GB1574479A - Process for brominating ergocryptine - Google Patents
Process for brominating ergocryptine Download PDFInfo
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- GB1574479A GB1574479A GB50918/77A GB5091877A GB1574479A GB 1574479 A GB1574479 A GB 1574479A GB 50918/77 A GB50918/77 A GB 50918/77A GB 5091877 A GB5091877 A GB 5091877A GB 1574479 A GB1574479 A GB 1574479A
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- United Kingdom
- Prior art keywords
- ergocryptine
- alpha
- bromo
- salt
- mmoles
- 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
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- 238000000034 method Methods 0.000 title claims description 33
- YDOTUXAWKBPQJW-NSLWYYNWSA-N alpha-ergocryptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-NSLWYYNWSA-N 0.000 title claims description 15
- 229950001817 alpha-ergocryptine Drugs 0.000 title claims description 15
- YDOTUXAWKBPQJW-UHFFFAOYSA-N alpha-Ergocryptinine Natural products C1=CC(C=2C(N(C)CC(C=2)C(=O)NC2(C(=O)N3C(C(N4CCCC4C3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=CNC3=C1 YDOTUXAWKBPQJW-UHFFFAOYSA-N 0.000 title claims description 14
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 28
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 150000004292 cyclic ethers Chemical class 0.000 claims description 8
- 239000003999 initiator Substances 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 7
- 239000011521 glass Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 6
- QRADPXNAURXMSB-UHFFFAOYSA-N 2-bromo-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(Br)C(=O)C2=C1 QRADPXNAURXMSB-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 102100024819 Prolactin Human genes 0.000 claims description 6
- 108010057464 Prolactin Proteins 0.000 claims description 6
- 229940073584 methylene chloride Drugs 0.000 claims description 6
- 229940097325 prolactin Drugs 0.000 claims description 6
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 108010051696 Growth Hormone Proteins 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 102100038803 Somatotropin Human genes 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 4
- 239000000122 growth hormone Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 4
- 230000028327 secretion Effects 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 230000031709 bromination Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000000532 dioxanyl group Chemical group 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 3
- 102000015554 Dopamine receptor Human genes 0.000 claims description 2
- 108050004812 Dopamine receptor Proteins 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 229960003638 dopamine Drugs 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical group CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 150000001450 anions Chemical class 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 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 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/02—Ergot alkaloids of the cyclic peptide type
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pyrrole Compounds (AREA)
Description
(54) A PROCESS FOR BROMINATING a
ERGOCRYPTINE
(71) We, LEK TOVARNA FARMACEVTSKIH IN KEMICNIH
IZDELKOV N.SOL.O., a Yugoslavian Body
Corporate, of Celovska 135, Ljubliana,
Yugoslavia, do hereby declare the
invention, for which we pray that a patent
may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to a process for brominating a-ergocryptine to produce 2-bromo-alpha-ergocryptine.
2-Bromoalpha-ergocryptine is a known compound inhibiting the secretion of the hormone prolactin and of the growth hormone. It is therapeutically applied in the treatment of amenorrheagalactorrhea (Del
Pozo et al., J. Clin. Endocrinol. Metab., 38:910, 1974) and of acromegaly (A. Liuzzi et al., J. Clin. Endocrinol. Metab., 38:910
1974). As inhibitor for prolactin it advantageously affects those types of cancer, above all breast cancer, in which the activation and reactivation depend on prolactin (R. W. Turkington, L. E.
Underwood and J. J. Van Wyk, N. Engl. M.
Med., 285 (1971) 707). It stimulates dopamine receptors in the central nervous system and is efficacious in the treatment of
Parkinsons's disease (D. B. Caine et al.,
Brit. Med. 4 (1974) 442).
The first process for preparing 2-bromoderivatives of ergotalkaloids was described by F. Troxler and A. Hofman in Helv.
Chim. Acta 40 (1957) 2160. In Swiss Patent
Specification No. 507 249, as brominating agents for ergocryptine there are cited Nbromosuccinimide, N-bromocaprolactan,
N-bromophthalimide and elementary bromine in dioxane. In spite of considerable excess of brominating agent, however, the reaction is neither selective nor quantitative. Owing to the great sensitivity of ergocryptine, side-reactions can occur so that a considerable part of the starting substance decomposes to dark coloured, partly resinous unidentified products. Also a part of the starting substance may remain unreacted.
