GB1565053A - Creation of Inventions and Patents with Artificial Intelligence

GB1565053A – Intermediate product for the preparation of cefazolin antibiotic
– Google Patents

GB1565053A – Intermediate product for the preparation of cefazolin antibiotic
– Google Patents
Intermediate product for the preparation of cefazolin antibiotic

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Publication number
GB1565053A

GB1565053A
GB4838376A
GB4838376A
GB1565053A
GB 1565053 A
GB1565053 A
GB 1565053A
GB 4838376 A
GB4838376 A
GB 4838376A
GB 4838376 A
GB4838376 A
GB 4838376A
GB 1565053 A
GB1565053 A
GB 1565053A
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United Kingdom
Prior art keywords
mixture
methyl
cephem
quinoline
carboxylic acid
Prior art date
1977-08-12
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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GB4838376A
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Proter SpA

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Proter SpA
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1977-08-12
Filing date
1977-08-12
Publication date
1980-04-16

1977-08-12
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Proter SpA

1977-08-12
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patent/GB1565053A/en

1980-04-16
Publication of GB1565053A
publication
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patent/GB1565053A/en

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Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems

C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom

C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms

Description

(54) INTERMEDIATE PRODUCT FOR THE PREPARATION
OF CEFAZOI IN ANTIBIOTIC
(71) We. PROTER S.p.A., an Italian Joint Stock Company, of Via
Lambro, 38Opera-(Milan), Italy, do hereby declare the invention for which we pray that a patent mav be granted to us, and the method by which It is to be performed, to be particularly described in and by the following statement:- This invention relates to an intermediate product for the preparation of an antibiotic named cefazolin. The invention relates also to a process for obtaining said intermediate product.
The cefazolin is a well-known antibiotic consisting of 7 – (IH – tetrazol – I yl)acetamido – 3 – (2 – methyl – 1,3,4 – thiadiazol- 5 – yl)thiomethyl – 3 cephem – 4 – carboxylic acid having the following structural formula:

At present the cefazolin is obtained from intermediates which in turn are obtained from Cephalosporin C.
The Cephalosporin C having the following formula:
is the main product of fermentation processes present in aqueous solutions (fermentation broths or resin eluates).
In addition to Cephalosporin C these fermentation broths contain by-products which are impurities to be eliminated.
In order to obtain the intermediates for the cefazolin, it is necessary for the
Cephalosporin C to be separated from the fermentation broths in the maximum purity grade. In this separation process several verv difficult operations are involved which are time consuming, of low yield and therefore expensive. Equally difficult and low yield reactions are involved for obtaining the intermediates from
Cephalosporin C and particularly the operations for separating the intermediate obtained in the desired purity grade from by-products of the reactions.
The intermediates used in the prior art for obtaining cefazolin antibiotic are:
a) 7 – amino – 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl – 3 cephem – 4 – carboxylic acid. This intermediate is condensed with I H – tetrazole 1 – acetic acid or with its reactive compounds such as a mixed anhydride or the chloride. Such reaction is carried out in an inert solvent, or in a mixture of inert solvents, or in a mixture of said solvents with water or with some other diluent For this process it is necessary to isolate the 7 – amino – 3 – (2 – methyl – 1 344 thiadiazol – 5 – yl)thiomethyl – 3 – cephem – 4 – carboxvlic acid and the indi;ited yields are low.
b) 7 – (5 – amino – adipamido) – 3 – (2 – methyl – 1,3,4 – thiidiaiol n – vl)thiomethyl – cephem – 4 – carboxylic acid or 7 ( i phenylcarbamoyl – amino – adipamido) – 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 yl)thiomethyl – 3 – cephem – 4 – carboxylic acid. These intermediates undergo a
reaction with silylating agents and then with an alkanol of low molecular weight
according to well known methods.
After concentration at reduced pressure, the residue undergoes condensation with 1H – tetrazole – 1 – acetic acid or with its reactive compounds. In this case intermediates not easily isolable are formed.
A concentration at reduced pressure is necessary in order to remove any volatile reagents interfering in the isolation of the final product.
c) The solvate with N,N – dimethylformamide of the hydrochloride of 7 amino – 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl – 3 – cephem – 4 carboxylic acid. This intermediate is condensed with IH – tetrazole – I – acetvl chloride in the presence of N,N – dimethylformamide or N,N – dimethylacetamide or with a mixture of acetonitrile and N,N – dimethylacetamide.
In this case it is requested that the chloride of I H – tetrazole – I – acetic acid is prepared by using phosgene which is an extremely unmanageable and toxic reagent: that is, because other chlorinating agents are not so suitable under the reaction conditions.
d) 7 – (IR – tetrazol – 1 – yl)acetamido – cephalosporanic acid. It is made to react in an aqueous solution with 2 – methyl – 5 – mercapto – 1,3,4 – thiadiazole. A very impure product is obtained with low yields.
In order to overcome the drawbacks of the prior art, an object of this invention is to provide a new intermediate product for the preparation of cefazolin antibiotic which is obtainable directly with high yield and purity grade from fermentation broths or resin eluates which contain Cephalosporin C.
Another object of this invention is to provide a process for obtaining said new intermediate.
According to this invention a new intermediate product is provided, consisting of a quinoline salt of 7 – (5 – acylamino – adipamido) – 3 – (2 – methyl – 1,3,4 thiadiazol – 5 – yl)thiomethyl – 3 – cephem – 4 – carboxylic acid having the following structural formula:
in which
R, is a linear or branched C,–C,, acyl group and
R2 is H or
R, and R2 together with an attached N-atom form a 5 or 6 membered ring.
According to one preferred aspect of this invention a new intermediate product is provided consisting of a quinoline salt of 7 – (5 – propionylamino adipamido)- 3 – (2 – methyl – 1,3,4 – thiadiazol- 5 – yl)thiomethyl – 3 cephem – carboxylic acid having the following structural formula:

A process according to this invention for obtaining the said new intermediate product comprises the steps of
,controlling the pH of an aqueous solution of a Cephalosporin C in the range of 8.5-9.2,
adding an acylating agent to the said aqueous solution while maintaining the pH thereof in said range,
adding 2 – methyl – 5 – mercapto – 1,3,4 – thiadiazole to the said aqueous solution,
heating said solution to 70o–750C for a predetermined time,
adding quinoline to the said heated aqueous solution while lowering the pH to a value in the range 3-3.5 thereby to obtain the quinoline salt of 7 – (5 acylamino – adipamido) – 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl 3 – cephem – 4 – carboxylic acid, as a crystalline product, and
filter separating, washing and drying said crystalline product.
The expression “aqueous solution” is intended to indicate throughout the following description the fermentation broths or resin eluates which contain
Cephalosporin C as a main product of fermentation processes.
The invention is further illustrated by the following detailed examples which are included by wav of illustration only.
EXAMPLE 1
The filtrate obtained from a whole broth Cephalosporin C fermentation containing 26 g (62.3 mmoles) of Cephalosporin C was treated with 10.4 F of borax.
The temperature of the mixture was lowered to about 15″C in an ice bath and the pH of the mixture was adjusted to 8.6 with 45.6 ml of 20 percent sodium hydroxide.
To the mixture, 17.9 (137 mmoles) of propionic anhydride in 50 ml of ethyl acetate were added and the mixture is maintained at 150C to 200C. The pH of the mixture was maintained between 8.6 and 9.1 during acylation with 53.8 ml of 20 percent sodium hydroxide.
When the pH remained constant (approximately 15 minutes after the complete addition of the anhydride) 9.7 g (73 mmoles) of 2 – methyl – 5 – mercapto – 1,3,4 thiadiazole were added.
The mixture was warmed and stirred for 30 minutes at 720–740C and then cooled in an ice bath and acidified to pH 2.5 by addition of 59.5 ml of concentrated MCI.
28.7 ml of quinoline were added to the mixture and the pH were again adjusted to 3.3 with concentrated HCI.
The acidified mixture was concentrated under vacuum to a volume of 5000 ml and stirred for 2 hours at room temperature.
The mixture was refrigerated overnight (5″C). The crystalline product was filtered, washed with 25 ml of cold water, 50 ml ethyl acetate and dried in a fluid bed dryer for 1.5 hours at about 40″C.
29.3 g (96.5 percent purity) of the quinoline salt of 7 – (5 – propionylamino adipamido)- 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl – 3 cephem – 4 – carboxylic acid was obtained, resulting in a yield of 67 percent.
The NMR and IR spectra were consistent with the desired structure. M.P.
118–120″C dec.
Analysis calculated for C20H25N5O7S3 . C9R7N. 1.5. H2O (percent):
C 49.77: H 5.04; N 12.00: S 13.74.
Found (percent):
C 49.34; H 5.01: N 11.79; S 13.81.
Water (KF): calculated 3.86 /”; found 3.78%.
Quinoline (GLC): calculated l8.45%; founXl8.45 ,^.
To the mixture of 53.8 g (76.8 mmoles) of the quinoline salt of the 7 – (5 propionylamino – adipamido) – 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 – yl) – thiomethyl – 3 – cephem – 4 – carboxylic acid in 470 ml of dichloromethane were added 70 ml of N,N – dimethylaniline, at 250C to 270C, and successively 82 ml of trimethylchlorosilane.
The mixture was gently refluxed for 30 minutes. Upon cooling at -60″C, 24 g
of PCl, were added and the slurry was stirred for 1 hour at 450 to -50″C; the
mixture was then chilled to about -60″C and 33 ml of methanol were added.
During the addition of methanol the temperature rose to –500C. After stirring
for I hour at -500/-600C, 17 ml of water were added.
The mixture was stirred for 30 minutes at -400C/-500C and 800 ml of methanol were added. Next, with cooling, 200 ml of triethylamine were added and the solution was treated with 22.5 g (153 mmoles) of IH – tetrazole – 1 – acetyl chloride in 120 ml of ethyl acetate. After stirring for I hour at -35″C and successively for I hour at -200C the reaction mixture was poured into 800 ml of water.
The mixture was separated into its components and the organic phase was extracted with 2x 150 ml portion of water.
The combined aqueous extracts were acidified to pH 2 with 20 percent HCI.
The solids were collected by filtration, washed with 50 ml of water, 50 ml of ethyl acetate and vacuum dried giving 10.2 g (55 /,) of cefaznlin P.F l980-20()0C det the NMR dnd IR spectra were consisting with the desired structure EXAMPLE 2
Ar aqueous solution containing 68 g (163 mmoles) of Cephalosporin C was treated with 27 g oi borax. The pH of the solution was adjusted to 8.8 by slowly adding 126 s g of 20% sodium hydroxide
To the mixture, 48.18 g (358 mmoles) of hexanovl chloride in 130 m of ethyl acetate were added at about l50C.
During the acylation reaction the pH of the mixture was maintained between 8.5 and 8.8 by adding 140 ml of 20 ,n sodium hydroxide.
After 15 minutes, 25.39 (190 mmoles) of 2 – methyl – 5 – mercapto – 1,3,4 thiadiazole were added and the resultant mixture was warmed to 720-740C for a period of 45 minutes.
After cooling in an ice bath the mixture was acidified to a pH of 2.5 with 162 ml concentrated hydrogen chloride.
75 ml of quinoline were then added to the mixture and when crystallization started. the pH of the mixture was adjusted to 3.2 with concentrated HCI.
The mixture was refrigerated overnight (5 C), and
The crystalline product was then filtered, washed with 65 ml of cold water. 130 ml of ethyl acetate, and dried.
89.2 g (98 Mn purity) of a quinoline salt of 7- (5 – hexanoylamino adipamido) – 3 (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl 3 – cephem – 4 – carboxylic acid were obtained. Yield: 72.3,…
The NMR and IR spectra were consistent with the desired structure. M.P.
880-900C dec
The intermediate product so obtained is treated as indicated in Example I in order to obtain cefazolin.
EXAMPLE 3
An aqueous suspension of 79.5 g (160 mmoles) of 7 – (5 – succinimidoadipamido – 3 – acetoxymethyl – 3 – cephem – 4 – carboxylic acid in 625 ml of water was treated with 37.5 g of sodium bicarbonate and 20 ml of ethvlacetate.
Then 25 g (189 mmoles) of 2 – methyl – 5 – mercapto – 1,3,4 – thiadiazole were added.
The mixture was warmed to 72 -75 C for a period of 30 minutes. After cooling the mixture the pH was adjusted to 2.5 by adding 115 ml of 6N HCI; thereafter 27 ml of quinoline were added.
The mixture’s temperature was maintained in the range of 250-300C for I hour while stlrrmg. The pH of the mixture was adjusted to 3.5 by adding 20 ml of 6N HCI.
The mixture was refrigerated overnight (+5 C) and the crystalline product was then filtered, washed with 120 ml cold water and 180 ml of ethylacetate, and then vacuum dried at 40 -45 C.
83.3 g (purity of 94 /n) of quinoline salt of 7 – (5 – succinimidoadipamido) – 3 (2 – methyl – 1,3,4 – thiadiazol – 5 yl)thiomethyl – 3 – cephem – 4 – carboxylic acid were obtained. Yield: 80.3.
The NMR and IR spectra were consistent with the desired structure. M.P.
980-l0l0C dec.
The i ltermediate product so obtained was treated as indicated in Example I in order to obtain cefazolin.
WHAT WE CLAIM IS:
1. A quinoline salt of 7 – (5 – acylamino – adipamido) – 3 – (2 – methyl 1,3,4 – thiadiazol – 5 – yl) – thiomethyl – 3 – cephem – 4 – carboxylic acid having the following structural formula
in which:
R1 is a linear or branched C1-C10 acyl group and
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (6)

**WARNING** start of CLMS field may overlap end of DESC **.
ethyl acetate and vacuum dried giving 10.2 g (55 /,) of cefaznlin P.F l980-20()0C det the NMR dnd IR spectra were consisting with the desired structure EXAMPLE 2
Ar aqueous solution containing 68 g (163 mmoles) of Cephalosporin C was treated with 27 g oi borax. The pH of the solution was adjusted to 8.8 by slowly adding 126 s g of 20% sodium hydroxide
To the mixture, 48.18 g (358 mmoles) of hexanovl chloride in 130 m of ethyl acetate were added at about l50C.
During the acylation reaction the pH of the mixture was maintained between 8.5 and 8.8 by adding 140 ml of 20 ,n sodium hydroxide.
After 15 minutes, 25.39 (190 mmoles) of 2 – methyl – 5 – mercapto – 1,3,4 thiadiazole were added and the resultant mixture was warmed to 720-740C for a period of 45 minutes.
After cooling in an ice bath the mixture was acidified to a pH of 2.5 with 162 ml concentrated hydrogen chloride.
75 ml of quinoline were then added to the mixture and when crystallization started. the pH of the mixture was adjusted to 3.2 with concentrated HCI.
The mixture was refrigerated overnight (5 C), and
The crystalline product was then filtered, washed with 65 ml of cold water. 130 ml of ethyl acetate, and dried.
89.2 g (98 Mn purity) of a quinoline salt of 7- (5 – hexanoylamino adipamido) – 3 (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl 3 – cephem – 4 – carboxylic acid were obtained. Yield: 72.3,…
The NMR and IR spectra were consistent with the desired structure. M.P.
880-900C dec
The intermediate product so obtained is treated as indicated in Example I in order to obtain cefazolin.
EXAMPLE 3
An aqueous suspension of 79.5 g (160 mmoles) of 7 – (5 – succinimidoadipamido – 3 – acetoxymethyl – 3 – cephem – 4 – carboxylic acid in 625 ml of water was treated with 37.5 g of sodium bicarbonate and 20 ml of ethvlacetate.
Then 25 g (189 mmoles) of 2 – methyl – 5 – mercapto – 1,3,4 – thiadiazole were added.
The mixture was warmed to 72 -75 C for a period of 30 minutes. After cooling the mixture the pH was adjusted to 2.5 by adding 115 ml of 6N HCI; thereafter 27 ml of quinoline were added.
The mixture’s temperature was maintained in the range of 250-300C for I hour while stlrrmg. The pH of the mixture was adjusted to 3.5 by adding 20 ml of 6N HCI.
The mixture was refrigerated overnight (+5 C) and the crystalline product was then filtered, washed with 120 ml cold water and 180 ml of ethylacetate, and then vacuum dried at 40 -45 C.
83.3 g (purity of 94 /n) of quinoline salt of 7 – (5 – succinimidoadipamido) – 3 (2 – methyl – 1,3,4 – thiadiazol – 5 yl)thiomethyl – 3 – cephem – 4 – carboxylic acid were obtained. Yield: 80.3.
The NMR and IR spectra were consistent with the desired structure. M.P.
980-l0l0C dec.
The i ltermediate product so obtained was treated as indicated in Example I in order to obtain cefazolin.
WHAT WE CLAIM IS:
1. A quinoline salt of 7 – (5 – acylamino – adipamido) – 3 – (2 – methyl 1,3,4 – thiadiazol – 5 – yl) – thiomethyl – 3 – cephem – 4 – carboxylic acid having the following structural formula
in which:
R1 is a linear or branched C1-C10 acyl group and
R2 is H or
R’ and R2 together with an attached N-atom form a 5 or 6 membered ring.

2. A quinoline salt of7 – (5 – propionylamino – adipamido) – 3 – (2 – methyl 1,3.4 – thiadiazol – 5 – yl) – thiomethyl – 3 – cephem – carboxylic acid having the following structural formula

3. A process for obtaining a salt of either of claims I or 2, comprising the steps of;
controlling the pH of an aqueous solution of Cephalosporin C in the range of 8.5-9.2,
adding an acylating agent to the said aqueous solution while maintaining the pH thereof in said range,
adding 2 – methyl – 5 – mercapto – 1,3,4 – thiadiazole to the said aqueous solution,
heating said solution to 70″–75″C for a predetermined time,
adding quinoline to the said heated aqueous solution while lowering the pH to a value in the range 3-3.5; thereby to obtain the quinoline salt of 7 – (5 acylamino – adipamido) 3 – (2 – methyl – 1,3,4 – thiadiazol – 5 – yl)thiomethyl 3 – cephem – 4 – carboxylic acid, as a crystalline product: and
filter separating, washing and drying said crystalline product.

4. A salt as claimed in Claim I and substantially as described in the examples.

5. A process as claimed in Claim 3 and substantially as described in the
Examples.

6. A salt according to claim 1 produced by a process as claimed in Claim 3 or
Claim 5.

GB4838376A
1977-08-12
1977-08-12
Intermediate product for the preparation of cefazolin antibiotic

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GB1565053A
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Intermediate product for the preparation of cefazolin antibiotic

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Intermediate product for the preparation of cefazolin antibiotic

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Intermediate product for the preparation of cefazolin antibiotic

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Cited By (2)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US5512454A
(en)

1994-02-03
1996-04-30
Bristol-Myers Squibb Company
Enzymatic acylation of 3-hydroxymethyl cephalosporins

US6642020B2
(en)

2001-04-19
2003-11-04
Bioferma Murcia S.A.
Process for preparing cephalosporin derivatives

1977

1977-08-12
GB
GB4838376A
patent/GB1565053A/en
not_active
Expired

Cited By (2)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

US5512454A
(en)

1994-02-03
1996-04-30
Bristol-Myers Squibb Company
Enzymatic acylation of 3-hydroxymethyl cephalosporins

US6642020B2
(en)

2001-04-19
2003-11-04
Bioferma Murcia S.A.
Process for preparing cephalosporin derivatives

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