GB2046248A - Preparation of ???-6-deoxy-5- hydroxytetracycline - Google Patents
Preparation of ???-6-deoxy-5- hydroxytetracycline Download PDFInfo
- Publication number
- GB2046248A GB2046248A GB8005761A GB8005761A GB2046248A GB 2046248 A GB2046248 A GB 2046248A GB 8005761 A GB8005761 A GB 8005761A GB 8005761 A GB8005761 A GB 8005761A GB 2046248 A GB2046248 A GB 2046248A
- Authority
- GB
- United Kingdom
- Prior art keywords
- deoxy
- hydroxytetracycline
- carried out
- reaction
- rhodium
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title description 2
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 8
- CIWBSHSKHKDKBQ-SZSCBOSDSA-N 2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one Chemical compound OC[C@H](O)C1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-SZSCBOSDSA-N 0.000 claims abstract description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 6
- 239000002211 L-ascorbic acid Substances 0.000 claims abstract description 6
- 235000000069 L-ascorbic acid Nutrition 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 4
- 239000010948 rhodium Substances 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000005695 dehalogenation reaction Methods 0.000 claims 1
- 230000000707 stereoselective effect Effects 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007210 heterogeneous catalysis Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 208000013840 Non-involuting congenital hemangioma Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- RBFQJDQYXXHULB-UHFFFAOYSA-N arsane Chemical group [AsH3] RBFQJDQYXXHULB-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- MQIKJSYMMJWAMP-UHFFFAOYSA-N dicobalt octacarbonyl Chemical group [Co+2].[Co+2].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-] MQIKJSYMMJWAMP-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- MHIGBKBJSQVXNH-IWVLMIASSA-N methacycline Chemical compound C=C([C@H]1[C@@H]2O)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 MHIGBKBJSQVXNH-IWVLMIASSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- 150000003003 phosphines Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 1
- 150000001629 stilbenes Chemical group 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
???-6-Deoxy-5-hydroxytetracycline is made by simultaneously dehalogenating and hydrogenating a salt or complex of 11a-bromo-6-demethyl- 6-deoxy-6-methylene-5-hydroxytetracyline by means of hydrogen, using rhodium as a catalyst and L(+)-ascorbic acid as a stereospecific reduction mediator.
Description
SPECIFICATION
Preparation of a-6-deoxy-5-hydroxytetracycline The present invention relates to a process for preparing a a-6-deoxy-5-hydroxytetracycline. This compound has the generic name Doxycycline and is a well-known broad spectrum antibiotic for use in the treatment of various infectious diseases.
It is well-known that 6-methylenetetracycline and 11 halo-6-methylenetetracyclines, esp.ecially 11 achlorn-6-methylenetetrncycline, especially 11 achlorn-6-methylenetetracycline, as well as acid salts and polyvalent metal complexes thereof, can be reduced by means of hydrogen, by heterogeneous catalysis in the presence of noble metals, to yield a- and ss-6-deoxytetracyclines in approximately equal ratios (US-PS 3,200,1 49). As only the a-isomer is of importance in medicine, several new methods and modifications of known methods were developed later, with the main purpose of obtaining quantities of the a-isomer which are as large as possible.By poisoning noble metals as catalysts (US-PS 3,444,198) or by employing them on special supports (PT-PS 52,217), a slightly larger quantity of the a-isomer than the p-isomer can be obtained. Further known disclosures relate to the use as catalysts of palladium on carbon, with hydrazine as the hydrogen source (DE-PS 2,131,944), or palladium on carbon, having a large surface area and a particle size under 1 A (HU-PS 12,042), as well as reduction with platinum oxide (DE-PS 2,136,621 and GB-PS 1,296,340). It appears that good results can be achieved by using rhodium on carbon in the presence of N-methyl pyrrolidone, triphenylphosphine and, as promoters, acids or SnCI2 (DE-PS 2,418,499).
In addition to heterogeneous catalysis, hydrogenation using homogeneous catalysis, hydrogenation using homogeneous catalysts is also known. Preferred examples of these include rhodium halo complexes containing tertiary phosphines, arsines or stilbenes as ligands (US-PS 3,639,439 and DE-PS 2,308,227 and 2,446,587), chlorobisethylenerhodium dimer with triphenylphosphine (DE-PS 2,403,714) and rhodium diacetate with phenylphosphine (DE-PS 2,554,564).
There is a very interesting method whereby 6-methylene-5-hydroxytetracycline is reduced to a6-deoxy-5-hydroxytetracycline in the presence of dicobalt octacarbonyl, triphenylphosphine and hydrochloric acid, without hydrogen, in an inert atmosphere of nitrogen or argon (US-PS 3,907,890).
It has now been found, in accordance with the present invention, that 11 bromo-6-demethyl- 6-deoxy-6-methylene-5-hydroxytetracycline in the form of a salt or complex (such as its sulphosalicylate) can be dehalogenated and hydrogenated in a single step by means of hydrogen in the presence of rhodium as catalyst and L( + )-ascorbic acid as a stereospecific reduction mediator, according to the following reaction scheme::
CH2 OH NICH3)2 OF' RhIC CONH2 LR ascorbic OH g Br g g acid H3C H OH NICH )2 > OH OH O OH O According to a preferred embodiment of the present invention, the reaction is carried out in the presence of 0.1-0.3 mole of 5% rhodium on carbon and 1 mole or mole-equivalent of
L( + )-ascorbic acid, per mole of 11 bromo-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracy- dine. The reaction product is practically exclusively a-6-deoxy-5-hydroxytetracycline. The reduction is stereo-specific to such an extent that any changes in the amount of reactant, catalyst or
mediator result in obtaining larger quantities of the p-isomer or other compounds, such as
anhydro derivatives or 6-demethyl-6-deoxy-6-methylene-5-hyd roxytetracycline.
