JPS5888368A - Manufacture of benzylpyrimidine derivative - Google Patents

Abstract

(57) [Summary] 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 a process for the preparation of a group of substituted 2,4-cyano-5-benzylpyryzines.
443.682, inter alia, formula (1) [wherein R1 and R1 are equal or different, and each is 01-3 alkyl, 01-4 alkoxy, 02-3 alkenyl or 0□~ 3 alkenyloxy (pl and 2 is a) or alkyl-substituted amino] and salts thereof. These compounds have been described as having antibacterial activity;
Then, 2,4-diamino-5-(4-amino-6,5
German patent application no. and 2 is amino or alkyl directly substituted aξ)] and salts thereof. These compounds have also been described as having antibacterial activity.

A new synthesis of compounds of formula (1) and (It) has now been discovered.

Therefore, the present invention provides formula (2) [wherein R4 and R41L are the same or different, Tob, each is a hydrogen atom or a 01-4 alkyl group, and static is a halogen, 01-4 alkyl or 01-4 alkoxy is 69, and R6 is haat”n,
01-4 alkyl or ol-4 alkoxy], the process comprises preparing a compound of formula (2) R6 in which R4, R5 and R6 are as defined above. , (1) Reacting 2,4-cyamino-5- with do-4-oxymethylpyrimidine or their cl-4 ether, (if) formaldehyde and secondary amine R'
Rilil! to obtain the compound 'ft of 2 M e , which in turn gives the compound 'ft of M e ', and when R9 is other than hydrogen, the group R't is then reacted with
- Reductive elimination [in the above formulas, R4, static 2 and R6
is as defined above, and p1R'F and R11 are both a, alkyl or R? RII HH represents morpholine or piperidine, and R- is hydrogen,
hydroxy% ol-4-furkylthio or mercapto], or
Subsequently, the resulting uracil derivative of formula (2) is successively alkylated (desired combination) at the 7-mino group, halogenated and adenated; ), optionally J) alkylating one compound of the formula (to) where R41L is hydrogen;
The process consists of obtaining a compound of

The method is particularly suitable for the preparation of compounds in which R4 is hydrogen. Suitable R8 and R6 are the same and each is methoxy, chlorine or 01-4 alkyl.

Variant (1) is carried out at non-extreme temperatures, e.g. between 25°C and 175°C, and in particular from 50°C to It is preferably carried out at a temperature of up to 150°C. The reaction is carried out with acids such as hydrochloric acid, acetic acid, methanesulfonic acid or: p-
It is preferably carried out in the presence of toluenesulfonic acid. The preferred solvent is acetic acid.

Production of compounds of 2) in modified process (Zeng), Miocque and Vierfoy
fonL)
France) l 97 Q.

(1896) under the conditions described for the preparation of Simannitz bases. The reaction is conveniently carried out in the presence of 0.5 mole of acid, such as acetic acid, for each mole of other components. The compound of formula (b) is then treated with an acid such as I)-)
The reaction is carried out with a slightly higher concentration of the compound in the presence of luenesulfonic acid. The reaction is usually carried out in a suitably high boiling medium, such as a glycol such as ethylene glycol, at elevated temperatures, e.g. 2N is particularly suitable for this process. This reaction is usually carried out by hydrogenolysis in
The reaction is carried out in a polar solvent such as an alkanol such as methanol or ethanol.

In the modified process (IN), the reaction between the compound of formula (2) and 5-dimethylannomethylucyl is usually carried out at 10 ff
For example, from 160℃ to 16σ
The process is carried out using an inert high-boiling polar mortar such as high-boiling point Oa to 6 mil 6-furkanol such as ethylene gellicol. The reaction is usually carried out under acidic conditions, for example in the presence of hydrochloric acid. Halodanation and subsequent adenation of compounds of formula (to) are carried out in a manner well known to those skilled in the art, for example as described in British Patent No. 875.562 or British Patent No. 1.132. ,082
This may be conveniently carried out by using the reaction conditions described in German Patent No. 2.258.238 or in German Patent Publication No. 2.258.238.

