JPS63310890A - 6-amino-substituted-1-methylcarbapenem derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> is amino-protecting group; R<2> is H or carboxy-protecting group). USE:A synthetic intermediate for 1beta-methyl-6-amino-substituted-2-substituted thio- carbapenem-3-carboxylic acid useful as an antimicrobial agent. PREPARATION:First, a thiazolidinethione compound is reacted with tin (II) triflate in the presence of a base (preferably N-ethylpyridine) to form an enolate, which is reacted with an azetidinone compound shown by formula III. Then the prepared azetidinon-2-one derivative shown by formula IV is made into an imidazolide and then reacted with a compound shown by the formula (R<2> OOCCH2CO2)2Mg to give a compound shown by formula V. Then this compound is reacted with an azide compound (preferably p-toluenesulfonylazide) in the presence of a base to give a diazo compound shown by formula VI, which is subjected to ring formation in the presence of a metallic catalyst.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a novel carbabenam derivative, in particular 6
The present invention relates to 6-amino-substituted-1-methylcarbapenam derivatives, which are important intermediates for amino-substituted-1-methylcarbapenam compounds.

[Prior Art and Problems] Many carbapenem antibiotics having carba-2-penem-3-carboxylic acid as a basic skeleton represented by the following formula () have been proposed in the past for the purpose of various antibacterial activities. .

For example, early carbapenem antibiotics were developed from Streptomyces ca.
It is a naturally occurring carbapenem compound such as chenamycin represented by the following formula (B) obtained by fermentation of A. ttleya). Chenamycin has an excellent antibacterial spectrum against a wide range of Durum-positive and Durum-negative bacteria, and was expected to be a highly useful compound due to its R-emission, but its chemical stability was poor and it was not put into practical use. It's not quite as long as it should be.

Therefore, many researchers have made efforts to develop a carbapenem compound represented by the above formula that retains the antibacterial activity of chenamycin and has ensured its chemical stability. Imipenem (imipenew; I N
N) has now appeared as a practical antibacterial agent.

However, although imibenem represented by the above formula (C) shows superior antibacterial activity to chenamycin and has a certain degree of chemical stability, it cannot be degraded and inactivated by renal dehydropeptidase (DHP) in vivo. It has the disadvantage that it occurs within a short period of time. Therefore, imipenem cannot be administered alone, and DHP
It must be used in combination with an inhibitor to suppress its decomposition and inactivation; therefore, a practical formulation of this compound is cilastatin, a DHP inhibitor.
It is a combination prescription of imibenem/cilascutin used in combination with atin (INN).

However, as a practical antibacterial agent used clinically, it is preferable that the antibacterial agent's original antibacterial activity be exhibited as is, and the DHP inhibitor used in combination may cause undesirable side effects in other tissues in the body. It goes without saying that it is better to avoid combination formulations as much as possible, as there may be a risk that they may have antibacterial activity and
There is a strong need for the development of carbapenem compounds that also possess resistance to HP.

Recently, various 1-methyl-rubabenem compounds, which have a methyl group introduced into the 1-position of the carbapenem skeleton, have been proposed as compounds capable of achieving the above-mentioned purpose. It has been reported that the resistance to decomposition and inactivation has been significantly improved, making it highly useful.

The above-mentioned carbapenem compounds are all compounds in which a hydroxyethyl group is introduced at the 6-position of carper 2-benem-3-carboxylic acid represented by the above formula [A], and are basically naturally derived carbapenem antibiotics. It belongs to the series of substances.

The present inventors investigated the search for new carbapenem compounds based on a concept completely different from those of the naturally derived 6-(hydroxyethyl)-rbapenem compounds,
As a result, we attempted to introduce an amino 1 substituent at the 6-position of the carbapenem skeleton.

By the way, as this 6-amino substituted carbapenem compound, for example, a compound represented by the following formula has been proposed by Merck & Co. (U.S. Pat. No. 4,217,453). However, in this compound, there is nothing in the first position. No substituent has been introduced, and the introduction of a 1-methyl group, which is thought to particularly enhance resistance to DHP, is still an unexplored field.

Therefore, the present inventors introduced an amine substituent in place of the hydroxyethyl group at the 6-position of the carbapenem skeleton, and
We studied the production of a compound in which a β-configured methyl group was introduced at the position, and as a result, we newly discovered that the compound provided by the present invention can serve as an important intermediate for the production of the above-mentioned target compound, and completed the present invention. did.

[Means for Solving the Problems] That is, the present invention provides a 1β-methyl-6-amino-substituted-2-substituted thio-carbapenem-3 represented by the following formula: Ra and Rb each represent an organic substituted residue. - Provides an important intermediate for the production of carboxylic acids, and specifically, the present invention provides the following formula I: where R1 represents an amino protecting group and R2 represents a hydrogen atom or a carboxy protecting group. It relates to a 6-amino-substituted-1-methylcarbapenam derivative represented by:

[Function] The carbapenam derivative represented by the formula I provided by the present invention can basically be produced by the reaction formula shown below.

(n) (I)<1'V)
(V) (Vl)
<In formula, R1 and R2
is as defined above, R3 and R4 are the same or different and represent a hydrogen atom or a lower alkyl group, and L represents a lower alkanoyloxy group, a lower alkylsulfonyl group or an arylsulfonyl group.

That is, an azetidinone compound represented by formula (1) and a thiazolidinethione compound represented by (2) are reacted in the presence of tin (■) triflate to form a compound represented by formula (2), and then M is added to the compound represented by formula (2). g (OOC
CH2COOR2) 2 is reacted with the mixture to form a compound represented by the formula (2). Thereafter, the compound represented by formula (1) is reacted with an azide compound in the presence of a base to form a diazo compound (2), and then a cyclization reaction is carried out in the presence of a metal catalyst, and if desired, R2
By removing the carboxy protecting group of , one can lead to the 6-amino substituted-1-methylcarbapenam derivatives of formula I of the present invention.

In this specification, the protecting group for the amino group represented by R' includes those commonly used as protecting groups for the amino group in peptide chemistry, such as phthaloyl group, benzyloxycarbonyl group, t-butoxy group. Examples include carbonyl group and phenoxyacetyl group.

Examples of the carboxyl protecting group J represented by R2 include ester residues, such as lower alkyl ester residues such as methyl, ethyl, n-propyl, and n-hexyl esters; benzyl; , p-nitrobenzyl, 〇-nitrobenzyl, p-methoxybenzyl and other aralkyl ester residues; acetoxymethyl, propionyloxymethyl, n-, 1so-
, butyryloxymethyl, pivaloyloxymethyl, and other lower aliphatic acyloxymethyl residues.

Further, the "lower alkyl group J represented by R3 and R4 may be linear or branched and preferably have 1 to 6 carbon atoms, such as methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, 5ea-butyl, tert-butyl, n
-pentyl, isopentyl, n-hexyl, isohexyl groups, and the like.

In addition, the "lower alkanoyloxy group" shown as
-〇- group, such as acetoxy, propionyloxy, butyryloxy group, etc., and "arylsulfonyl group" is an aryl-802- group in which the aryl moiety has the above meaning, such as benzenesulfonyl,
tolylsulfonyl, naphthylsulfonyl groups, etc. are included, and the "lower alkylsulfonyl group" is a lower alkyl-3O2~ group in which the lower alkyl moiety has the above meaning,
Specific examples include methanesulfonyl, ethanesulfonyl, and propanesulfonyl groups.

The production of the 6-amino-1-methyl-rubabenam derivative represented by formula I of the present invention will be explained in more detail below.

First, the first step is to prepare N-propionyl-1,3-
A thiazolidine-2-thione derivative is reacted with tin (■) triflate in the presence of a base to form erulate, which is then reacted with a compound of formula (1) to form the azetidin-2-one derivative (2). It consists of manufacturing.

The enolization reaction of the N-propionyl-1,3-thiazolidine-2-thousone derivative of the formula (■) with tin (■) triflate is usually carried out in a solvent inert to the reaction, for example,
Ethers such as diethyl ether and tetrahydrofuran; hydrocarbons such as toluene, xylene, and cyclohexane; and halogenated hydrocarbons such as dichloromethane and chloroform. Particularly preferred is tetrahydrofuran.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but is generally about -100°C to about room temperature, preferably about -7°C.
Relatively low temperatures of 8°C to about 0°C are used.

Although the amount of tin (■) triflate to be used relative to the compound of formula (■) is not critical, the amount of tin (■) triflate per mole of compound (2) is usually about 1 to about 2 moles, preferably 1 to about 2 moles. It can be used in a proportion of 1.5 moles.

The above enolization reaction is carried out under basic conditions, and examples of bases that can be used include triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2,
2,2] octane, N-methylmorpholine, N-ethylpiperidine, pyridine and other tertiary amines, etc.
Among them, N-ethylpiperidine is advantageously used. These bases can be used generally in an amount of about 1.0 to about 3 equivalents, preferably 1.0 to 2.0 equivalents, per mole of compound (2).

The enolization reaction can generally be completed in about 5 minutes to about 4 hours, thereby yielding erulate.

Following this enolization reaction, the produced erulate can be directly reacted with the compound of the formula (2).

The alkylation reaction between the erulate and the compound of formula (1) can generally be carried out at a temperature of from about -100°C to about room temperature, preferably from about -78°C to about 10°C. The amount of the compound of formula (1) to be used in this case is not critical and can be changed as appropriate, but is usually about 0.5 to about 5 mol per mol of the compound (2) used in the enolization reaction.
It is preferable to use it in a proportion of 0.5 to 2 moles.

Under such conditions, the reaction can generally be completed in about 5 minutes to about 5 hours, more generally about 5 minutes to about 2 hours.

The enolization reaction and the alkylation reaction described above are preferably, but not necessarily, carried out under an inert atmosphere, such as a nitrogen gas or argon gas atmosphere.

After i & the reaction product is treated with water. For example, after the reaction is completed, a phosphate buffer solution with a pH around 7 is added and stirred, insoluble materials are separated, and the compound of formula (■) is separated and purified by conventional methods such as extraction, recrystallization, chromatography, etc. Can be done.

Next, the azetidin-2-one derivative represented by ② produced in the above step was converted into an imidazolide by the formula (R
200CC)1. It is reacted with a magnesium malonate compound represented by cO□) 2 M g to obtain a compound represented by 2■.

The reaction is preferably carried out in an inert organic solvent, such as ether solvents such as ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as toluene, xylene and cyclohexane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; niacetonitrile; Among them, tetrahydrofuran is particularly preferably used.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but generally a relatively low temperature of about 0°C to about 100°C, preferably around room temperature, is used. .

The amount of magnesium malonate compound used is approximately equimolar to the compound of formula V, and the reaction is completed in about 50 hours, preferably about 20 hours.

In addition, examples of the magnesium malonate compound to be used include paranitrobenzylmagnesium malonate, benzylmagnesium malonate, methylmagnesium malonate, etc. Among them, it is preferable to use paranitrobenzylmagnesium malonate. .

Thereafter, the compound represented by the formula V obtained as described above is treated with an azide compound in the same inert organic solvent as exemplified above in the presence of a base to obtain the diazo compound represented by the formula obtain.

Examples of the azide compounds used include p-carboxybenzenesulfonyl azide, toluenesulfonyl azide, methanesulfonyl azide, dodecylbenzenesulfonyl azide, and bases include triethylamine, pyridine, diethylamine, etc. An example of the reaction is to add p-toluenesulfonyl azide, preferably in acetonitrile in the presence of triethylamine,
This can be carried out by treating at ~100°C, preferably at room temperature, for 1 to 50 hours, thereby making it possible to obtain the desired diazo compound of formula (1) in high yield.

Next, the thus obtained diazo compound represented by formula (1) is cyclized to form 6 (6) represented by formula I, which is the object compound of the present invention.
-Amino-substituted-1-methylcarbabenam derivatives. The cyclization reaction in this case is suitably carried out, for example, by preparing a compound of formula (1) in an inert solvent such as benzene, toluene, tetrahydrofuran, cyclohexane, ethyl acetate, dichloromethane, etc., preferably in toluene.
Bis(acetylacetonato)Cu(I[),CuO,, copper powder, R
hz (OCOCH3) 4, 0'dium octano x-) *
or by treatment in the presence of a metal catalyst such as a metal carboxylate compound such as Pb(OCOCH3)4. On the other hand, as an alternative method, the above cyclization step can also be carried out by preparing the compound of formula (1) in a solvent such as benzene, diethyl ether, etc.
5 to 2 hours, using a Pyrex filter (wavelength is 300n)
It can also be carried out by irradiating the light through the rays (larger than m).

Thus, the 6-amino substituted-1- of formula I according to the invention
Methylcarbabenam derivatives can be obtained, but by further introducing a substituted thio group at the 2-position, the compound represented by the formula (■) can be derived into a carbapenem compound represented by the following formula, which is expected to have excellent antibacterial activity. can be induced to Therefore, the present invention provides an intermediate compound which is particularly important as a synthetic intermediate for 6-amino-substituted 1β-methylcarbapenem compounds, which has not been actively investigated so far.

[Example] Next, the present invention will be explained in more detail with reference to Examples. Note that the symbols in each example have the following meanings.

Ph: phenyl group Ft: phthalimidosyl group PNB: para-nitrobendi J-ac niacetyl group Et: ethyl group Example 1: 798 mg of tin triflae was dissolved in 2.4 ml of anhydrous tetrahydrofuran and cooled to -40 to -50°C. Afterwards, 250 μl of N-ethylpiperidine and 369+*g of compound (2) in anhydrous tetrahydrofuran were added to this solution.
．． Add 2 m&solution. After stirring at the same temperature for 4 hours, a 2 ml solution of compound (1) in anhydrous dichloromethane was added, and the mixture was heated to 5°C.
Stir for 2 hours.

After the reaction was completed, a 0.1 molar phosphate buffer with a pH of 7.0 was added, and 50 ml of ethyl acetate was added thereto, followed by filtration through Celite. The P solution is washed successively with IN hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and brine, and then dried over Na2SO.

The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluted with dichloromethane:ethyl acetate = 9:1) to obtain 282 mg (68%) of compound (3) as yellow prism crystals with a melting point of 215-216°C. .

IR(CHC13) am-': 1780.17
65.1700.1680, NMR (CD C1s) δ: 0.96 (3H
, t), 1.26 (3H, d), 1.60-2.08
(2H.

m), 2.94 (IH, d), 3.53 (LH,
da), 4.30 (IH, aa), 4.84-5.2
4 (2H, m), 5.32 (LH, d), 6.82
(IH, brs), 7.60-7.96 (4H, m>
, [α] Amase+274. l°(c = 0, 34,
CHC13) Elemental analysis value: C+ * Hl! N
) 04 S 2 calculated value: C, 54, 67; H, 4,
59:N, 10.07 Actual value: C, 54,70,H,
4,60,N, 10.09 Example 2 2.54 g of tin triflate is dissolved in anhydrous tetrahydrofuran 8 and cooled to -40 to -50°C. To this solution was added 793u4 of N-ethylpiperidine, followed by the compound (2N, 18g solution in 5ml anhydrous tetrahydrofuran).
2 was added and stirred at the same temperature for 4 hours. Then compound (4
) 892II8 anhydrous tetrahydrofuran solution 5 cal
was added and stirred at 5°C for 1.5 hours. After the reaction was completed, a 0.1 molar phosphoric acid M buffer having a pH of 7.0 was added to the reaction solution, diluted with 50 IIIN of ethyl acetate, and filtered through Celite. The P solution is washed successively with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine, and dried with Ha and SO4. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (eluted with dichloromethane:ethyl acetate = 7:3) to give compound (5) as yellow prism crystals with a melting point of 64-65°C.
22g (68%) was obtained.

