tert-butoxycarbonyl-amino) -acetamido] cephalosporanate is replaced by an equimolar amount by weight of cephalosporanic acid, which can be obtained, for example, by acylating 7 ACA was obtained in the usual way with the following compounds:

2- (tert-butoxycarbonylaminomethyl) -1, 4-cyclohexadienyl-acetic acid,

D- (-) -a-tert-butoxycarboxamidophenylacetic acid,

2- (tert-butoxycarbonylaminomethyl) -l, 2-cyclohexenylacetic acid

acid,

2-tert-butoxycarbonylaminomethyl-4-hydroxyphenylacetic acid,

o- (tert-butoxycarbonylaminoethyl) phenylthioacetic acid,

ß- [o- (tert-butoxycarbonylaminomethyl) phenyl] propion-

acid,

D - (-) - N-tert-butoxycarbonyl-2- (3'-methyl-4'-hydroxyphenyl) glycine,

D - (-) - N-tert-butoxycarbonyl-2- (3'-methoxy-4'-hydroxyphenyl) glycine,

D- (-) -N-tert-butoxycarbonyl-2- (4-acetoxyphenyl) -glycine, D - (-) - N-tert-butoxycarbonyl-2- (l'-cyclohexenyl) -glycine, D- ( -) -N-tert-butoxycarbonyl-2- (3'-chloro-4'-hydroxyphenyl) glycine,

D- (-) -N-tert-butoxycarbonyl-2- (l ', 4'-cyclohexadienyl) glycine,

D - (-) - 2-tert-butoxycarboxamido-3- (l ', 4'-cyclohexadienyl) propionic acid,

D - (-) -2-tert-butoxycarboxamido-3- (4'-methoxy-l ', 4'-cy-clohexadienyl) propionic acid,

2-tert.-butoxycarbonylaminomethylphenylacetic acid, N-tert.-butoxycarbonyl-l-aminocyclohexane carboxylic acid, D - (-) -oc-tert.-butoxycarboxamido-3-thienylacetic acid, D - (-) -a-tert.-butoxycarboxamido-2- thienylacetic acid, ß- (2-tert-butoxycarbonylaminomethyl-l, 4-cyclohexadienyl) propionic acid,

ß- (2-tert-Butoxycarbonylaminomethyl-l-cyclohexenyI) -propionic acid or

D- (-) -N-tert-butoxycarbonyl-2- (4'-hydroxymethylphenyl) glycine,

so you get

7- (2-aminomethyl-l, 4-cyclohexadienylacetamido) -3- (l-car-

boxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (D-a-aminophenylacetamido) -3- (l-carboxymethyltetrazole-

5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (2-aminomethyl-l, 2-cyclohexenylacetamido) -3- (l-carboxy-

methyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (2-aminomethyl-4-hydroxyacetamido) -3- (l-carboxymethyl-

tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (o-aminomethylphenylthioacetamido) -3 - (1-carboxy methyl-

tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- (ß-o-Aminomethylphenylpropionamido) -3- (l-carboxyme-

40

thyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid, 7- [Da-amino-a- (3'-methyl-4'-hydroxyphenyl) acetamido] -3 - (1-carboxymethyltetrazole-5 - yl-thiomethyl) -3-cephem-4-car-bonic acid,

7- [D-a-Amino-a- (3'-methoxy-4'-hydroxyphenyl) acetami-

do] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-

carboxylic acid,

7- [Da-amino-a- (3-acetoxyphenyl) acetamido] -3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid, 10 7- [Da-amino- a- (l'-Cyclohexenyl) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid, 7- [da-amino-a- (3'-chloro -4'-hydroxyphenyl) acetamido] -3- (l-carboxymethyItetrazoI-5-yl-thiomethyl) -3-cephem-4-car-bonic acid,

7- [D-a-Amino-a- (l ', 4'-cyclohexadienyl) -acetamido] -3- (l-

carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carbon-

acid,

7- [D- (l ', 4'-Cyclohexadienyl) propionamido] -3- (l-carboxyme-

thyltetrazol-5-yl-thioethyl) -3-cephem-4-carboxylic acid,

7- [D- (4 '-Methoxy-1', 4 '-cyclohexadienyl) propionamido] -3 - (1 -

carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carbon-

acid,

25th

7- (2-Aminomethylphenylacetamido) -3- (l-carboxymethyItetra-zol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid, 7- (l-aminocyclohexane carboxamido) -3- (l-carboxymethyltetra-zol-5 -yl-thiomethyl) -3-cephem-4-carboxylic acid, 30 7- (D- (3-thienylacetamido) -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid, 7- (D- (2-thienylacetamido) -3- (l-carboxymethyltetrazol-5-yI-thiomethyl) -3-cephem-4-carboxylic acid, 7- (2-aminomethyl-l, 4-cyclohexadienylpropionamido) -3- (l- 35 carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid,

7- [ß- (AminomethyI-l-cyclohexenyl) propionamido] -3- (l-car-boxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid or

4n 7- [D-a-amino-a- (4'-hydroxymethylphenyl) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-car-bonic acid.

