IE46917B1 - Process for the production of pleuromutilin derivatives - Google Patents
Process for the production of pleuromutilin derivativesInfo
- Publication number
- IE46917B1 IE46917B1 IE110878A IE110878A IE46917B1 IE 46917 B1 IE46917 B1 IE 46917B1 IE 110878 A IE110878 A IE 110878A IE 110878 A IE110878 A IE 110878A IE 46917 B1 IE46917 B1 IE 46917B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- compound
- carbon atoms
- alkyl
- production
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical class C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 title description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- OBUUFWIMEGVAQS-UHFFFAOYSA-N Pleuromutenol Natural products CC1C(O)C(C)(C=C)CC(O)C2(C)C(C)CCC31C2C(=O)CC3 OBUUFWIMEGVAQS-UHFFFAOYSA-N 0.000 claims description 7
- 229960002771 retapamulin Drugs 0.000 claims description 7
- STZYTFJPGGDRJD-NHUWBDDWSA-N retapamulin Chemical compound C([C@H]([C@@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CS[C@@H]3C[C@H]4CC[C@H](N4C)C3)C)C[C@]32[C@H]1C(=O)CC3 STZYTFJPGGDRJD-NHUWBDDWSA-N 0.000 claims description 7
- 150000003839 salts Chemical group 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- -1 2-diethylaminoethyl Chemical group 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical group OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- QSRFYFHZPSGRQX-UHFFFAOYSA-N benzyl(tributyl)azanium Chemical group CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 QSRFYFHZPSGRQX-UHFFFAOYSA-N 0.000 claims 1
- 229940125758 compound 15 Drugs 0.000 claims 1
- 230000000063 preceeding effect Effects 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- XMBZUNHETOKKBH-UHFFFAOYSA-N Dihydro-Mutilin Natural products CC1C(O)C(CC)(C)CC(O)C2(C)C(C)CCC31CCC(=O)C32 XMBZUNHETOKKBH-UHFFFAOYSA-N 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- UDYGXWPMSJPFDG-UHFFFAOYSA-M benzyl(tributyl)azanium;bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 UDYGXWPMSJPFDG-UHFFFAOYSA-M 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- CMBJWSUWPPPZTH-UHFFFAOYSA-N 1-(diethylamino)ethanethiol;hydrochloride Chemical compound Cl.CCN(CC)C(C)S CMBJWSUWPPPZTH-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003849 aromatic solvent Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- CURCMGVZNYCRNY-UHFFFAOYSA-N trimethylazanium;iodide Chemical compound I.CN(C)C CURCMGVZNYCRNY-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
PROCESS FOR THE PRODUCTION OF PLEUROMUTILIN DERIVATIVES This invention concerns pleuromutilin derivatives.
More particularly, this invention provides a process for the production of compounds of formula I, . i - in which n is 2, 3, 4 or 5, ’ R^ is ethyl or vinyl, and either R2an<3 R^ ate the same or different and 10 ! each signifies alkyl of 1 to 4 carbon atoms, or R2 and R^, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally contain15. ing a second hetero moiety selected - from oxygen, sulphur or =N—R^, in which Rg is alkyl of 1 to 4 carbon atoms, - la 46817 or an acid addition salt form thereof, comprising reacting a compound of formula II, in which R^ is as defined above, and Rg is alkyl of 1 io 4 carbon atoms or phenyl, unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, with a compound of formula III, HS2 n \ III in which n, R^ and are as defined above, characterised in that the reaction is effected in the presence of a phase transfer catalyst.
The process is suitably effected by addition of a solution of the compound of formula II in an inert, water-immiscible solvent, for example an aromatic solvent, such as toluene, to an aqueous solution of the com pound of formula III, which is suitably in the form of 6917 an acid addition salt, for example in hycrochloride salt form. The reaction is conveniently effected at a temper- ature of from 25° to 70°C. Suitable phase transfer catalysts are conventional such catalysts, including benzyl tributylammonium bromide and tetrabutylammonium bromide. The catalyst is conveniently present in catalytic amounts, for example 1 to 2 mol %. The reaction mixture is then suitably made alkaline, for example by addition of aqueous alkali metal hydroxide, e.g. sodium hydroxide solution.
The resulting compounds of formula X may be isolated and purified in conventional manner. Where required, free base forms thereof may be converted into acid addition salt forms in conventional manner, and vice versa. Suitable salt forms include the hydrochloride and hydrogen fumarate.
The compounds of formula II are known and may be produced by reacting a compound of formula IV, - 3 4081^ in which R^ is as defined above, with a compound of formula V, in which A is the acid radical of a reactive ester.
The reaction may be effected in known manner, 5 for example as described in Example 1 hereinafter. A suitably signifies chlorine or bromine. The resulting compounds of formula II may, if desired, be isolated and purified using conventional techniques but are preferably employed without isolation in the subsequent step of '' producing compounds I.
The compounds of formula I are known antibiotics with anti-bacterial activity and may, for example, be used for treating (prophylaxis or therapy) microorganism infections in domestic animals, e.g. pigs and poultry.
The preferred compounds of formula I are those in which n is 2 or 3, in particular 2. R^ may be ethyl but is preferably vinyl. Rj and R^ are preferably each alkyl of 1 to 4, in particular 1 to 3, carbon atoms, more particularly 2 carbon atoms. They may,'however , as indicated, also form a heterocyclic ring together with the nitrogen atom to which they arc attached. Such ring suitably contains a second hetero moiety. When the ring contains 6 ring members, this is preferably para to the nitrogen atonu The second hetero moiety is preferably oxygeft or, more preferably, =N-Rg. Rg is preferably alkyl of 1 to 2 carbon atoms.
The. process of the invention is generally known. It has, however, been found that by carrying out .the process in the presence of a phase transfer catalyst, •not only are the yields improved somewhat but also the need to isolate the starting material of formula ucan be eliminated. In addition, the process may be effected in solvents such as toluene, which may more easily and completely be regenerated thus leading to decreased environmental problems. Finally, the required reaction time.is .diminished and working up is simplified.
• The following Examples illustrate the invention.. ' 6917 EXAMPLE 1: 14-Desoxy-14- ((2-diethylt'tminoethyl)mercaptoacetoxylmutilln 250 g of 14-desoxy-14-hydroxyacetoxymutilin are suspended in a mixture of 900 ml of toluene and 300 ml of 15% aqueous sodium hydroxide solution, at room temperature. The mixture is heated to about 60°C and mixed, with stirring, with a solution of 138 g of j5-toluenesulphonyl chloride in 350 ml of toluene. The mixture is stirred for 1^-/2 hours at 60°C and the still warm aqueous phase is separated off. The toluene phase containing 14-desoxy-14-tosyloxyacetoxymutilin is mixed with 112 g of diethylaminoethanethiol hydrochloride, 175 ml of water and 3.5 g of benzyltributylammohiurn bromide and 165 ml of concentrated caustic soda are added, with stirring to the resulting mixture at 60°C.
The mixture is stirred for 2 hours at 60°C, the aqueous phase is then separated off and the toluene phase is extracted with dilute sulphuric acid. The extract is made alkaline (pH = 12) with 2N caustic soda and precipitated heading compound extracted with tol.uene.
The toluene solution is evaporated to obtain the heading compound in the form of a yellow oil.
The resulting free base may be treated with fumarie acid in known manner to obtain the hydrogen fumarate salt form, in.p. 148-149°C.
C 4631? EXAMPLE 2: In manner analogous to Example 1 and employing appropriate starting materials in approximately equivalent amounts, the following compounds may be obtained:14-desoxy-14[(2-morpholinoethyl)mercaptoacetoxy]mutilin hydrochloride, softening point 70°C, 14-desoxy-14-[(2-diisopropylaminoethyl)mercaptoacetoxy]mutilin hydrochloride, 14-desoxy-14-ί(di-n-butylaminoethyl)mercaptoacetoxy)mutilin hydrochloride, softening point 85-9O°C 14-desoxy-14-f2-(4-methyl)piperazinoethyl)mercapfcoacetoxy]mutilin dihydroehloride, m.p. 185-188°C, 14-desoxy-14-[(2-dimethylaminoethyl)mercaptoacetoxy]dihydromutilin, trimethyl ammonium iodide, softening point 123-128°C, 14-desoxyrl4-[3-(di-n-butylaminopropyl)mercaptoacetoxy]mutilin hydrochloride, softening point 45-48°C, i 14-desoxy-14-[3-(di-n-butylaminopropyl)mercaptoacetoxy]dihydromutilin hydrochloride, softening points 90°C, 14-desoxy-14-[(2-thiomorpholinoethyl)mercaptoacetoxy)mutilin hydrochloride, softening point 120-125°C, and 14-desoxy-14-[2-(4-methylpiperazino)ethylmercaptoacetoxy) dihydromutilin, dihydroehloride m.p. 220° - 225°C. deal’? EXAMPLE 3: The procedure of Examples 1 and 2 may be effected in analogous manner but employing tetrabutylammonium bromide in place of benzyltributylammonium bromide, in an approximately equivalent amount, to obtain the compounds indicated.
Claims (10)
1. A process for the production of compounds of formula I, ' S in which n is 2, 3, 4 or 5, R^ is ethyl or vinyl, and either R 2 and R^ are the same or different a^d each signifies alkyl of 1 to 4 carbon atoms, 10 or R 2 and R^, together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally containing a second hetero moiety selected from oxygen, sulphur or =N-Rg, 15 in which R^ is alkyl of 1 to 4 carbon atoms, - 9 46917 or an acid addition salt form thereof, comprising reacting a compound of formula II, in which is as defined above, and Rg is alkyl > of 1 to 4 carbon atoms or 5 phenyl, unsubstituted cr substituted by alkyl of 1 to 4 carbon atoms, with a compound of formula III, / R 2 I III in which n, R^ and R, are as defined above, characterised in that the reaction is effected in the 10 presence of a phase transfer catalyst, and, where required, converting a resulting free base form of the compounds of formula I into an acid addition salt form, or vice versa.
2. A process according to Claim 1, in which the compound of formula II is produced by reacting a compound of formula IV, in which R^ Is as defined in Claim 1, 5 with a compound of formula V, R C SO_ A V v Z in which A is the acid radical of a reactive ester.
3. A process according to Claim 1, in which the phase transfer catalyst is benzyltributylammonium 10 bromide or tetrabutylammonium bromide.
4. A process according to Claim 1, in which the reaction is effected by mixing a solution of the compound of formula II, in an inert, water-immiscible organic solvent with an aqueous solution of the compound 15 of formula III or mixture of the compound of formula III with water. - 11 46917
5. A process according to Claim 4, in which the inert water-immiscible organic solvent is toluene.
6. A process for the production of a 5 compound of formula I, as defined in Claim 1, substantially as hereinbefore described with reference to any one of the Examples.
7. A compound of formula I, as defined in Claim 1, whenever produced by a process as claimed in any 10 one of the preceeding claims.
8. A process for the production of 14desoxy-14-[(2-diethylaminoethyl)mercapto-acetoxylmutilin comprising reacting 14-desoxy-14-tosyloxyacetoxymutilin with diethylaminoethanethioi hydrochloride 15 under alkaline conditions and in the presence of a phase transfer catalyst.
9. 14-Desoxy-14-[(2-diethylaminoethyl)mercaptoacetoxy]mutilin whenever produced by the process of Claim 8. according to 20
10. The compound / Claim 9, in hydrogen fumarate salt form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE110878A IE46917B1 (en) | 1978-06-01 | 1978-06-01 | Process for the production of pleuromutilin derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE110878A IE46917B1 (en) | 1978-06-01 | 1978-06-01 | Process for the production of pleuromutilin derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE46917B1 true IE46917B1 (en) | 1983-11-02 |
Family
ID=11022026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE110878A IE46917B1 (en) | 1978-06-01 | 1978-06-01 | Process for the production of pleuromutilin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IE46917B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875432A (en) * | 2012-10-18 | 2013-01-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of high-yield tiamulinfumarate |
-
1978
- 1978-06-01 IE IE110878A patent/IE46917B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875432A (en) * | 2012-10-18 | 2013-01-16 | 宁夏泰瑞制药股份有限公司 | Preparation method of high-yield tiamulinfumarate |
| CN102875432B (en) * | 2012-10-18 | 2014-10-15 | 宁夏泰瑞制药股份有限公司 | Preparation method of high-yield tiamulinfumarate |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |