CA1233826A - 4-(2-phenoxyethyl)-1,2,4-triazolone process - Google Patents
4-(2-phenoxyethyl)-1,2,4-triazolone processInfo
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- CA1233826A CA1233826A CA000468894A CA468894A CA1233826A CA 1233826 A CA1233826 A CA 1233826A CA 000468894 A CA000468894 A CA 000468894A CA 468894 A CA468894 A CA 468894A CA 1233826 A CA1233826 A CA 1233826A
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- Prior art keywords
- compound
- amide
- activating agent
- phenoxyethyl
- iii
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
Abstract
Abstract of the Disclosure An improved process for the preparation of 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazolone, a useful intermediate in the synthesis of antidepressant 1,2,4-triazolones typified by 2-[3-[4-(3-chloro-phenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxethyl)-2H-1,2,4-triazol-3(4H)-one, also known as nefazodone. The improved process is shorter and higher in yield than the former process, and the starting materials are cheap and readily available.
Description
B'~j 4-(2~PHENOXYETHYL)-1,2,4-TRIAZOLONE PROCESS
This invention describes an improved, more economical process for the synthesis of a valuable chemical intermediate (I) ~o ~N\H
~1) used in the manufacture of ~he antidepressant agent 2-[3-[4-~3-chlorophenyl)-1-piperazinyl]propyl3-5-ethyl-4-(2-phenoxy-ethyl)-2H-1,2,4-triazol-3-(4H)-one which is also known as nefazodone.
Cl O ~ ~ ~ N ~ ) nefazodone This suhje(t intermediate, 5-ethy~ 4~(2-ph~no~yethyl)-l,2,4-triazolonl, of Formuln I is also known as MJ 148]4 ancl its c~lrrellt synthesis, disclosed in ~.S. application SN 06/509~266 (now ~.S. Patent 4,338,317 issued July 6t 1982) as Example 5, is shown in Scheme 1. An overall yield of 33% for Scheme I is predicted from yield calculations of the individual steps in Example 5 of the ~.S. patent.
Sche~e 1 O 5t~p 1 ~ ~ 0 ~ Et OC H
(1~ (2) 2 5 (3~
0 Step 2 0~ ~ ~2NNH2-~20 1) ~2NN~2 (5) . 2) ~Cl Step 3 t 23 ~
6) NHNH2 ~4) ~Cl ¦ Step 4A
Step 5 [ ~ NGC~O ~ Step 4B [
~ rS~
(9) H20 ¦ ~OH Step 6 .
(I; MJ ~4814 !
As can b~ s~en ln Schem~ 1, the prep~r~tion sf MJ 14814 6t~rts with phenol and ethyl ~c~yl~te, ~n obnoxlou~ ~aterl~l ~ith a high vspor pre~ure. This pro ess hss been successfully scAled up snd u~ed repeatedly giving MLJ 14814 in 25-30% overall yield from 5 phenol.
MJ 14814 i6 converted to thc nntldepres~ant ~ge~e nefazodone (MJ 13754) as di~clo~ed ln the ~bove cited U.S. patent. This conver~ion lnvolves reac~ion of MJ 14814 with 1-~3-chlorophenyl)~4-(3-chloropropyl)pipera2ine hydrochloride ~10) ,~1 Cl (10) Preparation of MJ 14814 Yia Scheme 1 ~nvolYe6 6iX ~tep~ a~d four l~olated intermed$ate6, two o ~hich are liq~lds requirln~
purification by vacuum di6tillatisn.
By contrast, the ~mproved process described herelnafter i~; comprl~ed o f f our s~eps iDvol~ing only three lsolated intermediates, all of which are solids, ~lth an overall yield of ~J 14814 of 40-55X from phenol. In compari~on, the prior art me~hod, represented by Scheme I, is 8 lon~er proce~s requiring more labor and providing MJ 14814 ~n much lower yleld.
The following reference~ relate to component 6tep~ of the 20 iD6tant process described herein.
1. Dow Technical BulleeiD, "Developmental 2-Ethyl-2-Oxazoline XAS-1454 Ethyloxazollne: An Intermediate for Am$noethyl~tion."
Thi6 reference describe~ ~he 6ynthe~i~ of N-(2-phenoxyethyl)propion-a~ide, ~n ~nten~ediate c~mpound of the in~ant prvcess.
3~ x~,
This invention describes an improved, more economical process for the synthesis of a valuable chemical intermediate (I) ~o ~N\H
~1) used in the manufacture of ~he antidepressant agent 2-[3-[4-~3-chlorophenyl)-1-piperazinyl]propyl3-5-ethyl-4-(2-phenoxy-ethyl)-2H-1,2,4-triazol-3-(4H)-one which is also known as nefazodone.
Cl O ~ ~ ~ N ~ ) nefazodone This suhje(t intermediate, 5-ethy~ 4~(2-ph~no~yethyl)-l,2,4-triazolonl, of Formuln I is also known as MJ 148]4 ancl its c~lrrellt synthesis, disclosed in ~.S. application SN 06/509~266 (now ~.S. Patent 4,338,317 issued July 6t 1982) as Example 5, is shown in Scheme 1. An overall yield of 33% for Scheme I is predicted from yield calculations of the individual steps in Example 5 of the ~.S. patent.
Sche~e 1 O 5t~p 1 ~ ~ 0 ~ Et OC H
(1~ (2) 2 5 (3~
0 Step 2 0~ ~ ~2NNH2-~20 1) ~2NN~2 (5) . 2) ~Cl Step 3 t 23 ~
6) NHNH2 ~4) ~Cl ¦ Step 4A
Step 5 [ ~ NGC~O ~ Step 4B [
~ rS~
(9) H20 ¦ ~OH Step 6 .
(I; MJ ~4814 !
As can b~ s~en ln Schem~ 1, the prep~r~tion sf MJ 14814 6t~rts with phenol and ethyl ~c~yl~te, ~n obnoxlou~ ~aterl~l ~ith a high vspor pre~ure. This pro ess hss been successfully scAled up snd u~ed repeatedly giving MLJ 14814 in 25-30% overall yield from 5 phenol.
MJ 14814 i6 converted to thc nntldepres~ant ~ge~e nefazodone (MJ 13754) as di~clo~ed ln the ~bove cited U.S. patent. This conver~ion lnvolves reac~ion of MJ 14814 with 1-~3-chlorophenyl)~4-(3-chloropropyl)pipera2ine hydrochloride ~10) ,~1 Cl (10) Preparation of MJ 14814 Yia Scheme 1 ~nvolYe6 6iX ~tep~ a~d four l~olated intermed$ate6, two o ~hich are liq~lds requirln~
purification by vacuum di6tillatisn.
By contrast, the ~mproved process described herelnafter i~; comprl~ed o f f our s~eps iDvol~ing only three lsolated intermediates, all of which are solids, ~lth an overall yield of ~J 14814 of 40-55X from phenol. In compari~on, the prior art me~hod, represented by Scheme I, is 8 lon~er proce~s requiring more labor and providing MJ 14814 ~n much lower yleld.
The following reference~ relate to component 6tep~ of the 20 iD6tant process described herein.
1. Dow Technical BulleeiD, "Developmental 2-Ethyl-2-Oxazoline XAS-1454 Ethyloxazollne: An Intermediate for Am$noethyl~tion."
Thi6 reference describe~ ~he 6ynthe~i~ of N-(2-phenoxyethyl)propion-a~ide, ~n ~nten~ediate c~mpound of the in~ant prvcess.
3~ x~,
2. W. Reid snd A. C~ck, Ann. 676, pp. 121-129 (1964).
Thifi reference teaches the reR^tion of lmldoyl ethers ~ith e~hyl carbazste to ~ive am~drazones which ehen cyclize on further heaeing to 1,2,4-triazoles as outllned below in Sche~e 2.
Scheme 2 R ~ OR 2NNHCO2R --~ R NHNHCO R"
R" ~ ethyl ~owever, there i6 no di6closure of the use of N-substi~u~ed lmidoyl ethers which would be necessary to obtain a desired N-eub6tituted ~riazolone.
Thifi reference teaches the reR^tion of lmldoyl ethers ~ith e~hyl carbazste to ~ive am~drazones which ehen cyclize on further heaeing to 1,2,4-triazoles as outllned below in Sche~e 2.
Scheme 2 R ~ OR 2NNHCO2R --~ R NHNHCO R"
R" ~ ethyl ~owever, there i6 no di6closure of the use of N-substi~u~ed lmidoyl ethers which would be necessary to obtain a desired N-eub6tituted ~riazolone.
3. M. Pesson, et al., Bull. Soc. Chim., Fr., pp~ 13~7-71 (1962). This reference reports a very low yield synthesl6 (0.3~ of a triazolone w*th the de~ired ~ub~titution pattern via ~he proces6 fihown below in Scheme 3.
Scheme 3 OH H ~ ~ N
+ H2NHC02~t OMe ~ ~N ~ NH
0.3Z yield The author~ state that imidoyl ether6 of 6econdary amides are difficult to make (p. 1364, bottom 6econd column). Pesson, et al., do di~close preparation of a triazolone with the desired sub~t$tution patte m but ~ia 8 synthesi6, 6hown as Scheme 4, which is dlfferent from that in the instant process. The reference 6yn~hesi6 beglhs with ~n lmldoyl e~her of a primary ~mide to glve an in~ermedlate carbethoxy hydrazone which ls then reacted ~ith a primary amine.
Scheme 4 R ~ HCl ~ H2NNHC02Et e o R ~ OEt O
Note that the carbazate dl~places the imine function ln Sche~e 4 representing another feature di~tingui6hlng the proces6 of the instant lnventionO
Pesson, et al., 9160 di6clo6e that thioamide6 are more reactive than amides, giving N-6ubstituted amidrazones on reactlon with carbazate. Howevert whe~ the N-~ubstituent is alkyl, as required in the instant process, no reaction with ethyl carbazate was observed.
Finally, Pesson, et al., teach activation of a thiobenzamlde wlth dimethylsulfate followed by reaction with carbazste eo give the triazolone product. Again, there is no disclosure involving activation of alkyl carboxylic acid thioamides, a 6tructural prerequisite for the instant ~rocess.
In summary, references 2 and 3 es6entially descr~be reactions of certain smide derivatives with carbazate esters to eventually yield triazolone products but with di~einguishing variat$ons in structural relationship to the product produced by the instant process.
This invention relates to an improved synthetie pr4ces6 which can be adapted for large-scale preparation of the useful chemlc~l intermed$ate, 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triAzolone.
The l~stant process start6 from phenol and 2-ethyl-2-oxazoline, raw maeerials which are eheap and readily ~vailable. The ~ub~ect i~proved process offers advantages in economies of both material and labor costs by v~rtue of being Eh~rter in length, involving fewer intermediate isolatlons, and psoviding a higher yield of product.
The following flo~ chart, Scheme 5, illustrates the preparstion ~f MJ 14814 fr~m readily available ~t~rting materials utilizing ~he instant process.
Scheme 5 OH + ~ ~ l75 ~ ~ o (1) (V) SIV) Amide activation Step 2 (SOX2; Me2SO4;
~ POC13; COC12; etc.) ~ H2~C
02R r~ ~ 1 O~ ' HX ~ L EX
II ~ III
\ OH, heat Step 4 \
(I; MJ 14814) 40-55% yield In Scheme 5, R 1~ Cl ~ alkyl; X is Cl, Brp or SO4; ~ i6 Cl, Br, or OR; and amlde activation ls forma~ion of a reactive imidoyl halide or ester by treatment of the amide wl~h a suitable activating reagent fiuch a5 SOC12, SOBr2, POC13, dimethyl ~ulfate, phosgene, etc.
S Step 1 of the scheme outlined above lnvolves the reaction of phenol (1) and 2-ethyl-2-oxazoline ~V) to glve the lneer~ediate compound N-(2-pheno~yethyl)propionamide ~IV). ThP 6eartin~ ~aterial6 for step 1 are commercially available. Step 2, acti~at~on of the ~mide ~IV), is accomplihed by treatmen~ of IV with Rn amide-ac~i~ating reagent such as thionyl chloride~ thionyl bromide, phosphorus oxychloride, phosgene~dimet~l sulfate, and the like, to give an i~idoyl hal$de or ester ~ntermediate (III). The preferred agent~ are phosgene or phosphorus oxychloride. Intermedlate III is not l~olated but ls allowed to react ~ith ~n alkyl carbazate of for~ula ~2NNHCO2R, R ~ ~ethyl is preferred, in ~9tep 3 to give the novel triazolone precursor (II). In step 4 the hydrazinecarboxylate acid additlon salt (II) ~s converted to it6 ba6e form and cyclized to the desired triazulone product (1~ by heating.
This four-seep improved process involves lsolation of orly tWD intermediate products (IV and II) in addition to che target co~pound, I. By way of comparison9 the current process invDlve6 6lx ~teps and the isolation of four intermediates, two of which are liquld and require purification by vacuum distillation. The retuced handling of lntermediates in the lDstant process 61gnificantly reduces labor costs ln ~Anufscture.
The synthesis of ~J 14814 as represented in the ~mproved proce~s is preferably carried out ~s a ~eries of four ~teps going from the ~implest startiDg materialfi (phenol, 2-ethyloxazollne) to MJ 14814. The steps comprlsing the process ~re as follow6:
(1) Addlng 2-ethyl-2-oxazoline to hot (150) phenol nnd maintaining heating at about 175~ for 16 additional hours. The oil is then quenched in water to give N-(2-phenoxyethyl)propionsmide (IV) in approximately 90% yield.
(2) Adding phosgene or phosphorus oxychloride to a colution of IV containing a catalyeic amount of $mida~ole in m~thylene chloride to give a solution of the intPrmediate imidoyl chloride hydrochloride (III).
(3) Treating th~ solution of III with a ~olution of an alkyl carbazate to give alkyl [1-[(2-phenoxyethyl)amino]propylidene]-hydraz$ne carboxylate hydrochloride (II) 1~ about 75~ yield.
Scheme 3 OH H ~ ~ N
+ H2NHC02~t OMe ~ ~N ~ NH
0.3Z yield The author~ state that imidoyl ether6 of 6econdary amides are difficult to make (p. 1364, bottom 6econd column). Pesson, et al., do di~close preparation of a triazolone with the desired sub~t$tution patte m but ~ia 8 synthesi6, 6hown as Scheme 4, which is dlfferent from that in the instant process. The reference 6yn~hesi6 beglhs with ~n lmldoyl e~her of a primary ~mide to glve an in~ermedlate carbethoxy hydrazone which ls then reacted ~ith a primary amine.
Scheme 4 R ~ HCl ~ H2NNHC02Et e o R ~ OEt O
Note that the carbazate dl~places the imine function ln Sche~e 4 representing another feature di~tingui6hlng the proces6 of the instant lnventionO
Pesson, et al., 9160 di6clo6e that thioamide6 are more reactive than amides, giving N-6ubstituted amidrazones on reactlon with carbazate. Howevert whe~ the N-~ubstituent is alkyl, as required in the instant process, no reaction with ethyl carbazate was observed.
Finally, Pesson, et al., teach activation of a thiobenzamlde wlth dimethylsulfate followed by reaction with carbazste eo give the triazolone product. Again, there is no disclosure involving activation of alkyl carboxylic acid thioamides, a 6tructural prerequisite for the instant ~rocess.
In summary, references 2 and 3 es6entially descr~be reactions of certain smide derivatives with carbazate esters to eventually yield triazolone products but with di~einguishing variat$ons in structural relationship to the product produced by the instant process.
This invention relates to an improved synthetie pr4ces6 which can be adapted for large-scale preparation of the useful chemlc~l intermed$ate, 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triAzolone.
The l~stant process start6 from phenol and 2-ethyl-2-oxazoline, raw maeerials which are eheap and readily ~vailable. The ~ub~ect i~proved process offers advantages in economies of both material and labor costs by v~rtue of being Eh~rter in length, involving fewer intermediate isolatlons, and psoviding a higher yield of product.
The following flo~ chart, Scheme 5, illustrates the preparstion ~f MJ 14814 fr~m readily available ~t~rting materials utilizing ~he instant process.
Scheme 5 OH + ~ ~ l75 ~ ~ o (1) (V) SIV) Amide activation Step 2 (SOX2; Me2SO4;
~ POC13; COC12; etc.) ~ H2~C
02R r~ ~ 1 O~ ' HX ~ L EX
II ~ III
\ OH, heat Step 4 \
(I; MJ 14814) 40-55% yield In Scheme 5, R 1~ Cl ~ alkyl; X is Cl, Brp or SO4; ~ i6 Cl, Br, or OR; and amlde activation ls forma~ion of a reactive imidoyl halide or ester by treatment of the amide wl~h a suitable activating reagent fiuch a5 SOC12, SOBr2, POC13, dimethyl ~ulfate, phosgene, etc.
S Step 1 of the scheme outlined above lnvolves the reaction of phenol (1) and 2-ethyl-2-oxazoline ~V) to glve the lneer~ediate compound N-(2-pheno~yethyl)propionamide ~IV). ThP 6eartin~ ~aterial6 for step 1 are commercially available. Step 2, acti~at~on of the ~mide ~IV), is accomplihed by treatmen~ of IV with Rn amide-ac~i~ating reagent such as thionyl chloride~ thionyl bromide, phosphorus oxychloride, phosgene~dimet~l sulfate, and the like, to give an i~idoyl hal$de or ester ~ntermediate (III). The preferred agent~ are phosgene or phosphorus oxychloride. Intermedlate III is not l~olated but ls allowed to react ~ith ~n alkyl carbazate of for~ula ~2NNHCO2R, R ~ ~ethyl is preferred, in ~9tep 3 to give the novel triazolone precursor (II). In step 4 the hydrazinecarboxylate acid additlon salt (II) ~s converted to it6 ba6e form and cyclized to the desired triazulone product (1~ by heating.
This four-seep improved process involves lsolation of orly tWD intermediate products (IV and II) in addition to che target co~pound, I. By way of comparison9 the current process invDlve6 6lx ~teps and the isolation of four intermediates, two of which are liquld and require purification by vacuum distillation. The retuced handling of lntermediates in the lDstant process 61gnificantly reduces labor costs ln ~Anufscture.
The synthesis of ~J 14814 as represented in the ~mproved proce~s is preferably carried out ~s a ~eries of four ~teps going from the ~implest startiDg materialfi (phenol, 2-ethyloxazollne) to MJ 14814. The steps comprlsing the process ~re as follow6:
(1) Addlng 2-ethyl-2-oxazoline to hot (150) phenol nnd maintaining heating at about 175~ for 16 additional hours. The oil is then quenched in water to give N-(2-phenoxyethyl)propionsmide (IV) in approximately 90% yield.
(2) Adding phosgene or phosphorus oxychloride to a colution of IV containing a catalyeic amount of $mida~ole in m~thylene chloride to give a solution of the intPrmediate imidoyl chloride hydrochloride (III).
(3) Treating th~ solution of III with a ~olution of an alkyl carbazate to give alkyl [1-[(2-phenoxyethyl)amino]propylidene]-hydraz$ne carboxylate hydrochloride (II) 1~ about 75~ yield.
(4) The free base form of IIg resultlng from the trea~ent of II with a basifying agent, is heated in solution for 6everal hour~
~o yield I in about 75X.
Descr~ption Of Spec~fic Embodiments The process of this invention is illustrated in greater detail by the following examples directed to preferred embodiments of the here~nafter described process steps. These examples, however, should not be construed as limlting the scope of the present lnvention in any way. In exsmples which follow, used to illustrate the fore-going processe6, temperstures are expressed, as in the foregoing, in degrees centigrade (). Melting po~nts are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical sh$fts (~) expressed as parts per m$11ion (ppm) versu6 tetr~methyl-silane (~MS) as reference standard. The relative area reported for ehe varlous shlft6 ln the H NMR ~pectral data corresponds to the nu~ber of hydrogen atoms of a particular functional type in the molecule. The nature of the 6hift6 AS to multipliclty is reported as broad inglet (bs), ~inglet (B), doublet (d), tr~plet (t), quartet (q), or multiplet (m). Abbreviations employed are ~MSO-d6 (deutero-d1methyl6ulfoxide), CDC13 (deuterochloroform), and are otherwi6e conventional. The infrared (IR) 6pectral descr~ption6 include only absorpt~on wave numbers (cm 1) having functional group identification value. The IR determinations were employed using potassium bromlde (KBr) as diluent. The elemental analyses are reported as percent by weight.
EX~MPLE 1 Meth~l Carbazate An alternate name for this co~mercially available chemical is methyl hydrazinocarboxylate. Methyl carbazate ~ay also be ~ynthe6ized by adding 85% hydrazine hydrzte (5805 g, 1.00 mole) w~th stir~n~ to dimethyl carbonste (90.0 ~, 1.00 mole) over a 10 min period. The mixture quickly warmed to 64D and became clear. The solution was stirred for another 15 min and the volatile materials were 6tripped in vaeuo at 70. Upon cooling, the residue ~olid$fied. It ~as collected on a filter and after drying in a~r gave 69.3 g (76.9Z) of white 601id, m.p. 69.5-71.5.
N-(2-Phenoxyethvl)propionamide (IV) Phenol (13.1 mole6) was heated to 150 and 6tirred under N2 as 2-ethyl-2-oxazoline (12.2 moles) was added over 1 hr. The mixture was heated to 175 + 3D. After heating 16 hr the oil W8S cooled to _ g _ ~L~3' ~ ;d~
about 140, ~nd then it was poured in~o waeer (12 L) with vigorous stirring. The mixture was 6tlrred and cooled, and at about 25 the mixture was 6eeded with crystalline amide product. The mfiterial solidified and the supernatant was decanted. The residual 601id was ~tirred with 17 L of hot (85) water. The m~xture ~as cooled to 25, ~eeded with the amide product, and the mixture refrigeratet. The resulting granular ~olid was collected on a fileer~ rinsed with 6everal portions of water and left to a~r dry. Thls gave ~ 92% yield of material, m.p. 61.5-64~.
A. Methyl [1-[~2-Phenoxyethyl]amino]propyl~dene Hydrazinecsrboxylate Nydrochloride (II~ _ PhosgeDe (57.4 g, 0.58 ~ole) was added to a solution of N-(2-phenoxyethyl)propionamide (IV, 112.0 g, 0.58 uole) and imidazole ~0.4 g, 0.006 mole) in 450 mL methylene chloride over 1 hr employing cooliag 60 that the te~perature did not e~ceed 25~. The reactio~
~olution was then stirred at 25~ for an additional 2.5 hr. A ~Dlution of methyl carbazate (52.5 g, 0.58 mole) in 500 mL methylene chloride was stirred over 25 g of a molecular sieve for 15 min and theD the solution was filteret. The fll~rate was added under N2 over a 0.5 hr period to the amide/phosgene 601ution whlle employing cDoling 15-20.
A voluminous precipitate formed and the mixture was left to stir at 25 under ~2. After stirring for a total of 16 hrs, the mixture was filtered to isolate a solid. The 601id was stirred in 750 mL methylene chloride for 15 min, refiltered, and then dried in vacuo at 65 for 2 hrs to give 135 g (77~) white solid, m.p. 150-154. Recrystallization of the product from isopropanol glves analytically pure material, .p. 157-159.
An~l Calcd. for C13Hl~N303 ~Cl C~ 51-~4; H, 6-6~;
~, 13.92; Cl, 11.75. Found: C, Sl.73; ~9 6.76; N, 13.9h; Cl, 11.7B.
NMR (DMSO-d6): 1.15 (3,t 17.5 H~); 1.28 13.t [7.5 Hz~);
2.74 (2,m)9 3.66 ~3,6); 3.70 ~3,s); 3~81 ~2,m); 4.19 ~2,m); 6.g8 (3,m)~
~.31 (2,m); 9.67 (3,bt 16.8 H~]); 10.04 (3,bs); 10.40 ~3,bs~; 10.90 (3~bs); 11.72 (3,bs).
I~ (KBr): 695, 755, 1250, 1270, 1500, 1585p 1600, 1670, 1745, and 29Q0 cm 1, By appropriate modification of tbe above procedure (A), thionyl chloride, thionyl bromide, dlmethyl sulfate or ~thes amlde-activating agents may be employed in place of phos~ene. A elightly dif f erent procedure (B) may also be used.
B. Methyl [1~1~2-Phenoxyethyl~a~ino~propylid~ne Nydrazinecarboxylate (II Base Form) Phosphorus oxychloride t53.0 g9 0.346 mol2) ~as Blo~ly added to a solution of N-(2-phenoxyethyl)propionamide (IV, 100~0 g, 0.518 ~ole~
in 200 mL methylene chloride while being stirred under DierOgen. This sblution was stirred for 4 hrs at which tlme a solution (dried over moecular sieYe 4A) of methyl carbazate (46.4 g9 0.518 ~ole) in 600 mL
methylene chloride ~as added to the stirring solution ~ver a 0.5 hr period. The resulting mixture was stirred and hea~ed at gentle reflux under nitrogen for 18 hr. The mixture was then stirred ~ith 1.0 L
ice-water. The layers were separated and the aqueous layers extracted with an additional 200 mL methylene chloride. The aqueous layer was made basic (pH 12) with aqueous sodium hydroxide. Thi5 resulted in precipitation of the free base form of II which was collected by filtration, rinsed with water and dried in air to gi~e 65.8 g of product, m.p. 9~-99.
~1 q3~
Anal- Calcd- for C13H19N33 C~ 58-85; H~ 7-22; N~ 15-84-Found: C, 59.02; H, 7.24; N, 15.92.
When this free base form of II is e~ployed for the conversion to I, the preliminary basification ~tep outlined 1n Ex~mple 4 (which follows) i6 skipped. The ba~e fDrm of II is cyclized dirPctly by gently refluxing in xy;ene sccording to the procedure of Example 4.
~o yield I in about 75X.
Descr~ption Of Spec~fic Embodiments The process of this invention is illustrated in greater detail by the following examples directed to preferred embodiments of the here~nafter described process steps. These examples, however, should not be construed as limlting the scope of the present lnvention in any way. In exsmples which follow, used to illustrate the fore-going processe6, temperstures are expressed, as in the foregoing, in degrees centigrade (). Melting po~nts are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical sh$fts (~) expressed as parts per m$11ion (ppm) versu6 tetr~methyl-silane (~MS) as reference standard. The relative area reported for ehe varlous shlft6 ln the H NMR ~pectral data corresponds to the nu~ber of hydrogen atoms of a particular functional type in the molecule. The nature of the 6hift6 AS to multipliclty is reported as broad inglet (bs), ~inglet (B), doublet (d), tr~plet (t), quartet (q), or multiplet (m). Abbreviations employed are ~MSO-d6 (deutero-d1methyl6ulfoxide), CDC13 (deuterochloroform), and are otherwi6e conventional. The infrared (IR) 6pectral descr~ption6 include only absorpt~on wave numbers (cm 1) having functional group identification value. The IR determinations were employed using potassium bromlde (KBr) as diluent. The elemental analyses are reported as percent by weight.
