IE52876B1 - Preparation of amexinium metilsulfate - Google Patents
Preparation of amexinium metilsulfateInfo
- Publication number
- IE52876B1 IE52876B1 IE857/82A IE85782A IE52876B1 IE 52876 B1 IE52876 B1 IE 52876B1 IE 857/82 A IE857/82 A IE 857/82A IE 85782 A IE85782 A IE 85782A IE 52876 B1 IE52876 B1 IE 52876B1
- Authority
- IE
- Ireland
- Prior art keywords
- metilsulfate
- amezinium
- hydrogen
- dimethyl sulfate
- amide
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 150000005451 methyl sulfates Chemical class 0.000 title claims 2
- 229950000081 metilsulfate Drugs 0.000 title claims 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960002266 amezinium metilsulfate Drugs 0.000 claims abstract description 15
- 150000001408 amides Chemical group 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- ZEASXVYVFFXULL-UHFFFAOYSA-N amezinium metilsulfate Chemical compound COS([O-])(=O)=O.COC1=CC(N)=CN=[N+]1C1=CC=CC=C1 ZEASXVYVFFXULL-UHFFFAOYSA-N 0.000 claims abstract 7
- VXROHTDSRBRJLN-UHFFFAOYSA-O amezinium Chemical compound COC1=CC(N)=CN=[N+]1C1=CC=CC=C1 VXROHTDSRBRJLN-UHFFFAOYSA-O 0.000 claims description 10
- 229940009974 amezinium Drugs 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052717 sulfur Chemical group 0.000 claims 1
- 239000011593 sulfur Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 abstract description 3
- FSMPZHMHKJEXDT-UHFFFAOYSA-N 5-amino-2-phenylpyridazin-3-one Chemical compound O=C1C=C(N)C=NN1C1=CC=CC=C1 FSMPZHMHKJEXDT-UHFFFAOYSA-N 0.000 abstract description 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 7
- -1 amezinium compound Chemical class 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methyl urea Chemical compound CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YBBLOADPFWKNGS-UHFFFAOYSA-N 1,1-dimethylurea Chemical compound CN(C)C(N)=O YBBLOADPFWKNGS-UHFFFAOYSA-N 0.000 description 1
- QLAJNZSPVITUCQ-UHFFFAOYSA-N 1,3,2-dioxathietane 2,2-dioxide Chemical compound O=S1(=O)OCO1 QLAJNZSPVITUCQ-UHFFFAOYSA-N 0.000 description 1
- YVGSDKYJFMEPQW-UHFFFAOYSA-N 1-(2-ethylhexyl)-3-methylurea Chemical compound CCCCC(CC)CNC(=O)NC YVGSDKYJFMEPQW-UHFFFAOYSA-N 0.000 description 1
- IABRWXCXQSTUSS-UHFFFAOYSA-N 1-ethyl-3-methylurea Chemical compound CCNC(=O)NC IABRWXCXQSTUSS-UHFFFAOYSA-N 0.000 description 1
- ANNPPFCFVBLUPZ-UHFFFAOYSA-N 2-ethyl-n-propan-2-ylhexanamide Chemical compound CCCCC(CC)C(=O)NC(C)C ANNPPFCFVBLUPZ-UHFFFAOYSA-N 0.000 description 1
- JHWNWJKBPDFINM-UHFFFAOYSA-N Laurolactam Chemical compound O=C1CCCCCCCCCCCN1 JHWNWJKBPDFINM-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- CJYXCQLOZNIMFP-UHFFFAOYSA-N azocan-2-one Chemical compound O=C1CCCCCCN1 CJYXCQLOZNIMFP-UHFFFAOYSA-N 0.000 description 1
- YDLSUFFXJYEVHW-UHFFFAOYSA-N azonan-2-one Chemical compound O=C1CCCCCCCN1 YDLSUFFXJYEVHW-UHFFFAOYSA-N 0.000 description 1
- 239000011011 black crystal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- IXHFNEAFAWRVCF-UHFFFAOYSA-N n,2-dimethylpropanamide Chemical compound CNC(=O)C(C)C IXHFNEAFAWRVCF-UHFFFAOYSA-N 0.000 description 1
- ZFEBPJQSSNUJGT-UHFFFAOYSA-N n-cyclohexyl-2-phenylacetamide Chemical compound C1CCCCC1NC(=O)CC1=CC=CC=C1 ZFEBPJQSSNUJGT-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/22—Nitrogen and oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Steroid Compounds (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1. A process for the preparation of amezinium metilsulfate by reacting 1-phenyl-4-aminopyridaz-6-one with dimethyl sulfate and subsequently isolating the amezinium metilsulfate by crystallization, wherein unreacted dimethyl sulfate, before crystallization of the amezinium metilsulfate, is bonded to an amide of the formula R**1 -(NH)n -CO-NR**2 R**3 , where R**1 is hydrogen, C1 -C8 -alkyl, C1 -C6 -alkoxy or C1 -C8 -alkylamino, R**2 and R**3 are each hydrogen or C1 -C8 -alkyl, or R**1 and R**2 together are a C3 -C5 -alkylene radical, and n is 0 or 1, at least one of the radicals R**1 , R**2 and R**3 , however, denoting hydrogen, or to the corresponding thioamide.
Description
The present invention relates to a process for the preparation of amezinium metilsulfate (l-phenyl-4amino-6-methoxypyridazinium methosulfate).
The anti-depressant amezinium metilsulfate has been disclosed in German Published Application DAS 1,912,941 (cf. Exanple 1). It is obtained by reacting l-phenyl-4-aminopyridaz'6-one with dimethyl sulfate and filtering off the product under suction from the reaction mixture. The resulting amezinium compound is dark brown, contains residues of dimethyl sulfate, and cannot be purified without substantial loss.
We have found a route for obtaining the amezinium compound in good yield and quality.
The present invention provides a process for the preparation of amezinium metilsulfate by reacting 1phenyl-4-aminopyridaz-6-one with dimethyl sulfate and subsequently isolating the amezinium metilsulfate by crystallization, wherein unreacted dimethyl sulfate is bonded, before crystallization of the amezinium metilsul1 2 3 fate, to an amide of the formula R -(NH)n-CO-NR R , where r! is hydrogen, C^-Cg-alkyl, C^-Cg-alkoxy or C^-Cg2 3 alkylamino, R and R are hydrogen or C^-Cg-alkyl, or 1 2 R and R together are Cg-C^-alkylene, and n is 0 or 12 ? 1, provided that at least one of R , R and RJ is hydrogen, or to a corresponding thioamide.
The reaction of l-phenyl-4-aminopyridaz-6-one with dimethyl sulfate (DMS) may be carried out in a conventional manner. The DMS is advantageously used in excess, but it is also possible to combine it with other solvents (cf. German Published Application DAS 1,912,941 - 3 column 3, lines 4-10). However, if these solvents are used at all, only a limited amount should be added, so that the concentration of DMS is not too low, in particular towards the end of the reaction.
The reaction can be carried out at from 0 to 200°C, in particular at from 30 to 110°C, preferably, however, at from about 60 to 90°C. The reaction time is chosen such that the decomposition to give brownish black crystal slurries, which, for example, occurs In the course of one hour at 120°C, is substantially suppressed, for example 2 hours at 70"C being suitable. The reaction can be carried out continuously or batchwise, or semicontinuously, for example in cascades.
In accordance with the invention, an amide is added to the resulting reaction mixture, in .an amount sufficient to destroy the excess dimethyl sulfate.
Specific examples of amides that can be used are: formamide, N-methylformamide, N-methylacetamide, propionamide, isobutyric acid N-methylamide, 2-ethylhexanoic acid isopropylamide, phenylacetic acid cyclohexylamide, pyrrolidone, piperidone, caprolactam, C-methylcaprolactam, caprylolactam, oenantholactam, laurolactam, urea, N-methylurea, N,N-dimethylurea, Ν,Ν,Ν’-trimethylurea, N-methyl-N'-ethylurea, N,Ν'-dimethylurea, Ν,Ν'-diisopropylurea, N-methyl-N'-(2-ethylhexyl)-urea, ethyleneurea, propylene —--:52876 - 4 urea, N-methylpropylene urea, O-methylurethane, N,0dimethylurethane and N,O-diethylurethane.
The amide is added to the reaction mixture in a liquid or solid state or dissolved or suspended in a solvent. The reaction of the amide with DMS is carried out in a temperature range which depends on the concentration, the residence time and the reactivity of the amide, but which leaves the resulting amezinium compound unchanged. The temperature range is from 0 to 10 200°C, preferably from 20 to 120°C, and very particularly in the presence of the amide from 60 to 100°C.
The reaction parameters should be chosen such that the batchwise reaction of the DMS with the amide takes from 5 minutes to 5 hours, preferably from 0.5 to 2 hours.
The amezinium metilsulfate is isolated as a solid from the reaction mixture, if appropriate after dilution of the latter with solvents, for example the alcohols mentioned in German Published Application DAS 1,912,941, preferably methanol.
In contrast to the process described in German Published Application DAS 1,912,941, the amezinium metilsulfate obtained by the novel process is free from DMS. This is a great advantage, since the amezinium compound is unstable to bases and other nucleophilic compounds and the DMS therefore cannot be removed with the aid of the latter.
By the novel process, the amezinium metilsulfate is obtained directly, without further purification, in 5287b - 5 an almost colorless form and in good yields.
The Examples which follow illustrate the invention.
EXAMPLE 1 5 66.35 g of dimethyl sulfate are heated to 80°C, and 40 g of l-phenyl-4-aminopyridaz-6-one are added in the course of 40 minutes. The resulting slurry is stirred for a further 1.5 hours at from 78 to 82°C, and 40.36 g of caprolactam, dissolved in 27 ml of warm 1° methanol, are then added at 80°C, in the course of 15 minutes. Stirring is continued for a further hour at 90°C, 25 ml of methanol are added, and the mixture is cooled to 0°C. The slurry is stirred for 2 hours at from 0 to 5°C, and the crystals are filtered off under suction, washed with methanol and dried. 50.70 g (75.7%) of beige amezinium metilsulfate, melting point 173-175°C (decomposition), are obtained. 30.00 g of the resulting product are recrystallized from methanol and 25.50 g (85.0%) of colorless crystals, melting point 176-177’C (decompc20 sition), are obtained. The yield over both stages is 64.3%.
EXAMPLES 2 TO 10 Example 1 was repeated with the amides given in the Table, and the yields and melting points indicated « were obtained. The crude products were slightly colored, whilst the end products were almost colorless.
COMPARATIVE EXAMPLE If the amounts, given in Example 1, of 1-phenyl4-aminopyridaz-6-one are reacted as described in Example 53876 - 5 1 of German Published Application DAS 1,912,941, a 91% yield of a dark brown crude product of melting point 148-157°C is obtained. Recrystallization of the crude product gives 21% (based on l-phenyl-4-aminopyridaz5 6-one) of a brown product of melting point 162-164’C 16.6% of a pure product of melting point 174.5-175.5°C are obtained only after the recrystallization is repeated once again.
Claims (4)
1. A process for the preparation of amezinium metilsulfate by reacting l-phenyl-4-aminopyridaz-6-one with dimethyl sulfate and subsequently isolating the amezinium 5 metilsulfate by crystallization, wherein unreacted dimethyl sulfate, before crystallization of the amezinium metilsulfate, is bonded to an amide of the formula R 1 -(NH) n -CX-NR 2 R 3 where R 1 is hydrogen, C^-Cg-alkyl, C^-Cg-alkoxy or C^-Οθ
2. 2 10 alkylamino or together with R is C^-C^-alkylene, R 1 is hydrogen or Cj-Cg-alkyl or together with R is Cg-Cg-alkylene, R^ is hydrogen or C^-Cg-alkyl, X is oxygen or sulfur and n is zero or 1, provided that at 12 3 least one of R , R and R is hydrogen. 15 2. A process as claimed in claim 1, wherein the bonding of excess dimethyl sulfate to the amide is carried out at from 60 to 100°C, sufficient amide to react with all the excess dimethyl sulfate being added to the reaction mixture in a liquid or solid state or 20 dissolved or suspended in a solvent.
3. A process for the preparation of amezinium metilsulfate carried out substantially as described in any of the foregoing Examples 1 to 10.
4. Amezinium metilsulfate when prepared by a process 25 as claimed in any of claims 1 to 3.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813114496 DE3114496A1 (en) | 1981-04-10 | 1981-04-10 | METHOD FOR PRODUCING AMEZINIUM |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE820857L IE820857L (en) | 1982-10-10 |
| IE52876B1 true IE52876B1 (en) | 1988-03-30 |
Family
ID=6129850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE857/82A IE52876B1 (en) | 1981-04-10 | 1982-04-08 | Preparation of amexinium metilsulfate |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0063267B1 (en) |
| JP (1) | JPS57179166A (en) |
| AT (1) | ATE10627T1 (en) |
| DE (2) | DE3114496A1 (en) |
| DK (1) | DK159582A (en) |
| GR (1) | GR75519B (en) |
| IE (1) | IE52876B1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1912941C3 (en) * | 1969-03-14 | 1980-06-26 | Basf Ag, 6700 Ludwigshafen | 1-phenyl ^ -amino-e-methoxypyridazinium salts |
-
1981
- 1981-04-10 DE DE19813114496 patent/DE3114496A1/en not_active Withdrawn
-
1982
- 1982-03-02 GR GR67448A patent/GR75519B/el unknown
- 1982-03-31 AT AT82102697T patent/ATE10627T1/en not_active IP Right Cessation
- 1982-03-31 EP EP82102697A patent/EP0063267B1/en not_active Expired
- 1982-03-31 DE DE8282102697T patent/DE3261426D1/en not_active Expired
- 1982-04-07 DK DK159582A patent/DK159582A/en not_active IP Right Cessation
- 1982-04-08 IE IE857/82A patent/IE52876B1/en unknown
- 1982-04-09 JP JP57058413A patent/JPS57179166A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| DK159582A (en) | 1982-10-11 |
| GR75519B (en) | 1984-07-26 |
| JPS57179166A (en) | 1982-11-04 |
| ATE10627T1 (en) | 1984-12-15 |
| DE3114496A1 (en) | 1982-11-04 |
| EP0063267B1 (en) | 1984-12-05 |
| IE820857L (en) | 1982-10-10 |
| JPH0456033B2 (en) | 1992-09-07 |
| EP0063267A1 (en) | 1982-10-27 |
| DE3261426D1 (en) | 1985-01-17 |
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