An obiect of the process according to the present invention is the use of a milder and more selective brominating agent in the presence of a free radical initiator. As this reaction proceeds according to a free radical mechanism, it is made easier by compounds which can form free radicals.
According to the present invention there is provided a process for the preparation of a 2-bromo-alpha-ergocryptine, which process comprises brominating alphaergocryptine by the use of pyrrolidinone hydrotribromide or N-bromosaccharin in the presence of a free radical initiator.
The preferred process according to the present invention for preparing 2-bromoalpha-ergocryptine is characterised in that alpha-ergocryptine in an inert atmosphere is brominated with pyrrolidinone hydrotribromide or N-bromosaccharin in solution in a cyclic ether in the presence of a radical initiator at room temperature.
As the cyclic ether there can be used e.g.
tetrahydrofuran, tetrahydropyran or dioxane. The preferred cyclic ether is dioxane. The reaction in acetonitrile or chloroform is less selective. As the radical initiator there can be used 2,2'-azo-bis-(2methyl-propionitrile) (G. Bianchi and P.
Grunanger, Tetrahedron Letters 21 (1965) 817).
At room temperature, the reaction may be completed with stirring.
For the inert atmosphere any inert gas can be used, e.g. nitrogen.
The reaction is usually carried out by adding the brominating agent and the radical initiator to a solution of alphaergocryptine in a cyclic ether, with stirring in an inert atmosphere. The degree of formation of side-products in the course of this reaction is small, being considerably smaller than with other known brominating agents.
It is preferred that for each mole of alphaergocryptine 1 to 1.2 moles of brominating agent are used.
All starting substances mentioned are described in the literature and are normally available on the market.
2-Bromo-alpha-ergocryptine may be isolated from the reaction mixture by separation by chromatography using a column filled with microporous glass carrier, e.g. glass CPG-75 with 200400 mesh and pore diameter of about 69A a product of Electro Nucleonics, Fairfield,
New Jersey, USA, Chloroform can be used as the eluting agent.
From the eluate, after evaporation of the solvent and after crystallisation from diisopropylether, there is obtained pure 2bromo-alpha-ergocryptine.
2-Bromo-alpha-ergocryptine is a less polar compound that alpharergocryptine.
On a silica gel plate Merck (registered
Trade Mark) 60 upon development with mobile phase of chloroform/methanol 100:5 vol./vol., 2 - bromo - alpha - ergocryptine has an Rf-value of 0.40.
Pure 2 - bromo - alpha - ergocryptine has a M.p. of 2l50-2l70C (decomp.), its specific rotation is [a]0=-1900 to 1920 (c=l, methylenechloride).
2 - Bromo - alpha - ergocryptine in the form of the free base is insoluble and unsuitable for therapeutic use. Therefore, it is converted into a water-soluble, physiologically acceptable acid addition salt, preferably the salt of methanesulphonic acid.
The present invention provides a pharmaceutical or veterinary formulation which comprises such a salt formulated for pharmaceutical or veterinary use, respectively. The invention further includes a pharmaceutical or veterinary composition which comprises such a salt together with a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient. Such formulations and compositions may be in unit dosage form, e.g. capsules or tablets.
Also provided by the invention is a method for inhibiting the secretion of prolactin or growth hormone or for stimulating dopamine preceptors in the CNS of an animal comprising the administration of an effective amount of such a salt, a formulation of the invention or a composition of the invention.
The present process is illustrated, but is not limited by the following Examples.
Example 1
2.3 g. (4.0 mmoles) of alpha-ergocryptine are dissolved in 100 ml. of pure
dioxane at 200C in a nitrogen atmosphere.
With intensive stirring there is added a solution of 2 g. (4.03 mmoles)of pyrrolidinone hydrotribromide and 0.12 g.
(0.7 mmoles) of 2,2'-azo-bis-(2methylpropionitrile) in 90 ml. of dioxane.
After 30 minutes the reaction is interrupted and the solvent is evaporated in vacuo..
The dry residue is dissolved in 100 ml. of chloroform and extracted three times with 80 ml. portions of a 1% water solution of sodium carbonate. The chloroform phase is dried with sodium sulphate and evaporated to one seventh of the original volume. The concentrate is put on a column with a diameter of 5 cm., which is filled with 230 ml. of microporous glass CPG-75 wetted with chloroform. It is eluted with chloroform. The fractions containing 2bromo-alpha-ergocryptine are combined and evaporated to dryness in vacuo. The dry residue is recrystallized from diisopropylether. 2.05 g. or 78.2% of theory of 2-bromo-alpha-ergocryptine are obtained with a M.p. of 2150-2l70C and [tZ]20=190 (c=l, methylenechloride).
Example 2
2.3 g. (4.0 mmoles) of alpha-ergocryptine are dissolved in 100 ml. of pure tetrahydrofuran in a nitrogen atmosphere.
With stirring there is added a solution of 1.08 g. (4.12 mmoles) of N-bromosaccharin and 0.13 g. (0.78 mmoles) of 2,2'-azo-bis-(2 methylpropionitrile) in 90 ml. of tetrahydrofuran. After completion of the reaction at room temperature, the solvent is evaporated in vacuo.
The dry residue is isolated and purified as described in Example 1.
2.1 g. or 80.1% of theory of 2-bromoalpha-ergocryptine are obtained with a M.p.
of 2l50-2180C and Fa]020=-l920 (c=l, methylenechloride).
It should be clearly understood that we make no claim herein to a method for the prevention or treatment of disease in a human being.
Subject to the foregoing disclairner,
WHAT WE CLAIM IS:- 1. A process for the preparation of 2 bromo - alpha - ergocryptine, which process comprises brominating alphergocryptine by the use of pyrrolidinone hydrotribromide or N - bromosaccharin in the presence of a free radical initiator.
2. A process as claimed in claim 1,
wherein the bromination is effected in a
cyclic ether solution under an inert
atmosphere.
3. A process as claimed in claim 2, wherein the inert atmosphere comprises
nitrogen.
4. A process as claimed in claim 2 or
claim 3, wherein the cyclic ether is dioxane.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (17)
- **WARNING** start of CLMS field may overlap end of DESC **.It is preferred that for each mole of alphaergocryptine 1 to 1.2 moles of brominating agent are used.All starting substances mentioned are described in the literature and are normally available on the market.2-Bromo-alpha-ergocryptine may be isolated from the reaction mixture by separation by chromatography using a column filled with microporous glass carrier, e.g. glass CPG-75 with 200400 mesh and pore diameter of about 69A a product of Electro Nucleonics, Fairfield, New Jersey, USA, Chloroform can be used as the eluting agent.From the eluate, after evaporation of the solvent and after crystallisation from diisopropylether, there is obtained pure 2bromo-alpha-ergocryptine.2-Bromo-alpha-ergocryptine is a less polar compound that alpharergocryptine.On a silica gel plate Merck (registered Trade Mark) 60 upon development with mobile phase of chloroform/methanol 100:5 vol./vol., 2 - bromo - alpha - ergocryptine has an Rf-value of 0.40.Pure 2 - bromo - alpha - ergocryptine has a M.p. of 2l50-2l70C (decomp.), its specific rotation is [a]0=-1900 to 1920 (c=l, methylenechloride).2 - Bromo - alpha - ergocryptine in the form of the free base is insoluble and unsuitable for therapeutic use. Therefore, it is converted into a water-soluble, physiologically acceptable acid addition salt, preferably the salt of methanesulphonic acid.The present invention provides a pharmaceutical or veterinary formulation which comprises such a salt formulated for pharmaceutical or veterinary use, respectively. The invention further includes a pharmaceutical or veterinary composition which comprises such a salt together with a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient. Such formulations and compositions may be in unit dosage form, e.g. capsules or tablets.Also provided by the invention is a method for inhibiting the secretion of prolactin or growth hormone or for stimulating dopamine preceptors in the CNS of an animal comprising the administration of an effective amount of such a salt, a formulation of the invention or a composition of the invention.The present process is illustrated, but is not limited by the following Examples.Example 1 2.3 g. (4.0 mmoles) of alpha-ergocryptine are dissolved in 100 ml. of pure dioxane at 200C in a nitrogen atmosphere.With intensive stirring there is added a solution of 2 g. (4.03 mmoles)of pyrrolidinone hydrotribromide and 0.12 g.(0.7 mmoles) of 2,2'-azo-bis-(2methylpropionitrile) in 90 ml. of dioxane.After 30 minutes the reaction is interrupted and the solvent is evaporated in vacuo..The dry residue is dissolved in 100 ml. of chloroform and extracted three times with 80 ml. portions of a 1% water solution of sodium carbonate. The chloroform phase is dried with sodium sulphate and evaporated to one seventh of the original volume. The concentrate is put on a column with a diameter of 5 cm., which is filled with 230 ml. of microporous glass CPG-75 wetted with chloroform. It is eluted with chloroform. The fractions containing 2bromo-alpha-ergocryptine are combined and evaporated to dryness in vacuo. The dry residue is recrystallized from diisopropylether. 2.05 g. or 78.2% of theory of 2-bromo-alpha-ergocryptine are obtained with a M.p. of 2150-2l70C and [tZ]20=190 (c=l, methylenechloride).Example 2 2.3 g. (4.0 mmoles) of alpha-ergocryptine are dissolved in 100 ml. of pure tetrahydrofuran in a nitrogen atmosphere.With stirring there is added a solution of 1.08 g. (4.12 mmoles) of N-bromosaccharin and 0.13 g. (0.78 mmoles) of 2,2'-azo-bis-(2 methylpropionitrile) in 90 ml. of tetrahydrofuran. After completion of the reaction at room temperature, the solvent is evaporated in vacuo.The dry residue is isolated and purified as described in Example 1.2.1 g. or 80.1% of theory of 2-bromoalpha-ergocryptine are obtained with a M.p.of 2l50-2180C and Fa]020=-l920 (c=l, methylenechloride).It should be clearly understood that we make no claim herein to a method for the prevention or treatment of disease in a human being.Subject to the foregoing disclairner, WHAT WE CLAIM IS:- 1. A process for the preparation of 2 bromo - alpha - ergocryptine, which process comprises brominating alphergocryptine by the use of pyrrolidinone hydrotribromide or N - bromosaccharin in the presence of a free radical initiator.
- 2. A process as claimed in claim 1, wherein the bromination is effected in a cyclic ether solution under an inert atmosphere.
- 3. A process as claimed in claim 2, wherein the inert atmosphere comprises nitrogen.
- 4. A process as claimed in claim 2 or claim 3, wherein the cyclic ether is dioxane.
- 5. A process as claimed in any one ofclaims 2 to 4, wherein the bromination is carried out at room temperature with stirring.
- 6. A process as claimed in any one of claims 1 to 5, wherein from I to 1.2 moles of the brominating agent are used per mole of alpha-ergocryptine.
- 7. A process as claimed in any one of claims 1 to 6, wherein said free radical initiator is 2,2'-azo-bis-(2-methylpropionitrile).
- 8. A process as claimed in any one of claims 1 to 7, wherein a microporous glass carrier separation column is used chromatographically to isolate the 2-bromoalpha-ergocryptine from said reaction mixture.
- 9. A process as claimed in claim 1 and substantially as hereinbefore described in any one of the Examples.
- 10. A process as claimed in any one of claims 1 to 9 comprising the additional step of converting the 2-bromo-alpha- ergocryptine formed to a physiologically acceptable acid addition salt.
- I 1. 2-bromo-alpha-ergocryptine which has been prepared by a process as claimed in any one of claims 1 to 9.
- 12. A physiologically acceptable acid addition salt of 2-bromo-alpha-ergocryptine which has been prepared by a process as claimed in claim 10.
- 13. A salt as claimed in claim 12, wherein the anion of the salt is methanesulphonate.
- 14. A pharmaceutical or veterinary formulation which comprises a salt as claimed in claim 12 or claim 13 formulated for pharmaceutical or veterinary use, respectively.
- 15. A pharmaceutical or veterinary composition which comprises a salt as claimed in claim 12 or claim 13 together with a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient.
- 16. A formulation as claimed in claim 14 or a composition as claimed in claim 15 in unit dosage form.
- 17. A method for inhibiting the secretion of prolactin or growth hormone or for stimulating dopamine receptors in the CNS of an animal comprising the administration of an effective amount of a salt as claimed in claim 12 or claim 13, a formulation as claimed in claim 14 or claim 16, or a composition as claimed in claim 15 or claim 16.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU3134/76A YU39786B (en) | 1976-12-23 | 1976-12-23 | Process for preparing 2-bromo-alfa-ergocriptine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1574479A true GB1574479A (en) | 1980-09-10 |
Family
ID=25559398
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB50918/77A Expired GB1574479A (en) | 1976-12-23 | 1977-12-07 | Process for brominating ergocryptine |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5384997A (en) |
| BE (1) | BE903269Q (en) |
| CS (1) | CS215105B2 (en) |
| DD (1) | DD134101A1 (en) |
| DE (1) | DE2752532C3 (en) |
| ES (1) | ES465096A1 (en) |
| FR (1) | FR2375242A1 (en) |
| GB (1) | GB1574479A (en) |
| HK (1) | HK4786A (en) |
| HU (1) | HU176817B (en) |
| KE (1) | KE3572A (en) |
| PL (1) | PL106363B1 (en) |
| PT (1) | PT67340A (en) |
| RO (1) | RO71277A (en) |
| SG (1) | SG71885G (en) |
| SU (1) | SU795477A3 (en) |
| UA (1) | UA8031A1 (en) |
| YU (1) | YU39786B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU216177A (en) | 1977-09-09 | 1984-02-29 | Rudolf Rucman | Process for preparing 2-bromo ergosine |
| YU39849B (en) * | 1978-09-26 | 1985-04-30 | Lek Tovarna Farmacevtskih | Process for preparing 2-bromo-ergolene and 2-bromo-ergoline compounds |
| RU2274640C1 (en) * | 2004-09-15 | 2006-04-20 | Всероссийский научно-исследовательский институт лекарственных и ароматических растений ("ВИЛАР") | METHOD FOR BROMINATION OF α- AND β-ERGOCRYPTINES |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH507249A (en) * | 1968-05-31 | 1971-05-15 | Sandoz Ag | Process for the preparation of 2-bromo-a-ergocryptine |
| YU216177A (en) * | 1977-09-09 | 1984-02-29 | Rudolf Rucman | Process for preparing 2-bromo ergosine |
-
1976
- 1976-12-23 YU YU3134/76A patent/YU39786B/en unknown
-
1977
- 1977-11-24 DE DE2752532A patent/DE2752532C3/en not_active Expired
- 1977-11-29 PT PT67340A patent/PT67340A/en unknown
- 1977-11-29 HU HU77LE820A patent/HU176817B/en unknown
- 1977-12-02 CS CS778043A patent/CS215105B2/en unknown
- 1977-12-05 JP JP14522377A patent/JPS5384997A/en active Granted
- 1977-12-07 GB GB50918/77A patent/GB1574479A/en not_active Expired
- 1977-12-07 PL PL1977202697A patent/PL106363B1/en unknown
- 1977-12-12 RO RO7792428A patent/RO71277A/en unknown
- 1977-12-13 SU SU772553348A patent/SU795477A3/en active
- 1977-12-13 UA UA2553348A patent/UA8031A1/en unknown
- 1977-12-14 DD DD77202623A patent/DD134101A1/en unknown
- 1977-12-15 ES ES465096A patent/ES465096A1/en not_active Expired
- 1977-12-23 FR FR7738976A patent/FR2375242A1/en active Granted
-
1985
- 1985-09-20 BE BE1/011337A patent/BE903269Q/en not_active IP Right Cessation
- 1985-10-02 SG SG718/85A patent/SG71885G/en unknown
- 1985-10-11 KE KE3572A patent/KE3572A/en unknown
-
1986
- 1986-01-23 HK HK47/86A patent/HK4786A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HK4786A (en) | 1986-01-31 |
| JPS5550038B2 (en) | 1980-12-16 |
| DE2752532B2 (en) | 1979-12-06 |
| FR2375242B1 (en) | 1983-01-14 |
| PL106363B1 (en) | 1979-12-31 |
| DE2752532A1 (en) | 1978-06-29 |
| KE3572A (en) | 1985-11-08 |
| DE2752532C3 (en) | 1980-09-18 |
| SU795477A3 (en) | 1981-01-07 |
| ES465096A1 (en) | 1978-09-01 |
| PL202697A1 (en) | 1978-07-31 |
| DD134101A1 (en) | 1979-02-07 |
| YU39786B (en) | 1985-04-30 |
| BE903269Q (en) | 1986-01-16 |
| FR2375242A1 (en) | 1978-07-21 |
| HU176817B (en) | 1981-05-28 |
| YU313476A (en) | 1982-05-31 |
| RO71277A (en) | 1982-02-01 |
| PT67340A (en) | 1977-12-01 |
| JPS5384997A (en) | 1978-07-26 |
| SG71885G (en) | 1988-09-30 |
| CS215105B2 (en) | 1982-07-30 |
| UA8031A1 (en) | 1995-12-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| 704A | Declaration that licence is not available as of right for an excepted use (par. 4a/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 19971206 |