EX~MPLE 1 Meth~l Carbazate An alternate name for this co~mercially available chemical is methyl hydrazinocarboxylate. Methyl carbazate ~ay also be ~ynthe6ized by adding 85% hydrazine hydrzte (5805 g, 1.00 mole) w~th stir~n~ to dimethyl carbonste (90.0 ~, 1.00 mole) over a 10 min period. The mixture quickly warmed to 64D and became clear. The solution was stirred for another 15 min and the volatile materials were 6tripped in vaeuo at 70. Upon cooling, the residue ~olid$fied. It ~as collected on a filter and after drying in a~r gave 69.3 g (76.9Z) of white 601id, m.p. 69.5-71.5.
N-(2-Phenoxyethvl)propionamide (IV) Phenol (13.1 mole6) was heated to 150 and 6tirred under N2 as 2-ethyl-2-oxazoline (12.2 moles) was added over 1 hr. The mixture was heated to 175 + 3D. After heating 16 hr the oil W8S cooled to _ g _ ~L~3' ~ ;d~
about 140, ~nd then it was poured in~o waeer (12 L) with vigorous stirring. The mixture was 6tlrred and cooled, and at about 25 the mixture was 6eeded with crystalline amide product. The mfiterial solidified and the supernatant was decanted. The residual 601id was ~tirred with 17 L of hot (85) water. The m~xture ~as cooled to 25, ~eeded with the amide product, and the mixture refrigeratet. The resulting granular ~olid was collected on a fileer~ rinsed with 6everal portions of water and left to a~r dry. Thls gave ~ 92% yield of material, m.p. 61.5-64~.
A. Methyl [1-[~2-Phenoxyethyl]amino]propyl~dene Hydrazinecsrboxylate Nydrochloride (II~ _ PhosgeDe (57.4 g, 0.58 ~ole) was added to a solution of N-(2-phenoxyethyl)propionamide (IV, 112.0 g, 0.58 uole) and imidazole ~0.4 g, 0.006 mole) in 450 mL methylene chloride over 1 hr employing cooliag 60 that the te~perature did not e~ceed 25~. The reactio~
~olution was then stirred at 25~ for an additional 2.5 hr. A ~Dlution of methyl carbazate (52.5 g, 0.58 mole) in 500 mL methylene chloride was stirred over 25 g of a molecular sieve for 15 min and theD the solution was filteret. The fll~rate was added under N2 over a 0.5 hr period to the amide/phosgene 601ution whlle employing cDoling 15-20.
A voluminous precipitate formed and the mixture was left to stir at 25 under ~2. After stirring for a total of 16 hrs, the mixture was filtered to isolate a solid. The 601id was stirred in 750 mL methylene chloride for 15 min, refiltered, and then dried in vacuo at 65 for 2 hrs to give 135 g (77~) white solid, m.p. 150-154. Recrystallization of the product from isopropanol glves analytically pure material, .p. 157-159.
An~l Calcd. for C13Hl~N303 ~Cl C~ 51-~4; H, 6-6~;
~, 13.92; Cl, 11.75. Found: C, Sl.73; ~9 6.76; N, 13.9h; Cl, 11.7B.
NMR (DMSO-d6): 1.15 (3,t 17.5 H~); 1.28 13.t [7.5 Hz~);
2.74 (2,m)9 3.66 ~3,6); 3.70 ~3,s); 3~81 ~2,m); 4.19 ~2,m); 6.g8 (3,m)~
~.31 (2,m); 9.67 (3,bt 16.8 H~]); 10.04 (3,bs); 10.40 ~3,bs~; 10.90 (3~bs); 11.72 (3,bs).
I~ (KBr): 695, 755, 1250, 1270, 1500, 1585p 1600, 1670, 1745, and 29Q0 cm 1, By appropriate modification of tbe above procedure (A), thionyl chloride, thionyl bromide, dlmethyl sulfate or ~thes amlde-activating agents may be employed in place of phos~ene. A elightly dif f erent procedure (B) may also be used.
B. Methyl [1~1~2-Phenoxyethyl~a~ino~propylid~ne Nydrazinecarboxylate (II Base Form) Phosphorus oxychloride t53.0 g9 0.346 mol2) ~as Blo~ly added to a solution of N-(2-phenoxyethyl)propionamide (IV, 100~0 g, 0.518 ~ole~
in 200 mL methylene chloride while being stirred under DierOgen. This sblution was stirred for 4 hrs at which tlme a solution (dried over moecular sieYe 4A) of methyl carbazate (46.4 g9 0.518 ~ole) in 600 mL
methylene chloride ~as added to the stirring solution ~ver a 0.5 hr period. The resulting mixture was stirred and hea~ed at gentle reflux under nitrogen for 18 hr. The mixture was then stirred ~ith 1.0 L
ice-water. The layers were separated and the aqueous layers extracted with an additional 200 mL methylene chloride. The aqueous layer was made basic (pH 12) with aqueous sodium hydroxide. Thi5 resulted in precipitation of the free base form of II which was collected by filtration, rinsed with water and dried in air to gi~e 65.8 g of product, m.p. 9~-99.
~1 q3~
Anal- Calcd- for C13H19N33 C~ 58-85; H~ 7-22; N~ 15-84-Found: C, 59.02; H, 7.24; N, 15.92.
When this free base form of II is e~ployed for the conversion to I, the preliminary basification ~tep outlined 1n Ex~mple 4 (which follows) i6 skipped. The ba~e fDrm of II is cyclized dirPctly by gently refluxing in xy;ene sccording to the procedure of Example 4.
5-Ethyl-4-(2-phenoxyethyl)-2H-1 ? 2,4~triazol-3~4H)-one ~I) Methyl [1-[(2-phenoxyethyl)amino]propylidenejhydrazine carboxylate hydrochloride (II, 655.3 g, 2.17 ~ole) was ~tirred vigorously with 4.0 L methylene chloride, 2.4 L water and 179.4 g 50%
~aOH (2.24 moles). The layers were separated and the organic layer was dried (R2C03) and concentrated in vacuo. The residue was ctirred in 1.2 L xylene at gentle reflux for 2.5 hrs and then the ~olution was refrigerated. The solid was collected on a filter, rinsed wi~h toluene and left to air dry. The w~ite cry6talline solid ~eighed 89.5 g (76.9%), m.p. 134.5-138.
Additional purification ~ay be accomplished ~n the following manner. A portion of I (171.2 g~ 0.73 mole~ was dissolved iD a boiling ~olution of 41.0 g (0.73 mole) ROH in 3.0 L ~ater. The solution was treated with Celite filter-aid and activated charcoal and filtered. The filtrate was stirred in an ice bath, and 37Z HCl ~61.0 mL, 0.73 mole) was added. The sol$d was collected on a filter, 25 rinsed with water and air dried to give 166.0 g (97X recovery~ of fine white crystalline product, m.p. 137.5-138.
~aOH (2.24 moles). The layers were separated and the organic layer was dried (R2C03) and concentrated in vacuo. The residue was ctirred in 1.2 L xylene at gentle reflux for 2.5 hrs and then the ~olution was refrigerated. The solid was collected on a filter, rinsed wi~h toluene and left to air dry. The w~ite cry6talline solid ~eighed 89.5 g (76.9%), m.p. 134.5-138.
Additional purification ~ay be accomplished ~n the following manner. A portion of I (171.2 g~ 0.73 mole~ was dissolved iD a boiling ~olution of 41.0 g (0.73 mole) ROH in 3.0 L ~ater. The solution was treated with Celite filter-aid and activated charcoal and filtered. The filtrate was stirred in an ice bath, and 37Z HCl ~61.0 mL, 0.73 mole) was added. The sol$d was collected on a filter, 25 rinsed with water and air dried to give 166.0 g (97X recovery~ of fine white crystalline product, m.p. 137.5-138.
Claims (13)
IS CLAIMED ARE DEFINED AS FOLLOWS.
1. A process for preparing 5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one (I) (I) which comprises the consecutive steps of:
a) reacting phenol with 2-ethyl-2-oxazoline (V) (V) to give N-(2-phenoxyethyl)propionamide (IV) (IV) b) activating the amide functional group of compound IV by reacting compound IV with an amide-activating agent, so as to produce an imidoyl halide or ester intermediate of formula III;
III
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV., c) reacting the product of step b without isolating said compound III with a carbazate ester of formula H2NNHCO2R to give an alkyl [1-[(2-phenoxylethyl)amine]propylidene]hydrazine carboxylate acid addition salt (II) (II) wherein R is lower (C1-C4) alkyl, and X is an anion, generally corresponding to the anion of the amide-activating agent used in step b; and d) converting compound II into compound I by means of suitable thermal treatment of compound II in its free base form so as to form compound I.
a) reacting phenol with 2-ethyl-2-oxazoline (V) (V) to give N-(2-phenoxyethyl)propionamide (IV) (IV) b) activating the amide functional group of compound IV by reacting compound IV with an amide-activating agent, so as to produce an imidoyl halide or ester intermediate of formula III;
III
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV., c) reacting the product of step b without isolating said compound III with a carbazate ester of formula H2NNHCO2R to give an alkyl [1-[(2-phenoxylethyl)amine]propylidene]hydrazine carboxylate acid addition salt (II) (II) wherein R is lower (C1-C4) alkyl, and X is an anion, generally corresponding to the anion of the amide-activating agent used in step b; and d) converting compound II into compound I by means of suitable thermal treatment of compound II in its free base form so as to form compound I.
2. A process as in claim 1 wherein the activating agent is chosen from thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene and dimethyl sulfate.
3. The process of claim 1 wherein the amide-activating agent in step b is phosgene.
4. The process of claim 1 wherein the amide-activating agent in step b is phosphorus oxychloride.
5. The process of claim 1 wherein the thermal treatment of step d) comprises refluxing the free base of compound II in a suitable inert organic solvent.
6. A process for preparing the compound of formula II comprising:
a) reacting phenol with 2-ethyl-2-oxazoline (V) (V) to give N-(2-phenoxyethyl)propionamide (IV) ;
(IV) b) activating the amide functional group of compound IV by reacting compound IV with an amide-activating agent, so as to produce an imidoyl halide or ester intermediate of formula III;
;
III
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV., and c) reacting the product of step b without isolating said compound III with a carbazate ester of formula H2NNHCO2R
to give an alkyl [1-[(2-phenoxyethyl)amine]propylidene]-hydrazine carboxylate acid addition salt (II) (II) wherein R is lower (C1-C4) alkyl, and X is an anion, generally corresponding to the anion of the amide-activating agent used in step b.
a) reacting phenol with 2-ethyl-2-oxazoline (V) (V) to give N-(2-phenoxyethyl)propionamide (IV) ;
(IV) b) activating the amide functional group of compound IV by reacting compound IV with an amide-activating agent, so as to produce an imidoyl halide or ester intermediate of formula III;
;
III
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV., and c) reacting the product of step b without isolating said compound III with a carbazate ester of formula H2NNHCO2R
to give an alkyl [1-[(2-phenoxyethyl)amine]propylidene]-hydrazine carboxylate acid addition salt (II) (II) wherein R is lower (C1-C4) alkyl, and X is an anion, generally corresponding to the anion of the amide-activating agent used in step b.
