Method for preparation of resistant crystalline form of cephalosporins (its variants)

专利摘要:
PCT No. PCT/US86/01637 Sec. 371 Date Mar. 23, 1987 Sec. 102(e) Date Mar. 23, 1987 PCT Filed Aug. 12, 1986 PCT Pub. No. WO87/01116 PCT Pub. Date Feb. 26, 1987.Processes for the preparation of stable, crystalline cephalosporin intermediates of the formula <IMAGE> <IMAGE> wherein X is HI or HCl, and Nu and Nu(+) are certain N-containing heterocyclic rings attached via a sulfur atom or a ring nitrogen atom, respectively, which are substantially free of the DELTA 2 isomer; processes for intermediates in the preparation of the above compounds; and processes for the preparation of broad-spectrum cephalosporin antibiotics.
公开号:SU1736341A3
申请号:SU884355459
申请日:1988-03-18
公开日:1992-05-23
发明作者:П.Брандидж Стивен；Р.Бродфьюрер Пол；Сапино Чет (Младший)；Мао Ших Кун；Дж.Волкер Дональд
申请人:Бристоль-Мейерз Сквибб Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing (in a variant) a novel stable crystalline form of cefapoosporins, specifically a hydrbchloride or hydroiodide salt of the formula
ХМ-t-гЬ - „1Т +, -,
about L to K Lsnl (1)
WITH (G
where X is the hydrochloride or hydroiodide,
- Group
; Ј
CH3
+,
silt - woofer CHj
)
which is practically free of the D2-isomer impurity, and is used in (as an intermediate product for the conversion to cephalosporin antibiotics of a wide spectrum of action.
The purpose of the invention is to obtain new stable crystalline salts of the cephalosporin series, which are used as intermediates for the synthesis of cephalosporin antibiotics and allow to simplify the latter.
According to the method for producing a stable crystalline form of cephalosporins of the formula (I), which is practically free of the D2 isomer, a compound of the formula
(SK}) 3Ш-hL „l
(th)
COjSlWj
treated with 1.15 equivalents of iodotrimethylsilane for each equivalent of the compound of formula (II), the resulting compound of formula
(ad-to-r-l
-Nuch
"give,-}
about
garden
1,1,1-trichlorotriltoethane is reacted with a compound of the formula rtlr, ХХн „, / -
or SNZ-K, 0
with
%about
to give a compound of the formula
(School
3
, with "1KiL, SOGEDZ) 3
ten
- v
where Ny has the indicated values, which is treated in 1,1,1-trichlorotrifluoroethane with methanol to remove the silyl groups, followed by acidification with hydrochloric or hydroiodic acid to form the hydrochloride or hydroiodide salt of formula I-I (I) or option that the compound of formula (II) in 1,1,2-trichlorotrifluoroethane (freon TF) is treated with 1.4 equivalents of the compound of formula
sn
 s
or SNG} Ro
about
then 1.8 equivalents of iodotrimethylsilane for each equivalent of the compound of formula (II), followed by treatment with methanol to remove silyl groups and acidification with hydrochloric or i-hydroiodic acid to obtain hydrochloride or hydroiodide,
Q salt of formula (I).
Example 1. (6R, 7E.) - 7-amino-3- (1-methyl-1-pyrrolidinium) -methyl-cef-3-em-4-carboxylate hydrochloride or -hydroiodide in accordance with the single vessel reaction scheme.
5 A summary of the experiments and observations obtained during several repeated reactions using the same amounts of reagents, at the most temperatures, etc., is presented.
1. 50.0 rv (0.184 mol) of 7-amino cephalosporanic acid (7-APC) is added to 350 ml of CCleFCC1Fz (freon TF) in a stream of nitrogen (note 1).
5 2. 46.5 ml (0, 22 mol, 1.2 equiv. -T ribbon) of hexamethyldisilazane (SDS) are added to the slurry suspension of these materials in one portion.
3. In one portion, using a 0 syringe (note 2), add
0.78 ml (6.0 mmol, 0.03 equivalent) iodotrimethylsilane ().
4. The formed mixture is heated 5 and refluxed in a
for 7-10 hours (notes 3 and 4). The course of the reaction is monitored by means of an NIR spectral analysis (Note 5).
5. The silylation reaction mixture is cooled to room temperature, further diluted with 150 ml of Freon TF, and cooled in a stream of nitrogen to 5 ° C.
6. With good stirring, 26.83 ml (0.25 mol, 1.4 equivalents) of M-methylpyrrolidine are added over 10 minutes, keeping the reaction temperature below 10 ° C (note 6).
7. In the form of a weak current for 10-15 minutes, 47.1 ml (0.33 mol,
1.8 equivalent) TMSI. During the TMIC addition process, a slight exothermic temperature increase is observed. The reaction plan is stirred at 5 ° C. for 30 minutes under a stream of dry nitrogen.
8. The formed strain was gently heated and stirred at 35-36 ° C for 1 hour. Over the course of the substitution reaction was observed by means of high-resolution liquid chromatographic analysis J (Note 7).
9. Constantly monitor both the volume of the reaction mixture and the speed of its mixing. As necessary, an additional 100 ml of Freon TF is added (Note 8).
10. After completion of the reaction (less than 2% of 7-ACC according to high resolution liquid chromatographic analysis), the slurry is cooled in a stream of nitrogen to 5 ° C and 25 are added dropwise over an eight minute period at 5 ° C. ml (0.615 mol) of methanol (note 9).
11.11 l is subjected to substantial loosening, after addition of methanol it is additionally stirred for 15 minutes at 5-10 ° C.
12. The cooling bath is then removed and 125 ml of 3 N is added over 2 minutes with good stirring. hydrochloric acid solution (prepared by adding 250 ml of concentrated hydrochloric acid solution to 756 ml of water). The reaction temperature rises to 12-15 C.
13. Hydrolysis mixture as quickly as possible is heated to 20-25 C (not exceeding 25 ° C), after which it is additionally stirred for
15 min at 20-25 ° C.
14, -Oases are separated and the organic phase (lower layer) is back-extracted with 50 ml.
0
five
0
five
0
five
0
S
0
five
water. This aqueous phase is used as a washing liquid during the final filtration of the enriched aqueous solution.
15.In an enriched aqueous phase, stage 14, 2.5 g of diatomaceous earth is added and then filtered through a layer of 7.5 g of pre-laid diatomaceous earth. The diatomaceous cake filter cake is washed with the aqueous solution from step 14 (back extraction), and then
25 ml of deionized water.
16. The combined enriched aqueous solution and the washing liquid (approximately 270 ml, reddish brown) are stirred for 30 minutes at 21-23 ° C together with 10 g of decolorizing charcoal. 2.5 g of diatomaceous earth is added to the mixture and stirring is continued for
5 minutes.
17. The angle is removed by filtration through a filter from 7.5 g of the diatomaceous earth. The coal cake is washed with 75 ml of water and further dried by pumping the atmosphere for 5 minutes.
18. If necessary, additional amounts of freon TF contained in the lower part of the enriched aqueous solution are separated from the aqueous phase.
19.In a clear orange colored aqueous solution (in a volume of about 350 ml, pH = 9-1.15), isopropyl alcohol is added dropwise to the cloud point (note 10).

20. After stopping the addition of isoprosh alcohol at 21-23 ° C for 15 minutes, the crystallization process is allowed to proceed.
21.After this time, additional isopropyl alcohol is added to the sludge within 45-60 minutes (a total of 1.2 liters of isopropyl alcohol is added), and then the plan is stirred, cooled to 0-5 ° C, for 60 minutes .
22. The product is collected by filtration, and the cake is washed with two 100 ml portions (Note 11) of cold (0-5 C) mixture of isopropyl alcohol and water in a ratio of 9: 1 and 100 ml of acetone. The product (note 12) is dried by evacuating the atmosphere for an additional 15 minutes. The product is further dried in vacuum to constant weight, yielding 46-51 g (75-83% yield) crude, a mixture of hydrochloride and hydroiodide salts of the indicated substance (compound (I)) in the form of a crystalline solid from off-white to white. . The activity yield is 60-63.4%.
23. According to LR spectral analysis, the purity of the product is up to 95%. The potential according to high resolution liquid chromatographic analysis is 750-800 µg / mg of the analytical 3-form compound of compound (I) in the form of hydrochloride. The purity zone is above 95%.
Note 1. 7-LCC is an extremely dusty solid. It should be weighed in a fume hood or other place in which reliable ventilation is provided. A respirator and all other external clothing parts should be worn as protective equipment from 7-LCC.
2. All transactions with TMIC must be carried out with the creation of as good as possible anhydrous conditions.
3. The reaction time is variable and depends on the presence of TMSI (or its reactive equivalent) as a catalyst. If the reaction mixture turns out to be viscous, an additional amount of TMSI accelerates the completion of the reaction.
4. It is important to maintain vigorous reflux, since the removal of ammonia formed is the main driving force of this reaction.
5. When sampling from the reaction mixture, it is important to observe anhydrous environmental conditions. The same rule applies to all reactions of the specified sequence.
  6. Increasing the temperature to a level in excess of 10 ° C during the addition of NSH leads to an increase in the amount of undesirable D2 isomer relative to the normal ratio of isomers 1:26.
7. Samples must be analyzed using high-resolution liquid chromatography every 4-6 hours. In the course of this reaction, it is of crucial importance. The reaction time, time, concentration, and number of equivalents of TT1SI, as well as the basicity of the medium.
0
five
0
five
0
five
0
S
0
8. When the flame becomes very thick in order to simplify its mixing, it is necessary to add a certain amount of CC1HGSS1P2 to dilute it.
9. Before adding methanol, the slurry is so thick that lumps of material adhere to the walls of the reaction vessel, making it difficult to completely mix with methanol. Quality
and the completeness of mixing throughout the volume of the reaction vessel should be determined by visual observation.
10. This usually requires the addition of 0.5-1.0 volumes of isopropanol.
11. Such wash liquid is prepared by mixing 90 ml of isopropanol with
10 ml of water and cooling the mixture to 0-5 ° C in a base of ice water.
12. In a separate experiment, the product is isolated as a pure hydroiodide salt by treating the slurry from step 11 125 ml 3 n. a solution of hydroiodic acid instead of 125 ml 3 n. hydrochloric acid (as in stage 12). By treating the aqueous phase in the same way (stages 13-24), 44.3 of a white crystalline hydroiodide salt is obtained. The reduced potential for high resolution liquid chromatographic analysis is 105% against the analytical standard hydrochloride salt. The yield of activity in terms of 7-LCC is 56.7%.
Example 2. Recrystallization of (6R, 7R) -7-amino-3- (1-methyl-1-pyrrole and) methylcell-3-em-4-carboxylate hydrochloride (hydrochloride of formula (I)). Stage
1. 15.0 g (0.045 mol) of crude hydrochloride of the formula I are added in one portion in 125 ml (3.5 mol, 3.50 equivalents) of 1N. hydrochloric acid solution with good mixing.
2 .. The resulting mixture is stirred at room temperature for 5 minutes.
3. In a single batch, continuing good mixing, a total of 8.0 g of bleaching carbon is added. Bipam is stirred for an additional 45 minutes.
4. The coal slurry is filtered off by vacuum through a layer of 8.0 g of diatomaceous earth. This layer is washed with 35 ml of water and dried with
pumping out the atmosphere for 5 minutes.
5. The slightly clouded filtrate is subjected to final filtration by passing through a pmicronic millipore filter, obtaining a completely transparent, scholium in the external form with water (the total volume is 170 ml).
6.In a dropwise, 125 ml of isopropyl alcohol is added to the cloud point over 25 minutes with good stirring. At this point, the addition of isopropane is stopped. The flame is stirred at room temperature for 15 minutes, during which time a good seed layer of crystals is formed.
7. With good mixing during the process. In a 25 minute period, an additional 475 ml (note 3) of isopropyl alcohol is added dropwise.
8. The formed sludge is stirred with cooling on the base of water with ice for 1 hour.
9. The slurry is filtered and then successively washed with two portions of 120 ml (note 4) with cold (0-5CC) isopropanol / water mixture in a ratio of 9: 1 and 120 ml of acetone.
10. The filter cake is partially dried with a pumped out. Atmospheric. Calculated, element
Carbon46.77
Hydrogen 6.04
Nitrogen12,59
 Sulfur9.61 KF (water)
The rest (sulfatiro - bath ash)
According to the test data of this material, its potential is 99.5% against the standard liquid chromatographic high-resolution batch of the hydrochloride of formula (I). The Klettu number is 3 (100.0 mg of sample diluted to 10 ml in a Milli volumetric flask with water, filtered through a sample of a preparative filter for liquid chromatography with high resolution of Maylex, bluish

ten
3634110
ry for 15 min. As a result of additional drying in a vacuum (pumped out using a steam injector) for 15 hours at 40 ° C, 7.87 g (52% yield) of a snow white crystalline hydrochloride of formula (I) obtained Note 5. Note.
1. The number of moles of consumed hydrochloride of the formula I is given
in terms of 10% purity.
2. A normal hydrochloric acid solution is prepared by adding 83 ml of concentrated hydrochloric acid in
920 ml of distilled water.
3. The total volume of isopropyl alcohol used for crystallization is 600 ml, which is 3.5 times the volume of the filtrate finally filtered with water from step 5.
15
20
25
4. Wash mixtures of isopropanol with water consist of 108 ml of isopropanol and 12 ml of distilled water: the mixture is cooled to 0-5 ° C in an ice bath.
5. The following are given: elemental analysis data consistent with the recrystallized hydrochloride of formula (I).
deno, given for
% KF,%
46.0246.71
6.176.10
12.3112.49
9.50 9.64
1.47
Less than 0.1
light colored, about 1.2 cm long).
50 NGR spectrum (DZ0, 360 MHz, P20: H20 suppression): 2.14-2.32 (envelope, 4H, -N (CH3) (); 3.00 (s, 311, NC%); 3 46-3.67 (m, 5H, -N (CH3) CH2CH2, 8CHg); 3.96 (d, 1H,
55 16.9 Hz, -SCH2); 4.09 (d, III, 13.9 Hz, CC% N-); 4.73 (d, III; 13.9 Hz, CCIL, N-); 5.21 (d, 1H, 5.1 Hz, -COCIICHS-); 5.41 (d, 1H, 5.1 Hz, -COCHCHS-).
eleven
M.p. 251 ° С (section). X-ray powder diffraction data for compound (I):
73634112
by adding hydrochloric acid to the final mixture, containing some amount of Aormula (I) hydroiodide, obtained due to the presence of iodine in the previous intermediate product. Thus, although it is characterized by a high degree of antibacterial purity, it is common to recrystallize said product in order to remove the hydroiodide of formula (I).
ten
5.22 3.59 7.76 7.31 7.13 6.75 6.15 5.82 5.75 5.42 5.2; 5.12 4.92 4.8 4.6: 4.2:
4, o: s, 9;
3.7 (3.6 3.6 (
h, 5:
3.3
w, k
3.1
3.07 3.01
As stated, the crude hydrochloride of the formula (I) obtained by adding the initially crystallized hydroiodide of the formula (I) obtained by adding hydroiodic acid in the final reaction mixture is free of the hydrochloride of the formula (I). Thus, the hydroiodide of the compound (I) is usually obtained with a high degree of purity, so there is no need for its recrystallization.
Example 3. (6R, 7K) -trimethylsilyl-7- (trimethylsilyl) -amino-3-acetoxymethyl-3-e-4-carboxylate
S
thirty
35
40
The oven-dried flask and Friedrich cooler are cooled to room temperature in a stream of dry nitrogen. 10.0 g are then charged to the flask.
(36.7 mmol) 7-ACC (purity 97.2%) and 70 ml of dry 1,1,2-trichlorotrifluoroethane (freon TF, dried over molecular sieves). 9.3 ml (44.1 mmol 1.2 equivalents) of 98% 1,1,1,3,3,3-hexamethyldisilazane (HMDS) are added to the formed ipam with a syringe with good agitation and with protection against moisture penetration. ) and 0.16 ml (1.1 mmol, 0.03 equivalent) TMSI. This sludge is quickly heated and maintained at a temperature of intensive boiling under reflux for 710 hours, a weak stream of nitrogen passes through the system. Next, the reaction mixture is cooled to room temperature in a stream of dry nitrogen and diluted with 30 ml of fresh freon TF. H-NMR spectral analysis of an aliquot of a slightly turbid reaction mixture showed more than 95% conversion to the indicated product.
NMR (CDfcCl-., 360 MHz) 6: 0.23 (s, 9H, N-Si (CH3b); (s, 9H, -COOSi (C%) 3); 1.51 (d, 1H, 13.6 Hz, NH-); 2.09 (s, 3N, -COCH3); 3.41 (d, 111, 18.3 Hz, -5SHg-); 3.61 (d, 1H, 18.3 Hz, -SCHZ); 4.80 (dd, 1H, 4.5, 13.6 Hz, -COCH / NHSi (C%) 3); 4.83 (d, 111, 13.2 Hz, -CH2OSOCH, ); 4.91 (l, 1H, 4.5 Hz, COCH (NHSi (CH3) 3 CH-)); 5.11 (d, 1H, 13.2 Hz,
-sn2psosn3).
Example 4. (BK, 7K) -7-amino-3- (1-methyl-1-pyrrolidinium) -methyl-3-et-4-carboxylate monohydroiodide (compound II)
In a slightly turbid solution of (6R, 7E) -trimethylsilyl-7- (trimethylsilyl) -amino-3-acetoxymethyl-3-em-4-carboxylate in Freon TF (prepared according to Example 3) at 0-5 ° С in a stream of dry nitrogen, 5.35 ml (51.4 mmol, 1.4 equivalents) of dry 97% N-methylpyrrolidine (dried over molecular sieves) are added dropwise over 1-2 minutes with good stirring. Next, add a syringe over about 5 minutes, continuing good mixing, 9.40 ml (66.1 mmol, 1.8 equivalents) of TMSI. During this addition, the reaction temperature is maintained below 10 ° C. The resulting slurry is stirred at. 0-5 ° C for another 30 minutes After this time, the sludge is placed in an oil bath, the temperature of which
five
five
carefully regulate in the range of 35-36 ° C. The progress of the reaction is monitored by high resolution liquid chromatographic analysis. After 45-48 hours, the reaction is complete (less than 2% of 7-ACC) and the mixture is cooled to 0-5 ° C in a stream of dry nitrogen. With good stirring, a total of 5.0 ml (123 mmol, 3.35 equivalents) of methanol is added dropwise. The reaction temperature during the addition process is kept at less than 10 ° C. The resulting slurry is stirred at 0-5 ° C for another 15 minutes. Then, 25 ml (75 mmol, 2.0 equivalents) of a 3N aqueous solution of hydroiodic acid are added to the mixture in one portion. Upon completion of this addition operation, the cooling bath is removed and the biphasic mixture is quickly heated to 20-25 ° C. Intensive mixing is continued for 15 minutes. The phases are separated and the organic phase is back extracted with 10 ml of water. This backwash liquid is retained for further use.
