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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
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 |
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| 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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