US20020040141A1 - Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine - Google Patents
Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine Download PDFInfo
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- US20020040141A1 US20020040141A1 US09/811,433 US81143301A US2002040141A1 US 20020040141 A1 US20020040141 A1 US 20020040141A1 US 81143301 A US81143301 A US 81143301A US 2002040141 A1 US2002040141 A1 US 2002040141A1
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- methyl
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- aminomethylpyrimidine
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- OZOHTVFCSKFMLL-UHFFFAOYSA-N 4-amino-5-aminomethyl-2-methylpyrimidine Chemical compound CC1=NC=C(CN)C(N)=N1 OZOHTVFCSKFMLL-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 22
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052593 corundum Inorganic materials 0.000 claims description 8
- 229910001845 yogo sapphire Inorganic materials 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- NQHSRVYHHWWPCZ-UHFFFAOYSA-N 5-(methoxymethyl)-2-methylpyrimidin-4-amine Chemical compound COCC1=CN=C(C)N=C1N NQHSRVYHHWWPCZ-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 0 *OCC1=C(N)N=C(C)N=C1 Chemical compound *OCC1=C(N)N=C(C)N=C1 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- -1 benzyl halide Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 2
- 229960003495 thiamine Drugs 0.000 description 2
- 235000019157 thiamine Nutrition 0.000 description 2
- 239000011721 thiamine Substances 0.000 description 2
- BHADWYUSXWQCJV-UHFFFAOYSA-N $l^{2}-azanylidenemethanamine Chemical compound NC=[N] BHADWYUSXWQCJV-UHFFFAOYSA-N 0.000 description 1
- QBIDHEZNYLHWBR-UHFFFAOYSA-N 2-(methoxymethyl)pyrimidine Chemical compound COCC1=NC=CC=N1 QBIDHEZNYLHWBR-UHFFFAOYSA-N 0.000 description 1
- FAKUUZRCQVPHHR-UHFFFAOYSA-N C.CC(=N)N.CC(=O)NCC1=C(N)N=C(C)N=C1.CC1=NC2=C(C=N1)CNC(C)=N2.CCC(C#N)C(C)OC.COCC1=C(N)N=C(C)N=C1.COCCC#N Chemical compound C.CC(=N)N.CC(=O)NCC1=C(N)N=C(C)N=C1.CC1=NC2=C(C=N1)CNC(C)=N2.CCC(C#N)C(C)OC.COCC1=C(N)N=C(C)N=C1.COCCC#N FAKUUZRCQVPHHR-UHFFFAOYSA-N 0.000 description 1
- HNUALPPJLMYHDK-UHFFFAOYSA-N C[CH]C Chemical compound C[CH]C HNUALPPJLMYHDK-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229910001477 LaPO4 Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- WGVWLKXZBUVUAM-UHFFFAOYSA-N Pentanochlor Chemical compound CCCC(C)C(=O)NC1=CC=C(C)C(Cl)=C1 WGVWLKXZBUVUAM-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 239000002635 aromatic organic solvent Substances 0.000 description 1
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
Definitions
- the present invention relates to an improved process for preparing 2-methyl-4-amino-5-aminomethylpyrimidine of the formula 1 (hereinafter abbreviated as AMP),
- R is C 1 -C 6 alkyl.
- AMP 1 (formula 1) is the central intermediate in all industrially relevant processes for preparing vitamin B 1 (thiamine). Since the demand for this vitamin is continually increasing, many attempts have already been made to develop an advantageous process for preparing the pyrimidine part of thiamine.
- the desired product AMP is not obtained directly, but rather the processes essentially give firstly AMP derivatives which are either in the wrong oxidation state or bear an N-acyl function.
- the aminomethyl side chain of AMP has to be generated by complicated and expensive reduction processes (hydrogenation of a nitrile group (1) or reductive amination of a formyl group (2)) or by hydrolysis of the N-acyl group (3).
- the route via ⁇ -dialkoxypropionitrile 6 includes the abovementioned cumbersome reductive amination of a formylpyrimidine intermediate.
- ⁇ -aminopropionitrile is not unproblematical in terms of safety and is also a very toxic substance.
- ⁇ -alkoxypropionitriles are virtually nontoxic (Ullmann's Encyclopedie der ischen Chemie, 4th edition, volume 17 (1979), p. 330).
- the preparation of AMP from ⁇ -alkoxypropionitriles, which are readily handleable precursors because of their low toxicity, has been described repeatedly in the literature (cf., for example, Chem. Ber. 106 (1973), 893; Bull. Chem. Soc. Japan 45 (1972), 1127; DE-A 1016266).
- a particularly disadvantageous aspect of the process carried out hitherto is that an additional equivalent of the expensive acetamidine is consumed for introduction of the aminomethylene nitrogen.
- the resulting N-acetyl-AMP has to be saponified under drastic conditions to form the free amine:
- this process forms, as by-product, MMP which is not converted into AMP, thus adversely affecting the efficiency of the overall process.
- C 1 -C 6 -alkyl in the radical R is, either alone or in combination with, for example, alkoxy, a straight-chain, branched, saturated or unsaturated radical having 1-6 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl radical, preferably a methyl radical.
- 2 is initially charged in an inert organic solvent or in ammonia itself.
- solvents are aliphatic or aromatic organic solvents, for example cycloalkanes such as cyclohexane or decalin or else benzene, toluene, xylene or mesytilene.
- the solvents can be used either alone or in admixture with one another or with ammonia.
- 2 is preferably initially charged in ammonia itself.
- the reaction is carried out in a temperature range of about 50-400° C., preferably about 180-350° C., particularly preferably in a range of 210-300° C.
- Catalysts used are Lewis or Brönsted acids, preferably Lewis-acid oxidic compounds of the elements of groups IV A and III B, particularly preferably Al 2 O 3 .
- Ammonia is used in an amount of 1-500 equivalents, preferably 10-300 equivalents, particularly preferably 25-250 equivalents, per equivalent of 2.
- the ⁇ -alkoxypropionitrile is firstly converted into the alkali metal enolate of the corresponding ⁇ -formyl- ⁇ -alkoxypropionitrile by condensation with a C 1 -C 6 -alkyl formate in the presence of an alkali metal alkoxide or by pressure reaction with carbon monoxide in a lower alkanol in the presence of an alkali metal alkoxide (DE-A 2107990).
- the ⁇ -formyl- ⁇ -alkoxypropionitrile is alkylated (e.g. using dimethyl sulfate: R′′ ⁇ CH 3 ) to give the corresponding enol ether. Condensation with acetamidine gives the 5-alkoxymethylpyrimidine of the formula 2 (see Scheme 3).
Abstract
2-Methyl-4-amino-5-aminomethylpyrimidine of the formula 1
is prepared by reacting 2-methyl-4-amino-5-alkoxymethylpyrimidine of the formula 2
where R═C1-C6-alkyl, with ammonia in the presence of a catalyst.
Description
- The present invention relates to an improved process for preparing 2-methyl-4-amino-5-aminomethylpyrimidine of the formula 1 (hereinafter abbreviated as AMP),
- starting from a 2-methyl-4-amino-5-alkoxymethylpyrimidine of the formula 2,
- where
- R is C 1-C6 alkyl.
- The derivative of the formula 2 in which R=methyl will hereinafter be referred to as MMP(‘methoxymethylpyrimidine’).
- AMP 1 (formula 1) is the central intermediate in all industrially relevant processes for preparing vitamin B 1 (thiamine). Since the demand for this vitamin is continually increasing, many attempts have already been made to develop an advantageous process for preparing the pyrimidine part of thiamine.
- An up-to-date and comprehensive review of these processes has appeared in, for example, Ullmann's Encyclopedia of Industrial Chemistry, Vol. A 27 (1996), pp. 515-517. Starting materials used are generally acrylonitrile, malononitrile or acetonitrile.
- In all these processes, the desired product AMP is not obtained directly, but rather the processes essentially give firstly AMP derivatives which are either in the wrong oxidation state or bear an N-acyl function. In all these processes, the aminomethyl side chain of AMP has to be generated by complicated and expensive reduction processes (hydrogenation of a nitrile group (1) or reductive amination of a formyl group (2)) or by hydrolysis of the N-acyl group (3).
- Transformation of functional groups on valuable intermediates generally make a process cumbersome and thus uneconomical.
- The known processes are also unfavorable in respect of the starting materials. Malononitrile 3 is very expensive and not unproblematical in terms of safety. The formation of the pyrimidine skeleton starting from acetonitrile 4 is time-consuming and cumbersome because of the additional process steps for introducing the C 1 building block. The synthetic routes from acrylonitrile 5 go via either β-dialkoxypropionitriles 6, N-functionalized β-aminopropionitriles 8 or β-alkoxypropionitriles 7.
- The route via β-dialkoxypropionitrile 6 includes the abovementioned cumbersome reductive amination of a formylpyrimidine intermediate.
- On the other hand, β-aminopropionitrile is not unproblematical in terms of safety and is also a very toxic substance. In contrast, β-alkoxypropionitriles are virtually nontoxic (Ullmann's Encyclopedie der technischen Chemie, 4th edition, volume 17 (1979), p. 330). The preparation of AMP from β-alkoxypropionitriles, which are readily handleable precursors because of their low toxicity, has been described repeatedly in the literature (cf., for example, Chem. Ber. 106 (1973), 893; Bull. Chem. Soc. Japan 45 (1972), 1127; DE-A 1016266).
- A particularly disadvantageous aspect of the process carried out hitherto is that an additional equivalent of the expensive acetamidine is consumed for introduction of the aminomethylene nitrogen. The resulting N-acetyl-AMP has to be saponified under drastic conditions to form the free amine:
- Furthermore, this process forms, as by-product, MMP which is not converted into AMP, thus adversely affecting the efficiency of the overall process.
- In the literature, benzyl ethers of the type 2 have been subjected to various ether cleavages (Chim. Ther. 8 (1973) 1, 98; BE 590665; Khim.-Farm. Zh. 23 (1989), 11, 1374; U.S. Pat. No. 3,161,642; GB 953,875). These generally require drastic conditions (strong mineral acids).
- The corresponding benzyl halide formed is reacted with NH 3 in a further step (Otkrytiya, Izobret., Prom. Obraztsy, Tovarnye Znaki 1969, 46 (8), 22). The selectivity of the monoalkylation of NH3 with reactive halides is known to be poor. In view of the number and complexity of the steps, this process, too, is therefore very unfavorable.
- It is an object of the present invention to develop a process which starts from the precursor β-alkoxypropionitrile and leads directly in a few simple steps to AMP without having the disadvantages of the prior art.
- We have found that this object is achieved by converting 5-alkoxymethylpyrimidines of the formula 2, where R is C 1-C6-alkyl, directly into AMP (1) with high selectivity by reaction with NH3 in the presence of catalysts so as to replace the alkoxy radical.
- Unless indicated otherwise, C 1-C6-alkyl in the radical R is, either alone or in combination with, for example, alkoxy, a straight-chain, branched, saturated or unsaturated radical having 1-6 carbon atoms, e.g. a methyl, ethyl, propyl or isopropyl radical, preferably a methyl radical.
- In the process of the present invention, 2 is initially charged in an inert organic solvent or in ammonia itself. Preferred solvents are aliphatic or aromatic organic solvents, for example cycloalkanes such as cyclohexane or decalin or else benzene, toluene, xylene or mesytilene. The solvents can be used either alone or in admixture with one another or with ammonia. 2 is preferably initially charged in ammonia itself.
- After addition of the catalyst, the reaction is carried out in a temperature range of about 50-400° C., preferably about 180-350° C., particularly preferably in a range of 210-300° C.
- Catalysts used are Lewis or Brönsted acids, preferably Lewis-acid oxidic compounds of the elements of groups IV A and III B, particularly preferably Al 2O3.
- Ammonia is used in an amount of 1-500 equivalents, preferably 10-300 equivalents, particularly preferably 25-250 equivalents, per equivalent of 2.
- Starting materials for the amination are 2-methyl-4-amino-5-alkoxymethylpyrimidines of the formula 2. The synthesis of 2 from the corresponding β-alkoxypropionitriles is described in the prior art (Pharm. Chem. J. 5 (1971), 8, 495; Khim.-Farm. Zh., 12 (1978), 7, 106).
- For this purpose, the β-alkoxypropionitrile is firstly converted into the alkali metal enolate of the corresponding α-formyl-β-alkoxypropionitrile by condensation with a C 1-C6-alkyl formate in the presence of an alkali metal alkoxide or by pressure reaction with carbon monoxide in a lower alkanol in the presence of an alkali metal alkoxide (DE-A 2107990). The α-formyl-β-alkoxypropionitrile is alkylated (e.g. using dimethyl sulfate: R″═CH3) to give the corresponding enol ether. Condensation with acetamidine gives the 5-alkoxymethylpyrimidine of the formula 2 (see Scheme 3).
- The process of the present invention for the direct conversion of 2 into AMP (1) thus provides a short and attractive route to this valuable vitamin B 1 precursor, starting from a favorable and readily handleable starting material.
- The following examples illustrate the invention without restricting its scope.
- 1.25 g (8.2 mmol) of MMP and 5 g of Al 2O3 (D-10-10, BASF) together with 50 ml of toluene were placed in a 300 ml autoclave. After closing the autoclave, 30 g (1.76 mol, 215 equivalents) of ammonia were added and the mixture was heated at 230° C. for 4 hours while stirring at the autogenous pressure. After cooling, the reaction mixture was filtered, taken up in ethanol and analyzed by gas chromatography (Table 1, Example 1).
- 1.25 g (8.2 mmol) of MMP and 5 g of catalyst together with 50 ml of toluene were placed in a 300 ml autoclave. After closing the autoclave, 30 g (1.76 mol, 215 equivalents) of ammonia were added and the mixture was heated for 4 hours while stirring at the autogenous pressure. After cooling, the reaction mixture was filtered, taken up in ethanol and analyzed by gas chromatography (Table 1).
