JPS6064968A - Manufacture of benzylpyrimidine - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

The present invention relates to benzylpyrimidine conductors. More specifically, the present invention relates to benzylpyrimidine derivatives, methods thereof, and anti-i compositions containing the derivatives. 7<1 and RR each independently represent C1-3 alkyl: 4b t-, 3 represents a halogen atom, and A is Ii! bonded to one of the halogen atoms! Cumulative 1
5 represents a child, and L represents O or 1] and salts thereof. The term "C1-3 alkyl" as used herein means methyl, ethyl, propyl and isopropyl. A preferred version of the compound of formula 1 above consists of tL representing Ot-. Compounds of the formula I in which R'' represents an odor or a hook atom are also preferred.
4-diamino-5-(4-(bromo or fluoro)-
3,5-Dimethoxybenzyl]-pyrimidine By following the method provided by the present invention, the above benzylpyrimidine derivatives (i.e. the compounds of formula 1 and their derivatives) ij', α) general formula (20 [ In the formula, R4 represents a lower alkyl group, or both R's together represent a low gamma alkylene group, and RI' is
rortp) and Jul. R2 and R8 have the above meanings] Compound 5m is reacted with guanidine. 1.6) General formula [wherein, Or amino? , X in at least 111d represents something other than Princess Amino), and R', R'' and 13 represent the above q.
, HtI:] is reacted with ammonia fh, C) General formula c In the formula, Xl is a chlorine or a bromine atom or a hydrogen atom or a hydrogen atom, and R1, R" and R3 are 4
or d) subjecting the compound of formula I above, where n represents 0, to N-[culture; It is prepared by converting the thus obtained compound of formula I into a salt according to the composition. According to embodiment α) of the invention, a compound of formula l(α or 1115) is converted to guanidine. The symbol 1?” in a compound of formula UU represents an ether group (e.g. lower alkoxy groups such as methoxy and ethoxy groups), a thioether group (5
Sue is a lower alkylthio group) and the first! It is an amino group obtained by R4 from a 1 or 2-method amine. Examples of such amino groups are i) groups derived from primary aliphatic, aryl-but also aromatic amines, such as (lower alkyl)amino, benzylamino and naphthylamino. Arylamino groups, but especially phenylamino (anilino), in which case the Rkpheni/L' ring is optionally I
Q-i or higher quality halogen, low alkyl or low alkoxy + I, t ÷ base, and 11) secondary) 1 is fatty, aromatic or Stores derived from limited additive amines, e.g. N, N-
di(lower alkyl)amino and A'-(lower alkyl)-N-arylamino groups, 1 preferably N-methyl-A
'-Phenylamino (r'V-methylanilino), the 19-haphenyls optionally have I/i11'tj or higher halogen, lower alkyl or lower alkoxy [4 substituents, pyrrolidino, piperidino, piperazino and Particular preference is given to the 0anilino group which is morpholino being replaced by R''. (e.g. Belgian 'I'f':
No. 671,982 and ii', '746
．． 846)0 For example, this reaction can be performed using an alkanol ('
V'r (methanol or ethanol), dimethylformamide, dimethyl sulfoxide or one A-methylpyrazolone in a solvent of about 25°0 to 200°C.
C, preferably from 50 C to 170'Q.
20 [wherein R"1R", I8 and J (11 has the meanings given above]) can be produced in that phase from tautomeric compounds of formulas Ilb and Ilc. It can exist as a trans isomer or as a crystal combination thereof.According to b) of the present invention, the compound of 2 Oki is reacted with ammonia to form the compound f in pyrimidine, chlorine,
An alkylmercapto or alkylsulfonyl substituent is replaced with an amino group. This reaction is alkanol M liquid! The reaction is advantageously carried out in a methanol solution (eg using methanolic ammonia as a reaction component). This reaction is advantageously carried out at temperatures between about 80°C and 200°C, especially between about 100°C and 150°C. Since this crystallization temperature is higher than the boiling point of methanol, the reaction is slowed down (
According to embodiment C) of the process, the removal of the bromine or 14 atoms present in the compound of formula IV is carried out, for example in an autoclave). Mediatically activated water: 2 K (e.g. palladium in alcohol) -! or treated with lead/sodium hydroxide [7]. If Xl represents a hydroxy group, the compound of formula IV can be reacted with, for example, 1-phenyl-5-chlorotetrazole and the resulting 1-phenyltetrazol-5-yl ether then added bulk over palladium/carbon. . Also, formula 1
The compound of ~ can be reacted with cyanogen bromide in the presence of triethylamine, and the reaction product can then be water-cooled in the presence of palladium on carbon. According to the idea of this method α), b) and C), p1le represents 0, and R1,I? l and jo mean upper fi+2 jL
Compounds of formula I having lξ are attracted. 1g4 C)
In the case of a bow match, a suitable starting point Q'i of equation 1v is: 't't,
is one in which R3 is a fluorine atom or a bromine atom. According to yj-sama d), the above formula ■ where n represents 0
N-hawkification of the compound of A, according to a method known per se.
This can be carried out using conventional N-oxidizing agents. A particularly preferred A'-oxidizing agent is perbenzoate, especially In-chloroperbenzoate. For this N-f conversion, ψrie is 42C hydrocarbon 2 (13-!J is chloroform or bottle, methylene monide), alkano-/I/ (e.g. methanol or ethanol), dimethylformamide,
This A-oxidation can be carried out in an inert solvent such as dimethyl sulfoxide, water or dioxane at a temperature between the boiling point of the main melt, advantageously from about 10°C to about 60°C.
OI! , +j (0 approximately 10°C easily carried out at 1 degree of fortune)
Temperatures from about 20°C to about 20°C are preferred. The obtained 8-oxide can be extracted from the oxidized compound in a conventional manner, and when using m-chlorine or 14λ as the saponifying agent, the oxidized mixed QSJ can be obtained. Si water - alkaline sex (e.g. Keisei [;
The aqueous extract obtained was extracted with an aqueous sodium hydroxide solution, and the resulting aqueous extract was neutralized with a strong mollusc to precipitate it. Suntahaya \DX
It is true that it is possible to make the 4M property 7'l; Understood 〇 In general, by ON-oxidation, 7v1- and A mixture of W3-oxides is derived. The separation and production of the isomeric products described above can be carried out by chromatography (e.g. column chromatography) and/or recrystallization, preferably from organic solvents such as alkanols, water, etc. -P4 crystals.The compound of formula I can be prepared using an inorganic compound (for example, hydrogen chloride C
fluorine, sulfuric acid, phosphoric acid, etc.) or organic liquors (e.g. formic acid, vinegar, succinic acid, lactic acid, citric μ2, maleic acid, fumaric acid (1ρ, tartaric acid, methanesulfone μ), p, -F luenesulfone, etc.) etc.) to convert them into acid addition salts, especially those common in the preparation of oxidants.The benzylpyrimidine derivatives provided by the present invention (
That is, the compound of the above formula 1 and its acid addition salt) has anti-relaxation activity (
These are bacterial dihydrofolate-reducing enzymes (di/bytl; rofolaie red) that have antibacterial activity.
Sulfonamide compounds such as sulfituxase, sulfadimethoxine, sulfamethoxazole, 4-sulfanilamide-5,6-
Cymethoxypyrimidine, 2-sulfanilamide-4
, 5-dimethyl-pyrimidine, sulfaquinozarin,
Sulfadiazine, sulfamonomethoxine, 2-sulfanyl alcohol 4. S-dimethy-inquizazole and? 11. The above-mentioned benzylpyrimidine derivatives and sulfonamides '15 which have a mutualistic effect on the anti-box activity of other inhibitors against the enzymes involved in the synthesis, such as pteridine derivatives. It can be used as a medicament in a form suitable for oral, anal or non-oral administration. The ratio of methanesulfonamide to the compound of formula I can, of course, vary within a wide range, for example from 40 (parts by weight) to 1:1 (parts by weight).

[d, may be varied, preferably in a ratio between 1:2 and 1:10.Thus, t, j, and tablets contain the compound of formula 4K 8 Qπ
1 and 7 amethoxazole 400π7 can be added to the children's gun M''J (I's home 4).
20r4 and sulfamethoxazole/L/100F:q
'f can be added and syrup (5 items snoring 19
) can be enriched with 40 tby of the compound of formula I and 200 p,y of sulfamethoxazole. 2. The benzylpyrimidine derivatives provided by the present invention exhibit significant anti-reactive activity or a significant synergistic effect in combination with sulfonamides. ). They also have good compatibility. The starting materials used in the method provided by the present invention may be used, even if they are unknown or not listed in the examples below (see below). Example 1゜Anhydrous methanol 220i, 7! Sodium in 16.7
A solution of 4-bromine, -3,5-dimethoxy-α-(methoxymethane) dimethylsulfonate 110*/ was treated with anti-Bl nitrile at 200 V, and the internal crystallinity was 70 At l which becomes °0, Fi Moeya (70°
0) was heated above. This mixture was stirred for another 1 hour at 4 degrees. Then, while stirring, 63.52 guanidine carbonate was added.
gradually heated until . During this time, about 120 al of methanol was collected in the connected water vessel. The mixture was stirred for an additional hour at 110°C and then heated to 5°C.
The mixture was cooled, treated with 250 al of water, and stirred for 0.5 hour while cooling. The resulting precipitate was filtered #-1 under vacuum and thoroughly washed with cold water and benzene. Crystals in hydrochloric acid approx.
000+! With the understanding, suction f, passing, occurred 2, 4
-Diamino-5-(4-bromo-3,5-dimethoxybenzi/L/)-pyrimidine hydrochloride was recrystallized from hot water (charcoal); melting point 280-285°C. The crystallized 2,4-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine was stirred in 400 ml of ammonium at room temperature for 30 minutes and was separated by suction and thoroughly washed with water. g
Dry at 70°C under air for 151 hours; melting point 2
34-235℃. The starting material was prepared as follows: 238 t of thionyl chloride was mixed with 4602 4-bromo-3,5-dimethoxybenzene 7=L Nr acid in 1200 ml of anhydrous benzene and 25 ml of dimethylformamide. or cloudy liquid 1
The mixture was heated under stirring for 3 hours under flowing water. The resulting feed liquid was washed to dryness under vacuum. The residue was dissolved twice in 100 ml of water and benzene, and the dissolved liquid was removed in each case.Dissolved in the remaining pure benzene, and this solution was dissolved in 100 ml of benzene, and then dissolved in a low boiling point of petroleum ether.The precipitated chloride was separated under vacuum and dried; melting point 128-130°C. 1000 mAK of xylene was dissolved in the mixture.While bubbling QX gas, 102 g of radium/habarium sulfate was added, and then one person was blown into the mixture for 30 minutes, followed by stirring at 121°C for four months. At the same time, hydrogen was added to this mixture.The reaction J#M was produced.
