CN1061968A - The method for preparing Ranitidine HCL - Google Patents
The method for preparing Ranitidine HCL Download PDFInfo
- Publication number
- CN1061968A CN1061968A CN91110542A CN91110542A CN1061968A CN 1061968 A CN1061968 A CN 1061968A CN 91110542 A CN91110542 A CN 91110542A CN 91110542 A CN91110542 A CN 91110542A CN 1061968 A CN1061968 A CN 1061968A
- Authority
- CN
- China
- Prior art keywords
- methylamine
- reaction
- ranitidine hcl
- formula
- ranitidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- C07D307/36—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
The present invention relates to the 1-{2-[(5-dimethylamino methyl-2-furyl of a kind of preparation formula (I))-methylthio group]-ethyl }-amino-1-methylamino--2-nitroethylene (popular name; Ranitidine HCL) novel method, this method comprise makes the reaction of diketene imine derivative and methylamine, most important advantage of the present invention be and can make the Ranitidine HCL that has good quality to be higher than 90% productive rate by simple method.
Description
The present invention relates to a kind of 1-for preparing formula I the 2-[(5-dimethylamino methyl)-the 2-furyl)-methylthio group]-ethyl-amino-1-methylamino--2-nitroethylene (popular name: novel method Ranitidine HCL).
Known formula I compound is a kind of efficient H-2 receptor antagonist, and it is the effective constituent that is used for several excellent medicines of anti-gastric-ulcer and duodenal ulcer.
British patent specification 1,565 has been described first with three kinds of different modes for No. 966 and have been prepared the formula I compound.Yet these methods will be passed through many steps, and productive rate is quite low, in addition, need purifiedly could obtain pure products.
After the formula I compound becomes a kind of important medicine, many new preparation methods except aforesaid method, have been developed.Nowadays the known preparation method that Ranitidine HCL more than 10 kinds is arranged, but every kind of method all has some shortcomings.A part of method is from corresponding thiol derivative (seeing for example US Patent specification 4,497,961 and 4,440,938), yet these methods need contain the reactant (for example aziridine derivative) of nitro, and its preparation is quite difficult.
European patent application 0,055,625 and 0,219,225 disclose a kind of original method, have wherein introduced the dimethylamino methyl that is connected on the furan nucleus 2-position in the synthetic final step.The defective of these methods is that the productive rate of final step gained is shockingly low owing to various side reactions.
From the synthetic method of various other types, Hungarian patent specification 196,979 is worth emphasizing, in view of the above, and can be by a kind of compound formula I compound that is assumed to the ketene imines.This compound is not separated, and its chemical property does not show yet.Reaction is (the 5g/360ml solvent) that carries out in extremely rare solution and has used a large amount of Silver Nitrates (reach products therefrom weight 50%).According to the embodiment of this specification sheets, under the methylamine effect,, just directly obtain thick Ranitidine HCL without separating then by handle the ketene imine derivative that methylthio group-nitro-derivative has obtained on-site preparation with Silver Nitrate.For recrystallization Ranitidine HCL productive rate that methylthio group-nitro-compound calculated for not being higher than 58-73%.
Therefore, the purpose of this invention is to provide a kind of method for preparing the Ranitidine HCL end product with high yield and plant-scale plain mode.
The present invention is based on from up to the present still unknown a kind of new diketene imine compound and can reach purpose of the present invention very effectively through single step reaction, the productive rate of Ranitidine HCL is near 100% this understanding.
That is, in inventor's investigation process, have been found that the diketene imine derivative of formula II,
（Ⅱ）
(chemistry 1-by name 2-[(5-N, N-dimethylamino methyl-2-furyl)-methylthio group]-ethyl }-2-2-[(5-N, N-dimethylamino methyl-2-furyl)-methylthio group]-the 1-ethylamino }-3-nitro-4-methylene radical nitro-2-azetine; Hereinafter to be referred as: diketene imine derivative), be easy to make from Merkamin hydrochloride and furfuryl group derivative, its can the fixed mol ratio and methylamine react well, simple reaction at room temperature takes place, the ranitidine alkali that obtains having good quality.
Therefore, the present invention relates to a kind of 1-for preparing formula I 2-[(5-dimethylamino methyl-2-furyl)-methylthio group] ethyl-method of amino-1-methylamino--2-nitroethylene, this method comprises diketene imine compound and the methylamine reaction that makes formula II.
Methylamine uses with the form of the gaseous state or the aqueous solution, is preferably under the temperature between 0 ℃-70 ℃ and uses.
According to the preferred embodiments of the invention, under 20 ℃-25 ℃, make diketene imine derivative and 10 moles of 40%(weight of formula II) the aqueous methylamine solution reaction.The reaction mixture of clarification gained filters and extraction.The compound that from organic phase, directly or indirectly separates formula I, i.e. Ranitidine HCL.
The most important advantage of the present invention is to use very simple technological process promptly can the productive rate more than 90% to make the purpose compound of formula I.The alkali that so makes can change its salt simply into.
Can describe the present invention in detail by following non-limiting examples.
Embodiment 1
With 8.5g(0.015mol) diketene imine derivative of formula II is dissolved in 30ml water, at room temperature, in 15 minutes, adds 41g(0.5mol) 40% aqueous methylamine solution.Stir after 1 hour,, filter then with 0.5g diatomite and 0.5g gac clarified mixture 15 minutes at room temperature.Use the 40ml chloroform extraction filtrate, and then extracting twice, the 20ml chloroform used at every turn.Make the extract siccative of merging with anhydrous sodium sulphate, the filtering siccative, evaporating solvent, make oily resistates recrystallization with the 35ml ethyl acetate, obtain 9g(94%) 1-2-[(5-dimethylamino methyl-2-furyl) methylthio group]-ethyl }-amino-1-methylamino--2-nitroethylene, m.p.:71-73 ℃.This product does not contain any pollution, and this available thin layer chromatography (TLC) is identified.
Embodiment 2
Follow embodiment 1 described method, different is at room temperature the gaseous state methylamine slowly to be introduced in the aqueous solution of diketene imine derivative, till the reacting completely of diketene imine.(available thin layer chromatography shows, development system is acetone/ethyl acetate/ammonium hydroxide=5: 5: 1.) the Ranitidine HCL productive rate that obtains by this way is 9.1g(95.5%), m.p.:71-73 ℃, this product does not contain the pollution that TLC can measure.
Embodiment 3
A) follow embodiment 1 described method, different is only to use 8g(0.1mol) 40% aqueous methylamine solution reacts, and adds the back stirred reaction mixture 2 hours.The productive rate of gained Ranitidine HCL is 8.9g(93.4%).
B) the wet crystallization with ranitidine alkali is dissolved in 30ml ethanol, at room temperature this solution is stirred 30 minutes with 0.5g diatomite and 0.5g gac.Behind the filtering finings, add 30% ethanol solution hydrochloride, filtrate is acidified to pH5-6.After the cooling (in 0 ℃ of bath), stir product precipitation down.After the filtration, be lower than 5 ℃ washing with alcohol product with 10ml.The ethanol that is used to wash can be used as the medium of next batch.Obtain 8.05g(76.1% by this way) ranitidine hydrochloride.
Embodiment 4
Implement the method for embodiment 1 by this way, be about to evaporate chloroform after resulting oily product be dissolved in the 30ml dehydrated alcohol, add the concentrated hydrochloric acid ethanolic soln pH value of solution transferred to 5-6.After adding crystal seed, 5-10 ℃ of following stirred solution 1 hour.At room temperature filter crystalline precipitate, use washing with alcohol, be cooled to 5 ℃, drying under reduced pressure at room temperature obtains 9.4g(89% then) ranitidine hydrochloride.
Embodiment 5
Implement the method for embodiment 4 with 1000 times scales, obtain 950g(89.9%) ranitidine hydrochloride.
Claims (6)
1, a kind of 1-{2-[(5-dimethylamino methyl-2-furyl for preparing formula I)-methylthio group]-ethyl }-method of amino-1-methylamino--2-nitroethylene,
2, this method comprises diketene imine derivative and the methylamine reaction that makes formula II.
3, the described method of claim 1, this method comprise the methylamine that uses gaseous state or aqueous solution form.
4, the described method of claim 1, this method are included under 0 ℃-70 ℃ reacts.
5, the described method of claim 1, this method comprise diketene imine derivative and the 2.2-35 mole 20-50%(weight that at room temperature makes formula II) aqueous methylamine solution reaction.
6, the described method of claim 1, this method are included in the reaction uses 10 moles of 40%(weight) aqueous methylamine solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU907074A HU207308B (en) | 1990-11-09 | 1990-11-09 | Process for producing 1- /2-/5-/dimethyl-amino-methyl/-2-/furyl-methyl-thio/-ethyl//- -amino-1-/methyl-amino-2-nitro-ethylene |
| HU7074/90 | 1990-11-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1061968A true CN1061968A (en) | 1992-06-17 |
Family
ID=10972142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91110542A Pending CN1061968A (en) | 1990-11-09 | 1991-11-09 | The method for preparing Ranitidine HCL |
Country Status (16)
| Country | Link |
|---|---|
| KR (1) | KR920009813A (en) |
| CN (1) | CN1061968A (en) |
| AR (1) | AR248017A1 (en) |
| AT (1) | AT400146B (en) |
| CA (1) | CA2055189A1 (en) |
| CZ (1) | CZ280197B6 (en) |
| DK (1) | DK184291A (en) |
| ES (1) | ES2036479B1 (en) |
| FI (1) | FI915265A (en) |
| GR (1) | GR1002225B (en) |
| HU (1) | HU207308B (en) |
| NO (1) | NO179208C (en) |
| PL (1) | PL166616B1 (en) |
| PT (1) | PT99470A (en) |
| RU (1) | RU2032681C1 (en) |
| YU (1) | YU177391A (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2115111B (en) * | 1982-01-25 | 1987-01-14 | Ava Int Corp | Fail safe gate valves and actuators therefor |
| ES543966A0 (en) * | 1982-11-22 | 1986-03-01 | Medichem Sa | PROCEDURE FOR THE PREPARATION OF N- (2 - ((((5- (DIMETILA-MINO) -METIL-2-FURANIL) METHYL) THIO) ETIL) -N'-METHYL-2-NITRO-1,1- ETENDIAMINE |
| YU42819B (en) * | 1982-11-22 | 1988-12-31 | Lek Tovarna Farmacevtskih | Process for preparing n-/2-///5-(dimethyl-amino)-methyl-2-furanyl/methyl/thio/ethyl-n'-methyl-2-nitro-1,1-ethene diamine |
| PT79699B (en) * | 1983-12-22 | 1986-12-10 | Pfizer | Process for preparing quinolone inotropic agents |
| HU196979B (en) * | 1985-01-11 | 1989-02-28 | Gyogyszerkutato Intezet | Process for producing basic thioether and salt |
| ES8603706A1 (en) * | 1985-06-12 | 1986-01-16 | Medichem Sa | Nitro:ethylidene di:amine deriv. |
-
1990
- 1990-11-09 HU HU907074A patent/HU207308B/en not_active IP Right Cessation
-
1991
- 1991-11-06 RU SU915010152A patent/RU2032681C1/en active
- 1991-11-06 AT AT0220391A patent/AT400146B/en not_active IP Right Cessation
- 1991-11-07 GR GR910100451A patent/GR1002225B/en unknown
- 1991-11-07 YU YU177391A patent/YU177391A/en unknown
- 1991-11-08 CA CA002055189A patent/CA2055189A1/en active Granted
- 1991-11-08 PL PL91292327A patent/PL166616B1/en unknown
- 1991-11-08 AR AR91321118A patent/AR248017A1/en active
- 1991-11-08 CZ CS913403A patent/CZ280197B6/en unknown
- 1991-11-08 FI FI915265A patent/FI915265A/en not_active Application Discontinuation
- 1991-11-08 PT PT99470A patent/PT99470A/en not_active Application Discontinuation
- 1991-11-08 DK DK184291A patent/DK184291A/en unknown
- 1991-11-08 NO NO914376A patent/NO179208C/en unknown
- 1991-11-08 ES ES9102480A patent/ES2036479B1/en not_active Expired - Lifetime
- 1991-11-09 CN CN91110542A patent/CN1061968A/en active Pending
- 1991-11-09 KR KR1019910019914A patent/KR920009813A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO914376L (en) | 1992-05-11 |
| NO179208C (en) | 1996-08-28 |
| NO914376D0 (en) | 1991-11-08 |
| GR1002225B (en) | 1996-04-18 |
| PT99470A (en) | 1992-10-30 |
| KR920009813A (en) | 1992-06-25 |
| AR248017A1 (en) | 1995-05-31 |
| ATA220391A (en) | 1995-02-15 |
| FI915265A (en) | 1992-05-10 |
| HUT59916A (en) | 1992-07-28 |
| HU907074D0 (en) | 1991-05-28 |
| GR910100451A (en) | 1992-10-08 |
| AT400146B (en) | 1995-10-25 |
| YU177391A (en) | 1994-01-20 |
| RU2032681C1 (en) | 1995-04-10 |
| ES2036479A1 (en) | 1993-05-16 |
| ES2036479B1 (en) | 1993-12-16 |
| HU207308B (en) | 1993-03-29 |
| FI915265A0 (en) | 1991-11-08 |
| CZ280197B6 (en) | 1995-11-15 |
| DK184291A (en) | 1992-05-10 |
| PL166616B1 (en) | 1995-06-30 |
| CS340391A3 (en) | 1992-05-13 |
| CA2055189A1 (en) | 1992-05-10 |
| CA2055189C (en) | 1992-05-10 |
| DK184291D0 (en) | 1991-11-08 |
| PL292327A1 (en) | 1992-07-13 |
| NO179208B (en) | 1996-05-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |