CA1273347A - 2-alkoxymethylene-3,3-dialkoxy-propanenitrile compounds and process - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
There is disclosed a process for preparing a compound by the formula (II) wherein R1, R2 and R5 may be the same or different and each rep-resent a lower alkyl group, or R1 and R2, bonding to each other to form a ring, are a lower alkylene group, which comprises reacting a compound represented by the formula (V) wherein R1 and R2 have the same meanings as defined above and M
represents an alkali metal, with an alcohol which boils azeotrop-ically with water, in the presence of an acid, while removing said alcohol and produced water from the reaction system by azeotropic distillation which is a intermediate in the prepara-tion of the 4-amino-5-dialkoxymethylpyrimidine derivative which is utilized as an intermediate for the synthesis of Vitamin-B1 and its analogues.

Description

~73;3~7 Thls Inventlon relates to a process for preparln~ a ~~
amlno-5-dlalkoxymethylpyrlmldlne derlvat~ve. In par~lcuiar the present Inventlon relates to a process for the preparatlon of a propanenltrlle der~vatlve whlch Is a Intermedlate In the prepara-tlon of the 4-amlno-5-dlalkoxymethylpyrlmldlne derlva-tlve.

Thls applIcatlon Is a dlvlslonal applIcatlon o~ copend-lng applIcatlon No. 432,781 flled July 19, 19~3.

The 4-amlno-5-dlalkoxymethylpyrlmldlne derlvatlve Is utlllzed as an Intermedlate for the synthesls of Vltamln-B1 and Its analogues.

Conventlonally, as a method for the preparatlon of a 4-16 amlno-~-dlalkoxymethylprylmldine derlvatlve, the followlng method has been dlsclosed In Chem. Ber. 106, 3743 (1973).

Flrst, a 4,6-dlchloro-5-formylpyrImldlne Is reacted wlth ammonla. Then, the so obtalned ~-amlno-5-formyl-6-chloro-pyrlmldlne Is reacted wlth hydrogen to derlve a 4-amlno-5-formyl-pyrlmldlne, whlch 15 subsequently reacted wl~h ~ trlal~oxymethane to prepare the deslred 4-amlno-5-dlalkoxymethylpryimldlne. Thls ; method has Industrlal problems In that the reactlon steps are many In number and complIcated and that the synthesls of the startlng pyrImldlne derlvatlve Is not easy.

The present Inventors have formed a process by whlch the 4-amlno-~-dlalkoxymethylpyrImldlne derlvatlve can advanta-geously be prepared Industrlally.
It~has thus now been found and Is the subJect matter of the copendln~ appllcatlon that, when a propanenltrlle derlvatlve represented by the ~eneral formula (~ or ( ~) ~73:~7 R10~
~CII--Cl-l--CM -- - ( I ) 5OR' R O CilOR5 15 whereln R1, R2, R3, R4 and R5 may be the same or dlfferent and each represent a lower-alkyl group; or R1, R2, R3 and R4 may be lower-al~ylene groups whlch are bonded to each other to form a rlng or rlngs, Is reacted wlth an amldlne represented by the gen-eral formula ( M~12 whereln R6 represents a hydrogen atom, a iower-alkyl group or a phenyl group of whlch the hydrogen atom or atoms may be replaced by a lower-alkyl group, a lower-alkoxy group or a halogen atom, a 4-amlno-5-dlalkoxymethylpyrlmldlne derlvatlve represented by the general formula ( N ~N~ 17/
\oE~2 ~7 whereln R1, R2 and R6 have the same meanlngs as deflned above can be prepared wlth extreme Industrlal advantage.

As the R1, R2, R3, R4 and R5 In the 2-dlalkoxymethyl-3,3-dlalkoxypropanenltrlle of the general formula (I) and the 2-alkoxymethylene-3,3-dlalkoxypropanenltrlle of the above general formula (r~) whlch are the startlng materlal of thls Inventlon and In the 4-amlno-5-alkoxymethylpyrlmldlne derlvatlves of the above general formula (~) whlch Is an obJect compound, there may be mentloned a lower-alkyl group havlng 1 to 5 carbon atoms such as methyl, ethyl, propyl and butyl.

Alternatlvely, R1, R2, R3 and ~4 may be lower-alkylene groups havlng 1 to 5 carbon atoms, whlch are bonded to each other to form a rlng or rlngs, and there may speclfIcally be mentloned methylene, ethylene, propylene and butylene. These R1, R2, R3, R4 and R5 may all be the same, may partlally be the same or may all be dlfferent groups.

One of the startlng materlal represented by formula (T) may be prepared In hlgh yleld by reactlng 2-dlchloromethyl-3-chloro-2-propanenltrlle, whlch Is a product obtalnabl0 by the hlgh temperature vapor phase chlorlnatlon of methacrylonltrlle, wlth an alcohol In the presence of a sodlum alcoholate ~see Yaku-25 gaku Zasshl, 1294, 93 (1973) and IbId., 1285, 93 (1973)].
The 2-alkoxymethylene-3,3-dlalkoxypropanenltrlle (Il), Is a compound and forms the subJect matter of the present Inven-tlon and, may be obtalned by, for example, reactlng a 3-alkoxy-2-propanenltrlle or a 3,3-dlalkoxypropanenltrlle wlth a formylatlng agent such as a formlc acld ester and carbon monoxlde In the pre-sence of an alkall metal alcoholate at a temperature of O to 100C to obtaln an alkall metal salt of a 2-hydroxy-methylene-3,3-dlalkoxypropanenltrlle and then reactlng the thus obtalned salt wlth an alkylatlng agent such as a dlalkylsulfurlc acld and an alkyl halIde or wlth a mlneral acld In an amount of not less 1~7;~

than an equlvalent for neutralIza~lon In an alcohol.

Partlcularly preferred proces~ accordlng to thc presen~
Inventlon for preparlng the 2-alkoxymethylene-3,3-dlalkoxypro-panenltrlle of formula ( ~ ) Is a process whlch comprlses reactlngan alkall metal salt of a 2-hydroxymethylene-3,3-dlalkoxypropane-nltrlle wlth a alcohol whlch bolls azeotroplcally wlth water, In the presence of an acld, whlle removlng sald alcohol and produced water from the reactlon system by azeotroplc dlstlllatlon.

Accordlng to thls process the deslred 2-alkoxymethy-lene-3,3-dlalkoxypropanenltrlle (Il) can be prepared In an extremeiy hlgh yleld of around 90%.

Next, the process for preparlng the 2-alkoxymethylene-3,3-dlalkoxypropanenltrlle (Il) wlll be descrlbed In detall.

The alkall metal salt of the 2-hydroxymethylene-3,3-dlalkoxypropanenltrlle, whlch Is the startlng materlal for the synthesls of 2-alkoxymethylene-3,3-dlalkoxypropanenltrlle (II), can be represented by the followlng general formula ~) \ CH C CN
R O ll

2 CHOM

In the formula R1 and R2 have the same meanlngs as deflned above and M may Include an alkall metal such as sodlum, potasslum, llthlum and rubldlum.

As the acld to be used In the process for preparlng the compound of formula (Il), there may be mentloned such as Inor-ganlc acld as concentrated sulfurlc acld, concentrated hydrochlo-rlc acld, hydrogen chlorlde, and concentrated phosphorlc acld, ~73~7 and such an or~anlc acld as p toluene-sulfonlc acld and acetlc acld.

- 4a -~73~4~7 !~

These acids are used in an amoun-t of not less -than an e~uivalent ~or neutralization, typically l -to lO equi-valen-ts, preferably ] to 5 equivalents against the alkali metal salt of the 2-hydroxymethylene-3,3-dialkoxypropanenitrile.

As the representa-tive examples of the alcohol which evaporates azeotropically with water, there may ~e mentioned e~anol, propanols, bu-tanols, pen-tanols and the like.
A~ove all, n-bu-tanol is most pre~erable. I~ese alcoholsr~y be employed typically in an amount of 3 to 200 parts by weiyht, preferably in an amount of S to lO0 parts by weight per one part by weight of the alkali metal salt of the 2-hydroxy-meth~lene-3,3-diaIkoY.ypropanenitrile, since the progress of the reaction becomes insufficient when the amount to be used thereof is too small and thus the yield of the desired product is decreased, and since the use of iarger amount thereof is less economical although any excess amoun-t thereof does not affect badly the reaction.

The reaction is carried out under ambient or reduced ; pressure at a temperature of 0 to 120C for 1 to 10 hours while removing the formed water from the reaction system by azeotropic distillation wi-th the used lower-alcohol. In cases where the reaction is not conducted while removing the wa-ter from the reaction system, the yield of the desired product becomes extremely low.

In the process for preparing the compound of formula (II) any solvent is not necessarily needed. ~Iowever, -the azeo-tropic evaporation of the water formed by the reaction may be promoted by usincJ a solvent inert to -the reaction which forms an azeotropic mixture of a ternary system with water and -the lower-alcohol. As such solvents, there may be mentioned hydrocarbon group solvents such as benzene, toluene, hexane, heptane and cyclohexane; and ~ ~7~
-` 1, halogena-ted hydrocarbon yroup solvents such as carbon tetrachlorlde, me-thylene chloride, ethylene dichloride, trichloroethylene and te-trachloroethylene.
.
- The thus formed produc-ts, 2-alkoxymethylene-3,3-dialkoxy-p~op~nenitrlles (II) ma~ be re~cte~ a5 5UCIl, ~ithout isolation thereoE, with amidines in the next step to obtain desired end products.

The products, 2-alkoxymethylene-3,3-dialkoxypropanenitriles - (II) may readily be isolated and purified by optionally adopting a procedure or procedures such as fil-tration, neutralization, extraction, dis-tillation and so forth. The -tllus isola-ted products may also be used as the starting material for obtaining the final desired product.

The s-tarting material of formula (I) may also be obtained 1~ easily by sub~ecting a 2-alkoxyme-thylene-3,3-dialkoxy-propanenitrile (II) to reaction with a corresponding aliphatic alcohol in the presence of an alkali metal alcohola-te corresponding to the alkoxyl group to be introduced at a temperature of 0 to 150C for 0.1 to 2 hours.

~s the alcohol to be used, there may be mentioned methanol, ethanol, propanol, butanol and the like.

The amount of the alcohol to be used is in the range of 10 to 500 moles per one mole of the 2-alkoxymethylene-

3,3~dialkoxypropanenitrile (II).

As the alkali metal to be used for the alcoholate, theremay be men-tioned sodium, potassium and so on. The amount of the alcoholate to be used is in the range of 0.05 to 5 mo].es per one mole of the star-tillgcompound (II). Further, the above-mentioned reac-tion may be carried ou-t in an inert solvent, for example, an ether group solvent, such as tetrahydrofuran, dioxane, dimethoxyethane, diethyl ehter ~ ~73;~4~7 and diisopropyl ether, and a hydrocarbon group solvent such as benzene, toluene, xylene, hexane and heptane.

: The isolation of the thus ormed compound (IX) may xeadily be carried out by optionally adoptinc~ such a procedure as neutralization, filtra-tion, ex-trac-tion, concentra-tion, dis-tillation and so on.

. In the present invention, the above-mentioned s-tarting propanenitriles represented by the above general formula (I) or (II) may either be employed alone or may be used in -the s-tate of a mixture.

Further, as the amidine represented by the above general formula (III) which is the o-ther starting me-terial, there may be mentioned, for example, formamidine, acetamidine, propioamidine, butanoamidine, pentanoamidine, benzamidine, toluamidine, ethylbenzamidine, propylbenzamidine, methoxy-benzamidine, ethoxybenzamidine, chlorobenzamidine, bromo-benzamidine and the lik`e. Since these amidines are uns-table compounds, it is preferred to use them in the form of a salt with an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid or with an organic acid such as acetic acid and to obtain a free amidine in the reaction system. ~s the use~ul base to be used Eor . ~ obtaining a free amidine in the reac-tion system, there may be mentioned a sodium alcoholate, an alkali hydroxide, an alkali carbonate, an alkali bicarbonate, a strongly basic ion exchan~e resin and so on. The amidine salt may be used in an amoun-t of 0.5 to lO moles, preferably 1 to 5 moles per one mole of the propanenitrile represen-t-ed by the above general formula (I) or (II). The above-mentioned base is employed in an amount of around ane~uivalent for neutralization.

The reaction may be carried ou-twithout any solvent or may be carried out in a solvent which is inert to the reaction.
~s such solven-ts, an aliphatic alcohol such as methanol, :

73~7 "
- B -etl~anol, propar,ol and butanol is most preferable. Il0~7ever, ether group solvents such as dioxane, tetrahydrofuran, dimethoxyethane, diethyl ethex, diisopropy]. ether and dibutyl ether; aroma-tic hydrocarbon group solven-ts such 5- as benzene, toluene and xylene; haloyenated hydrocarbon group solven-ts such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitrile group solvents such as acetonitrile, propionitrile and benzo-" ni-trile; and so on may also be used for the reac-tion.
These solvents may preferably be employed in an amount of 0.5 to 20 parts by weight per one part by weight of the compound represented by the general formula (I) or (II) (in case of a mixture, per one par-t of the to-~al amoun-t thereof).

The reaction is carrled out at a temperatu~e of 0 to 150C
under ambient pressure or under positive pressure for 0.1 to 24 hours. The reaction may be carried out either by a ba-tch system or by a continuous system. The isolation of the desired product from the reaction mixture may readily be conducted by optionally adopting a procedure such as fil-tration, concentration, extraction, recrystal-lization and so forth.

~ccording to the process of this invention, the 4-amino-; 5-dialkoxymethylpyrimidine derivative represen-ted by the ; 25 above general formula (IV) can be prepared in a more simplified method as compared with the processes known to ` the art.

The 4-amino-5-dialkoxymethylpyrimidlne derivative repre-sented by the above general ~ormula (IV) ob-tained by -the process of thls inven-tion may readily be converted into a

4-amino-5-aminomethylpyrimidine derivative, which is an important compound as an intermediate for the synthesi.s of Vitamin-Bl, by, for example, hydrolysis thereof in the presence of an acid Eollowed by reductive amination of the thus obtained 4-amino-5-formylpyrimidine derivative.

~7~47 g Ne.Yt, Exalllp:les ~nd Syntl~sls ~xam~les will l~e :~llustrated below.

Example 1 In a 300 mQ four-necked flask equipp~d with a stirrer,

5 a dropping funnel, a thermometer and a condenser arranged downwardl~, there were introduced 8.25 g (50 mmoles) of sodium salt of 2-hydroxymethylene-3,3-dimethoxypropanenitrile and 160 g o n-butanol. Then, with stirring -the mixture at room temperature, 3.06 g 10 (30 mmoles) of conc. sulfuric acid was gradually added dropwise thereto. ~fter s-tirring for one hour, tlle mixture was heated under a reduced pressure of 23 to 25 mmHg and the temperature of the liquid was maintained at 43 to 45C to distil out such lower-boiling 15 frac-tions as alcohol and water. After 1.5 hours from the s-tarting of the distilling out, 120 g of n-butanol was further added dropwise thereto, and the reac-tion was continued for further 2 hours while distilling out the lower-boiling fractions under the same temperature and the 20 same pressure as in the above-mentioned conditions to obtain 170 g in total of a dis-ti.lla-te.

Af-ter cooling, the reaction mixture was subjected to ` fil-tration to remove the insoluble inorganic salt.
t ` Thereafter, the filtrate was concen-trated followed by - 25 distillation under reduced pressure to remove the low-boiling fraction to obtain 12.7 g (yield: 90~ of a colorless oil boiling a-t 153 -to 156C/0.5 mm~lg.

The thus ob-tained product was confirmed to be 2-n-bu-toxyme-thylene-3,3-di-n-butoxypropanenitrile from the 30 analyses by NMR, IR and MS.

Example 2 In-to the same apparatus as in Example 1, were in-troduced ~7;~
-~.25 g (50 mmoles) o~ sodium salt oE 2-hydxo~rlnethylene-3,3-dimethoxypropanenitrile and 120 y of n-butanol. ~1ith s-tirring the mixture at room tempera-ture, 80 g (hydrogen chloride 100 mmoles) of a 4.6 wt~ solution of hydrogen chloride in n-butano]. was gradually added. ~fter .
stirr.tng ~or one hour, the mlxture was heated under a reduced pressure of 23 -to 25 mmHg and -the temperature of the liquid was maintained at 43 -to 45~C to distil out such a low-boiling fraction as alcohol ànd water. After s-tar-ting -the distilling ou-t, the reaction was continued for 2 hours to ob-tain 130 g of a distillate.

~fter cooling, the reaction mixture was subjected to gas chroma-tographic analysis according -to the internal : standard method for quanti-ta-tive determination. As a result, it was confirmed that 2-n-butoxymethylene-3,3-di-n-butoxypropanenitrile was produced in a yield of 92~.

~xample 3 Into the same appara-tus as in Example 1, were in-troduced 7.47 g (30 mmoles) of sodium salt of 2-hydroxymethylene-3,3-di-n-butoxypropanenitrile and 40 g of n-bu-tanol.
with s-tirring at room -temperature, 1.73 g (17 lluno]es) of conc. sulfuric aci.d was gradually added thereto. ~fter stirring for one hour, the mixture was heated under a reduced pressure of 33 to 35 mmHg and the tempera-ture of the liquid was maintained at 50 to 52C -to distil ou-t such a low-boiling fraction as n-butanol and water.
~fter starting of the distilling out, 160 g of n-butanol was added dropwise there-to over 3 hours while maintaining the tempera-ture and pressure at the same level as in the above and the reac-tion was continued further :Eor 0.5 hour to obtain 160 g in to-tal of a dis-tillate~

~fter cooling, the reaction mixture was subjected to quantitat:ive analysis in -the same manner as in ~xample 2.

., , -- 1], --`` ~5 a result, it was confirmed that 2-n-butoxyTfleth~]ene-3,3-di-n-bu-toxypropaneni~rile was produced in a ~ield of 93~.

Example .
Into the same appara-tus as in Example 1, were in-troduced 3.86 g (20 mmoles) of sodium salt of 2-hydroxymethylene-3,3-diethoxypropanenitrile, lOO g of ethanol and 100 g : of n-hexane. With s-tirring at room temperature, 1.22 g ; (12 mmoles) of conc. sulfuric acid was yradually added dropwise thereto. After s-tirring for one hour, the mixture was heated under ordinary pressure and such a low-boiling fraction as e-thanol, n-hexane and wa-ter was distilled out at a distillation temperature of 56 to 58C.
After starting of the distilling out, a mixture of 250 g of ethanol and 900 g of n-hexane was added dropwise thereto over six hours while main-taining the distillation temperature at -the same level and the reaction was further conducted for one hour to obtain 1250 g in total of a distillate.
I`
Subsequently, the reaction mixture was treated in the same manner as in Example 1 to ob-tain 3.58 g (yield: 90%) o~ a colorless tr~nsparent oil boiling a-t 120 to ` 123C/2 mm~lg. The thus obtained product was confirmed to be 2-ethoxymethylene-3,3-diethoxypropanenitrile according to the analyses by NMR, IR and MS.
~ ~ .
Example 5 . .
Into the same apparatus as in Example 1, were introduced 7.~7 g (30 mmoles) of sodium salt of 2-hydroxymethylene-3,3-di-n-butoxypropanenitrile and 200 g of n-butanol.
~`~ 30 With stirring the mixture at room temperature, 1.73 g (17 mmoles) o~ conc. sulfuric acid was gradually added dropwise thereto. After stirring for one hour, the temperature of ~he liquid was maintained at 50 to 52C

.. ... ~ .

t~ ~73~7 . .
alld ~he reac~ioll was carrled ou~ ~or 3.5 llour~;

Af-ter cooling, the reac-tion mixture was subjected to quantitative analysis in the same manner as in ~xample 2 to confirm that 2-n-butoxymethylerle-3,3-di-n-butox~-propanenitrile was produced in a yield of 57%.

Example 6 , .
In a 300 m~ autoclave made o stainless steel, -there were placed 16.6 g (200 mmoles) of 3-methoxy-2-propene-nitrile, 13.0 g (240 mmoles) of sodium methylate, 12.8 g (~00 ~noles) of methanol and 65 mQ of toluerle. After the atmosphere of the reac-tion system was replaced by nitro~en, the mixture was heated up to around ~0C under : stirring and CO was pressured in the autoclave so that the pressure migh-t be around 50 kg/cm2G. The consumed CO was supplemented condinuously 'and the reaction was continued for 3 ho~rs. After cooling of the reaction mixture, -the gas ln the autoclave was purged off and ''the reaction mix-ture was -transferred completel~ to a 300 mQ four-necked flask equipped with a calcium chloride tube, a stirrer, a dropping funnel and a thermometer.
~hile maintaining the liquid temperature at around 20C
or less, 30.3 g (240 mmoles) of dimethylsulfuric acid was added dropwise thereto over 30 minutes with stirring the con-tents in the flask, and the reaction was carried out at around 50C for about 4 hours.
.
- After the reaction mix-ture was cooled and the insoluble substance was removed by filtra-tion, the collected insoluble were washed with toluene and the washing was combined with the filtrate followed by washing with a 50 wt~ aqueous sodium hydroxide and then with water.
Subsequently, af-ter drying over sodium sulfate, the toluene layer was evapora-ted under reduced pressure to remove low-boiling fractions and to obtain 17.6 g (v;eld: 56~) oE~coloxless transparen-t oil boiling at 73;~47 104 - 106C/2mmHg.
?

The thus obtained product was confirmed to he 2-methoxy-methylene-3,3-dimethoxypropaneni-trile according to analyses by MM~, IR and MS.
_ . .... ...
~xample 7 ; . .
In a 200 mQ flask equipped with a condenser arrangea downwardly, -there were placed 50.0 g (0.32 mole) of 2-methoxymethylene-3,3-dimethoxypropanenitrile and 20.0 g (0.32 mole) of ethylene glycol. Then, -the mixture was heated on a bath, which was maintained at 100C, for 2 hours under ambient pressure to distil out methanol.
Subsequently, the resulting mixture was evaporated under reduced pressure to remove a fraction boiling at low tem-peratures, followed by fractionation to give 33.0 g (yield:
15 67 ~) of a colorless transparent oil boiling at 133 - 135~C/
2mmHg. The thus obtained product was confirmed -to be methoxymethylenecyanoacetaldehyde ethylene acetal according to analyses by NM~, IR and MS.

Example 8 , 20 In a mixed solvent of 100 mQ of toluene and 50 mQ of mcthanol was dissolved 7.85 g (50 mmoles) of 2-methoxy-methylene-3,3-dimethoxypropanenitrile. To the resulting solution was added 9.65 g (50 mmoles) of a 28 wt% solution of sodium methylate in methanol and the mixture was stirred at room temperature for one and a hal~ hours. Sub~
sequentlyj the reaction mixture was concentrated under reduced pressure to remove the methanol by distillation.
To the resulting residue was added 25 mQ of water and the toluene layer was separated followed by drying over 3P anhydrous sodium sulfate. The thus dried toluene solution was distilled to obtain 8.50 g (45 mmoles) of 2-dimethoxy-~L~73~7 --` !
`._, .

methyl-3,3-dimethoxypropaneni-trile as a colorless -trans-parent oil boiling at 90 - 93C/2 mmn Example 9 In 100 mQ o~ n-butanol was dissolved 8.~9 g (30 mmoles) S of 2-n-butoxymethylene-3,3-di-n-butoxypropanenitrile.
To the resulting solution was added 0.87 g (9 mmoles) of sodium n-butylate at room temperature, and the mixture was stirred at room temperature for one hour. Then, the reaction mix-ture was neutralized with a solution o~ sul~uric acid in butanol and the resul-ting inorganic salt was removed by fil-tration. The filtrate was distilled under reduced pressure to ob-tain 9.10 y (25 mmoles) of 2-di-n-butoxymethyl-3,3-di-n-butoxy-propanenitrile as a colorless transparent oil boiling at 170 - 175C!2mmHg.
.. . .
In the following Examples, the starting materials have been obtained by one of the processes as described above in Examples 1 to 6 and ln Synthesis examples 1 and 2.

Example lO

In a 50 mQ four-necked flask equipped with a calcium-chloride tube, a thermometer and a reflux condenser, there were placed 11.6 g (60 mmoles) of a 28 wt% solution of sodium methylate in methanol and 10 mQ of methanol.
Thereto was added with stirrring 5.67 g of acetamidine hydrochloride (60 mmoles) and the mixture was sti.rred at room temperature for 30 minutes. Then, 7.85 g (50 mmoles) of 2-me-thoxymethylene-3,3-dimethoxypropanenitrile was added thereto and the mixture was heated and refluxed fox 5 hours. After completion o~ the reaction, the reac-tion mixture was cooled and then the insoluble sodium chloride was removed by filtration. Af-ter concen-.

1~7~ 47 tration of the solvent, rnethanol, 50 mQ of ~,7ater wasadded there-to and -the mixture was extracted four times with 2() mQ of me-thylene chloride. Af-ter -the extract was - dried over sodium sulfate, the sodium sulfate w~s removed by filtration and the filtrate was concentrated to dryness to obtain a white crude crystal. The thus obtained product was recrystallized ~rom ~ mixed solven-t of 50 mQ of hexane and 25 m~ of toluene to obtain 8.05 g (yield: 88~) of 2-methyl-4-amino~5-diméthoxymethyl-pyrimidine melting a-t 102 ~ 104C.

Example 11 In the same reaction apparatus as in Example lO, there was placed 11.6 g (60 mmoles) of a 28 wt~ solu-tion of sodium methylate in methanol. Thereto was added wi-th s-tirring 5.67 g (60 mmoles) of acetamidine hydrochloride, and the mixture was stirred at room temperature for one hour.
Subse~uen-tly, 9.95 g (50 mmoles) of 2-dimethoxymethyl-3,3-dimethoxypropanenitrile was added thereto and the mixture was heated and refluxed for 5 hours. ~fter completion of the reaction, -the reaction mixture was cooled and the insoluble sodium chloride was removed by filtration.
The filtrate was analyzed by gas chromatography according to the internal standard method. As the result, it was confirmed that 8.51 g (yield: 93%) of 2-methyl-4-amino-5-dimethoxymethylpyrimidine had been formed.

Example 12 ~n experiment was carried O~lt in the same manner ~s in Example 11 except tha-t a mixture containing 3.31 g of 2-dime-thoxymethyl-3,3-dimethoxypropanenitrile (17.5 mmoles) and 5.10 g (32.5 mmoles) of 2-me-thoxymethylene-3,3-di-methoxypropanenitrile was used in place of the 2-dimethoxymethyl-3,3-dimethoxypropanenitrile. The yield of 2-methyl-4-amino-5-dimethoxymethylpyrimidine was 91~.

.

j w ~

Example 13 n ~he sallle ~ppara~us ~s in ~xaml~le ~o, there we~ placed ` ~.8~ g (30 mmoles) of acetamidine hydrochloride and 15 mQ
- of ethanol. Thereto was added with stirring 2.0~ g (30 mmoles) of sodium ethylate and the mixturewas stirred at room temperature for 30 minutes. Subsec~uently, a mixture containing 2.45 g (10 mmoles) of 2-diethoxymethyl-3,3-diethoxypropanenitrile and 2.99 g (15 }~noles) of 2-ethoxymethylene-3,3-diethoxypropanenitrile was added thereto and the mixture was heated followed by reflux for hours. After cooling, sodium chloride was removed and the filtrate was subjected to gas chxomatographic analysis.
The yield of 2-methyl-4-amino-5-diethoxymethylpyrimidine was 88%.

.
- 15 Example 14 .
In the same apparatus as in Example 10, 2.84 g (30 mmoles) of acetoamidine hydrochloride was added to an n-butanolic ~ solution of sodium butylate which had been prepared with 0.69 g (30 mg a-toms) of sodium and 15 mQ of butanol, and the mix-ture was stirred at room temperature for 30 minutes.
Then, 7.08 g (25 mmoles) of 2-n-butoxymethylene-3,3-di-n-butoxypropanenitrile was added thereto and the mixture was heated. Thereafter, the resulting mixture was stirred under heating at about 90C for 5 hours. After cooling, the sodium chloride was removed and the remaining liquid was subjected to gas chromatographic analysis for quantitative determination. The yield of 2~methyl-4-amino-5-di-n-butoxymethylpyrinidine was 85~.

Example 15 An experiment was conducted ln the same manner as in Example 10 except that 9.40 g (60 mmoles) of benzamidine /
~73;~7 hydrochloride was used in place o~ the acetamidine hydro-chlorlde to o~-tain white crude crystals. These cr~ys'cals -thus ob-tained were recrystallized from a mi~ed solvent : of hexane and toluene (vo]ume ratio 2:1) to obtain 10.~ g (yield: 85~) of 2~phenyl-4-amino-5-dimethoxymethyl-pyrimidine melting at 116 - 118C.

Example 16 An experiment was carried out in the same manner as in Examplell except that 7.75 g (50 mmoles) of me-thoxy-methylenecyanoacetaldehyde ethylene acetal was used in ! place of 2-dimethoxymethyl-3,3-dimethoxypropanenitrile.

The yield of ethylene acetal of 2-me-thyl-4-amino-5-formyl-` pyrimidine was 83~.

Example 17 An experiment was conducted in the same manner as in I Example ll excep~ that ~.83 g (60 rnmoles) of formamidine hydrochloride was used in place of acetamidine hydrcchloride.
The yield of 4-amino-5-dimethoxyme-thylpyrimidine was 90~.

Example 18 .. ... ..
An experiment was conducted in the same manner as in Example 11 except that 6.51 g (60 mmoles) of propioamidine hydrochloride was used in place of acetami~ine hydro-chloride.

The yield of 2-ethyl-~-amino-5-dime-thoxymethylpyrimidine was 89%.

Example 19 In a 200 mQ four-necked flask e~uipped wi-th a stirrer, ~73;:~47 , a dropping funnel, a ~hermorneter and a condenser arranged downwardly, there were introduced 8.25 g (50 mmoles) of sodium salt of 2-hydroxymethylene-3,3-dimethoxypropane-nitrile and 60 ~ of n-butanol. To the mixtllre wa.s gradually added dropwise, with stirring, 2.76 g (27 mrnoles) of conc. sulEuric acid. After s-tirring for one hour, the temperature of the mixture was raised under a reduced pressure of 33 - 35 mmHg, and then was maintained at 50 to 52C to distil out such a low-boiiing fraction as an alcohol and wa-ter. After starting of the distilla-tion, 160 g of n-butanol was added dropwise thereto over 2 hours while maintaining the temperature and the pressure a-t the same level, and the reaction was further continued for 30 minutes to obtain 160 g in total of a disti~late when the heating was stopped and the reac-tion system was returned to an ordinary pressure. Subsequently, the downwardly arranged condenser was replaced with a reflux condenser equipped with a calcium chloride tube. Then, - a mixture of 5.20 g (55 mmoles) of acetamidine hydro-20 chloride and 30.0 g (62.5 mmoles) of a 20 wt~ solution of sodium n-bu-tylate in n-butanol, which had been stirred under reduced pressure in a dry atmosphere for 30 minutes, was gradually added dropwise, with stirring, to the flask from the dropping funnel.

Thereafter, the temperature of the mixture was raised and the resulting mixture was stirred under heating at 85 to 90C for around 4 hours.

After cooling, sodium chloride was removed by fil-tration and the filtrate thus obtained was sub-jecte~ -to quanti-tative analysis by gas chroma-tography. As the result, it was found that Ll.0 g (41.2 mmoles) of 2-methyl-4-amino-5-di-n-butoxymethylpyrimidine was obtained. The yield of the produc-t is 82~ based on the star-ting material, i.e., sodium salt of 2-hydroxymethylene-3,3-dime-thoxy-propanenitrile.

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound represented by the formula (II) wherein R1, R2 and R5 may be the same or different and each rep-resent a lower alkyl group, or R1 and R2, bonding to each other to form a ring, are a lower alkylene group, which comprises reacting a compound represented by the formula (V) wherein R1 and R2 have the same meanings as defined above, and M
represents an alkali metal, with an alcohol which boils azeotrop-ically with water, in the presence of an acid, while removing said alcohol and produced water from the reaction system by azeotropic distillation.

2. A process according to claim 1, wherein the alkali metal is selected from the group consisting of sodium, potassium, lithium and rubidium.

3. A process according to claim 1, wherein the acid is selected from the group consisting of conc. sulfuric acid, conc.

hydrochloric acid, hydrogen chloride, conc, phosphoric acid, p-toluenesulfonic acid and acetic acid.

4. A process according to claim 1, wherein the amount of the acid to be used is in the range of 1 to 10 equivalents against the compound represented by formula (v).

5. A process according to claim 1, wherein the alcohol is selected from the group consisting of ethanol, propanols, butanols and pentanols.

6. A process according to claim 5, wherein the alcohol is n-butanol.

7. A process according to claim 1, wherein the amount of the alcohol to be used is in the range of 3 to 220 parts by weight per one part by weight of the compound represented by formula (v) .

8. A process according to claim 1, wherein the reaction for forming the compound represented by formula (II) is carried out under ambient or reduced pressure at a temperature of 0 to 120°C.

9. A compound represented by the formula (II) wherein R1, R2 and R5 may be the same or different and each represent a lower alkyl group, a lower alkylene group.