The alkylation of the amino group in variant (Ml) is carried out under conditions familiar to those skilled in the art, which do not overshadow the uracil part of the molecule, e.g. with ammonium and formic acid and suitable It is carried out by reaction with a faint aldehyde. Preferably, the reaction may be methylation, in which case the aldehyde may be formaldehyde. The optional alkylation of the anno group NR411 is carried out under conditions that do not affect the amino group attached to the pyridine ring.

Also known to those skilled in this art, for example, in reactions with formic acid and suitable aldehydes, compounds of the formula <VM), (Vl) are novel. is an important intermediate and as such forms an important part of the invention. formula(
The compounds of [2] in which R4, RM and R6 are as defined above are also novel intermediates forming part of the present invention.

Example 1 Preparation of 2.6-diisozolopyl-4-piperidinomethylaniline Miocque and Vierfond (BulL
8oc, Chin.

2,6-diitzorobylaniline (17
, 73 g, 0.10 mol), 37% aqueous formaldehyde (8.1 mls O, 10 mol), pipericin (8.52 g, 0.10 mol), acetic acid <! 1
．． 0011゜0.05 mol) and ethanol (
25 m) were boiled together until the temperature reached 92°C. The solution was then refluxed for 24 hours. The product is vacuumed (0
, 7-0.8 mm) to give the title compound (17.57, f, 64%).

IHM (CDCl2): δ1.25 ((!, 12,
CH3), 1.50 (m, 6, (CHa)r5), 2.
35 (m, 4, N(CH2)2), 2.95 (m, 2,
CM), 3.35(8,2, Ar-CH2), 3-
70 (Plow P8.2, NHa), 7-0 (
s,2,Ar-H).

Example 2 Production of 2.6-diethyl-4-biperizonomethylaniline 2.6-diethylaniline (29,85,9,0,20
mol), 37% aqueous formaldehyde (16,211
j, [), 20 mol), giberidine (17, []
33g0.20 mol), acetic acid (6,00,!i
', 0.10 mol) and ethanol (2511
The solution of 14) was reacted under the same conditions as in Example 1.

The title compound (28.49 g, 57.8%) was purified by vacuum distillation (
0.05 mm at 115-125°C). IH Nagigo (CDCl2): δ1.25 (t.

6, c) I, , ), 1.50(m16, ((Hl)a
), 2.55 (m, 4, N(CHI)R1), 2.5
5 (q, 4, CH2Me), 3.45 (s, 2, ArC
H2), 3.55 (Broad B, 2, NHs), 6.
90 (s, 2, ArH).

Example 6 Preparation of 2.6-diitzolopyru-4-(y@N-zomethylaminomethyl)aniline 2.6-zisoderobylaniline (55.45 g, 0.5 g,
20 mol), 37% aqueous formaldehyde (16-2
111s 0.20 mol), N, N-zomethi/
L/7min (9-02JFs O, 20 mol)% acetic acid (6,00N.

0.10 mol) and ethanol (255111/
) was reacted under the same conditions as in Example 1.

The title compound (12.05 g, 26%) was purified by vacuum distillation (11
2-120℃, 0.2mm) or 0IHN'
MR (CDur3): δ1.25 (d, 12, CH5)
, 2.20 (s, is, NMe2), 2.95 (m,
2, CH), 3.35(s, 2, ArCI(1), 3.
70 (pro ra, 2, NH,), 7.0 (s, 2
, ArH).

Example 4 Production of 2.6-diituderobyl-4-morpholinomethylaniline 2.6-diituderobylaniline (35,4511,0
-20 mol), 37% aqueous formaldehyde r(16
, 2WLl, 0.20 mol), morpholine (1
7,42#s0.20mol), acetic acid (6,00, f-
A solution of 1Q, 1Q mol) and ethanol (2511) was reacted under similar conditions as in Example 1. After concentration on a rotary evaporator, the residue was dissolved in diethyl ether and washed with aqueous sodium bicarbonate and water. After drying the ether solution, hydrogen chloride (0,20
mol) solution was added. Filtration and drying.

is the hydrochloride salt of the title compound C47,581/, 76.0%
) was given. This salt (20.0g, 0.(S mol)
) was dissolved in acetone and treated with solid potassium bicarbonate. Filtration and evaporation of the solvent yielded the title compound (
16,27i 92.2%) was obtained.

Elemental analysis value: Calculated value as Cx7H2s'1i20:
c 73.87; H10,21; N 10.1
3 measurement value: c 74.04; H10,31; N
10.17 Example 5 Preparation of 2,4-diamino-5-(4-amino-3,5-diisopropylbenzol)-6-methylthiogirimicin 2,4-diamino-5-(4-amino-3,5-diisopropylpenzol)-6-methylthiogirimicin in ethylene glycol (50 aJ) at 114°C 6-methylthiobilimicin (1,5
61,10,0 mmol), Ethi L/Ngri:l
-/L/ (25m) Nakano V (R,==H,R,:
R,=C'KMes% NRyR6: Morpholino, 3.
32. F, 12.0 mmol) and p-
Toluenesulfonic acid monohydrate (0,19#, 1.
0 mmol) was added.

The temperature was maintained between 125°C and 140°C for 6 hours and 15 minutes. The solvent was distilled in vacuo and 3N hydrochloric acid (20 ml
) was added to the residue. Crude hydrochloride of the title compound (3,441
! , 90.0%) was dissolved in methanol, treated with activated carbon, filtered, and evaporated until crystallization began. The slurry was diluted with isopropanol, filtered and dried to give the purified hydrochloride salt of the title compound (2.58 g, 6
8%).

The title compound was hydrochloride (1.67 g, 4.57 mmo
It was obtained by adding concentrated ammonium hydroxide (61) to the aqueous solution of 1). - filtering and drying the title compound (
1.38g, 91.4%).

lHNMR (CDCj, ): δ1.30 (d, 12
, CH3).

2.60 (15, Vl, 8CH3), 3.0 (m, 2,
CH), 3.6 (broad 8.2, ArNH2), 3.
35 (a.

2, ArCHa), 4-7 (broad 8.4,
NH2), 7-0 (a,2, ArH).

In a similar way, vt (R, = 13CH3,1,56
,9.

10.0 mmol) to V (R4:” Hs R5
= R6 = CHMe2, NR,, R, = Giberidino, 3
．． 29 g, 12. React with [l mmol),
The title compound (1.41 g, 41%) was obtained.

Also, under the same condition, Vl (R9 = 8C!) (
511,56 g, 10.0 mmol) to V (R4
= HlRs =R6= CHMe2 , R,=
R8=cH3, 2,81g, 12.0mm
ol) to give the title compound (0.97N).

28.4%).

Example 6 Production of 2.4-diamino-5-(4-amino-6,5-zoisoderovirpenzyl)-giri sewing machine Methyl cellosolve (10 m) and water ([), 5 m in No'II (R4=
” HN RB = R6 = CHMe2, R9 = BC
H,, 0.50 g, 1.45 mmol) solution in T
-1 Raney nickel (6 g) and refluxed for 6 hours. The solution was filtered and evaporated and the residue was triturated with hot hexane to give the title compound (0.36 g, 84%); mp 17
7-180℃.

Example 7 Preparation of 2.4-cyamino-5-(4-amino-3,5-diisozologylbenzol)-6-hydroxybilimicin 120(R,
=O)(,1,44,!i'% 10.Ommol)
, V (R4=H, R3=R6=CHMe2)
,NR2RB=:morpholino,3,6211s
12. A solution of p-) luenesulfuric acid monohydrate (0,19F, 1.Ommol) was heated at 133-138<0>C for 4.5 hours. The solvent was distilled off under vacuum and 3N hydrochloric acid (20 Itl) was added to the residue. The resulting hydrochloride salt was isolated, dissolved in water, and neutralized by addition of concentrated ammonium hydroxide to yield the title compound (2,361174, 9%). The title compound was purified by recrystallization from ethanol (1.41+
, 45.7%).

IHNMR (DM80-d, ): δ1.05 (d
, 6% CH3), 2.90 (m, 2, CH)
, 3.50 (s, 2, ArcI(*), 4.15 (
Broad8.2, ArNH2), 5.45 (,Broad-,2,NH,), 4.15 (Broad8.2,
NH, ), 6.80 (g, 2, A
rH), 9.90(8,1,O)().

The title compound is prepared by a sequential reaction with methane 1 sulfonyl chloride to give (Rg = 0802Me) followed by catalytic hydrogenation with palladium to give (R9=H), as in GB 1,542,804. Convert it to ■ (R9=H) by.

Example 8 Preparation of 2.4-diamino-5-(4-amino-6,5-diisozolopyrbenzol)pyrimicin 'II (Ro = H, 1,10 g, in ethylene glycol (5C1)
10.0 mmol), V (R4= HsR5=
R6=CHMe2, NR7R15=morpholino, 6.
62 g, 12.0 mmol) and p-toluenesulfonic acid monohydryl) (0.19 g, 1.0 mmol)
ol) was heated at 150-160°C for 5.5 hours. The solvent was distilled under vacuum and 3N hydrochloric acid (20#
IJ) was added to the residue. The resulting solution was washed with methylene chloride, the oil was evaporated, and it was left for 6 years.
More crystallized. The crystals are mixed with inderononol,
Filter and dry to obtain the hydrochloride salt of the title compound (1,5
1&, 45%), which was recrystallized from ethanol (1.04 g, 68.9%).

The title compound ([
], 50 g, 76%). 1H turtleffi (I
)NH0-d6) ” 1.15 (dz 12, CH
), 2.95 (m12, CH), 3.50 (S, 2,
*rCH2), 4.50 (Broad S12, ArNH
4), 6.15 (broad 8.2, NH2), 6.5
5 (broad β, 2, NH2), 6.80 (S, 2,
ArH), 7.40 (S.

1. Pyrimidine 5-I()O melting point 179-182°C.

Example 9 Production of 5-zomethylaminomethyluracil hydrochloride Uracil (56.05 g, 0.5 D mol) was
Zomethylamine hydrochloride (81,5
After evaporation of 5 g, 1.0 mol) and 37% aqueous formaldehyde and trituration of the product with methanol and drying, the title compound (isolated (
8 0.6 9, 78.6%) 011( NMR (
DM80 - (16+DsO)'δ2.90
(s, 6, NMe2), 4.10 (s, 2, NCH2
), 7.95 (sl 1, uracil-6H).

Example 10 5-(4-amino-3,5-diisozolopylpencil)
Preparation of uracil 5-dimethylaminomethyluracil hydrochloride (10.28 g) in ethylene glycol (75R7).

50, O mmol) and 2,6-diitzorobirua, Nilin (10.64,9,60.O
mmol) was heated at 164-167° C. for 4.5 hours. After cooling, the title compound was filtered, washed with ethanol and dried (5.51, 37%).

A second group was obtained from the mother liquor by standing (5.2 4
9, 21, 5%). The two groups were combined and recrystallized from methanol to give the purified title compound (5.8
4g, 68.8%) was obtained.

. Calculated value as elemental analysis value 2017H93N3011: c67.75; H7,69: N13.94
Measured value: c67.59; n7.75; N13.
88 title compound is described, for example, in British Patent No. 875,562.
(No. 8: H%
R5=R6=CHMe2, Rg=H).

Example 11 2.4-cyamino-5-(4-amino-3,5-dimethoxybenzyl)biIJ Preparation of sewing machine 2.4-cyamino-5-cyanopyrimidine to British% pestle No. 1,413,4
2,4-diamino-5-hyroxymethylpyrimidine (4,30,!i'
130. Ommol), 2゜6-dimethoxyaniline (s, o 51 s 33-Ommol), acetic acid (60
A mixture of d) and concentrated hydrochloric acid (4.2jE/) was refluxed for 4.5 hours, cooled and filtered to give the hydrochloride salt of the title compound (7.15g, 76.2%).

The salt was dissolved in water and the solution made basic with concentrated ammonium hydroxide. The precipitate formed was filtered, washed with water and dried to give the title compound (5.18 g, 62.7
%) was obtained.

Elemental analysis value: Calculated value as C13H17N502: C
56,72: H6,22; N25.44 Measured value: C56,63; H6,29: N25.39 Other compounds of Nika produced by modified method (1) of this method are illustrated in Table 1. .

5-[(dimethylamino)methyl]uracil hydrochloride [Roth (B, Roth
), Strelitz (, T, Z, 5trelitz) and Hockman (B, 8.) (auckman), Zu, Journal, Oshi, Zu, Medical, Chemistry (J,
Med, Chem, ), 23.379 (1980))
10.04 g (49 mmol) and 2,6-dimethoxyaniline (melting point 76-74.5°C; O nick from 2,6-dimethoxybenzoic acid, reactions (O
rg, Reactions), 3.330 (194
6) Manufactured by the method in) 7.481 (49 mmo
The mixture of l) was heated at 145° for 5 hours. The mixture was cooled and the precipitated solid collected, suspended in 300 d of boiling ethanol and collected to yield the title compound 5.
Obtained 91 g (29%); mp 243-245°C (decomposition).

Elemental analysis value: Cx3HxalJ304・l/4H20
Calculated value as: C55,41; H5,54; N
14.91 Measured value: C55,46; H5,54;
N 14.94 second group 2.0.9 (15%) was obtained by concentration of the ethanolic extract.

17) 5-(4-7 mi/-
6,5-dimethoxybenzyl)-2,4-(IH.

6dan)-pyrimidinedione (5,4,!i' s 19
．． 37% formaldehyde (1
,75,! ? ) was added. After refluxing for 18 hours, the reaction mixture was cooled and concentrated H (J 2 d) was added. The solution was evaporated and the residue was dissolved in 200 d of water. This solution was diluted with 5N hydroxide in IJ. The sum gave the title compound 5.25 fI (89%); mp 228-2
60°C (decomposition).

Elemental analysis value: C15H19N3o4・0.1H2o and calculated value: 058.667)! 6.30; N1
3.68 measurement value: C58,55: H6,30;
N13.69 5-(3°5-dimethoxy-4-dimethylaminobencyl)-2,4-(1) in 100d of 4-dimethylaminobencyl)pyrimidinephosphoryl chloride
3H)-pyrimidinedione 5.02 g (16,
4 mmol) was heated under reflux for 90 minutes. Excess POCl2 is removed in vacuo and the residue is dissolved in dichloromethane and neutral aqueous bicarbonate (IJ).
solution and then washed with water. The solution was dried over Mg804 and then passed through a silica sol column eluting with dichloromethane:methanol/19:1. Both parts containing the product were combined and concentrated to an oil; 5.75 g (
67%).

The structure was confirmed in sequence.

2.4 in 200aJ of ethanol saturated with ammonia
-dichloro-5-(3,5-dimethoxy-4-dimethylaminobencyl)virimicin 6.47g (10.1m
8 mol) solution in an autoclave at 150°
heated for an hour. The solvent was removed in vacuo and the residue was triturated and collected.

Dissolve this in dichloromethane:methanol/4:1,
Adsorbed onto silica gel and placed on top of a silica gel column. Elution with the same solvent yielded the title compound 2.27
F (74%). One portion was converted to the dihydrochloride salt by recrystallization from 95% ethanol in concentrated Hα; mp 2
28-260° (decomposition).

Elemental analysis value: Cl5H211J, 02-2 HCj
- Calculated value as H, O: C45,69; H6,3
9; N17.76; Cj17.9B measurement value: c 4
5.70; H6,40; N17.77; Cj1
7.86 Agent Akigai Asamura 4 people

Claims (1)

[Claims] U) Formula (2) [wherein R4 and H4a are equal or different and To9, and each is hydrogen and 0. ~4 alkyl, and Ha and R6)\logen, C1
-4 alkyl and 01-4 flukoxy], comprising a compound of formula 1-6, and comprising: a) a compound of formula *t-2,4-diamino; b) Reacting the larger compound with formaldehyde and secondary amines R'', R[wherein R'F and R8 are Both 01-
4 alkyl, or R〒, R''NH represents morpholine or piperidine] to obtain a compound of formula (7), which is then reacted with a compound of formula (b) [where Be is hydrogen, hydroxy, 01- 4 alkylthio or mercapto] to form the formula (
2) obtaining a compound of formula (1), followed by reductive removal of the group R9 when R9 is other than hydrogen; and O) reaction with a compound of formula t-S-dimethylaminomethyluracil, followed by sequential alkylation of amino groups (if desired),
A process consisting of a reaction (sequential) selected from the group consisting of carrying out halogenation and amination. (2) Formula (2) [wherein 1j4 is selected from hydrogen and 01-4 alkyl, and BIS and R6 are] 10rn, 'l-4
selected from alkyl and 01-4 alkoxy]; The method according to the range M1'fJ4. (3) Formula (2) [wherein the total is selected from hydrogen and 0□~, alkyl, and R5 and R6 are selected from I*r/, C~4 alkyl and 01-1 alkoxy] A compound of formula a 6 is treated with formaldehyde and a secondary amine RTR to prepare a compound of
8N)1 [wherein R'F and R8 are both 01-4 alkyl, or R7R'1N)L represents morpholine or piperidine] to obtain a compound of 2M 6 , which then has the formula (To) [In the formula, R9 is hydrogen, hydroxy, luteo or mercapto in 01-4] to obtain the compound (2) When He is something other than hydrogen, subsequently the group R9 A method according to claim S paragraph 1 consisting of reductively removing the car(4) of formula (2) [wherein 14 is selected from hydrogen and 01-4 alkyl Rikishima et al., and RIS and R6 are To prepare a compound of hydrogen 0x-i" and 01-4 alkoxy], the compound of R5 6 is reacted with 5-dimethylaminomethyluracil, followed by successively A method according to claim 1, which comprises halogenating and aminating. (5) A method according to claim 1g, 2, in which the reaction is carried out in the presence of an acid. (6) A method in which the nucleic acid is hydrochloric acid, acetic acid, Methanesulfonic acid and P-
) luenesulfonic acid, qIllIV-
Method 0 according to claim 5 (7) The method according to claim 5I5, wherein the acid is hydrochloric acid. (8) Method 0 according to claim 5, wherein the nucleic acid is selected from methanesulfonic acid and R-toluenesulfonic acid (9) Formula (2) [wherein static is selected from hydrogen and 01-4 alkyl] and R5 and R6 are selected from halogen, 0□-4 alkyl and 01-1 flukoxy].
The compound of formula (7) is obtained by reacting with @NI [(in the formula, R〒 and R@ are both 01-1 alkyl, or R''R axis yo represents morpholine or piperidine]), and is then reacted with a compound of formula (b) [wherein R11 is hydrogen, hydroxy or 01-4 flukithio] to obtain a compound of formula (4)%, and if R9 is other than hydrogen. A process according to claim 1, comprising the subsequent reductive removal of the group 1 (9i) when (IG is selected from halogen, 01-4 alkyl and 01-4 alk-oxy, and R9 is selected from hydroxy %01-4 furkylthio and mercapto] and their acid addition salts. Compounds of [wherein ■ is selected from hydrogen and 01-4 alkyl, and R6 and R6 are selected from) 10 den, 0□-4 alkyl and 01-4 alkyl; and acid addition salts thereof] a3 200 million) l 6 [wherein R4 is selected from hydrogen and 01-4 alkyl, and Rδ and R6 are selected from) 10 den, 00-4 alkyl and 0□-4 alkoxy] and Acid addition salts thereof 0 ual A process according to claim 3, in which the reaction of the compound of formula (-) and the compound of formula (-) is carried out in the presence of an acid.Q4) ll#tp-toluenesulfone Process according to claim 13, in which O ae reaction is carried out in the presence of an acid. Process according to claim 15, in which 11 gl is hydrochloric acid Formulas (9) and (b) and HQ are within the scope of claims l
l! consisting of the reaction of a compound of formula (b) with a compound of formula (b), as defined in connection with item 1, and subsequent reductive removal of the group R9 when R9 is other than hydrogen. , claim ii! I. Process for preparing a compound of formula (2) as defined in paragraph 1. A formula as defined in claim 1 consisting of the amination of a compound of the following formula (wherein R', B41L, R6 and R6 are as defined in claim 1) Method for producing (to) the compound 〇