JPS60109561A - Preparation of beta-lactam compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound of (3S, 4S) useful as an intermediate for a compound having antimicrobial action and inhibitory action on beta-lactamase, by using an easily obtainable L-aspartic acid as a starting raw material, converting it into an azetidine compound which is sterically specific (4S). CONSTITUTION:Amino group of aspartic acid is protected, it is then dehydrated, and reduced to give a compound shown by the formula I (R4 is amino-protecting group). Hydroxyl group of this compound is protected, the amino-protecting group is deprotected, to give a compound shown by the formula II (R1' is OH- protecting group), which is subjected to ring closure to give a compound shown by the formula III. Imino group of this compound is protected, to give a compound shown by the formula IV (R1' is hydroxy-protecting group; R2' is iminoprotecting group), which is oximated to give a compound shown by the formula V, which is reduced, optionally amino group of this compound is protected, and optionally R1' and/or R2' is deprotected to give a compound shown by the formula VI (R1 is H, or R1'; R2 is H, or R2'; R3 is H, or amino-protecting group). USE:An intermediate for bicyclic beta-lactam compound and monobactam antibiotic.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing β-lactam compounds, more specifically,
The following general formula (1), (wherein 1 represents a hydrogen atom or a hydroxyl group-protecting group, R2 represents a hydrogen atom or an imino group, and R3 represents a hydrogen atom or an amino group-protecting group) This invention relates to a novel method for producing the represented compounds.

The compound of formula (1) is useful as an intermediate for synthesizing a compound having antibacterial activity and β-lactamase inhibitory activity.

Examples of the compound of formula (1) include monobactam antibiotics, J and Am, which are described in, for example, the specifications of JP-A-58-77861 and JP-A-58-121269.

Chem, 8oc, 99 2352.2353 (197
It is an important intermediate for producing the bicyclic β-lactam compound described in 7).

According to the present invention, the compound of formula (1) is produced according to the following reaction scheme.

Asno-Q lagging acid (in the formula, %R1° represents a hydroxyl group-protecting group, R2' represents an imino group-protecting group, R41d represents an amino group-protecting group, and the other symbols have the above-mentioned meanings), that is, the present invention protects the amino group of as, e-lagic acid, and then dehydrates to form N-protected anhydride) Q-line acid (
tl), this product is then reduced to give compound 1), the hydroxyl group is protected, the amine group is removed to give compound (IV), and this product is ring-closed to give compound (IV). Then, after preserving the imino group of this compound, it is converted into an oxime to form a compound (Vl), which is then reduced, and further the diamino group is protected as desired, and then the diamino group is protected as desired. II and/or R2'
This is a method for producing compound (I) by eliminating.

Next, each of the above-mentioned reactions of the present invention will be explained in detail.

(2) Asno Q digic acid → ω) Compound (II) is obtained by subjecting the amine 7 groups of as and Q lagging acid to a dehydration reaction. As the protecting group for the amine 7 group, known ones commonly used in conventional pezotide synthesis can be used. Examples of these supporting groups include alkyloxycarbonyl groups such as ethyloxycarzenyl group, tertiary butyloxycarbonyl group, and tertiary amyloxycarbonyl group; cycloalkyloxycarbonyl group such as dichlorohexyloxycarbonyl group; o-
Examples of nitrophenoxylic include aryloxycarzenyl groups such as nyl groups; aralkyloxycarzenyl groups such as pencyloxycarbonyl group and p-methoxypencyloxycarbonyl group; lower acyl groups such as acetyl group and zolopionyl group. It will be done. Introduction of a protecting group can be carried out by a conventional method.

For the dehydration reaction of N-protected as, Q lagic acid, it is preferable to use a method in which dehydration mJk is applied in a solvent. As the dehydrating agent, acetyl chloride, thionyl chloride, phosphoryl chloride, acetic anhydride, etc. can be used. As the solvent, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, etc. can be used, but the above-mentioned dehydrating agent can also be used in excess to serve as a solvent. The reaction is completed in several minutes to several hours at room temperature to 200°C.