7. A process as in claim 6 wherein the amide activating agent is chosen from thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, and dimethyl sulfate.
8. The compound methyl [1-[(2-phenoxyethyl)-amino]propylidene]hydrazine carboxylate or an acid addition salt thereof.
9. A process as in claim 6 which comprises forming the hydrochloride salt of the product of formula II.
10. The compound methyl [1-[(2-phenoxyethyl)-amino]propylidene]hydrazine carboxylate hydrochloride.
11. A process for the preparation of an imidoyl halide or ester of formula III as defined in claim 6 III
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV; said process comprising the step of activating the amide functional group of compound IV
(IV) by reacting compound IV with an amide activating agent.
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV; said process comprising the step of activating the amide functional group of compound IV
(IV) by reacting compound IV with an amide activating agent.
12. A process as in claim 11 wherein the amide activating agent is chosen from thionyl chloride, thionyl bromide, phosphorus oxychloride, phosgene, or dimethyl sulfate.
13. An imidoyl halide or ester of formula III as defined in claim 11 III
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV.
wherein Y is a halogen or alkoxy moiety and wherein X is an anion which results from the reaction between said amide activating agent and compound IV.
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| Application Number | Priority Date | Filing Date | Title |
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| US55672783A | 1983-11-30 | 1983-11-30 | |
| US556,727 | 1983-11-30 |
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| JP (1) | JPS60132969A (en) |
| KR (1) | KR890000990B1 (en) |
| AT (1) | AT387571B (en) |
| AU (1) | AU576338B2 (en) |
| BE (1) | BE901165A (en) |
| CA (1) | CA1233826A (en) |
| CH (1) | CH663613A5 (en) |
| CY (2) | CY1472A (en) |
| DE (1) | DE3443820C2 (en) |
| DK (3) | DK159970C (en) |
| ES (2) | ES8609282A1 (en) |
| FI (1) | FI81785C (en) |
| FR (1) | FR2555582B1 (en) |
| GB (2) | GB2150567B (en) |
| GR (1) | GR81110B (en) |
| HK (2) | HK16389A (en) |
| IE (1) | IE74871B1 (en) |
| IT (1) | IT1178641B (en) |
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| LU (1) | LU85657A1 (en) |
| NL (1) | NL8403635A (en) |
| SE (3) | SE456993B (en) |
| SG (1) | SG80588G (en) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5900485A (en) * | 1996-07-29 | 1999-05-04 | Apotex, Inc. | Methods for the manufacture of neofazodone |
| US6596866B2 (en) | 2001-09-10 | 2003-07-22 | Brantford Chemicals Inc. | Process for the preparation of nefazodone hydrochloride |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19902960A1 (en) | 1999-01-26 | 2000-07-27 | Bayer Ag | Production of high-purity methyl carbazate comprises adding hydrazine and dimethyl carbonate simultaneously to solvent, distilling off solvent and low boilers and purifying product |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1126882B (en) * | 1960-05-03 | 1962-04-05 | Boehringer Sohn Ingelheim | Process for the preparation of 1,2,4-triazolonen- (5) |
| DE1545646B1 (en) * | 1965-12-15 | 1969-09-18 | Boehringer Sohn Ingelheim | 1,3-Dimethyl-4- (2 ', 4'-dichlorophenyl) -1,2,4-triazolon- (5) and process for its preparation |
| US4338317A (en) * | 1981-03-16 | 1982-07-06 | Mead Johnson & Company | Phenoxyethyl-1,2,4,-triazol-3-one antidepressants |
| US4487773A (en) * | 1981-03-16 | 1984-12-11 | Mead Johnson & Company | 1,2,4-Triazol-3-one antidepressants |
| US4613600A (en) * | 1983-09-30 | 1986-09-23 | Mead Johnson & Company | Antidepressant 1,2,4-triazolone compounds |
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- 1984-11-29 CA CA000468894A patent/CA1233826A/en not_active Expired
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- 1984-11-29 IT IT23808/84A patent/IT1178641B/en active
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- 1984-11-30 JP JP59252083A patent/JPS60132969A/en active Granted
- 1984-11-30 KR KR1019840007553A patent/KR890000990B1/en not_active IP Right Cessation
- 1984-11-30 AT AT0380884A patent/AT387571B/en not_active IP Right Cessation
- 1984-11-30 GB GB08430275A patent/GB2150567B/en not_active Expired
- 1984-11-30 AU AU36092/84A patent/AU576338B2/en not_active Expired
- 1984-11-30 DE DE3443820A patent/DE3443820C2/en not_active Expired - Lifetime
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1986
- 1986-03-31 ES ES553547A patent/ES8706320A1/en not_active Expired
- 1986-05-20 YU YU826/86A patent/YU45325B/en unknown
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- 1988-11-30 SG SG805/88A patent/SG80588G/en unknown
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5900485A (en) * | 1996-07-29 | 1999-05-04 | Apotex, Inc. | Methods for the manufacture of neofazodone |
| US6596866B2 (en) | 2001-09-10 | 2003-07-22 | Brantford Chemicals Inc. | Process for the preparation of nefazodone hydrochloride |
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