US3036129A - Preparation of 7-halo-6-deoxy-tetracyclines - Google Patents

Preparation of 7-halo-6-deoxy-tetracyclines Download PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
deoxytetracycline
demethyl
hydroxy
milligrams
preparation
Prior art date
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.)
Expired - Lifetime
Application number
US845304A
Inventor
Hlavka Joseph John
Boothe James Howard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US845304A priority Critical patent/US3036129A/en
Priority to ES0255664A priority patent/ES255664A1/en
Priority to GB483760A priority patent/GB922598A/en
Priority to MC205A priority patent/MC198A1/en
Priority to DK70460AA priority patent/DK103350C/en
Priority to BE587982A priority patent/BE587982A/en
Priority to CH211960A priority patent/CH403745A/en
Priority to FR837211A priority patent/FR482M/fr
Application granted granted Critical
Publication of US3036129A publication Critical patent/US3036129A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

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.

Landscapes

  • 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.
US845304A 1958-04-25 1959-10-09 Preparation of 7-halo-6-deoxy-tetracyclines Expired - Lifetime US3036129A (en)

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.
DK70460AA DK103350C (en) 1959-02-26 1960-02-24 Process for the preparation of 7-, 11a- or 7,11a-halogenated tetracyclines.
BE587982A BE587982A (en) 1959-02-26 1960-02-24 Halogenated tetracyclines and process for their manufacture.
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

ID=25294917

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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

Similar Documents

Publication Publication Date Title
US3338963A (en) Tetracycline compounds
US3043875A (en) Halogenated tetracycline derivatives and processes for their preparation
Heidelberger et al. Tryptophan Metabolism: Concerning the mechanism of the mammalian conversion of tryptophan into nicotinic acid
US4235892A (en) 1-Aryl-2-acylamido-3-fluoro-1-propanols, methods for their use as antibacterial agents and compositions useful therefor
Hoover et al. Metabolite Analogs. VI. Preparation of Some Analogs of 4-Amino-5-imidazole-carboxamide1
CZ289195B6 (en) 6-Demethyl-6-deoxytetracyklines, processes and intermediates for their preparation as well as pharmaceutical preparations based thereon
US3036129A (en) Preparation of 7-halo-6-deoxy-tetracyclines
Rogalski Chemical modification of the tetracyclines
CA1247627A (en) Distamycin derivatives and process for their preparation
US3219671A (en) Substituted 6-deoxytetracyclines and 6-demethyl-6-deoxytetracyclines
US3948913A (en) New 5-nitrofuryl derivatives
Stein et al. The reaction of camphene with hydrogen cyanide
US2922817A (en) 12alpha-deoxyanhydrotetracyclines
Cailla et al. Succinyl derivatives of adenosine 3′, 5′-cyclic monophosphate: Synthesis and purification
US3301753A (en) Antibiotic
Abdel-Ghany et al. Synthesis, radioiodination and biological evaluation of novel dipeptide attached to triazole-pyridine moiety
Conrow et al. Some 2, 3-fused diaza-heterocycles of estra-1, 3, 5 (10)-trien-17-one
US5760229A (en) Crystal modification of 2,4-diamino-6-hydroxymethylpteridine hydrobromide
Green et al. Chemistry of the tetracycline antibiotics. II. Bromination of dedimethylaminotetracyclines
Gibson et al. A note on the urinary uroporphyrin in acute porphyria
Florey Cephradine
US3627756A (en) N-dialkylaminoalkyl-n-(2{62 ,19-epoxy-5{60 -androstan-17{62 -yl)amines/formamides and 3{60 -halo derivatives thereof
US3697509A (en) N-(3-oxopregna-4, 17(20)-dien-21-yl) quaternary salts and }9-nor derivatives corresponding
KOBAYASHI et al. Polyphosphoric Acid-catalyzed Beckmann Rearrangement of 3-Keto-steroid Oximes
US3857888A (en) Halo/nitro-substituted benzaldehyde bis(dialkylaminoalkyl) mercaptals and congeners