After about 6 hours, which was followed by hydrogen chloride 11 determination (the 90th section of hydrogen chloride silica+i, a-breakage left behind), the reaction was stopped and suspended MkF,! The catalyst was cooled under a vacuum, and P was removed from the catalyst under vacuum. ? Concentrate jJ reed to half its volume, 40
Leveling the weight? The mixture was stirred vigorously for 2 hours with 1.5 kg of sodium chloride solution and then left overnight. 61' occurred!
! The fermentation liquid was diluted with water, and the aqueous phase was washed with benzene.
While stirring and cooling, the aldehyde was diluted with 50 φ sodium hydroxide solution to pH (directly 10°C). The aldehyde was passed under 9% and dissolved in benzene. Heat to a boil, boil for 14 hours, and evaporate. After ladle and crystallize from heptane, 4-brome-3,5-
Dimethoxybenzaldehyde is 1,
β-Methoxypropionitrile 160r and 4-, which had a 7-it point, were frequently added to 500 l of anhydrous methanol with r<S j・i''.
Bromo-3,5-dimethoxybenzaldehyde 233t
anhydrous methanol/I/400 ml of sodium 11.
The solution 7+, i (no aldehyde could be detected any longer) was cooled and left overnight in a refrigerator. ~ did 0 occur f・co・;? 1 was removed by suction, washed with a small amount of methanol, and dried. After crystallization from methanol with i < 5, 4-bromo-35-dimethoxy-α-(methoxymethy/I/)-cinnamic rd nitrile was heated at 113-114 °C.
IA
'1.5 with 140 m/methanolic guanidine bath solution
Heat the solvent under reflux for an hour at 160°C on an oil bath.
This mass was slurried with 80-100 uu of water, and then heated in a Yi wave with 0 for 15-20 minutes until completely solidified into a crystalline mass. did. 2゜4-diamino-5-(4-
Chloro/l/-3,5-dimethΦdibenzyl)-pyrimidine was obtained.To purify the product with acetic acid 15
0m7! The solution was cooled, and the crystallized salt was removed by suction. ! Water 150m7
Dissolve I(C) and treat with charcoal while heating this bath solution 3-1
! l,ta. Treat the ring group with ammonia to change from 1st to +1−
) 4 points 222-223'Q. The starting materials are the following: 2271 g of acetoacetic acid and 196 g of methyl methane mixed with 6 g of methanol.
45 g of sodium in 70 ra, l was added to 76 ml. The mixture was heated under low pressure for 5 hours with stirring. After cooling, the rum salt was removed from the mixture by suction. Mother's gift? ,? The 42 and 3rd 7-radions of the sodium salt were prepared by 1-1. The combined sodium and salt fractions split into iI.
The C solution was made acidic with acetic acid to obtain 6-methyl-cyclohexadione-2,4-carboxylic methyl ester having a melting point of 126°C. 121v of 6-methyl-cyclohexadione-2,4-carboxylic methyl ester was dissolved in dimethylformamide
0rr, IK general screen. This solution was immersed in an ice/salt mixture and stirred at 0-5°C with 196t of sulfuryl chloride. 1. I handled the subordinates. The mixture is then heated to 0-5°C for an additional lb,! The mixture was stirred for several hours at room temperature for 7 hours. Next, this mixed fJ-thing total 2.5 hours 11j
J Heat to 80℃ and remove the cancer under reduced pressure on a water bath! , 7. Add the residue to +'4'l:rm λ ether 700 ra
It was dissolved in i as 1'+jf. Water 300mA each
! The crystalline residue was dissolved in toluene 300 to 400 ml.
00ml Kame crystallized, +a point 122~125℃ 3-
Chlo/l/-2,4-dihydroxy-6-methylbenzoic acid methyl ester was obtained. An analytical sample was obtained by recrystallization from toluene and had a knitting point of 129°C. 3-chloro-2,4-dihydroxy-6-methylamino-methylnisder 143t in 3N sodium hydroxide:
The socks were heated for 30 minutes with 4 hours of heat.
KoO? i'1Jthf, r 101V (E, il + invasion 400 pr/l'tefi, making it fiλ-like, 4+Q
'i! 4 by adding 300-4001 ammonium
-Chloro-3,5-dihydroxytoluene was salted out. 4-chloro-3 at 138-139° C., crystallized from Hc-soaking water, extracted with ethyl overnight and allowed to absorb the medium under reduced pressure. ,5-dihydroxytoluene was obtained04-chloro/l/-3,,5-dihydroxytoluene 126.5f lcmethanol-/I/
150rr! 1, 1, reconnaissance lambda dimethyl 18
Treated with 2yJ. Next, water 180i/! A solution of 92 g of sodium hydroxide in the solution was added dropwise over 45 to 60 minutes with stirring at l-40 to 45°C. This mixture 'tf: i'M flowing under the same horn 1 for 20 minutes]
The heated mixture was diluted with water and extracted with ether to obtain 4-chloro/I/-3,5-dimethoxytoluene with a maximum melting point of 72°C. 77.5 l of 4-chloro-3,5-dimethoxytoluene was added to 1030 ml of pyridine. )? I understand. This reaction was heated under reflux to produce a mixture of 1'7'J) Lium 97 ? yg'='a
iTe1 voice J'l! Heat the mixture for an additional 30 minutes [14] under 4 streams.
Next, 1700 mJ of the pyridine/water mixture was distilled off, and the 1 [0 residue was separated by suction when hot. After cooling, the 84 liquid was
h <p:::j゛Public acid 600 ml made into a dragon.0
The precipitate was separated and extracted with ether to recover unreacted starting material. 4-chloro-3,5-dimethoxydiamine with a melting point of 247° was recovered. Chlor-3,5-dimethoxyalone, t971,
Weathered thionyl 64? and dimethylformamide 3)y
Add 1 k-A chloride to ligroin (boiling point 60-120'O) for 2.5 hours in a deep pit.
It was crystallized from 0.00 to 0.000 g and dried over paraffin and soda lime; mp 102-103'O. Above 1: Mechloride Q, η28v to moonkamethylene 200
rr, l! The solution was heated to 0~5°OVC/'I
I'm near al l. Add 5.62 g of ethyleneimine to 12 g of trienalamine (with stirring for 20 minutes, 7.
Take out this mixture with water on a bed that has been exposed to rain at 0 to 5°C, <L:f, and B, E on magnesium.
4. The 0 residue obtained by evaporation under reduced pressure was dissolved in 300 ml of tetrahydrofuran and localized with 1.8 f of water-purple lithium aluminum at -5°C to 0°C.
For 5 minutes, 130 ml of 5N i
Add 75f of lan ammonium to the blade, and use it for 1 minute.
Then, 4-ri o,v-3,5-dimethoxybenzaldehyde having one point of 119°0 was obtained. Methanolic sodium methylate solution (methanol 1
O (prepared by dissolving 1.159'6% sodium in Ld), β-methoxypropionitrile 171 and 4-chloro-3,5-dimethoxybenzaldehyde 20
A mixture of 9 flasks of 1 was heated under reflux for 3.5.13 hours. Cooled '3J,315-dimethoxy-4-chloro-(1-
(Methoxymethyl)-silicon anti-nitrile crystallized;
m1 point 112-113°C. 1'8 of sodium 4.6F in methanol 70+rJ
*3. - 5-dimethoxy-4-chloro-α-(methoxymethyl)-cinnamate treated with nitrile IA. The mixture was heated under reflux for 24 hours, the reaction was stopped by dipping in water, and the mixture t, +4 and extracted with methylene chloride. k47′ζ, let it grow under reduced pressure, ?・At 5? i
Uzen Zen 2-Hyakusho from Flobanol 0 peak point 84°
0's 4''' chloro-35-dimethoxy7-α-cyanohydrocinnamaldehyde dimethel acecool '41'
) It has been since Example 3゜ Sodium 0.57 in absolute ethanol 32FJ?
Guanidine horse enemy salt 2. llF and 3-anilino-2
-(4-chloro-3,5-dimeth;, dibenzyl)-
Acrylonitrile 2.4? Processed with 1y, 9. , for 20 hours under stirring? J I Poetry CO Etano
was removed under reduced pressure, and the liquid was taken on ice, separated under a window, washed with water, and crystallized from dimethylformamide/methanol. 2,4-diamino-5-(4-chloro-3,5-dimethoxybenzyl)-pyrimidine having a melting point of 232°C was obtained. Starting material No. 4 was prepared as follows: A mixture of 252 kg of 4-chloro-3,5-dimethoxybenzene wax and 50 rrJ of thionyl chloride was stirred under flowing water for 1 hour to obtain a clear solution. I made it. The mixture was evaporated to dryness under pressure, the residue was dissolved in benzene, the benzene was distilled off, and the residue was dissolved again in benzene ξIr. Ethanol (300 n/'□f) was added to this solution for 5 ii. This mixture was boiled for 30 minutes under 10 minutes,
Evaporate to dryness and dissolve the residue in benzene. The benzene solution was rinsed with water, a sodium bicarbonate bath and again with water, dried and evaporated.
After recrystallization from t-Q ethyl/petroleum ether, fl,
4-chloro-3,5-dimethoxybenzoic acid ether ester with a Q point of 100-102''0 was obtained. ) dispersion) 3.6$ll/D heart!
Stir at 50°C for 2 hours without removing moisture.
Stop the water at zero, add 4-chloro-3,5-dimethoxyamin +'r'L incense 1'+'2 ethyl ester, heat to 63°C, and pour this mixture into a mould. Add another liter of water to 511 - 100ml of water, dilute with 200 g of water, and add 100 ml of soybean powder to 400 ml of water.
The 4'-chloro-3' solution was shaken, dried over charcoal, and left to stand overnight on a cold carpet. 5'-dimethoxy-2-methylsulfonyl-acetophenone was crystallized from ethyl acetate/petroleum ether 11?
L189~190''Cc) Dust! 47-chloro-3' in 0 ethanol 3g and 10ml water
, 5〆-dimethoxy 2-methylsulfonyl-acetophenone 4,7v? In Mi' i5- water 4rnl
The melting point of sodium borohydride o, 2r in (water i″=,
0.1 t of sodium chloride was added). This mixture was stirred in a room for 21 hours, cooled with ice, separated under a 1-color bath, washed with ice water, and washed with ethanol.
J' R: ('i crystallized. fl, H (4-chloro-3,5-dimethoxy-α-(methylsulfonyl-methyl)-benzyl alcohol with point 171'O was obtained. Anhydrous dimethyl sulfoxide 10 th7 !) 0.6F, 4-chloro-3,5-dimethoxy-α~(methylsulfonyl-methyl)-benzyl alcohol 2.92 and anilinopropionitrile 1.62
The mixture was heated at 40°C for 5 hours under nitrogen and excluding moisture.
1 work ``Extracted with diethyl 100i/! i'q'I'
I calculated L Noethyl's chances of attack, and then I washed my sake bag. rI
After 11 dashes over aluminum Example 4゜β-methoxypropionitrile 1.6!i' and 4-fluoro-3,5-dimethoxybenzaldehyde 1.65
2 to anhydrous methanol 15W1/! Sodium inside < Shiba 0. Dissolved in a solution of LIF,
0 fever. The mixture was evaporated and the residue was dissolved in benzene 5
' Ornl and water 10m/. The water a was washed twice with 20 g of benzene. The combined benzene extracts were dried and evaporated. The resulting 4-fluoro-3,
5-dimethoxy-α-(methoxymethylene)-hydrosiliconitrile was used in the following reaction. A solution of 0.172 ml of sodium in 4 ml of anhydrous methanol and 2 ml of dimethyl sulfoxide was dissolved in 4-fluoro-
3,5-dimethoxy-α-(methoxymethylene)-hydrocinum-branched nitrile 1.5. Processed with Off. This mixture; lJ was heated on an oil bath at 70°C until the internal temperature was 70°C. The mixture was stirred for an additional hour in this volume. Next, add guanidine carbonate 9.64F,
gradually heating the mixture until the internal temperature reaches 110°C;
During this time, add methanol: 11! After 1 hour of incubation in a sealed water vessel, the mixture was cooled and washed with water.
! L, 30 minutes same 1. =? The resulting precipitate was stirred to pH under full vacuum and washed with cold water and benzene. Red from methanol? 1 item and after 7 hours, θ point '216~220°C 2
, 4-diamino-5-(4-fluoro-3,5-dimethoxybenzyl)-pyrimidine was obtained. The starting q-sided shellfish was prepared as follows: Sodium 13.81 methanol 9 Q Q Ir+
4. To this solution was added 46.817 g of 3-hydroxy-5-keto-3-cyclohexenecarboxylic acid. The mixture was stirred and maintained between -4°C and -8°C in a cooling bath, containing 27.9 f of aniline, 4 b of water, 4 b OM! , dark jj
xIi in +1 Jiffi 72 ml and 90 ml water
, bpr, y sodium 21, treated for 30 minutes with a phenyldiazonium chloride solution prepared from sodium chloride. This mixture was stirred for a further 1 hour at -5 °C to -10 °C. 94 separation under vacuum,
It was washed with about 1000 r11 of water. 14 points 218°C 3
-Hydroxy-5-keto-4-phenylazo-3-cyclohexenecarboxylic acid is 1'J 3-hydroxy-5-keto-4-phenylazo-3-cyclohe:'C cenecarboxylic acid is 60F, methanol-/ l/
21') Oaf! , benzene 12 L) OrJ and 1)-toluenesulfone 5 together on a water distributor between 3J+(1ijj and 18k1.:i -lJ details:, %
did. ? E1: 11'il< zzo, '←'' 5φ
5 (10Ir+
I washed it with 6, washed it with water, dried it, soaked it, and put it in the air. ``i'g +4t -Iσ5・I to ethyl, aluminum kazim a chloride (5009
, the i-occupancy level was 1). Acid 1! After evaporating +7t ethyl, methyl 3-hydroxy-5-keto-4-phenylazo-3-cyclohexanecarboxylic acid was obtained at 1 leak point 144'O (benzene/stone mill ether C)nj, 5 products). The ester obtained was 0 3-hydroxy-5-keto-4-phenylazo-3-cyclohexenecarbon r,'2 methyl ester 54.8
? , acetamide 1201 and bromoimide 2.01i' were stirred in a chloroform 600 r, ql, chloroform 40 t) nt, and then heated in a bathtub, 1
- It was subjected to downstream treatment with Ve3202. Anti-Y "1.・1 degree: 5" C or less k] I did it. Acetamide common hydroxide t'+Ji 7:l2;,・"] started soon.This τkoncombination 4- was 1 star, and it was a 30-minute song j i',: stirred. , Acetamide military water payo t salt meeting v4 separation Ichichi ○≧!
