GB2053211A - Synthesis of 2-isopropylamino- pyrimidine - Google Patents
Synthesis of 2-isopropylamino- pyrimidine Download PDFInfo
- Publication number
- GB2053211A GB2053211A GB8019773A GB8019773A GB2053211A GB 2053211 A GB2053211 A GB 2053211A GB 8019773 A GB8019773 A GB 8019773A GB 8019773 A GB8019773 A GB 8019773A GB 2053211 A GB2053211 A GB 2053211A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pyrimidine
- synthesis
- isopropylamino
- yield
- solvent
- 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.)
- Granted
Links
- FTCYIGBVOHNHCD-UHFFFAOYSA-N isaxonine Chemical compound CC(C)NC1=NC=CC=N1 FTCYIGBVOHNHCD-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 title claims description 21
- 230000015572 biosynthetic process Effects 0.000 title claims description 19
- 239000002904 solvent Substances 0.000 claims abstract description 13
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010992 reflux Methods 0.000 claims abstract description 9
- OIGXNHYFKZCTCH-UHFFFAOYSA-N 2-methylsulfonylpyrimidine Chemical compound CS(=O)(=O)C1=NC=CC=N1 OIGXNHYFKZCTCH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 22
- FOEMIZSFFWGXHX-UHFFFAOYSA-N 2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC=N1 FOEMIZSFFWGXHX-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- KVJHGPAAOUGYJX-UHFFFAOYSA-N 1,1,3,3-tetraethoxypropane Chemical compound CCOC(OCC)CC(OCC)OCC KVJHGPAAOUGYJX-UHFFFAOYSA-N 0.000 claims description 2
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 claims description 2
- MFIQZHWDRVKGAK-UHFFFAOYSA-N 2-propan-2-ylguanidine;sulfuric acid Chemical compound OS(O)(=O)=O.CC(C)NC(N)=N.CC(C)NC(N)=N MFIQZHWDRVKGAK-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000007098 aminolysis reaction Methods 0.000 claims description 2
- 239000007900 aqueous suspension Substances 0.000 claims description 2
- 230000005587 bubbling Effects 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 2
- 238000003408 phase transfer catalysis Methods 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000004809 thin layer chromatography Methods 0.000 claims description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
2-Isopropylamino pyrimidine, useful in the preparation of pharmaceuticals, is prepared by refluxing isopropylamine with 2-methylsulphonyl- pyrimidine in the absence of a solvent.
Description
**WARNING** start of DESC field may overlap end of CLMS **.
SPECIFICATION
Synthesis of 2-isopropylamino-pyrimidine
Description
The invention relates to a process for the synthesis of 2-isopropylamino-pyrimidine, a compound of use in the preparation of pharmaceuticals. Several syntheses have been proposed for 2-isopropylaminopyrimidine. For example European Patent Application No.79400393.9 describes the synthesis of 2-isopropylamino-pyrimidine by the action of an alkali borohydride and a carboxylic acid on 2 aminopyrimidine in the presence of acetone. Our British Patent Application No. 8019772 (filed herewith) describes the cyclisation of bis(isopropylguanidine) sulphate with 1,1 ,3,3-tetraethoxypropane. The aminolysis of 2-chloropyrimidine with isopropylamine is also known.
The invention provides a process for the synthesis of 2-isopropylamino-pyrimidine, the process comprising refluxing isopropylamine with 2-methysulphonyl-pyrimidine in the absence of a solvent. Using this technique, the 2-isopropylamino-pyrimidine may be obtained in a substantially quantitiative yield.
The synthesis of the starting material, 2-methylsulphonyl-pyrimidine, is described by Brown D.J. & Ford
P.W. (J.Chem. Soc (C) 1967 568) with 50% yield starting from 2-methylthio-pyrimidine. The technique described by Brown and Ford comprises bubbling chlorine through an aqueous suspension of 2-methylthiopyrimidine at from 0 C to + 5"C. We prefer to vary this technique by passing the chlorine more slowly and reducing the reaction temperature to from -5 C to O C, thus obtaining a yield of approximately 90%.
The preparation of 2-methylthio-pyrimidine was first described by Boarland M.P.V. and McOmie J.P.W.
(J.Chem. Soc. 1952, 3716) with a yield of 62% starting from 2-mercapto-pyrimidine and methyl sulphate.
Hunig S. and Oette K.F. (Liebig's Annalen der Chemie, 1961,640, 98) obtained a yield of 83%. We prefer two apply the phase transfer catalysis technique of Dou, H. et. a/. (Phosphorus and Sulphur and the related elements, 1977, 3, 355), thus obtaining the 2-methylthio-pyrimidine in quantitative yield.
The following reaction scheme illustrates the synthesis starting from 2-mercapto-pyrimidine.
The following Example illustrates the invention.
EXAMPLE (a) S /nthesis of2-methylsulphonyl-pyrimidine Into a 200 ml reactor, there were introduced lOg (0.0794 mole) of 2-methylthiopyrimidine and 100 ml of water.
Chlorine was bubbled through slowly at slightly below 0 C. After 5 minutes, a solution was obtained.
Chlorine passage was continued, slowly, for 1 hour while maintaining the same temperature. During this time, the progress s-ithe reaction was confirmed by thin layer chromatography. The chlorine supply was then interrupted. The flask was shaken for 1 extra hour at 0oC. The pH was adjusted to 8 using potassium carbonate. The reaction mixture was extracted with chlorinated solvent. The organic phase was dried using anhydrous sodium sulphate, and the solvent was then evaporated off.
There was obtained a white product which was recrystallized twice from ethanol.
Yi Id 11.3 g : 90%. MP 70 to 72 C (literate 73-74"C).
Kbi Synthesis of2-isoprop ylamino-p yrimidine
2g (0.0126 mole) of 2-methylsulphonyl-pyrimidine were suspended in 20 ml of isopropylamine.
Refluxing was carried out, rapidly obtaining a solution. After 1 hour (the progress of the reaction being confirmed by .hin layer chromatography) the refluxing was stopped and excess isopropylamine was removed. 1O0 ml water was added and the pH was adjusted to 9 using soda wash. The reaction mixture was extracted with a chlorinated solvent. The organic phase was dried over anhydrous sodium sulphate and the solvent was evaporated off. 1.7 g (1 000/0 yield) of 2-isopropylamino-pyrimidine was obtained.
The product could be used as such or in the form of its salts.
CLAIMS
1. A process for the synthesis of 2isopropylamino-pyrimidine, the process comprising refluxing isopropylamine with 2-methylsulphonyl-pyrimidine in the absence of a solvent.
2. A process for the synthesis of 2-isopropylamino-pyrimidine, the process being substantially as described in subsection (b) of the Example.
Claims (2)
1. A process for the synthesis of 2isopropylamino-pyrimidine, the process comprising refluxing isopropylamine with 2-methylsulphonyl-pyrimidine in the absence of a solvent.
2. A process for the synthesis of 2-isopropylamino-pyrimidine, the process being substantially as described in subsection (b) of the Example.
**WARNING** end of CLMS field may overlap start of DESC **.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8019773A GB2053211B (en) | 1979-07-04 | 1980-06-17 | Synthesis of 2-isopropylamino-pyrimidine |
| IT23210/80A IT1220968B (en) | 1979-07-04 | 1980-07-03 | SYNTHESIS PROCEDURE OF 2-ISOPROPILAMINE-PYRIMIDINE |
| MY355/84A MY8400355A (en) | 1979-07-04 | 1984-12-30 | Synthesis of 2-isopropylamino-pyrimidine |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7923224 | 1979-07-04 | ||
| GB8019773A GB2053211B (en) | 1979-07-04 | 1980-06-17 | Synthesis of 2-isopropylamino-pyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2053211A true GB2053211A (en) | 1981-02-04 |
| GB2053211B GB2053211B (en) | 1983-06-02 |
Family
ID=26272060
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8019773A Expired GB2053211B (en) | 1979-07-04 | 1980-06-17 | Synthesis of 2-isopropylamino-pyrimidine |
Country Status (3)
| Country | Link |
|---|---|
| GB (1) | GB2053211B (en) |
| IT (1) | IT1220968B (en) |
| MY (1) | MY8400355A (en) |
-
1980
- 1980-06-17 GB GB8019773A patent/GB2053211B/en not_active Expired
- 1980-07-03 IT IT23210/80A patent/IT1220968B/en active
-
1984
- 1984-12-30 MY MY355/84A patent/MY8400355A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IT8023210A0 (en) | 1980-07-03 |
| GB2053211B (en) | 1983-06-02 |
| MY8400355A (en) | 1984-12-31 |
| IT1220968B (en) | 1990-06-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |