US3036129A - Preparation of 7-halo-6-deoxy-tetracyclines - Google Patents
Preparation of 7-halo-6-deoxy-tetracyclines Download PDFInfo
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- US3036129A US3036129A US845304A US84530459A US3036129A US 3036129 A US3036129 A US 3036129A US 845304 A US845304 A US 845304A US 84530459 A US84530459 A US 84530459A US 3036129 A US3036129 A US 3036129A
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- deoxytetracycline
- demethyl
- hydroxy
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- 238000002360 preparation method Methods 0.000 title description 12
- 239000004098 Tetracycline Substances 0.000 title description 9
- 229940040944 tetracyclines Drugs 0.000 title description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 17
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 15
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 14
- 239000011707 mineral Substances 0.000 claims description 14
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 3
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- XDVCLKFLRAWGIT-ADOAZJKMSA-N sancycline Chemical compound C([C@H]1C2)C3=CC=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O XDVCLKFLRAWGIT-ADOAZJKMSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 229960002180 tetracycline Drugs 0.000 description 7
- 235000019364 tetracycline Nutrition 0.000 description 7
- 150000003522 tetracyclines Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229930101283 tetracycline Natural products 0.000 description 6
- MTCQOMXDZUULRV-ADOAZJKMSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O MTCQOMXDZUULRV-ADOAZJKMSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000194017 Streptococcus Species 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- -1 i.e. Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- CIJFGLCHAOVWRZ-QKYUADJBSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O CIJFGLCHAOVWRZ-QKYUADJBSA-N 0.000 description 1
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical compound [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000607132 Salmonella enterica subsp. enterica serovar Gallinarum Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- CPELXLSAUQHCOX-NJFSPNSNSA-N bromine-82 Chemical compound [82BrH] CPELXLSAUQHCOX-NJFSPNSNSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Definitions
- R is CH when R is OH.
- halodeoxytetracyclines of this invention may be prepared by dissolving asuitable 6-deoxytetracycline, i.e. 6-deoxytetracycline itself, 6-demethyl-fi-deoxytetracycline or 5-hydroxy-o-deoxytetracycline, in a suitable solvent,
- haloamide such as concentrated mineral acid, i.e., hydrochloric acid, sulfuric acid, etc.
- a halogenating agent such as an N-haloamide, i.e., N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, N-chlorosuccinimide, N- iodosuccinimide, etc.
- the reaction with the haloamide is preferably carried out at temperatures of from about 0 C. to about 20 C. until the reaction is complete.
- the bromination may be carried out with bromine in a strong mineral acid, i.e., HBr and in a suitable organic solvent such as a lower alkanoic acid, i.e.
- halodeoxytetracycline so-formed is isolated from the reaction mixture by any convenient method as, for example, by precipitation with ethyl ether or the like, and the product may be purified by recrystallization from an alcohol-acetone-ether solution in a standard manner.
- the halodeoxytetracyclines are biologically active and have the broad-spectrum antibacterial activity of the previously known tetracyclines.
- the antibacterial spectrum of certain of these compounds representing the amount required to inhibit the growth of various typical bacteria, was determined in a standard manner by the agar dilution streak technique which is commonly used in testing new antibiotics.
- the minimal inhibitory concentrations, expressed in gamrnas per milliliter, of 7- bromo-o-demethyl-6-deoxytetracycline, 7 bromo-6-deoxytetracycline and 7-iodo 6 deoxy-tetracycline against various test organisms are reported in the table below. For comparison purposes the antibacterial activity of tetracycline against the same organisms is also included.
- the 7-iododeoxytetracycline and 7- bromodeoxytetracycline appear to concentrate in rapidly proliferating tissue such as found in tumor growths.
- These compounds may be rendered radioactive by incorporation of iodine 131 or bromine 82 in the 7-position of the ring nucleus.
- These radio labeled compounds by virtue of their gamma rays and beta particle emissions allow the detection, localization and diagnosis of neoplastic tissue.
- the chemical methods for preparing these radio-labeled compounds are similar to those preparative methods already described for the preparation of non-radioactive compounds with the obvious exception that the radioisotope of the appropriate halogens are used.
- Example 1 PREPARATION OF 7-BROMO-G-DEOXYTETRACYCLINE
- 6-deoxytetracycline J.A.C.S. 80, 5324 (1958)
- 10 milliliters of concentrated sulfuric acid at 0 C. is added 76 milligrams of N-bromosuccinimide.
- the reaction mixture is kept at 0 C. for 30 minutes, and then added slowly drop-wise to 200 milliliters of cold ether. A solid precipitates which is filtered and dried.
- the product weighs 160 milligrams. This product is crystallized from ethanol-acetone-ether solution to give milligrams of purified product. This product is 1.21.5 times as active biologically as tetracycline.
- Example 2 PREPARATION OF 7-BROMO-6-DEMETHYL-6-DEOXY- TETRACYCLINE
- Example 3 PREPARATION OF 7-CHLORO-6-DEOXYTETRACYCLINE
- N-chlorosuccinirnide is used as the halogenating agent.
- the product is isolated as in Example 1 and 7-chloro-6- deoxyltetracycline is obtained.
- Example 4 PREPARATION OF 7-CHLORO-6-DEMETHYL-6-DEOXY- TETRACYCLINE
- N-chlorosuccinimide is used as the halogenating agent.
- the product is isolated as in Example 2 and 7-chloro-6- demethyl-6-deoxytetracycline is obtained.
- Example 5 PREPARATION OF 7-BROM0-6-DEOXYTETRACYCLINE 85.6 milligrams of 6-deoxytetracycline is dissolved in 3.9 milliliters of acetic acid and 1 milliliter of 30% HBracetic acid is added. With stirring, 0.22 milliliter of 1 molar bromine in acetic acid is added excess of 1 equivalent). After standing about 65 hours at room temperature, 10 milliliters of ether are added and a yellow crystalline solid slowly deposits. After 6 hours the solid is filtered off and dried; weight, 68.4 milligrams.
- Example 6 PREPARATION OF 7-BROMO-5-HYDROXY-6-DEOXY TETRACYCLINE
- Microbiological activity equals 45% of tetracycline (activity of starting S-hydroxy-6-deoxytetracycline equals 30% of tetracycline).
- Example 7 PREPARATION OF 7-IODO-6-DEOXYTETRACYCLINE SULFATE A solution of 200 milligrams (0.38 m mole) of 6-deoxytetracycline sulfate and 85.5 milligrams (0.35 m mole) of N-iodosuccinimide in 5.0 milliliters of concentrated sulfuric acid is stirred at 0 C. for forty minutes. The mixture is added dropwise to 250 milliliters of cold ether. The sOlid that separates Weighs 0.16 grams. A portion (50 milligrams) of this material is recrystallized from methyl cellosolve/chloroform; yield 22 milligrams.
- Example 8 PREPARATION OF 7-IODO-5-HYDROXY-6-DEOXYTETRA- CYCLINE SULFATE
- the procedure of the preceding example is following except that 5-hydroxy-6-deoxytetracycline is used. 7- iodo-5-hydroxy-6-deoxytetracycline is obtained.
- Example 9 7-10DO-6-DEMETHYL-6-DEOXY'IETRACYCLINE SULFATE To a solution of 0.2 gram (0.39 m mole) of 6-demethyl-6-deoxytetracycline sulfate in 5.0 milliliters of cold (0 C.) concentrated sulfuric acid is added 88 milligrams (0.39 m mole) of N-iodosuccinimide. The mixture is stored at 0 C.
- R is a member of the group consisting of bromine, chlorine and iodine and R is a member of the group consisting of hydrogen and methyl when R is hydrogen and R is methyl when R is hydroxy which comprises treating a compound of the group consisting of 6-deoxytetracycline, 6-demethyl-6-deoxytetracycline and 5-hydroxy-6-deoxytetracycline with an N-haloamide of the group consisting of N-bromosuccinimide, N-bromoacetamide, N-bromophthalirnide, N-chlorosuccinimide, and N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-bromo-6-deoxytetra cycline which comprises treating 6-deoxytetracyc1ine with N-bromosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-bromo-6-demethyl-6-deoxytetracycline which comprises treating 6-demethyl-6- deoxytetracycline with N-bromosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-chloro-6-deoxytetracycline which comprises treating 6-deoxytetracycline with N-chlorosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-chloro-6-demethyl-6-deoxytetracycline which comprises treating 6-demethyl-6- deoxytetracycline with N-chlorosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-bromo-5-hydr0xy-6-deoxytetracycline which comprises treating 5-hydroxy-6-deoxytetracycline with N-bromosuccinirnide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-iodo-6-deoxytetracycline which comprises treating 6- deoxytetracycline with N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- the method of preparing 7-iodo-5-hydroxy-6-deoxytetracycline which comprises treating 5-hydroxy-6-deoxytetracycline with N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
- R is a member of the group consisting of hydrogen and methyl when R is hydrogen and R is methyl when R is hydroxy which comprises reacting a compound of the group consisting of 6-deoxytetracyc1ine, 6- demethyl-6-deoxytetracycline and S-hydroxy 6 deoxytetracycline with bromine in a strong mineral acid, and in the presence of an organic solvent at a temperature of from about 10 C. to about 50 C.
- the method of preparing 7-bromo-6-doxytetracycline which comprises reacting 6-deoxytetracycline with bromine in a strong mineral acid and in the presence of an organic solvent at a temperature of from about 10 C. to about 50 C.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
United States Patent This invention relates to the preparation of 7-halo-6- deoxytetracyclines which may be represented by the following general formula 112. H R2 R3 (C s)2 -CONH2 (at E ii wherein R is Br, C1 or I and R is H or CH when R, is
H, and R is CH when R is OH.
The halodeoxytetracyclines of this invention may be prepared by dissolving asuitable 6-deoxytetracycline, i.e. 6-deoxytetracycline itself, 6-demethyl-fi-deoxytetracycline or 5-hydroxy-o-deoxytetracycline, in a suitable solvent,
such as concentrated mineral acid, i.e., hydrochloric acid, sulfuric acid, etc. and adding a halogenating agent such as an N-haloamide, i.e., N-bromosuccinimide, N-bromoacetamide, N-bromophthalimide, N-chlorosuccinimide, N- iodosuccinimide, etc. The reaction with the haloamide is preferably carried out at temperatures of from about 0 C. to about 20 C. until the reaction is complete. Alternatively, the bromination may be carried out with bromine in a strong mineral acid, i.e., HBr and in a suitable organic solvent such as a lower alkanoic acid, i.e. acetic acid, propionic acid, etc, at temperatures of from about 10 C. to about 50 C. The halodeoxytetracycline so-formed is isolated from the reaction mixture by any convenient method as, for example, by precipitation with ethyl ether or the like, and the product may be purified by recrystallization from an alcohol-acetone-ether solution in a standard manner.
The halodeoxytetracyclines are biologically active and have the broad-spectrum antibacterial activity of the previously known tetracyclines. The antibacterial spectrum of certain of these compounds, representing the amount required to inhibit the growth of various typical bacteria, was determined in a standard manner by the agar dilution streak technique which is commonly used in testing new antibiotics. The minimal inhibitory concentrations, expressed in gamrnas per milliliter, of 7- bromo-o-demethyl-6-deoxytetracycline, 7 bromo-6-deoxytetracycline and 7-iodo 6 deoxy-tetracycline against various test organisms are reported in the table below. For comparison purposes the antibacterial activity of tetracycline against the same organisms is also included.