'Y+,'i'4(慴、'ζI to dry, ??,
Put Qi'i￥ into ethanol with a small amount of stitches, pass it under vacuum for 7J, and then wash it with ethanol for 4p at 01' sitting point 21.
3,5-dihydroxy-4-phenylazo-benzoic methyl ester was obtained at 6-218°C. Add 50% water to the I/64r mixture while stirring.
Treated with a solution of sodium 23F in mA for 45 minutes. Use a cooling bath to reduce the temperature to 55°C.
I was careful not to find any females. This mixture was stirred at room temperature for an additional hour [
Stir for 1 hour, cool with ice water, filtrate under vacuum, and recrystallize from 400 ml of ethanol.
3,5-dimethoxy-4-phenylazobenzobenzoic acid methyl ester was obtained as egg-colored crystals of 0.0%. 3.5-dimethoxy-4-phenylazo-benzoic acid
Chilleste/l/12F was dissolved in 400 liters of ethanol, and after overflowing with 0.8 of palladium supported on charcoal, it was heated to water at atmospheric pressure and room temperature. % added. Ya\ warm up, 1
．． 2 moles of hydrogen were absorbed in 5 hours. Separate the eastern part,
The f solution was arsenated under vacuum. The resulting aniline was hydrodistilled and after cooling to 0, the water ratio)゛,...iH? , the 4-amino-3,5-dimethoxybenzo synthetic methyl ester remaining as a salt was ff' ilmed under vacuum, and jν"l'F'
l: Recrystallized from cyclohexane; 1 point 115
~116℃. 5. 214 g of dimethyl sulfone and sodium hydride (50% dispersion in oil) in 400 me of anhydrous dimethyl sulfoxide 7s, 2r of J7. The mixture was stirred at 50°C for 3 hours under nitrogen and with removal of water. The mixture was cooled to 30°C and 4-amino, /+ 3°5
-Dimethoxybenzoic='nidimethyl ester 137f was added and the humidity rose to 50'Q. After stirring under electric power for about 1 hour, the resulting viscous mass was dissolved in water to which ice had been added after stirring for several hours. This t: Phantom one person with rice vinegar: PB by the waves I
I versed in 6-7. Lit while cooling with water, Gaku IR
J (next to pressing a, crystallized 4'-amino-3/, 5
/-dimethoxy-2-methylsulfonyl-acetophenone 84 times, washed with water, dried 'b4',
Recrystallized from ethyl chloride; melting point 166-167
℃0 Alcohol 1.51 ζ 4'-amino-3', 5'-
Dimethoxy 2-methelsulfonyl-acetophthonone 1
Sodium borohydride (23) and Sodium borohydride (682) were layered with Sosei 1 solution and left for 20 hours. Add this 41w1 solution to 1.
It was diluted with 51. The alcohol was evaporated under vacuum and the remaining 4-amino-3,5-dimethoxy-α-(methylsulfonyl-methyl)-benzyl alcohol was removed with suction, washed with 7jC and dried; Melting point 17
8-179°C0 Dimethyl sulfoxide 250a 4-amino-3,5
-dimethoxy-α-(methylsulfonyl-mefyl)-benzyl alcohol 138v to sodium amide 9.75v
It was processed using The warm mixture ')'.σ was stirred at room temperature for 1.25 hours and then poured into 2 il of water. The resulting precipitate is YT+ +-i! 4) with ethyl 24! +
The aqueous phase was again extracted with 111'i Geethyl 21. Wash white 11 twice with 11 volumes of water to remove ions, and dry over magnesium overnight.
a'a L, r, 5. 'l'mi, 710 under the hole
Generate A power at °C/? :, o Shao Ching Immediately・Ichi) h to heat 1
;, Dissolve in 250 cJ of methanol, and add 1 part of this solution to water.
The crystallized 4-amino-3,5-dimethoxybenzaldehyde, which was treated with 50 Tll of water and incubated at 4'C for 18 i, was filtered off with suction and washed with a mixture of 40 ml of methanol and 20 rr of water. IF'i 5: center; t;
-1.1 point 90~93'Q050% boron tetrafluoride 20
Add 1.4 f of 4-amino-3,5-dimethoxybenzaldehyde in the bottom e to about 2 m of water at 0°C.
h bli acid sodium 0.599 LOr) f4
Dare-(Nidiazo 1hi(, 6 hours jj on u7fi!
! : ) E water Cp, 1 uy Fu (Banau, NK
6620) irradiated with I, six along I was extracted with ether, and Ete/l/Pak-de IW-'E'+,'iζ
12 dried on magosium and isN +
'i6 L/ta0 heptane to '+'S After using the supplies,
! [3.5-dimethane with an Ω point of 97 to 98°C from the serum?