7- [D-a-Amino-a- (4'-hydroxymethylphenyl) acetamido] -3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem-4-car-45 bonic acid.

Example 5

Sodium 7- {Da- [3- (2-furoyl) -ureido] -4-hydroxyphenylace-tamido} -cephalosporanate so 6.4 ml (0.0454 mol of triethylamine and 12.7 g (0.1039 mol) 2 Furoyl isocyanate is added to an ice-cooled suspension of 20.8 g (0.0413 mol) of 7- (da-amino-4-hydroxyphenylacetamido) -cephalosporanic acid (as dimethylformamide water solvate) in 175 ml of dry dimethylformamide The ice bath is removed after 1 minute and the mixture is stirred for 1 hour, the dark solution is diluted with 600 ml of water, covered with ethyl acetate and the aqueous phase is acidified to pH 2.5 with 42% phosphoric acid Phases and extracts the aqueous dimethylformamide phase ad four more times with ethyl acetate, the combined organic extracts are washed five times with water, treated with activated carbon, filtered and concentrated under reduced pressure to remove remaining water, fresh ethyl acetate is added and the stirred solution is treated slowly with (> 515.1 ml (0.0408 mol ) Sodium 2-ethylhexanoate in 1-butanol, which causes the product to crystallize. 18.1 g of product (75.5%) are obtained. The IR spectrum is in line with the desired product.

41

623 330

7- {D-a- [3- (2-Furoyl) -ureidoJ-4-hydroxyphenylacetamido} -

3- (l-carboxymethyltetrazol-5-yl-thiomethyl) -3-cephem4-car-

bonic acid disodium salt

A mixture of 4.0 g (0.0069 mol) of sodium 7- {Da- [3- (2-furoyl) -ureido] -4-hydroxyphenylacetamido} -cephalosporanate, 1.83 g (0.00895 mol ) 5-Mercapto-l-tetrazole acetic acid re-disodium salt and 200 ml of 0.1 M phosphate buffer of pH 6.4 are heated to 75 ° C. under a nitrogen atmosphere for 6 hours. The reaction mixture, which was placed in a refrigerator overnight, is filtered to remove a small amount of precipitate. The filtrate is adjusted to pH 2 with 6N HCl and the mixture is extracted three times with ethyl acetate. The mixture is filtered during the first extraction to remove a small amount of insoluble material. The combined ethyl acetate extracts (volume = 500 ml) are washed twice with water, dried (sodium sulfate), filtered and treated with 5.1 ml (0.0138 mol; 2 equivalents) of sodium 2-ethylhexanoate in 1-butanol, whereby the separation of an oil is effected. The solvent is concentrated a little to remove water and the mixture is placed in the refrigerator. The solvent is decanted off and the gummy product is triturated with acetone, giving a filterable solid. The yield is 2.0 g. The product is dried in a vacuum over phosphorus pentoxide. The IR spectrum is in line with the desired product.

It is found that samples of the compounds prepared in Example 5, after dissolving in water and diluting with nutrient broth, have the following minimum inhibitory concentrations (MIC) in y / ml against the indicated microorganisms, determined by overnight incubation at 37 ° C. by tube dilution .

In Vitro Antibacterial Activity M.I.C. ((xg / ml)

Organisms

5

Str. Pneumoniae * (10 "3) ** A9585 Str. Pyogenes * (IO-3) A9604 S. aureus Smith (IO-4) A9537 S. aureus-50% Serum (10 ~ 4) A9537 ioS. Aureus BX1633 ( 10 ~ 3) A9606 S. aureus BX1633 (10 "" 2) A9606 S. aureus Meth-Res (IO-3) A15097 Sai.enteritidis (10 ~ 4) A9531 E. coli Juhl (10 ~ 4) A15119 is E. coli (IO "" 4) A9675 K. pneumoniae (10 "~ 4) A9977 K. pneumoniae (IO-4) A15130 Pr. mirabilis (10_ 4) A9900 Pr. morganii (10" "4) A15153 2o Ps. aeruginosa ( 10 ~ 4) A9843A Ser. marcescens (10 ~ 4) A20019 Ent. cloacae (10_ 4) A9656 Ent. cloacae (IO-4) A9657 Ent. cloacae (IO-4) A9659

25th

Example 5

0.13 0.13

> 1

> 63

2nd

63 0.5 16 16 1

125 0.5 32 16> 125> 125 63> 125

R-C0NH

N—

> s "^ n

Hj CH2C00 (H, K, Na) Na)

* 45% antibiotic test broth

+ 50% broth

+ 5% serum

** Dilution of overnight broth culture

C.

Claims (12)

623 330 PATENT CLAIMS 1. Process for the preparation of a compound of formula I. i ^ \ R-NH-Ch-CH clip ° c, C-OH II 0 wherein R1 stands for acyl or an ester or a non-toxic, pharmaceutically acceptable salt thereof, characterized in that a compound of the formula N il -s-c N ii N (i) i ch. COOH ri-nh-ch- ff (in) 'a) implementation of an isocyanate of formula VI O II R ») 0_O-C -CH2-N = C = S (VI) ch2occh3 cooh in which Rlno is alkyl having 1-6 carbon atoms, phenyl, phenylalkyl or substituted phenyl or substituted phenylalkyl, with sodium azide to give the thiolester of the formula VII in which R1 is acyl, or a salt or an easily hydrolyzable ester thereof with a compound of formula IV N N || i! (IV) N ' ! ch. 30th 35 N N hs-jl j1 N I CH CO R and (VII) 100 cooh implements. b) hydrolysis of the thiolester obtained. 3. The method according to claim 1, characterized in that a compound of formula I is prepared in which R1 2. Application of the method according to claim 1 has one of the following meanings: starting compound of the formula IV which has been prepared 40 by ch2nh2 h2-nh2 ch2-co-, ch2nhch3 ^ -ch2co- or ! ch2nhch3 ch2nh2 ch2co- ch2nhch3 ( et ch2-nh-ch3 11 ch2-i- H0 \> ch2co- 4. The method according to claim 1, characterized in that a compound of the formula I prepared in the R1 of the formula ch2nh2 h2co- corresponds. 5. The method according to claim 1, characterized in that one produces a compound of formula I in which R! has the D - (-) configuration and corresponds to the formulas Vv Ç3-C0- Eo /> f-co- hhg * x nhg A K ko "v y — chco- çh- \ == / m2 '- NHg hqchg-v. y) —ch-co- ^ 'HHg L? jjt)) - chco-, qba-q- ^ ~ \ ~ cszo- ^ 'NHg ^' HH ^ / y — chco- k y-cb ^ rarco- ^ 'HHg' ^ KHg c ^ tv chp ^ co- »/ / çhco-p hh2 n nhg n — n t [—chco ** QLçhco-, t j £ a WIjj corresponds. 623 330 6. The method according to claim 1, characterized in that one produces a compound of formula I, in which R1 has the D - (-) configuration and the formulas 43 -ch-co- or CH wherein Y represents hydrogen, chlorine, bromine, fluorine, trifluoromethyl, 10. 7. The method according to claim 1, characterized in that Amino, nitro, hydroxy, lower alkyl with 1 to 4 carbon - that one produces a compound of formula I in which R1 is the atom or lower alkoxy with 1 to 4 carbon atoms Structure: stands. ceigco- • o chgco- * / y-r5-chgco- ^ ch2c0- 'cn' | ^ \ - ch2co-, Or- K— «> - 'WHg or C 1 0 = c- m! • ch «cq- VN * "2 corresponds. 55, where R16 is for (lower) alkyl or an aralkyl group. 8. The method according to claim 1, characterized in that the formula: that a compound of the formula I is prepared in which R1 of the formula y "- (ch2) ■ £ ~ X ' ho2c-ch- (ch2) 3-c - * m y 33 'R NH I f.5, where m is an integer from 1 to 6 inclusive Represents C = 0 and R17 and R18, which are the same or different, I each has the meanings H, Cl, Br, F, N02, (lower) alkyl or Own OR16 (low) alkoxy. 5 623 330 9. The method according to claim 1, characterized in that one produces a compound of formula I, in which R1 the formula O II H02C-CH- (CH2) 3-C- I. NH I. c = o I. NH I. rio, wherein R19 is (lower) alkyl) or a group of formula - (ch „) at , 18th 10. The method according to claim 1, characterized in that one produces a compound of formula I, in the R1 of the formula O m H02C-CH- (CH2), -C-I NH I. R20 corresponds in which R20 is a-halogen or a, a-dihalogen-C2-C4-alkanoyl or R20 is N-isobornyloxy-15 carbonyl or R20 is the group of the formula -C-N X R21 r22 or-C-O-R23 II O where m is an integer from zero to 6 and R17 and R18, which are the same or different, each represent H, CI, Br, F, NO2 (lower) alkyl or (lower) alkoxy. 30th where R21 and R22 are each hydrogen, lower alkyl, phenyl, halophenyl, tolyl, lower alkoxyphenyl or naphthyl, X is oxygen or sulfur and R23 is lower alkyl, or wherein R20 is hydrogen. 11. The method according to claim 1, characterized in that a compound of formula I is prepared in which R1 has the D configuration on the a-carbon atom and one of the formulas ç \ -çh-c0-hh --o çh-co- nh k Cl b- ch-co-I r 623 330 O chco-nh k O chlchco— 2 i nh « A CH ^ O-U wp ^ 'nh i A 0-ï chc0- nh I. A or corresponds, where A for li N tjL O. > —R m chco- o i A -chco * "nh stands in which Z has the meanings (lower) alkyl, cycloalkyl having 4.5, 6 or 7 carbon atoms, monohalogen (lower) alkyl, 3o dichloromethyl, trichloromethyl, (lower) alkenyl having 2 to 6 carbon atoms, _ »H0- ,? - 0-, U-.K). or. ch, ^ ör. r 7 623 330 and has, in which m represents an integer from zero to 3 inclusive and each of the radicals R3 and R4 represents hydrogen, nitro, di (lower) alkylamino, (lower) alkanoylamino, (lower) alk- anoyloxy, (lower) alkyl, (lower) alkoxy, sulfamyl, chlorine, iodine, bromine, fluorine or trifluoromethyl.