TABLE 7-Bromo-6- 7-Bromo-6- 7-I0d0- Organism Tetra- Deoxytetradernethyl-6- 6-dcoxycycline cycline deoxytctratetracycline cycline Mycobacterium rauae 1 0. 5 0.25 4 lllycobacteriurn smeumatis ATOC 607 1 l 0. 25 8 Staphylococcus aureus 209P. 2 1 1 2 Sarciua luteo 1001 2 1 0.5 2 Bacillus subtilis AICO 6633- 0. 5 0. 25 0. 25 0. 5 Streptococcus pyogeues C203. 0. 5 0. 25 0. 5 2 Streptococcus 'y N o. 11..- 250 4 4 4 Staphylococcus albus N o. 69. 250 8 8 15 Streptococcus B N o. 250 4 2 4 Staphylococcus aureus NY 104 2 1 1 2 Bacillus cereus N o. 0. 25 0.25 0. 5 2 Pseudomouas acruginosa 15 250 31 250 Proteus vulaaris 8427 15 8 2 31 Escherichia coli ATCC 9637- 15 250 31 250 Salmonella gallinarum 8 250 31 250 Escherichia coli No. 22 4 15 8 62 The 7-iododeoxytetracycline and 7-bromodeoxytetracycline are particularly useful as diagnostic agents in the detection of cancer. The 7-iododeoxytetracycline and 7- bromodeoxytetracycline appear to concentrate in rapidly proliferating tissue such as found in tumor growths. These compounds may be rendered radioactive by incorporation of iodine 131 or bromine 82 in the 7-position of the ring nucleus. These radio labeled compounds by virtue of their gamma rays and beta particle emissions allow the detection, localization and diagnosis of neoplastic tissue. The chemical methods for preparing these radio-labeled compounds are similar to those preparative methods already described for the preparation of non-radioactive compounds with the obvious exception that the radioisotope of the appropriate halogens are used.
The invention will be described in greater detail in conjunction with the following specific examples.
Example 1 PREPARATION OF 7-BROMO-G-DEOXYTETRACYCLINE To a solution of 0.2 gram of 6-deoxytetracycline [J.A.C.S. 80, 5324 (1958)] in 10 milliliters of concentrated sulfuric acid at 0 C. is added 76 milligrams of N-bromosuccinimide. The reaction mixture is kept at 0 C. for 30 minutes, and then added slowly drop-wise to 200 milliliters of cold ether. A solid precipitates which is filtered and dried. The product. weighs 160 milligrams. This product is crystallized from ethanol-acetone-ether solution to give milligrams of purified product. This product is 1.21.5 times as active biologically as tetracycline.
Example 2 PREPARATION OF 7-BROMO-6-DEMETHYL-6-DEOXY- TETRACYCLINE A solution of 200 milligrams (0.045 m mole) of 6- demethyl-6-deoxytetracycline hydrochloride [J.A.C.S. 80, 5 324 (1958)] and 80 milligrams (0.45 m mole) of N- bromosuccinimide in 5.0 milliliters of concentrated sulfuric acid is stored at ice-bath temperature for 30 minutes. The reaction mixture is slowly added to 250 milliliters of cold ether and the solid that separates weighs 0.2 gram. A portion (25 milligrams) of this material is recrystallized from ethanol/ether yielding 19 milligrams of pure 7-brorno-6-demethyl-6-deoxytetracycline which is 2.2 to 2.5 times as active as tetracycline.
Example 3 PREPARATION OF 7-CHLORO-6-DEOXYTETRACYCLINE The procedure of Example 1 is followed except that N-chlorosuccinirnide is used as the halogenating agent. The product is isolated as in Example 1 and 7-chloro-6- deoxyltetracycline is obtained.
Example 4 PREPARATION OF 7-CHLORO-6-DEMETHYL-6-DEOXY- TETRACYCLINE The procedure of Example 2 is followed except that N-chlorosuccinimide is used as the halogenating agent. The product is isolated as in Example 2 and 7-chloro-6- demethyl-6-deoxytetracycline is obtained.
Example 5 PREPARATION OF 7-BROM0-6-DEOXYTETRACYCLINE 85.6 milligrams of 6-deoxytetracycline is dissolved in 3.9 milliliters of acetic acid and 1 milliliter of 30% HBracetic acid is added. With stirring, 0.22 milliliter of 1 molar bromine in acetic acid is added excess of 1 equivalent). After standing about 65 hours at room temperature, 10 milliliters of ether are added and a yellow crystalline solid slowly deposits. After 6 hours the solid is filtered off and dried; weight, 68.4 milligrams.
Example 6 PREPARATION OF 7-BROMO-5-HYDROXY-6-DEOXY TETRACYCLINE A solution of 200 milligrams (0.42 m mole) of S-hydroxy-6-deoxytetracycline hydrochloride [J.A.C.S. 80, 5324 (1958)] and 75 milligrams (0.42 m mole) of N- bromosuccinimide in 5.0 milliliters of concentrated sulfuric acid is stirred at ice-bath temperature for 10 minutes. The reaction solution is slowly poured into 250 milliliters of cold ether. The solid is filtered and dried; yield 1.8 grams. This material is converted to the free base by dissolving in water, adjusting the pH of the solution to 6.5 with 1 N sodium carbonate and extraction with n-butanol; yield 75 milligrams.
Microbiological activity equals 45% of tetracycline (activity of starting S-hydroxy-6-deoxytetracycline equals 30% of tetracycline).
Example 7 PREPARATION OF 7-IODO-6-DEOXYTETRACYCLINE SULFATE A solution of 200 milligrams (0.38 m mole) of 6-deoxytetracycline sulfate and 85.5 milligrams (0.35 m mole) of N-iodosuccinimide in 5.0 milliliters of concentrated sulfuric acid is stirred at 0 C. for forty minutes. The mixture is added dropwise to 250 milliliters of cold ether. The sOlid that separates Weighs 0.16 grams. A portion (50 milligrams) of this material is recrystallized from methyl cellosolve/chloroform; yield 22 milligrams.
Example 8 PREPARATION OF 7-IODO-5-HYDROXY-6-DEOXYTETRA- CYCLINE SULFATE The procedure of the preceding example is following except that 5-hydroxy-6-deoxytetracycline is used. 7- iodo-5-hydroxy-6-deoxytetracycline is obtained.
Example 9 7-10DO-6-DEMETHYL-6-DEOXY'IETRACYCLINE SULFATE To a solution of 0.2 gram (0.39 m mole) of 6-demethyl-6-deoxytetracycline sulfate in 5.0 milliliters of cold (0 C.) concentrated sulfuric acid is added 88 milligrams (0.39 m mole) of N-iodosuccinimide. The mixture is stored at 0 C. for forty minutes and slowly poured 7 -halo-6-deoxytetra- 'M H a a s)2 CONH2 l H OH O OH O wherein R is a member of the group consisting of bromine, chlorine and iodine and R is a member of the group consisting of hydrogen and methyl when R is hydrogen and R is methyl when R is hydroxy which comprises treating a compound of the group consisting of 6-deoxytetracycline, 6-demethyl-6-deoxytetracycline and 5-hydroxy-6-deoxytetracycline with an N-haloamide of the group consisting of N-bromosuccinimide, N-bromoacetamide, N-bromophthalirnide, N-chlorosuccinimide, and N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
2. The method of preparing 7-bromo-6-deoxytetra cycline which comprises treating 6-deoxytetracyc1ine with N-bromosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
3. The method of preparing 7-bromo-6-demethyl-6-deoxytetracycline which comprises treating 6-demethyl-6- deoxytetracycline with N-bromosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
4, The method of preparing 7-chloro-6-deoxytetracycline which comprises treating 6-deoxytetracycline with N-chlorosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
5. The method of preparing 7-chloro-6-demethyl-6-deoxytetracycline which comprises treating 6-demethyl-6- deoxytetracycline with N-chlorosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
6. The method of preparing 7-bromo-5-hydr0xy-6-deoxytetracycline which comprises treating 5-hydroxy-6-deoxytetracycline with N-bromosuccinirnide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
7. The method of preparing 7-iodo-6-deoxytetracycline which comprises treating 6- deoxytetracycline with N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
8. The method of preparing 7-iodo-6-demethyl-6-deoxytetracycline which comprises treating 6-demethy1-6- deoxytetracycline with N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
9. The method of preparing 7-iodo-5-hydroxy-6-deoxytetracycline which comprises treating 5-hydroxy-6-deoxytetracycline with N-iodosuccinimide in the presence of a concentrated mineral acid at a temperature of from about 0 C. to about 20 C.
wherein R is a member of the group consisting of hydrogen and methyl when R is hydrogen and R is methyl when R is hydroxy which comprises reacting a compound of the group consisting of 6-deoxytetracyc1ine, 6- demethyl-6-deoxytetracycline and S-hydroxy 6 deoxytetracycline with bromine in a strong mineral acid, and in the presence of an organic solvent at a temperature of from about 10 C. to about 50 C.
11. The method of preparing 7-bromo-6-doxytetracycline which comprises reacting 6-deoxytetracycline with bromine in a strong mineral acid and in the presence of an organic solvent at a temperature of from about 10 C. to about 50 C.
References Cited in the file of this patent UNITED STATES PATENTS Ritter Feb. 28, 1956 OTHER REFERENCES Geschickter: J. Am. Med. Assoc., Feb. '1, 1930, pages 326328.
Fieser et 211.: Natural Products Related to Phenanthrene, pages 388-389, 458; 533-536. Reinhold Pub. Co., New York (1949).
Abbott Laboratories, Diagnostic Procedures With Radioisotopes, pages 23, 28 (January 1955).
Migrdichian: Organic Synthesis, vol. II, page 924, Reinhold Pub. Co., New York (1957).
Rall et al.: Journ. US. National Institute of Cancer,
20 pages 79-83 (July 1957).
Stephens et al.: I. Am. Chem. Soc., vol. 80, pages 5324-5 (October 1958).
Claims (1)
1. THE METHOD OF PREPARING 7-HALO-6-DEOXYTETRACYCLINES OF THE FORMULA: WHEREIN R1 IS A MEMBER OF THE GROUP CONSISTING OF BROMINE, CHLORINE AND IODINE AND R2 IS A MEMBER OF THE GROUP CONSISTING OF HYDROGEN AND METHYL WHEN R3 IS HYDROGEN AND R2 IS METHYL WHEN R3 IS HYDROXY WHICH COMPRISES TREATING A COMPOUND OF THE GROUP CONSISTING OF 6-DEOXYTETRACYCLINE, 6-DEMETHYL-6-DEOXYTETRACYCLINE AND 5-HYDROXY-6-DEOXYTETRACYCLINE WITH AN N-HALOAMIDE OF THE GROUP CONSISTING OF N-BROMOSUCCINIMIDE, N-BROMOACETAMIDE, N-BROMOPHTHALIMIDE, N-CHLOROSUCCINIMIDE, AND N-IODOSUCCINIMIDE IN THE PRESENCE OF A CONCENTRATED MINERAL ACID AT A TEMPERATURE OF FROM ABOUT 0*C. TO ABOUT 20*C.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US845304A US3036129A (en) | 1959-10-09 | 1959-10-09 | Preparation of 7-halo-6-deoxy-tetracyclines |
| ES0255664A ES255664A1 (en) | 1959-02-26 | 1960-02-10 | A procedure to produce halogenated tetracyclines (Machine-translation by Google Translate, not legally binding) |
| GB483760A GB922598A (en) | 1958-04-25 | 1960-02-11 | Halo-6-deoxytetracyclines |
| MC205A MC198A1 (en) | 1959-02-26 | 1960-02-19 | Process for manufacturing halogenated tetracycline. |
| BE587982A BE587982A (en) | 1959-02-26 | 1960-02-24 | Halogenated tetracyclines and process for their manufacture. |
| DK70460AA DK103350C (en) | 1959-02-26 | 1960-02-24 | Process for the preparation of 7-, 11a- or 7,11a-halogenated tetracyclines. |
| CH211960A CH403745A (en) | 1958-04-25 | 1960-02-25 | Process for manufacturing halogenated tetracyclines |
| FR837211A FR482M (en) | 1959-02-26 | 1960-08-30 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US845304A US3036129A (en) | 1959-10-09 | 1959-10-09 | Preparation of 7-halo-6-deoxy-tetracyclines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3036129A true US3036129A (en) | 1962-05-22 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US845304A Expired - Lifetime US3036129A (en) | 1958-04-25 | 1959-10-09 | Preparation of 7-halo-6-deoxy-tetracyclines |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3036129A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3200149A (en) * | 1960-05-23 | 1965-08-10 | Pfizer & Co C | alpha-6-deoxytetracycline derivatives and process |
| US3226435A (en) * | 1962-12-26 | 1965-12-28 | American Cyanamid Co | Novel 7,11a-dihalotetracyclines and the process of preparing them |
| US3326761A (en) * | 1964-11-16 | 1967-06-20 | Pfizer & Co C | 6-demethyl-6-deoxytetracycline, anti-tumor antibiotic |
| US3914299A (en) * | 1969-06-12 | 1975-10-21 | Research Corp | Tetracyclines |
| EP0582791A1 (en) * | 1992-08-13 | 1994-02-16 | American Cyanamid Company | Method for the production of 9-amino-6-demethyl-6-deoxytetracycline |
| US20110207951A1 (en) * | 2000-05-15 | 2011-08-25 | Paratek Pharmaceuticals, Inc. | 7-Iodo Tetracyclines and Related Methods |
| JP2012031185A (en) * | 1999-09-14 | 2012-02-16 | Trustees Of Tufts College | Method of preparing substituted tetracycline with transition metal-based chemistries |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2736725A (en) * | 1954-03-11 | 1956-02-28 | American Cyanamid Co | Complexes of tetracycline antibiotics and preparation of same |
-
1959
- 1959-10-09 US US845304A patent/US3036129A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2736725A (en) * | 1954-03-11 | 1956-02-28 | American Cyanamid Co | Complexes of tetracycline antibiotics and preparation of same |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3200149A (en) * | 1960-05-23 | 1965-08-10 | Pfizer & Co C | alpha-6-deoxytetracycline derivatives and process |
| US3226435A (en) * | 1962-12-26 | 1965-12-28 | American Cyanamid Co | Novel 7,11a-dihalotetracyclines and the process of preparing them |
| US3326761A (en) * | 1964-11-16 | 1967-06-20 | Pfizer & Co C | 6-demethyl-6-deoxytetracycline, anti-tumor antibiotic |
| US3914299A (en) * | 1969-06-12 | 1975-10-21 | Research Corp | Tetracyclines |
| EP0582791A1 (en) * | 1992-08-13 | 1994-02-16 | American Cyanamid Company | Method for the production of 9-amino-6-demethyl-6-deoxytetracycline |
| JP2012031185A (en) * | 1999-09-14 | 2012-02-16 | Trustees Of Tufts College | Method of preparing substituted tetracycline with transition metal-based chemistries |
| US20110207951A1 (en) * | 2000-05-15 | 2011-08-25 | Paratek Pharmaceuticals, Inc. | 7-Iodo Tetracyclines and Related Methods |
| US8288570B2 (en) * | 2000-05-15 | 2012-10-16 | Paratek Pharmaceuticals, Inc. | 7-iodo tetracyclines and related methods |
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