■(It) → 01) Compound (II) When k F2 elements, a compound (poetry) is obtained.

Particularly preferred for the reduction is a method using a complex metal hydride such as lithium aluminum hydride, sodium borohydride, potassium fluoride hydride, etc. as a reducing agent. The reaction is carried out by allowing the reducing agent to act on the compound (II) in a solvent such as ether or tetrahydrofuran at -30°C to +60°C for 1 minute to 10 hours.

■ (Seal) → (IV) Compound (mV) is obtained by protecting the hydroxyl group of compound (1) and removing the protecting group from the amine group. Examples of the hydroxyl protecting group include t-butyl group, N-7 thalimidomethyl group, benzoylmethyl group, naphthoylmethyl group, nitrobenzoylmethyl group, pencil group, nitropencyl group,
A methoxypencyl group, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, etc. can be used. Since the compound (1) has a carxyl group in addition to a hydroxyl group, the carboxyl group is also preserved when the reaction to preserve the hydroxyl group with the retention group described in "2" is generally carried out. Therefore, after both functional groups are bound, it is necessary to remove only the bound group of the carboxyl group.

An example of this reaction is shown below.

(1) Using asno-qlaginic acid in which the 7 groups are bound with a pencyloxycarbonyl group (abbreviated as 2) as a raw material, a compound (υR475i2) is obtained by the reactions of (1) and (2) above. C) Compound side) (R4=Z) is treated with t-butyldimethylsilyl/-ride, and the carboxyl group and hydroxyl group are protected by a t-i tyldinotylsilyl group (hereinafter referred to as ken+). , (3) Compound (1) in which the amine group is supported by 2 and the carboxyl group and the hydroxyl group 'ts'4+
A weak acid (for example, dilute hydrochloric acid) or a weak base (for example, a dilute sodium hydroxide water bath) is applied to remove the protecting group of the carboxyl group. Compound 1) in which the amine group and the hydroxyl group are coercive with 2 and 81+ is subjected to catalytic reduction to form the coercive group 2 of the amino group.
to detach.

■(iV) → (y> When compound (ff) is closed, compound (■) is present.The reaction should be carried out in a solvent in the presence of a compound, catalyst, etc. that converts the carboxyl group of compound (1v) into an oily substance. is preferred.

Compounds that activate carboxyl groups include compounds that form acids, hydrothermal hydrates, active amides, active esters, active thioesters, etc. (Although compounds that form thioesters such as dipyridyl disulfide can also be used) Particular preference is given to using compounds such as triphenylphosphine as catalyst.

Tri-n-butylphosphine, triphenylphosphite, etc. can be used. As a solvent, hydrocarbons such as benzene, toluene and n-hexane; halogenated hydrocarbons such as chloroform and methylene chloride; ethyl compounds such as ether, tetrahydrofuran and dioxane; and acetonitrile, zomethylformamide, Dimethyl sulfoxide and the like can be used alone or in combination. The reaction is 0
It progresses in several minutes to several tens of hours at ~150'C.

(2) Concave (Vl) Compound (vI) is obtained by preserving the imino group at the 1-position of compound (V) and then converting it into an oxime. As a protecting group for the imino group, it is also possible to use the above-mentioned holding group or acyl group such as Ushioba 2, but since this protecting group is removed in the catalytic reduction reaction carried out in the next step, , R2 in object (1)
When a metal other than a hydrogen atom is desired, it is preferable to use a protective group that does not leave off in a catalytic reduction reaction, such as a trialkylsilyl group. Introduction of the B-retaining group is carried out by a conventional method.

The oxime formation of compound (g) can be carried out by activating the third bond of the lactam ring (forming an anion) and then reacting with a nitrite compound. Activation of the 3rd position is carried out, for example, by the action of a strong organic base such as lithium diisoglobilamide at low temperature. As a nitrous acid compound, nitrite has 1 to 6 carbon atoms.
Lower alkyl esters of , etc. can be used. Activation and oximation can be carried out in the same reaction system, for example, under an inert gas atmosphere such as nitrogen or argon.
The desired product is prepared by reacting the lithium diisozorobylamide with lithium diisozorobylamide for several minutes to several hours, and then adding, for example, amyl nitrite and allowing the reaction to occur for several minutes to several hours. This reaction is carried out in a solvent, and as the solvent, those exemplified in the reaction (2) above can be used. According to this reaction, two types of isomers (syn type and anti type) are obtained, but these can be easily separated by, for example, silica gel chromatography. however,
When used as a raw material for the next step, even if these are used as a mixture without separation, the steric coordination of the target product (1) will not be affected.

■(Vl) -(11 Compound (1) is obtained by catalytic reduction of compound (vl). Examples of catalysts used at this time include NoQ2zoum, oxide, Q radium, Noqlazoum black, platinum, Examples include platinum oxide, nickel, nickel oxide, Raney nickel, rhodium, ruthenium, etc.Solvent, !-t
For example, alcohols such as methanol, ethanol, pro, Q-nol, ethyl acetate, etc. can be used. The reaction is carried out under normal pressure or increased pressure, -30-Zo.

Hydrogenation is completed at 1 to 20 hours at ℃. At this time, regardless of the ratio of isomers regarding the 3-position oxime of compound (vl), the ratio of cis-trans isomers between the 3- and 4-positions of compound (1) to be produced is approximately 7:1. These can be easily separated using, for example, silica gel Chromadog 5F.

By the above reaction (R1-H, R1-4IN.

Compound (1) with R, = II) is obtained, and if desired, coercion of the amino group at the 3-position or removal of the imide group at the 1-position and the side chain hydroxyl group at the 4-position is carried out by a conventional method. be able to.

The target compound of the present invention (in D, the compound (38°4s) of the following formula is a particularly important intermediate for producing biologically active compounds, and according to the present invention, it can be easily obtained as a raw material compound. By using L-asnoqlagic acid, the compound stereospecifically (4B) can be prepared by
Compound (I) t- (3s, 4s) can be produced industrially with advantage.

! -Asu/Q Lagi/Ii! (V) (4B) (wherein,
(Each symbol has the meaning described above) Next, an explanation will be given with reference to an example.

Example 1 Preparation of N-benzyloxycarbonyl-L-asnoQ2 gic acid: L-asnoQ laginic acid 26.6f and magnesium oxide 29. Of was suspended in water at 300 dK, and while cooling with water and stirring, 40.91 g of penzoloxycarzenyl chloride was added, and the mixture was stirred overnight at room temperature.

The cine solution was removed from the reaction solution, and the solution was made acidic with concentrated hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was distilled off. The residue was crystallized from ether-hexane to obtain the desired product 50.1F (yield 94%) with a melting point of 115-120°C.

3340.3400-2500.1710-1690゜1275.1195.1065 Real MAM2 Production of N-bensyloxycarbonyl-L-asnoqlagic anhydride; Suspended in ethyl 3511j, thionyl chloride 161
1 t was added dropwise and stirred for 1 hour. The solvent was distilled off from the reaction solution, and the residue was recrystallized from ether-petroleum ether.
The desired product 5.1 Of (yield 93-) was obtained with a melting point of 108-1111::.

Specific optical rotation; [α) -41,9° (c 1.08 , acetic acid) Implementation PII3 (3B)-3-pencyloxycarbonylamino-4-
Production of hydroxybutyric acid: Sodium borohydride 75.6Qt-tetrahydro7
The acid anhydride obtained in Run M2 (49°8
A solution dissolved in was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. 2N hydrochloric acid was added to the reaction solution to adjust the pH to l, then saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried, and then the solvent was distilled off. When the residue is crystallized with methylene chloride, the desired product 27 with a melting point of 109-110°C is obtained.
0 hits (yield 53-) was obtained.

Specific optical rotation: [α) -10,6° (C1, methanol) Example 4 (3B) Production of -3-amino-4-t-butyldimethylsilyloxybutyric acid: Satsuma Hydroxy Acid 5068F!
and 725 kg of t-butylzomethylchlorosilane were dissolved in 81 kg of dimethylformamide, and 61 kg of imidazole was dissolved under cooling with water.
8189 was added and stirred at room temperature overnight. After ice-cooling the anti-F5 solution and adding ether, it was washed with cold IN-hydrochloric acid, ice water, and saturated brine, and after drying, the solvent was distilled off.

The residual tetrahydro7ran was dissolved in 18 mA and cooled under water cooling.
．． 51i of hydrochloric acid 2- was added and stirred for 25 minutes. Ice water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with water and saturated brine, dried, and the solvent was distilled off. The residue was applied to a silica gel column, eluted with ethyl acetate, and the solvent was distilled off.

The residue was dissolved in methanol 10IIIA and 5 qb of e
Lazoimu Carbon 80# was added and hydrogenated at 3 to 15°C for 1 hour and at room temperature for 1 hour under normal pressure. Thereafter, the product was separated and purified by a conventional method, and the target product 466η (substantially quantitative) was obtained.

Specific optical rotation; [α) D-13,6° (C1, methanol) Example fl15 (4B) Production of -4-((t-pterzomethylsilyl)oxymethyl]-azetizon-2-one: Obtained in Example 4 1871 g of the 〇-bond compound and 212 g of zobilisolzosulfide were mixed with 361 g of acetonitrile.
The suspension was heated to 80°C, and a solution of 252 μm of triphenylphosphine in 36 μm of acetonitrile was added dropwise.
Stir for hours. The solvent was distilled off from the reaction solution using a tube, and the residue was separated and purified by chromatography on silica gluca to give the desired product g s, s my (yield 56%).

Specific optical rotation: [α), +31.2° (C1, chloroform) Example 6 (4B)-1-(t-gylzomethylsilyl)-4-[
Production of (t-gylzomethylsilyl)oxymethyl]-azetizone-2-one: azetidine compound 66019 obtained in Example 5 and triethylamine? 10.512111j
was dissolved in dimethylformamide 51, and t-glyzomethylctetrasilane 556 was dissolved in dimethylformamide 51 and cooled with water under an argon atmosphere.
The mixture was stirred for 10 minutes under water cooling and overnight at room temperature. The reaction solution was poured into ice water and extracted with ether. The extract was washed with saturated brine, dried, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography [solvent: ether-n-hexane (1:2)] to obtain the desired product 1.0f (yield 99%) as a colorless oil.

2 凰, S Specific optical rotation: [α) -29.4° (c 1.11, aa form) 2950.2880, 1730.1465 NMR value: δ
0DOh e pp” 0.07 (11=6H)to, 23(s, 3H)0.
24 (s, 3H), 0.90 (s, 9H) 0.96
(El#911).

2.75 (ad, J=1&4 e 2.5Hz, IH
) 3.07 (dd, J=15.4, 4.8Bg, IH)
3.5 o~a, so (m, 3B) Mass spectrum value; m/θ 329 (M), 314.272 9117 (4El)-1-(t-pterzomethylsilyl-4-(
Production of (t-gylzomethylsilyl)oxymethyl-3-hydroxyiminoazethizon-2-one: To a 1.4 ml solution of lithiumzoin fO biramide 71.2 myQ tetrahydrofuran was added the zosilyl compound 76.6149 obtained in Example 6. Tetrahit 07 run 9.4
7N solution was added dropwise at -70°C for 15 minutes and at -50°C for 1 hour.
The reaction mixture was stirred for 0 minutes, then cooled again to -70°C, and 0.089JIJ4 of nitrous acid 1-soamyl ester was added to the mixture, and 70t of chi was added.
The mixture was stirred for 1 hour at Add 0.106 Nt of acetic acid to the reaction solution.
was added, the mixture was returned to room temperature, the reaction solution was pressurized to a mixture of ethyl acetate and saturated sodium chloride water, and the organic layer was separated. This organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica Glusoleno Q Latepe thin layer chromatography [solvent: ether-〇-hexane (1:1)] to yield the desired product (A) as a colorless oil, 40.3■ and (
B) 12.1 was obtained.

) Properties of thin layer chromatography [silica gel, ether-D-
Hexane (1:1)) Rf = 0.38 Specific rotation: [α), +32.9° (cl, 94.chloroform) R value: 0HOj.

wax, sub-1 338012950, 2850, 1750, 14601
1MR value: δ0DOIs # PPm0.07(s, 6
H)yO,30(e,6H).

1-88 (s, 9H), 1.99 (s e 9H) +
3.92 (da - J = 11.3.3.OH5g, I
H) 4.04 (ddtJ=IL3t3.5Hm, IH)
4.42 ((id, J=3.5.3.0H, IH)9.
64 (br, s, IH) Mass spectrum value: m/e 341.305 Properties of (B) Thin layer chromatography [silica gel, ether-n-
Hexane (1:1)) Rf=0.26 lum) 3390.2940.2860.1750.

465 NMR value: δ0DOIs, I’Pm 0.07 (8,6FI), 0.32 (8#6H).

1.88(e, 9B,), 1.98(e, 9H)=3
, 86 (d = J = 3.5 Hw e 2 H)
4.22 (t, J=3.5Hz, IH)8
．． 80 (br, s, lH) Mass spectrum value: m / @ 341.305 Example 8 (3R and B, 4B)-3-amino-1-(t-glyzomethylsilyl)-4-[(a- Production of oxymethyltoazetidin-2-one: oxime compound obtained in Example 7 (mixture of A and B)
94111Fl was dissolved in 1.01 ml of ethyl acetate, 30 II g of platinum oxide was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction solution was filtered through Celite, and the p solution was concentrated under reduced pressure. Residual tube silica glutoleno 9 latip thin layer chromatography [solvent: ether-n-hexane (4:1)]
After purification, 65.4 N of the (3B)-amino compound and 9.0 of the (3R)-amino compound were obtained as colorless oils.

Properties of (3B)-amino compound (cis form)
Roform) 3420.2950.2870,1735°47O NMR value: δ0DOI@, ppm 0.11 (day, 611) + 0.19 (8e 3
H) eo, 29 (et3EI), 0.91 (II1
9H).

0.95 (B, 9H) 11.96 (8, 2H).

3゜60-3.70 (m, IH), 3.88 (rn
, 2H).

4.23(d,,T=5.8111g,IH)(3
R)-Properties of amino compound (trans form)
f value: 0.43 Specific optical rotation: [α), +6.5° ((!0.99.
holm) 3350 (br, ), 2950, 2880, 1740°47O NMR value: δ0DCIs -Pp” 0.07 (s -6JI), 0.23 (s e 3
H).

0.25(s, 3H)IO, 90(11e9H)-0,
96(tg*911) -1-95(s-2H
).

3.35 (dd, J=4.2.7H1, IH le 3.67
(dd, J=11.3.4Hg, 11).

3.82 (dd, J=11.3.4Hz, IH).

3.95 (d, J = 2.7 Hz, IH)
Mass spectrum value: ym/e 329.301,287 Actual #Example 9
1-(t-dityldimethylsilyl)-4-((t-dityldimethylsilyl)oxymethyl]-azethi-2-2
-Production of (3S)-amino compound 9189 obtained in Example 8 was dissolved in a mixture of 1.01 of tetrahydrof7ran and 0.5 of water, and under water cooling, sodium bicarbonate 3111F and pencil oxycarbonate chloride were added. 0.0
45jIj was added and stirred for 2 hours under water cooling.

Reaction g is added to a mixture of ethyl acetate and saturated saline,
The ethyl acetate layer was separated. This organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel PreIQ Latip thin layer sunset mudgraphy [solvent: ether-n-hexane (6:5)] to obtain the desired product 126q (quantitative) as a colorless oil.

Specific optical rotation: [α) -11.6° (cl, 25. chlor.

Holm) ■R value Niji OHOIs m&X, cm-” 3450.1745.1?20,1515t465 11Mfl value: δCD01z, Pp!11O,0
8(a-6H)eO, 20(s, 311).

0.31 (s = 3H)e O,90(8,9H)
ro, 96 (se9H), 3.68-3.95 (m, 3
B).

5.12 (s, 2H).

5.22(dd, J=10.5.5.5Hg, lH
).

5.77 (d = J = 10.5 Hz e I
H).

7.32 (s, 5H) Mass spectrum value: m/e 478 (M), 464, 421 that's all

Claims (1)

[Scope of Claims] 1. A compound represented by the general formula (in the formula, Rlo represents a hydroxyl group-protecting group and R2' represents an imino group-protecting group) is converted into an oxime to form a compound represented by the general formula (in the formula, Rlo and R2 ° has the above-mentioned meaning), this is then reduced, further optionally amino-protected, and then optionally) the protecting groups R,l and/or R,1 are removed. (wherein R1 represents a hydrogen atom or a hydroxyl group-protecting group, R2 represents a hydrogen atom or an imino group-protecting group, and R3 represents a hydrogen atom or an amino-protecting group) Method of making the compounds represented. 2. Compounds represented by the general formula (wherein, Rlo represents a hydroxyl group-protecting group and R2' represents an imino group-protecting group), as well as compounds represented by the general formula (wherein, R1 represents a hydrogen atom or a hydroxyl group-protecting group). , R3 represents a hydrogen atom or a protecting group for an imino group, and R3 represents a hydrogen atom or a protecting group for an amino group. 3. A compound represented by the general formula % formula % (in the formula, R1' represents a hydroxyl group protecting group) is ring-closed to form a compound represented by the general formula (in the formula, R and e have the above meanings). Next, after protecting the imino group of this compound, it is converted into an oxime to obtain a compound represented by the general formula (in the formula, R1' represents a protecting group for the imino group, and n11 has the above meaning), and then this compound (wherein R1 is a hydrogen atom or R3 represents a protecting group for a hydroxyl group, R3 represents a protecting group for a hydrogen atom or an imino group, and R3 represents a protective group for a hydrogen atom or an amino group. 4. The amino group of Asuno-Q lagging acid is protected by ML, then dehydrated to give N-protected Asuno-Q lagging anhydride, and this is then reduced to form the general formula (wherein R4 represents a protecting group for the amino group). ), then protect the hydroxyl group, remove the protecting group for the amino group to form a compound represented by the general formula (in the formula, R1' represents a protecting group for the hydroxyl group), and then this compound is ring-closed to form a compound represented by the general formula (in the formula, RS has the above-mentioned meaning), and then the imino group of this compound is retained and then converted into an oxime to form the general formula (in the formula, R1 is the imino group). This compound is then reduced, and the diamino group is further preserved in one margin of 7 Jr., and then, if desired, the compound is reduced. Base u,
A snore characterized by the elimination of l and/or n, t
A compound represented by the formula (wherein R1 represents a hydrogen atom or a hydroxyl group protecting group, R represents a hydrogen atom or an imino group protective group, and R3 represents a 3° hydrogen atom or an amino group protecting group) Manufacturing method. 5, L-as, Q lagic acid, general formula (in the formula, R1'
represents a hydroxyl group-protecting group, and R2' represents an imino group-protecting group. 5. The method according to claim 4, for producing a compound represented by the following formula (Rs represents a hydrogen atom or a protecting group for an amine 7 group).