IR(CHC13) am-': 1750.16
50, NMR (CDCl,) δ: 0.9B (3H,
t), 1.20 (3H, d>, 1.60-2.06
(3H.

m), 2.90 (LH, d), 3.46 (IH
, dd), 3.98 (IH, dd), 4.42 (2
H.

s), 4.80-5.20 (3H, m), 6.74
〜〜7.40 (5H, m), 7.72 (IH, d)
, [α]V: +252.4° (c =
O-34, CHCI 3) Elemental analysis value: C+5
HzsNsOnS calculation value: C, 54, 14, H, 5,
50, N, 9.98 Actual value: C, 54, 15, H, 5
, 56, N, 9.81 Example 3 2.10 g of the compound (5) obtained in Example 2 and 680 mg of imidazole were dissolved in 40 w11 of anhydrous tetrahydrofuran, and stirred at room temperature for 3 hours.
g (OOCCH2COOPNB) z 6,
25 g was added and stirred at 55-60°C for 22 hours.

After the reaction is completed, the reaction solution is diluted with 400 wIc of ethyl acetate, and the organic layer is washed successively with IN HCI, a saturated aqueous sodium bicarbonate solution, and brine, and then dried with NJL2S04. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluted with dichloromethane:ethyl acetate=1=1) to obtain 1.72 g (74%) of compound (6) as a white solid with a melting point of 137-140°C. Obtained.

TR(CHCl3) cm-': 1755.1
730.1710.1670, NMR(CDC1s)δ:1.25 (3H,
d), 3.15 (IH, quint), 3.6
6 (2H,s), 3.80-3.96 (I
H,rn), 4.46 (2H.

s), 4.6C)-4,88<LH,m), 5.
24 (2H, s), 6.23 (IH, bs)
, 7.48 & 8.19 (48, aromatic ring proton) [α Kose: + 1 0.0 (cm0.2. C
HCl 3) Elemental analysis value: C23H23N 30 m
Calculated value: C, 58, 83; ■, 4.94. N, 8.9
5 Actual measurement values: C, 59,04, H, 5, 11, N, 8.
69 Example 4 1.60 g of the compound (6) obtained in Example 3 and 982 mg of p-toluenesulfonyl azide were added to 40 g of acetonitrile.
ml and cooled to 0°C. Next, 474 ui' of triethylamine was added dropwise to this solution and stirred for 1 hour at the same temperature. After one reaction, the reaction solution was concentrated and the residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=
1:1 elution) to give compound (7) with a melting point of 159-1
1:68g <quantitative) was obtained as pale yellow crystals at 62°C.

IR(CHCIs)c++-':2150.1760.
1710.1685.1640, NMR (CDC13) δ: 1.22 (3H, d), 3
．． 78-4.14 (2H, m), 4.46 (2H
.

s), 4.85 (IH, dd), 5.35 (2H.

s), 6.31 (IH, bs), 6.82-7.42
(5H, m>, 7.53 & 8.23 (4H, aromatic ring proton) [α] Amase+3.Q° (c = 0, 2, CHC
l s ) Elemental analysis value: C2s H21N s Om
Calculated values: C, 55, 74; H, 4, 27: N, 14.
14 Actual measurement value: C, 55, 45,! (,4,39,N,
13.87 Example 5 49.5 mg of the compound (7) obtained in Example 4 was dissolved in 1 vml of anhydrous chloroform and heated in an oil bath at 70°C. .4
Add anhydrous chloroform suspension of tag and incubate at the same temperature for 1
After 6 hours of stirring, the reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (eluted with dichloromethane:ethyl acetate = 2 = 1) to obtain compound (8) with a melting point of 66~
4.5 theoretical g (89%) was obtained as a solid at 68°C.

IR(CHCli)cm-': 1760, 1740.
1715.1675, NMR (CDC1s) δ: 1.36 (3H, d), 2
．． 83 (IH, qujnt), 4.22 (IH,
dd), 4.52 (2H, s), 4.77 (IH,
s), 5.12-5.42 (38, m), 6.85
~7.70 (5H, m), 7.49 & 8.18 (
4H, aromatic proton) [α Kose: +128.3° (C=1.46.C
HCl,) Mass: m/e 466 (M”-1)
High Mass: C23H2ON: IOa calculated value: 466.1201 Actual value: 466.1225

Claims (1)

[Claims] 1. The following formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R^1 represents a protecting group for an amino group, and R^2 is a hydrogen atom or a carboxy protecting group. 6, which represents
-Amino-substituted-1-methylcarbapenam derivatives.