4-Fluorobenzaldehyde obtained 0 Conducted @ 5° methanol 10rr+, sodium remainder in l, +-41
Treatment with a solution of 10Rr9 separated guanidine salt r.)1m from guanidine7-f;;j7. After separating the sodium chloride under a window, the 11-segment was dissolved into 4-iodine.
3,5-dimethoxy-α-(methoxymethylene)-hydrochloride was treated with nitrile 0.97 g, and the mixture was heated under water for 5 hours. After cooling to ζ0, the compound 1 was separated, Recrystallized from methanol. Melting point 238-240
2,4-diamino-5-(4-iodo-3,5-
dimethoxybenzyl)-pyrimidine 0.7gz? Rabbit) The starting materials and qualities were as follows:
I♂ of 5F I111C tanodium 92 in water 3QIJ
; 4rt of crying. 4-Amino- in 315 lrg of IN salt with stirring.
3I5-dimethoxybenzaldehyde 23.9f solution was added at 0 to 5° C./day (potassium iodide test, test: negative), and the mixture was further stirred for 10 minutes. The resulting diazonium salt was dissolved in 26 liters of potassium iodide in 15 liters of water.
．． After the melt of No. 29 was treated in the room and the generation of nitrogen gas stopped, room 7
The mixture was stirred for 15 minutes at 1 ton of crystal and 45 minutes at 5 Q'Q. After cooling, the resulting precipitate and snout were separated into 11-1 under the A window,
Add 1 cup of j to about 1.54 ether/ζ0 ether 4
□-1 to 2jV water l-/sodium chloride 200 ml each
Wash twice with water and three times with 200 ml of water,
On Magnesium: 'Z r, fi L, and 4
; 0 me 1 year old, 7 Fuhebukun to 1 (+? After crystallization / After this, Rini Nagisa to 3.5 with a melting point of 127-128 ° C
- Cymethoxy 4-iodobenzaldehyde 19.2 tons was taken from Ishima Island. β-Methoxypropionitrile 0.84 F was added to a solution of 79 m9 of sodium metal in 10 ml of anhydrous methanol, the mixture was treated with 3,5-dimethoxy-4-iodobenzaldehyde 299 F, and Heat again for an hour. Next is this mixture! After cooling the quotient, it precipitated 4
-Iodo-3,5-ditoxy-α-(methoxymethylene)-hydrosilicate nitrile was crystallized from methanol;
゜Guanidine charcoal! Yotsuba 2205g to anhydrous methanol 2J
Oi? ＋、Excess sodium inside・、Winter 2.69 so'
Ji 72i to power [1e, tono! :;Si? = *y
<, 4i1: under a for 15 minutes)
c+α-(anilinomethylene)-4-iodo-3,5-
Dimethoxy-hydrocinnamic acid nitrile 16 groups
After 0.1 h, this mixture was poured into r, 18:01i; J Tonichi had a fever. After cooling, the solid product was separated under a window, poured into 100 rrr of water, and stirred in a room for 2 hours. −
3,5-dimethoxybendi)L/)-pyrimidine Separated under total vacuum and recrystallized from hot methanol; 1 peep point 2
38-240'C. departure! rj5jA was prepared as follows: 15.32 g of β-morpholinopropionitrile was stirred and then dimethyl sulfotide was added to 20 ml of sodium methylate (sodium gold A, 1.56 p.
3.5-dimethoxy-4-
After addition of iodobenzaldehyde 242 (anchor degree is 40°
C), and the solution was stirred at 40° C. for a further 30 min. After cooling, add 1 part methanol until the mixture remains cloudy.
5TrL/! and water was added. The crystallizing mixture was stirred for a further 15 minutes and the crystals were separated under vacuum. After recrystallization from methanol, 4-iodo-3,5-dimethoxy-tZ-(% sulfolinomethylene)-hydrosilicon anti-nitrile 24.51/% was obtained with a melting point of 121-125"C. It has been crystallized several times since then, and this one is 1
It had an angle of 36-138°0. Isopropano-/l/5 (J tnl Aniline 6.871
-dimethoxy-α-(sulfolinomethylene)-hydrocinnamic acid nitrile 23. While stirring with a mixed sound of FM', heat the blade under the stream for 1 [・r, and after cooling for 100 minutes, α-(
(anilinomethylene)-4-iodo-3,5-dimethoxy-hydrosilicon (1');'
IL, recrystallized from methanol; mp 154-15
5°0° Example 7° 24-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine 3,4v in dioxane 40+
a/, and without stirring, add 3-chloroverbenzened f(5
The 0i altitude treated with i:r'22.41 was raised to 38°C, and after 5 minutes (no more oxidizer was released), an additional 3-chloro/l/1 .I hit the 2nd floor. The resulting 9h clear solution r[E! d. After stirring for 15 minutes, he began to stir. After 2:00 p.m., the white precipitate was separated under a vacuum cleaner, washed with dioxane of 14:1, and crystallized from ethanol. 1 point 277~278'' (IQ) 2.4-
Diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine h1-oxide was obtained by condensing the OIP throat under vacuum, and the resinous residue was combined with a small amount of dichloromethane and tylene. It is crushed and separated in a furnace under vacuum. The crystalline material was suspended in 5% sodium bicarbonate solution and
Stirred for 0 minutes, vacuumed, washed with water 7, and dried. Recrystallized from ethanol (Saitake benzene/petroleum ether), 2,4-diamino-5-(4-bromo-3°5-dimethoxybenzyl)- with a melting point of 245-246°C.
Pyrimidine N3-oxide was obtained. Example 8 2.4-diamino-6-chloro-5-(4-bromo-3
, 5-Dimethoxybenzyl)pyrimidine in 155 mg of glacial acetic acid was added to a solution of 18.4 g of mercury(II) pyrimidine in 16 ml of water.
) Add a solution of 0.8 g of chloride and 14.3 g of zinc powder. The mixture was heated to reflux with stirring overnight. The reaction mixture was then heat-warmed and the zinc powder was dissolved in 90% acetic acid!
Wash with 50 mA and add to the combined solution for 20 m
400° C. of concentrated ammonia is added dropwise. Mixture at 20℃
The mixture was stirred for 1 hour, filtered, and the precipitate was washed with water and dried. , melting point 234-2a after recrystallization from 90% ethanol
2,4-diamino-5-(4-bromo-3°5-
Dimethoxybenzyl)pyrimidine 10. T,,,i are obtained. The starting material is prepared as follows: 4-bromo3,5-dimethoxybenzaldehyde O5
1 mole, ethyl 7anoacetate 11.3! ! and pyridine 3
The drop mixture is heated to 120 DEG C. in an open vessel to obtain ethyl 4-bromo-.alpha.-cyano-3,5-dimethoxycinnamate at 0.degree. C. (from ethyl acetate). 4-bromo-α-cyano-3
, 6.6 g of ethyl 5-dimethoxycinnamate are hydrogenated in 100 rrdt of ethanol in the presence of 0.259 radium on carbon at 1 atm and room temperature. The catalyst is separated from the furnace, and the P liquid is concentrated under reduced pressure and distilled. Melting point 85-86
4-bromo-α-cyano-3 at °C (from ethanol)
, ethyl 5-dimethoxyhydrocinnamate is obtained. A solution of 2.3 grams of sodium in 100 grams of ethanol contains 34.29 grams of ethyl 4-bromo-α-cyano-3,5-dimethoxyhydrocinnamate, 2.3 grams of sodium, 100 grams of ethanol, and 10 grams of guanidine hydrochloride. Add the solution prepared from 1. The reaction mixture is heated to reflux with stirring for 1 hour, evaporated to dryness and the residue is taken up in a small amount of water. The solution is filtered and made acidic by adding acetic acid. The precipitate is collected and recrystallized from ethanol/water. Melting point 266~2
2,4-diamino-5-(
4-bromo-a,5-dimethoxybenzyl)-6-hydroxypyrimidine is obtained. 2,4-diamino-5-(4-
Bromo-3,5-dimethoxybenzyl)-6-hydroxypyrimidine 35.5! ! 25.5 ml of dimethylaniline, S', was added dropwise to the suspension while stirring. The mixture' ([-heated at 1 to boiling within 1 hour,
Time flows quickly. About 50-60% pOcl is distilled off under reduced pressure, the residue is poured onto about 800 g of ice, and after standing for 6 days at room temperature, 324.9 g of concentrated ammonia is added to the precipitate with stirring.
is added so that the temperature does not exceed 20°C. After standing for 2 hours, the solid mass was separated and the dimethylaniline was removed by steam distillation. After cooling, the suspension is aspirated, triturated with 300 ml of acetone and aspirated dry. 2,4-diamino- with melting point 259-261°C (decomposition)
5-(4-bromo-3,5-dimethoxybenzyl)-6
- Chlorpyrimidine is obtained. The main embodiments of the present invention are as follows. 1) Represents an oxygen atom bonded to the general formula, and L is O or 1
In producing benzylpyrimidine and its salt, (α) general formula [wherein R4 represents a lower alkyl group, or both R4s together represent a lower alkylene group, represents a leaving group and l (l , R'' and R3 have the meanings given above) is reacted with guanidine, or (b) a compound of the general formula [wherein X is chlorine or !A atom] is reacted with guanidine; or an alkylmercapto, alkylsulfonyl or amine group (wherein at least Ni's EC> In the compound of the general formula [wherein Xi represents a chlorine or bromine atom or hydroxyta, 13, and R'', R'' and It3 have the above meanings] j?4 groups x1 -I radically removing or (subjecting a compound of formula I in which di represents 0 to N-tilation and optionally converting the compound of formula I thus obtained into a salt. A method for producing a cylinder of benzylpyrimidine and its salt of the above general formula l where 94i is 02) Formula ■ where n represents 0
Compound '1. Method 1 according to the above method 03) when R3 is produced according to lju-like (α); Method according to 2. gesell shaft

Claims (1)

[Claims] General formula % formula % [In the formula, l? 1 and R2 are each independently C4~. represents an alkyl group, Bs represents a halogen atom, and Xl represents a chlorine or bromine atom or a hydroxy group], and, if necessary, the compound thus obtained is converted into a salt. A method for producing benzylpyrimidine and its salts, characterized in that the general formula is changed [wherein R'XR2 and R3 have the above meanings].