The main aqueous phase is stirred at 20-25 ° C for 10 minutes together with 0.5 g of diatomaceous earth. The sludge is filtered through a layer of 1.5 g of diatomaceous earth (previously washed with 50 ml of water). This layer is washed with a reverse wash water liquid from the previous step, and then with 5 ml of water. The cake is partially dried by pumping the atmosphere for 5 minutes. In total, 2.0 g of bleaching carbon is added and the slurry is stirred at 20-25 ° C for 30 minutes. After this time, 0.5 g of diatomaceous earth is added and stirring is continued for additional
5 5 min. Sham is filtered through a layer of 1.5 g of diatomaceous earth (previously washed with 50 ml of water), then this layer is washed with 5 ml of water. The layer of diatomaceous earth is partially dried with kakyvanie atmosphere for 5 minutes. The filtrate is finally filtered through a pmicron millipore filter.
The product is planted by adding dropwise 3.5 volumes of isopropanol in
0
transparent aqueous phase amber color at 20-25 ° C. The resulting slurry is cooled to 0-5 ° C and allowed to stand for 1 hour. The sludge is filtered and washed with two 20 ml portions.
14.24 10.16 9.30 8.04 6.91 6.41 5.98 5.71 5.34 4.90
COi CH3
This compound is obtained from a solution in freon TF (6R, 7E) -trimethylsilyl-7- (trimethylsilyl) amino-3-acetoxymethyl-3-em-4-carboxylate (at a rate of 50.0 g of 7-LCC) analogously to the example 4, except that instead of N-methylpyrrolidine in this case, use 28.3 ml (257 mmol, 1.4 equivalents) of dry N-methylmorpho17
lina (dried over molecular sieves). The reaction was monitored using high-resolution liquid chromatographic analysis; it was established that it ended after 7–8 h at 35–36 ° C. The reaction mixture is further processed analogously to example 4 (due to an increase in the amount of reagents, the consumption of materials increases by five times), obtaining 36.0 g (41% yield) of a somewhat off-white crystalline (6R, 7K) -7-amino-3 - (4-methylmorpholinium) -methylceph-3-em-4-carboxylate monohydroiodide. According to liquid chromatographic analysis, the purity zone exceeds 95%.
 p-NMR spectrum (360 MHz,) S1: 3.30 (s, 3H,); 3.60 (m, 4H,
3.68 (d, 1H,
-muxdasnl)
10 Hz, -SCHar); 4.04 (d, 1H, 10 Hz, -80%), 4.2 (m, 4H,
(SSHGKGOYDONG),
5.30 (d, III, 5 Hz, C-6 beta-lactam),
5.53 (d, 1H, 5 Hz, C-7 beta-lactam),
NK spectrum (bromidkali): 3460, 1795 and 1600.
Calculated,%: C35.40, H 4.34, N 9.53. ,
with en19n
Found,%: C 34.99, H 4.38, N 8.35.
Example 6. (6R, 7K) -7-amino-3- (1-methyl-1-pyrrolidinium) -methylceph-3-em-4-carboxylate monohydroiodide.
Furnace-dried flasks and cold flashers of Frederick are cooled to room temperature in a stream of dry nitrogen under excess pressure. Then 10.0 g (36.7 mmol) of 7-ACC and 80 ml of 1,1,1-trichlorotrifluoroethane (dried over molecular sieves) are charged to the flask. With good stirring, a total of 9.3 ml (44.1 mmol) is added in one portion using a syringe.
ten
15
20
25
3634118
1.2 equivalent) PWH. Immediately thereafter, 0.16 ml (1.1 mmol, 0.03 equivalent) of TMSI is added in one portion using a syringe. The final slurry is subjected to a boiling temperature under reflux with good stirring under conditions of protection against moisture penetration for 6.0 hours. Examination of an aliquot using NMR spectral analysis () shows more than 95% conversion to target trimethylsilyl-7- (trimethylsilyl) -amino-3-acetoxymethyl-3-em-4-carboxylate.
The mixture of silylium from the previous step is cooled to room temperature. Then, using a syringe as a weak current, 6.0 ml (42.2 mmol, 1.15 equivalents) of TMSI are added within 2-3 minutes. The resulting sludge. stirred at room temperature for 1.0 h. At the end of this period, an aliquot study by means of an 1111P spectrogram shows more than 95% conversion to the target 3-iodomethylcepham. After 1.25 hours, the slurry is cooled to 0-5 ° C and maintained at this temperature for 15 minutes. This slurry is filtered under nitrogen overpressure through a Schlenk funnel into a receiving flask cooled with a mixture of water and ice. The collected solid was washed with 17 ml of fresh 1,1,1-trichlorotrifluoroethane.
To a filtrate containing trimethylsilyl-7- (trimethylsilyl) -amin o-3-iodomethylceph-3-em-4-carboxylate, at 040-5 ° C in an inert atmosphere of dry nitrogen, add dropwise with a syringe 3 , 82 ml (36.7 mmol, 1.0 equivalent) of 97% N-methylpyrrolidium (dried over molecular sieves) at a rate that keeps the reaction temperature below 10 ° C. The slurry formed is mixed in for an additional 15 minutes at 0-5 ° C. After this
50 times of time, 5.0 ml (123 imol, 3.35 equivalents) of methanol are added dropwise, keeping the reaction temperature at a level below l 10 ° C. The formed slime of the sand is stirred for 15 minutes at 0-5 ° C. The solid material is filtered off under vacuum, washed with 100 ml of TF Freon and partially dried, and the atmosphere is evacuated for 15 minutes. AT
14
As a result of further drying in vacuum at room temperature to a constant weight, 10.27 g (66% yield) of (6R, 7R) -7-amino-3- (1-methyl-1-pyrrolidinium methylceph-3 -em-4-carboxispat monohydroiodide. The H-NMR spectral analysis at 360 MHz of this raw material (DЈ0) shows a ratio of: 3 and amp 2 isomers of 5.4: 1.0. Data liquid chromatographic analysis of high-resolution salt shows that the ratio between the D3 and A 2 isomers in terms of the percentage of zones is
173634120
8.1: 1.0. The activity yield for the conversion of 7-LCC to 7-amino-3- (1-methyl-1-pyrrolidinium) -methyl cepheme-3-em-4-carboxylate is 43.5% (as determined by quantitative liquid chromatographic high-resolution salt analysis versus the comparative standard of the target D e-isomer).
The results of some experiments in examples 4 and 5 are summarized in the table.
