JPS6034957A - 2-substituted methylene-2-(2-aminothiazol-yl)-acetic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H or amino-protecting group; R<2> and R<3> are H, cyano, -COOR<5> (R<5> is H or carboxyl-protecting group) or group of formula II (R<6> and R<7> are H or lower alkyl); R<4> is H or carboxyl- protecting group]. EXAMPLE:2-(2-Tritylaminothiazol-4-yl)-3-tert-butoxycarbonyl-acrylic acid allyl ester. USE:A modifying agent for antibiotic substance, especially penicillin-type antibiotics and cephalosporin-type antibiotics. It has broad antibacterial spectrum, and exhibits strong antibacterial activity even to the Gram-negative bacteria and Gram-positive bacteria. PREPARATION:The compound of formula I can be prepared, e.g. by reacting the compound of formula III with the phosphorane compound of formula IV in a solvent at a temperature between 0 deg.C and the boiling point of the solvent for 30min-10hr.

Description

DETAILED DESCRIPTION OF THE INVENTION Tree 5t=IJJ is a novel 2-substituted methylene-2-(
Regarding 2-aminothian-4-yl) acetic acid derivatives and the fuco method for their production, more specifically, novel 2-substituted methylene compounds useful as modifiers for antibiotics, penicillin antibiotics, and cephalosporin antibiotics. -2-(2-amino/thian-ru-4-yl) V-resistant derivative and method for producing the same.

Penicillin and cephalosporin antibiotics exhibit broad antibacterial activity against Gram-positive and Gram-negative bacteria, and various semi-synthetic penicillin and cephalosporin antibiotics are commercially available. Even now, extensive research is being carried out to improve the antibacterial spectrum and IF properties.

The present inventors have a broad antibacterial spectrum, and
With the aim of searching for β-lactam antibiotics that are effective against resistant bacteria, various ja substituents are currently being investigated.
When we succeeded in synthesizing the 4-yl) vinegar m 1iii conductor and used this compound as a modifier for β-lactam antibiotics such as penicillin, cephalosporin, and monobactam, we obtained new penicillin, cephalosporin, etc. β-lactam antibiotics have a broad antibacterial spectrum and are powerful antibacterial agents against not only Gram-positive bacteria but also Gram-negative bacteria, particularly pathogenic bacteria that are of clinical concern, and even tropic Gram-negative bacteria. The present invention was completed based on this discovery.

That is, the present invention represents the following formula (I) - R2R3 [wherein R1 represents a hydrogen atom or protection of an amine group], (represents R2 and R3, which may be the same or different, and a hydrogen atom, a cyanide group, group, a substituent of the following formula: C00R5 (wherein, R5 represents a hydrogen atom or a protecting group for a carboxyl group) or a substituent of the following formula: CON\7 (wherein, RG and R' are They may be the same or different and represent a hydrogen atom or a lower alkyl group. The present invention relates to a characteristic 2-substituted methylene-2-(2-aminothiazol-4-yl)acetic acid derivative and a method for producing the same.

In the formula (1), representative protecting groups for the amine 7 group include a triphenylmethyl group (trityl group), a chloroacetyl group, a formyl group, a tert-phthoxycarbonyl group, and the like. Typical protecting groups for carboxyl groups include lower alkyl groups, allyl groups, aryl groups such as p-nitrobenzyl group, p-methoxybenzyl group; henshydryl group, trialkylsilyl group! A
'J can be mentioned. Furthermore, in the present invention, lower alkylno^ refers to a linear, branched, or cyclic alkyl group having 1 to 4 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, etc. group, n-butyl group, isobutyl group, 5ee-butyl group, tert-butyl group, and the like.

Examples of the compound represented by the formula (1) of the present invention include the following.

@2-(2-aminothiazur-4-yl)-3-carboxyl-H, R2=H, R3=C0OH, R4=H)2-(2-
aminothiazol-4-yl)-3-cyano-(Z)-
Acrylic acid (R1=H.

R2=H, R3=CN, R4=H) 2-(2-aminothiazol-4-yl)-3-rupamoyl-(Z)-acrylic acid (R1=H, R2=H, R
3=C0NH2, R4=H) 2-(2-ami/thiazol-4-yl)-3-carboxyl-(E)-acrylic acid (R1=H, R2=C0OH, R3=H, R4=H)
2-(2-aminothian-4-yl)-3-cyano-(E)-acrylic acid (RI=H.

R'=CH, R3=H, R4=H) 2-(2-aminothiazol-4-yl)-3-carbamoyl-(E)-acrylic M(R'=H, R2=C0
NHt, R3=H, R'=H) 2-(2-aminothiazol-4-yl)-3,3-dicarboxylacrylic acid (R'=H, R2=R3=COOH, R'=H)
2-(2-aminothiazol-4-yl)-3,3-dicyanoacrylic acid (R1=H, R2=R3=CH, R4
=H) 2-(2-aminothiazol-4-yl)-3,3-dicarboxylacrylic acid (R1=H, R2=R3=C0
NH2, R4=H)2-(2-)rithylaminothiazol-4-yl)-3-tert-butoxycarbonyl-
(Z)-Rithyl acrylate (R'=), R2=H.

R3=COOC(CH3)3, R4=H)2-(2-
Chloroacetylaminothiazol-4-yl)-3-t
ert-butoxycarbonyl-(Z)-acrylic acid (R
'=chloroacetyl.

R2=H, R3=COOC(CH3)3, R'=H) 2-(2-aminothiazol-4-yl)-3-(N,
N-dimethylcarbamoyl)-(Z)-acrylic acid (R
'=H, R2=H, R3=C0N (CH3)2,
R4=H) 2-(2-)ditylaminothiazol-4-yl)-3
-tert-butoxycarbonyl-(E)-acrylic acid (R1=trityl, R2=COOC(CH3)3, R
”=H, R4=H) 2-(2-chloroacetylaminothiazol-4-yl)-3-tert-butoxycarbonyl-(E)-acrylic acid (R1=chloroacetyl.

R2=COOC(CH3)3, R3=H, R4=H) 2-(2-aminothiazol-4-yl)-3-(N,
N-dimethylcarbamoyl)-(E)-acrylic acid (R
1=H, R2=C0N (CH3) 3. R3=H, R
4=H)2- (2-) dithylaminothiazole-4-
yl)-3,3-di-tert-butoxycarbonyl acrylic COOC (CH A ) 3 , R 4 =H) and ester derivatives of these compounds protected with the aforementioned carboxyl group-protecting groups.

The compound of the present invention represented by the above formula (, I) can undergo tautomerization as shown below to form two types of tautomer structures.

(In the formula, R1.R2, R3 and R4 have the same meanings as above.) The compound of the present invention can be produced, for example, according to the following methods, that is, Methods A to C.

[Method A] (II) (m) (I) (wherein R'.) 12 , R3 and R4 have the same meanings as above. ) The target compound (I) can be obtained by treating compound (n) with a phosphorane compound (m) in a suitable solvent.

Preferred solvents include hydrocarbon solvents such as hexane, toluene and benzene; aprotic polar solvents such as ethyl ether, dioxane and tetradimethyl sulfoxide; alcoholic solvents such as methanol and ethanol, and water. The reaction temperature generally ranges from 0°C to the boiling point of the solvent, particularly preferably from 0 to 50°C.

The reaction time varies depending on the solvent used and the reaction temperature, but is generally 30 minutes to 10 hours, particularly preferably 1 to 4 hours.

(+, I) When the compound to be detected is a mixture of (E) monomer and (Z) monomer, the target compound can be isolated by separation and purification by conventional methods, if necessary. .

The starting materials, compounds (II) and (I[[), are known compounds.

[Method B] (IV) (V) (I) (In the formula, R1, R2, R3 and R4 have the same meanings as above.) Compound (IV) is added to compound (IV) in an appropriate solvent as necessary. The target compound (I) can be obtained by treatment with V).

As the solvent, the same solvent as in Method A is used. The reaction temperature generally ranges from 0°C to the boiling point of the solvent, particularly preferably from 0 to 50°C. The reaction time varies depending on the solvent used and the reaction temperature, but is generally from 30 minutes to 10 hours, and preferably from 1 to 44 hours.

When the resulting compound is a mixture of (E) monomer and (Z) monomer, the target compound can be isolated by separation and purification by conventional methods, if necessary.

[Method C (Vl) (V) (Vl') (In the formula, R', R2, R3 and R4 have the same meanings as above.) Compound (II), if necessary, in a suitable solvent, The desired compound (1) can be obtained by treating with compound (V) in the presence of salt 1 and then carrying out a water reaction with 11 (a).

In this V, we will discuss the compound (■゛) or i! which is one reaction intermediate! However, the target compound (I) can be obtained by carrying out a dehydration reaction by an appropriate means without isolation.

As the solvent, the same solvent as in [Method A] is used. As the base, alkali metals such as sodium and potassium; alkali metal hydrides such as sodium hydride and potassium hydride; sodium 1, methoxide, potassium ter
Alkali metal alkoxides such as t-butoxide; n-
Organic alkali metals such as butyllithium and phenyllithium can be used. It is sufficient that the amount of the base used is from equimolar to 3 times the molar amount, and particularly preferably from equimolar to 2 times the molar amount.

The reaction temperature is preferably -70 to 0°C. The reaction time varies depending on the solvent used and the reaction temperature, but is generally 1 to 10 hours, particularly preferably 1 to 2 hours.

The dehydration reaction can be carried out by treating the alcohol (■') with a base or by heating it. In this case, the dehydration reaction can be carried out more easily by converting the hydroxyl group of the alcohol (■゛) into a substituent that is easily eliminated, such as a tosyl group, mesyl group, or acetyl group, and then carrying out the above treatment.

stomach! The compound represented by I is (E) monolithic and (Z) monolithic 2 l
In the case of a compound, the target compound can be obtained by separating and purifying it using a conventional method, if necessary.

As a separation/purification method for (Z) integral and (E) integral, ordinary column chromatography or thin layer chromatography can be appropriately used.

In addition, in the present invention, the target compound is free 7-7,
(Or, if the compound has a carboxyl group, it can be protected with an appropriate protecting group as necessary, and after the reaction, the protecting group can be removed to obtain a desired compound.) I can do it.

Next, the arrangement of double bonds in the compound of the present invention will be explained in detail.

The following formula (I a) or (I b): (Ia) (Z configuration) (Ib)' (E configuration) (wherein, R
1 and R4 have the same meanings as above, and R゛ is the above-mentioned R2.
Or represents R3. The disubstituted olefin represented by ) has (Z)-configuration and (E)-configuration geometric isomers. The configuration of the double bond in the compound of the present invention can be determined by nuclear magnetic resonance spectroscopy (NMR) or the like.

The compound represented by the formula (I) of the present invention is useful as a side chain such as the 6-position of penicillin or the 7-position of cephalosporin as described above, and the synthesis of various antibiotics using the compound of the present invention is as follows: carried out by a peptide-forming reaction between 6-aminopenicillanic acid, 7-aminocephalosporanic acid and their derivatives and the compound represented by formula (I),
Known techniques can be used for this reaction.

The β-lactam antibiotics obtained by using the compounds of the present invention have a broad antibacterial spectrum,
Not only Durham-positive bacteria but also Gram-negative bacteria and 1mlml
It exhibits strong antibacterial activity even against Lagram-negative bacteria.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples, but these Examples and Reference Examples do not limit the scope of the present invention in any way.

2-year-old xo2-(2-)ditylaminothiane-4
After dissolving 400 mg of allyl acetate in 10 ml of dry dimethylpolamide under an atmosphere of hydrogen, HO mg of triphenyl carbo-tert-butoxymethylenephosporan was added, and the mixture was stirred at room temperature for 24 ml. The reaction solution was concentrated under reduced pressure, dissolved in 50 ml of ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained product was transferred to Wako Gel C-20.
Purification was performed by column chromatography (system: toluene-ethyl acetate) using 021g of the product to obtain each isomer of the desired product.

(Z)-isomer 361ωg NMR spectrum [80MHz, δ value (1) Ilm)
, CDCM3]1.4Ei(9H,s), 4
．． 77 (2H, b, d,), 5.15-5.45 (2)
1. m).

5.75-6.15 (IH, m), 8.40 (IH
,s), 8.50(IH,s).

6.84 (LH, b, s,), 7.28 (15H, b
, s, ) IR spectrum (Nujol) 3350 , 1730 , 1700 , 1810c ``'
(E)-isomer 51 mg NMR spectrum [80 MHz, δ value (ppm), c
oc9.3 ] 1.4ff (9H, s), 4.70
(2H, b, s,), 5.15-5.40 (2H, m)
.

5.85-f(,15(IH,m), 6.50(I
H, b, s, ), 8.75 (IH, s).

8.85 (IH, s), 7.30 (15H, b, s,
) IR spectrum (Nujol) 3350, 1720, 1700, 1810c "1
2.4 g of 4-2-oxo-2-(2-chloroacetylaminothiazol-4-yl)acetic acid ethyl ester of 4-yl-3-tert-p]oxycarbonyl acrylic ethyl ester was added to dry dimethyl ester under a nitrogen atmosphere. After dissolving in 50 ml of formamide, 3.7 g of triphenylcarbot-tert-butoxymethylenephosphorane was added and stirred at room temperature for 24 H+1I. The reaction solution was concentrated under reduced pressure and diluted with 150 ml of ethyl acetate.
1, washed with water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained product was transferred to Wako Gel C.
Column chromatography using -200210g (
System: toluene-ethyl acetate) to obtain each isomer of the target product.

(Z)-isomer 1.14g NMR spec 1, )ly [80MHz, δ value (Ppm
), CDCfL, ]I13fi(3H,t,J=
7.2Hz)', 1.48(9H,s), 4.2
5 (2H, s).

4.37 (2H, q, J=7.2Hz), f(,E
iO(IH,s), ? , 05(1)1. s).

9.80 (III, b, s,) (E)-isomer 1.0 Lg NMR spectrum [80 MHz, δ value (ppm), l
:Dc: Sentence 3] 1.32 (3H, t, J=7.2Hz)
, 1.46 (9H, s) , 4.25 (2H, s
).

4.28 (2H, [T, J=7.2H2), 6.90 (
IH, s), 7.85 (IH, s).

9.75 (IH, b, s,) 550 mg of 2-oxo-2-(2-chloroacetylaminothiazol-4-yl) sodium acetate flH was suspended in 10 ml of dry tetrahydrofuran, and 0.5 g of Molecular Sheep 4A was added. While cooling with water, 0.375 ml of trimethylsilyl chloride was added, and the mixture was stirred at the same temperature for 30 minutes. 917 mg of triphenyl carbo tert-butoxymethylenephosphorane was added to 5 mL of dry tetrahydrofuran.
ml of the solution was added and stirred at room temperature for 17 hours. Insoluble matter was removed, and the furnace liquid was concentrated under reduced pressure. ethyl acetate 5
The mixture was added to a mixed solution of 0 ml and 10 portions of water, and the pH was adjusted to 7.2 using sodium hydrogen carbonate solution while cooling with water. Wash with ethyl acetate and adjust to pH 2 using 5% hydrochloric acid under water cooling.
5, and then extracted with ethyl acetate. After washing with water, it was dried over magnesium sulfate and concentrated to dryness under reduced pressure. 2-(
2-chloroacetylaminothiazol-4-yl)-3
-tert-butoxycarbonyl acrylic resistance is 400 as a mixture of Z configuration isomer and E configuration isomer (7:3)
[1g obtained. This product was dissolved in 10 ml of tetrahydrofuran without separation, and a n-hexane solution of diphenyldiazomethane was added thereto, followed by stirring at room temperature for 17 hours. After concentrating the reaction solution under reduced pressure, Wako Kel C-2001
Purification was performed by column chromatography using 00 g of each isomer of the target product (11).

(Z)-isomer 210mg NMR spec) /l/ [80MH2, δ value (ppm
), CDCl 311.42 (9H, s), 4.
25 (2H, s), 6.50 (IH, s).

6.58 (IH, s), 7.12 (IH, s),
7.28 (IOH, s).

! ], G2 (IH, b, s,) (E)-isomer 35flIg NMR spec h /shi[80MHz, δi+Q (pp
m), cncx, ]I14G(9H,s), 4
．． 25 (2H, s), 8.95 (IH, s).

7.02 (IH, s), 7.28 (IOH, s),
7.76 (IH, s) 1 self-pulling A 2-(2-tritylaminothiazol-4-yl)-3
-tert-Butoxycarbonyl acrylic acid allyl ester (Z isomer) 361ag was dissolved in 10w1 of ethyl acetate. Under water cooling, tetrakistriphenylphosphine palladium (0) 10mg,! - Added 10 mg of rifhenylphosphine, and further added 5 ml of an ethyl acetate solution in which 12,011 g of potassium 2-ethylhexanoate was dissolved. After stirring at room temperature for 1 hour, the reaction solution was diluted with 50% n-hexane.
Added to 1. One portion of the precipitate was taken and dried. The obtained potassium salt was suspended in 30 ml of ethyl acetate, and the p)I was adjusted to 2.0 using 5% hydrochloric acid under water cooling. After washing with water and drying with magnesila sulfate J., it was concentrated to dryness to obtain 291 mg of the title compound.

NMR spectrum [80 MHz, δ4rti (pp
m), 000 sentences, ]I142(9H,s), E
i, 49 (IH, s), 13.57 (IH, s)
.

7.24 (IBH, b, s,) By treating in the same manner as in Example 1, except using triphenylcarbomethoxymethylenephosphorane instead of triphenylcarbotert-butomethylenephosphorane, Each isomer of the title compound was obtained.

(Z)-isomer NMR spectrum [80 MHz, δ value (ppm), C
DCl333, [10(3H,s), 4.75(2
H, b, d,).

5.20-5.46 (2H, m), 5.80 (IH
, m), 8.45 (IH, s).

6i, 52 (IH, s), 7.26 (+5H, b,
s,)(E)-isomer NMR spectrum [80MHz, δ value (PPffi),
to I [text,] 3, [12 (3) 1. s), 4.7
5 (2H, b, s, ), 5.20-5.48 (2H, m
).

5.80 (IH, m), 8.72 (IH, s),
8.84 (IH, s).

7.25 (15H, b, s,) pot "raw" 30 ml of dry dimethylformamide and 5 ml of methylene chloride
The mixed solution with 1 O was cooled to -10°C, 35 mg of phosgene dimer was added thereto, and the temperature was gradually raised to +10'C while stirring. After 30 minutes, it was cooled to -30℃, and 2~(
2-tritylaminothiazol-4-yl)-2-te
rt-butoxycarbonyl acrylic acid (ZX form) 1
5 ml of a methylene chloride solution containing 86 mg of triethylamine and 90 mg of triethylamine was added, and the mixture was reacted at -30 to -20°C for 30 minutes. Add 7-amino-3-(1-methyl-
IH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester 180m
3 ml of methylene chloride solution containing g was added dropwise. -20～
After stirring at -10°C for 1 hour, ice water was added to adjust the pH to 1.5, and the mixture was extracted with methylene chloride. The organic layer was diluted with NaHCO3
The pH was adjusted to 7.0 using an aqueous solution, dried, and concentrated to dryness. Purification was performed by column chromatography using Wako Gel C-200 (system: toluene-ethyl acetate) to obtain 120+ mg of the title compound.

NMR spectrum JL/[80MHz, δ value (ppm)
, CDCl 311.42 (9H, s), 3.2
5 (2H,,s), 3.80 (3H,s).

4.35 (2H, ABq), 5.05 (IH, d,
J=4.8)1g)5.85(IH,d,d,,J=4
．． 8Hz, 9Hz), 6.50(IH, 5)Ei, 8
5(It(,s), fl, 85(1)1.s),
7.30(18B) 7-[2-(2-tritylaminothiazol-4-yl)-2-tert-butoxycarbocolmethyleneacetamito] -3-(1-methyl-IH-tetrazol-5-yl ) Thiomethyl-3-cephem-4-carboxylic acid benzhydryl ester too
mg was dissolved in 1 ml of anisole, 2 ml of trifluoroacetic acid was added under water cooling, and the mixture was stirred for 2 hours and 1 tJI fl at 0 to 5°C. The reaction solution was concentrated under reduced pressure and then powdered with isopropyl ether to obtain 32 mg of the title compound.

NMR spectrum [80MHz, δ value (Ppm), DM
SOd6] 3.84 (2H, d), 3.80 (3H, s
), 4.22 (2H, m).

5.05(l)l, d, J=4.8Hz).

5.70 (IH, cl, d,, J = 4.61 (z, ll
t, 0) 1z), 8.30 (IH, s).

6.55 (IH, s), 9.30 (IH, d, J=
9.0Hz) The antibacterial activity of the compound obtained in Reference Example 2 was measured, and the results shown in the table below were obtained. In addition, the antibacterial activity is the minimum inhibitory concentration (unit: nilg/ml)
It was expressed as

Procedural auxiliary device October 6, 1981 Kazuo Wakasugi, Commissioner of the Patent Office], case description 1981 Patent Application No. 142558 52, title of the invention 2-substituted methylene-2-(2-aminothiazole-4-
(609) Meiji Seika Co., Ltd. (609) Meiji Seika Co., Ltd. (609) Meiji Seika Co., Ltd. (609) Meiji Seika Co., Ltd. ” he corrected.

Claims (4)

[Claims] (1) The following formula: [In the formula, RI represents a hydrogen atom or a protective group for an amine group, R2 and R3 may be the same or different, and a hydrogen atom, a cyano group, a , R5 is a hydrogen atom or a 1δ substituent represented by (represents a protecting group for) a carboxyl group, or 6/Con\7 (wherein, R6 and R7 may be the same or different, and hydrogen 2-substituted methylene-2-(2-amino thiazol-4-yl) vinegar HA conductor. (2) The following formula: (In the formula, R1 represents a hydrogen atom or a protecting group for an amino group, and R4 represents a hydrogen atom or a protecting group for a carboxyl group.) 2 / The following formula: (C6R5)3 P=C\3 [In the formula, R2 and R3 are the same or different (they may be a hydrogen atom, a cyano group, the following formula COOR5 (wherein, R5 is a hydrogen atom or a carboxyl group) ) or a substituent represented by 6 / represented by the following formula CON\7 (wherein R6 and R7 may be the same or different and represent a hydrogen atom or a lower alkyl group) 2-substituted methylene represented by the following formula: (wherein R1, R2, R3 and R4 have the same meanings as above), which is treated with a phosphorane compound represented by - A method for producing a 2-(2-aminothiazol-4-yl) intoxication derivative. (3) The following formula: (In the formula, R1 represents a hydrogen atom or a protecting group for an amine group, and R4 represents a hydrogen atom or a carboxyl group protecting group.) A compound represented by the following formula: 2 \ The following formula: C-0/3 [wherein, R2 and R3 may be the same or different, and may be a hydrogen atom, a cyan group, the following formula, -COOR5 (wherein, R5 represents a hydrogen atom or a protecting group for a carboxyl group) .) or a substituent represented by the following formula: CON\7C In the formula, R6 and R7 may be the same or different and represent a hydrogen atom or a lower alkyl group. ) represents a substituent represented by ] 2-substituted methylene-2 represented by the following formula: % formula % (wherein p, I, R2, R3 and R4 have the same meanings as above) - A method for producing a (2-aminothian-4-yl) intoxication derivative. (4) A compound represented by the following formula: (wherein, R1 represents a hydrogen atom or a protecting group for an amine group, and R4 represents a hydrogen atom or a protecting group for a carboxyl group) in the presence of a base. , 2 \ Following formula: C=0/3 [In the formula, R2 and R3 may be the same or different, and are a hydrogen atom, a cyan group, and the following formula: C00R5 (In the formula, R5 is a hydrogen atom or a carboxyl group. ) or a substituent represented by 6 / represented by the following formula CON\7 (wherein R6 and R7 may be the same or different and represent a hydrogen atom or a lower alkyl group) represents a substituent. ] The following formula is characterized by treatment with a compound represented by: A method for producing a 2-substituted methylene-2-(2-aminothiazol-4-yl)acetic acid derivative represented by 2R3 (wherein R1, R2, R3 and R4 have the same meanings as above).