CA1262913A - Process for preparing a basic thioether and the salt thereof - Google Patents
Process for preparing a basic thioether and the salt thereofInfo
- Publication number
- CA1262913A CA1262913A CA000499391A CA499391A CA1262913A CA 1262913 A CA1262913 A CA 1262913A CA 000499391 A CA000499391 A CA 000499391A CA 499391 A CA499391 A CA 499391A CA 1262913 A CA1262913 A CA 1262913A
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- Prior art keywords
- formula
- furylmethylthio
- dimethylaminomethyl
- hydrochloride
- base
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
A b s t r a c t The invention relates to a new process for preparing 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)--ethy]}amino-1-methylamino-2-nitroethylene of the for-mula (I) (I) and its hydrochloride, which comprises reacting an 1--{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}--amino-1-(substituted thio)-2-nitroethylene of the general formula (VI), (VI) wherein R stands for an optionally substituted alkyl group containing 1 to 4 carbon atoms or an oxoalkyl, aryl, aralkyl, or oxoaralkyl group, with an agent capable of splitting off a mercaptan, in an organic solvent, optionally in the presence of an acid-binding agent, then reacting the in situ prepared 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethy]} --3-nitroketeneimine of the formula (VII)
Description
~L26~
PROC~SS FOR Pn~P~R~NG ~ BASIC THIO~rHER ~ND THL s~L~r TH~R~OF
Thls inver~tion rela-tes to a new process for preparing l- {2-[~-dimethylaminornethyl-2-(furylmethyl-thio)-ethyl]~_am-Lno-l-methylamino-2-nitroethylene o~
tho forrmlla ~I) N-H~Cr,,~-CI12-S-(CH~)-NH-C-NII-CH3 ~3C (I) C ~ - N 2 arld the hydrochloride thereo~, Being a selective histamine ~-2 receptor anta-gonist~ the compound of formula (I) (generic name:
ranitidine) is an outstanding cdrug against gastric and cduodenal ulcers, For therapeutical purposes the hydro-chloride of the cornpound of formula (I) is usecd, Fo:r preparing the hyd:roch.loride of the com-pound of` ~ormuLa (I), the following processes are, des-cribed in the literature, a) According to ~xample 32 (page 7~) reported in the published German patent applica-tion No, 2,734,070,
PROC~SS FOR Pn~P~R~NG ~ BASIC THIO~rHER ~ND THL s~L~r TH~R~OF
Thls inver~tion rela-tes to a new process for preparing l- {2-[~-dimethylaminornethyl-2-(furylmethyl-thio)-ethyl]~_am-Lno-l-methylamino-2-nitroethylene o~
tho forrmlla ~I) N-H~Cr,,~-CI12-S-(CH~)-NH-C-NII-CH3 ~3C (I) C ~ - N 2 arld the hydrochloride thereo~, Being a selective histamine ~-2 receptor anta-gonist~ the compound of formula (I) (generic name:
ranitidine) is an outstanding cdrug against gastric and cduodenal ulcers, For therapeutical purposes the hydro-chloride of the cornpound of formula (I) is usecd, Fo:r preparing the hyd:roch.loride of the com-pound of` ~ormuLa (I), the following processes are, des-cribed in the literature, a) According to ~xample 32 (page 7~) reported in the published German patent applica-tion No, 2,734,070,
2~ the hydrochloride of the compound of formula (I) is prepared by dissolving the base of ~ormula (I) in ethanol ancl precipitati~g the hydrochloride ~ormed by adding ethyl aceta-te to give a 89,6 ~0 yield o~
the hydrochloride as calculated ~or the base ~LZ~:;Z9:~L3 -usc(l as starl;:Lrlg Inaterial b) Accordin~ to ~alrlple l (pag~ 8) o~ -thc Belgian pa-tent specification No, 890,~74, the hydrochlorlde o~ -the compound of ~oxmula (I) is prepared by adding concentrated aqueous hydrochloric acid to a solution and precipitating the hydrochloride formed by aclding a further amount of isopropa~ol to gi~e a 93,9 yield of the hydrochloride as calculated for -the base, Thus, the starting material for both processes is the base of formula ~I), Therefore, based on the processes known at prese~t, the base of -for~ula (I) should first be prepared i~ an appropriate quality for the formation of the hydrochloride, According to ~xample l~ 24 (page 68) of the above-cited published German patent applicatio~ No, 2,734,0707 this base is prepared by re-acti~g first 2~~(2-aminoethyl)-thiomethyl]-~-dimethyl-aminome-thylfuran of the ~formula (II) N H2~ o, C H2 S (C H2) N H~
with l,l-bis(methylthio~-2-nitroethylene of the for-2~ mula (III) ~Z~ lL3 ~ - 3 -., /
02N C H ~ C ( III) ~CH~
in acetonitrile solution at the refl~x t~mperature for 14 hours, then removing the solvent and boiling -the : crude distillation residue und0r re~lux with a me-thano-lic solutio~ (Hereinafter, this process is called as literature process "A") According to the descrlption~
the yield is 79 9 5~ A considerable deficiency of -this description consists in the Pact that the product of the fir~t step of this two-step reac-tion is not charac-l~ terized An other defici.ency is tha-t~ concerning the ~: final produot, ~xample 1~ (page 61) of the published ~:` patent application cited abo~e -Ls quo-ted where, howe~er, >
the exact condltions for the recrys-tallization are not gi~en, altllo1lgh thcy bear a decisi~e impor-tance both on the yield and quality of the base of formula (I) : While in~es-tigating the process described in ~xample 24 of this published German application, it was found that by ~ollowing this process a ~ery irnpure oily product was formed in the ~irst step which could be 2~ characterized by the formula (IV) ~, _ L~ _ N-H~C~ob~- ( H2-s-(cH2)~ NH-C-S-CH3 H3C (I~) C H ~ ~ 2 from which, however, in the way described i.n the Fxample, the base o~ -formula (I) could not be obtalned in a quality suitable to prepare the hydrochloride of the base of for-mula (I).
[~ccording to our experimen-ts~ the crude prod~
uct of formula (IV) prepared by using the method described in the abo~e ~xample could only be purified and made homo-geneous with high losses, in a tedious and complicated 1~ way (e g by column chromatography separa-tion)]. Further on, it has been found that, by using the process described in Fxa~ple 24, a base of the ~ormula (I) with a quality satisfying the above requirements could not be prepared e~en from a p~e compound of l-he ~ormula (IV) For the prepara-tion of the base of formula (I) an other process is repor-ted in the Hungarian patent application No 1827/83 published under No. T/3111~, according to which the compound o~ formula (IX) S~CH3 O~N C H=C (IX) N H~CH3 . .
~z~
i9 -tr~nsf`ormed to 1-methyl-3-nit:roketen~imine of the form~ll.a (~) 02N CH--C-N-CH3 (v) by using a heavy metal salt, e g silve:r nitrate or cuprous chloride, in the presence o~ a proton-binding agent, and the ~eteneimine of formula (V) is brough-t into an addition reaction with the base of formula (II) to gi~e the base of formula (I). This pate~t appli-cation contai~s two ~xamples, none of which can, how-e~er, be e~aluated as -the yields are not mentioned ~rhe purification process of the crude base of formula (I) is also not reported~] Hereinafter, this process is lS called as literature process "B" Co~cerning -the iden-tity and quality of the product ob-tained, spectro-scopical proofs are quoted which are, howe~er, not described On the other hand~ ths product obtained is statecl to be identical wlth the ranitidine base pre-pared as described in ~xample 1~ of -the published Ger-man patent application No. 2,734,070 Howe~er, accord-ing to our own in~estigations this latter base is not suitable to prepare ranitidi~e hydrochloride wi-th satisfying purity.
2~ Thus, the aim of the present in~e~tion is to provide a process for the preparation of the base of ~ormula (I) and of its hydrochloride, which renders possible to produce thcse compounds in a good yield and ( , .
~Z~9 ,~ in a si.mple way at an industrial sc~le, too, Now i-t has been found -that thLs aim can e~-tirely be achieved when a 1-~2-[~-dimethylaminome-thyl--2-(furylmethylthio)-e-th-y~ -amino-l-(subs-titu-ted thio)--2-nitroe-thylene o~ the ger..leral formula. (VI), HC
N- H2C rOo,L C H2-S-(CH7)2 NH ~C-S-R
. H3C - C H-N~2 7 (~I) wherein R stands for an optional substi-tuted alkyl or 1~ oxoalkyl group as well as a~ aryl, aralkyl or oxoaralkyl groupy i~ in situ -transformed to 1-~2-[~-dime-thylaminome-thyl-2-:1 _ ~ urylmethylthio)-ethyl~-3-nitroketeneimine of the I formula (VII) ~ r N-~lzC~/L'CH2S-(CH2)2N=C-CH-NO~
2~ (VII) in a simple wa.y and in an excellent yield and then the keteneimine o~ the ~ormula (VII) is reacted with methyl min~, 9~3 Th:is recognition i5 surp:risi~ for a number of reasons, Hither-to, ln -the litera-ture9 the simply struc-tured ni-t.roketeneimine of the formula (V) cited in con-nection with literature proce.ss "B" has only been known which has been publishecl only recently. It was not foreseeable tha-t the rather complicatedly structured nitroketeneimine o~ the ~ormula (VII) can be formed from a compound of the general formula (VI) wi-thin an extraordinarily short time (i,e, within a few minutes) without any alteration of -the molecular moieties not participating in the aimed reaction of eith~r the start-ing compound of the general ~ormula (VI) or the formed product of formula (VII); similarly it could no-t be expected that the complicatedlY structured nitrokètene-: 15 imine of the formula (VII) goes into an addition reac-tion with methylamine within a very short time to gi~e a base of the formula (I) with a ~ery high purity and~
acoordin~ to our obser~ations, nearly without any side :reaction, Thus, the present in~ention rela-tes to a new process for preparing 1-r2-[~-dimethylaminome-thyl-2-.
-/furylmethylthio)-ethy~ ~-amino-l-methylamino~2-nitro-ethylene and its hydrochloride, which comprises react-ing a 1-~2-[~-dimethylaminomethyl-2-(furylmethylthio)-2~ -ethy~} -amino-l-(substituted -thio)-2-nitroethylene of the general formula (VI), wherein : R stands for an optionally substituted alkyl ~, ' ~29~
group containing 1 to 4 carbon a-toms or an oxoallcyl, aryl, aralkyl or o~oaralkyl group, wi-th an agen-t capable of splitting out a mercaptan, ln an organic solvent, optionalLy in the presence of an acid-binding agent, then reacting the in s:i-tu prepared 1-{[2-[~-dimethylaminomethyl-2-(furylrnethylthio)-e-thyll~-
the hydrochloride as calculated ~or the base ~LZ~:;Z9:~L3 -usc(l as starl;:Lrlg Inaterial b) Accordin~ to ~alrlple l (pag~ 8) o~ -thc Belgian pa-tent specification No, 890,~74, the hydrochlorlde o~ -the compound of ~oxmula (I) is prepared by adding concentrated aqueous hydrochloric acid to a solution and precipitating the hydrochloride formed by aclding a further amount of isopropa~ol to gi~e a 93,9 yield of the hydrochloride as calculated for -the base, Thus, the starting material for both processes is the base of formula ~I), Therefore, based on the processes known at prese~t, the base of -for~ula (I) should first be prepared i~ an appropriate quality for the formation of the hydrochloride, According to ~xample l~ 24 (page 68) of the above-cited published German patent applicatio~ No, 2,734,0707 this base is prepared by re-acti~g first 2~~(2-aminoethyl)-thiomethyl]-~-dimethyl-aminome-thylfuran of the ~formula (II) N H2~ o, C H2 S (C H2) N H~
with l,l-bis(methylthio~-2-nitroethylene of the for-2~ mula (III) ~Z~ lL3 ~ - 3 -., /
02N C H ~ C ( III) ~CH~
in acetonitrile solution at the refl~x t~mperature for 14 hours, then removing the solvent and boiling -the : crude distillation residue und0r re~lux with a me-thano-lic solutio~ (Hereinafter, this process is called as literature process "A") According to the descrlption~
the yield is 79 9 5~ A considerable deficiency of -this description consists in the Pact that the product of the fir~t step of this two-step reac-tion is not charac-l~ terized An other defici.ency is tha-t~ concerning the ~: final produot, ~xample 1~ (page 61) of the published ~:` patent application cited abo~e -Ls quo-ted where, howe~er, >
the exact condltions for the recrys-tallization are not gi~en, altllo1lgh thcy bear a decisi~e impor-tance both on the yield and quality of the base of formula (I) : While in~es-tigating the process described in ~xample 24 of this published German application, it was found that by ~ollowing this process a ~ery irnpure oily product was formed in the ~irst step which could be 2~ characterized by the formula (IV) ~, _ L~ _ N-H~C~ob~- ( H2-s-(cH2)~ NH-C-S-CH3 H3C (I~) C H ~ ~ 2 from which, however, in the way described i.n the Fxample, the base o~ -formula (I) could not be obtalned in a quality suitable to prepare the hydrochloride of the base of for-mula (I).
[~ccording to our experimen-ts~ the crude prod~
uct of formula (IV) prepared by using the method described in the abo~e ~xample could only be purified and made homo-geneous with high losses, in a tedious and complicated 1~ way (e g by column chromatography separa-tion)]. Further on, it has been found that, by using the process described in Fxa~ple 24, a base of the ~ormula (I) with a quality satisfying the above requirements could not be prepared e~en from a p~e compound of l-he ~ormula (IV) For the prepara-tion of the base of formula (I) an other process is repor-ted in the Hungarian patent application No 1827/83 published under No. T/3111~, according to which the compound o~ formula (IX) S~CH3 O~N C H=C (IX) N H~CH3 . .
~z~
i9 -tr~nsf`ormed to 1-methyl-3-nit:roketen~imine of the form~ll.a (~) 02N CH--C-N-CH3 (v) by using a heavy metal salt, e g silve:r nitrate or cuprous chloride, in the presence o~ a proton-binding agent, and the ~eteneimine of formula (V) is brough-t into an addition reaction with the base of formula (II) to gi~e the base of formula (I). This pate~t appli-cation contai~s two ~xamples, none of which can, how-e~er, be e~aluated as -the yields are not mentioned ~rhe purification process of the crude base of formula (I) is also not reported~] Hereinafter, this process is lS called as literature process "B" Co~cerning -the iden-tity and quality of the product ob-tained, spectro-scopical proofs are quoted which are, howe~er, not described On the other hand~ ths product obtained is statecl to be identical wlth the ranitidine base pre-pared as described in ~xample 1~ of -the published Ger-man patent application No. 2,734,070 Howe~er, accord-ing to our own in~estigations this latter base is not suitable to prepare ranitidi~e hydrochloride wi-th satisfying purity.
2~ Thus, the aim of the present in~e~tion is to provide a process for the preparation of the base of ~ormula (I) and of its hydrochloride, which renders possible to produce thcse compounds in a good yield and ( , .
~Z~9 ,~ in a si.mple way at an industrial sc~le, too, Now i-t has been found -that thLs aim can e~-tirely be achieved when a 1-~2-[~-dimethylaminome-thyl--2-(furylmethylthio)-e-th-y~ -amino-l-(subs-titu-ted thio)--2-nitroe-thylene o~ the ger..leral formula. (VI), HC
N- H2C rOo,L C H2-S-(CH7)2 NH ~C-S-R
. H3C - C H-N~2 7 (~I) wherein R stands for an optional substi-tuted alkyl or 1~ oxoalkyl group as well as a~ aryl, aralkyl or oxoaralkyl groupy i~ in situ -transformed to 1-~2-[~-dime-thylaminome-thyl-2-:1 _ ~ urylmethylthio)-ethyl~-3-nitroketeneimine of the I formula (VII) ~ r N-~lzC~/L'CH2S-(CH2)2N=C-CH-NO~
2~ (VII) in a simple wa.y and in an excellent yield and then the keteneimine o~ the ~ormula (VII) is reacted with methyl min~, 9~3 Th:is recognition i5 surp:risi~ for a number of reasons, Hither-to, ln -the litera-ture9 the simply struc-tured ni-t.roketeneimine of the formula (V) cited in con-nection with literature proce.ss "B" has only been known which has been publishecl only recently. It was not foreseeable tha-t the rather complicatedly structured nitroketeneimine o~ the ~ormula (VII) can be formed from a compound of the general formula (VI) wi-thin an extraordinarily short time (i,e, within a few minutes) without any alteration of -the molecular moieties not participating in the aimed reaction of eith~r the start-ing compound of the general ~ormula (VI) or the formed product of formula (VII); similarly it could no-t be expected that the complicatedlY structured nitrokètene-: 15 imine of the formula (VII) goes into an addition reac-tion with methylamine within a very short time to gi~e a base of the formula (I) with a ~ery high purity and~
acoordin~ to our obser~ations, nearly without any side :reaction, Thus, the present in~ention rela-tes to a new process for preparing 1-r2-[~-dimethylaminome-thyl-2-.
-/furylmethylthio)-ethy~ ~-amino-l-methylamino~2-nitro-ethylene and its hydrochloride, which comprises react-ing a 1-~2-[~-dimethylaminomethyl-2-(furylmethylthio)-2~ -ethy~} -amino-l-(substituted -thio)-2-nitroethylene of the general formula (VI), wherein : R stands for an optionally substituted alkyl ~, ' ~29~
group containing 1 to 4 carbon a-toms or an oxoallcyl, aryl, aralkyl or o~oaralkyl group, wi-th an agen-t capable of splitting out a mercaptan, ln an organic solvent, optionalLy in the presence of an acid-binding agent, then reacting the in s:i-tu prepared 1-{[2-[~-dimethylaminomethyl-2-(furylrnethylthio)-e-thyll~-
-3-nitroketeneimine of the f`ormula (VII) wi-th methylamine and ~inally, if desired, separating the obtained base of fo:~mula (I), purifying it and/or, if desirecl, -transform-ing it to its hydrochloride.
The compound of the formula (VII) formed asan intermediate in the process of the inventiorl is new The formation of this compound has been supported by the fact that on the interaction of 1-~2-[~-dimethylamino-1~ methyl-2-(furylmethylthio)-ethy~ -amino-l-methylthio--2-nitroethylene [compound o~ the forula (IV)J with silver nitrate sil~er me-thylmercaptide was obta-Lned in a nearly quantitati~e yield, as -Lt is desoribed below One of the compounds of general formula (VI) used for preparing the compound of formula (VII), name-ly the compound of ~ormula (IV), can be considered to be a known substance on the basis of comparison of the gene:ral formula reported in the process ~ariant b) of 2~ claim 37 (page 7) of the published German paten-t appli-cation No. 2,7347070 with ~amole 24 (page 68), al-though no characteristics (including the chemical-name) of this substance aro given No other compound of the formula :.
~Z~9~3 (VI) is mon-t:Loned -in -this pa-tent appllcation, Accordirlg ~ to ~ample 1 of -the published European pate~t applica-; tion No, 0,002,930, the compound of formula (IV) mel-ts at 71 C, To the best of our knowloclge~ no othe.r com-pound of the ~ormula (VI) has been described in the literat~re, Thus, the co~pounds of general ~ormula (VI) are new, e~cept the compound of formula (IV), These - compounds may be prepared in a known manner by react-j ing the base of formula (II) with a compound of the f~rmula (VIII)~
S-R
2 N C ~ = C \ (VIII) ~ 15 S-R
wherein R is as defined abov0, A part of the compounds of general form~tla (VIII) ~s known [Ao-ta Chem, Scand, 21~, 2797 (1967);
Chem, Ber, 100, ~91 (1967)], The new compounds of the general ~ormula (VIII) can be prepared in a known way.
As a compound of the general formula (VI), the compound of formula (IV) is useful e,g, for pre-paring the nitroketeneimine of formula (VII), Metal 2~ salts, motal oxides or finely distributed metals may ~ ba employed as agents capable of splitting off a mer-'~ captan, It is convenient to use e,g, silver nitrate ~ or cuprous chloride as metal salts, Organic bases are .
~26~3 _ 10 --suitable acid-binding agents Bo-th the formation and the reaction with me-thylalnine of the compund of ~or-mula (VII) are preferably carried ou-t at a temperature eq-ual -to or somewha-t lower than room temperature Or-ganic solvents such as lower alipha-tic alcohols, e g ethanol, may s-uitably be used.
~ Rreferre~ embodiment of the invention comprises treating a solution or suspension of the compound of formula (IV) in absolute ethanol with silver nitrate at ~ to 30 C and adding methylamine after the precipita-tion of the directly formed silver mercaptide, then filtar-ing the reaction mixture, removing the solvent from the filtrate and working up the residue in the -usual way, wherein the residue consists of the base of formula (I) 1~ in addition to the appropria-te salt of methylamine If desired, the thus-ob-tained rani-tidine is reorystallized and, if desired, it is transformefl to its hydrochloride An o-ther preferred ernbodirnent of the invention oomprises adding dropwise an e-thanolic methylamine sol-ution con-taining silver nitrate to the ethanolic suspen-sion of the compound of ~ormula (IV)and then following the process described above.
The advantages of the process of the invention can be swnrnarized as follows 2~ _ Both steps of the process of the invention, i e the formation and reaction with methylamine of the cornpound of ~ormula (VII) rapidly pro-ceed at a temperature equal to or somewhat 2~3 :Lower than room temperature, Thi.s fact results in the stability of -the compound of formula ; (VII) which will not decompose and thus the base of forl~ula (I) formed will not be con-ta~
~ minated by decomposition products, An other result is the energy sa~ing, As a consequence of -the short processing ti.me (production period), the pool of the equipments can e~ficiently be utilized.
- The rapid proceeding of the reaction is rendered possible for -the most part by the fact that methylamine, being i~ a gaseous form under normal conditions, can be used in an optional excess and after the reaction -this excess can 1~ easily be removed without any heat demand, In a sharp contrast there-to~ when -the base of ~; formula (I) is prepared by using the abo~e--oited literature "B" process~ i,e, by -trans-forming the compound of formula tIX) to the nitro 20 keteneimine of formula (V) and by bringing the latter compound to an addition reaction with the base of formula (II)~ then the bass of formula (II) can only be usod in a stoichiometric amount and thus the addition reac-tion cannot 2~ be accelerated by u~ing an excess o~ the base of formula (II), since this base is unstable~
sensitive to heat, it can only bc removed under a high vacuum at a higher temperature, Ei2~L3 and a par-tial clecomposition of the base cannot be avoided during clistillation, Thus, the ob-tained base of form~la (I) becomes severely contaminatecl by either the remained amount o~
the base or by -the decomposition products arising from the distillation of -the excess base of formula (II)~
- In contrast to the literature process "A", wherein one mole of methyl mercaptan each is liberated in both steps, this toxic gas is bound in the form of a harmless, un~olatile metal mercaptide in the process of the in~ention and thus the en~ironmen-t is not polluted, - The yield of the crude base of formula (I) 1~ obtained by using the process of the inven-tion is nearly quantitati~e, This crude product contains only a ~ery little amount of contamina-tions (except the salt of the used acicl-binding agent), By using a simple puri~ying process, a completely homogeneous base of the formula (I)~ which is useful in forming the hydrochloride, is obtained in a very good yield (about 7~ %), The thue-obtained hydrochloride does not need any further purifi~ation, 2~ Base~ on these facts, the process o~ the in~en-tion is useful for the gimple preparation o-~ the base of formuia (I) and its hydrochloride in a good yield at an industrial scale, too, ., , .
i2~3 The proce~ of the inverl-tion i9 illustra-ted in detail by the following non-limiting ~xamples, ~xatnple 1 Preparation of 1-~2-[~-dimethylaminomethyl-2--(~urylmethylthio)-ethy~-amino-l-methylamino-~2-nitroethylene Cbase of the formula (I)~
~1,0 g (0,30 mole) of ailver nitrate dissolved in 4000 ml of absolu-te ethanol are added -to a solution containing 99.S g (0,30 mole) o~ 2-[~-dimethylamino-methyl-2-(furylmethylthio)-ethy~} -anlino-l-methylthio--2-nitroethylene [compound of the formule (IV)~ in 2500 ml of absolute ethanol a-t 10 C within one minute to form immediately silver methylmercaptide, Then ~7 ml of a 1~ 29,2 ~ ethanolic methylamine solution are added and the mixture is stirred a-t room temperature for 2 hours, The precipitate (which is silver methyl mercaptide in a yield o~' 98,1 ~p according to its weight and composition) is filtered and the filtrate is evaporated -to dryness at room temperature. The evaporation residue is taken up in 600 ml of water and extracted eight times with 1200 ml of ethyl acetate each while adjusting the pH value to 10, if needed. The organic phase~ are combined, dried and evaporated under reduced pressure, The crude ranitidine 2~ is obtained as an evaporation residue in a yield of 79 g (81~ %), For the preparation of the hydrochloride, the ~2,62913 - 14 _ crude rani-tldine base is dis~olve,d in 380 ml of absolute ' ethanol ~nd the pH va.Lue of the solution is adju~ted -to ' 5,5 by adding concentrated aqueous hydrochlorlc acid at . 0 to 5 C, The mix-tuxe is s-tirred at 0 C for additional ;~ 5 40 minut~s, -~ The crystalline precipitate is filtered out~
