JPS58118563A - Manufacture of heterocyclic acetic acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention The present invention relates to the general formula (■): (wherein Y1 and Y2 are removable carbonyl protecting groups,
Preferably, together they form a ketal group or a thio analogue thereof, and X is a selectively removable esterification group, preferably an arylmethyl or diarylmethyl group. .

The compound of general formula (1) is chenamycin (thiena
mycin) and is a key intermediate in the synthesis of chenamycin analogs. Alternative methods of making these compounds 4111XI are described in co-pending patent applications.

Chenamycin, which has a broad spectrum of activity, was initially developed using microbiosophistical methods (U.S. Pat. No. 3,950,357) &
It was made by C and later by chemical synthesis (DE 2,751,597) by K.

Applicant's aim is to elaborate a new method for the synthesis of chenamycin and its analogues, in which an azetidinone backbone and an α-hydroxyethyl side chain, or a side chain that can be easily converted to an α-hydroxyethyl group, is elaborated. were made simultaneously in the early stages of the synthesis, and the resulting basic intermediate was then converted into the desired final product. The dialkyl (protected amino)-malonate was acylated with diketene and the resulting acylated product was It has been found that when reacting with iodine and an alkali metal alcoholade, azetidinone compounds of the general formula (■) containing an α-acetyl side chain are obtained, which can be used as basic intermediates in the synthesis.

In the above formula, y represents a removable amif-protecting group, preferably a phenyl or benzyl group having one or more O1 alkoxy substituents, and 2 represents a C1
-5 alkyl group.

Intermediates of general formula (■) and their preparation are described in detail in the applicant's previous Hungarian Patent Application No. 2262/80. The preparation of these intermediates is also described in the Examples of this application.

The keto group of the α-C-acetyl side chain is protected by a group that can be removed in a later step of the synthesis, in particular a ketal group or its thio analogue, before converting the intermediate of general formula (■) to chenamycin or its analogues. It has been observed that it is preferable to It is particularly preferred that ethylene glycol or its analogues such as mercazotethanol can be applied to form an ethylene ketal or hemithioketal protecting group. The resulting general formula (■) in which Yl and Y2 together form a temporary protecting group for the carbonyl moiety, preferably an ethylene ketal group or an analog thereof, and y and 2 are as defined above. ) is then reacted with an alkali metal halide in pyridine or a related solvent or aqueous dimethyl sulfoxide to form a compound of general formula (VI), where R', Z, Y' and Y2 are as defined above. ) to obtain a compound.

The resulting compound of general formula (Vl) is a mixture of cis and trans isomers. Isomers can be separated from each other by chromatography or on the basis of their different solubility. The separated trans isomer of general formula (Vla) can be converted by hydrolysis to the transcarzanoic acid of general formula (V). This is preferred because the reaction is selective, ie only the transester is converted to the respective carboxylic acid.

The isolated transcarboxylic acid of the general formula (■) is first reacted with a promoter for the carboxy group and then with diazomethane, and the resulting compound of the general formula (IVI) is subjected to a Wolff rearrangement in the presence of water. The process gives azetidinoacetic acid of general formula (III), which is the starting material for the process according to the invention: general formula (V),
(mV) and (I[I) R', yl and Y
2 is as defined above.

Some new compounds of the general formula (machi) have been described in the applicant's previous Hungarian patent application no. The compounds up to 1) are described in the applicant's co-pending fraudulent application.

The preparation of these compounds is also described in the Examples of this application.

Compounds of general formula (1) can be converted into new esters of general formula (1) by methods known per se, and then the protective group R' of the resulting ester is removed to form a new ester of general formula (1). The compound is obtained. These latter compounds can be converted to chenamycin or chenamycin analogs as shown in diagram (A). Illustration Q is a C1-5 alkyl group or a substituted benzyl group')s Qlha01-57
alkyl group, substituted benzyl group, hydrogen atom or alkali metal ion, and R' is benzyl, aminoethyl or N-acylaminoethyl group.

Based on the above, the present invention relates to a process for the preparation of compounds of the general formula CI), in which Yl and Y8 together form a removable carmenyl protecting group, preferably a ketal group or a thio analogue thereof; and X is a selectively removable esterification group, preferably an ester-methyl or diarylmethyl group, in which compounds of the general formula (I[[), where yl and Y8 are as defined above, and R' is a removable ado-protecting group other than a phenyl group, preferably a phenyl or benzyl group with one or more 01-4 alkoxy substituents) can be generally prepared by methods known per se. Formula (■) (in the formula, X, R', y
l and Y2- are as defined above) and the protecting group Fe of the resulting ester
is then removed, or the general formula (1) (in which X%
I'P, yl and Y2 are as defined above)
The protective group R' of the compound is removed.

In the first step of the above process, the azetidine-acetic acid of the general formula CM) is reacted with an esterification agent which gives a selectively removable esterification group. ! basic esterifying agent,
It is particularly desirable to apply arylmethyl or diarylmethyl groups which can be subsequently removed by reduction. Phenyldiazomethane and diphenyldiazomethane proved to be the preferred esterifying agents.

The resulting ester of general formula (I) is, if desired, separated from the reaction mixture or subjected to a direct step in the reaction medium in which it was formed.

The protecting group R' can be removed by oxidation methods. When the dimethoxybenzyl protecting group is to be removed, a peroxysulfate type compound, preferably potassium or sodium peroxysulfate (IC2820B, Na
282011) 'lk: Applicable as oxidizing agent 6o'
The reaction is carried out in the presence of water and an organic solvent, and the mixture is buffered to pH ~7.

When the methoxyphenyl protecting group is to be removed, it is desirable to apply a cerium (IV) salt as an oxidizing agent in the presence of an acid. A solution of hexasium ammonium in dilute aqueous sulfuric acid has proven particularly suitable for this purpose. The conversion is carried out in the presence of an organic solvent.

The invention will be explained in detail with the help of the following non-limiting examples.

Example 1 3.05.9 (15.75 mmol) of diphenyldiazomethane was dissolved in 5.48.9 (15 mmol) of [trans-1-(
2,4-dimethoxybenzyl)-3-(2-methyl-1
, 6-Sioquinran-2-yl)-4-oxo-2-azetidinylcouacetic acid to the stirring solution. When nitrogen evolution has stopped, a few drops of acetic acid are added to the mixture to destroy excess diphenyldiazomethane. The solution was evaporated to dryness and to a residue weighing 6.77.9:84i
Dissolve u in acetonitrile. 16.20. F(60j
Potassium peroxydisulfate (K2S Yuki Og
), 21.60 # (120 mmol) of disodium hydrogen phosphate hydrate (1ia2HPO4.H20) and 5
Add 4- of water to the solution, stir the mixture vigorously for 4 hours, boil, and then cool. The cold reaction mixture is filtered and the two phases of the filtrate are separated from each other. Aqueous phase 30 times each time
Extract 6 times with 1 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated. The residue was dissolved in benzene and the solution was processed by column chromatography [adsorbent: diatom ±6Q (Kiese: Lgel 60).

da=0.050-0.200s+s, eluent; 7:2 mixture of benzene and acetone) 2.68 g (47 g)
The title compound is obtained; melting point: 130°C (ethanol).

Analysis: 022H23NO5 (387,41) For kC: Calculated value: O: 69.27 yen, H: 6.08%
.

N: 5.67; Actual value: O: 69.15; n: 6-20
fbyN: 5.5 5 chi.

Engineering R (KBr): 3250, 2900, 1760°17
40 Son-1゜lH, NMR (ODC13): δ=1.39 (a,
31).

2.63 (aa, 2B, J = 4-4 Hz)t 2-89 (eL (1°2
n, J=9.1 Fiz), 5.97(I
ll, 5 H) t 6.12 ("el n
)t 6-9 ('t I HL7.28 (8,
10111) The 99m6 starting material is prepared as follows: a) 2.4- of 109.811 (0-66 mol)
A mixture of dimethoxybenzaldehyde, 72xtC0, 66 mol) be/zylamine and 660 v methanol is stirred at room temperature for 20 minutes, so that a clear solution is obtained from the suspension. Cool the solution with ice water, and
3.2 g (0.33 mol) of sodium hydride are added in small portions.

The progress of the reaction is monitored by thin layer chromatography (diatomaceous earth G according to 5tah1; developing solvent: a 9:1 mixture of benzene and acetone), and at the end of the reaction the mixture is evaporated to dryness in vacuo.

Add 300 m of water to the residue [500 m of water-based mixture]
Extract with ether, 200'11t and 2001. The ethereal solutions were combined, dried over magnesium sulfate, filtered, and then 1121j (0.66 mol) of diethyl malonate and 931 (·0.66
mol) of triethylamine to the filtrate. Stir the reaction mixture at room temperature for 2-6 days. 1 kill of ammonium triethyl bromide is separated, removed and washed with ether. The mother liquor is evaporated and the residue Y150111j is recrystallized from ethanol. The resulting 210 g of crude product was recrystallized again from 400 ml of ethanol to give 19711 (72To)
Malonate is obtained; melting point 62-63°C (ethanol).

Engineering R (KBr): 1751L 1725c+a-”
s (16b) 5VcL as described in section a) above,
6 1.79 (0,149 mol) of diethyl N-benzyl-N (2y 4-dimethoxybenzyl)-amino malonor)'t'500- in the presence of about 20 g of palladium on charcoal catalyst [
Hydrogenate under atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated to give 47.1 g (9716) of diethyl (2.4-dimethoxybenzylamino)-malonate. The product can be converted to its hydrochloride salt by reacting with hydrochloric acid. Salt II salt is 122-12 after recrystallization from ethyl acetate.
Melts at 4°C.

Analysis: Two calculations for C15H,,01NO6 (361,82): O: 53.11 h, H: 6.69 h.

01: 9.80chi, N: 3.87*; Actual value: O
: 52.51 chi, H: 6.77 vo.

01: 10.30%, N: 4.09も.

Engineering R (film): 3250, 2900゜2B50
．． 1730゜1720cIL-1゜lHNMR (ODO13): δ= 1.3 (t,
6H), 3.78(s e 5 H) + 3-
82 (s.

3u) + 4.21 (q, 4n).

6.20 (s, 2H), 6.4-6.6 (
m, 2H) + 7.3-7.55(m*I
HL 7-7 (wide 6° 1H) ppm.

C) 3 made by 51C as described in item b) above
9.6 & (0,122 mol) of diethyl (2,4-
dimethoxybenzylamino)-malonate and 8ONt
of glacial acetic acid and 12.59 (11,21j, 0.146
mol) of diketene is boiled for 0.5 hour.

Distill the wood vinegar in a vacuum over a water bath and leave an oily residue)k1
Grind with 50M water. The resulting crystalline substance is 601
of ethyl acetate and precipitated with petroleum ether. 29.611<60%) of diethyl N-'e
2t4-dimethoxybenzyl)-6-hydroxy6-
Obtain methyl-5-oxo-2°2-virolidine-dicarboxylate and/or its tautomer; melting point:
106-107°C.

Analysis: 11m total for 020H2,N0II (409,45): O: 58.67%, H: 6.65%.

N: 3.42 yen; Actual measurements: C: 58.79 h, H: 6.33 h.

N: 3.34%.

IR (KBr): 3400. 2950. 2850°1730 (1740, sh).

1710cm-”.

IHMMR (ODOI3): δ= 1.1 (t
, 3H)t 1.17(t, 3H),
1.52 (s.

~3 B), 2.8 (<0.IH).

2.65 (wide 512n) t 3.75 (s, 6H), 5.8-4.15 (m
, 4H), 6.7 (wide θ# 2Il) 1
6.25-6-45 (m) + 7.0-7.2
5(m, 3III) ppm0 d) 20 prepared as described in section C) above
．． 5 II (50 mmol) of the product 15I: suspended in 5 Qm dry ether and a solution of 3.45 g (150 mmol) sodium metal in 1001 dry ethanol and 12.5 II in 1501 dry ether. 7g
Once a solution of iodine (50 mmol) is added dropwise from two vials to the vigorously stirred suspension while cooling with ice water. Then 5 g of sodium hydrosulfite dissolved in 200 ml of saturated aqueous sodium chloride solution is added to the stirred mixture. Place the mixture in a separate pot and 60d
Add water to dissolve the separated inorganic salts. The organic phase is removed, dried over magnesium sulphate, filtered and the filtrate is evaporated. 30 m of oily residue weighing 18.5.9
2- Crystallize from propatool. 10.99 (5
4%) of diethyl 3-acetyl-1-(2,4-dimethoxybenzyl)-4-oxo-2,2-azetidine-dicarboxylate is obtained; melting point: 84-85°C
(2-Proper Tools).

Analysis: 020H25NOB (407,41) For K: Calculation [:O: 58.96%, H: 6.191°N
: 3.44 *; Analysis value: C: 58.99, H: 6.04LN:
5.57 chi.

Engineering R (xBr): 2900, 1780, 1740°17
10cm-”.

IHnMR (apex3): δ=1.12 (t, 5
11) pl, 21 (t, 3B), 2-! 1
1 (8,3EL) e 3-76 (@.

6H) # 3-8 5-4 (m.

4n), 4.53(a, 1B)+4.63
(a, I H), 4.69 (st I
I, 6.3-6.4 (m, 2E) + 7.07
(+L.

I H) PPm.

・) Trifluoride of 179 # (0,484 mol) of diethyl 3 is stirred vigorously while adding boron diethyl ether complex compound dropwise.
-acetyl-1-(2,4-dimethoxybenzyl)-4
-oxo-2,2-azetidine-dicarboxylate and 107m (120,!i+, 1.936 mol) of ethylene glycol are added to a solution of 5001 in dry dioxane under ice-water cooling. The reaction mixture was allowed to stand at room temperature for one day, during which time the mixture was stirred occasionally. That+
415.9 (1,452 mol) of NIL2005.I
Q 120 f is added to the stirring mixture with ice water cooling and the mixture is stirred for 15 minutes. Then 1 part of ether and 11 parts of water are added and the phases are separated from each other.

The aqueous phase is shaken twice with each portion of 50011j of diethyl ether. Dry the ethereal phase over magnesium sulfate,
Filter and evaporate the filtrate. 33.9 (0,58 mol) sodium chloride, 17.416 (0,968 mol)
of water and 220 g of dimethyl sulfoxide are added to the residue and the mixture is stirred on an oil bath at 180°C. The progress of the reaction was monitored by thin layer chromatography (adsorbent: 5ta
Diatomaceous earth G according to hl, developing solvent: 6:4 mixture of benzene and ethyl acetate). At the end of the reaction,
Thus, after about 15 hours, the mixture is poured into 1100111j of saturated aqueous sodium chloride solution, and the resulting mixture' is shaken with 100011t and then twice each 5001 of diethyl ether. The ethereal solutions were combined, decolorized with charcoal, dried over magnesium sulfate, and the filtrate was evaporated to a final volume of approximately 200 dK. When this concentrated solution was cooled with ice water, 59 g (35%) of trans-ethyl 1-(2°4-dimethoxybenzyl)-3-(
2-Methyl-1,3-dioxolan-2-yl)-4-
Obtain oxo-2-azetidine-carzaxilade; melting point = 95°C.

f) 0,5 made as described in section d) above
．． 9 (1,2 mmol) of diethyl 3-acetyl-1
-(2,4-dimethoxybenzyl)-4-oxo-2,
A mixture of 2-azetidine-dicarboxylate and 31 dry tetrahydro7lane and 0.53.9 (3.6 mmol) mercapto-ethanol was boiled for 4 hours, then 101 water and 10 sc/chloroform. is added to the reaction mixture. The organic phase was separated, washed with an aqueous solution of IJ (5% hydrogen carbonate), dried over magnesium sulfate, filtered and the product was dispersed from the filtrate by thin layer chromatography (adsorbent: diatoms ±60 PFgg4 + 3sg).
% developed ffi compound:) 8:2 mixture of toluene and acetone) Separated by K. 0.30.9 (5311t
) diethyl 1-(2,4-dimethoxybenzyl)-3
-(2-methyl-1,3-oxathiolan-2-yl)
-4-oxo-2,2-azetidine-carboxylade is obtained.

lHNMR(CD('ls):' =0-8 1-
55 (m y 6 H) el, 72+ 1.77
(d, 3B).

2.9-3.4 (m, 2B)# 3.75 (s, 6H)t 4.0-5-0 (
m p 9 H) e 6-4 (m.

2 B) + 7.1 (am in) ppm.

g) 60mf) Solubility in water 5.21 II (0,13
4 1.2N (0,109
mol) of trans-ethyl 1-(2,4-1'methoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azetizone-carpoxylate 59m in ethanol under stirring and cooling with ice water and stirring is continued until a clear solution is obtained (approximately 20 minutes). Then add 1 oo of water to the solution and shake in the ether of mixture Y10011j.

The aqueous phase is acidified to −=1 with concentrated salt and then shaken rapidly with 100 m and twice with 53 m of dichloromethane. The dichloromethane solutions are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated. Crystallization of the oily residue from a mixture of toluene and petroleum ether yields 35II (92) trans-1-(2,4
-dimethoxybenzyl)-3-(2-methyl-1,3-
Dioxolan-2-yl)-4-oxo-2-azetidine-carzanoic acid is obtained; melting point: 117-118°C (toluene) 0 Analysis: Oz? HaINO〒(351,35) For K, Te: Total g[:O: 58.11%, H'', 6.05 hours.

N: 3.99chi; Fruit 11 ([:C: 58.17%, H: 6.301G.

N: 4.24 chi.

IR (ICBr): 3500-2500.2900゜17 60, 1720 m-1゜IIi NMR (ODO13): δ = 1.39 (s,
3m).

5.50 (d-I He I=2-5Hz13.7
7 (s, 3H), 5.79 (s e 3
H) *3-86(1*I H,:r=2.5 H
z), 3.96(m, 4H), 4.2
1+4.56(a, 2 H, :r, B= 15 n
jI) +6.44 (m, 21) +7-15 (+L, IH, J = 10Hz).

7.58 (wide"y IH) PPm.

h) 1 prepared by the K reaction of 7,3ν (52,5 mmol) of triethylamine as described in section g) above.
7.6 g (50 mmol) of trans-1-(2,
4-dimethoxybenzyl)-3-(2-methyl-1,6
-thioxolan-2-yl)-4-oxo-2-azetidine-carboxylic acid in 15011 Lt of dry tetrahydrofuran and then 5. Oysl (5
2.5 mmol of ethyl chloroformate is added to this solution while cooling with ice.

The mixture is cooled to -15°C, stirred at this temperature for 20 minutes, and the triethylamine salt which has separated out at the same temperature under an Albin atmosphere is filtered. A solution of 150 mmol of diazomethane in cold diethyl ether of 2301 is added to the filtrate.

