CN1061968A - Process for preparing ranitidine - Google Patents
Process for preparing ranitidine 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
- ranitidine
- reaction
- formula
- described method
- 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.)
- Pending
Links
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 title abstract description 5
- 229960000620 ranitidine Drugs 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 30
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 5-dimethylaminomethyl-2-furyl Chemical group 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 3
- NESLOYMMIUOLMU-UHFFFAOYSA-N 1-n'-methyl-2-nitroethene-1,1-diamine Chemical group CNC(N)=C[N+]([O-])=O NESLOYMMIUOLMU-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 5
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical group [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 abstract 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 229960001520 ranitidine hydrochloride Drugs 0.000 description 3
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical class [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- WZUCWMVNONEJSO-UHFFFAOYSA-N [N+](=O)([O-])N1C=CC1 Chemical compound [N+](=O)([O-])N1C=CC1 WZUCWMVNONEJSO-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000002425 furfuryl group Chemical group C(C1=CC=CO1)* 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- 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
本发明涉及一种制备式(I)的1-{2-[(5-二甲 氨基甲基-2-呋喃基)-甲硫基]-乙基}-氨基-1-甲 氨基-2-硝基乙烯(俗名；雷尼替丁)的新方法，该方 法包括使双烯酮亚胺衍生物与甲胺反应，本发明的最 重要的优点在于可通过简单的方法以高于90％的产 率制得质量上乘的雷尼替丁。
The present invention relates to a preparation formula (I) of 1-{2-[(5-dimethylaminomethyl-2-furyl)-methylthio]-ethyl}-amino-1-methylamino-2- The new method of nitroethylene (common name; ranitidine), which involves the reaction of diketene imine derivatives with methylamine, the most important advantage of the present invention is that it can be obtained by a simple method with a ratio of more than 90%. The yield is high quality ranitidine.
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 | Process for preparing ranitidine |
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) | FI915265A7 (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 |
| ES8604917A3 (en) * | 1982-11-22 | 1986-03-01 | Medichem Sa | Prepn. of ranitidine for treatment of ulcers - by reacting 2-(((5-(di:methylamino)-methyl-2-furanyl) methyl) thio ethanamine with 1-nitro-3-methyl ketenimine |
| 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 DK DK184291A patent/DK184291A/en unknown
- 1991-11-08 CZ CS913403A patent/CZ280197B6/en unknown
- 1991-11-08 AR AR91321118A patent/AR248017A1/en active
- 1991-11-08 CA CA002055189A patent/CA2055189A1/en active Granted
- 1991-11-08 PL PL91292327A patent/PL166616B1/en unknown
- 1991-11-08 PT PT99470A patent/PT99470A/en not_active Application Discontinuation
- 1991-11-08 NO NO914376A patent/NO179208C/en unknown
- 1991-11-08 FI FI915265A patent/FI915265A7/en not_active Application Discontinuation
- 1991-11-08 ES ES9102480A patent/ES2036479B1/en not_active Expired - Lifetime
- 1991-11-09 KR KR1019910019914A patent/KR920009813A/en not_active Withdrawn
- 1991-11-09 CN CN91110542A patent/CN1061968A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| HU907074D0 (en) | 1991-05-28 |
| ES2036479B1 (en) | 1993-12-16 |
| DK184291D0 (en) | 1991-11-08 |
| AT400146B (en) | 1995-10-25 |
| GR910100451A (en) | 1992-10-08 |
| ATA220391A (en) | 1995-02-15 |
| HUT59916A (en) | 1992-07-28 |
| CZ280197B6 (en) | 1995-11-15 |
| PT99470A (en) | 1992-10-30 |
| KR920009813A (en) | 1992-06-25 |
| CS340391A3 (en) | 1992-05-13 |
| NO914376D0 (en) | 1991-11-08 |
| FI915265A0 (en) | 1991-11-08 |
| FI915265A7 (en) | 1992-05-10 |
| HU207308B (en) | 1993-03-29 |
| PL292327A1 (en) | 1992-07-13 |
| RU2032681C1 (en) | 1995-04-10 |
| NO914376L (en) | 1992-05-11 |
| DK184291A (en) | 1992-05-10 |
| CA2055189C (en) | 1992-05-10 |
| YU177391A (en) | 1994-01-20 |
| CA2055189A1 (en) | 1992-05-10 |
| AR248017A1 (en) | 1995-05-31 |
| GR1002225B (en) | 1996-04-18 |
| PL166616B1 (en) | 1995-06-30 |
| NO179208C (en) | 1996-08-28 |
| ES2036479A1 (en) | 1993-05-16 |
| NO179208B (en) | 1996-05-20 |
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| AD01 | Patent right deemed abandoned | ||
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