KR810000471B1 - Process for preparing antibacterial agents - Google Patents

Abstract

Antibacterial agents(I; n = 2-9; R100 = C1-6 alkylphenyl, phenylalkyl, substituted phenyl, substituted phenyl alkyl) wee prepd. by hydrolysis of thioesters(III) which were obtained by treating isocyanates(II) with sodium azide. Thus, 20 ml acetone soln. of D-(-)-α-formyloxyphenylacetylchloride 1.5 g was added in the 25 ml water soln. of 7-amino-3-(1-carboxy ethyltetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid 1.6 g and sodium bicarbonate 2.1 g, stirred for 1 hr and then acetone was removed to give 7-(D-α-hydroxyphenylacetamido)-3-(1-carboxyethyltetrazole-5-ylthiomethyl)-3-cephem-4-dipotassium carboxylate 500 mg (m.p. 140≰C).

Description

Method of Preparation of Antimicrobial Agents

The present invention relates to novel compounds represented by the following general formula (I) and their esters or pharmaceutically acceptable non-toxic salts thereof.

Wherein R ¹ is acyl or hydrogen, n is an integer from 2 to 9 and R ³ is hydrogen or methoxy.

The above-mentioned ester of the compound of formula (I) is a group having the following structure.

Where W is hydrogen, Z is (lower) alkanoyl, benzoyl, naphthoyl, furoyl, tenoyl, nitrobenzoyl, methylbenzoyl, halobenzoyl, phenylbenzoyl, N-phthalimido, N-succinimi N-saccharino, N- (lower) alkyl carbamoyl, (lower) alkoxy, (lower) -alkylthio, phenoxy, carvalcoxyl, carbobenzoic, carbamoyl, benzyloxy, chlorobenzyloxy When carbophenoxy, carbo-tert-butoxy or (lower) alkylsulfonyl and W is carbalcoxyl, Z is carbal cooxy, and when W is phenyl, Z is benzoyl or cyano, or W And Z both represent 2-oxocycloalkyl containing 4-8 carbon atoms.

In a specific example of the present invention, R ₂ is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, P-nitrobenzyl, β, β, β-trichloroethyl, 3- Phthalidyl or 5-indanyl.

As further detailed below, the present invention also provides salts of these acids. Stereochemistry of the bicyclic nucleus revealed that it was cephalosporin C.

Acyl (R ¹ ) includes, but not limited to, groups having the following structural formula.

(A) R ^u C _u H _2n CO-, wherein R ^u is aryl (carbocyclic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, or nonaromatic or mesoionic heterocyclic group, n is It is an integer of 1-4. Such groups are for example phenyl acetyl, substituted phenylacetyl, ie fluoro phenylacetyl, nitrophenylacetyl, aminophenylacetyl, β- (0-aminomethylphenyl) -propionyl, 0-aminomethyl-phenylthioacetyl, 0- , m-, and P-guanidino-phenyl acetyl, 0-, m- and P-aminomethylphenyl acetyl, acetoxy phenyl acetyl, methoxy phenyl acetyl, methyl phenyl acetyl, or hydroxy phenyl acetyl, N, N- Bis- (2-chloroethyl) amino phenyl propionyl, thien-2- and -3-acetyl, 4-isoxazolyl- and substituted 4-isoxazolyl acetyl, 1-cyclohexyl acetyl, 2-amino-methyl -1-cyclo hexenyl-acetyl, 1, 4-cyclo hexadienyl-acetyl, 2-aminomethyl-1, 4-cyclo hexadienyl-acetyl, pyridyl acetyl, tetrazolyl acetyl (other heterocyclic rings of this type) Acetyl bacteria are known from US Pat. Nos. 3,819,623 and 3,516,997), or Lifting acetyl group has been known in US Patent No. 3,681,328, 3,530,123 and 3,563,983 call. The substituted 4-isoxazolyl group may be a 3-aryl-5-methyl isoxazolyl-4-yl group, where the aryl group is phenyl, halo phenyl, ie chloro- or bromo-phenyl. This form of the acyl group is 3-0-chlorophenyl-5-methylisoxazol-4-yl-acetyl, the other is known from US Pat. No. 3,551,440 which is substituted with isothiazole instead of isoxazole. Other acyl groups in this form are: Cyano acetyl (and similar compounds are known in US 3,719,673), 3,5,7-triaza-1 -azonia-1-adamantyl) -acetyl (known in US 3,720,669), m- Amino pyridinium acetyl (known in US 3,757,013), 0-, m- and P- (2'-amino ethoxy) phenyl acetyl (known in US 3,759,905), 4, 5-dimethoxycarbonyl- 1, 2, 3-triazol-1-ylacetyl or 4-cyano-1, 2, 3-triazole-1, ylacetyl (known in US 3,821,206), imidazole- (1) -acetyl ( US Pat. No. 3,632,810), P-aminomethyl phenyl acetyl (known in US Pat. No. 3,382,241), 0-aminomethyl-P-hydroxyphenyl acetyl (known in US Pat. No. 3,823,141), β- (0-amino methyl- Phenyl) propionyl (known in US 3,813,391), α-amino-2, 4, 6-cycloheptatrienyl-acetyl (known in US 3,539,562) and lower alkoxy carbonyl acetyl (known in US 3,557,104)

(B) C _n H _{2n + 1} CO-, where n is an integer from 1 to 7; Alkyl groups are linear or branched and, if necessary, may be interposed between oxygen or sulfur valences or substituted with cyano groups. Enumerating such groups include cyanoacetyl, hexanoyl, heptanoyl, octanoyl, butylthio acetyl and trifluoro methyl thio acetyl.

(C) C _n H _2n-1 CO-, where n is an integer from 2 to 7; Alkenyl groups are straight or branched, and if necessary can be interposed between oxygen or sulfur valences. Enumerating such groups is allyl thio acetyl.

(ㄹ)

Wherein R ^u is as defined in (a) and further adds benzyl and R ^v and R ^w are the same or different from each other and are hydrogen, phenyl, benzyl, phenethyl or lower alkyl, respectively. The list of such groups is as follows. Phenoxyacetyl, 2-phenoxy-2-phenyl-acetyl, 2-phenoxypropionyl, 2-phenoxy-butythyl, benzyl-oxycarbonyl, 2-methyl-2-phenoxy propionyl, P-cre Soxyl acetyl and P-methylthiophenoxy acetyl.

(ㅁ)

Where R ^u is as defined in (a) and further, benzyl and R ^v and R ^w are as defined in (d). For example, such a group is as follows. S-phenylthio acetyl, S-chlorophenyl-thio acetyl, S-fluoro-phenyl thio acetyl, pyridyl thioacetyl and S-benzyl thio acetyl and 0-aminomethyl-phenyl thioacetyl, P-amino methyl phenyl-thio Acetyl (known US 3,663,540), and hetero cyclylmercapto acetyl (known US 3,627,760).

(Iii) R ^u Z (CH ₂ ) _m CO- where R ^u is as defined in (ㅁ), further adding benzyl, Z is oxygen or sulfur atom, m is an integer of 2-5. Listing such groups include S-benzyl thio propionyl.

(S) R ^u CO-, where R ^u is as defined in (ㅁ). Examples of such groups include benzoyl, substituted benzoyl (ie, amino benzoyl), 4-isoxazolyl and substituted 4-isoxazolyl-carbonyl, cyclopentane carbonyl, cydnon-carbonyl, naphthoyl and substituted Naphthoyl (ie 2-ethoxynaphthoyl), canoxalinyl-carbonyl and substituted quinoxalinylcarbonyl (ie 3-carboxy-2-quinoxalinyl carbonyl). Other possible benzoyl substituents include alkyl, alkoxy, phenyl or carboxyl alkyl amido, cyclo alkyl amido, morpholino carbonyl, pyrrolidino carbonyl, piperidino carbonyl, tetra hydropyridino, pullulil amido Or phenyl substituted with N-alkyl-N-anilino or derivatives thereof such substituents are in 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2.6-dimethoxy benzoyl, 2-biphenyl-carbonyl, 2-methylamino benzoyl and 2-carboxybenzoyl. R ^u is a substituted 4-isoxazolyl group wherein the substituents are as listed in (a). Such 4-isoxazole groups include 3-phenyl-5-methyl isoxazol-4-yl-carbonyl, 3-0-chlorophenyl-5-methyl-isoxazol-4-yl-carbonyl and 3- (2 , 6-dichlorophenyl) -5-methylisoxazol-4-yl-carbonyl.

또는

(O)

or

Where R ^u is defined in (a), X is hydrazino, guanidino, ureido, thio ureido and substituted thio ureido (known in US 3,741,962), allophan amino (in US 3,483,188) Known), 3-guanyl-1-ureido (see US 3,579,501), cyan amino (see US 3,796,709), amino, substituted amino (ie acylamido or amino groups and / or groups with 7-side chains) Or ketones, ie functional groups obtained by reaction with formaldehyde, acetaldehyde, butyl aldehyde, acetyl-acetone, methyl acetoacetamide, benzaldehyde, salicylic aldehyde, acetone, methyl ethyl ketone or ethyl acetoacetate), hydroxy, Carboxy (known in US 3,282,926 and US 3,819,601), esterified carboxy (known in US 3,635,926) triazolyl, tetrazolyl, cyano, halogeno, acyl (I.e., formyloxy or lower alkanoyloxy) or etherified hydroxy group.

Such acyl groups include α-amino-phenyl acetyl, α-carboxy phenyl acetyl, 2, 2-dimethyl-5-oxo-4-phenyl-imidazolidinyl, α-amino-P-hydroxyphenylacetyl, α -Amino-acetoxy-phenylacetyl, α-hydroxy phenyl acetyl and α-formyl oxyphenyl acetyl or other acyl groups of this type (known in US 3,812,116 and US 3,821,017) and α-amino-2- or 3 -Thienylacetyl (see US 3,579,506) and other α-amino- and α-hydroxy-heterocyclyl-acetyl groups (known in US 3,821,207).

여기서 R^x, R^y및 R^z는 동일하거나 상이하며 각각 저급 알킬, 페닐 또는 치환된 페닐기이다. 그러한 아실 군을 예로 들면, 트리페닐카르보닐이다.At

Wherein R ^x , R ^y and R ^z are the same or different and are each lower alkyl, phenyl or substituted phenyl group. An example of such an acyl group is triphenylcarbonyl.

여기서 R^u는 (ㄱ)에서 정의한 바와 같고, 더 부가하면 수소, 저급 알킬 또는 할로겐 치환 저급 알킬이고, Y는 수소 또는 유황 원자이다. 그러한 군들을 예로 들면 Cl(CH₂)₂NHCO이다.(ㅊ)

Wherein R ^u is as defined in (a), further added is hydrogen, lower alkyl or halogen substituted lower alkyl, and Y is hydrogen or sulfur atom. Examples of such groups are Cl (CH ₂ ) ₂ NHCO.

(ㅌ)

Wherein X is as defined in (o) and n is an integer from 1 to 4 and such acyl groups are, for example, 1-amino-cyclohexane-carbonyl.

(E) amino acyl, for example R ^w CH (NH ₂ )-(CH ₂ ) _n -CO (where n is an integer from 1 to 10) or H ₂ NC _n H ₂ n Ar (CH ₂ ) _n CO m is 0 or an integer of 1 to 10, and n is 0.1 or 2.

R ^w represents a hydrogen atom or a group defined by alkyl, aralkyl or carboxyl groups or R ^u , and Ar is an arylene group, ie P-phenylene or 1,4-naphthylene. Taking such a group as an example, it is known from British Patent No. 1,054,806. Groups of this type include P-aminophenyl acetyl groups. Another acyl group is δ-amino adipoyl, ie N-benzoyl-δ-amino adifoyl, derived from naturally occurring amino acids and their derivatives.

(K) substituted glyoxylyl groups of the general formula R ^y , CO, CO-, wherein R ^y is an aliphatic, araliphatic, or aromatic group, which is a thienyl group, a phenyl group or a mono-, di- or tri-substituted phenyl group And substituents include one or more halogen atoms (F, Cl, Br, or I), methoxy groups, methyl groups or amino groups or fused benzene rings (known in US Pat. Nos. 3,546,219 and 3,573,294).

(xiv)

Wherein, R ¹⁶ is (lower) alkyl or an aralkyl al device following structural formula.

Wherein n is an integer from 1 to 6 and R ¹⁷ and R ¹⁸ are the same or different and are H, Cl, Br, F, NO ₂ , (lower) alkyl or (lower) alkoxy, respectively.

(XV)

R ¹⁹ is (lower) alkyl or a functional group of the following structural formula.

Wherein n is an integer from 0 to 6 and R ¹⁷ and R ¹⁸ are the same or different and are H, Cl, F, NO ₂ , (lower) alkyl or (lower) alkoxy, respectively.

(XVi)

Wherein R ²⁰ is α-halo or α, α-dihalo C ₂ -C ₄ alkane oil or R ²⁰ is N-isobornyloxycarmonyl or R ²⁰ as known from US Pat. No. 3,819,619 or R ²⁰ is Qi.

또는

or

Wherein R ²¹ and R ²² are each hydrogen, lower alkyl, phenyl, halophenyl, tolyl, lower-alkoxyphenyl or naphthyl, X is hydrogen or sulfur and R ²³ is lower alkyl known from US Pat. No. 3,819,621 or R ²⁰ is hydrogen (in cephalosporin C).

(XVii)

Wherein R ^u is as defined in (4), X is oxygen or imino, Y is oxygen or sulfur, Z is (lower) alkyl, C ₄ , C ₅ , C ₆ or C ₇ cyclo alkyl, Mono-halo (lower) alkyl, dichloromethyl, trichloromethyl, (lower) alkenyl of C ₂ -C ₆ ,

N is an integer from 0 to ³ and R ³ and R ⁴ are each hydrogen, nitrogen, di (lower) alkylamine, (lower) alkanoylamino, (lower) -alkanoyloxy, (lower) -alkyl (linear and Branched saturated C ₁ -C ₆ aliphatic groups), (lower) -alkoxy, sulfamoyl, chloro, iodine, bromo, fluoro or trifluoro methyl.

More preferably R ^u is phenyl, P-hydroxy-phenyl or 2- or 3-thienyl and Z is 2-furyl or phenyl. Such examples include those known from U.S. 3,687,949 and 3,646,024.

또는

또는

(XViii)

or

or

Where R ^u is as defined in (a) and Z is as defined in (XVii). Such examples include those known from US Pat. Nos. 3,626,024 and 3,692,779.

(XiX)

Wherein R ^u is defined in (a) and R ²⁴ is lower alkyl, cycloalkyl, allyl or any heterocyclic group. Such examples include those known from US 3,778,436.

As for the specific compound of general formula (I) of this invention, R <^1> is the following structure.

Another specific compound of the present invention is the general formula (I) D-diffraction in the 7-side chain, wherein R ¹ is the following structural formula.

Another specific compound of the present invention has a D-diffraction in the 7-side chain of general formula (I), and R ¹ is of the following structural formula.

또는

or

In the formula, Y is hydrogen, chlorine, clear, lower alkoxy of fluorine, trifluoromethyl, amino, nitro, hydroxy, C ₁ -C ₄ lower alkyl or C ₁ -C ₄ to the.

In a specific compound of the present invention, R ^{1 in the} compound of formula (I) has the following structure.

In a specific compound of the present invention, R ^{1 in} formula (I) has the following structure.

In a specific compound of the present invention, R ^{1 in} formula (I) has the following structure.

Among these, Z is (lower) -alkyl or cycloalkyl of C ₄ , C ₅ , C ₆ or C ₇ , mono-halo (lower) alkyl, dichloromethyl, trichloromethyl, (lower) of C ₂ -C ₆ Alkenyl, a group having the formula:

n is an integer from 0-3 and R ³ and R ⁴ are each hydrogen, nitro, di (lower) alkyl amino, (lower) alkanoyl-amino, (lower) alkylnoyl oxy, (lower) -alkyl, (lower) Alkoxy, sulfamoyl, chloro, iodine, bromo, fluoro or trifluoro methyl. Most preferred Z is phenyl, 2-thienyl, 3-thienyl, 2-furyl or 5-nitro-2-furyl.

More specific formula (I) of the present invention is D-diffraction in the 7-side chain and R ¹ is a compound of the formula

In the above, Z is (lower) alkenyl of (lower) alkyl, 4, 5, 6 or 7 cycloalkyl and monohalo- (lower) -alkyl, dichloromethyl, trichloromethyl, C ₂ -C ₆ , Is a group of the following structural formula.

또는

or

n is an integer from 0-3 and R ³ and R ⁴ are each hydrogen, nitro, di (lower) alkylamino, (lower) alkanoyl-amino, (lower) -alkanoyloxy, (lower) -alkyl, (lower) Alkoxy, sulfamoyl, chloro, urethra, bromo, fluoro or trifluoro methyl. Most preferred Z is phenyl, 2-thienyl, 3-rienyl, 2-furyl or 5-nitro-2-furyl.

Another preferred compound of the invention is a compound of formula (I) wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is an integer of 2-9 and R ₁ is a group of the formula

In the formula, R ¹⁶ is (lower) alkyl or an aralkyl group of the following structural formula.

Wherein m is an integer from 0-6 and R ¹⁷ and R ¹⁸ are the same or different and are hydrogen, chlorine, cancelled, fluorine NO ₂ , (lower) alkyl or (lower) alkoxy, respectively.

Another preferred compound of the invention is a compound of formula I wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is an integer from 2-9 and R ¹ is a group of the formula

In the above, R ¹⁹ is (lower) alkyl or a group of the following structure.

Wherein m is an integer from 0-6 and R ¹⁷ and R ¹⁸ are the same or different and are hydrogen, chlorine, cancelled, fluorine, NO ₂ , (lower) alkyl or (lower) alkoxy, respectively.

Other preferred specific examples of the invention include compounds of formula (I), wherein R ³ is methoxy, n is an integer of 2-9, R ² is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, Acetonyl, peracyl, P-nitro benzyl or β, β, β-trichloroethyl and R ¹ is a group having the formula:

또는

or

Wherein X is oxygen or imino, Y is oxygen or sulfur, Z is amino, (lower) alkyl, 4, 5, 6 or 7 cycloalkyl, monohalo (lower) alkyl, dichloromethyl, Trichloromethyl, (lower) alkenyl of C ₂ -C ₆ , which is a group of the formula

또는

or

In the above, n is an integer of 0-3 and R ³ and R ⁴ are each hydrogen, nitrogen, (lower) alkanoyloxy, (lower) alkyl, (lower) alkoxy, sulfamoyl, chloro, iodine, bromo, pullo Methyl as rho or trifluo.

Other more specific of the present invention are compounds of formula (I), wherein R ³ is hydrogen or methoxy, n is an integer from 2-9 and R ² is hydrogen, pivaloyloxy-methyl, acetoxymethyl, meth Methoxymethyl, acetonyl, phenacyl, P-nitro-benzyl or β, β, β-trichloro-ethyl, with D-diffraction in the 7-side chain and R ¹ is a group of the formula

또는

or

Wherein X is oxygen or imino, Y is oxygen or sulfur and Z is amino, (lower) alkyl, 4, 5, 6 or 7 cycloalkyl, monohalo (lower) -alkyl, dichloromethyl, trichloro Romethyl, (lower) alkenyl of C ₂ -C ₆ , which is a group of the formula

또는

or

n is an integer from 0-3 and R ³ and R ⁴ are each hydrogen, nitrogen, di (lower) alkylamino, (lower) alkanoyl amino, (lower) alkanoyloxy, (lower) alkyl, (lower) alkoxy, Sulfamoyl, chloro, iodine, bromo, fluoro or trifluo methyl.

Other more specific of the present invention is a compound of formula (I), wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is an integer of 2-9 and R ¹ is D-diffraction in alpha carbon It is a group of structural formula.

또는

or

In the above formula, A is a group of the following structural formula,

Wherein Z is (lower) alkyl, C ₄ , C ₅ , C ₆ , C ₇ cycloalkyl, mono-halo (lower) alkyl, dichloromethyl, trichloromethyl, (lower) alkenyl of C ₂ -C ₆ , Is a group of the following structural formula.

n is an integer from 0 to ³ and R ³ and R ⁴ are each hydrogen, nitro, di (lower) alkylamine, (lower) alkanoyl amino, (lower) alkanoyloxy, (lower) alkyl (straight and branched C) _{1 to C 6} saturated aliphatic groups), (lower) alkoxy, sulfamoyl, chloro, iodine, bromo, fluoro or tripulomethyl.

More specifically, the compound is a compound of formula (I), wherein R ³ is hydrogen or methoxy, n is an integer from ² to 9, R ² is hydrogen, pivaloyloxymethyl, methoxymethyl, Acetonyl, phenacyl, P-nitrobenzyl, or β, β, β-trichloroethyl, and R ¹ is as follows.

Phenyl acetyl,

o-, m- and p-fluorofluorophenyl acetyl

o-, m- and p-nitrophenyl acetyl

o-, m- and p-guanidinophenyl acetyl

o-, m- and p-acetoxy phenyl acetyl

o-, m- and p-methoxy phenyl acetyl

o-, m- and p-methylphenyl acetyl

o-, m- and p-hydroxy phenyl acetyl

N, N'-bis- (2-chloroethyl) amino phenyl propionyl,

Thien-2-acetyl

Thien-3-acetyl

4-isoxazolyl acetyl

1-cyclo hexenyl acetyl

1,4-cyclohexadienyl acetyl

Pyridyl acetyl, cydnon acetyl, 3-0-chlorophenyl-5-methyl-isoxazol-4-yl-acetyl, cyano acetyl, 3,5,7-triaza-1-azonia-1-adama Acetyl acetyl, m-amino pyridinium acetyl, o-, m- and p- (2'-amino ethoxy) phenyl acetyl, 4, 5-dimethoxycarbonyl-1, 2, 3-triazol-1-yl Acetyl, 4-cyano-1,2,3-triazol1-yl acetyl, imidazole- (1) -acetyl, m- and p-aminomethyl phenyl acetyl, α-amino-2,4,6-cyclo Hepta trienyl-acetyl, lower alkoxycarbonyl acetyl, cyano acetyl, hexanoyl, heptanoyl, octanoyl, butylthio acetyl, trifluorouromethylthio acetyl, allylthio acetyl, phenoxy acetyl, 2-phenoxy 2-phenyl acetyl, 2-phenoxy propionyl, 2-phenoxy butyryl, benzyloxy carbonyl, 2-methyl-2-phenoxy propionyl, P-creoxy acetyl, P-methyl thiophenoxy acetyl , S-phenylthio acetyl, S-chloro phenyl thi Acetyl, S-Pluoro phenyl thio acetyl, pyridyl thio acetyl, S-benzyl thio acetyl, P-amino methyl phenyl thio acetyl, cyano methyl thio acetyl, 4-pyridyl thio acetyl, S-benzyl thio propionyl, Benzoyl, amino benzoyl, 4-isoxazolyl-carbonyl, cyclopentane-carbonyl, cydnon-carbonyl, naphthoyl, 2-ethoxy naphthoyl quinoxalinyl, 3-carbonyl3-carboxy-2-quinoxy Salinyl-carbonyl, 2,6-dimethoxy benzoyl, 2-biphenyl carbonyl, 2-methyl amino benzoyl, 2-carboxy benzoyl, 3-phenyl-5-methyl isoxazol-4-yl-carbonyl, 3 -0-chlorophenyl-5-methyl-isoxazol-4-yl-carbonyl or 3-2 ', 6'-dichlorophenyl-5-methyl isoxazol-4-yl-carbonyl.

Another preferred specific embodiment of the invention is the compound of formula (I), wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is an integer of 2-9, R ¹ is

(Z is amino (lower (alkyl, N- (lower) alkyl-amino (lower) -alkyl or N, N-di (lower) alkyl amino (lower) -alkyl)), or R ¹ is a group of the structural formula, or

Wherein Z is amino phenyl, amino phenyl (lower) -alkyl, N- (lower) alkyl amino phenyl, N, N-di (lower) -alkyl amino phenyl, N- (lower) alkyl amino phenyl (lower) -alkyl, N, N-di (lower) alkyl amino phenyl (lower) alkyl, phenyl amino (lower) alkyl, phenyl (lower) alkyl amino- (lower) alkyl, substituted phenyl amino (lower) alkyl or substituted phenyl (lower) Alkyl amino (lower) alkyl, wherein substituted phenyl can be represented by the group of the formula

Wherein X ¹ and X ² are the same or different and each is hydrogen, fluorine, chlorine, cancelled, (lower) alkyl, (lower) alkoxy, nitro, amino, trifluuro methyl and phenyl, and R ¹ is ,

R ¹ is

Where n is 1 or 2, and R ¹ is

Where Z is the following structural formula

또는

or

Wherein R ³ is (lower) alkyl, (lower) alkenyl or (lower) -alkynyl, R ¹ is

Wherein R ₄ , R ⁵ and R ⁶ are each (lower) alkyl, (lower) alkynyl, (lower) alkenyl or (lower) cyclo-alkyl and R ⁵ may be hydrogen, and R ¹ is a group of the formula Or

Where X is fluorine or chlorine and R ¹ is of the structure

X is oxygen or sulfur, B is di (lower) alkyl amino group, alkyl group is the same or different piperidino, methyl piperidino, dimethyl piperidino, pyrrolidino, methyl pyrrolidino, dimethyl py Lolidino, morpholidino, methyl morpholino, dimethyl morpholino, N '-(lower) alkyl piperazino, N'-(lower) alkyl-methyl piperazino, N '-(lower) alkyl-dimethyl Piperazino, trimethylene imino, hexamethylene amino or of the following structure,

N is 0, 1, 2 or 3, R ⁷ is (lower) -alkyl and Ar is of the structure

또는

or

Wherein R ⁸ and R ⁹ are each hydrogen, fluorine, chlorine, cancelled, (lower) alkyl or (lower) alkoxy.

Another more specific aspect of the present invention is a compound of formula I, wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is an integer of 2-9, and R ¹ is of the following structure.

Wherein R ³ and R ⁴ are each hydrogen, chloro, bromo, fluoro, urethra, nitro, (lower) alkyl, (lower) alkoxy, (lower) alkylthio, di (lower) alkylamino, (lower) -alka Noyl amino, (lower) alkanoyl or (lower) alkyl-sulfonyl.

Another more specific aspect of the present invention is a compound of formula I, wherein R ² is hydrogen, R ³ is hydrogen or methoxy n is an integer of 2-9, R ¹ is the following structure.

Where Ar is

Wherein R ⁵ and R ⁶ are each hydrogen, fluorine, chlorine, methoxy or methyl and R ³ and R ⁴ are each hydrogen, cancellation, chlorine, and another more specific of the invention is a compound of formula I wherein R ² is hydrogen , R ³ is hydrogen or methoxy, n is an integer of 2 to ⁹ and R ¹ is of the structure

또는

or

Wherein R ³ ′ and R ⁴ are each hydrogen or (lower) alkyl and R ¹ is of the structure

또는

or

X is hydrogen or (lower) alkyl and R ¹ is of the structure

또는

or

또는

or

Wherein R ¹² is hydrogen or (lower) alkyl, R ¹³ is hydrogen, chlorine, cancelled, iodine, fluorine, trifluoromethyl, (lower) alkyl, (lower) alkoxy, (lower) alkylthio, carboxymethoxy, (Lower) alkylsulfonyl, phenyl, benzyl, phenoxy, benzyloxy and as:

과 함께 헤테로 환상을 이룰 수도 있는데, 즉, 피롤리디노, 피페리디노, 모르폴리노, 1,2,5,6-테트라하이드로피리디노, N-(저급) 알킬 피페라지노 및 헥사메틸렌이미노이고, n는 0∼3의 정수이다. R¹은 다음 구조의 것이거나Wherein R ⁵ and R ⁶ are each hydrogen, (lower) alkyl, phenyl, benzyl, cycloalkyl of C _{3 to} C ⁷ ,

Heterocyclic with ie, pyrrolidino, piperidino, morpholino, 1,2,5,6-tetrahydropyridino, N- (lower) alkyl piperazino and hexamethyleneimino And n is an integer of 0-3. R ¹ is of the structure

또는

or

Wherein R ⁷ , R ⁸ and R ⁹ are hydrogen, nitro, di (lower) -alkyl amino, (lower) alkanoyl amino, lower) alkanoyl-oxy, (lower) alkyl, (lower) alkoxy, sulfamoyl, chlorine , Iodine, cancellation, fluorine and trifluoroluomethyl, X and X 'are the same or different and each is hydrogen, and R ¹ is of the following structure.

R ¹⁰ and R ¹¹ are hydrogen, chlorine, cancelled, iodine or methyl.

Another more specific aspect of the present invention is a compound of formula I, wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is 2 to 9, R ¹ is

Where X is a covalent bond such as -O- or -S-, and R ³ and R ⁴ are each (lower) alkyl, chlorine, canceled or

Wherein R ⁶ R ⁷ and R ⁸ are each hydrogen, fluorine, cancelled and chlorine, and R ⁵ is hydrogen, (lower) alkyl, or of

Wherein R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, fluorine, cancelled or chlorine, and when combined with a benzene group, R ⁴ and R ⁵ are each a vinyl group, and R ¹ is of the structure

Wherein R ¹² and R ¹³ are nitro, (lower) alkyl, (lower) alkoxy, (lower) alkanoyl amino, chlorine, cancelled, iodine, fluorine, hydroxy, (lower) alkylthio, cyclohexyl, cyclo Pentyl, cycloheptyl, (lower) alkoxy carbonyl, mercapto, (lower) alkalsulfonyl, (lower) alkanoyl, (lower) alkanoyloxy or a group of the following structure,

Wherein n is an integer from 0 to 3, and R ²⁰ , R ²¹ and R ²² are hydrogen, fluorine, cancelled, chlorine, iodine, trifluomethyl, (lower) alkyl, (lower) alkoxy, hydroxy, nitro or Amino, R ¹⁴ is hydrogen, (lower) alkyl, or of the following structure,

Wherein R ²⁰ , R ²¹ and R ²² are as defined above, R ¹⁵ is hydrogen or (lower) alkyl group, R ¹⁶ is hydrogen and R ¹² is as defined above and R ¹⁷ and R ¹⁸ are each (lower) Alkyl, (lower) alkoxy, chlorine, clear, iodine, fluorine, cyclohexyl, cycloheptyl, cycloheptyl, a group of the following two structures,

Wherein n is an integer from 0 to 3, R ²⁰ , R ²¹ and R ²² are as described above, R ¹⁹ is hydrogen and R ¹⁷ is as described above. R ¹ is a group of the structure

Wherein R ²³ and R ²⁴ are each (lower) alkyl, (lower) alkyl, (lower) alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, styryl, phenylethyl, phenylpropyl, furyl, Thienyl, naphthyl or a group of the following structure.

Wherein R ²⁶ , R ²⁷ and R ²⁸ are hydrogen, fluorine, chlorine, chloro, cancelled, urethra, tripulouromethyl, (lower) alkyl, (lower) alkoxy, nitro, methylsulfonyl, cyano, di (lower) Alkylamino or methyl mercapto.

R 'is a group of

Wherein R ²⁹ , R ³⁰ and R ³¹ are hydrogen, chlorine, cancelled, iodine, trifluomethyl, fluorine, methylsulfonyl, nitro, (lower) alkoxy and R ³⁵ is (lower) alkyl. R 'is a group of the following structure.

Wherein R ³³ and R ³⁴ are hydrogen, chlorine, cancelled, iodine, (lower) alkyl, (lower) alkoxy or tripulouro-methyl and R ³⁵ is (lower) alkyl.

Another preferred specific embodiment of the invention is the compound of formula I, wherein R ³ is hydrogen or methoxy, n is an integer from ² to 9 and R ² is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl , Acetonyl, phenacyl, P-nitrobenzyl or β, β, β-trichloroethyl and R ¹ is a group of the following structure.

Wherein A is -H or -OH.

Another preferred of the present invention is a compound of the formula

Wherein R ³ is hydrogen or methoxy, n is an integer from ² to 9, R ² is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, n-nitro-benzyl or β, β, β-trichloroethyl, D-diffraction in the 7-side chain, wherein R ¹ is a group of the following structure.

Another preferred specific embodiment of the invention is the compound of formula I wherein R ³ is hydrogen or methoxy, n is an integer from ² to 9, R ² is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl , Acetonyl, phenacyl, P-nitrobenzyl or β, β, β-trichloroethyl, with D-diffraction in the 7-side chain, wherein R ¹ is a group of the following structure.

Another specific embodiment of the present invention is a compound of the formula

Wherein R ³ is hydrogen or methoxy, n is an integer from 1 to 9, R ² is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, P-nitrobenzyl or β, β, β-trichloroethyl, with D-diffraction in the 7-side chain, R ²⁰⁰ is a group of the following structure:

Another specific aspect of the present invention is a compound of formula I, wherein R ² is hydrogen, R ³ is hydrogen or methoxy, n is an integer from 2 to 9 and R ¹ is a group of the following structure.

이며 여기서 -Ar은 다음 구조의 기이다.Wherein R ⁴ is hydrogen, amino, carbobenzoxiamine, phenyl, pulluro, chloro, bromo, iodine, hydroxy, (lower) alkanoyloxy or (lower) alkoxy; X is oxygen or sulfur; R ⁵ and R ⁶ are each hydrogen, phenyl, benzyl, phenethyl, or (lower) alkyl, and R ⁷ is (lower) alkyl; R ⁸ and R ⁹ are (lower) alkyl, (lower) -alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, phenethyl, phenylpropyl, furyl, thienyl, naphthyl or Ar- ; R ¹⁰ is (lower) alkyl amino, di (lower) alkyl amino, C ₃ -C ₇ cyclo-alkylamino, allylamino, diallyl amino, phenyl (lower) alkyl amino, morpholino, (lower) alkylamino , Pyrrolidino, (lower) alkyl pyrrolidino, di (lower) alkyl-pyrrolidino, N, N-hexamethylene amino, piperidino, (lower) alkyl piperidino, di (lower) alkyl piperi Dino, 1,2,5,6-tetrahydro pyridino, N- (lower) -alkyl-piperazino, N-phenyl piperazino, N- (lower) -alkyl (lower) alkylpiperazino, N -(Lower) alkyl-di- (lower) alkyl piperazino, pullulylamino, tetra-hydro fufuryl amino, N- (lower) alkyl-N-pulfuryl amino, N-alkyl-N-anilino or ( Lower) alkoxy anilino; Z ¹ , Z ² and R ³ are each (lower) alkyl, or -Ar; R ¹¹ is (lower) alkyl, (lower) cyclo alkyl, naphthyl, benzyl, phenethyl or

Where -Ar is a group of the following structure:

In this structure R ¹² , R ¹³ and R ¹⁴ are each hydrogen, chlorine, cancellation, iodine, trifluomethyl, phenyl (lower) alkyl or (lower) alkoxy and only one R group represents a phenyl group.

The present invention relates to a process for preparing the compounds of formula (I) or their esters or their nontoxic salts,

Where R ¹ is acyl, R ³ is hydrogen or methoxy and n is an integer from 2 to 9

The compounds of the following structural formulas, or their salts or their esters which are readily hydrolyzed,

(R ¹ is hydrogen or acyl and R ³ is as described above) and reacted with a compound of the formula

(n is an integer from 2 to 9), when R ¹ is hydrogen, the resulting compound is treated with an acylating agent of the structure

R'-X

(X is a halide or their functionally equivalent group) When R ¹ is an acyl, ie acyl group is a free amino or hydroxyl group, the group is blocked with conventional protecting groups and then removed to give compound I, if necessary, produced The free acid, salt or easily hydrolyzed ester of the compound of formula (I) is converted into the corresponding ester or pharmaceutically acceptable non-toxic salt and, if necessary, the salt or readily hydrolyzed of the compound of formula (I) Is converted to the corresponding free acid of the compound of formula (I).

The present invention also relates to a method for producing an antimicrobial agent having the following structural formula,

(R ³ is hydrogen or methoxy, n is an integer of 2-9 R ¹ is acyl) A compound of formula (II)

(R ³ and n are the same as described above) or their salts or esters which are readily hydrolyzed or their Schiff bases of benzoaldehyde or salicylic aldehyde (US 3,284,451 and UK 1,229,453 and US 3,249,622 at 7-amino penicillin acid Used silyl esters and UK 1,073,530 and in particular pivaloyl-oxymethyl, acetoxymethyl, methoxymethyl, acetonyl, phenacyl, P-nitrobenzyl, β, β, β-trichloroethyl, 3-phthalidyl And 5-indanyl ester) as an acylating agent, with organic monocarboxylic acid chlorides or functionally equivalent groups.

Such functionally equivalent groups include the corresponding acid anhydrides, mixed anhydrides and especially mixed anhydrides of lower aliphatic or carboxylic acids with strong acids such as alkyl and aryl sulfonic acid monoesters and mixed anhydrides with more closed acids such as diphenylacetic acid. It belongs here. Particularly useful anhydrides are N-carboxy-anhydrides (see so-called Ruch's anhydrides US 3,850,356 and 3,206,455) D-mandelic acid carboxylic anhydrides (US 3,167,549) or the corresponding substituted D-mandelic acid carboxylic anhydrides. In addition, acid azide or active esters or thio esters (e.g., P-nitrophenyl, 2,4-dinitrophenol, thiophenol, thioacetic acid) and the like can also be used, or their free acids are initially added to N, N N, N'-carbonyl-di or by reacting with '-dimethyl-chloroform iminium chloride or by using the enzymes (see UK 1,008,170 and Novak and Y. Xu, XXI, 6,360 (1969)) or enzymes Imidazole or N, N'-carbonylditriazole [cf. South American Patent Application 63/2684] or carbodiimide reagent, in particular N, N '= dicyclohexyl-carbodiimide, N, N'-diiso Propyl carbodiimide or N-cyclo-hexyl-N '-(2-morpholino ethyl) carbodiimide, see Shihan and Heis, J. Am. Chem. Soc. 77, 1967, (1955)], or alkylamine reagents [R. beads and etch. G. Beehye, Angew, Chem, internotiond Edd. 3,582, (1964) or isoxazolium salt reagents [see, Al. ratio. Woodward, R. a. Olofson and Eccchmeier, J. Am. Chem. Sot. 83 1010 (1961) or ketene imine reagent [cf. Stevenson and M. this. Munk J. Am. Chem. Soc. , 80, 4065 (1958) or hexachloro cyclo triphospha triazine or hexabromo cyclo lipotriazine (US Pat. No. 3,651,050) or diphenyl phosphoryl azide DPPA; J.Am. Chem. Soc. 94, 6263 6205 (1972)] or diethyl phosphoryl cyanide (DEPC; Tetra Hedron 18, 1595 1598 (1973)] or Diphenylphosphite [Tetra Hedron 49, 5047 5050 (1972)]. The free acid can be reacted and then coupled with compound (II) Other equivalent groups of the acid chlorides are the corresponding azolides, ie the amides of the corresponding acids, the amides comprising at least two nitrogen atoms Aromatic five-membered rings, for example, imidazole, pyrazole, triazole, benzimidazole, benzotriazole and substituted derivatives thereof The general preparation of the azolide is N, N'-carbonyl- When the diimidazole is reacted with an equimolar carboxylic acid at room temperature in tetra-hydrofuran, chloroform, dimethylformamide or similar inert solvent, it is particularly quantitatively carbon dioxide and 1 mole of imidazole. The carboxylic acid imidazole is produced while the dicarboxylic acid becomes di imidazole The imidazole precipitation as a by-product separates and isolates the imidazolide This reaction produces cephalosporin The method of isolating cephalosporins and isolating them is already well known in the art, and the use of enzymes to couple free acids with compound (II) has been mentioned above. Methods of acting with enzymes are within the scope of the present invention and include literature on microorganisms that produce enzymes: L. Takahashi and his co-workers, American Chemical Society, 94 (11), 4035 4037 (1972) and T. Nara and his co-workers Antimicrobial magazine (Japan) 24 (5), 321-323 (1971) and US 3,682,777

Coupling the organic carboxylic acid with compound (II), not limited to substituted or unsubstituted D-mandelic acid (with or without protecting groups on the α-hydroxyl group), and as a coupling agent a phosphonitrile-chloride trimer ( J. Org. Chem., 33 (7), 2979 81, 1968) or N-ethoxy-1,2-dihydroquinoline (EEDQ) (J.Am. Chem. Soc. 90, 823 824 and 1652 1653 ( 1968) or US Patent, 3,455,925. The reaction is suitably reacted in benzene, ethanol or tetrahydrofuran at 30 to 35 ° C, and is isolated by a conventional isolation method to remove the protecting group.

In addition to the process of the invention, the 3-acetoxy group of 7-acyl amino cephalosporranic acid (7-amino cephalosporranic acid is substituted with 3-thiolated-7-amino cephalosporranic acid Manufactured) to thiol of the following structural formula

(n: an integer from 2 to 9) Substitute and remove if there is any previously protected group. The protecting group is an α-hydroxy or α-amino or carboxyl group. Substitution of such a thiol with a 3-acetoxy group is carried out in a solution such as water or aqueous-acetone, at least at room temperature, suitably at a temperature of about 50 ° to 100 ° C., in the presence of a moderate base, especially near pH6. desirable. Excess thiol can be used, and the reaction mixture can be carefully acidified and then extracted with an organic solvent that is miscible with water to obtain the reaction product. Substituted or unsubstituted D-mandelamido-cephalosporonic acid is prepared by the methods described in I Med Chem 17 (1), 34-41 (1974) and the references described therein. As described above, several 7-acylamido cephalosporane acids are prepared in particular and by the methods described in the scientific literature, ie US Classification 260-243 ° C.

When the organic carboxylic acid has a functional group such as an amino or hydroxyl group, it is preferable to first block (protect) the amino or hydroxy group, to undergo a coupling reaction, and finally to chemically remove the protecting group.

As mentioned above, methods for preparing antibiotics by acylating using organocene mono carboxylic acids or their acid chlorides or other equivalent functional compounds are particularly within the scope of the present invention. Examples of compounds having other equivalent functions that have already been used to acylate 6-amino peniclanic acid are as follows. US patent 2941995 2951839 2985648 2996501 3007920 3028379 3035037 3040033 3041332 3041333 3043831 3053831 3071575 3071576 3079305 3079306, 3080356 3082204 3093547 3093633 3116285 3117119 3118877 3120512 3120513 3131514 3127394 3140282 3040032 3142673 3147247 3174964 3180863 3198804 3202653 3202654 3202655 3210337 3157639 3134767 3132136 UK in the patent specification 874414 874 416 876 516 876 662 877 120 877 323 877 531 878 233 880 042 880 400 882 335 888 110 888 552 889 066 889 069 889 070 889 168 889 231 890 201 891 174 891 279 891 586 891 777 891 938 893 518 894 247 894 457 894 460 896 072 899 199 900 666 902 703 903 785 904 576 905 778 906 383 908 787 914 419 916 097 916 204 916 205 916 488 918 169 920 177 920 300 921 513 922 278 924 037 925 281 931 567 932 644 938,066 938,321939,708 940,488 943,608 944,417 A number of Belgian patents, for example, 593,222 595,171 595,857 602,494, 603,703 609,039 6 16,419 617,181 and South African patent applications, for example 60/2882 60/3057 60/3748 61/1649 61/2751 62/54 62/4920 63/1612 and 63/2423.

Herein, "lower" alkyl C is a C _{1 to} C ₁₀ linear and branched aliphatic hydrocarbon, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl, 2-ethylhexyl, heptyl, decyl and the like. Similarly, "lower" is used as a moiety to denote other groups, and what is referred to as juice (lower) alkoxy "refers to the same alkyl moiety as linked above as" lower "alkyl.

The invention also relates to the preparation of antibiotics of the structure

(R ³ is hydrogen or methoxy, n is an integer of 2 to 9, R ¹ is acyl).

The compound of the following structural formula,

(R ¹ is acyl, R ³ is hydrogen or methoxy, cephalosporin C itself)

Obtained by reaction with a mixture of the following structural formulas.

(n is an integer from 2 to 9)

In the case of compounds having an amino group substituted in the 7-side chain, first, an unsubstituted amino group (free or primary) is formed, and the resultant is reacted with a suitable reagent to obtain a final substance having an acyl group as defined above in Viii, XVii and XViii. It is preferable to prepare.

The invention also relates to a process for the preparation of novel and valuable intermediates of the structure

(n: integer of 2 to 9 R ³ : hydrogen or methoxy)

Prepared by removing the 7-side chain from the compound of formula

Wherein n is an integer from 2 to 9 and the acyl group (R ¹ ) converts the aforementioned silylated form of the compound to imino-chloride (to PCl ₅ ), to imino-ether (to methanol) and to hydrolysis It is one of those described in XiV, XV and XVi produced by conversion to the final material by (with water). Such reactions are known as follows.

United States 3,575,970: 3,573,295 and 3,573,296

The invention also relates to a process for the preparation of novel and valuable intermediates of the following structure:

(n: integer from 2 to 9)

7-amino cephalosporranic acid or salts or easily hydrolyzed esters or their Schiff bases are reacted with a compound of the structure

(n: an integer from ² to 9, where HSR ^{2 may} also be)

Such salts include non-toxic carboxylic acid salts; non-toxic metal salts include sodium, potassium, calcium and aluminum, and ammonium salts or substituted ammonium salts, ie triethyl-amine, pro, as salts of non-toxic amines. Caine, dibenzene amine, N-benzyl-beta-phen ethylamine, 1-ephenamine, N, N'-dibenzyl-ethylene diamine, dehydroabiethylamine, N, N'-bis-dehydroabi ethylenediamine , N- (lower) -alkylpiperidine, ie N-ethylpiperidine and other amines that form salts with benzyl ferricillin, non-toxic acid addition salts (amine salts) are inorganic acid addition salts, hydrochloride, embrittlement Hydrochlorides, hydrodes, sulfates, sulfites, phosphates, and organic acid addition salts include maleates, acetates, tartarates, oxalates, succinates, citrates, nomarates, malates, mandelates, and ascorbates And so on.

The method for blocking amino groups in the present compounds (intermediates or metabolic precursors) with the following substituents also belongs to the present invention. G-yodoethoxy-carbonyl (UK 1,349,673), tert-butoxy-carbonyl, carbonbenzyloxy, formyl 0-nitrophenyl sulphenyl, β, β, β-trichloroethoxy carbonyl, 4 Oxo-2-phenphenyl-2,1-carbomethoxy-1-propenyl-2 and the like. In particular such blockers include ketones (particularly acetone) and aldehydes (particularly formaldehyde and acetaldehyde), as known in US Pat. Nos. 3,198,804 and 3,347,851, and beta-ketone esters and beta-dikerone esters, in US Pat. No. 3,325,479. Known, there is β-ketone amide (Japan 71/24714, Farmdoc 47,321 S).

Preferred esters of the cephalosporins of the present invention are pivaloyloxy methyl, acetoxymethyl, methoxymethyl, acetonyl and phen acyl esters. All of these are useful intermediates for the preparation of cephalosporins with free carboxyl groups, and the first three mixtures are very interesting because they have different rates of absorption and absorption at the time of administration and different concentrations of active antibiotics in the form and tissue. to be.

As mentioned above, these five esters of 7-amino-cephalosporranic acid are prepared by known methods and the best method is the corresponding active chloro or bromo compound (ie phenacyl bromide, chloroacetone) as US Pat. No. 3,284,451. , Chloromethyl ether, pivaloyloxy methyl chloride (also referred to as chloro methyl pivalate), acetoxymethyl chloride to esterify sodium cephalosporin, US Pat. Nos. 3,575,970 and J. Antibiotcs XXiV (11) 767-773 Enzymatically remove the thienyl-acetic acid side chain as in (1971) Another preferred method is to directly react the triethylamine salt of 7-aminocephalospanoic acid with an active halogenated compound, as in British Patent 1,229,453. This is how you do it.

This ester of 7-aminocephalosporranic acid is reacted with the former electron HSR ^{2 in the} same manner as listed in 7-aminocephalosporranic acid itself. The 3-thiolated ester of 7-aminocephalosporranic acid is coupled with an organic carboxylic acid, ie D-(-)-2-phenyl glycine. Before or after the removal of a protecting group, i.e., an amino or hydroxy group, from the 7-side chain, US Pat. As known in the penicillin system by 29 (7), 2006 2008 (1964), esterification by treatment with sodium thiopexoxide, by acidic or alkaline hydrolysis or by water or enzymatic hydrolysis (human serum or animal serum) By removing the fire groups, the resulting esters of cephalosporins are converted to their free acids. Another suitable synthesis method is to prepare 3-thiolated 7-aminocephalosporranic acid as described herein, acylate at the 7-amino group, and finally to convert the appropriate alcohol to the final cephalosportinol thionyl chloride. It is a method of esterifying by reacting with an acid chloride prepared by the action or by other acid esterification.

The invention also relates to a process for the preparation of new and valuable intermediates of the following structure:

In an anhydrous solvent to form a lithio derivative of a thiol of the structure

Hydrolysis of the compound produced by the reaction of the above lithio derivatives with carbon dioxide produces a compound of the following structural formula.

The invention also relates to a process for the preparation of novel and valuable intermediates of the structure

(n: integer of 2-9)

A) an isocyanate of the formula

n: integer of 2-9

R ¹⁰⁰ : (lower) alkyl of C ₁ -C ₆

Functional group of the following structural formula,

(Wherein R ¹ is hydrogen, cancellation, oxo, chlorine, (lower) alkyl or alkoxy of fluorine C _{1 to} C ₆ , alkoxy, NO ₂ , Z is an integer of 0 to 4) and reacted with sodium azide to form a thiol-ester of Create

(n and R ¹⁰⁰ are the same as described above)

B) The thiol esters are hydrolyzed to afford thiol-acids of the formula

(n: same as above)

In the treatment of bacterial infections in humans, the compound of the present invention is intravenously injected or administered in an amount of about 5 to 200 mg / kg / day, and preferably about 5 to 20 mg / kg / day in three to four times a day. Administration. Dosage units comprising 125,250 or 500 mg of the active ingredient in a suitable physiologically acceptable excipient or carrier are administered. The dosage unit is in liquid form, such as liquid or suspending agent.

Starting material

end. 1-carboxymethyl-5-mecaptotetrazole

A) recrystallization of 1-methyl-5-mercaptotetrazole

fair :

1. Slurry with 110 g of 1-methyl-5-mercapto tetrazole in boiling chloroform and bring the solution to near solution.

2. Heat-solution (50-60 °) is a heated auxiliary blower funnel (11 cm, SS NO. 604) supplemented 1/4 third inch. Filtration rapidly under reduced pressure through (Supercel). Wash the filter plate with 50 ml of 50 ° 60 ° chloroform and combine the wash with the filtrate.

3. Cool the filtrate to about 0-6 ° C and hold it at 0-6 ° C for 2 hours. The crystals formed at this time are filtered at 0 to 6 ° C, washed with 60 ml of chloroform at 0 to 6 ° C, and combined with the filtrate. The crystal (fraction A) is air dried at 37-45 ° C. for 18 hours.

4. Concentrate the filtrate to about half the volume on a rotary reduced pressure evaporator (bath at 60 ° C.). The resulting slurry is cooled to 0-6 ° C and held at 0-6 ° C for 2 hours. The crystals are filtered to 0-6 DEG C, washed with 40 ml of chloroform at 0-6 DEG C and added to the filtrate. The crystal (fraction B) is air dried at 37 to 45 ° C for 18 hours. Crystals A and B combined together yield about 65% weight.

5. Repeat the filtrate of oil fraction B from step 4 as described in step 4 and regenerate an additional 15%.

B) Di-sodium salt preparation of 1-carboxymethyl-5-mercaptotetrazole

1. Add 500 ml of pure and anhydrous tetrahydrofuran to a 2-liter three-necked flask equipped with a stirrer and cool to −10 ° C. in a salt-acetone-ice bath. Dry nitrogen gas is brown at the surface of the liquid.

2. Add 500 ml of 15.06% (1.6 N) hexane solution of butyl lithium (Foote Minerol Co) for 10 minutes under dry nitrogen and stir tetrahydrofuran. When it is in solution, it is cooled down to -5 ~ 10 ℃.

3. 46.4 g of 1-methyl-5-mercaptotetrazole (recrystallized as described above) is dissolved in 200 ml of pure and dry tetrahydrofuran (THF), and when the solution is cloudy, it is filtered and cooled to 5-10 ° C. do.

4. Add the three cooled solutions for 10 minutes with stirring and to butyliridium solution under dry nitrogen. The temperature should be maintained from -5 ° C up to 10 ° C, and a precipitate forms.

5. The mixture is stirred at 0-10 ° C. for 1 hour 30 minutes under dry nitrogen.

6. Agitate rapidly for 15 to 30 minutes with rapid passing of anhydrous carbon dioxide gas. Suitable temperature is 0 ~ 10 ℃ and should not exceed 20 ℃.

7. Filter the white precipitate and wash with about 75 ml THF.

8. Dissolve the precipitate in 250 ml of water (pH 8.5-9.5). There is a second layer of THF, which is removed in a reduced pressure rotary evaporator (50 ° C. bath).

9. Adjust the aqueous solution to pH 1.6-2.0 with concentrated hydrochloric acid.

10. Extract the acid aqueous solution twice with 250 ml of ethyl acetate. Each 250 ml ethyl acetate extract was back extracted with 100 ml of water, the water-extract was discarded, and the ethyl acetate extracts (without water layer) were combined by filtration.

11. The combined ethyl acetate extracts are concentrated to dryness on a reduced pressure rotary evaporator (60 ° C. bath).

12. Add 300 ml of chloroform to the crystals in the flask and heat for about 2 minutes. Heat-slurry (50-60 degreeC) is filtered under reduced pressure through the heated Buchner funnel (11 Cm-SS-604 paper). The crystals are washed with about 75 ml of chloroform at 50 ° C. The crystals are air dried at room temperature for about 3 hours and brought to about 100-200 mesh.

13. The crystals of 100-200 meshes are treated with boiling chloroform as described in step 12 (thermal-chloroform almost eliminates unreacted 1-methyl-5-mercapto tetrazole). Yield: 1-carboxymethyl-5-mercapto tetrazole crystals About 45-50 g of crystals contain 0.02 to 0.05 mol of 1-methyl-5-mercapto-tetrazole.

14. Slurry the crystals of step 13 with 250 ml of ethyl ether for 3-5 minutes at room temperature. The mixture is filtered. Insoluble matter (0.5-5%) is contaminated with symmetric mercaptotetrazol ketones,

Caution: This compound explodes at approximately 205-210 °.

15. The ether filtrate of step 14 is evaporated to dryness on a rotary vacuum evaporator (50 ° C. bath). About 42-48 g of 1-carboxymethyl-5-mercaptotetrazole containing about 0.01-0.05 moles of -methyl-5-mercapto tetrazole is recovered.

16. Dissolve the crystals in 420 ml of absolute ethanol (about 100 mg / ml). The solution is warmed to 50-60 ° C.

17. Add 310 ml of isopropanol solution of 41% sodium 2-ethyl hexanate (S state) to the heat-solution in step 16 for 10 minutes with rapid stirring. Crystalline precipitate is formed. The mixture is a slurry at 50 to 60 ° C. for 20 minutes.

18. The mixture is filtered on heat through a heated Buchner funnel (11 cm-SS-604). The crystals are washed with 75 ml of 50 ° C. ethanol.

19. Ethanol-containing crystals (18 steps) are slurried in 200-300 ml of ethanol. The slurry is passed through a 200 mesh sieve and heated to 50 to 60 ° C. for 5 minutes with rapid stirring of the slurry. (Unreacted sodium 1-methyl-5-mercaptotetrazole is very soluble in thermal ethanol)

20. The crystals are filtered at 50-60 ° C. through a heated Buchner funnel (11 cm-SS-604). The crystals are washed with 75-100 ml of ethanol and dried under reduced pressure at 50-60 ° C. for 24-48 hours. Yield: 40-48 g of disodium 1-carboxymethyl-5-mercaptotetrazole (no 1-methyl-5-mercapto-tetrazole as observed by NMR)

I. 7-Amino-3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cepem-4-carboxylic acid

1.18 g (0.066 mol) of 7-amino-cephalosporranic acid and 300 ml of 0.1 M, pH 6.4 phosphate buffer (20.7 g of sodium phosphate) in a three-necked flask with agitator, temperature, controller, thermometer and nitrogen inlet tube , Mono-basic) 2H with 1H ₂ O + 8.5g sodium phosphate, di-basic, anhydride.

2. As described in step 1, while stirring the mixture, add 16 g (0.078 mol) of sodium bisulfite 1.5 and 1-carboxymethyl-5-mercaptotetrazole disodium.

3. Continue stirring while passing nitrogen gas through the mixture for 10 minutes.

4. Continue stirring, heating to 56 ° C. over 20 minutes while feeding nitrogen, and 6.5 g of sodium hydrogen carbonate are added in small portions during this time interval.

5. The temperature of the solution is kept at 56 ° C. for 4 hours while stirring and nitrogen feeding. pH should be maintained between 6.2 and 6.6.

6. Cool the reaction mixture to 5 ° C. in an ice bath.

7. Add 50 ml of a solution of phosphoric acid / water (1: 1) or concentrated hydrochloric acid to 2.0-3.0.

8. Filtration yields the product. The filtrate is washed with 20 ml of cold water and 200 ml of cold-methanol.

9. Dry in air until solid is weighed (usually 14.5 g of product). The product is yellowish-dark brown.

10. Pass the product through a 200 mesh stainless steel body.

11. Suspend 10 g of 200 mesh powder in 200 ml of n-propanol with rapid stirring.

12. Add 2.0 ml of concentrated hydrochloric acid and stir vigorously for 30 minutes at room temperature.

13. Filter the slurry. The brown solid is washed with 200 ml of n-propanol and the wash is added to the filtrate. (To ensure that the product no longer appears in the filtrate)

14. 1.5 g of activated carbon (Darco G-60) is added to the n-propanol filtrate of step 13. The activated carbon is filtered off and the activated carbon is washed with 20 ml of n-propanol and the wash is added to the filtrate.

15. With rapid stirring, triethyl-amine is added to the n-propanol filtrate to pH 3.0 to form crystals. It is made into a slurry for 10 minutes.

16. The white crystals are collected by filtration, washed with 30 ml of 50 ml of n-propanol methanol and dried under reduced pressure at 40 ° C. for 24 hours. Yield: 4-8 g of 7-amino-3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

17. 7-Amino-3- (1-carboxymethyl tetrazol-5-ylthio methyl) -3-cefe-4-carboxylic acid is purified by either of the following methods.

A) 10 g of a 200 mesh product (from step 10) is slurried in 75 ml of 1 N hydrochloric acid at room temperature for 10 to 15 minutes. Dark brown solids are filtered off.

B) 2.5 g of activated carbon (Darco G-60) is added and slurried for 30 minutes.

C) Filter the activated carbon, wash the carbon with 15 ml of water and add the washing solution to the filtrate.

D) With rapid stirring, concentrated ammonia is added to the filtrate to pH 2.5-3.0 to form crystals.

ㅁ) The crystal mass is slurried for 25 minutes. Make a decision. The crystals are washed with 30 ml water, 50 ml of methanol and dried under reduced pressure at room temperature. Yield: 4-7 g of white crystals.

Other reagents used in the compounds of the present invention may be synthesized by other known synthetic methods (eg, patents and publications mentioned above). For example, the D-(-)-α amino acids used in the present invention are described in US Pat. Nos. 3,198,804; 3,342,677 or 3,634,418 or Fries and Chem. Scand. 17, 2391 2396 (1966) or Biochemistry (Wash) 5 203 213 (1966) by Nimes and co-workers or other publications relating thereto. The synthesis of carboxylic acids with free amino groups blocked with tert-butoxycarbonyl is listed below.

All. 2- (tert-butoxycarbonylaminomethyl) -1,4-cyclo-hexadienyl acetate

Slowly dilute 1.5 l of 16.6 g (0.1 mole) of 0-amino-methyl phenyl acetate liquid ammonia (treated with 50 mg of lithium to remove all moisture) to 500 ml of dry tert-butanol. 3.4 g (0.5 molecules) of lithium are added to the solution in small portions over 4 hours, and the mixture is stirred at room temperature for 16 hours to remove liquid ammonia from the hood, and then evaporated to dryness at 40 ° C or below. The residue is taken up in 500 ml of water and the solution is chromatographed on a column of IR-120 (H +, 700 ml) resin and eluted with 1% ammonia hydroxide solution. The ninhydrin positive fractions of the eluate are combined and evaporated to dryness. The residue was washed four times with 50 ml of heat-acetox and recrystallized from 500 ml of ethanol-water (1: 1) to give 11.2 g of colorless needles, 0- (2-aminomethyl-1,4-cyclohexadienyl) acetic acid. Get Melting point, 183 ℃

1630,1520,1380,1356cm^-1 IR:

1630,1520,1380,1356cm ^-1

), 3.01(2H, S, CH₂CO), 3.20 (2H,S,CH₂-N), 5.78(2H,S, H＞C=)NMR; δD ₂ O + K ₂ CO ₃ 2.72 (4H, S, H ₂ C

), 3.01 (2H, S, CH ₂ CO), 3.20 (2H, S, CH ₂ -N), 5.78 (2H, S, H> C =)

Elemental Analysis: C ₁₉ H ₁₃ NO ₂ :

Calculated Value: C, 64.65: H, 7.84: N, 8.38

Found: C, 64.77: H, 8.06: N, 8.44

Improved Preparation of 0- (2-aminomethyl-1,4-cyclohexadienyl) -acetic acid

D-2-amino-2- (1,4-cyclo hexadienyl) acetic acid is prepared by applying the method of Wellhi, Dolpini and Giaruso of US Pat. No. 3,720,665 (Example 1). A 830 ml solution of distilled liquid ammonia is dried under argon atmosphere to 40 mg of lithium. While stirring the solution, 11.0 g (0.07 mol) of 2-aminomethyl phenyl acetate and 340 ml of tertiary butyl alcohol are added. A total of 1.6 g of lithium is added to the vigorously stirred solution over 2 hours.

The brown mixture is treated with 35 g of triethylamine (TEA) hydrochloride (0.215 mol) and stirred overnight at room temperature for 18 hours. The white residue resulting from the removal of the tertiary butyl alcohol at 40 ° C. (15 mm) was dried overnight over phosphorus pentoxide under reduced pressure. The solid is dissolved in 30 ml of methanol-water (1: 1) and stirred at 5 ° C. with 3.5 L of chloroform-acetone (1: 1) added. The mixture was stirred for 20 minutes, and amino acid, α- (2-aminomethyl, 1-, 4-cyclo-hexadienyl) acetic acid was added, and the resultant mixture was dried under a oxidative oxidation at 16 hours under reduced pressure for 16 hours. Obtain g (58%). The structure was determined by IR and NMR spectroscopy.

A 152 ml solution of 19.31 g (0.135 mole) of tetrahydrofuran (THF) in tert-butoxycarbonyl azide was prepared using 14.89 g (0.09 mole) of 2-aminomethyl-1,4-cyclohexadienyl acetate and 7.20 g of sodium hydroxide ( 0.18 mol) to 281 ml of an aqueous solution. The solution is stirred for 18 h at 25 ° C. and filtered through diatomaceous earth (Super-cel).

The remaining solution from which THF has been removed at 40 ° (15 mm) is washed with ether (2 x 175 ml) and acidified with 6N hydrochloric acid.

The mixture was stirred in an ice bath, precipitated and dried over 18 hours at 25 ° over P ₂ O ₅ to give a white powder of 2- (tert-butoxy carbonylamino methyl) -1,4-cyclo-hexadienyl- Obtain 17.3 g (72.6%) of acetic acid.

The structure is determined by IR and NMR spectroscopy.

la. D-(-)-P-hydroxy-α-tert-butoxy carboxy-amidophenylacetic acid

In the oil base, 5.65 g (0.14 mole) of magnesium oxide and 11.7 g (0.07 mole) of D-(-)-P-hydroxyphenyl glycine are ground and added to 177 ml of 50% dioxane. Slowly add 20.0 g (0.14 mole) of tert-butoxycarbonyl azide to the vigorously stirred mixture and stir at 45 ° -50 ° for 20 hours. The mixture is diluted with 710 ml ice water and 177 ml ethyl-acetate and filtered to separate the filtrate in two phases. The organic phase is washed with 3 x 50 ml of sodium bicarbonate solution and 3 x 50 ml of water. All water phases are combined and cooled to pH 5.0 with concentrated hydrochloric acid. The product is extracted with 3 x 125 ml of ethyl acetate. Ethyl-acetate is washed with 2 x 50 ml of water, dried over magnesium sulphate and evaporated to 35 ° C. 15 mm to give an oil phase. Dissolving the oily substance in petroleum ether yields white solid D-(-)-P-hydroxy-α-tert-butoxycarboxido phenylacetic acid. This was taken and dried under reduced pressure at 25 ° for 18 hours under a 5 oxidation increase to yield 13.5 g (72.2%) of white powder. The structure is determined by melting point 102 ° IR and NMR spectroscopy.

hemp. D-(-)-α tert-butoxycarboxidophenylacetic acid

The reaction is carried out as above using D-(-)-P-hydroxy-α-tert-butoxycarboxamide phenyl acetate.

Melting point 82 °, yield 5.2g (30%) is obtained. The structure is determined by R and NMR.

bar. 2- (tert-butoxycarbonylaminomethyl) -1,2-cyclo-hexenyl acetic acid, aka [2- (N-tert-butoxycarbonylamino) -methyl-1-cyclohexenyl-yl Acetic acid

A) α- [2- (tert-butoxycarbonylaminomethyl) -1,4-cyclohexadienyl] acetic acid (1)

tert-butoxycarbonyl azide 10.3 with stirring 150 ml of an aqueous solution of 8.0 g (0.048 mol) of α- (2-aminomethyl-1,4-cyclohexadienyl) acetic acid and 3.8 g (0.096 mol) of sodium hydroxide g (0.072 mol) of THF80ml solution is added and the mixture is stirred for 18 hours at room temperature. THF is removed under reduced pressure and the residual solution is washed with ether (2 × 100 ml), acidified with 6N hydrochloric acid and extracted with ether (3 × 100 ml). Combine the extracts and wash with water (2 x 100 ml) and saturated brine (100 ml). Dry with magnesium sulfate and evaporate to dryness. Dissolving the oily residue in n-hexane yields 10.5 g (82%) of a colorless powder with a melting point of 113 °.

3370,1715,1640,1530,1280,1160cm^-1 IR:

3370,1715,1640,1530,1280,1160cm ^-1

1.45(9H, S,t-Bu-H), 2.73(4H,S,H₂

) 3.16(2H,S, CH₂CO), 3.76(2H, d, 6Hz, CH₂N) 4.90(1H, m, NH), 5.66(2H, S, H＞Cn), 10.6(1H, br-S, COOH)NMR:

1.45 (9H, S, t-Bu-H), 2.73 (4H, S, H ₂

) 3.16 (2H, S, CH ₂ CO), 3.76 (2H, d, 6 Hz, CH ₂ N) 4.90 (1H, m, NH), 5.66 (2H, S, H> Cn), 10.6 (1H, br- S, COOH)

Elemental Analysis: C ₁₄ H ₂₁ NO ₄

Calculated Value: C, 62.90: H, 7.92: N, 5.24

Found: C, 63.13: H, 8.21: N, 5.26

B) [2- (N-tert-butoxycarbonyl amine) methyl-1-cyclohexane-1yl] -acetic acid (2)

A solution of 3% ammonia hydroxide (10 ml) of 2- (N-tert-butoxycarbonylamino) methyl-1,4-cyclo-hexadien-1-ylacetic acid (1), (1.33 g, 5 mmol) Hydrocracking with carbon-platinum (10%, 0.2 g) at 40 PSi. The theoretical value of hydrogen is performed for 3 hours. The catalyst is filtered off, adjusted to pH 2 with ash-hydrochloric acid and extracted with ethyl acetate (2 × 50 ml). The combined extracts are washed with water (20 ml), dried over magnesium sulfate and evaporated under reduced pressure to form an oil which solidifies upon standing for several days.

Recrystallization with n-hexane-ethyl acetate yields 1.2 g of (2) as a colorless prism having a melting point of 118 to 119 °.

3450, 1730, 1660, 1510cm^-1 IR:

3450, 1730, 1660, 1510 cm ^-1

1.58(9H, S, t-buty1-H), 1.50-1.90NMR:

1.58 (9H, S, t-buty1-H), 1.50-1.90

(4H, m, -CH _2- ), 1.90-2.20 (4H, m, allyl methylene-H), 3.18 (2H, S, CH ₂ -CO), 3.78 (2H, d, 6 Hz, CH ₂ N) , 5.00 (1H, br-S, NH), 8.98 (1H, br-S, COCH),

Elemental Analysis: C ₁₄ H ₂₃ NO ₄ :

Calculated: C, 62.43; H, 8.81; N, 5.20

Found: C, 62.12; H, 8. 77; N, 5.37

four. 2-3-butoxycarbonylaminomethyl-4-hydroxy-phenyl acetate is prepared, for example, according to US Pat. No. 3,823,141.

Ah. 0- (tert-butoxycarbonylaminomethyl) phenyl-thio acetate is prepared, for example, according to US Pat. Nos. 3,657,232 and 3,813,390.

character. Beta- [0- (3-tertbutoxycarbonylamino methyl) -phenyl] -propionic acid is prepared, for example, according to US Pat. No. 3,813,391.

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

2- (3'-methyl-4'-hydroxyphenyl) glycine

A 100 ml aqueous solution of 59.02 g (0.6 mol) of 75% glyoxylic acid was added to a suspension of 54.6 g (0.5 mol) of 2-methylphenol and 400 ml water of 140 ml concentrated-ammonia aqueous solution at room temperature, and the mixture was raised to 37 ° and at room temperature. Stir for 65 hours. Crystals are formed by adjusting the original solution of pH 10.1 to pH 6.8 with 6N hydrochloric acid. The product was taken by filtration, washed with water and dried under reduced pressure over phosphorus pentaoxide to give 31.5 g (34.8%) of 2- (3'-methyl-4'-hydroxyphenyl) glycine. Determine the structure of the target in a 196-199 ° IR and NMR spectrometer.

Reference: Belgian Patent 774,029, Misery Group. 1972 (Farmdoc 27,122T) reported a melting point of 205-207 ° C.

Elemental Analysis: C ₉ H ₁₁ NO ₃

Theoretical: C, 59.66; H, 6. 13; N, 7.73

Found: C, 57.63; H, 6. 23; N, 7.47; H ₂ O 2. 34

2.34% H ₂ O was corrected in found, C, 59.06; H, 6. 12; N, 7.67

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

A suspension of 20.2 g (0.112 mol) of D, L-2- (3'-methyl-4'-hydroxyphenyl) glycine in 175 ml of water is adjusted to pH 10.3 with 20% caustic soda. The solution is cooled in an ice bath, acetic anhydride (38.2 g, 0.224 mol) is added all at once and added until the pH is changed with 20% caustic soda to maintain the pH of the reaction mixture at 10 and the reaction mixture is stirred for 10 more minutes under cooling. .

The reaction mixture is brought to pH 2 with 6N hydrochloric acid to form crystals. The resulting crystals are filtered off, washed with water and air dried. Recrystallization with 200 ml of hot water gives 13.7 g (47.4%) of D, L-N-chloroacetyl-2- (3'-methyl-4'-hydroxyphenyl) glycine. Confirm the components of the target by IR and NMR spectroscopy.

Elemental analysis: C ₁₁ H ₁₂ NO ₄ Cl. H ₂ O

Calculated: C, 47.92; H, 5. 118; N, 5.081

Found: C, 48.11; H, 5. 16; N, 5.15

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

D, LN-chloroacetyl-2- (3'-methyl-4'-hydroxy-phenyl) glycine (5.0 g, 0.0194 mole) and L-ephenamine acetate (6.1 g, 0.0113 mole) were heated on the rooftop Dissolve in 50 ml of isopropyl alcohol. Water (50 ml) is added and cooled to form crystals of the L-ephenamine salt. The salt is filtered off and air dried.

=185.9°(Cl,, 95%에탄올). IR 및 NMR 분광기로 생성물을 확인한다.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% caustic soda. The layers are separated and the aqueous layer is extracted two more times with methylene chloride. Crystals are formed by adjusting the aqueous layer to pH 2.0 with 6N hydrochloric acid. The product was filtered off and dried under reduced pressure at a pentoxide impression to yield 0.9 g (36.1%) of D-(-)-N-dichloroacetyl-2- (3'-methyl-4'-hydroxy-phenyl) glycine. Melting point 170-172 °,

= 185.9 ° (Cl, 95% ethanol). The product is confirmed by IR and NMR spectroscopy.

Elemental Analysis: C ₁₁ H ₁₂ NO ₄ Cl

Calculated: C, 51.27; H, 4.696; N, 5.436

Found: C, 51.21; H, 4.77; N, 5.29

It is called 1,2-diphenyl-2-methyl amino ethanol, also known as phenamine (Federal Register, June 7, 1951).

The compounds also contain N-methyl-1,2-diphenyl-2-hydroxy-ethylamine or alpha, beta-diphenyl-beta-hydroxy-N-methyl-ethylamine or 1,2-diphenyl-2 Also called -methylamino-1-ethanol.

The present invention is only useful with the Levo-erythro isomer. Its preparation and reaction with Pericillin G have been described in US Pat. Nos. 2,645,638 (V.V.Young) and 2,768,081 (F.H. Buckwalter). The latter is the double oil. ratio. Whitley and his collaborators, J.Org. Chem. 18 (11), 1564-1571 (9153). Xuhan and his collaborators, J. Am. Chem. Soc., 81, P. 3039 3094 (1959) reported a method of cleaving racemiphenoxy penicillin. In particular, see page 3091.

D-(-)-2- (3'-methyl-4'-hydroxy-phenyl) glycine

=-152.6℃ 1,1N-염산), IR 및 NHR분광기로 목적물을 확인한다.100 ml of 2N hydrochloric acid was added to D-(-)-N-dichloroacetyl-2- (3'-methyl-4'-hydroxy-phenyl) glycine (11.1 g, 0.0431 mol) and refluxed for 1 hour 30 minutes. The solution is cooled and adjusted to pH 5.0 with 20% caustic soda to form a crystal. The crystals were filtered off, washed with water and dried under reduced pressure over phosphorus pentaoxide to yield 7.4 g (94.7%) of D-(-)-2- (3'-methyl-4'-hydroxyphenyl) glycine at 205-209 ° of decomposition. Get

= -152.6 ° C. 1,1N hydrochloric acid), IR and NHR spectroscopy to confirm the target.

Elemental Analysis: C ₉ H ₁₁ NO ₃

Calculated: C, 59.66; H, 6. 13; N, 7.73

Found: C, 58.62; H, 5.49; N, 7.78; H ₂ O 1.46

Found, C, 59.48, corrected for 1.46% H ₂ O; H, 5.41; N, 7.84

D-(-)-N-tert-butoxycarbonyl-2- (3'-methyl-4'-hydroxy-phenyl) glycine

A slurry of 7.2 g of D-(-)-2- (3'-methyl-4'-hydroxyphenyl) glycine and 3.2 g (0.08 mol) of magnesium oxide powder was stirred in 100 ml of 50% dioxane, 9.7 g (0.068 mol) of butoxy-carbonyl azide are added dropwise. The reaction mixture is heated to 42-45 ° C. under nitrogen atmosphere for 19 hours. Dilute the mixture to 100 ml of ice water. The ethyl acetate layer, from which the solution was extracted with ethyl acetate, was filtered to remove insoluble matters. The aqueous-layer of the filtrate is separated and extracted twice more with ethyl acetate. The aqueous solution is adjusted to pH 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 magnesium sulfate and the solvent is removed under reduced pressure leaving an oily phase.

Drying the oily substance under reduced pressure over phosphorus pentoxide yielded 10.6 g (95%) of D-(-)-N tert -butoxycarbonyl-2- (3'-methyl-4'-hydroxy phenyl) glycine. IR and NMR spectroscopy confirm the components of the object.

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

2- (3'-methoxy-4'-hydroxyphenyl) glycine

100 ml of an aqueous solution of 59.2 g (0.6 mol) of 75% glyoxylic acid is added to a suspension of 61.07 g (0.5 mol) of 2-methoxyphenol and 140 ml of concentrated ammonia hydroxide in 400 ml of water at room temperature. The temperature of the mixture is raised to 35 ° C. and stirred at room temperature for 65 hours. The crystals are filtered off, washed with water and then washed with acetone and dried under reduced pressure at a oxidative impression to give 57.4 g (58.2%) of 2 (3'-methoxy-4'-hydroxy-phenyl) glycine. Decompose 218-220 ° (240 ° in literature) IR and NMR spectroscopy.

Elemental Analysis: C ₁₉ H ₁₁ NO ₄

Calculated: C, 54.82; H, 5. 62; N, 7.10

Found: C, 53.77; H, 5.91; N, 6.97, H ₂ O 1.13

Actual value corrected for 1.13% H ₂ O

C, 54.38; H, 5.85; N, 7.05

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

Cleavage of 2- (3'-methoxy-4'-hydroxyphenyl) glycine

A: methyl-2- (3'-methoxy-4'-hydroxyphenyl) glycinate

A cooled suspension of 94 g (0.476 mole) of 2- (3'-methoxy-4'-hydroxyphenyl) glycine in 500 ml of absolute ethanol was rapidly passed through hydrochloric acid for 20 minutes. After 20 hours, at first becoming a clear solution and then quantitatively separating the crystals, the methyl ester hydroclyde is filtered and washed with methanol. Air drying gives 99.6 g of product. Adjusting the cooled solution of hydrogen chloride in 800 ml of water to pH 8 (NaOH) produced a crystallization of the ester free base; Verify the configuration with 81.3 g, IR and NMR spectroscopy.

Elemental Analysis: C ₁₀ H ₁₃ NO ₄

Calculated: C, 56.86 H, 6.20; N, 6.63

Found: C, 56.46; H, 6. 28; N, 6.55; H ₂ O, 0.59

B: 50 g (0.237 mol) of B-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine methyl-2- (3'-methoxy-4'-hydroxyphenyl) glycinate ), A mixture of 19 ml (0.333 mol) acetic acid and 1 liter of iso-propanol is added to reflux with dibenzoyl-d-tartrate monohydrate (89.2 g, 0.237 mol) with boiling heating and stirring well. The salt begins to crystallize. Stop heating and allow the flask to cool slowly to room temperature. After cooling in ice cubes, the precipitate is taken off. The filtrate is concentrated to one-third of its initial volume to produce a small amount of salt. Yield 54.1 g (Solid A: see below) The filtrate is concentrated until the solvent is gone, 300 ml of 1N hydrochloric acid is added to the adhesive residue and extracted with 400 ml of chloroform. The chloroform layer is extracted twice with 100 ml of 1N hydrochloric acid. The hydrochloric acid extract is concentrated until the remaining chloroform is removed and refluxed for 1 hour. The solution is concentrated to allow the amino acid hydrochloride to crystallize. The crystals are filtered off and recrystallized with 50 ml of 1N hydrochloric acid. The solution dissolved in 200 ml of water was adjusted to pH 4.5 (NaOH), heated and boiled until boiling to precipitate D-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine in needle crystals. Is obtained. Cool overnight and the product is filtered off, washed with water and methanol and dried at 40 °.

=-136.5°(C1, 1N 염산) IR 및 NMR분광기로 확인한다.8.7 g,

= -136.5 ° (C1, 1N hydrochloric acid) Check with IR and NMR spectroscopy.

Elemental analysis: C ₁₉ H ₁₁ NO ₄ . H ₂ O

Calculated: C, 50.23; N, 6.09; N, 6.51; H ₂ O, 8.37

Found: C, 50.43; H, 6. 23; N, 6.51; H ₂ O 8.95

L-(+)-2- (3'-methoxy-4'-hydroxyphenyl) glycine

Solid A (54.1 g) above is suspended in 300 ml of 1N hydrochloric acid and 500 ml of chloroform with good stirring. Since salts do not break well in this system, chloroform is separated as well as possible and 300 ml of MIBK is added with stirring. The MIBK phase is extracted three times with 200 ml of 1N hydrochloric acid. The extracts are combined and the hydrochloric acid extract is filtered and concentrated to remove residual solvent and then heated to reflux for 1 hour to hydrolyze the ester. The reaction mixture is concentrated and cooled in an ice bath followed by filtration of crystalline amino acid hydrochloride. Recrystallize with 75 ml of 1N hydrochloric acid, dissolve in 500 ml of water while warming, and adjust to pH 4.5 (NaOH) to be positive ion for filtration and crystallization of the solution. The mixture is heated, filtered and cooled to form a crystal product, L-(+)-2- (3'-methoxy-4'-hydroxyphenyl) glycine precipitate. This precipitate is filtered off, washed with water and dried at 40 ° C.

=+127.2(Cl 1N 염산), IR 및 NMR분광기로 확인한다.9.6 g

= + 127.2 (Cl 1 N hydrochloric acid), confirmed by IR and NMR spectroscopy.

Elemental analysis: C ₉ H ₁₁ NO _4. · H ₂ O

Calculated: C, 50.23; H, 6.09; N, 6.51; H ₂ O, 8.37

Found: C, 50.53; H, 6.06; N, 6.62; H ₂ O, 7.46

D- (1-)-N- (tert-butoxycarbonyl))-2- (3'-methoxy-4'-hydroxy-phenyl) glycine

8.6 g (0.04 mole) of D-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine, 3.2 g (0.08 mole) of tert-butoxycarbonyl azide and 240 ml The 1: 1 dioxane-water mixture is stirred and heated to 45-50 ° for 20 hours in a nitrogen atmosphere. The cooled reaction mixture is diluted with 240 ml of ice water, filtered and extracted once with ethyl acetate. The acidic (pH 2) aqueous phase is extracted five times with ethyl acetate. The extracts were combined and the dried (Na ₂ SO ₄ ) ethyl acetate extract was concentrated under reduced pressure until the solvent was gone to give 6.3 g of a viscous oily substance.

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

This compound is prepared by using an equivalent of D-(-)-2- (4-acetoxyphenyl) glycine in place of D-(-)-2- (3'-methyl-4'-hydroxyphenyl) glycine. React as follows.

Preparation of D-(-)-2-amino-2- (4-acetoxyphenyl) acetic acid.

Preparation method (using acetic acid as a solvent)

203.5 (1 mole) of D-(-)-P-hydroxyphenyl glycine chloride, 800 ml of acetic acid and 314 g (4 moles) of acetylchloride mixture are stirred at room temperature for 48 hours. Take a solid and wash with acetone (3 × 250 ml) and ethanol (2 × 250 ml) and dry at 40 °. Yield: 210 g (85.4%). This hydrochloride is dissolved in 3.0 liters of water and the solution is cooled to 5-10 ° C. and adjusted to pH4.5 with 20% ammonium hydroxide. The suspension is stirred for 1 hour at 5 °, the solids are taken, washed twice with water twice with acetone and dried at 40 ° C. Yield: 133 g (64% from D-(-)-P-hydroxy-phenylglycine) αD (0.1 N hydrochloric acid 0.1 N) =-104.5

Preparation method b (using methylene chloride as solvent)

4.07 g (0.02 mol) of D-(-)-P-hydroxyphenylglycine hydrochloride, 30 ml of methylene chloride and 6.28 g (0.08 mol) of acetylchloride mixture are stirred at room temperature for 48 hours. The solid is taken up and washed twice with acetone and twice with ethanol. Yield: 4.17 g (84.5%) Elemental Analysis Cl = 14.8% (Calculated 14.4%)

Preparation c (in trifluoroacetic acid)

1.67 g (0.01 mol) of D-(-)-P-hydroxyphenyl-glycine is added to 10 ml of trifluoro acetic acid at room temperature with stirring. After dissolution, 1.57 g (0.02 mole) of acetylchloride is added. After a slight exothermic reaction, a solid appears. The suspension is stirred for 1 hour 30 minutes at room temperature and acetic acid is removed with trifluoluco under reduced pressure. The remaining solid is taken and washed with methylene chloride and with ethanol. D-(-)-2-amino-2- (4-acetoxyphenyl) acetic acid is identical to that produced in formula A or I. Yield: 1.9 g (75%)

la. D-(-)-N-tert-butoxycarbonyl-2- (1'-cyclohexenyl) glycine

This compound substitutes the equivalent of D-(-)-2- (1-cyclohexenyl) -glycine in place of the above D-(-)-2- (3'-methyl-4'-hydroxy-phenyl) glycine. To Belgian Patent 773,773 (Farmdoc 25,515T) or US Patent 3,824,237.

hemp. D-(-)-N-tert-butoxycarbonyl-2- (3'-chloro-4'-hydroxyphenyl) glycine is prepared according to US Pat. No. 3,489,751.

F. D-(-)-N-tert-butoxycarbonyl-2- (1 ', 4'-cyclo-hexadienyl) glycine

This compound is equivalent to D-(-)-2- (1 ', 4'-saccyclohexadienyl) in place of the above-mentioned D-(-)-2- (3'-methyl-hydroxy-phenyl) glycine Prepared by US Pat. No. 3,458,819 using glycine (aka D-2-amino-2- (1,4-cyclohexadienyl) acetic acid).

four. D-(-)-2-tert-butoxycarboxamido-3- (1 ', 4'-cyclohexadienyl) propionic acid

This compound is equivalent to D-2-amino-3 (1,4-cyclohexadienyl) propionic acid instead of the above-mentioned D-(-)-2- (3'-methyl-4'-hydroxyphenyl) glycine Is prepared by US Pat. No. 3,458,819.

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

This compound is equivalent to D-2-amino-3- (4'-methoxy-1,4 instead of D-(-)-2- (3'-methyl-4'-hydroxyphenyl) glycine -Cyclohexadienyl) -propionic acid using US Pat. No. 3,485,819.

character. 2-3-butoxycarbonylaminomethylphenyl-acetic acid is prepared, for example, by US Pat. No. 3,766,175.

car. N-tert-butoxycarbonyl-1-aminocyclohexane-carboxylic acid

The present compound is prepared using 1-amino-cyclohexanecarboxylic acid in an amount instead of D-(-)-2- (3'-methyl-4'-hydroxyphenyl) glycine.

Ka. D-(-)-alpha-tert-butoxycarboxamido-3-thienyl-acetic acid is prepared, for example, by US Pat. Nos. 3,634,418 and 3,198,804 and suitable literature there.

Get. D-(-)-alpha-tert-butoxycarboxamido-2-thienyl-acetic acid is produced by, for example, US 3,634,418 and 3,198,004 and suitable literature there.

wave. Beta- (2--3-butoxycarbonylamino methyl-1,4-cyclohexadienyl) propionic acid

A) Liquid ammonia (1000 ml) of beta- (2-aminomethyl-1,4-cyclohexadienyl) -propionic acid, beta- (0-aminomethylphenyl) propionic acid (10.74 g, 60 mmol) (removes traces of water) Solution pretreated with 50 mg of lithium), carefully dilute with anhydrous tert-butanol (300 ml). To this solution is added dropwise lithium (2.08 g, 0.3 atoms) over 3 hours and stirred overnight to remove liquid ammonia. The residue is dissolved in water (200 ml), chromatographed on an IR-120 (H + type, 500 ml) column and eluted continuously with water (2000 ml) and 5% ammonium hydroxide (about 2000 ml). The ninhydrin positive fractions are combined, evaporated to solidity and the residue crystallized from 90% ethanol to give colorless acicular crystals. 96.8 g of beta (2-aminomethyl-1,4-cyclohexadienyl) propionic acid are obtained. (89%) Melting Point 228-229 ℃

2130, 1540, 1300cm^-1 IR:

2130, 1540, 1300cm ^-1

2.68(4H, S, CH₂CH₂CO), 2.74NMR:

2.68 (4H, S, CH ₂ CH ₂ CO), 2.74

(4H, S, methylene ring), 3.68 (2H, S, CH ₂ N), 5.79 (2H, S, vinyl-H ring)

Elemental Analysis: C ₁₀ H ₁₅ NO ₂

Calculated: C, 66.27; H, 8.34; n, 7.73

Found: C. 66.25, 66.31; H, 8.35, 8.52; N, 7.61, 7.71

B) beta- (tert-butoxycarbonylaminomethyl-1,4-cyclohexadienyl) propionic acid

To a mixture of 50% THF aqueous solution (20 ml) of beta- (2-aminomethyl-1,4-cyclohexadienyl) -propionic acid (1.40 g, 7.7 mmol) and tri-ethylamine (2.02 g, 20 mmol) Then, THF (5 ml) tert-butyl azidoformate (1.43 g, 10 mmol) solution is added and stirred overnight at room temperature. The mixture is washed with ether (2 x 20 ml) and the aqueous layer is acidified with dilute hydrochloric acid to pH2. The mixture is extracted with chloroform (4 x 30 ml) and the combined extracts are washed with water and dried. Evaporation under reduced pressure affords colorless oily beta- (2-tert-butoxy-carbonyl aminomethyl-1,4-cyclohexadienyl) -propionic acid. Yield 2.10 (97%)

1700, 1510, 1240, 1160cm^-1 IR:

1700, 1510, 1240, 1160 cm ^-1

1.47(9H, S, t-Bu-H), 2.45(4H, S, CH₂CH₂) 2.69(4H, S, 메틸렌 환) 3.80(2H, d, 5Hz, CH₂N) 5.70 (2H, S, 비닐-H 환)NMR:

1.47 (9H, S, t-Bu-H), 2.45 (4H, S, CH ₂ CH ₂ ) 2.69 (4H, S, methylene ring) 3.80 (2H, d, 5 Hz, CH ₂ N) 5.70 (2H, S , Vinyl-H ring)

Come on. Beta- (2-tert-butoxycarbonylaminomethyl-1-cyclohexenyl) propionic acid

Beta- (2-tert-butoxycarbonylaminomethyl-1,4-cyclohexadienyl) propionic acid (0.92 g, 3,2 mmol) is dissolved in 3% ammonia water (20 ml) and carbon-palladium at 30 PSi Hydrogenate in a Parr vessel for 3 hours with (10%, 0.1 g). The mixture is filtered, the filtrate is brought to pH ₂ with dilute hydrochloric acid and extracted with ethyl acetate (3 x 30 ml). The combined extracts are washed with a small amount of water and dried. Removal of the solvent under reduced pressure gives an oily substance of beta- (tert-butoxy-carbonylaminomethyl-1-cyclohexenyl) propionic acid. Yield 0.84 (91%)

3350, (NH), 3200-2400(COOH), 1750(co), 1250, 1165(BOC)IR:

3350, (NH), 3200-2400 (COOH), 1750 (co), 1250, 1165 (BOC)

1.48(9H, S, t-Bu), 1.5-1.8(4H, m, CH₂CH₂), 1.8-2.2(4H, m, 알릴-CH₂), 2.4(4H, CH₂CH₂-CO), 3.72(2H, S, N-CH₂).NMR:

1.48 (9H, S, t-Bu), 1.5-1.8 (4H, m, CH ₂ CH ₂ ), 1.8-2.2 (4H, m, allyl-CH ₂ ), 2.4 (4H, CH ₂ CH ₂ -CO) , 3.72 (2H, S, N-CH ₂ ).

Cha. D-(-)-N-tert-butoxycarbonyl-2- (4'-hydroxy-methyl-phenyl) glycine

The present compound (also known as D-(-)-N-tert-butoxycarbonyl-P-hydroxymethyl-phenylglycine) is prepared by South Africa 73/4055 as follows.

500 ml of dry THF solution of lithium tri (tert-butoxy) aluminum hydrate (104.0 g, 0.410 mol) in nitrogen in an ice bath in 200 ml of anhydrous THF 200 ml of 1,4-benzenedicarboxaldehyde (50.0 g, 0.373 mol). Drop it off. After stirring for an hour and a half in an ice bath, the mixture is poured into 2 l of cooled 2N-hydrochloric acid. The aqueous solution is extracted four times with 800 ml of ether and the ether layer is washed with 500 ml of cooled 5% sodium bicarbonate and 500 ml of saturated saline. After drying, the ether is removed under reduced pressure to yield 46 g of crude P-hydroxymethyl-benzal dehydro. It is chromatographed on 1 kg of natural alumina and the ether eluted fractions are concentrated. Upon cooling, crystals of P-hydroxymethylbenzaldehyde (17.0 g, 35%) are produced. Melting point 44.5-46 ° C. P-hydroxymethylbenzaldehyde (10.0 g, 0.0735 mole) and 110 ml of 60% ethanol solution of ammonium carbonate (17.1 g, 0.15 mole) are heated to 50 ° C. with stirring and sodium cyanide (4.0 g 10 ml of an aqueous solution of 0.081 mol) is added dropwise. The mixture is heated to 55-60 ° C. for 3 hours and raised to 85 ° C. for 1 hour. Cool in an ice bath, adjust to pH 6 with concentrated hydrochloric acid, cool overnight to precipitate precipitate, wash with cold water and dry. 5- (P-hydroxy phenyl) hydantoin (11.0 g, 72%), melting point 189-196 ° (decomposition) is used for amino acid preparation without further purification.

A 125 ml mixture of 5- (P-hydroxymethylphenyl) hydantoin (10.9 g, 0.053 mol) and barium hydroxide (octahydrate) (25.5 g, 0.081 mol) is stirred and refluxed for 18 hours. Cool in an ice bath and dilute with 125 ml of water. Acidify to pH 1 with concentrated sulfuric acid, filter barium sulfate and raise to pH 6 with lead carbonate. Filter the lead sulfate and the filtrate is saturated with saturated hydrogen sulfite salts and the lead sulfite is filtered. The aqueous solution is azeotropic with ethanol under reduced pressure and concentrated to 100 ml. After cooling, P-hydroxymethylphenylglycine (5.2 g, 54%), melting point 228-229 ° (decomposition) is precipitated, and recrystallization with ethanol-water gives melting point 230-231 ° (decomposition).

Elemental Analysis: C ₉ H ₁₁ NO ₃

Calculated: C, 59.66; H, 6. 12; N, 7.73

Found: C, 59.46; H, 6. 24; N, 7.93

Tert-butoxy-carbonylazide (6.95 g, 0.049 mol) dissolved in 120 ml THF in 160 ml aqueous solution of P-hydroxymethylphenyl glycine (8.0 g, 0.044 mol) and triethylamine (8.8 g, 0.087 mol) Was added and stirred overnight at room temperature, then the mixture was washed twice with 200 ml of ether. The aqueous layer is covered with ether and acidified to pH 3-3.5 with 3N hydrochloric acid in an ice bath. The acidic solution is extracted three times with 200 ml of ether. The ether layers are combined, washed with saturated brine, dried and the ether is evaporated under reduced pressure. The oily substance was dissolved in chloroform-hexane and the solid was filtered to give dl-N-tert-butoxycarbonyl-P-hydroxymethylphenyl-glycine (7.74 g, 63%) melting point 139-141.5 ° (decomposition) .

Elemental Analysis: C ₁₄ H ₁₉ NO ₅

Calculated: C, 59.78; H, 6.81; N, 4.98

Found: C, 59.67; H, 6.76; N, 4.69

-149.8 C=1, 메탄올)을 3회 재결정화하여 분할한 염(4.6g, 융점 205-6°분해

-163.4 C=1, 메탄올)을 얻는다. 더 이상 재결정해도 광합적인 회전은 증가하지 않았다.dl-N-tert-butoxycarbonyl-P-hydroxymethylphenyl-glycine (7.560 g, 0.0269 mole) and quinine (10,199 compound, 0.0269 mole) are mixed and dissolved in 110 ml of boiling ethanol. The solution is cooled to room temperature and left overnight to crystallize. Filter the salt and repeat the crystallization three times. Salt (17.76 g, melting point 198-201 ° decomposition,

-149.8 C = 1, methanol), recrystallized three times, salt (4.6 g, melting point: 205-6 deg.

-163.4 C = 1, methanol). Recrystallization no longer increased the photosynthetic rotation.

The (-) quinine salt of (-)-N-tert-butoxycarbonyl-P-hydroxymethyl phenyl-glycine is suspended in 75 ml of water and 175 ml of ether in an ice bath and brought to pH 2.5 with 3N hydrochloric acid. The ether layer is removed and the aqueous layer is extracted twice with 100 ml of ether. The ether layer is washed with 100 ml of saturated brine, dried and the ether is removed under reduced pressure. The residue was dissolved in chloroform-hexane and filtered to give decomposition of d-(-)-N-tert-butoxycarbonyl-P-hydroxymethyl phenyl glycine (1.68 g, 98% regeneration) (melting point 111-113.5 °) Get

=-136.5(C=1, 메탄올)

= -136.5 (C = 1, methanol)

Here, before the acylation in the nucleus, such as II, the use of the 7-sided chainene-amino ＂protecting group with free amines is already known, for example in U.S. Patent 3,223,141, U.S. Patent 3,813,390, U.S. Patent 3,813,391 U.S. Patent 3,823,141 and Belgian Patent 773,773 are described by reference to the following process.

2- [N (1-Carbetoxypropyn-2-yl) amino methyl-1,4-cyclo hexadienel sodium acetate salt (4)

To a stirred solution of 460 mg (0.02 mol) of metallic sodium in 100 ml of anhydrous alcohol was added 3.34 g (0.02 mol) of 2-aminomethyl-1,4-cyclohexadienyl acetate and 3.1 g (0.024 mol) of ethylacetone acetate, and the mixture was It is heated to reflux for 4 hours with stirring. Filtration of the heat-reaction mixture and keeping the filtrate overnight cooled gave 2.0 g of colorless needles (4). Melting point 264 캜. Further concentration of the mother liquor is produced again. (3.3 g) The total yield is 5.3 g (88%).

3300, 1635, 1600, 1570, 1300, 1275, 1170, 1090IR:

3300, 1635, 1600, 1570, 1300, 1275, 1170, 1090

1.23(3H, t 7Hz, CH₂CH₃), 1.96 2.25(3H, S, C=C-CH₃, cis trans), 2.70(4H, S,

), 3.04(2H, S, CH₂CO) 3.66 3.95(2H, S, CH₂-N, cis trans), 4.07(2H, q, 7Hz, CH₂CH₃), 4.45 4.56(1H, S,

, cis trans), 5.76(2H, S,

).NMR:

1.23 (3H, t 7 Hz, CH ₂ CH ₃ ), 1.96 2.25 (3H, S, C = C-CH ₃ , cis trans), 2.70 (4H, S,

), 3.04 (2H, S, CH ₂ CO) 3.66 3.95 (2H, S, CH ₂ -N, cis trans), 4.07 (2H, q, 7 Hz, CH ₂ CH ₃ ), 4.45 4.56 (1H, S,

, cis trans), 5.76 (2H, S,

).

Elemental Analysis: C ₁₅ H ₂₀ NO ₄ Na

Calculated: C, 59.79; H, 6.69; N, 4.64

Found: C, 59.69; H, 6.76; N, 4.75

D-N- (2-methoxy carbonyl-1-methylvinyl) -alpha-amino-alpha- (3'-methyl-4'-hydroxy phenyl) sodium acetate.

To a solution of 3.02 g (0.07 mol) of caustic soda and 320 ml of ethanol, 0.08 mol of D-(-)-2- (3'-methyl-4'0hydroxy phenyl) glycine was added, and the mixture was heated to reflux, To 80 ml of methyl aceto acetate 9.6 ml (0.088 mol) was added for 30 minutes. After refluxing for another 30 minutes, methanol is distilled off while dorolol toluene is added at the same capacity as the rate of distillation. 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 under reduced pressure until it is weighed over phosphorus pentoxide to give DN- (2-methoxy-carr A solid of the carbonyl-1-methylvinyl) -alpha-amino-alpha- (3'-methyl-4'-hydroxy phenyl) sodium acetate salt is obtained.

D-N- (2-methoxycarbonyl-1-methylvinyl) -alpha-amino-alpha- (3'-methoxy-4'-hydroxyphenyl) sodium acetate

0.08 mole of D-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine was added while stirring a caustic soda 3.02 g (0.078 mole) of 320 ml of solution 9.6 while heating and refluxing. A 80 ml solution of menanol of ml (0.088 mol) methyl aceto acetate is added for 30 minutes. After refluxing for another 30 minutes, toluene is added at the same rate to keep the same volume while distilling the methanol. 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 under reduced pressure at 5 o'clock to yield a constant weight, then the compound labeled above. This produces

Similarly, the use of both as protecting groups such as acid chloride hydrochloride is known as listed in the following method.

D-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine chloride hydrochloride is prepared in very high purity and is effectively prepared by the following process.

About 0.06 mole of D-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine is slurried in 100 ml of dioxane. The slurry is stirred and passed through phosgene, maintaining the temperature at 50-58 ° C. The phosgene is passed for 3 hours 30 minutes. It is a yellow solution and purified with nitrogen to remove excess phosgene. The solution is stirred and diluted with a small amount of ether to obtain a small amount of crystals to use as seed. The solution was stirred at 20-25 ° C. for 16 hours, filtered off the slurry of hydrochloride crystals with D-(-)-2- (3'-methoxy-4'-hydroxyphenyl) glycine chloride, and the filtrate was dioxane and Washing with methylene chloride and drying over phosphorus pentaoxide in a vacuum desiccator yields about 7 g of the compound mentioned above.

Preparation of D-(-)-2-amino-2- (4-acetoxyphenyl) acetyl chloride hydrochloride

83.6 g (0.40 mol) of D-(-)-2-amino-2- (4-acetoxyphenyl) acetic acid and 1.25 L of methylene chloride anhydride are cooled to -5C while stirring. 152 g of phosphorus pentachloride is slowly added, followed by 4 ml of dimethyl formamide. The mixture is stirred at 0 ° C. for 4 hours, the solids are taken, washed with methylene chloride anhydride and dried under reduced pressure at room temperature.

Yield: 61 g (57.5%)

Assay: Whole chlorophyll = 27.2% (26.9% theory)

Preparation of D-Mandelic Acid Carboxylic Hydride

D-mandelic acid carboxy anhydride (2)

The phosgene is passed through an aqueous THF solution of 2.0 g (0.013 mol) of D-(-)-mandelic acid (1) for 30 minutes. The solution is heated to reflux for 10 minutes and then left overnight. Removal of the solvent under reduced pressure yields oily turf, which is dissolved in n-hexane (20 ml). The product is filtered off and dried under reduced pressure on caustic carry. 2.3 g of D-mandelic acid carboxy anhydride is obtained.

1895, 1875, 1780cm^-1 IR:

1895, 1875, 1780 cm ^-1

The most active compound of the present invention is a compound having a D-type arrangement at the 7-branched α-carbon atom, as described herein, D-2-phenyl-glycine or D-mandelic acid or mono-substituted-D- Prepared with 2-phenyl glycine or D-mandelic acid. In other words, the arrangements in the two kinically active and asymmetric centers of beta-lactamhex are found in 7-amino-cephalosonic acid, which is a derivative of cephalosporin C or gide produced in fermentation.

The present invention is described in detail below.

Where temperature is centigrade. 7-amino cephalosporranic acid was omitted as 7-ACA. The ACA is represented by the following structure:

로 표시할 수 있다. 메틸 이소부틸 케톤은 MIBK로 나타냈다. ＂스켈리솔브 B＂는 주로 n-헥산을 함유한 비점 60-68℃의 석유 에테르 분획이다.So 7-ACA is

Can be displayed as Methyl isobutyl ketone is shown as MIBK. Chexkelysolve B 'is a petroleum ether fraction having a boiling point of 60-68 ° C. containing mainly n-hexane.

LA-1 resin is a mixture of secondary amines having the structure:

Wherein R ¹ , R ² and R ³ are single-bond aliphatic hydrocarbon groups, and R ¹ , R ² and R ³ are aggregates of C ₁₁ to C ₁₄ . This particular mixture of secondary amines, sometimes referred to in this example as “liquid amine mixture II”, is a clear amber liquid and has the following physical properties. Viscosity 70 Cpd at 25 ° C., specific gravity 0.0826 at 20 °; Refractive index 1.4554 at 25 ° C, -0.5% at distillation range 170 ° C or above at -10mm, -3% at 170-220 ° C, -90% at 220-230 ° C, -6.5% above 230 ° C IR-120 IR-120, commercially available as a strong cation exchange resin of the polystyrenesulfonic acid type. It is a nucleus sulfonated polystyrene resin intersected with divinylbenzene and manufactured by the method of Kunin, ion exchange resin 2nd edition (1958), John, Illand, Sons Corporation.

Preferred Specific Method

Preparation of 1-carboxyethyl terazole-5-thiol

A) 2-carboethoxy ethyl isocyanate

Beta-alanine ethyl ester hydrochloride (93.6 g), triethyl amine (123.5 g) and methylene chloride (400 ml) are admixed and cooled to -10 ° C. Chloroform (150 ml) of bisulfated carbon (46.5 g) was added over 2 hours, during which the temperature was kept at -10 ° C. After complete addition, warm the temperature to 10 ° C for about 10 minutes. The solution was again cooled to -10 DEG C and 66.9 g of ethyl chloroformmate in 60 ml of chloroform was added dropwise while stirring for 40 minutes, the temperature was raised to room temperature for 30 minutes, cooled to 0 DEG C, and 61.6 g of triethylamine was added at 0 DEG C, The solution is stirred for 3 hours at room temperature. The mixture is treated with water and the organic layer is taken, washed with 2N hydrochloric acid (2 × 250 ml), followed by neutral bath (2 × 250 ml) and then water (2 × 250 ml). The organic layer was dried over sodium sulfate and dried under reduced pressure to obtain the target product in the oil phase (93.7 g). Analyze the structure with IR and NMR spectroscopy.

B) 1-carboxyethyltetrazol-5-thiol

Sodium azide (29.7 g) is dissolved in 400 ml of water and heated to 60 ° C. in a nitrogen atmosphere. A solution of 2-carboethoxy-ethyl-isocyanate (46.9 g) in 50 ml Skelesolve B (mainly n-hexane) is added to a heated sodium azide solution. The solution is stirred for 150 minutes at 70-72 ° C. and cooled to 30 ° C. in an ice bath. The solution is brought to pH 12 with 50% caustic soda solution, heated at 70 ° C. for 40 minutes and cooled to 15 ° C. in an ice bath. Adjust to pH 2 with concentrated hydrochloric acid and extract with ethyl-acetate (4 x 150 ml). The ethyl-acetate extract is washed with water and dried over soda sulfate. Concentration under reduced pressure removes the solvent and crystallizes with chloromethylene to give 19.5 g of the desired product.

Preparation of 1-carboxyalkyltetrazol-5-thiol

Instead of replacing 1-carboxyethyltetrazol-5-thiol with beta-alanineethyl ester, the use of a suitably substituted amino acid ester of C ₄ -C ₁₀ gives the corresponding 1-carboxy (C ₁ -C ₉ alkyl) tetrazole -5-thiol, ie,

1-carboxypropyl tetrazol-5-thiol

1-carboxy butyl tetrazol-5-thiol

1-carboxypentyl tetrazol-5-thiol

1-carboxyhexyl tetrazol-5-thiol

1-carboxy heptyl tetrazol-5-thiol

1-carboxyoctyl tetrazol-5-thiol

1-carboxynonyl tetrazol-5-thiol

Preparation of 7-amino-7-methoxy-3- (1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

Generally, the above starting material preparation in the preparation of 7-methoxy substituted-7-amino cepanlosporonic acid according to US Pat. No. 3,875,146 is as follows.

Preparation I

1. In a three-necked flask equipped with a stirrer, temperature controller, thermometer and nitrogen inlet tube, 18 g of 7-amino-7-methoxy cephalosporranic acid and 300 ml of 0.1 M pH 6.4 phosphate buffer (20.7 g of phosphoric acid). Sodium salt, first salt of 1H ₂ o, +8.5 g of sodium phosphate dibasic, and anhydrous 2 liters in total) is added.

2. While stirring the mixture of the first step, 1.5 g of sodium bisulfite and 16 g (0.078 mole) of 1-carboxy-methyl-5-mercaptotetrazol disodium are added.

3. Continue stirring while passing nitrogen through the mixture for 10 minutes.

4. Heat the slurry to 56 ° C. for 20 minutes while continuing stirring and nitrogen injection. During this time, add 6.5g of medium tank.

5. Continue stirring and nitrogen feeding, keeping the temperature of solution at 56 ° C for 4 hours and pH at 6.2-6.6.

6. Cool the reaction solution to 5 ° C. in an ice bath.

7. Add 50 ml of a solution of phosphoric acid / water (1: 1) or concentrated hydrochloric acid to pH 2.0-3.0.

8. The product is filtered off and washed with 20 ml of cold water followed by 200 ml of cold-methane.

9. Air-dried until the solid is weighed, resulting in a yellowish-dark brown product.

10. Pass this 200 mesh stainless steel body.

11. Suspend 10 g of 200 mesh powder in 200 ml of -propanol with rapid stirring.

12. Add 2.0 ml of concentrated folic acid and stir vigorously for 230 minutes at room temperature.

13. Filter the slurry, wash the brown solid with 20 ml n-propanol and combine with the filtrate. (To ensure that the product is possible and not contained in the filtrate)

14. Add 1.5 charcoal activated carbon (Darco G-60) to the filtrate in step 13, and slurry for 30 minutes. The carbon is filtered off and the carbon is washed with 20 ml of n-propanol and combined with the filtrate.

15. Triethyl-amine is added to the n-propanol filtrate with rapid stirring to bring the crystals to pH 3.0 to precipitate crystals. Slurry for 10 minutes.

16. Filter the crystals, wash with 30 ml of n-propanol, 50 ml of methanol and dry under reduced pressure at 40 ° C. for 24 hours.

Preparation II

In which Z is benzyl ester.

end). 7-Amino-3- (1-carboxymethyl tetrazol-5-ylthio-methyl) -3-cepem-4-carboxylic acid is dissolved in dioxane in the presence of a catalytic amount of P-torene-sulfonic acid. . Methanol is added and the solution is dried under reduced pressure several times, followed by addition of anhydrous dioxane. Diphenyldiazomethanol and 2 moles per mole of cephalosporin are added. When the solvent is removed under reduced pressure, 7-amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid dibenzhydryl ester (1) is produced.

I). The dibenzhydryl ester is dissolved in methylene chloride and P-nitrobenzaldehyde is added at a molar ratio of aldehyde to cephalosporin of 1: 1. After adding a small amount of anhydrous magnesium sulfate and stirring at room temperature for 30 minutes, 7- (P-nitro-benzylideneamino) -3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cepem-4 It is obtained with carboxylic acid dibenzhydryl ester (II).

All). The compound (II) obtained in step (b) was dissolved in anhydrous tetrahydrofuran and the solution was cooled to -78 ° C under a nitrogen atmosphere.

]를 디메틸설폭사이드(DMSO) : 헥사메틸포스포타마이드 1 : 1로 가한다. 메톡실화 반응 혼합물을 10분간 -50℃에서 교반하고 실온으로 가온하면 7-메톡시-7-(P-니트로벤질리덴 아미노)-3-(1-카르복시메틸 테트라졸-5-일-티오메틸)-3-세펨-4-카르복실산 디벤즈하이드릴 에스테르(III)Phenyldium is added quantitatively to the cephalosporin amount at -78 deg. The temperature was raised to -50 ° C., and the just prepared 0-methyl-dimethylsulfonium methosulfate [

] Is added as dimethylsulfoxide (DMSO): hexamethylphosphotamide 1: 1. The methoxylation reaction mixture was stirred for 10 minutes at -50 ° C and warmed to room temperature when 7-methoxy-7- (P-nitrobenzylidene amino) -3- (1-carboxymethyl tetrazol-5-yl-thiomethyl ) -3-cepem-4-carboxylic acid dibenzhydryl ester (III)

la). Compound (III) obtained in step (c) is treated with an animal amount of aniline and hydrochloride in methanol and hydrolyzed at room temperature for 1-24 hours.

Preparation of 7-amino-7-methoxy-3- (1-carboxyalkyl-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

Thiols suitable in the above preparation, i.e., 1-carboxypropyl-5-metocaptotetrazol disodium, 1-carboxybutyl-5-metocaptotetrazole disodium, 1-carboxypentyl-5-metocaptotetrazol disodium, 1 -Carboxyhexyl-5-metocaptotetrazol disodium, 1-carboxyheptyl-5-methocaptotetrazol disodium, 1-carboxyoctyl-5-metocaptotetrazole disodium and 1-carboxynonyl-5-mercapto The use of tetrazole disodium gives the corresponding 7-amino-7-methoxy-3- (1-carboxyalkyl) tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

Preparation of 3-Aminomethyl-2-thiophene Acetic Acid

end). Thiophene-3-carboxaldehyde dimethyl acetal (2a)

Methanol (200 ml) solution of thiophene-3-carboxaldehyde 1) (322 g, 1.9 mol), trimethoxymethane (636 g, 6 mol) and IR-120 resin (H ⁺ , 6 g) was refluxed for 4 hours. Let's do it. The resin is removed and the filtrate is evaporated under reduced pressure to yield a colorless oil. Yield 423g (94%), Boiling point 90-95 ° C 13mmHg

3150, 1045, 1025cm^-1 IR:

3150, 1045, 1025cm ^-1

3.21(6H, s. OCH₃), 5.43(1H, s,

), 7.0-7.4(3H,), thiophene-H)NMR:

3.21 (6H, s. OCH ₃ ), 5.43 (1H, s,

), 7.0-7.4 (3H,), thiophene-H)

One). S-Gronowitz, Arker, kemi., 8, 411 (1955).

I). 2-formylthiophene-3-carboxaldehyde dimethylacetal (3a)

A solution of 2a (423 g, 2.68 moles) in anhydrous ether (1 L) was added dropwise for 1 hour while stirring to reflux under dry nitrogen for a while. After refluxing for 30 minutes, anhydrous ether (0.3 L) solution of DHF was added dropwise with vigorous stirring for 45 minutes. After all were added dropwise, the mixture was stirred overnight, stuck to ice (1 kg) with stirring and raised to room temperature. The organic layer is separated, the aqueous layer is saturated with brine and extracted thoroughly with ether (2 × 200 ml). The ether extracts are combined, dried over magnesium sulfate and concentrated. Distillation of the residue under reduced pressure yields a pale yellow oily substance.

3110, 1660, 1100IR:

3110, 1660, 1100

3.40(6H, s, OCH₃), 5.86(1H, s,

), 7.27(1H, d, J=6Hz, 티오펜-H3), 7.81(1H, d-d, J=6Hz. 티오펜-Hz), 10.34(1H, d, J=1.5Hz, -CHO).NMR:

3.40 (6H, s, OCH ₃ ), 5.86 (1H, s,

), 7.27 (1H, d, J = 6 Hz, thiophene-H3), 7.81 (1H, dd, J = 6 Hz. Thiophene-Hz), 10.34 (1H, d, J = 1.5 Hz, -CHO).

All). 1-methylsulfinyl-1-methylthio-2- (3-carboxaldehyde-ethylene (4b)

Compound 4b is K. It is prepared by the method of Oggle and his collaborators 4). THF (5 ml) of Triton B (40% in methanol, 2 ml), methylmethylthiomethyl sulfoxide 2) (2.5 g, 20 mmol) and 2-formyl-3-thiophenecarboxal-dehydro ethylene acetal 3 (3b) to the solution. The mixture is refluxed for about 1 hour and concentrated under reduced pressure. The residue is taken up in benzene- (150 ml) and extracted with water (3 x 20 ml). The organic layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is taken up in benzene (150 ml) and extracted with water (3 x 20 ml). The organic layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is column-chromatated on silica gel (80 g) and compound 4b is isolated from benzene (500 ml) and chloroform precipitate (4.9 g, 85%). Light yellow oily.

3110, 1600cm^-1 ir:

3110, 1600 cm ^-1

2.42(3H, x, S-CH₃), 2.78(3H, S, SO-CH₃), 4.15(4H, m, CH₂CH₂-), 6.12(1H, s,

), 7.34(1H, d, J=4.5Hz, 티오펜 -Hβ), 7.40(1H, d, J=4.5Hz, 티오펜-Hα), 8.28(1H, s, -CH=).nmr:

2.42 (3H, x, S-CH ₃ ), 2.78 (3H, S, SO-CH ₃ ), 4.15 (4H, m, CH ₂ CH _2- ), 6.12 (1H, s,

), 7.34 (1H, d, J = 4.5 Hz, thiophene-Hβ), 7.40 (1H, d, J = 4.5 Hz, thiophene-Hα), 8.28 (1H, s, -CH =).

Semacarbazone of 4 is usually prepared by the method and recrystallized from ethanol -DMF. Melting point 212-213 °

Elemental Analysis: C ₁₀ H ₁₃ N ₃ O ₂ S ₂

Calculated: C, 39.58; H, 4. 32; N, 13.85; S, 31.70

Found: C, 39.46; H, 4. 24; N, 14.05; S, 31.63

2) K. Ogura, et al., Bull, Chom. soc. (Japan), 45, 2203 ('72)

3) D.W. Hc Dowell et al., J. Ong, Chem. 31.3592 ('66)

4) K. Ogura, et al., Tetrahedron Letters, 1383 (1972).

D) 1-methylsulfinyl-1-methylthio-2- (3-carboxydehydrate-dimethylacetyl-2-thienyl) ethylene (4a)

Compound 4b is prepared by a method similar to 4b. Triton B (40% in methanol, 50 ml) is added to a solution of methyl methylthio methylsulfoxide (72 g, 0.58 mol) and 3a (108 G, 0.58 mol) THF (300 ml) and refluxed for 4 hours. Column chromatography with silica gel (400 g) eluted with chloroform (5 L) and separated gave 130.5 g (78%) of light yellow oily 4a.

3100, 1580, 1100, 1050^-1 ir:

3100, 1580, 1100, 1050 ^-1

2.42(3H, s, S-CH₃), 2.70(3H, s, SO-CH₃), 3.34(6H, s, OCH₃), 5.56(1H, s, CHO), 7.20(1H, d, J=6Hz, 티오펜-Hβ), 7.40(1H, d, J=6Hz, 티오펜-Hα), 8.12(1H, s, -CH=nmr:

2.42 (3H, s, S-CH ₃ ), 2.70 (3H, s, SO-CH ₃ ), 3.34 (6H, s, OCH ₃ ), 5.56 (1H, s, CHO), 7.20 (1H, d, J = 6 Hz, thiophene-Hβ), 7.40 (1H, d, J = 6 Hz, thiophene-Hα), 8.12 (1H, s, -CH =

hemp). Ethyl 3-formyl-2-thienyl acetate 4) (5)

Anhydrous hydrogen chloride (33 g) is absorbed in anhydrous ethanol (500 ml), 4a solution (130 g, 0.45 mol) is added and heated at reflux for 5 minutes. The reaction mixture is diluted with water and evaporated under reduced pressure. The residue is extracted with benzene (2 x 100 ml) and the benzene extracts are combined, washed with water (150 ml), dried over magnesium sulfate and evaporated to dryness. The oily residue is color-chromatography on silica gel and eluted with chloroform (5 L). The fractions containing the desired product are combined and concentrated. Distillation of the oily residue (60 g) under reduced pressure yields 5,23 (23%) of the desired product at a melting point of 126-126 ° / 1 mmHg.

3110, 1730, 1670cm^-1 ir:

3110, 1730, 1670 cm ^-1

31.30(3H, t, J=6Hz, -CH₂CH₃), 4.25(2H(q, J=6Hz, -CH₂CH₃), 4.26(2H, s, -CH₂CO), 7.25(1H, d, J=5Hz, 티오펜-Hβ), 7.48(1H,- d, J=5Hz, 티오펜-Hα), 10.15(1H, s, CHO).nmr:

31.30 (3H, t, J = 6 Hz, -CH ₂ CH ₃ ), 4.25 (2H (q, J = 6 Hz, -CH ₂ CH ₃ ), 4.26 (2H, s, -CH ₂ CO), 7.25 (1H, d, J = 5 Hz, thiophene-Hβ), 7.48 (1H, -d, J = 5 Hz, thiophene-Hα), 10.15 (1H, s, CHO).

The analytical sample of 5 was replaced with 2,4-dinitrophenylhydrazone crystallized from chloroform. Melting point 178-179 °

1720, 1610, 1570ir:

1720, 1610, 1570

Elemental analysis: C ₁₅ H ₁₄ N ₄ O ₆ S

Calculated: C, 47.62; H, 3.73; N, 14.81; S, 8.47

Found: C, 47.33; H, 3.47; N, 14.77; S, 8.68

In a similar manner, 2.2 g (7.6 mmol) of ethylene acetal 4b was treated with 800 ml of anhydrous ethanol, 1.1 g of anhydrous ethanol, yielding 5. This was subjected to column-chromatography on silica gel (30 g) and eluted with chloroform to give 633 mg of pale yellow oily substance 5.

bar). Ethyl 3-formyl-2-thienyl acetate oxime (6)

Sodium carbonate (1.7 g, 16 mmol) is added to 5% of aldehyde 5 (3.14 g, 16 mmol) to a 50% ethanol aqueous solution (40 ml) solution of hydroxide hydrochloride (2.2 g, 32 mmol) at 5 ° C while stirring. The reaction mixture is allowed to warm up to room temperature and after 2 hours 30 minutes, the reaction mixture is concentrated under reduced pressure. The residue was extracted with benzene (3 x 50 ml); The benzene extract is washed with water (10 ml), dried over magnesium sulfate and evaporated under reduced pressure. Column-chromatography on silica gel (60 g) gives 2.7 g (80%) of a colorless oily phase (6):

3400, 1730, 1620cm^-1 ir:

3400, 1730, 1620cm ^-1

1.23(3H, t, J=7.5Hz, -CH₂CH₃), 4.01(2H, s, -CH₂CO), 4.14(2H, q, J=7.5Hz, -CH₂CH₃), 7.31(2H, s, Tniophene-H), 8.26(1H, s, -CH-N), 10.15(1H, s, NOH, D₂O를 가하면 소실된다).nmr:

1.23 (3H, t, J = 7.5 Hz, -CH ₂ CH ₃ ), 4.01 (2H, s, -CH ₂ CO), 4.14 (2H, q, J = 7.5 Hz, -CH ₂ CH ₃ ), 7.31 ( 2H, s, Tniophene-H), 8.26 (1H, s, -CH-N), 10.15 (disappears when 1H, s, NOH, D ₂ O is added).

four). Sigma-lactam of 3-aminomethyl-2-thienylacetic acid (7)

Formulation A: Catalytic Reduction, Oxime 6 (2.65 g, 12.4 mmol), 10% charcoal-platinum, anhydrous ethanol (68 ml) mixture of anhydrous hydrogen chloride (1.4 g, 37.2 mmol) was hydrolyzed at room temperature and atmospheric pressure. The catalyst is stirred twice and the reaction is carried out for 3 days.

The catalyst is removed and the filtrate is concentrated under reduced pressure. To the residue is added water (10 ml) and the mixture is washed with ethyl acetate (2 × 10 ml). The aqueous layer is adjusted to pH 9 with sodium carbonate, saturated with salt and then extracted with ethyl acetate (3 x 20 ml). The methyl acetate extract is dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure. Recrystallization with ethyl acetate yields 417 mg (22%) of colorless needles 7 with melting points of 194-195 ° C.

Preparation: Zinc-Powder Reduction

Zinc powder (17 g, 258 mmol) was added dropwise to the solution of oxime 6 (18.3 g, 86 mmol) in acetic acid (200 ml) for 1 hour with vigorous stirring at 40-50 ° C., stirred at room temperature overnight, and heated at 60 ° C. for 4 hours. do. Filtrate and concentrate the filtrate under reduced pressure. Water (100 ml) is added to the remaining oil and washed with ether (2 x 50 ml). Extract with ethyl acetate, adjust to pH 10 with sodium carbonate and filter the precipitate. The filtrate is extracted with ethyl acetate and the extract is washed with water (10 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residual solid was dissolved in benzene and crystallized with ethyl acetate to give 2.7 g (21%) of lactam 7 which was the same as that of Preparation A in IR and NMR spectroscopy.

Ah). 3-Aminomethyl-2-thienyl acetic acid (8)

A mixture of lactam 7 (2.88 g, 18.8 mmol) and 6b hydrochloric acid (50 ml) is heated to reflux for 3 hours and concentrated. Water (20 ml) was added to the residue, treated with activated charcoal and evaporated under reduced pressure. Dissolving the residue in THF gives amino acid 8 hydrochloride (3.72 g, 95%; melting point 171-172 ° C.)

ir (KBr) cm ^-1 : 3450, 3000, 1700, 1200 nmr (D ₂ O) ppm: 4.80 (2H, s, -CH ₂ CO), 4.27 (2H, s, CH ₂ -N), 7.26 (1H) , d, J = 6 Hz, thiophene-Hβ), 7.53 (1H, d, J = 6 Hz, thiophene = Hα).

Hydrochloride (3.71 g, 17.9 mmol0) is dissolved in water (10 ml), chromatographed on an IR-120 (H, 30 ml) column and developed in the order of water (100 ml) and 5N-ammonium hydroxide (2 L). The residue is crystallized from aqueous acetone to give 3.0 g (98%) of 8. Melting point 223-225 ° C.

3300, 1620, 1520cm^-1 ir:

3300, 1620, 1520 cm ^-1

nmr: δ D ₂ O-Na ₂ CO ₃ 3.2 (SH, s, -CH ₂ OC), 4.13 (2H, s, CH ₂ H), 7.04 (1H, d, J = 6 Hz, thiophene-Hβ), 7.30 (1H, doublet, J-6.Hz, thiophene-Hα).

Elemental Analysis: C ₇ H ₉ NO ₂ S:

Calculated: C, 49.10; H, 5. 30; N, 8.18; S, 18.73

Found: C, 48.53; H, 5. 22; N, 7.98; S, 18.97

character). 3-tert-butoxycarbonylaminomethyl-2-thienyl-acetic acid (9)

To a mixture of 50% aqueous acetone (80 ml) of 3-aminomethyl-2-thienylacetic acid 8 (3.1 g, 18 mmol) and triethylamine (8 g, 80 mmol) was stirred for 3 minutes at 0 ° C. for 20 minutes. Butoxycarbonyl azide (5.7 g, 40 mmol) is added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The concentrate is washed with ether (2 x 20 ml), adjusted to pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate (2 x 50 ml). The ethyl acetate extract is washed with saturated brine, dried over magnesium sulfate, treated with activated charcoal and evaporated under reduced pressure. The residue is taken up with n-hexane and crystallized with n-hexane and benzene to give 4.5 g (92%) of colorless crystals 9. Melting Point: 62-63 ℃

3350, 1700cm^-1 ir:

3350, 1700 cm ^-1

1.43(9H, s, BOC-H), 3.27(2H, s, CH₂CO), 4.16(2H, d, J=6Hz, CH₂-H, 중수를 가한단일선, 500(1H, br, -NH-, 중수를 가하면 소실), 6.30(1H, broad s, -COOH, 중수를 가하면 소실), 6.86(1Hd, J=6Hz, 티오펜-Hβ), 7.06(1H, d, J=6Hz, 티오펜-Hα)nmr:

1.43 (9H, s, BOC-H), 3.27 (2H, s, CH ₂ CO), 4.16 (2H, d, J = 6 Hz, CH ₂ -H, single line with heavy water, 500 (1H, br,- NH-, disappeared with heavy water), 6.30 (1H, broad s, -COOH, lost with heavy water), 6.86 (1Hd, J = 6Hz, thiophene-Hβ), 7.06 (1H, d, J = 6Hz, T Offen-Hα)

Elemental Analysis: C ₁₂ H ₁₇ NO ₄ S:

Calculated: C, 52.89; H, 6. 29; N, 5.14; S, 11.77.

Found: C, 53.30; H, 6.39; N, 5.13; S, 11.72.

car). Selective Synthesis of 1-carboxymethyl-5-mercaptotetrazole.

125 ml of 7.47 g (0.115 mol) of sodium azide is added while stirring a mixture of 13.95 g (0.10 mol) of glycine ethyl ester hydrochloride, 8.0 g (0.20 mol) of caustic soda and 8.37 g (0.11 mol) of carbon dihydride . The solution is heated to reflux for 6 hours 30 minutes and left at 25 ° for 16 hours. The dark brown mixture is filtered and the filtrate is acidified to pH 1.5 with concentrated hydrochloric acid. The solution is treated with carbon and the yellow filtrate is extracted with ethyl acetate (4 x 100 ml). The ethyl acetate layer is washed with water, dried over magnesium sulfate and evaporated at 40 ° (15 mm) to form an oil phase. The oily substance is dissolved in methylene chloride and filtered off. Dry under reduced pressure at 25 ° for 16 hours on phosphorus pentoxide. The structure is determined by IR and NMR spectroscopy. Reference: West German Patent 106645.

hemp). Preparation of 7β- (0-N-t-butoxycarbonylamino-methylphenylacetamido) 7α-methoxycephalosporonic acid.

One). Benzhydryl 7- (0-N-t-butoxycarbonylamino-methylphenyl acetamido) cephalosporate.

Hwanggamhong (16.12 g, 74 mmol) was added to a solution of a mixture of anhydrous ether (100 ml) of benzophenone-hydrazone (5.88 g 30 mmol) and anhydrous sodium sulfate (8 g), and stirred with KOH-saturated ethanol (1.5 ml ) Is added and stirred for 1 hour and 30 minutes at room temperature.

The mixture is filtered and the filtrate is added to a solution of 7- (0-N-t-butoxycarbonylaminomethylphenylacetamido) cephalosporanic acid (10.38 g, 20 mmol) in THF (60 ml). The reaction mixture is stirred for 3 hours at room temperature and evaporated under reduced pressure. The residue is taken up in n-hexane (200 ml) and filtered. Crude product is dissolved in heat-benzene (100 ml) and treated with a small amount of carbon. The filtrate is diluted with ether (500 ml) and left overnight in the refrigerator to give the abovementioned compound a colorless crystalline solid. Yield: 12.25 g (89%); Melting point 150-153 ℃

3340, 3300, 1785, 1740, 1720, 1680, 1540, 1230, 1170cm^-1 ir:

3340, 3300, 1785, 1740, 1720, 1680, 1540, 1230, 1170cm ^-1

263nm(ε 8580)uv:

263 nm (ε 8580)

: +5°, (C=1.0, Chloroform)

: + 5 °, (C = 1.0, Chloroform)

31.45(9H, s, t-Bu-H), 2.02(3H, s, OAc), 3.39(2H, m, z-H), 3.68(2H, s, CH₂CO), 4.32(2H, d, 4Hz, CH₂N 중수 첨가로 실글레트 D₂O), 4.72(1H, d, 14Hz, 3-H), 4.93(1H, d, 4Hz, 6-H), 5.05(1H, d, 14Hz, 3-H), 5.35(1H, br, CH₂NH, 중수 첨가로 소실 D₂O), 5.86(1H, d-d, 4Δ 8Hz, 7-H, 중수 첨가로 J=4Hz와 다블레트 D₂O), 6.95(1H, s, ph₂CH), 7.2-7.6(14H, m, phenyl-H).nmr:

31.45 (9H, s, t-Bu-H), 2.02 (3H, s, OAc), 3.39 (2H, m, zH), 3.68 (2H, s, CH ₂ CO), 4.32 (2H, d, 4 Hz, CH ₂ N heavy water added with Sileglet D ₂ O), 4.72 (1H, d, 14 Hz, 3-H), 4.93 (1H, d, 4 Hz, 6-H), 5.05 (1H, d, 14 Hz, 3-H ), 5.35 (1H, br, CH ₂ NH, lost D ₂ O with heavy water addition), 5.86 (1H, dd, 4Δ 8 Hz, 7-H, J = 4 Hz with heavy water addition Dablet D ₂ O), 6.95 (1H, s, ph ₂ CH), 7.2-7.6 (14H, m, phenyl-H).

Elemental Analysis: C ₃₇ H ₃₉ N ₃ O ₈ S: 64.80; H, 5.73; N, 6.13; S, 4.68

Found: C, 64.70, 64.65; H, 5.95, 5.70; N, 6. 12, 6.00; S, 4.12, 6.00; S, 4.82, 4.68

2). Benzhydryl 7β- (0-N-t-butoxycarbonylamino-methylphenyl acetamido) -7α-methoxy-cephalosporanic acid.

A cooled (-65 ° C.) solution of the compound (3050 mg, 4.45 mmol) obtained in the first step in dry THF (20 ml) was poured in small portions into methanol-THF (12 ml; 20 ml) in a solution of lithium (108 mg, 15.6 mmol) and iced water. -Cool to -65 ° C in acetone bath. After 1 minute tert-butylhypochlorite (529 mg, 0.58 ml, 4.9 mmol) is added and stirred at the same temperature for 15 minutes. To terminate the reaction, acetic acid (1 ml) is added, poured into water (200 ml) and extracted with ethyl acetate (4 x 50 ml). The combined extracts are washed with water and evaporated under reduced pressure. The residue is taken up in heat-benzene (20 ml) and treated with a small amount of carbon. The filtrate is diluted with ether (200 ml) and placed in the refrigerator to read the crystals of the compound. Yield: 2094 mg (64%) Melting point 171-173 ℃ Recrystallized from benzene-ether, melting point 174-175 ℃

3350,3250, 1785, 1750, 1735, 1680, 1525, 1230, 1170, 1080cm^-1 ir:

3350,3250, 1785, 1750, 1735, 1680, 1525, 1230, 1170, 1080cm ^-1

247nm(ε6790), 267, nm(ε7070).uv:

247 nm (ε6790), 267, nm (ε7070).

: +98°(C=0.5, 클로로포름).

: + 98 ° (C = 0.5, chloroform).

3 1.43(9H, s, t-Butl), 2.00(3H, s, OAC), 3.2-3.4(2H, m, 2-H), 3.49(3H, s, DMe). 3.72(H, s, CH₂DO), 4.34(2H, d, 6Hz, 중수의 첨가로 싱글레트 D₂O, CH₂N), 4.74(1H, α, 14Hz, 3-H), 5.04(1H, s, 6-H), 5.10(1H, d, 14Hz, 3-H), 6.93(1H, S, CHPh₂), 7.2-7.5(14H, m, phenyl-H), 원소분석 : C₃₈H₄₁N₃O₉S, 계산치 C, 63.76; H, 5.77; N, 5.87; S, 4.38nmr:

3 1.43 (9H, s, t-Butl), 2.00 (3H, s, OAC), 3.2-3.4 (2H, m, 2-H), 3.49 (3H, s, DMe). 3.72 (H, s, CH ₂ DO), 4.34 (2H, d, 6 Hz, singlet D ₂ O, CH ₂ N by addition of heavy water), 4.74 (1H, α, 14 Hz, 3-H), 5.04 (1H , s, 6-H), 5.10 (1H, d, 14Hz, 3-H), 6.93 (1H, S, CHPh ₂ ), 7.2-7.5 (14H, m, phenyl-H), Elemental Analysis: C ₃₈ H ₄₁ N ₃ O ₉ S, calc. C, 63.76; H, 5.77; N, 5.87; S, 4.38

Found: C, 63.62, 63.67; H, 5.83, 5.65; N, 5.87, 5.73; S, 4.89, 4.72

3). 7β- (0-amino methylphenylacetamido) -7α-methoxy cephalosporan acid

The mixture of the compound obtained in the second step (4.60 g, 6.43 mmol) and trifluoroacetic acid (8 ml) was stirred at 0-20 ° C. for 20 minutes to form a viscous solution. TFA salt precipitates. Filter this and dissolve in acetonitrile (200 ml). Treat the solution with a small amount of carbon. The mixture of concentrated-ammonium hydroxide-acetonitrile (1: 1) is added dropwise while stirring until no further precipitation is seen. The compound is filtered off, washed with acetonitrile (50 ml) and dried. Yield 2.49 g (86%): Melting point 161-165 ° C (decomposition)

3600-2400, 1770, 1740(sh), 1665, 1600, 1230, 1135cm^-1 ir:

3600-2400, 1770, 1740 (sh), 1665, 1600, 1230, 1135cm ^-1

3237nm(ε 6300), 265nm(ε7700).uv: λ

3237 nm (ε 6300), 265 nm (ε 7700).

32.10(3H, s, OAC), 3.15(H, d, 18 Hz, 2 H), 3.53(3H, s, OCH₃), 3.62 (1H, d, 18Hz, 2 H), 3.90(2H, s, CH₂N), 5.12(1H, s, 6-H), 7.45(4H, s, phenypH).nmr:

32.10 (3H, s, OAC), 3.15 (H, d, 18 Hz, 2H), 3.53 (3H, s, OCH ₃ ), 3.62 (1H, d, 18 Hz, 2H), 3.90 (2H, s, CH ₂ N), 5.12 (1H, s, 6-H), 7.45 (4H, s, phenypH).

Elemental analysis: C ₂₀ H ₂₃ N ₃ O ₇ S. 2H ₂ O

Calculated: C, 49.48; H, 5.61; N, 8.65; S, 6.60.

Found: C, 49.64, 49.38; H, 4.93, 4.86; N, 8.86, 8.92; S, 6.57.

4). 7β- (0-N-t-butoxycarbonylaminomethylphenyl-acetamido) -7α-methoxycephalosporane

50% water soluble of tertiary compound (00 mg, 1.8 mmol), t-butyl 3.6-dimethylpyridine-2 ylthio-carbonate (864 mg, 3.7 mmol) and triethylamine (273 mg, 0.38 ml, 2.7 mmol) The mixture of -THF (12 ml) is diluted with ethyl acetate (100 ml) and washed several times with 10 ml of 6N hydrochloric acid until the yellow color of the aqueous layer disappears. The organic layer is washed with water and dried. Evaporation under reduced pressure produces the above compounds. It is filtered off, washed with n-hexane and dried. Yield: 568 mg (50%), melting point 102-106 ° C (decomposition)

3300, 1780, 1720, 1770, 1515, 1230, 1165cm^-1 ir:

3300, 1780, 1720, 1770, 1515, 1230, 1165cm ^-1

244nm(ε6630), 266nm(ε 7150).ur:

244 nm (ε 6630), 266 nm (ε 7150).

1.48(9H, s, t-Bu-H), 2.08(3H, s, COCH₃), 3.3-3.4(2H, m, 2-H), 3.48(3H, s, OCH₃), 3.78(2H, s, CH₂CO₂), 4.30(2H, d, 6Hz, asinglet by addition of D₂O), 4.82(1H, d, 15Hz, 3-H), 5.08(1H, s, 6-H), 5.12(1H, d, 15Hz, 3-H), 7.26(4H, s, phenyl-H), 8.20(1H, br, 중수 NH 또는 COOH의 첨가에 의하여 소실된다), 8.85(1H, br s, 중수의 첨가에 의하여 소실된다)nmr:

1.48 (9H, s, t-Bu-H), 2.08 (3H, s, COCH ₃ ), 3.3-3.4 (2H, m, 2-H), 3.48 (3H, s, OCH ₃ ), 3.78 (2H, s, CH ₂ CO ₂ ), 4.30 (2H, d, 6 Hz, asinglet by addition of D ₂ O), 4.82 (1H, d, 15 Hz, 3-H), 5.08 (1H, s, 6-H), 5.12 (1H, d, 15 Hz, 3-H), 7.26 (4H, s, phenyl-H), 8.20 (disappeared by addition of 1H, br, heavy NH or COOH), 8.85 (1H, br s, heavy water Is lost by addition)

Elemental analysis: C ₂₅ H ₃₁ N ₃ O ₉ S:

Calculated: C, 54.63; H, 5.69; N, 7.65; S, 5.84.

Found: C, 54.33, 54.42; H, 5.73, 5.59; N, 7.44, 7.39; S, 6.01, 5.97

Example 17

7- (D-α-hydroxyphenylacetamido) -3- (1-carboxyethyl tetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid dipotassium salt

1.6 g (0.08 mol) of 7-amino-3- (1-carboxyethyltetrazole) at 5 ° C. was added to a 20 ml acetone solution of 1.5 g (0.0039 mol) of D-(-)-α-formyloxyphenyl-acetylchloride. To a cooled solution of -5-ylthiomethyl) -3-cepem-4-carboxylic acid and 2.1 g of sodium bicarbonate and 25 ml of water. The solution is stirred for 1 hour, the acetone is removed under reduced pressure and the layer is layered with 50 ml of ethyl acetate. The mixture is acidified to pH 2 with phosphoric acid 1: 1. Ethyl acetate is washed with water, lyophilized to 15 mm pressure and slurried with ether. The product is filtered off and dried in vacuo over phosphorus pentoxide to give 500 mg of product. Melting Point: 140 ℃ (Decomposition)

Elemental analysis: C ₂₁ H ₂₀ N ₆ O ₈ S ₂ (C ₂ H ₅ ) ₂ O:

Calculated: C, 48.23; H, 4. 84; N, 13.49

Found: C, 48.12; H, 4.31; N, 12.02

The structure is determined by IR and NMR spectroscopy. When the compound was injected intramuscularly at 10 mg / kg, the blood concentration after 15 minutes was 16.0 mg / ml.

Example 18

7- (D-α-hydroxyphenylacetamido-7-methoxy-3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cefe-4-carboxylic acid dipotassium salt

Equimolar amount of 7-amino-3- (1-carboxypentyl in place of 7-amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid of Example 2 The above compound is obtained using tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

Example 19

7- (D-α-aminophenylacetamido-7-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

Instead of the 7-amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid of Example 3, 7-amino-7-methoxy-3- ( The above compound is obtained using 1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

Example 20

7- (D-α-aminophenylacetamido) -3 (1-carboxy- [C _1-9 -alkyl] -tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

Instead of the 7-amino-3- (1-carboxymethyltetrazol-5-thiomethyl) -3-cepem-4-carboxylic acid of Example 3, 7-amino-3- (1-carboxy [C _{1- 9} alkyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid, for example 7-amino-3- (1-carboxypropyltetrazol-5-ylthiomethyl) -3-cepem The above compound is obtained by using -4-carboxylic acid, 7-amino-3- (1-carboxybutyltetrazol-5-ylthiomethyl) -3-cefe-4-carboxylic acid, and the like.

Example 21

7- (2-aminomethyl-1,4-cyclohexadienylacetamido) -3- (1-carboxyethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

7-amino-3- (1-carboxyethyltetrazole instead of 7-amino-3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cepem-4-carboxylic acid of Example 4 The above compound is obtained using -5-ylthiomethyl) -3-cepem-4-carboxylic acid.

Example 22

7- (D-α-amino-4-hydroxyphenyl-acetamido) -3- (1-carboxyethyltetrazol-5-yl-thiomethyl) -3-cepem-4-carboxylic acid

7-amino-3- (1-carboxyethyltetrazole instead of 7-amino-3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cepem-4-carboxylic acid of Example 5 Using -5-ylthiomethyl) -3-cepem-4-carboxylic acid gives the above compound.

Example 24

7- (3-aminomethyl-2-thionylacetamido) -3- (1-carboxyethyltetrazol-5-thiomethyl) -3-cepem-4-carboxylic acid

7-amino-3- (1-carboxyethyl) of an animal in place of the 7-amino-3- (1-carboxymethyltetrazol-5-yl-thiomethyl) -3-cepem-4-carboxylic acid of Example 23 Tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid gives the above product.

Example 25

7- (3-aminomethyl-2-thienyl acetamido) -7-methoxy-3 (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid

Example 7 animal 7-amino-7-methoxy-3- (instead of 7-amino-3- (1-carboxymethyltetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid in Example 23 The above compound is obtained by using 1-carboxymethyl-tetrazol-5-ylthiomethyl) -3-cepem-4-carboxylic acid.

Example 26

7- (2-aminomethylphenyl acetamido) -3- (1-carboxymethyl-tetrazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid

A) potassium-0- (1-carbomethoxy-propen-2-yl amino-methyl (-phenylacetate (enamine)

1. Add 1000 g of 0-aminomethylphenylacetic acid, 340 g of potassium hydroxide, 1412 g of methyl acetoacetate and 32,400 ml of anhydrous methanol to the tank.

2. The mixture is heated to reflux for 4 hours with stirring.

3. The reaction solution is concentrated under reduced pressure <50 ° until it is about half of the initial volume.

4. Add 10,000 ml of MIBK to the concentrate and continue to depressurize until methanol is removed.

5. Add the necessary amount to slurry 10,000 ml of MIBK or concentrate.

6. Cool the mixture to 5-10 ° for 30 minutes and stir.

7. Filter the slurry and wash the filtrate with 5000 ml of MIBK and again with 5000 ml of acetone.

8. The product is dried in a 40 ° C. flow air oven.

9. The yield is 1605-1680 g or 88-92% of white crystals.

Melting point 140-142 ℃

B) 7- (2-aminomethylphenylacetamide) -13- (1-carboethyltetrazol-2-thiomethyl) -3-cepem-4-carboxylic acid

A ') The enamine (4.09 g) and tetrahydrofuran 90 ml obtained in step (a) are blended into a three-necked flask with a stirrer and a drying tube and cooled in a dry-ice acetone bath. Eight drops of N, N-dimethylbenzylamine are added and the mixture is cooled to -38 ° C. Isobutylchloroformate (1.95 g) is added and stirred for 15 minutes.

B ') 7-amino-3- (1-carboxyethyltetrazol-2-ylthiomethyl) -3-cepem-4-carboxylic acid (3.5 g) is dissolved in 50 ml of water and 2.29 g of N-methyl- Add morpholine and then cool to 2 ° C. The anhydride of step (a ') is added with stirring, and the mixture is stirred at 2 ° C for 1 hour 30 minutes. Tetrahydrofuran is removed under vacuum, the remainder is layered with ethyl acetate and adjusted to pH 3. Stir in an ice bath and take the product. 250 mg, melting point 140 ° C. (decomposition).

Analyze by IR and NMR. About 20% of impurities and starting materials are present. Intramuscular injection of this compound at 10 mg / kg per mouse body weight results in a blood concentration of 22.3 mg / ml after 15 minutes.

Claims (1)

The isocyanate represented by the following general formula (IIIa) is treated with sodium azide to obtain a thiol ester represented by the following general formula (IIIb), and the thiol ester is hydrolyzed to obtain the desired thiol acid. Method for producing a compound represented by).

Wherein n is 2 to 9 and R ¹⁰⁰ is alkylphenyl, phenylalkyl or substituted phenyl or phenylalkyl having 1 to 6 carbon atoms.