US3288781A - Process for deacylating anhydro-lyxofuranosyl with nitrogen base - Google Patents

Process for deacylating anhydro-lyxofuranosyl with nitrogen base Download PDF

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US3288781A
US3288781A US419552A US41955264A US3288781A US 3288781 A US3288781 A US 3288781A US 419552 A US419552 A US 419552A US 41955264 A US41955264 A US 41955264A US 3288781 A US3288781 A US 3288781A
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anhydro
lyxofuranosyl
benzoyl
nitrogen base
uracil
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US419552A
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James H Hunter
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Pharmacia and Upjohn Co
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Upjohn Co
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Priority to IL24689A priority patent/IL24689A/en
Priority to NL6516393A priority patent/NL6516393A/xx
Priority to CH1738565A priority patent/CH460788A/en
Priority to DE19651620617 priority patent/DE1620617A1/en
Priority to FR42783A priority patent/FR1460359A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

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  • the invention provides a process for selectively removing a 5-benzoyl group from a 1-(2,3- anhydro-5'-O-benzoyl-lyxofuranosyl) 2 ketopyrimidine nucleoside by reaction with a nitrogen base without cleaving the 2',3 '-anhydro group.
  • a 1-(2',3'-anhydro-5-O- benzoyl-B-D-lyxofuranosyl)-2-ketopyrimidine nucleoside is converted to the corresponding 1-(2',3'-anhydro-,B-D- lyxofuranosyl)-2-ketopyrimidine nucleoside by reaction with ammonia at about 0 C.
  • Equation 1 A representative embodiment of the process of this invention is as shown in the following Equation 1:
  • the pyrimidine base, uracil, depicted above can be replaced by any pyrimidine base having a keto group in the 2-position, e.g., other 2-ketopyrimid ine bases such as cytosine, azauracil, thymine, S-fluorouracil, other substituted uracil-s, and the like.
  • Y Letting the symbol Y signify this variable, the general representation of the process of the invention is as shown in the following Equation 2:
  • the process of the invention contemplates aminolysis (including ammonolysis) of, for example, l-(2',3-anhydro-5'-O-benzoyl fi-D lyxofuranosyl)uracil, 1-(2',3'-anhydro-5'-O-benzoyl-fi-D-lyxofuranosyl)thy: mine, 1-(2',3'-anhydro-5-O-benzoyl-B-D-lyxofuranosyl)- S-fluorouracil, 1-(2',3'-anhydro-5'-O-benzoyl-B-D-lyxofuranosyl)cytosine, and the like.
  • the process is novel because it was not heretofore known in the art. It is useful because it provides 1-(2',3'-anhydro-lyxofuranosyl)-2-ketopyrimidine nucleosides that can be converted into therapeutic agents.
  • the process of the invention is unobvious, because it was not known that aminolysis of a 1-(2,3-anhydro 5'-O benzoyl-lyxofuranosyl) -2-ketopyrimidine nucleoside could be carried out under temperature conditions which would yield the corresponding 1- 2,3 -anhydro-lyxofuranosyl) -2-ketopyrimidine nucleoside.
  • the art well knows the removal of acyl groups from nucleosides with alcoholic ammonia and amines; and the art well knows the reaction of 2',3-anhydronucleosides with alcoholic ammonia and amines to form amino deoxy-nuwithout cleaving the 2',3-anhydro (i.e., 2',3-epoxide) linkage and forming an amino deoxy-lyxofur-anoside.
  • the novel process of this invention is effected by reacting a 1-(2,3-anhydro-5-O-benzoyl-1yxofuranosyl)-2- ketop-yrimidine nucleoside with .a nitrogen base at a temperature in the range of about -20 C. to about 25 C.
  • a convenient and preferred temperature for the reaction is about 0 C.
  • Nitrogen bases suitable for the reaction include primary and secondary amines, ammonia, and hydrazine, said nitrogen bases being characterized ⁇ by having dissociation constants in water (K in the range about 1.0 10 to about 1.0 10- Nitrogen bases having dissociation constants in water (K in the range about 1.0x 11) to about 1.0 l0- are preferred.
  • suitable primary and secondary amine are methylamine, dimethylamine, ethylamine, di-
  • pentylamin'e isopentylamine, benzylamine, cyclohexylamine, ethylenediamine, p-phenylenediamine, piperazine, piperidine', and the like.
  • the 1-(2',3+anhydro-5'-'O- benzoyl-lyxo-furanosyl)-2-ketopyrimidine and a nitrogen base are reacted in the presence of an inert solvent, illustratively an alkanol, e.'g., methanol, ethanol, propyl alcohol, and the like.
  • the debenzoylated 1-(2 ,3'-anhydro-lyxofuranosyl)-2-ketopyrimidine is re covered from the reaction mixture by removing the solvent (e.g., evaporation) and purifying the product by conventional methods such as solvent extraction, solvent evaporation, and crystallization.
  • solvent e.g., evaporation
  • the 1-'(2',3'-anhydro-5'-O benzoyl-B-D-1yxofuranosyl) uracil of Formula In is a known compound. It can be prepared according to the method described by Codington et al., J. Org. Chem. 27, 163 (1962). According to a preferred method, 2',3',5'-trimesyloxyuridine [1-(2', 3',S'tri-O-mesyl-B-D-ribofuranosyl)uracil] is heated, for a short time at to C., with sodium benzoate according to the method described by Codington et al., J.A.C.S.
  • EXAMPLE 1 Ammonolysis of 1 (2',3-5'-O-benzoyl-B-D-lyxofumnosyl) uracil to produce 1-(2',3-anhydro-fi-D-lyxofuranosyl)uracil Two mixtures, one consisting of 41.3 g. (0.125 mole) of 1-v2',3'-anhydro-SObenzoyl-B-D-lyxofuranosyl)uracil and 1.9 l. of methanol (previously saturated with anhydrous ammonia at C.) in a stoppered 3-1. pressure flask, the other consisting of 14.8 g.
  • the evacuated syrup was then thoroughly dispersed in a mixture of 150 ml. of chloroform and 75 ml. of water.
  • the chloroform was permitted to separate and was removed.
  • the aqueous layer was extracted times with fresh 100-ml. portions of chloroform.
  • the aqueous layer thus obtained was a yellowish partially emulsified mixture. It was treated was activated charcoal and the mixture was filtered through a diatornaceous earth filter aid (Celite modified by two washings with 6 N hydrochloric acid, separate washings with water, warm:methanol, and ether, and drying).
  • the filter cake was washed with water and the washings were combined with the original filtrate and refrigerated at 0 C. overnight.
  • GEL-1 Green oil mull

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Description

United States Patent 3,238,781 PROCESS FOR DEACYLATING ANHYDRO-LYXO- FURANOSYL WITH NITROGEN BASE J ames H. Hunter, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed Dec. 18, 1964, Ser. No. 419,552 Claims. (Cl. 260-2115) This invention pertains to a novel, useful, and unobvious chemical process. More particularly, the invention is directed to a new process for preparing 1-(2,3 anhydro-lyxofuranosyl) 2 ketopyrimidine nucleosides. Further descriptively, the invention provides a process for selectively removing a 5-benzoyl group from a 1-(2,3- anhydro-5'-O-benzoyl-lyxofuranosyl) 2 ketopyrimidine nucleoside by reaction with a nitrogen base without cleaving the 2',3 '-anhydro group. In a preferred embodiment of the process of the invention, a 1-(2',3'-anhydro-5-O- benzoyl-B-D-lyxofuranosyl)-2-ketopyrimidine nucleoside is converted to the corresponding 1-(2',3'-anhydro-,B-D- lyxofuranosyl)-2-ketopyrimidine nucleoside by reaction with ammonia at about 0 C.
A representative embodiment of the process of this invention is as shown in the following Equation 1:
In a more general representation of the process of this invention the pyrimidine base, uracil, depicted above, can be replaced by any pyrimidine base having a keto group in the 2-position, e.g., other 2-ketopyrimid ine bases such as cytosine, azauracil, thymine, S-fluorouracil, other substituted uracil-s, and the like. Letting the symbol Y signify this variable, the general representation of the process of the invention is as shown in the following Equation 2:
{ -ti-oon2 Y HooI-n l O l O 16$ I as 1 Ha T IIb wherein Y is a pyrimidine base having a keto group in the 2-position.
Although the representative embodiment shown in equation 1 and the general representation shown in equation 2 utilize S-D-lyxofuranosides, the process of the invention operates in the same way for u oriented lyxofuranosides as well as the L forms of these monosaccharide derivatives. The operability of the process of this invention on lyxopyranoside 2-ketopyrimidine nucleosides has not yet been determined.
In accordance with the general representation shown in equation 2, the process of the invention contemplates aminolysis (including ammonolysis) of, for example, l-(2',3-anhydro-5'-O-benzoyl fi-D lyxofuranosyl)uracil, 1-(2',3'-anhydro-5'-O-benzoyl-fi-D-lyxofuranosyl)thy: mine, 1-(2',3'-anhydro-5-O-benzoyl-B-D-lyxofuranosyl)- S-fluorouracil, 1-(2',3'-anhydro-5'-O-benzoyl-B-D-lyxofuranosyl)cytosine, and the like.
nitrogen base Y solvent Nothwithstanding the general applicability of the process of this invention, the following description is par-ticularly directed to the preparation of 1-(2,3-anhydro-,8 D-lyxofuranosyl)uracil (Formula Ib) which is a key intermediate in a process for preparing the naturally occurring nucleoside 1-B-D-arabinofuranosyluracil (spongouridine), which in turn can be transformed by the process described in US. Patent No. 3,116,282 into the unique antiviral nucleoside 1-,8-D-arabinofuranosylcytosine.
Those skilled in the art will readily recognize the novelty, usefulness and unobviousness of the new process. The process is novel because it was not heretofore known in the art. It is useful because it provides 1-(2',3'-anhydro-lyxofuranosyl)-2-ketopyrimidine nucleosides that can be converted into therapeutic agents. The process of the invention is unobvious, because it was not known that aminolysis of a 1-(2,3-anhydro 5'-O benzoyl-lyxofuranosyl) -2-ketopyrimidine nucleoside could be carried out under temperature conditions which would yield the corresponding 1- 2,3 -anhydro-lyxofuranosyl) -2-ketopyrimidine nucleoside.
More particularly with respect to unobviousness, the art well knows the removal of acyl groups from nucleosides with alcoholic ammonia and amines; and the art well knows the reaction of 2',3-anhydronucleosides with alcoholic ammonia and amines to form amino deoxy-nuwithout cleaving the 2',3-anhydro (i.e., 2',3-epoxide) linkage and forming an amino deoxy-lyxofur-anoside.
The novel process of this invention is effected by reacting a 1-(2,3-anhydro-5-O-benzoyl-1yxofuranosyl)-2- ketop-yrimidine nucleoside with .a nitrogen base at a temperature in the range of about -20 C. to about 25 C. A convenient and preferred temperature for the reaction is about 0 C. Nitrogen bases suitable for the reaction include primary and secondary amines, ammonia, and hydrazine, said nitrogen bases being characterized \by having dissociation constants in water (K in the range about 1.0 10 to about 1.0 10- Nitrogen bases having dissociation constants in water (K in the range about 1.0x 11) to about 1.0 l0- are preferred. Examples of suitable primary and secondary amine are methylamine, dimethylamine, ethylamine, di-
ethylamine, isopropylamine, butylamine, sec-butylamine,
pentylamin'e, isopentylamine, benzylamine, cyclohexylamine, ethylenediamine, p-phenylenediamine, piperazine, piperidine', and the like. The 1-(2',3+anhydro-5'-'O- benzoyl-lyxo-furanosyl)-2-ketopyrimidine and a nitrogen base are reacted in the presence of an inert solvent, illustratively an alkanol, e.'g., methanol, ethanol, propyl alcohol, and the like. The debenzoylated 1-(2 ,3'-anhydro-lyxofuranosyl)-2-ketopyrimidine is re covered from the reaction mixture by removing the solvent (e.g., evaporation) and purifying the product by conventional methods such as solvent extraction, solvent evaporation, and crystallization.
The 1-'(2',3'-anhydro-5'-O benzoyl-B-D-1yxofuranosyl) uracil of Formula In is a known compound. It can be prepared according to the method described by Codington et al., J. Org. Chem. 27, 163 (1962). According to a preferred method, 2',3',5'-trimesyloxyuridine [1-(2', 3',S'tri-O-mesyl-B-D-ribofuranosyl)uracil] is heated, for a short time at to C., with sodium benzoate according to the method described by Codington et al., J.A.C.S. 82, 2794 01960) to obtain 2,2-ar1hydro1-(5'-O- bezoyl 3'-O 'rnesyl fl D arabinofuranosyDuracil which is then hydrolyzed with acid to 1 (5' O benzoyl-3 O mesyl B Daarabinofuranosyl)uracil. Reaction of the latter with ammonium hydroxide displaces the 3'-mesyl group and storms the 2',3'-epoxide to give 1 (2',3'-anhydro-5'-O-benzoyl-,8-D-lyxoturanosyl)uracil. Other 1- (2',3'-anhydro-5'-O-benzoyl-lyxofuranosyl) 2 lcetopyrimidine nucleosides can be prepared in the manner described, and the 5-O-benz.oyl group removed in accordance with the new process of this invention.
The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.
EXAMPLE 1 Ammonolysis of 1 (2',3-5'-O-benzoyl-B-D-lyxofumnosyl) uracil to produce 1-(2',3-anhydro-fi-D-lyxofuranosyl)uracil Two mixtures, one consisting of 41.3 g. (0.125 mole) of 1-v2',3'-anhydro-SObenzoyl-B-D-lyxofuranosyl)uracil and 1.9 l. of methanol (previously saturated with anhydrous ammonia at C.) in a stoppered 3-1. pressure flask, the other consisting of 14.8 g. (0.0448 mole) of the same nucleoside and 650 ml. of the chilled, ammoniasaturated methanol in a stoppered 2-]. pressure flask, were cooled to 0 C. The mixtures Wire swirled intermittently during the first hour. After permitting the reaction to proceed at 0 C. for 95 hrs., each reaction mixture was filtered through a plug of cotton. The filtrates were combined and concentrated by evaporating the volatile components at 45 C. under reduced pressure. The syrup thus obtained was evacuated at 1-3 mm. of mercury pressure and a bath temperature of about 40 C. for a short time; and evacuated at 10-20 mm. of mercury pressure and about 25 C. for about 40 hrs. The evacuated syrup was then thoroughly dispersed in a mixture of 150 ml. of chloroform and 75 ml. of water. The chloroform was permitted to separate and was removed. The aqueous layer was extracted times with fresh 100-ml. portions of chloroform. The aqueous layer thus obtained was a yellowish partially emulsified mixture. It was treated was activated charcoal and the mixture was filtered through a diatornaceous earth filter aid (Celite modified by two washings with 6 N hydrochloric acid, separate washings with water, warm:methanol, and ether, and drying). The filter cake was washed with water and the washings were combined with the original filtrate and refrigerated at 0 C. overnight. The next day, a small amount of chloroform which had separated was removed with a micropip-ette and the practically colorless aqueous solution was evaporated under reduced pressure at a temperature of about 45 C. The amorphous residue thus obtained weighted about 40 g. 'It was suspended in hot 95% ethanol. Crystallization initiated rapidly, :and after most of the ethanol was removed by evaporation under reduced pressure, there was obtained a cake of white crystalline crude 1-'(2,3'-an hyd-rofl-D-lyxofuranosyl)uracil. The cake was crushed and held at 1020 mm. of mercury pressure for a short time, and then evacuated for 1.5 hrs. under 1-3 of mercury pressure at a temperature of about 45 C. The white, crystalline mass was crushed and suspended in 100 ml. of hot absolute ethanol. The slurry was regricferated at C. or several hours and then further chilled in a bath of solid carbon dioxide and ethanol. The crystalline 1 (2',3' anhy=dro-18 D- lyxofuranosyDuracil was collected on a filter, washed repeatedly with absolute ethanol which has been chilled in a bath of solid carbon dioxide and ethanol, and dried in air. There was thus obtained 33.13 g. (86.3%
4 yield) of 1-(2',3-anhydro-B-D-lyxofuranosyl)uracil having a melting point of 143 to 145 C.; [a] +32.2 (c., 0.93 in water).
AnaIysis.Calcd for C H N 'O N, 12.39. Found: N, 12.13.
Ultraviolet absorption:
tra 228-229 my. (62,153); with? 258 my (6 9,980)
Characteristic infrared absorption frequencies (GEL-1) (mineral oil mull):
OH/NH3425, 3 180 Unsat. C-H3 17.0, 3 105 R 0.375 (nbutanol:water, 84:16, descending) EXAMPLE 2 Following the procedure of Example 1, but substituting methylamine, dimethyl-amine, ethylamine, diethylamine, hydrazine, ethylenediamine, piperazine, benzy-lamine, and pentyl amine, respectively, for ammonia, there was prepared, in each instance, l-(2',3'-anhydro-[3-D-lyxofuranosyl)uracil.
EXAMPLE 3 Following the procedure of lilxantplev 1, but substituting 1 (2,3-anhydro-5 O benzoyl-fi-O-lyxofuranosyl) thymine, l- (2',3'-anhydro 5' O benzoyl fl D lyxofuranosyl) 5 fiuorouracil, 1(2',3'-anhydro 5'- 0 benzoyl a L lyxofiuransoyburacil, and 1 (2',3' anhydro 5 O benzoyl-{i-D-lyxofuranosyl)cytosine for 1 (2',3'-an=hydro 5' O 'benzoyl B D lyxocturanosyDuracil, there were prepared l-'(2.',3'-anhydro- 3 D lyxofuranosyDthymine, 1-'(2' ,3'-.anhy dro f3 D- lyxofuranosyl) 5 fiuorouracil, 1 (2',3'-an-hydro-a-L- lyxofuranosyl)uracil, and 1 (2',3 anhydro-fi-D-lyxofuranosyl)cystosine, respectively.
I claim:
1. The process which comprises reacting 1-(2',3-'anhydro-5'-O=benzoyl-lyxofuranosyl) 2 ketopyrimidine nucleoside with nitrogen base characterized by a dissociation constant in water, K in the range about 1.0 10 to about 1.0 l0* in the presence of an inert solvent at :a temperature in the range about 20 C. to about 25 C., and recovering 1-(2',3'-anhydro-lyxofuranosyl)-2- ketopyrimidine nucleoside.
2. Process according to claim 1 wherein the nitrogen base has a dissociation constant in water in the range about 10x10 to about 1.0X10- 3. The process which comprises reacting 1-(2,3-anhydro 5'O-benzoyl-fl-Dlyxofuranosyl)2-ketopyrimidine nucleoside with nitrogen base characterized by a dis sociation constant in water, K in the range about 1.0 l0 to about 1.0 10- in the presence of alkanol No references cited.
LEWIS GOTTS, Primary Examiner.
JOHNNIE. R. BROWN, Assistant Examiner.

Claims (1)

1. THW PROCESS WHICH COMPRISES REACTING 1-(2'',3''-ANHYDRO-5''-O-BENZOLYL-LYXOFURANOXYL) -2- KETOPYRIMIDINE NUCLEOSIDE WITH NITROGEN BASE CHARACTERIZED BY A DISSOCIATION CONSTANT IN WATER, KB, IN THE RANGE ABOUT 1.0X10-3 TO ABOUT 1.0X10-9, IN THE PRESENCE OF AN INERT SOLVENT AT A TEMPERATURE IN THE RANGE ABOUT -20*C. TO ABOUT 25*C., AND RECOVERING 1-(2'',3''-ANHYDRO-LYXOFURANOSYL) -2KETOPYRIMIDINE NUCLEOUSIDE.
US419552A 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base Expired - Lifetime US3288781A (en)

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Application Number Priority Date Filing Date Title
US419552A US3288781A (en) 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base
GB49968/65A GB1114870A (en) 1964-12-18 1965-11-24 Process for the preparation of pyrimidine nucleosides
IL24689A IL24689A (en) 1964-12-18 1965-11-26 Process for preparing 1-(2',3'-anhydrolyxofuranosyl)-2-ketopyrimidine nucleosides
NL6516393A NL6516393A (en) 1964-12-18 1965-12-16
CH1738565A CH460788A (en) 1964-12-18 1965-12-16 Process for the preparation of 1- (2 ', 3'-anhydro-lyxofuran-osyl) -2-ketopyrimidine nucleosides
DE19651620617 DE1620617A1 (en) 1964-12-18 1965-12-16 Process for the preparation of 1- (2 ', 3'-anhydrolyxofuranoxyl) -2-ketopyrimidine nucleosides
FR42783A FR1460359A (en) 1964-12-18 1965-12-17 Manufacturing process of 1- (2 ', 3'-anhydro-lyxofuranosyl) -2-ketopyrimidine nucleosides

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US419552A US3288781A (en) 1964-12-18 1964-12-18 Process for deacylating anhydro-lyxofuranosyl with nitrogen base

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CH (1) CH460788A (en)
DE (1) DE1620617A1 (en)
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GB (1) GB1114870A (en)
IL (1) IL24689A (en)
NL (1) NL6516393A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4941921A (en) * 1988-01-11 1990-07-17 Cerestar Holding Dv Method of adding boric acid of a borate to a mixing CER-1 or reaction zone
US20050080065A1 (en) * 2002-02-04 2005-04-14 Coote Steven John Process for the production of 6.alpha.,9.alpha-difluoro-17.alpha.-(1-oxo-propoxy-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4-diene-17.beta.-carbothioic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4941921A (en) * 1988-01-11 1990-07-17 Cerestar Holding Dv Method of adding boric acid of a borate to a mixing CER-1 or reaction zone
US20050080065A1 (en) * 2002-02-04 2005-04-14 Coote Steven John Process for the production of 6.alpha.,9.alpha-difluoro-17.alpha.-(1-oxo-propoxy-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-androst-1,4-diene-17.beta.-carbothioic acid

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DE1620617A1 (en) 1970-05-14
CH460788A (en) 1968-08-15
IL24689A (en) 1969-05-28
NL6516393A (en) 1966-06-20
FR1460359A (en) 1966-11-25
GB1114870A (en) 1968-05-22

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