Mix 1M', stir, warm to room temperature, and evaporate to dryness after stirring for 2 hours. Dark brown residue v2oM
of benzene, and the product is separated by column chromatography (adsorbent = 150 diatoms ±
60.96=0.063-0.200 l1ls IF
Exit 111: 7:2 mixture of benzene and acetone). 1
2.0P (64%) of trans-4-(diazoacetyl)-1-(2,4-dimethoxybenzyl)-3-(2-
Methyl-1,6-thioxolan-2-yl)-2-azetidinone is obtained.

Analysis: 01sHsINsOs (375,37) I
Two calculated values for c: O: 57.59, a:
Actual measurement value: 5.641b: O: 57.781. H:
5.391゜Work R (KBr): 2900. 21
10. 176OcIt-1゜1) 2,25,! made as described in item h) above. i+ (6
mmol) of trans-4-(diazoacetyl)-1-
(2,4-dimethoxybenzyl)-1-(2-methyl-
A mixture of 1,5-dioxolan-2-yl)-2-azetidinone, 1001 peroxide-free tetrahydrofura/and 501 water was submerged in a reaction vessel made of Pyrex glass using a high-pressure mercury lamp (HPK 125).
) under an argon atmosphere. The solution was evaporated in vacuo to a final volume of 50117, the concentrate was diluted to 1601 with water, 2.41 parts of 10% aqueous sodium hydroxide was added to the aqueous mixture, and the alkaline mixture was diluted with 201117 parts each of dichloromethane. Washed 6 times with

The aqueous phase is then acidified 1=2 with concentrated hydrochloric acid. The acidic solution is extracted three times with 20 g of dichloromethane each time, the extracts are combined, dried over magnesium sulfate, filtered and the filtrate is evaporated to dryness.

Crystallize the residue with ether. 1.82g (86
h) [trans-1-(2,4-dimethoxybenzyl)-3-C2-methyl-1,3-dioquinran-2-yl]-4-oxo-2-azetidinyl]-acetic acid is obtained.

Melt A: 124°C (ether).

Analysis: C Engineering 8] 1123 No. (365, 37) For K: Calculated value: O: 59.17L H: 6. ′
54 vomit.

N: 3.83*; Actual value: O: 59.22s, H: 6.49LN:
4.07 Ch.

Engineering R (KBr): 3500 2300. 2900
゜1730, 1700 Dal.

Example 2 Benzhydryltrans-(3-(2-methyl-1,3-dioxolan-2-yl)-4-(4-methoxyphenyl)-4- of 0.28, P (0.65 mmol)
Oxo-2-azetidinyl]-aceter) Y211/0,9,! dissolved in acetone and dissolved in 2 ml of pentahydrous sulfuric acid. i+ (1,6 mmol) of cerium ammonium nitrate (0s(Nl(4)2(NOa)
Add the solution of s) dropwise to the stirring mixture at room temperature. The reaction mixture was stirred for an additional 2 minutes and then carefully neutralized with 50% aqueous bicarbonate solution. This mixture is then extracted three times with 4 m each of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated in vacuo. Preparative thin layer chromatography for oily residue (adsorbent: quartzite earth 60. y5 = 0.050-0.20
0 m, eluent: a 7:2 mixture of benzene and acetone) to yield 0.06 g (30%) of the desired compound. This compound is identical to the product prepared as described in Example 1.

The starting materials are prepared as follows: a) 24.69 (0.2 mol) of 4-methoxyaniline and 23.9 g (17 w1. 0.1% l)
Bromide of ff.

The mixture with diethyl phosphate is stirred at room temperature for 2 days. The resulting mass Y100111j was triturated with diethyl ether and separated 4-methoxya = IJ
7. Filter off the hyroderomide and wash with a small amount of diethyl ether. The mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13.2 # (47%) of diethyl (4
-methoxyanilino)-malonate; melting point: 64
−65°C (ethanol).

Analysis: For 0141119NOI5 (281,31): Calculated value: O: 59.77chi, 5: 6.81
blood.

N: 4.99 regrets; Actual measurements: O: 59.99cm 9111: 6.97cm.

N: 5.25*@, 't, 4゜ENGRCKBr): 33"00. 1'775;
172"5aR-'.

lHNMR (CDCl5): δ = 1.23 (t,
6 Tie”iT=, 7.2ai), 3,6
7 (s, 3H).

4.2<,q,4H,J=7.2HI).

4.62 (s, IE), 4.1-4.5
(Wide A' t 1 m) + 6-55 (2B) + 6
．． 73 (2E.

Am'B B', x=9 Jig) pPm.

b) 1 made as described in item a) above
1.29 (0.04 mol) of diethyl (4-methoxyanilino)-malonate and 151 of glacial acetic acid and 4 g (3,
7, 0.048 mol) of diketone and 0.5
Boil for an hour. The solution is evaporated in vacuo, the oily residue is triturated with diethyl ether and the solids are filtered off. j O
,5,F (72%) to obtain diethyl 1-(4-methoxyphenyl)-3-hydroxy-6-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or its tautomer ; Melting point: 136-137℃ (
Ethyl acetate).

Analysis: C'18B23NO7 (565,38) K vs Te: Calculated value: C! : 59.17 Section #H: 6.3
99G.

N: 3.83°: Actual value: O: 58.98%, H: 6.901°N:
4.04 chi.

IR (KBr): 3600-31000, 1760°1
740.1685crt-”.

lHNMR (CDCl3): δ=1.07 (t,
311. J=7-2 His ) e 1-2
8 (te 3 H.

J=7.2Eg)1 1.58 (893H), 2
．． 76 (a, 2B).

3.64 (a, I B), 3.76 (・t
3 n ), 4.1 (qt 2H.

J-=7.2Eg), 4.27 (qp2L
J=7.2 Hz), 6.7(21)+7.0
(2H, M A'B 'If, J"" 9 Hz) pPII
.

C) Was it made as described in item b) above? ,
1, F (0,025 mol) diethyl 1-(4-methoxyphenyl)-3-heroxy 3-methyl-5-
oxo-2,2-pyrrolidine-dicarxylar)t'
5 Qm of dry diethyl ether and a solution of 1.72.9 of sodium metal in 301 dry ethanol and 50M! A solution of 6.35 g (0.025 mol) of iodine in dry diethyl ether is simultaneously added dropwise to the vigorously stirred and ice-cooled suspension. The mixture is then saturated with chloride of 1001114)
Pour into the IJ solution and add 21 parts of sodium dorosulfite and 21 parts of glacial acetic acid. The ethereal phase is separated and the aqueous phase is extracted six times with 5 Qml of diethyl ether each time. The ethereal phases are combined, dried over magnesium sulphate, filtered, and the filtrate is evaporated. The oily residue was triturated with t2-gropanol to give crystalline diethyl 3-acetyl-1-(4-methoxyphenyl)-4-oxo-2,2 of 6.2 fIC6B%).
-Azetidine-dicarboxylate Y obtained; melting point near o
~71°C (ethanol).

Analysis: 0xsIhlNOy (363,38) For K: Calculated values: O: 59.50%, H: 5.82%.

N: 3.85 inches; Actual fillfi: O: 59.04%, H: 5.84
%.

N: 4.08chi.

Engineering R (KBr): 1760. 1735. 172
0an-'.

lHNMR (CDCl2): δ=1.2o(t, 6H2
J=7.2 H5! ) p 1-22 (t e
3H.

J=7-2 Hsi) w 2-33 (8t3B
), 3.7 (a, 3H).

4-1 7 (qp 2 H# ni 7-2
．． 19 (q, 2B,, T=7.2Hz).

4.7 (s, I H), 6.7 (2H)+
7.31 (2B, M A'BB'.

J = 9 Hz) ppm.

d) Neutralization made as described in item C) above 6
g (0,0165 mol) of diethyl 3-acetyl-1
-(4-methoxyphenyl)-4-oxo-2,2-azetidine-dicarboxylate in 201 g of dry dioxane and 4.1 g (6,75 shoulders!).

0.066 mol) of ethylene glycol.

7.19 (6"zml, 0.05 mol) of boron trifluoride-diethyl ether complex is added dropwise to the ice-cooled stirring solution and the reaction mixture is stirred for a further 2 hours at room temperature. The solution is made alkaline with saturated aqueous sodium bicarbonate solution, then 100 ml of water is added and the mixture is extracted with 6 ml of diethyl ether. The organic phases are combined, dried over magnesium sulfate and filtered. and the filtrate was evaporated. The oily residue was triturated with diethyl ether to give crystalline diethyl 3-(2-methyl-1,3-dioxolane-2) of 69 (89=4).
-yl)-1-(4-methoxyphenyl)-4-oxo-2,2-azetidine-dicarxylate; melting point: 82-83°C (ethanol).

Analysis: For c20a25No8 (407,43):
Calculated value: O: 58.96chi, a: 6-18
'AyN: 3.44 Chi; Actual value: C! : 58.7096. H: 5.
68 chi.

N: 6.65 Chi.

Engineering R (xBr): 1740 cm-” (wide).

1) I NMR (CDCl2): δ=1.17
(t, 3B, J=7.2 Hz), 1.2
6 (t, 31°: r=7.2Hz L 1.5
(5t3H), 6-7Cts, 3H)F 3.9 (m, 4H), 4.2 (m.

5 H), 6.67 (2H) + 7.34 (2H
, MA'B'If t J =91iz)pm
e) 1 made by doing 5K as described in item d) above.
1 g (0,0245 mol) of diethyl 6-(2-methyl-1,".6-thioxolan-2-yl)-1-(
4-Methoxyphenyl)-4-oxo-2,2-anetidine-dicarboxylate was dissolved in 2ON dimethyl sulfoxide, 1.729([), 0295 mol) of sodium chloride and 0.9d(0,049 mol) of water is added and the mixture is stirred at 175° C. until complete reaction is obtained. The progress of the reaction was monitored by thin layer chromatography (adsorbent: diatomaceous earth G according to 5 tahl; developing solvent: 6:4 mixture of benzene and ethyl acetate).
J) K-yo and observe.

The mixture is cooled, poured into an aqueous solution of 1,501 um and extracted 6 times with 501 ml of diethyl ether each time. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated.

The resulting 6 g of oily residue was dissolved in 25 - 96 ethanol and 0,72 # (
A solution of 0.018 mol) of aqueous sodium dispersion is added to the alcoholic mixture under ice-water cooling. Stir the mixture for 30 minutes, then dilute with 501 ml of water and wash twice with 251 Rt dichloromethane each time. The aqueous phase is acidified to 121 with concentrated hydrochloric acid and then extracted 6 times with 251 of dichloromethane each time. The organic phases are combined, dried over magnesium sulphate, filtered and the filtrate is evaporated.

The oily residue is crystallized from benzene. 411 (54
h) trans-6-(2-methyl-1,6-sioxolan-2-yl)-1-(4-methoxyphenyl)-4
-Oxo-2-azetidine-carboxylic acid is obtained.

Analysis: Two calculated values for 015Hxfu NO6 (307,32): c: 58.63chi, H: 5.57.

N: 4.56%; Analysis value: O: 58.401. H: 5.80%.

N: 4.66 section.

Engineering! A (xBr): 3400-2700.1750
(Wide) cWL-1°”HNMR (C!DO13): δ=1.5 (a,
3 H)t 3.7(a, I H,, T=2.
5 ax).

3.76 (B, 3)1), 4.0 (m,
4H), 4.38 ((1゜1H, J = 2-
5 Tits ) e 6. s 2 (2H) + 7.26 (
2H, AA'BB', T = 9.5 decimal), 9.2:' -, (8, I H) ppm.

f) 1.11 F (1,5611,0,011 mol) of dry triethylamine dissolved in 3 g (0.01 mol) of dry tetrahydrofuran prepared as described in item e) above. Add to the solution. The solution was cooled to -15°C and 1.2 g (1,06
m, 0.011 mol) of ethyl chloroformer)Y
Add dropwise to the stirring solution.

After stirring for 20 minutes, the separated particles were filtered away under a nitrogen atmosphere.
and 4.8.9 (0,025
mol) of diazomethane is added to the filtrate at room temperature. After stirring for 2 hours, the excess shear methane is destroyed with acetic acid and the solution is evaporated in vacuo. The oily residue gradually crystallizes. 3g (90%) trans-4
-(Diazoacetyl)-3-(2-methyl-1,3-dioxolan-2-yl)-1-(4-methoxyphenyl)-2-azetidinone is obtained: melting point: 95-96 °C (
Benzene and ether)0 Engineering R (KBr): 2200. 1760. 1640
cm-'.

3.51 (a, IH,:r=2.6mz).

3.75 (s, 3H), 44-05 (, 4
H), 4.31 (d.

i H, J = 2.6 Hz), 5.47 (8,
IH) p 6.85 (2H)+7.30
(2H, AA'BB'.

J = 9 Hz) ppm0 g) 3, which was made by K as described in the item above)
3 g (0.01 mol) of trans-4-(diazoacetyl)-3-(2-methyl-1,3-dioxolane-2
-yl)-1-(4-methoxy7<enyl)-2-azetidinone'k 50142 is dissolved in a mixture of water and 100M1 tetrahydrofuran. The mixture was irradiated with a high-pressure mercury lamp in a photorsactor under a nitrogen atmosphere, and the progress of the reaction was monitored by thin layer chromatography (adsorbent: diatomaceous earth G according to 5 tahl, developing solvent: benzene and 70% of acetate). :1 mixture).

When the reaction has ended, the tetrahydrofuran is distilled off under vacuum, the residue is hydroxylated (20 parts), made alkaline with IJum solution, and the solution is washed twice with 151 portions of dichloromethane. p) 11- by adding concentrated acid to the aqueous phase.
Acidify to 2 and then extract 6 times with 2 om-t" dichloromethane. Combine the living phases, dry over magnesium sulfate, filter, and evaporate the filtrate. 1
．． 6, @ (50%) [trans-6-(2-λ:
Thiru-1,6-thioxolan-2-yl)-1-(4-
methoxyphenyl)-4-oxo-2-azetizonyl]
- Obtain acetic acid.

Analysis; 016M19NO6 (321,33) Busy:
Calculated values: O: 59.80 chill H: 5.96%.

N: 4.36chi; Actual measurements: 0: 59.60 inches, H: 5.76 inches.

N: 4.08chi.

Engineering R (film): 3500-2500゜1760-1
700cm-1゜h) 1 made as described in item g) above,
0 g (3.12 mmol) of the compound was dissolved in 1011 J of dichloromethane and 0.53 g (3.12 mmol) of diphenyldiazomethane dissolved in 101 J of dichloromethane was added dropwise to the stirring solution at room temperature. Add. Evaporate the solution in vacuo when gas evolution has stopped. 1.45g (98g) of benzhydryltrans-C3-(2-methyl-1,3-dioquinrane-2-
yl)-1-(4-methoxyphenyl)-4-oxo-
2-Azetidinylcouacetate is obtained.

Analysis: For C2oH2oHO6 (48,7-55): Calculated: c: 1.44%, H: 5.99ch.

N: 2.87 inches; Actual value: O: 71.13 inches H: 6-21 inches.

N: 2.93 section.

IHNMR (ODO13): δ=1.35(s, 3H
).

2-7 3-1 (my 2 HC 3,38 (6, IH, J=2.5Hz).

3.72 (B, 3HL 3.8-4.1 (m
, 4H), 4.1-4.5(m, 1n)t
6-85 (s.

1 B), 6.7-7.4 (m.

14H)ppm.

Agent Asamura Kogai 4Continued from page 1 0 Inventor Gyula Similag Hungarian Budapest 12 Holosii Ny 25 0 Inventor Power Rory Zarael Hungarian Szentendre Bykos Part 43 0 Inventor Tibor Gizr Budapest, Hungaria 8 Koltoy E. Ny 12 @R Aktor Karman Harsanj Budapest, Hungaria 12 Fodor Ny 12 0 Inventor György Hökete Budapest, Hungaria 2 Suzeher Ny 62 0 Inventor Laszlo Suzporny, Budapest, Hungary 11 Száborks Li M. N. 7 0 Inventor Gyorgy Hayos Budapest, Hungarian 2 Gabor E. N. 59

Claims (1)

[Claims] (1) Two-pronged formula (1) (wherein Yl and Y2 together form a removable carbonyl protecting group, preferably a ketal group or a thio analog thereof, and or can be selectively removed) esterification group, preferably an arylmethyl or diarylmethyl group, wherein Yl and Y2 are as defined above and R
' is a removable amide protecting group other than a phenyl group, preferably a phenyl or benzyl group having one or more 1-4 alkoxy substituents). R', yl and Y2 are as defined herein) by methods known per se, and the protecting group R' of the resulting ester is removed, or the general formula (I), ( Protecting group R' of a compound of formula (X, R', Yl and Y2 are as defined above)
A method for producing a compound of general formula (1), characterized by: removing. (2) General formula (If), (R', yl and Y2 in the formula
, as defined in claim (1)) with phenylzoazomethane or diphenyldiazomethane. (3) The protecting group R' of the compound of general formula (fl) is protected by cerium (
IV) The method according to claim 1, characterized in that the removal is carried out by means of salt. (4) () lance-(2,4-dibenzyl in diphthalate)-
3-(2-methyl-1,6-thioxolan-2-yl)
-benzhydryltrans-C5-C2-methyl-1,6-sioxolan-2-yl) characterized in that 4-oxo-2-azetidinylcyacetic acid is reacted with diphenyldiazomethane and the method is reacted with beroxydisulfate. A method according to claim (1) for producing -4-oxo-2-azetidinyltoacetate. (5) [trans-6-[2-methyl-1,6-sioquinran-2-yl)-1-(4-methoxyphenyl)-
4-oxo-2-azetizonyl]-benzhydryltrans-[6-(2-methyl- Claim No. (1) 11 for producing 1,6-thioxolan-2-yl)-4-oxo-2-azetidinyltoacetate
The method described in. (6) General formula (1) (wherein Yl and Y2 are a removable carbonyl protecting group, preferably a ketal group or its thio analogue), or a selectively removable esterification group, preferably an arylmethyl or a diarylmethyl group, and K is a removable amino) F protecting group other than a phenyl group, preferably a phenyl or benzyl group with one or more 01-4 alkoxy substituents. (Ca Benzhydryl trans-(3-(2-methyl-1,6-sioxolan-2-yl)-1-(4-methoxyphenyl)-4-oxo-2-azetidinyl two-acetate. Hydryltrans-(1-(2,4-dimethoxybenzyl)-3-(2-methyl-1°6-thioxolan-2-yl)-4-oxo-2-azetidinyltoacetate.