Preferably, the reaction is carried out in a C14 alkanol as the reaction medium, under a pressure of 3-30 atms and, most preferably, 3-20 atms at ambient or elevated temperature.
The advantage of the present process, in addition to its excellent reaction stereospecificity, is its simple mode of execution, using a simple, widely-available and completely harmless mediator.
The invention is illustrated by the following Examples:
Example 1
A solution of 11 a-bromo-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline sulphosalicylate (740 mg, 1 mmole) in methanol (75 ml) was added to a de-aerated suspension of 5% rhodium on carbon (1.12 g) and L(+)-ascorbic acid (176 mg, 1 mmole) in methanol (75 ml).
The reaction mixture was then de-aerated under the same conditions and hydrogenated for 3 hours under a pressure of 5 atms and at ambient temperature.
After filtering off the catalyst, the filtrate was evaporated to dryness. The residue was dissolved in water and partitioned by chloroform. The aqueous layer was evaporated to a smaller volume (about 5 ml) and left overnight at 0 C. The crystalline product was filtered off by suction and washed with ethanol. 300 mg of the product was obtained (63% with reference to the base). Thin layer chromatography showed the presence practically solely of a-6-deoxy-5-hydroxytetracycline.
For analysis, the product was purified by conventional methods. All analytical data were identical with the data obtained for an authentic sample.
Example 2
The process was carried out as in Example 1, with the only difference that ethanol was used instead of methanol. The yield was the same as in Example 1.
Example 3
The process was carried out as in Example 1, with the only difference that isopropanol was used instead of methanol. The yield was the same as in Example 1.
Example 4
The process was carried out as in Example 1, with the only difference that 0.450 g of 5% rhodium on carbon was used instead of 1.1 2 g of the same catalyst. The yield was 270 mg.
Example 5
The process was carried out as in Example 4, with the only difference that the reaction was carried out under a pressure of 20 atms. The yield was 293 mg.
Example 6
The process was carried out as in Example 1, with the only differences that the reaction was carried out under a pressure of 20 atms and with the reaction time reduced to 1 hour. The yield was the same as in Example 1.
Example 7
The process was carried out as in Example 1, with the only difference that the reaction was carried out under a pressure of 15 atms. The yield was 316 mg (67% with reference to the base).
Example 8
The process was carried out as in Example 1, with the only differences that the reaction took place under a pressure of 3 atms and at a temperature of 40"C. The yield was the same as in
Example 1.
Claims (5)
1. A process for preparing a-6-deoxy-5-hydroxytetracycline, which comprises subjecting 11 a bromo-6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetracycline in the form of a salt or complex to dehalogenation and hydrogenation in a single step by means of hydrogen in the presence of rhodium as a catalyst and L( + )-ascorbic acid as a steriospecific reduction mediator.
2. A process according to claim 1, wherein the reaction is carried out in the presence of 0.1-0.3 mole of 5% rhodium on carbon and 1 mole of L( + )-ascorbic acid per mole of 11 a bromo-6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline.
3. A process according to claim 1 or 2, wherein the reaction is carried out in a C14 alkanol under a pressure of 3 to 30 atms and at ambient or elevated temperature.
4. A process according to claim 1, substantially as described with reference to any of the foregoing Examples.
5. a-6-Deoxy-5-hydroxytetracycline, when prepared by a process according to any preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU598/79A YU41480B (en) | 1979-03-12 | 1979-03-12 | Process for obtaining alpha-6-deoxy-5-hydroxytetracycline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2046248A true GB2046248A (en) | 1980-11-12 |
| GB2046248B GB2046248B (en) | 1982-12-01 |
Family
ID=25550617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8005761A Expired GB2046248B (en) | 1979-03-12 | 1980-02-20 | Preparation of a-6 deoxy-5-hydroxy-tetracycline |
Country Status (6)
| Country | Link |
|---|---|
| AT (1) | AT374169B (en) |
| CH (1) | CH644583A5 (en) |
| DE (1) | DE3009063C2 (en) |
| GB (1) | GB2046248B (en) |
| IT (1) | IT1129806B (en) |
| YU (1) | YU41480B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1430859A (en) * | 1960-05-23 | 1966-05-25 |
-
1979
- 1979-03-12 YU YU598/79A patent/YU41480B/en unknown
-
1980
- 1980-02-20 GB GB8005761A patent/GB2046248B/en not_active Expired
- 1980-02-20 CH CH137880A patent/CH644583A5/en not_active IP Right Cessation
- 1980-03-03 AT AT0115180A patent/AT374169B/en not_active IP Right Cessation
- 1980-03-10 DE DE3009063A patent/DE3009063C2/en not_active Expired
- 1980-03-11 IT IT67379/80A patent/IT1129806B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| CH644583A5 (en) | 1984-08-15 |
| ATA115180A (en) | 1983-08-15 |
| YU59879A (en) | 1982-10-31 |
| DE3009063C2 (en) | 1982-10-28 |
| GB2046248B (en) | 1982-12-01 |
| YU41480B (en) | 1987-08-31 |
| AT374169B (en) | 1984-03-26 |
| IT1129806B (en) | 1986-06-11 |
| IT8067379A0 (en) | 1980-03-11 |
| DE3009063A1 (en) | 1980-09-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |