NL8500431A - 2-Alkyl:pyrimidine cpds. prepn. from 2-alkyl-tetra:hydro:pyrimidine - by gas phase dehydrogenation using carbon mon:oxide and hydrogen reactant - Google Patents

Abstract

Prepn. of a 2-propyl or 2-butylpyrimidine (I) by gas phase dehydrogenation of the corresp. 2-alkyl-1,4,5,6-tetrahydropyrimidine (II) using a Pd-contg. catalyst is characterised by the use of a CO-H3 gas phase reactant. Reaction is pref. at 250-400 deg. C, pref. using a 2-50 fold molar excess (on (II)) of CO-H2, which may be supplied as EtOH or MeOH.

Description

* 'STAMICARBON B.V. (Licensing subsidiary of DSM) JAS / WCH / JB / WP / mjh

Inventors: Antonius J.J.M Teunissen in Geleen

Cornells G.M. van de Moesdijk in Elsloo Hubertus J.A.V. Dejahaye at Voerendaal -1- PN 3617

PROCESS FOR THE PREPARATION OF PYRIMIDINE

The invention relates to a process for the preparation of pyrimidine. Pyrimidine is used, inter alia, as an intermediate in the synthesis of organic compounds such as, for example, plant protection products.

A method as described in the opening paragraph is known from Yakugaku Zasshi 1005-1012 (1976). This article actually relates to the gas phase synthesis of 2-alkylpyrimidines from diaminopropane and aldehydes in the presence of four catalysts, namely Pd (2%) - Al203, Pt (2%) - Al203, Rh (2%) - Al203 and 10 Pt (1%) - Rh (1%) - Al2 O3. In the various ring closure experiments, according to this article, the best results were obtained with the Pt-Rh catalyst and with the Rh catalyst. The Pd catalyst was hardly active. By the way, the article mentions a 6% yield of pyrimidine from diaminopropane and formaldehyde (in addition to 6 15% 2-methylpyrimidine and 19% 2-ethylpyrimidine). It can be deduced from table I of this article that the Pt-Rh catalyst was used in this experiment. At the end of their article, the authors sought an explanation for the low yield of pyrimidine in the instability of the proposed intermediate hexahydropyrimidine, as well as in the susceptibility to side reactions of this intermediate. Generally, the authors of this article discourage the use of Pd catalysts in cyclization reactions as described by them.

In the same research group, Yakugaku Zasshi 97_: 373-381 (1977) describes the reaction of diaminopropane with methanol to pyrimidin in 7% yield. Details on this reaction will be m 8500431

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-2- not given, but probably Pt (1%) - Rh (1%) - Al2O3 was also used here as catalyst.

The invention now provides a process for the preparation of pyrimidine, characterized in that a nitrogen reactant is selected from the reaction product of formamide with 1,2-diaminopropane in the liquid phase, 1-amino-3-formamidopropane, 1,4. 5,6-tetrahydropyrimidine and / or 1,3-diformamidopropane in the gas phase at a temperature between 200 and 550 ° C in the presence of a carbon monoxide-hydrogen reactant and contacting a palladium-containing catalyst and obtained from the resulting pyrimidine reaction mixture wins. This achieves that it is possible to prepare pyrimidine in a yield based on the nitrogen reactant of 40-60%. Incidentally, it is quite possible to recycle unreacted 1,3-diaminopropane or formamide after separation thereof and to re-use it in the liquid phase reaction as described. In particular, it is the magnitude of the yield that determines the value of the gas phase conversion as described above.

The reaction of 1,3-diaminopropane (DAP) with liquid phase formamide is known per se from German Offenlegungsschrift No. 20 2748976. According to this publication, the reaction of 1,3-diaminopropane with formamide occurs, optionally in the presence of an inert solvent , at a temperature between 50 and 200 ° C 1-amino-3-formamidopropane, hereinafter further referred to as AFP. In a second step, AFP can then be converted to 1,4,5,6-tetrahydropyrimidine, hereinafter referred to as THP, by DE-A-274 8976 by pyrolysis under reduced pressure.

Applicant has found, however, by NMR analysis, as well as by mass spectrometry, that the liquid phase reaction between formamide and a molar excess of 1,3-diaminopropane 30 yields a reaction mixture which (after removal of excess 1,3-diaminopropane) in addition to AFP also contains a significant amount of THP. According to experiments, such a mixture may contain even more THP than AFP, calculated on a molar basis.

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The applicant has also found that the embodiment, in which a 2-fold molar excess of formamide with 1,3-diaminopropane is used, yields a reaction mixture containing mainly 1,3-diformamidopropane (DFP).

Subsequently, the applicant has found that both the AFP and THP-containing mixture and the DFP-containing mixture can be converted in the gas phase in a high yield into a pyrimidine-containing reaction mixture.

Instead of the crude reaction mixture containing various substances as described above, it is also possible to convert the pure THP in the gas phase into pyrimidine. Pure THP can be obtained, for example, by pyrolysing AFP according to DE-A-274 8976. It is also possible to contact the AFP with a known dehydration catalyst, for example alumina, at an elevated temperature. It is also possible to prepare THP from HCN and DAP according to Chemische Berichte 98: pp. 1342-1349 (1965}). Pyrimidine is therefore presumably formed from the intermediate THP, also when starting from pure AFP. AFP can for instance also be prepared according to the method described in FR-A-976959 from acrylonitrile and formamide and then hydrogen The applicant has not been able to obtain certainty about the reaction mechanism with nickel or cobalt catalysts, however, and the invention is not limited to any theory on this point.

The applicant has no explanation for the way in which DFP is converted into pyrimidine, but perhaps THP also plays a role here as an intermediate, see for instance DE-A-3245109. Incidentally, the embodiment with a 2-fold molar excess of formamide compared to DAP via DFP is technically attractive, because no purification is then required.

It is noted that the preparation of substituted pyrimidines from DAP and an alkane carboxylic acid amide in the gas phase in the presence of a palladium catalyst is known from US-A-4376201. A carbon monoxide-hydrogen reactant is not used. The yield here appears to vary between 5 and 9%, based on the molar amount of the amide.

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The process according to the invention is preferably carried out at a temperature between 2 ^ 50 and 400 ° C, because under such a condition the yield to pyrimidine is the highest.

The process of the invention is carried out in the presence of a carbon monoxide-hydrogen reactant. The molar amount, calculated as the total of CO and H2, is generally 0.5-100, preferably 2-50 times the amount of A.FP, THP and / or DFT to be converted. With an amount of carbon monoxide-hydrogen reactant smaller than a 2-fold molar excess, the yield decreases to pyrimidine. Amounts greater than a 50-fold molar excess offer no additional benefit, but require a relatively large reactor volume, which adversely affects the fixed costs of the process. The CO: H2 ratio is not particularly critical, and may e.g. range from 1: 10 to 10: 1.

Carbon monoxide-hydrogen reactant in this application is understood to mean a mixture of carbon monoxide and hydrogen, and also a compound which can decompose at least partly in carbon monoxide and hydrogen under the reaction conditions. Such compounds are, for example, alcohols such as methanol and ethanol. In addition to the carbon monoxide-hydrogen reactant, an inert gas such as, for example, nitrogen or helium, can be passed through the reactor in order to obtain uniform evaporation of the starting mixture. The use of methanol has the advantage, on the one hand, that part of it decomposes under the reaction conditions into carbon monoxide and hydrogen in a ratio favorable for the reaction and, on the other hand, that undecomposed methanol ensures uniform evaporation of the starting mixture.

Palladium-containing catalysts are used in the process according to the invention. These catalysts generally contain 0.1-10 wt% palladium, preferably 0.5-5 wt%, based on the total catalyst. An alkali metal can also be added to the catalyst in amounts between 0.1-2% by weight, based on the total catalyst.

The catalyst can be used on a carrier known per se. Such carriers can contain, for example, aluminum oxide, carbon and silicon oxide.

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Catalysts as described above are usually commercially available.

For the practical realization of the process according to the invention, the per se known embodiments of gaseous phase reactions are suitable, for example the embodiment in which the gaseous starting mixture is passed over the catalyst in the form of a fixed bed or a so-called fluid bed. The spatial throughput can be varied, for example between 0.001 and 2 g of starting compound per milliliter of catalyst material (shaking volume) per hour. The pressure at which the reaction takes place in the gas phase is not important per se, so that the reaction will generally be carried out at autogenous pressure.

The work-up of the pyrimidine obtained in the reaction can take place in a manner known per se by cooling and then by, for example, carrying out a distillation or extraction.

The invention is further illustrated in the following examples.

Example I

In a 5 liter round bottom flask, 296.5 g (4.0 mol) of 20 1,3-diaminopropane (DAP) was heated to 130 ° C. 126 g (2.8 mol) of formamide was then added at this temperature with stirring. The ammonia gas formed in the reaction was collected in dilute sulfuric acid and titration showed that the amount of ammonia formed was consistent with the amount of formamide metered, calculated on a molar basis. After all the formamide was added, the excess DAP, along with some water formed during the reaction, was distilled off at 10 mbar. The collected DAP-water mixture was found to contain 1.84 mol DAP. The 202 g residue was a mixture of AFP, THP and some DFP. It was found that 10.7 mmol DAP per gram of this starting mixture was incorporated (4.0-1.84 mol DAP in 202 g residue). .

This starting mixture to be evaporated was placed in a 10-fold excess of methanol. (0.107 mol methanol per g starting mixture) and the whole was brought to a temperature of 350 ° C in an evaporator. The methanol-containing starting mixture was passed through a 85 0 0.4 3 1

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guided a tubular reactor (length 400 mm, diameter 20 mm), in which there was a zone of 20 ml of catalyst. This catalyst was a Pd (1%) - Na (1%) -Al 2 O 3 catalyst. The spatial flow rate (LHSV) based on the starting mixture was 0.23 ml per ml of catalyst per hour. At the same time, 3.6 liters of hydrogen per hour were passed through the reactor, on the one hand to make evaporation more evenly, on the other hand to maintain a reducing environment in the catalyst bed.

The reaction gas was condensed and collected via a three-stage cooling system (12 ° C, 10 ° C and -80 ° C). The amount of pyrimidine was determined by gas-liquid chromatography (GLC) and the amount of condensed reaction product collected over a 4 hour period. The yield of pyrimidine was calculated based on the amount of pyrimidine in the reaction product based on the amount of DA.P. incorporated in the starting mixture. This is based on the assumption that theoretically, one mole of pyrimidine can be formed per mole of DAP.

Table I lists the yield of pyrimidine at different reaction times. The temperature of the catalyst bed was always 350 ° C.

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Table 1

Operating time before Sample yield in hours_pyrimidine in% _ 4 54, 3 2 5 24 - 51.7 47 .54, 0 115 52.0 143. 50.2 188 51.6 30 215 '49.0 bath © ®g0n $ l4 3 1 -7-

Example II

In the manner described in Example I, pyrimidine was prepared from the starting liquid mixture, varying the amount of methanol. The amount of methanol is expressed in 5 moles per mole (in the starting liquid mixture) built-in DAP. Each experiment lasted 24 hours, after which the yield of pyrimidine was determined from the amount of reaction product collected during this time. The results are shown in Table 2.

Table 2 10 Amount of methanol Yield of mol / mol built-in DAP_pyrimidine in% _ 0 23.2 2.5 41.3 5 48.6 .15 10 53.6 20 '54.8 30 52.2 /

Example III

In the manner described in Example II, ethanol was dosed in place of methanol and varied. The results are shown in Table 3.

Table 3

Amount of ethanol Yield of mol / mol built-in DAP pyrimidine in% 25 0 23, 1 2.5 24, 9 5. 38.8 10 43.0 20 4 2.1 '30 30 42.2 BAD 3 1 -8-

Example IV

In the manner described in Example II, a CO2 / H2 mixture was dosed in place of methanol. The results are shown in Table 4. It is noted here that the amount of hydrogen dosed at 3.6 liters per hour according to Example I is included in the amounts given in Table 4. In one case, therefore, no hydrogen was dosed at all.

Table 4 mol / mol built-in PAP_j. Yield of 10 _CO | pyrimidine in 7.0-6 14.3 6 3 47.0 7 0 3 1.4 11 3 56.3 15. 12 6 51.0

Example V

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In the manner described in Example I, 24 hour experiments were done at different temperatures and LHSV values. The results are shown in Table 5.

20 Table 5

Temperature LHSV Yield at ° C_ml / ml. hr ~ 1_pyrimidine in% _ 3 27 0.23. 34, 8 .34 1 0.23 4 5.8 25 351 0.23 53, 6 351 0.10 53, 0 351 0.50 '30.0 36 1 0.23 5 5.3 bae & ^ i8iiQa4 3 1 -9-

Example VI

In the manner described in Example 1, instead of the starting mixture obtained in the liquid phase, pure THP was dissolved in a 7-fold molar excess of methanol and the whole was passed over the catalyst. The LHSV was 0.25 ml per ml of catalyst per hour. The pyrimidine yields obtained by dehydrogenation of THP are shown in Table 6 for different reaction times.

Table 6

Operating time before Yield to 10 sampling in hours_pyrimidine in% _ 4 '56.1 24 5 5.7 4 8 54, 6 72 '55.0

Example VII

In the manner described in Example VI, an excess of a CO / H 2 mixture was metered in a molar ratio to THP of 3 for CO and 7 for H 2 instead of methanol.

As in example IV, all the dosed hydrogen was calculated in the excess H2. After 24 hours of reaction, a pyrimidine yield of 58.8% was found.

Example VIII

Example VII was repeated with a molar excess of CO and H 2 over THP of 3.3 and 10, respectively. After 24 hours, the pyrimidine yield was 57.3%.

Example IX

In the manner described in Example 1, a liquid phase reaction was carried out of 360 g of formamide (8.0 mol) with 296.5 g of DAP (4.0 mol). 503 g of DFP were obtained. It thus 8 5 0-0 4 3 1

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DFP obtained was dissolved in a 10-fold molar excess of methanol and passed to the evaporator. The gas phase reaction was further carried out in the manner described in Example I with an LHSV of 0.20 ml per ml of catalyst per hour. The yields of pyrimidine after 5 different reaction times are shown in Table 7.

Table 7

Operating time before Sample yield in hours of pyrimidine in% 6 45.1 10 20 44.3 50.43.4

Example X.

Under the reaction conditions as described in Example I, the yield of pyrimidine, starting from the starting mixture, was determined after 24 hours of gas phase reaction for various catalysts. The results are shown in Table 8.

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Table 8

Catalyst Yield of pyrimidine in% 20 Pd (1%} - AI2O3 '59.0

Pd (0.5%) - AI2O3 56.3

Pd (2.0%) - AI2O3 52.2

Pd (0.5%) - AI2O3 43.5

Pd (0.5%) - Zn02 25.3 25 Pd (0.5%) - Zn02 / Al203 50, i

Pd (0.5%) - MgO 24.0

Pd (1%) - Si02 4,3 BADORlbWP 'L1Al5 ° 8 3plnel 15'6 8500431 -11-

Example XI

Purified AFP was prepared by coupling formamide with acrylonitrile as described in "FR-A-97 6959 followed by hydrogenation in the liquid phase under elevated pressure in alkaline ammonia medium with a cobalt catalyst. The purified AFP was prepared in a 10-fold according to Example I molar excess of methanol dissolved and passed through the gas phase evaporator over the catalyst The condensation product was collected for 16 hours and analyzed for pyrimidine A yield of 49.7% based on AFP was found.

Example XII

In a 205 hour experiment of Example 1, 1 kg of starting mixture was dissolved in 3.4 kg of methanol and passed over the catalyst via the gas phase evaporator. A total of 3.52 kg of condensed product was collected. It was found to contain 442 g of pyrimidine. Purification of this pyrimidine by distillation gave 397 g of pyrimidine, mp 21-22 ° C and purity greater than 99.7%. The water content was less than 0.01%.

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Claims (11)

1. Process for the preparation of pyrimidine, characterized in that a nitrogen reactant is selected from the reaction product of formamide with 1,2-diaminopropane in the liquid phase, 1-amino-3-formamidopropane, 1,4,5,6- tetrahydropyrimidine and / or 1,3-diformamidopropane in the gas phase at a temperature between 200 and 550 ° C in the presence of a carbon monoxide-hydrogen reactant, is contacted with a palladium-containing catalyst and pyrimidine is obtained from the reaction mixture obtained. 2. Process according to claim 1, characterized in that the reaction product is started from by reacting formamide with 1,3-diaminopropane in the liquid phase and separating an excess of one of the two starting materials. 3. Process according to any one of claims 1-2, characterized in that the gas phase reaction is carried out at a temperature between 250 and 400 ° C. 4. Process according to any one of claims 1-3, characterized in that the carbon monoxide-hydrogen reactant is used in a 2-50 fold molar excess, calculated with respect to the nitrogen reactant. 5. Process according to any one of claims 1-4, characterized in that the carbon monoxide-hydrogen reactant used is methanol or ethanol. 6. Process according to any one of claims 1-5, characterized in that the catalyst contains 0.5-5% by weight of palladium, based on the total catalyst. 7. Process according to any one of claims 1-6, characterized in that the catalyst also contains 0.1-2 wt.% Alkali metal, based on the total catalyst. Process according to any one of claims 1 to 7, characterized in that the catalyst contains an aluminum oxide support. 9. Process according to any one of claims 1-8, characterized in that the reaction product is obtained by reacting formamide with 1,3-diaminopropane in the liquid phase in a molar 9500431 BAD ORIGINAL 'y -13 ratio of 0.1-10, if desired after separation of an excess of one of the two starting materials. 10. Method as substantially described and / or further elucidated in the examples. 5 Pyrimidine obtained using the method according to any one of the preceding claims. / 8500431 BAD ORIGINAL