JPS6167A - Preparation of beta-lactam compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound which is a synthetic intermediate for carbapenem based antibiotics easily in high yield, by treating a 5-substituted- 3-oxo-2-azabicyclo[2.2.0]hexane, etc. with a reducing agent under basic solvolysis conditions. CONSTITUTION:A 5-X<1>-3-oxo-2-azabicyclo[2.2.0]hexane or 5-X<2>-3-oxo-2-azabicyclo [2.2.0]hex-2-ene (X<1> is acyloxy or oxo; X<2> is acyloxy), e.g. a compound expressed by formula I (R<1> and R<2> are H or alkyl; R<3> is R<1> or alkenyl; A<1> is acyloxy and A<2> and A<3> are H or together linked or A<1> and A<2> are oxo and A<3> is H; A<4> is R<1>) is reduced and saturated if the bond between the 5- and the 6-positions is double bond, and treated with a reducing agent in an alcohol solvent in the presence of an inorganic alkali or organic amine, etc. to give the aimed compound 4-(2-hydroxyethyl)azetidin-2-one, e.g., a compound expressed by formula II.

Description

[Detailed description of the invention] The present invention relates to a novel method for producing β-lactam compounds.

More specifically, 5-X-3-oxo-2-azabicyclo[2,2,0]
Hexanes are 5-X-8-oxo-2-azabicyclo[2,0]-\xar-5-enes (X means acyloxy violet or oxo, X means acyloxy).

), and the double bond in the 5th place page! The present invention relates to a method for producing 4-(2-hydroxyethyl)acetidin-2-ones by reducing and saturating the 4-(2-hydroxyethyl)acetidin-2-ones, and then treating with a reducing agent under basic solvolysis reaction conditions.

5-x-B-oxo-2-azabicyclo[2,2,0]
Hexanes are 5-X-g-oxo-2-azabicycloC2,2,0: ]] As the hex-5-ene, for example, general formula CI) [wherein R and are the same or different] In the formula, every hydrogen atom represents a lower alkyl group, R represents a hydrogen atom, and every lower alkyl group represents a lower alkenyl group. A represents an acyloxy group, A and A
represents a hydrogen atom, or represents A1 oacyloxy group, A2 and A form a bond, or A
and A together represent an oxo group, and A3 represents a hydrogen atom. A represents one or more hydrogen atoms or a lower alkyl group. ] A compound of the general formula CIO can be used, and if the method of the present invention is carried out using this compound as a raw material, it has the general formula CIO [wherein, ul, holes 2, 1 (4 and A4 are the same as above]). 4-(2-hydroxyethyl)azetidin-2-ones can be produced.

Here, examples of the lower alkyl group include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-furobyl, isopropyl, and n-butyl. Examples of lower alkenyl groups include propen-3-yl, 2-
Methylbutyl]peret-3-yl, 1-laten-3-yl,
Examples of the acyloxy group include alkenyl groups having 1 to 4 carbon atoms such as 2-buten-4-yl.
Examples of λ include lower alkanoyloxy groups and aroyloxy groups. Further, examples of the alkyl moiety of the lower alkanoyloxy group include the same examples as the above-mentioned lower alkyl group, and examples of the aryl group in the aroyloxy group include, for example, a tuunyl group.

Carbapenem antibiotics, including chenamycin, have been the synthetic targets of many researchers due to their structural specificity and strong antibacterial activity.

4-(2-Hydroxyethyl]astotidin-2-ones obtained by the method of the present invention are important compounds as intermediates for the production of such carbapenem compounds and their analogs.

As a method for producing 4-(2-hydroxyethyl)acetidin-2-ones, for example, l-acetoxybutadiene and chlorosulfinyl isocyanate 7I-junka are combined.
Thereafter, a method is known in which chlorosulfonyl &yr is removed reductively to obtain acetoxyhinyl acetidinone, and then hydrogenated and deacetylated to produce 4-(2-hydroxyethyl)azetidin-2-one. .

(D, B, B,, John! Iton et al.
, J. Am. Chem.

Soc, IQQ, 318 (1978) i
F, A, Bouffard et"""#-nij1em,, 45, 1180 (19
80)) Under such circumstances, the inventors of the present invention discovered that 4-(2-hydroxyethyl)azetidine-2-2-ones could be obtained simply and in high yield by the method of the present invention described above. Completed the invention.

The method of the present invention will be explained in more detail below, taking as an example the case where a compound represented by the general formula [1] is produced from a compound represented by the general formula [E].

The compound represented by the general formula CI) is treated with a reducing agent under basic solvolysis reaction conditions to lead to the compound represented by the general formula [II].

Examples of the reducing agent used in this reaction include otorium borohydride, lithium borohydride, calcium borohydride, etc., but it is convenient to use sodium borohydride.

As a base, inorganic alkalis such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, N-
Autogenous amines such as methylmorpholine are used.

This reaction is generally carried out in a solvent, and alcohol solvents such as methanol, ethanol, and isopropyl alcohol are selected as the solvent.The reaction usually proceeds satisfactorily under water cooling or at room temperature, and takes about several hours. finish.

In the starting compound represented by the general formula CI), when A and the group represented by A mean a bond, this compound, that is, the general formula [I8] 几 [in the formula, 1・Shi ・Bon and A are the same as above. A represents an acyloxy group. ] By subjecting the compound formed by catalytic hydrogenation to a reduction reaction by catalytic hydrogenation, the compound of the general formula [Ib:] [wherein) Ll, R2, , 11'' and A4 are the same as above. R31 is This represents a hydrogen atom or a lower alkyl group.] It is also possible to carry out a method in which a compound is prepared as follows, and then treated with a reducing agent under the above-mentioned basic solvolysis reaction conditions.

The catalytic hydrogenation reaction is generally carried out in a solvent in the presence of a catalyst, and such catalysts include platinum oxide, platinum activated carbon, palladium-coated activated carbon, Raney nickel, etc., and palladium-coated activated carbon is convenient. The solvent used in the reaction is not particularly limited, but alcoholic solvents such as methane and ethanol are used, and the reaction proceeds at room temperature and pressure.

In addition, in the catalytic hydrogenation reaction, when the group represented by the hole is a lower alkenyl group, -J, the double bond of this alkenyl group is also saturated at the same time.

The method of the present invention can be carried out as described above, but in the above method, the compound represented by the general formula [Ia] is directly treated with a reducing agent under basic conditions without catalytic hydrogenation. When subjecting to treatment, a solvolysis reaction may first be carried out, and then a treatment with a reducing agent may be carried out. In this case, a compound of the general formula Ic which is a product of the solvolysis reaction [wherein R'', It, R3 and A are the same as above] is released. This compound may be treated with a reducing agent, which is used in the treatment with a base reducing agent used in the solvent decomposition reaction.The reducing agent, the reaction solvent in these reactors, and the reaction conditions are compatible with both reactions. This is the same as when both are implemented at the same time.

The target compound of the present invention thus obtained can be treated with a carbapenem antibiotic according to a known method (for example, the method of John John et al. or B (method of Illford et al.) described above) or a method analogous thereto. In particular, when A4 is an alkyl group, it can be used as an intermediate in the production of carbapenem antibiotics in which the lower alkyl at the 1-position is substituted.

5-X-8-oxo-2-azabicyclo[2,2,0:] hexanes and 5-X-8-oxo-2-azabicyclo[2,2,
03 Hex-5-enes can be easily produced in a kettle according to a known method. (0hi
kara Kaneko etal,, Chem,
Comm,, 1980, H'l'l) D', T
The method of the present invention will be explained in more detail by showing an actual example.

Reference example 1 5-acetoxy-8-oxo-2-7zabicyclo[2,
0] Hex-5-ene 4-acetoxy-2-pyridone (
158.5q) was dissolved in a mixed solvent of acetonitrile (87.5m) and ether (182.5mg), and irradiated with a 450W high-pressure mercury lamp in a Pyrex lamp for 1 hour under an argon atmosphere. The solvent was removed and the lead layer compound (,147,'
5~, yield 93.1%) was obtained.

Melting point 108-105℃ (dichloromethane-ether)
Colorless brism crystal.

NM几(CI)c13')δ(P,P-m,): 2
．． 15 (s, 8H).

4.81 (S, 2EI), 5.69 (8, IH).

6.47 (bs, IH) Reference example 2 5-acetoxy-1,2-dimethyl-8-oxo-2-
Azabicyclo[2,2,0]hex-5-ene 4-acetoxy-1,6-dimethyl-2-pyridone (3
18,8ki) was dissolved in ether (840me) and irradiated for 15 hours with a 450W high pressure mercury lamp in a Pyrex container under an argon stream. The solvent was distilled off, and the residue was purified by silica gel column chromatography using dichloromethane-methanol (99/1) as an eluent to obtain a lead layer compound (2
5,6,4Tnl, yield 81.7%) was obtained.

, melting point 65. h 66.5°C (hexane-ether) colorless prismatic crystals. , N 5t R (CDOI 3) δ (P, P, n
l-): 1.60 (s, 311
).

2.18 (s, 8■), 2.70 (s, 8H), 4.0
0 (bs, IEI), 5.74 (d, J
=1. gLlz, tH) Reference Example 3 Toxi-3-oxo-4-(2-゛robenyl)-2-azabicyclo[2,2゜0''hex-5-ene 4-aceto4cy-3(2'-purbenyl) in 5-7 )-2-pyridone (200,5”i) in acetonitrile (37,5d
) and ether (1B2.5 mff) in a mixed solvent and irradiated with a 450 Vv commercial pressure mercury lamp in a Pyrex container for 1.5 hours under a stream of alcon. The solvent was distilled off to obtain a lead layer compound (176F).

” Melting point 92.5-93.5℃ Example 4 5-acetoxy-8-oxo-6-methyl-2-a→J
°bicyclo[2,2,0]hex-5-ene 4-acetoxy-5-merol-2-pyridone (, i
14.9q) was dissolved in 170 yne of acetonitrile-ether (1m) mixed solvent, and the mixture was heated under an argon atmosphere for 4 hours.
50W high pressure mercury lamp Pyrex container medium 2 u,'r song 4
5 minutes of irradiation and 1 photo. The solvent was distilled off and purified by silica gel chromatography using rAP, 'J. dichloromethane-methanol (98/2)'i; .

Melting point 90.5-91.5℃ (ether) NMtt ((
3DO13) δ(1), P, m,)? 1.73C
d, J=1.711z,,8R,), 2.15(s
, 8H), 4.10 (d.

J=2.5H7,, 11(), 4.88(m,
1tl), 6.40 (bs, 1lj) Nako ion (m/Z) at high-resolution mass II''J1
Calculated value 167.0581 Actual value 167.0561 ChiM [i Example 1 (1) 5-acetoxy-3-oxo-2-azapink O
r 2 , 2 , 0 ] Hexane hardness 5-acetoxy-3-oxo-2-azapine black obtained in Example 1 [:2
, 2.0] Dissolve hex-5-ene (49.6 mL) in methanol (3 mL), add 10 thipalladium-attached activated aluminum (8 mL), and bring to room temperature and pressure under a hydrogen atmosphere with stirring. After 1 hour of reaction, the reaction solution was filtered and the solvent was distilled off (
), and the residue was purified by silica gel chromatography using dichloromethane-methanol (98/2) as the eluent to obtain a lead layer compound (50.8 m?). Melting point 61
-3°C (hexane-ether), colorless prismatic crystals.

NMR (CDCI a) δ (P-P-'', ): 2
．． 08 (s, 8tl).

2.16 (dd+1.J=4..8, 1.0.18.5
H2, 1tI) 2.79 (ddd, J=8.8.4.5
, 18.5 Hz, , IH).

3.78 (d II (J= 2.5, 4, b,
l, QIIz, I H)4.0 t (d t
, J=7.5, 2.5■Z, LH), 5
．． 18 (ddtl, J=7.5.8.8, 4.8
1(z, In).

6.81 (b s ) l ) l',) Elemental analysis calculated value (07I (9NOa) CB, N (%) 54.19 5.85 9.08 Actual value 54.81 5.88 8.96 (2+4 −(
2-Hydroxyethyl)acetidin-2-one obtained in Example 1-41) 5-acetoxy-3-oxo-2-azapink (:l [2,2,O]hexane (28,6+'l? ) in methanol (5-),
Sodium borohydride (69,8"?) and potassium carbonate (5 lv) were added and stirred at room temperature for 1 hour. Acetone (0,5+++/!) IP was added to the reaction solution, and then lθ% mechnol acetate was added. was added to neutralize, and then concentrated to obtain a lead layer compound.

This product was dissolved in acetic anhydride (2td) and pyridine (1-), and stirred at room temperature for 46 hours.

The reaction solution was concentrated under reduced pressure, water was added, extracted with dichloromethylene, and 4-(2-acetoxyethyl)azetidine-2
-one (21.7 mm, yield 74.9 mm).

Melting point 44-47°C (ether) NMR (CDC13) δ (11, P, m,): 1.
98 (m, 2J.

2.07(3,8I(+, 2.62(ddd, , J=
13°2.8.1.0Hz, II(), 8. l
a(ddd, J = 18°4, .5, 1.911z,
IH),, 8.71 (m, IH).

4.18 (m, 2u), 6.56 (bs, IEI)-1
.

IR(OfIC13)r+=-1767, 1742
The melting point and spectral data of this product completely matched those described in the literature.

Example 2 (J) 5-acetoxy-1,2-dimethyl-8-oxo-2-azapinechloro[2,2,0:]hexane 5-acetoxy-1°2-dimethyl- 3-Oxo-2-azabicyclo[2,2,0:)hex-5-ene (177,2■) was dissolved in methanol (10,
5d) and activated carbon with 10% palladium (28■)
After adding , the mixture was treated in the same manner as in Actual Example 1-(1) to obtain a lead layer compound (155.8 cm, yield 87.0 cm). Melting point 70
．． 5-71.5°C (hexicane-ether), colorless prism.

NMR (CDCI3) δ (P-p-m, ): 1.4
7(s, ati).

2.00 (S, 8R,), 2.10 (dd, J=5.2
°Ig, 5tIz, IH), 2.48 (da, J = 8.
0゜1a, 5H2, 11 (), 2.78 (S, 81),
8.68 (d, J=g, OHz, IH), 5.15 (t
d, J=8.0, 5.2 Fiz, IH) (2
i1,4-dimethyl-4-(2-hydroxyethyl97
5-acetoxy-1,2-one obtained in Example 2-(1)
Dimethyl-3-oxo-2-azabicyclo[:2,2.
0] Hexane (49,8) was dissolved in methanol (7d), sodium borohydride (102,9) and potassium carbonate (70) were added, and the mixture was stirred for 1 hour at room temperature.

The reaction solution was treated in the same manner as in Example 2-(2+) to obtain the compound to be used. This was mixed with acetic anhydride (2-), pyridine (1-
ml) and stirred for 24 hours, Example 2-(
The product was treated in the same manner as in Example 21 and isolated as 1,4-dimethyl-4-(2-acetoxyethyl)acedicy-2-one (48 µ, yield 95.3%). Oily substance N M B, (CDOI 3) δ (p, P9m,)
: 1.37 (S, 8B).

196(,t, J=6.5Hz, 2Ii),
2.00 (S.

3J, 2.60 (d, J = 14.51 (Z, 8u).

2.68 (s, 3R), 2.90 (d, J=14.5H
z.

-H,), 4.09 (t, J=6.51(z
, 2I],) Molecular ion (m/Z,) in component angle II quality analysis Calculated value 185.1050 Actual value 185.1049 Example 3 (1) 5-acetoxy-8-oxo-6- Bumi Building-2
-AzabicycloC2,2,0'J hexane 5-acetoxy-8-oxo-6 obtained in Reference Example 8
-(2-propenyl]-2-azabicyclo[2,2,0
] Hex-5-ene (184,6~)7i-methanol (8-) was dissolved in 10% palladium-coated activated carbon (20y
After adding V), the same treatment as in Example 1-(11) was carried out. The product was purified by silica gel column chromatography using dichloromethane-methanol (98/2) as an eluent to obtain the title compound (120,8 , yield 87.7%] was obtained. Oily substance NM [(CDC13)δ<P-plm-
): 0.75-1.1 (m, 8)1), 1.1
~2.0 (In, 41i), 2.02 (dd
d.

J=14.5.4.0.1.0ELz, Iti)
, 2.08 (s.

aH), 2.70 (arid, J=14.5,
8.5.4.2Fiz, 1Ii), 8.64(
d, J=4.2H2,tH).

4.95(dd, J=8.5.4.0Hz, l
]:T), 6.82(bs, 1f(1 (2+4-(2-hydroxyethyl)-3-propyl-
aceticinol 2-onwa, : Example 8- (5-acetoxy-3 obtained with l+
--4xo-6-proyl-2-asahishikushi1 [2,
2,01hexane<28.6～) and methanol (4ml
) and stirred after adding sodium borohydride (45 η) and potassium carbonate (40 η). The reaction solution was treated in the same manner as in Example 1-(2) to obtain one compound. Add this to r + c acetic acid (2 ml!), pyridine (1 furnace e)
4-(2-acetoxyethyl)-3-propyl-acetidin-2-one (27,61 ng) was dissolved in tl
jlko.

NMR(CI>CI3)δ(P-P-m):
o415 (t, , tT=6.7H1,3i()
, 1.25~2.10 (,nl, 6t(),
2.07 (S, 3H,), 2.07-2.9
5 (m, 1 t-I), 8.88 ('d',
J=2.5.6.0, 6.8fly, , IH,
).

8, 95-4.4 (ni, 2■), 6.41 (b
s, 1■) Example 4 (5-ace1-oxy-3-oxo-6-methyl-2
-Azabicyclo[2,2,0'l'\kizan 5-acetoxy-3-oxo6-methyl-2 obtained in Reference Example 4
-Azabicyclo[2゜2.0]hex-5-ene (58
, 8 my) was dissolved in methanol (3 m/liter), and after adding 10% palladium-attached activated carbon (8 μ), the mixture was stirred for 4 hours at room temperature under a hydrogen stream (1 atm).The reaction solution was poured into the door. j4“4
The solvent was then distilled off to obtain the title compound (59,0).

This was recrystallized from dichloromethane-ether to give colorless prism crystals (,'38.0■)7! -Toko3, melting point 120.5-122℃ NMH (CDC/!3) δ0'-1+0m,'):
1.07<d, J=7. OHz, 3H)
, 2. o5(s, al-N, 2.65-8.15(m,
IIJ), 3.8'2 (ddd, , l=4.7.2
．． 7゜], 5Hz, l)]), 3.98
(Apparatus 1. J=8.8, 2.7f:1.z, 1
4() , 5.22(ddd, , 1 = 3.8.7
．． 5゜1.5Fly, , LH), 6.50'(
5-acetoxy-3-oxo-6-methyl-2 -Azahicyclo[2,2,0]hexane (300 ~) dissolved in methanol (5 m),
Water-accumulated sodium boronate (67■), potassium carbonate (7
0++v, ) was added and stirred at *warm temperature for 2.5 hours. The reaction solution was treated in the same manner as in Jipeng Example 1-(21) to obtain a lead layer compound. This was mixed with acetic anhydride (2 mg), hiricine (1
Example 1-(
21 and isolated as 4-(1-methyl-2-acetoxyethyl)azetidin-2-one (80,41η). , colorless prism crystal (ether) Melting point 68-70℃ NMR (CDC7a) δ (P, P, m,): 0.9
5 (d, J=6.7Hz, 81:l), 1
．． 6-2.15 (m, IH), 2.08 (s, 8
Ll), 2.60 (ada, J=14.5, 2.B.

1.2tlz, II('l, 8.05(add
, J = 14,5°5.0.2.5tlZ, IJ, 3
．． 40 (ddd, J=8.5°5.0.2.8Hz, 1
0) + 8.88(dd, J=lO, 3°5, 'lZ,
1tl) , 4.20(drl, , 1=10.8
．． 4.811z, lH), 6.28 (118,1”) (
28 completed)

Claims (2)

[Claims] (1) 5-X^1-3-oxo-2-azabicyclo[2
,2,0]hexanes or 5-X^2-3-oxo-
2-azabicyclo[2,2,0]hex-5-enes (X^1 means acyloxy or oxo, X^2 means acyloxy), 5
- If the double bond is present at the 6-position, the 4-(2-hydroxy A method for producing ethyl) azetidin-2-ones. (2) 5-X^1-3-oxo-2-azabicyclo[2
,2,0]hexanes or 5-X^2-3-oxo-
2-Azabicyclo[2,2,0]hex-5-enes have the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different, and hydrogen Represents an atom or lower alkyl group, R^3
represents a hydrogen atom, a lower alkyl group or a lower alkenyl group. A^1 is an acyloxy group, A^2 and A^3
represents a hydrogen atom, or A^1 represents an acyloxy group and A^2 and A^3 form a bond, or A^1 and A^2 together represent an oxo group, A
^3 indicates a hydrogen atom. A^4 represents a hydrogen atom or a lower alkyl group] The manufacturing method according to claim 1, which is a compound represented by the following formula.