; washed w:ith ethanol and dried to give ranitidine hydro-chloride in a yield of 57.45 g (54,6 ~0)~ m,p,: 143 C, A second crop of 23,15 g (22,0 %) is obtained ~rom tha mother liquor~ m,p, 143 C, ~ l-t2-[5-Dimethylaminomethyl-2-(furylmethyl-thio)-,} -ethy~ -amino-l-methylthio)-2-nitroethylene [compound of the formula (IV)] used as star-ting material can be ~' prepared e,g, according -to ~xample 1 of tho published ' 15 ~uropean patent application No, 0,002,930, , ; ~xample 2 ~ Preparation of 1-~2-[5-dime-thylaminomethyl-2--(furylmethylth~o~-ethy~ -amino-l-methylamino-' 20 -2-nitroethylene [base of the formula (I)] and ; its hydrochloride A solution containing 2,55 g (0,015 mole) of sil~er nitrate in 200 ml of absolute ethanol is added to a solution containing 5 g (0,01~ mole) of 1-~2-E5--dimethylaminomethyl-2-(furylmethylthio)-ethy~ -amino--l-methylthio-2-nitroethylene [compound of the formula (IV)] in 125 ml of absolute e-thanol within one minute while stirring at 6 C to form immediately silver methyl-~6f~ 3 mercapticl~ The mix-ture is st:Lrred at ~ C ~or additional 3 minut~s, -then 30 ml of a 27 ~ e-thanollc m~-thylamine solution are addecl. The mix-ture is stlrred a-t room tempera--ture ~OI` 2 hours and then filtered. The filtrate is set aside at ~ C overnight~ filtered again and -the ~i]-trate is evapora-ted at room temperature under reduced pressure After adding ~0 ml of water to the residue, -the pH val-ue is adjusted to ~ 5 by adding 1 N aqueous hydrochloric acid The mixture is extracted twice wi-th 70 ml of dichloro-methane each, then the pH value of the a~ueous phase isadjusted to lO by adding 1 N sodium hydroxide solution and extracted ~our times with 70 ml of dichloromethane each The orgar.~ic phases obtained from the latter extrac-tions are combined, dried, e~aporated and ~our volumes of ethyl acetate are added to the e~aporation residue The precipitated crystals are filtered and dried to give 3.02 g (64 0 %) of the aimed ba~e, m p : 68-70 C. After repeated evaporation of the mo-ther liquor a~d recrystall---zation of the residue, an additional amount of 0 55 g (11 2 %)~of the aimed base is ob-tained The base prepared according to ~x~mple 2 may be trans~ormed to its hydrochloride e g as ~ollows 3.5 g of crude ranitidine are dissol~ed in 17 5 ml of absolute ethanol and the pH ~alue of this solutio~ is adjusted to 5 to 5 5 by adding concentrated aqueous hydrochloric acid a-t 0 C while stirring. The mixture is stirred at 0 C for additional 40 minutes and then set aside at 0 to ~ C o~ernight The crystalline ~Z~ L3 prec-ipi-tate is ~iltered, washed with e-thanol and clriecl -to give 3,72 g (84.4 ~p) of the aimed hydrochloricle, m,p,: 143 C, nple 3 Preparation of 1-~2-[~-dirnethylaminomethyl--2-(furylmethylthio)-e-thy~3 -amino-l-methylamirlo--2-nitroethylene ~base of the formula (I)~
A solution prepared from 0~8~ g (0~00~ mole) of silver nitrate with 10 ml of an ethanolic methylamine solution is added to 1,66 g (0,005 mole) of 1-~2-[~--dimethylaminomethyl-2-(furylmethylthio)-ethy~ -amino--l-methylthio-2-nitroethylene ~compound of the forlnula (IV)] suspended in 10 ml of absolute ethanol at room 1~ temperature while stirring. The mixture is stirred a-t room temperature for additional 30 minutes, then filtered and evaporated under reclucecl pressure, The working-up is oarried out cLS desoribed :in ~xample 2 to giv0 1,21 g (77,1 ~/~) of the aimed base~ 111, p, 68-70 C, ~xample 4 Preparatio~ of 1-~2-[~-dimethylami~omethyl-2--(furylmethylthio)~ethy~ -amino-l-methylamino--2-nitroethylene [baae of the formula (I)]
2~ A solution containing 0,8~ g (0.00~ mole) of silver nitrate in 60 ml of allyl alcohol is portionwise added to a solution containing 1,66 g (0,00~ mole) of 1-~2 [~-dimethylaminomethyl-2-(furylmethylthio)-ethy~ }-~L2~;2~
~ 17 -amino-l-methylthio-2-nitroethylene ~compou~cl of the ~orn~la (IV)~ in 20 ml of allyl alcohol wi-thin 2 -to 3 min-utes at 8 to 10 C while s-tirring, Then 8 ml of an ethanolic methylamine solution are added at the same temperature within 1 to 2 minutes and the mi~-ture is stirred at room -temperature for 2 hours, The working-up is carri~d out as described in ~xample 2 to give 0,9~ g (60,~ ~0) of the aimed base, m,p,: 70-72 C, F~ample ~
Control experiment : The following control e~perimcnt was carried ou-t in order to support that, in the process of the in-~ention, 1-.~2-[~-dimethylaminomethyl-2-(furylmethylthio)-1~ -ethy~ -amino-1-methylthio-2-nitroethylene [compound of the formula (IV)] reac-ts first with silver ni-trate ~ and then, si~ultaneously with the precip-L-tation of sil~er mothyl mercaptide, -tho thus-formed 1-~2-C~-cli-methylaminomethyl-2-tfurylmethylthio)-othyl]~-3-nitro-kctene:imi~e [compound of -the formula (VII)I reacts with methylamine, The process described in ~xample 1 was followed, except that, after adding the sil~er nitrate, -the pre-cipitate. formed in the solution was filtercd, washed, 2~ dried and analyzed, The precipitate weighed 2,28 g (98,1 %) Analysis ~or CH3AgS (molecular weight 1~4,98) Calculated: C 7,7~ ~p; H 1,9~ ~: Ag 69,6 ~o, Found: C 7,69 %; H 1,36 %~ Ag 69,1 %,
The compound of the formula (VII) formed asan intermediate in the process of the inventiorl is new The formation of this compound has been supported by the fact that on the interaction of 1-~2-[~-dimethylamino-1~ methyl-2-(furylmethylthio)-ethy~ -amino-l-methylthio--2-nitroethylene [compound o~ the forula (IV)J with silver nitrate sil~er me-thylmercaptide was obta-Lned in a nearly quantitati~e yield, as -Lt is desoribed below One of the compounds of general formula (VI) used for preparing the compound of formula (VII), name-ly the compound of ~ormula (IV), can be considered to be a known substance on the basis of comparison of the gene:ral formula reported in the process ~ariant b) of 2~ claim 37 (page 7) of the published German paten-t appli-cation No. 2,7347070 with ~amole 24 (page 68), al-though no characteristics (including the chemical-name) of this substance aro given No other compound of the formula :.
~Z~9~3 (VI) is mon-t:Loned -in -this pa-tent appllcation, Accordirlg ~ to ~ample 1 of -the published European pate~t applica-; tion No, 0,002,930, the compound of formula (IV) mel-ts at 71 C, To the best of our knowloclge~ no othe.r com-pound of the ~ormula (VI) has been described in the literat~re, Thus, the co~pounds of general ~ormula (VI) are new, e~cept the compound of formula (IV), These - compounds may be prepared in a known manner by react-j ing the base of formula (II) with a compound of the f~rmula (VIII)~
S-R
2 N C ~ = C \ (VIII) ~ 15 S-R
wherein R is as defined abov0, A part of the compounds of general form~tla (VIII) ~s known [Ao-ta Chem, Scand, 21~, 2797 (1967);
Chem, Ber, 100, ~91 (1967)], The new compounds of the general ~ormula (VIII) can be prepared in a known way.
As a compound of the general formula (VI), the compound of formula (IV) is useful e,g, for pre-paring the nitroketeneimine of formula (VII), Metal 2~ salts, motal oxides or finely distributed metals may ~ ba employed as agents capable of splitting off a mer-'~ captan, It is convenient to use e,g, silver nitrate ~ or cuprous chloride as metal salts, Organic bases are .
~26~3 _ 10 --suitable acid-binding agents Bo-th the formation and the reaction with me-thylalnine of the compund of ~or-mula (VII) are preferably carried ou-t at a temperature eq-ual -to or somewha-t lower than room temperature Or-ganic solvents such as lower alipha-tic alcohols, e g ethanol, may s-uitably be used.
~ Rreferre~ embodiment of the invention comprises treating a solution or suspension of the compound of formula (IV) in absolute ethanol with silver nitrate at ~ to 30 C and adding methylamine after the precipita-tion of the directly formed silver mercaptide, then filtar-ing the reaction mixture, removing the solvent from the filtrate and working up the residue in the -usual way, wherein the residue consists of the base of formula (I) 1~ in addition to the appropria-te salt of methylamine If desired, the thus-ob-tained rani-tidine is reorystallized and, if desired, it is transformefl to its hydrochloride An o-ther preferred ernbodirnent of the invention oomprises adding dropwise an e-thanolic methylamine sol-ution con-taining silver nitrate to the ethanolic suspen-sion of the compound of ~ormula (IV)and then following the process described above.
The advantages of the process of the invention can be swnrnarized as follows 2~ _ Both steps of the process of the invention, i e the formation and reaction with methylamine of the cornpound of ~ormula (VII) rapidly pro-ceed at a temperature equal to or somewhat 2~3 :Lower than room temperature, Thi.s fact results in the stability of -the compound of formula ; (VII) which will not decompose and thus the base of forl~ula (I) formed will not be con-ta~
~ minated by decomposition products, An other result is the energy sa~ing, As a consequence of -the short processing ti.me (production period), the pool of the equipments can e~ficiently be utilized.
- The rapid proceeding of the reaction is rendered possible for -the most part by the fact that methylamine, being i~ a gaseous form under normal conditions, can be used in an optional excess and after the reaction -this excess can 1~ easily be removed without any heat demand, In a sharp contrast there-to~ when -the base of ~; formula (I) is prepared by using the abo~e--oited literature "B" process~ i,e, by -trans-forming the compound of formula tIX) to the nitro 20 keteneimine of formula (V) and by bringing the latter compound to an addition reaction with the base of formula (II)~ then the bass of formula (II) can only be usod in a stoichiometric amount and thus the addition reac-tion cannot 2~ be accelerated by u~ing an excess o~ the base of formula (II), since this base is unstable~
sensitive to heat, it can only bc removed under a high vacuum at a higher temperature, Ei2~L3 and a par-tial clecomposition of the base cannot be avoided during clistillation, Thus, the ob-tained base of form~la (I) becomes severely contaminatecl by either the remained amount o~
the base or by -the decomposition products arising from the distillation of -the excess base of formula (II)~
- In contrast to the literature process "A", wherein one mole of methyl mercaptan each is liberated in both steps, this toxic gas is bound in the form of a harmless, un~olatile metal mercaptide in the process of the in~ention and thus the en~ironmen-t is not polluted, - The yield of the crude base of formula (I) 1~ obtained by using the process of the inven-tion is nearly quantitati~e, This crude product contains only a ~ery little amount of contamina-tions (except the salt of the used acicl-binding agent), By using a simple puri~ying process, a completely homogeneous base of the formula (I)~ which is useful in forming the hydrochloride, is obtained in a very good yield (about 7~ %), The thue-obtained hydrochloride does not need any further purifi~ation, 2~ Base~ on these facts, the process o~ the in~en-tion is useful for the gimple preparation o-~ the base of formuia (I) and its hydrochloride in a good yield at an industrial scale, too, ., , .
i2~3 The proce~ of the inverl-tion i9 illustra-ted in detail by the following non-limiting ~xamples, ~xatnple 1 Preparation of 1-~2-[~-dimethylaminomethyl-2--(~urylmethylthio)-ethy~-amino-l-methylamino-~2-nitroethylene Cbase of the formula (I)~
~1,0 g (0,30 mole) of ailver nitrate dissolved in 4000 ml of absolu-te ethanol are added -to a solution containing 99.S g (0,30 mole) o~ 2-[~-dimethylamino-methyl-2-(furylmethylthio)-ethy~} -anlino-l-methylthio--2-nitroethylene [compound of the formule (IV)~ in 2500 ml of absolute ethanol a-t 10 C within one minute to form immediately silver methylmercaptide, Then ~7 ml of a 1~ 29,2 ~ ethanolic methylamine solution are added and the mixture is stirred a-t room temperature for 2 hours, The precipitate (which is silver methyl mercaptide in a yield o~' 98,1 ~p according to its weight and composition) is filtered and the filtrate is evaporated -to dryness at room temperature. The evaporation residue is taken up in 600 ml of water and extracted eight times with 1200 ml of ethyl acetate each while adjusting the pH value to 10, if needed. The organic phase~ are combined, dried and evaporated under reduced pressure, The crude ranitidine 2~ is obtained as an evaporation residue in a yield of 79 g (81~ %), For the preparation of the hydrochloride, the ~2,62913 - 14 _ crude rani-tldine base is dis~olve,d in 380 ml of absolute ' ethanol ~nd the pH va.Lue of the solution is adju~ted -to ' 5,5 by adding concentrated aqueous hydrochlorlc acid at . 0 to 5 C, The mix-tuxe is s-tirred at 0 C for additional ;~ 5 40 minut~s, -~ The crystalline precipitate is filtered out~
; washed w:ith ethanol and dried to give ranitidine hydro-chloride in a yield of 57.45 g (54,6 ~0)~ m,p,: 143 C, A second crop of 23,15 g (22,0 %) is obtained ~rom tha mother liquor~ m,p, 143 C, ~ l-t2-[5-Dimethylaminomethyl-2-(furylmethyl-thio)-,} -ethy~ -amino-l-methylthio)-2-nitroethylene [compound of the formula (IV)] used as star-ting material can be ~' prepared e,g, according -to ~xample 1 of tho published ' 15 ~uropean patent application No, 0,002,930, , ; ~xample 2 ~ Preparation of 1-~2-[5-dime-thylaminomethyl-2--(furylmethylth~o~-ethy~ -amino-l-methylamino-' 20 -2-nitroethylene [base of the formula (I)] and ; its hydrochloride A solution containing 2,55 g (0,015 mole) of sil~er nitrate in 200 ml of absolute ethanol is added to a solution containing 5 g (0,01~ mole) of 1-~2-E5--dimethylaminomethyl-2-(furylmethylthio)-ethy~ -amino--l-methylthio-2-nitroethylene [compound of the formula (IV)] in 125 ml of absolute e-thanol within one minute while stirring at 6 C to form immediately silver methyl-~6f~ 3 mercapticl~ The mix-ture is st:Lrred at ~ C ~or additional 3 minut~s, -then 30 ml of a 27 ~ e-thanollc m~-thylamine solution are addecl. The mix-ture is stlrred a-t room tempera--ture ~OI` 2 hours and then filtered. The filtrate is set aside at ~ C overnight~ filtered again and -the ~i]-trate is evapora-ted at room temperature under reduced pressure After adding ~0 ml of water to the residue, -the pH val-ue is adjusted to ~ 5 by adding 1 N aqueous hydrochloric acid The mixture is extracted twice wi-th 70 ml of dichloro-methane each, then the pH value of the a~ueous phase isadjusted to lO by adding 1 N sodium hydroxide solution and extracted ~our times with 70 ml of dichloromethane each The orgar.~ic phases obtained from the latter extrac-tions are combined, dried, e~aporated and ~our volumes of ethyl acetate are added to the e~aporation residue The precipitated crystals are filtered and dried to give 3.02 g (64 0 %) of the aimed ba~e, m p : 68-70 C. After repeated evaporation of the mo-ther liquor a~d recrystall---zation of the residue, an additional amount of 0 55 g (11 2 %)~of the aimed base is ob-tained The base prepared according to ~x~mple 2 may be trans~ormed to its hydrochloride e g as ~ollows 3.5 g of crude ranitidine are dissol~ed in 17 5 ml of absolute ethanol and the pH ~alue of this solutio~ is adjusted to 5 to 5 5 by adding concentrated aqueous hydrochloric acid a-t 0 C while stirring. The mixture is stirred at 0 C for additional 40 minutes and then set aside at 0 to ~ C o~ernight The crystalline ~Z~ L3 prec-ipi-tate is ~iltered, washed with e-thanol and clriecl -to give 3,72 g (84.4 ~p) of the aimed hydrochloricle, m,p,: 143 C, nple 3 Preparation of 1-~2-[~-dirnethylaminomethyl--2-(furylmethylthio)-e-thy~3 -amino-l-methylamirlo--2-nitroethylene ~base of the formula (I)~
A solution prepared from 0~8~ g (0~00~ mole) of silver nitrate with 10 ml of an ethanolic methylamine solution is added to 1,66 g (0,005 mole) of 1-~2-[~--dimethylaminomethyl-2-(furylmethylthio)-ethy~ -amino--l-methylthio-2-nitroethylene ~compound of the forlnula (IV)] suspended in 10 ml of absolute ethanol at room 1~ temperature while stirring. The mixture is stirred a-t room temperature for additional 30 minutes, then filtered and evaporated under reclucecl pressure, The working-up is oarried out cLS desoribed :in ~xample 2 to giv0 1,21 g (77,1 ~/~) of the aimed base~ 111, p, 68-70 C, ~xample 4 Preparatio~ of 1-~2-[~-dimethylami~omethyl-2--(furylmethylthio)~ethy~ -amino-l-methylamino--2-nitroethylene [baae of the formula (I)]
2~ A solution containing 0,8~ g (0.00~ mole) of silver nitrate in 60 ml of allyl alcohol is portionwise added to a solution containing 1,66 g (0,00~ mole) of 1-~2 [~-dimethylaminomethyl-2-(furylmethylthio)-ethy~ }-~L2~;2~
~ 17 -amino-l-methylthio-2-nitroethylene ~compou~cl of the ~orn~la (IV)~ in 20 ml of allyl alcohol wi-thin 2 -to 3 min-utes at 8 to 10 C while s-tirring, Then 8 ml of an ethanolic methylamine solution are added at the same temperature within 1 to 2 minutes and the mi~-ture is stirred at room -temperature for 2 hours, The working-up is carri~d out as described in ~xample 2 to give 0,9~ g (60,~ ~0) of the aimed base, m,p,: 70-72 C, F~ample ~
Control experiment : The following control e~perimcnt was carried ou-t in order to support that, in the process of the in-~ention, 1-.~2-[~-dimethylaminomethyl-2-(furylmethylthio)-1~ -ethy~ -amino-1-methylthio-2-nitroethylene [compound of the formula (IV)] reac-ts first with silver ni-trate ~ and then, si~ultaneously with the precip-L-tation of sil~er mothyl mercaptide, -tho thus-formed 1-~2-C~-cli-methylaminomethyl-2-tfurylmethylthio)-othyl]~-3-nitro-kctene:imi~e [compound of -the formula (VII)I reacts with methylamine, The process described in ~xample 1 was followed, except that, after adding the sil~er nitrate, -the pre-cipitate. formed in the solution was filtercd, washed, 2~ dried and analyzed, The precipitate weighed 2,28 g (98,1 %) Analysis ~or CH3AgS (molecular weight 1~4,98) Calculated: C 7,7~ ~p; H 1,9~ ~: Ag 69,6 ~o, Found: C 7,69 %; H 1,36 %~ Ag 69,1 %,
Claims (6)
1. A process for the preparation of 1-{2--[5-dimethylaminomethyl-2-(furylmethylthio)-ethy]}--amino-1-methylamino-2-nitroethylene of the formula (I) (I) and its hydrochloride, which comprises reacting a 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}
-amino-1-(substituted thio)-2-nitroethylene of the general formula (VI), (VI) wherein R stands for an alkyl group containing 1 to 4 carbon atoms or an oxoalkyl, aryl, aralkyl or oxoaralkyl group, with an agent capable of splitting off a mercaptan, in an organic solvent, then reacting the in situ prepared 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketene-imine of the formula (VII) (VII) with methylamine and, when required, converting the free base obtained into its hydrochloride.
-amino-1-(substituted thio)-2-nitroethylene of the general formula (VI), (VI) wherein R stands for an alkyl group containing 1 to 4 carbon atoms or an oxoalkyl, aryl, aralkyl or oxoaralkyl group, with an agent capable of splitting off a mercaptan, in an organic solvent, then reacting the in situ prepared 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketene-imine of the formula (VII) (VII) with methylamine and, when required, converting the free base obtained into its hydrochloride.
2. A process as claimed in claim 1, which comprises using silver nitrate as an agent suitable for splitting off methyl mercaptan.
3. A process as claimed in claim 1 or 2, which com-prises using a lower aliphatic alcohol as an organic solvent.
4. A process as claimed in claim 1 or 2, in which the reaction with the agent splitting off of methyl mercaptan is effected in the presence of an acid binding agent.
5. A process as claimed in claim 1 or 2, in which the free base is separated.
6. A process as claimed in claim 1 or 2, in which the free base is purified.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU104/85 | 1985-01-11 | ||
| HU85104A HU196979B (en) | 1985-01-11 | 1985-01-11 | Process for producing basic thioether and salt |
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| CA1262913A true CA1262913A (en) | 1989-11-14 |
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| KR (1) | KR920010926B1 (en) |
| CN (1) | CN1005630B (en) |
| AR (1) | AR242200A1 (en) |
| AT (1) | AT391470B (en) |
| CA (1) | CA1262913A (en) |
| CS (1) | CS261232B2 (en) |
| DK (1) | DK10486A (en) |
| ES (1) | ES8703864A1 (en) |
| FI (1) | FI90419C (en) |
| GB (1) | GB2169600B (en) |
| GR (1) | GR860058B (en) |
| HU (1) | HU196979B (en) |
| IT (1) | IT1203727B (en) |
| NO (1) | NO170542C (en) |
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| HU207308B (en) * | 1990-11-09 | 1993-03-29 | Richter Gedeon Vegyeszet | Process for producing 1- /2-/5-/dimethyl-amino-methyl/-2-/furyl-methyl-thio/-ethyl//- -amino-1-/methyl-amino-2-nitro-ethylene |
| HU210849B (en) * | 1990-11-09 | 1995-08-28 | Richter Gedeon Vegyeszet | Process for preparing furil derivatives |
| CN1048984C (en) * | 1991-12-20 | 2000-02-02 | 多坎化学有限公司 | Preparation of form 1 ranitidine hydrochloride |
| CN102010389B (en) * | 2009-09-04 | 2012-11-14 | 江苏汉斯通药业有限公司 | Method for preparing ranitidine hydrochloride |
| CN102010388B (en) * | 2009-09-04 | 2012-09-05 | 江苏汉斯通药业有限公司 | Preparation method of ranitidine |
| CN110590717B (en) * | 2019-09-18 | 2022-08-26 | 上海大学 | Polysubstituted ketene imine and synthetic method thereof |
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| GB2014561B (en) * | 1977-12-23 | 1982-11-03 | Glaxo Group Ltd | Amine derivatives their preparation and pharmaceutical compositions containing them |
| US4233302A (en) * | 1977-12-23 | 1980-11-11 | Glaxo Group Limited | Amine derivatives and pharmaceutical compositions containing them |
| US4203909A (en) * | 1978-09-26 | 1980-05-20 | Bristol-Myers Company | Furan compounds |
| ES497514A0 (en) * | 1980-12-05 | 1981-10-16 | Liade Sa Lab | PROCEDURE FOR OBTAINING A HETEROCICLICAL PRIMARY AMINE DERIVATIVE |
| EP0057981A3 (en) * | 1981-02-09 | 1982-08-25 | Beecham Group Plc | Aromatic compounds, processes for their preparation and their use |
| ES8300326A1 (en) * | 1981-05-02 | 1982-11-01 | Especialidades Farmaco Terape | Procedure for obtaining a compound derived from aminomethylphurane. (Machine-translation by Google Translate, not legally binding) |
| ES8206506A1 (en) * | 1981-11-16 | 1982-08-16 | Pharmedical Sa Lab | Manufacture of aminoalkyl-furans or thiophenes |
| PT76557B (en) * | 1982-04-16 | 1986-01-21 | Inke Sa | Process for preparing furan derivatives and addition salts thereof and of pharmaceutical compositions containing the same |
-
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- 1985-01-11 HU HU85104A patent/HU196979B/en not_active IP Right Cessation
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- 1986-01-10 KR KR1019860000116A patent/KR920010926B1/en not_active IP Right Cessation
- 1986-01-10 IT IT47517/86A patent/IT1203727B/en active
- 1986-01-10 NO NO860071A patent/NO170542C/en unknown
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| HUT38922A (en) | 1986-07-28 |
| GR860058B (en) | 1986-05-13 |
| NO860071L (en) | 1986-07-14 |
| GB2169600B (en) | 1988-04-20 |
| SU1419519A3 (en) | 1988-08-23 |
| FI860123A0 (en) | 1986-01-10 |
| ES550809A0 (en) | 1987-03-01 |
| FI90419B (en) | 1993-10-29 |
| IT1203727B (en) | 1989-02-23 |
| KR860005802A (en) | 1986-08-13 |
| CN86100111A (en) | 1986-11-26 |
| AR242200A1 (en) | 1993-03-31 |
| FI90419C (en) | 1994-02-10 |
| NO170542C (en) | 1992-10-28 |
| GB8600530D0 (en) | 1986-02-19 |
| ES8703864A1 (en) | 1987-03-01 |
| NO170542B (en) | 1992-07-20 |
| GB2169600A (en) | 1986-07-16 |
| CS261232B2 (en) | 1989-01-12 |
| DK10486A (en) | 1986-07-12 |
| FI860123A (en) | 1986-07-12 |
| IT8647517A0 (en) | 1986-01-10 |
| CN1005630B (en) | 1989-11-01 |
| PT81824A (en) | 1986-02-01 |
| DK10486D0 (en) | 1986-01-10 |
| PT81824B (en) | 1987-11-30 |
| KR920010926B1 (en) | 1992-12-24 |
| ATA3486A (en) | 1990-04-15 |
| HU196979B (en) | 1989-02-28 |
| AT391470B (en) | 1990-10-10 |
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