The compounds of Examples 4 and 5 were isolated after the reaction was terminated by adding aqueous hydrochloric acid solution to the methanol sludge.
ten
15
 The data given are area in
percent for each isomer on high resolution liquid chromatographs of the isolated hydroiodide salt. Compounds of formula (I) can be easily
convert to antibiotics
broad spectrum by acylation with acid with acceptable lateral
chain. For example, a compound of formula I
(X - hydrochloride or hydroiodide) is subjected to conversion in 7- / oЈ- / 2-aminothiazol-4-yl / -o6 - / - / g / methoxyiminoacetamine G
(I / in j
. . . . ,, This reaction is easily carried out either in
to / -3 - // 1-methyl-1-pyrrolidino / -methyl / -40 in the presence of c, N-dimethylaniline in
3-cephem-3-carboxylate by N-acylation
1-benzotriazolyl- / g / -2- / 2-aminothiazol-4-yl / -2-methoxyiminoacetate
at room temperature for 10-20 hours, or by dissolving compound (I) in water and dimethylformamide and adding sodium bicarbonate with ice cooling, and then reacting at room temperature for about 30 minutes to 5 hours, or by dissolving the compound ( I) in water, cooling the solution to 5-15 ° C, adding dropwise a solution of sodium hydroxide to a pH of 5.5-6.0, adding tetrahydrofuran, again NaOH solution, bringing the pH to 6.7-6.9 by adding active ether reagent and reaction for 1-5 hours at room temperature temperatures.
on air
x-vdl
SI
Gqq
(I)
aih
(I / in j
-40 in the presence of n, N-dimethylaniline in
45
50
55
at room temperature for 10-20 hours, or by dissolving compound (I) in water and dimethylformamide and adding sodium bicarbonate with ice cooling, and then reacting at room temperature for about 30 minutes to 5 hours, or by dissolving the compound ( I) in water, cooling the solution to 5-15 ° C, adding dropwise a solution of sodium hydroxide to a pH of 5.5-6.0, adding tetrahydrofuran, again NaOH solution, bringing the pH to 6.7-6.9 by adding active ether reagent and reaction for 1-5 hours at room temperature temperatures.
The following examples 7-10 show the use of compounds of formula (I) as intermediates
l synthesis of cephalosporin antibiotics.
Example 7. Conversion of compound-, and I (X - HC1) to compound VIII.
21.72 g (0.0612 mol) of sample of compound I (X is hydrochloride) solution in 190 ml of water at 25 ° С with stirring. The mixture is then cooled to 8-10 ° C and its pH is adjusted to 2.5-5.88 (within 5.7-5.9) by adding dropwise 30.5 ml of h (0.061 mol, 1.0 equivalent) 2 n. sodium hydroxide solution. The total volume is 214 ml.
555 ml of tetrahydrofuran (THF) are then added in three portions. The temperature of the mixture after each such addition rises to 12–13 ° C, so before adding each next batch it is lowered to 8–10 ° C. The total addition time is 10 minutes, the pH of the mixture is adjusted to 5.8–6.1. Next, the pH of the mixture was adjusted to 6.8 (in the range of 6.7-6.9) by adding dropwise 2.0 ml (0.004 mol) of 2N. sodium hydroxide solution.
A sample (29.5 g, 0.0927 mol) of 1-benzotriazole- / 2 / -2- / 2-aminothiazol-4-yl / -2-methoxyiminoacetate active ether. After the first portion of active ester has been added, the cooling bath is removed. The pH of the reaction mixture was again adjusted to 6.5 (range 6.5-6.7) after 5-10 minutes after completion of each operation for adding the active ester by adding 2 n dropwise. sodium hydroxide solution.
The clear, pale orange reaction mixture was stirred at 25 ° C for 2 to 3 hours. For the first 30 minutes, the pH was adjusted again to 6.5 (range 6.5 to 6.7) every 5-10 minutes by adding dropwise m 2 n. sodium hydroxide solution. During the rest of the reaction time, the pH is adjusted to 6.5 every 15 minutes (a total of 29.5 ml of 2N sodium hydroxide solution, 0.059 mol, 0.97 equivalent) are added. The completion of the reaction is judged by high resolution liquid chromatographic analysis.
Then the solids present in the reaction mixture were removed by filtration and washed with two 5 ml portions of water. The filtrate is subjected
o
five
0
five
extraction with methyl isobutyl ketone (MIBK, 790 ml) and the aqueous layer is separated. The organic phase is washed with 64 ml of water and the aqueous phases are combined, followed by stirring f together with 1h, 1 g of Dicalite for 10 minutes. The solids are then separated by vacuum filtration and washed with two portions of 5 ml of water.
The 314 ml of the resulting clear orange solution is acidified with good stirring to a pH of 3.7 (in the range of 3.5-4.0) by adding dropwise 14.5 ml of 4N. hydrochloric acid. At this point, the mixture becomes turbid, since the crystallization of the acidic adduct of sulfuric acid (VIII) has begun.
Crystallization is allowed to continue for 10-15 minutes, after which the pH is adjusted to 3.0 (in the range of 2.9-3.1) by adding dropwise 7.5 ml of 4N. sulfuric acid. Next, the mixture is cooled to 0-5 ° C and the remaining 63.5 ml 4N are added over a period of 20-30 minutes. sulfuric acid, resulting in a pH value of 1.3-1.5. After completion of the sulfuric acid addition operation, the slurry re® is stirred for 1 hour at 0-5 ° C.
The white crystalline product is removed by vacuum filtration and washed with 63.5 ml of 0.5N. sulfuric acid. The solid material is partially dried.
5 with evacuation of the atmosphere for 15 minutes, and then washed with two portions of 100 ml of acetone. The solid product is again partially dried, by evacuating the atmosphere for 10 minutes,
0 after which it is suspended for 1 h in 400 ml of acetone with good stirring. The solid product is removed by vacuum filtration, washed with two portions of 100 ml of acetone and
5 is dried in vacuum (under a residual pressure of 10–15 mm Hg) at 35–40 ° C to a constant weight for 3–6 h.
28.79 g (yield 81.4%) of the product
0 acidic adduct of sulfuric acid (VIII), is isolated in the form of a white crystalline solid slightly affected by electrostatic charge.
e Example 8. The conversion of compound (I) (X - HJ) to compound (VIII). The general procedure of Example 7 is repeated completely, except that in this case the starting material
23
(Compound (I), X - HC1) is replaced by an equimolar amount of Compound (I) (X - HJ), as a result of which compound (VIII) is obtained.
Example 9. 7-0 & Ј-2-aminothiazole-4-yl) - / g / -methoxyiminoacetamide-to-3 // 1-methyl-1-p: irro-1 / methyl 3-cephem 4-carboxylate
. $
in
gu-oh if
u coi cib
OCHJ KK LDH
to
S.
ON
- - n xqfUfJ
С0г СК}
In general, 12.76 g (30 mmol) (6R, 7R) - 7-amino-3- (1-methyl-1-pyrrolidinium) - methylceph-3-em-4-carboxylate monohydro-iodide (prepared according to example 4) - suspended in 87 ml of water with good stirring at 20-25 C. The IPam is cooled to 8-10 ° C and the pH is raised to 5.80 at 7 ° C by adding dropwise 13.0 ml (26 mmol, 0.87 equivalent) 2 n. sodium hydroxide solution for 35 minutes. After that, 555 ml of tetrahydrofuran is added and the pH of the prepared solution is raised to 6.8 at 10 ° C by adding dropwise 1.9 ml (3.8 mmol, 0.13 equivalent) of 2N. sodium hydroxide solution. The cooling bath was removed and 14.75 g (92.7 mmol, 1.5 equivalents) of HOBT active syn-2- (2-aminothiazole) ester was added in two equal portions of 7.38 g each over 30 minutes. -4-yl) 2-methoxyiminoacetic acid.
After the completion of each operation such an addition, the pH is again adjusted to 6.5 every 5-10 minutes by adding 2N dropwise. sodium hydroxide solution. In the remaining reaction time, the pH was again adjusted to 6.5 by adding dropwise 2 n. sodium hydroxide solution every 15 minutes (a total of 28.6 ml of 2N hydroxide solution, 57.2 mmol, 1.91 equivalents are used). The completion of this reaction will be recognized by high-resolution liquid chromatographic analysis.
-
7363412k
After 1.75 hours, the dark solution is taken up in 365 ml of methyl isobutyl ketone and the lower aqueous phase is separated. The organic phase is subjected to reverse extraction with 30 ml of water. The combined aqueous phases are stirred for 10 minutes at 20-25 ° C together with 2.35 g of diatomaceous earth. Insoluble material is removed by vacuum.
filtering and filter cake washed with 5 ml of water. The amber aqueous phase is subjected to final filtration through a five-microin millipore filter. At 17 ° C, the pH of the solution is 6.40,
With good stirring, a total of 6.7 ml of 4N is added dropwise. sulfuric acid solution to mute
The solution is at pH 3.82 at 18 ° C. The product is crystallized with good stirring for 5 minutes. An additional 3.5 ml of 4 N is then added. sulfuric acid solution, obtaining a slurry with a pH of 3.09 at 20 ° C. This
the slurry is cooled to 0-5 ° C and a total of 30 ml of 4 N is added dropwise over the course of 20 minutes. sulfuric acid solution. The prepared sludge is stirred for 1 h at 0-5 ° C. The precipitate is filtered off and washed with 30 ml.
0.5 n. sulfuric acid solution. The filter cake is partially dried by siphoning the mixer for 15 minutes. After this time, the cake is broken off in two portions of 50 ml of acetone and again subjected to partial drying, with the atmosphere being drained for 15 minutes. This cake is re-suspended in 200 ml of acetone.
at 20-25 ° C for 1 hour. The salt is filtered off, washed with two portions of 50 ml of acetone and partially dried, with air being pumped out for 15 minutes. As a result of further drying in vacuum at 40 ° C to constant weight, 12.41 g (72% yield) of a crystalline, somewhat off-white compound is obtained in the form of its sulfate salt.
H-NIR spectrum (360 MHz, D20 with solvent added) S1: 2.16-2.33 (envelope, 4H,
 H (SHDONGMGNGVN)
55 3.01 (s, 311, rf-CHj); 3.45-3.64 (m,
45H, -n (sn) atsnasn -sna ,, -SCH-),
251736341
3.95 (d, III, 17 Hz,); 4.04
(d.shZHGts. Q); 4.08 (c, NN,
I
14
IH3
OC); 4.75 (d, III, 14 Hz,
- - four
- SNO-K / L0}; (d 1P 5 Hz with
1H, 111,
5 Hz, 0-7 C-5 thiaC 39.43, II 4.53,
. AND}
beta-lactam), 5.86 (d, beta-lactam), 7.16 (s, ev).
Found,% N, 14.53, S, 16.63.
CWH24N605S2-H2S04.
Calculated,%: C 39.40, If 4.47, N 14.39, S 16.60.
Example 10. 7 - ("(- / 2-aminothia-sol-4-yl / -o (- / g / -methoxyiminoacetam-, up to / -3 - // 4-methyl-4-morpholinium / -methyl / 3- cephem-4-carboxylate
 Q ttvAjlJ
do siz
QGH3
ND
to and
CL: pfao
COH CH
The compound is obtained from 54.0 g (122 mmol) of (BK, 7K) -7-amino-3- (4-methyl-4-morpholinium) methyl acetate-3-em-4-carboxylate monohydroiodide (prepared according to Example 5) and - 59.0 (184 mmol, 1.5 equivalents) of syn-2- / 2-aminothiazol-4 yl / -2-methoxyimino acetic acid in the form of HOBT-active ester according to Example 9. According to this procedure 60.1 g (84% yield) of the white crystalline compound is charged as its sulfate salt.
H-Ya1P-spectrum1 (360 LHz, D20: lIaDCO,) 3.30 (s, AE, JSN); 3.55 (m, 5H, -N (CH5) CHZCH2.0CH2CH2,
-SCH-); 4.05 (d, 1H, 16 Hz, -SCH2-); 4.10 (s, 3N, - OC1C), 4.1 (m, 4H, -NCCH CHfcCH OCHgCHfc); 4.21 (d, 1H,
26
one
+
14 Hz, -CH $ iJ O); 4.95 (d, 1H, U
14 Hz, —CHlH Jo); 5.47 (d, 1H,
k
5 Hz, C-6 beta-lactam), 5.96 (d, 1H, 5 Hz, C-7 beta-lactam), 7.10 (s, 1H, C-5 thiazole).
15 Calculated,%: C 38.37, H 4.41, N 14.13, S 16.18.
With „Ng4NbOb52.Ng504. Found,%: C 38.16, H 4.32, N 14.08, S 16.14.
20 Thus, the compounds of formula I, when used as intermediates for the synthesis of cephalosporin antibiotics, simplify the preparation of
25 of the latter due to the elimination of the release stages of carboxyl groups.

权利要求:
Claims (2)
[1]
Invention Formula
301. The method of obtaining sustainable
crystalline form of cephalosporins formula
BUT
x-kn.
3S
COO
where X is hydrochloride or hydroiodide, Ni is a group
-JO m -JD
CH3 CH3
which is practically free of the D 2-isomer impurity, which is also distinguished by the fact that the compound is in the form of (SVDZShL-A p
.
COzSi№)}
h
1,1,1-trichlorotrifluoroethane is treated with 1.15 equivalents of iodine-trimethylsilane for each equivalent
{WELCOME
about
VCH 3 (-1
C02ODz) 3
1,1,1-trichlorotrifluoroethane is reacted with a compound of the formula | + Xv. +, -v
-K j or -o
R
CH3 GKj
to give a compound of the formula
eight .;
№3SUW About
t
CfliSlWj
(; v
wherein Hz has the indicated values, which is treated in 1,1,1-trichlorotristorane ethane with methanol to remove silyl groups, followed by acidification with hydrochloric or hydroiodic acid to form the hydrochloride or hydroiodide salt of formula (I).
2. The method of obtaining a stable crystalline form of cephaloporin formula
[2]
Njjj - group
ten
- 40 ISCN
15 which is practically free of the D 2-isomer impurity, which also differs in that the compound of formula
0
(SCQ
about
to
.
U-YDOS
five
COzSUGHj)
, 0
 W
 s
in 1,1,2-; trichlorotrifluoroethane (freon TF) is treated with 1.4 equivalents of a compound of formula
or SNu-N About
then 1.8 equivalents of iodotrimethylsilane per equivalent of the compound of formula (II) followed by treatment with methanol to remove silyl groups and acidification with hydrochloric or hydroiodic acid to obtain the hydrochloride or hydroiodide salt of formula (I).

类似技术:

---

公开号 | 公开日 | 专利标题

---

KR100442717B1|2004-08-02|Crystalline amine salt of cefdinir

---

US20020128469A1|2002-09-12|Beta-lactam production

---

FI60565B|1981-10-30|CEFALEXIN-BIS- | -SOLVAT ANVAENDBART SOM MELLANPRODUKT VID FRAMSTAELLNINGEN AV CEFALEXIN OCH FOERFARANDE FOER FRAMSTAELLNING AV DETTA

---

SU1736341A3|1992-05-23|Method for preparation of resistant crystalline form of cephalosporins |

---

KR20090014985A|2009-02-11|Cefdinir synthesis process

---

US4003896A|1977-01-18|Method of preparing a sparingly soluble complex of cephalexin

---

EP0432297A1|1991-06-19|A method for the preparation of the sodium salt of O-formyl cefamandole

---

FI74709C|1988-03-10|TRIMETHYLSILYLOXYCARBONYL-7-AMINODECEFALOSPORANSYRA-TRIMETHYLSILYLESTER FOR OIL MUSHROOMS AND OIL PRODUCTS FOR FRAMSTAELLNING AV DENNA.

---

EP0414904B1|1995-03-29|Preparation of enol silyl ether compounds

---

EP0007689B1|1982-08-04|Production of sodium cephamandole derivatives

---

EP0166580A2|1986-01-02|Improvements in or relating to ceftazidime

---

EP0015629B1|1986-01-02|New intermediates for the preparation of cephalosporins and process for the preparation of the intermediates

---

EP0101148B1|1987-12-23|Thiazole derivative, process for its preparation and use in the preparation of beta-lactam antibiotics

---

EP0001149B1|1981-06-03|Process for the preparation of 3-bromomethyl-3-cephem-sulphoxide derivatives

---

SU1563595A3|1990-05-07|Method of producing a stable crystalline form of cephalosporins

---

JP4749533B2|2011-08-17|Cephalosporin crystal

---

EP0588964A1|1994-03-30|Method for separation of gibberellin mixtures

---

TWI452048B|2014-09-11|Crystalline |-7-{2-|-2-[|-trityloxyimino]-acetylamino}-3-[|-1&#39;-tert-butoxycarbonyl-2-oxo-[1,3&#39;]bipyrrolidinyl-|-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester; its

---

Southwick et al.1989|SYNTHESIS OF PURPURATE-1, 1′-DIACETIC ACID | TRIPOTASSIUM SALT. A NEW CALCIUM INDICATOR FOR BIOLOGICAL APPLICATIONS

---

JP2015017077A|2015-01-29|Method of producing urea compound

---

KR790001070B1|1979-08-24|Process for preparing cephalosporin

---

JP2018108979A|2018-07-12|Method for producing lactone compound and method for producing biotin using the lactone compound

---

FR2460954A1|1981-01-30|PROCESS FOR PRODUCING 7- | -3- | -3-CEPHEM-4-CARBOXYLIC ACID

---

JPH0770122A|1995-03-14|Rolacarbef hydrochloride lower alcohol solvate and its usage

---

US3048589A|1962-08-07|S-ukacilsulfonic acid derivatives

同族专利:

---

公开号 | 公开日

---

US4868294A|1989-09-19|

---

DD268947A5|1989-06-14|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

GB1591439A|1976-10-01|1981-06-24|Glaxo Operations Ltd|7-syn cephalosporins|

---

US4223135A|1979-03-19|1980-09-16|Bristol-Myers Company|Production of cephalosporins|

---

US4316017A|1979-03-19|1982-02-16|Bristol-Myers Company|Cephalosporin intermediates|

---

US4336253A|1981-03-11|1982-06-22|Eli Lilly And Company|Cephalosporin antibiotics|

---

US4382931A|1981-09-08|1983-05-10|Eli Lilly And Company|3'-Substituted quinolinium cephalosporins|

---

US4382932A|1981-09-08|1983-05-10|Eli Lilly And Company|Isoquinolinium substituted cephalosporins|

---

GR76701B|1981-09-08|1984-08-29|Lilly Co Eli|

---

US4379787A|1981-10-02|1983-04-12|Eli Lilly And Company|Oximino-substituted cephalosporin compounds|

---

US4406899A|1982-03-04|1983-09-27|Bristol-Myers Company|Cephalosporins|

---

DE3316798A1|1983-05-07|1984-11-08|Hoechst Ag, 6230 Frankfurt|METHOD FOR PRODUCING CEPHEM COMPOUNDS|

---

DE3588014D1|1984-11-23|1995-06-01|Biochemie Gmbh|METHOD FOR PRODUCING BISSILYLATED 3-IODETHYLCEPHALOSPORINE DERIVATIVES.|

---

US4703118A|1985-04-08|1987-10-27|Eli Lilly And Company|Synthesis of 3-iodomethyl cephalosporins|US5359057A|1986-02-07|1994-10-25|Hoffmann-La Roche Inc.|Acylation of amines|

---

US5698703A|1991-09-10|1997-12-16|Bristol-Myers Squibb Company|Syn-isomer of thiazolyl intermediate and process for the preparation thereof|

---

US5594129A|1991-09-10|1997-01-14|Bristol-Myers Squibb Company|Process for the preparation of a cephalosporin antibiotic|

---

CA2099692C|1992-07-24|2003-09-30|Gary M. F. Lim|Process for preparing cephalosporin intermediates|

---

EP1773845A1|2004-07-16|2007-04-18|Hetero Drugs Limited|Process for preparing pure cephalosporine intermediates|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US06/882,107|US4714760A|1985-08-20|1986-07-11|Cephalosporin intermediates|

---