TABLE 1 Ex- Yield Selec- am- Temp. NH3/MMP CMMP of AMP tivity ple Catalyst [° C.] [mol/mol] [%] [%] [%] 1 Al2O3 230 215 87 80 92 2 Al2O3 230 55 45 39 87 3 Al2O3 270 215 98 42 43 4 Al2O3 210 215 40 34 86 5 H3PO4 270 215 25 23 90 6 LaPO4/TiO2 270 215 55 13 24 7 SiO2 230 215 2 1 50 8 TiO2 230 215 41 37 90 9 ZrO2 230 215 25 19 78
Claims (8)
1. A process for preparing 2-methyl-4-amino-5-aminomethylpyrimidine of the formula 1
by reacting 2-methyl-4-amino-5-alkoxymethylpyrimidine of the formula 2
where R═C1-C6-alkyl, with ammonia in the presence of a catalyst.
2. A process as claimed in claim 1 , wherein an inert, organic solvent is used as solvent.
3. A process as claimed in claim 1 or 2, wherein ammonia is used as solvent.
4. A process as claimed in any of claims 1 to 3 , wherein the catalyst used is a Lewis or Brönsted acid.
5. A process as claimed in any of claims 1 to 4 , wherein the catalyst used is a Lewis-acid oxidic compound of an element of group IV A or III B, preferably Al2O3.
6. A process as claimed in any of claims 1 to 5 , wherein the catalyst used is Al2O3.
7. A process as claimed in any of claims 1 to 6 , wherein the compound of the formula 2 is 2-methyl-4-amino-5-methoxymethylpyrimidine.
8. A process as claimed in any of claims 1 to 7 , wherein after addition of the catalyst the reaction is carried out in a temperature range of 50-400° C.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10015470.0 | 2000-03-29 | ||
| DE10015470A DE10015470A1 (en) | 2000-03-29 | 2000-03-29 | Process for the preparation of 2-methyl-4-amino-5-aminomethyrimidine |
| DE10015470 | 2000-03-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US6365740B1 US6365740B1 (en) | 2002-04-02 |
| US20020040141A1 true US20020040141A1 (en) | 2002-04-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/811,433 Expired - Fee Related US6365740B1 (en) | 2000-03-29 | 2001-03-20 | Preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US6365740B1 (en) |
| EP (1) | EP1138675A3 (en) |
| JP (1) | JP2001316377A (en) |
| CN (1) | CN1176912C (en) |
| DE (1) | DE10015470A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101277352B1 (en) * | 2005-01-28 | 2013-06-20 | 디에스엠 아이피 어셋츠 비.브이. | Process for the manufacture of a precursor of vitamin b1 |
| WO2011060624A1 (en) * | 2009-11-23 | 2011-05-26 | Fudan University | Process for preparing 2-methyl-4-amino-5-cyanopyrimidine |
| CN103420918B (en) * | 2013-07-22 | 2015-04-22 | 新发药业有限公司 | Simple and convenient preparation method of key intermediate (2-methyl-4-amino-5-amino methyl pyrimidine) for vitamin B1 |
| CN109369540B (en) * | 2018-12-26 | 2020-09-01 | 浙江本立科技股份有限公司 | Synthesis method of 2-methyl-4-amino-5-formamido methylpyrimidine |
| CN114315738B (en) * | 2022-01-15 | 2023-08-18 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH244837A (en) * | 1945-09-06 | 1946-10-15 | Hoffmann La Roche | Process for the preparation of primary amines. |
| DE1016266B (en) | 1954-09-01 | 1957-09-26 | Shionogi & Co | Process for the preparation of 2-methyl-4-amino-5-acetaminomethylpyrimidine |
| US3161642A (en) * | 1959-11-20 | 1964-12-15 | Merck & Co Inc | Preparation of pyrimidine derivatives by ether cleavage |
| JPS5946274A (en) * | 1982-09-10 | 1984-03-15 | Ube Ind Ltd | Preparation of 2-alkyl-4-amino-5-aminomethylpyrimidine |
| DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
-
2000
- 2000-03-29 DE DE10015470A patent/DE10015470A1/en not_active Withdrawn
-
2001
- 2001-03-15 EP EP01106525A patent/EP1138675A3/en not_active Withdrawn
- 2001-03-20 US US09/811,433 patent/US6365740B1/en not_active Expired - Fee Related
- 2001-03-28 JP JP2001094120A patent/JP2001316377A/en not_active Withdrawn
- 2001-03-29 CN CNB011123079A patent/CN1176912C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DE10015470A1 (en) | 2001-10-11 |
| CN1176912C (en) | 2004-11-24 |
| JP2001316377A (en) | 2001-11-13 |
| CN1319592A (en) | 2001-10-31 |
| EP1138675A3 (en) | 2004-01-02 |
| EP1138675A2 (en) | 2001-10-04 |
| US6365740B1 (en) | 2002-04-02 |
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