JP2657150B2 - Benzylpyrimidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for preparing a group of substituted 2,4-diamino-5-benzylpyrimidines.

[0002]

BACKGROUND OF THE INVENTION German Patent Application No. 2,443,682 discloses, inter alia, formula (I)

Embedded image Wherein R ¹ and R ² are equal or different and each is C _1-3 alkyl, C _1-4 alkoxy, C _2-3 alkenyl or C _2-3 alkenyloxy; And Z is amino or alkyl-substituted amino], and salts thereof. The compounds are stated to have antibacterial activity, and 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) pyrimidine is subsequently disclosed to possess good diuretic activity.

German Patent Application No. 2,634,358 discloses, inter alia, formula (II)

Embedded image Wherein R ³ is a halogen atom and Z is amino or alkyl-substituted amino, and salts thereof. The compounds are also described as having antibacterial activity.

[0004]

The formulas (I) and (I)
A new synthesis of the compounds of I) has now been discovered.

[0005]

Accordingly, the present invention provides a compound of formula (II)
I)

Embedded image[Wherein, R^FourAnd R^4aAre equal or different
And each is a hydrogen atom or C_1-4With an alkyl group
Yes, R^FiveIs halogen, C_1-4Alkyl or C _1-4A
Lucoxy and R⁶Is halogen, C_1-4Archi
Or C_1-4Alkoxy)]
Provided, wherein the method is of the formula (IV)

Embedded image Wherein R ⁴ , R ⁵ and R ⁶ are as defined above, with (i) 2,4-diamino-5-hydroxymethylpyrimidine or their C _1-4 ethers (Ii) reacting with formaldehyde and a secondary amine R ⁷ R ⁸ NH to form a compound of formula (V)

Embedded image Of the formula (VI)

Embedded image With a compound of formula (VII)

Embedded image Wherein R ⁹ is other than hydrogen, followed by reductive removal of the group R ⁹ [wherein R ⁴ , R ⁵ and R ⁶ are as defined above; ⁷ and R ⁸
_Are both C _1-4 alkyl or R ⁷ R ⁸ NH represents morpholine or piperidine, and R ⁹ is hydrogen,
Hydroxy, C _1-4 alkylthio or mercapto], or

(Iii) reaction with 5-dimethylaminomethyluracil and subsequent formation of formula (VIII)

Embedded imageAlkylation of uracil derivatives of amino groups continuously (where
If desired), halogenation and amination;
In law (i), (ii) or (iii),
More R^4aIs a compound of formula (III)
R^4aIs C _1-4Formula (III) which is alkyl
To obtain the compound.

The process is particularly suitable for preparing compounds where R ⁴ is hydrogen. Suitable R ⁵ and R ⁶ are the same and each is methoxy, chlorine or C _1-4 alkyl. Variant (i) is carried out in a solvent which can dissolve both reactants (polar non-phenolic solvents are particularly suitable), at non-extreme temperatures, for example between 25 ° C and 175 ° C, and especially between 50 ° C and 150 ° C. It is preferably carried out up to. The reaction is suitably carried out in the presence of an acid such as hydrochloric acid, acetic acid, methanesulfonic acid or p-toluenesulfonic acid. A preferred solvent is acetic acid.

The preparation of the compounds of the formula (V) in variant (ii) can be carried out by means of Miocque and Vierfond [Buretin, de la, Societe, Simic, de, France (Bull. Soc. Ch.).
im. France, 1970, 1896] under the conditions described for the preparation of Mannich bases. The reaction is conveniently carried out in the presence of 0.5 mole of acid, such as acetic acid, per mole of each of the other components. Formula (VI)
Is then reacted with a slight excess of the compound of formula (V) in the presence of an acid such as p-toluenesulfonic acid. The reaction is usually carried out in a solvent having a suitably high boiling point, for example in glycols such as ethylene glycol.
It is carried out at an elevated temperature, for example from 100 ° C to 200 ° C. Desulfurization is preferably effected by hydrogenolysis in the presence of a transition metal catalyst, Raney nickel being particularly suitable for this process. The reaction is usually carried out in a polar solvent such as a C _1-4 alkanol such as methanol or ethanol.

In variant (iii), the reaction of the compound of formula (IV) with 5-dimethylaminomethyluracil is usually carried out between 100 ° C. and 200 ° C., for example 13
The reaction is carried out in an inert high boiling polar solvent between 0 ° C. and 160 ° C. in a high boiling C _2-6 alkanol such as ethylene glycol. The reaction is usually carried out under acidic conditions.
For example, in the presence of hydrochloric acid. Formula (VIII)
Halogenation and subsequent amination of the compounds of formula (I) are well known to those skilled in the art, for example, from GB 875,562 or 1,132,082, or from Germany. Patent Publication No. 2,
This can be conveniently done by using the reaction conditions described in US Pat.

The alkylation of the amino group in variant (iii) does not affect the uracil part of the molecule, under conditions well known to those skilled in the art, for example amines and formic acid. And reaction with an appropriate aldehyde. Preferably, the reaction can be a methylation, in which case the aldehyde can be formaldehyde. The optional alkylation of the amino group NR ⁴ H is performed under conditions that do not affect the amino group attached on the pyrimidine ring. Suitable conditions are also known in the art, for example to those skilled in the reaction with formic acid and the appropriate aldehyde.

The compounds of the formulas (VII), (VIII) are novel intermediates and as such form an important part of the invention. Formula (IX)

Embedded image The compounds of the formula wherein R ⁴ , R ⁵ and R ⁶ are as defined above are also novel intermediates which form part of the present invention.

[0012]

【Example】

Example 1 Preparation of 2,6-diisopropyl-4-piperidinomethylaniline Miocque and Vierfond (Bull. S.
oc. Chim. France 1970 , 1896)
According to the conditions described by 2,6-diisopropylaniline (17.73 g, 0.10 mol), 37% aqueous formaldehyde (8.1 ml, 0.10 mol),
Piperidine (8.52 g, 0.10 mol), acetic acid (3.00 g, 0.05 mol) and ethanol (2
5 ml) were boiled together until the temperature reached 92 ° C. The solution was then refluxed for 24 hours. The product was distilled under vacuum (122-140 ° C. at 0.7-0.8 mm) to give the title compound (17.57 g, 64%). ¹ H NMR (CDCl ₃ ): δ1.25 (d, 1
2, CH ₃ ), 1.50 (m, 6, (CH ₂ ) ₃ ),
2.35 (m, 4, N (CH ₂ ) ₂ ), 2.95 (m,
2, CH), 3.35 (s , 2, Ar-CH 2), 3.
70 (broad s, 2, NH ₂ ), 7.0 (s, 2, A
rH).

Example 2 Preparation of 2,6-diethyl-4-piperidinomethylaniline 2,6-diethylaniline (29.85 g, 0.20 m
ol), 37% aqueous formaldehyde (16.2 ml,
0.20 mol), piperidine (17.03 g, 0.2
0 mol), a solution of acetic acid (6.00 g, 0.10 mol) and ethanol (25 ml) were reacted under the same conditions as in Example 1. The title compound (28.49 g, 57.8)
%) Under vacuum distillation (115-125 at 0.05 mm).
C). ¹ H NMR (CDCl ₃ ): δ
1.25 (t, 6, CH ₃ ), 1.50 (m, 6, (C
_{H 2) 3), 2.35 (} m, 4, N (CH 2) 2),
2.55 (q, 4, CH ₂ Me), 3.45 (s, 2,
ArCH ₂ ), 3.55 (broad s, 2, NH ₂ ),
6.90 (s, 2, ArH).

Example 3 Preparation of 2,6-diisopropyl-4- (N, N-dimethylaminomethyl) aniline 2.6-Diisopropylaniline (35.45 g, 0.4 g)
20 mol), 37% aqueous formaldehyde (16.2)
ml, 0.20 mol), N, N-dimethylamine (9.02 g, 0.20 mol), acetic acid (6.00 g,
0.10 mol) and a solution of ethanol (25 ml) were reacted under the same conditions as in Example 1. The title compound (1
2.05 g, 26%) by vacuum distillation (112-120 ° C,
0.2 mm). ¹ H NMR (CDCl
₃ ): δ1.25 (d, 12, CH ₃ ), 2.20
(S, 6, NMe ₂ ), 2.95 (m, 2, CH),
_{3.35 (s, 2, ArCH 2} ), 3.70 ( broad _{s, 2, NH 2),} 7.0 (s, 2, ArH).

Example 4 Preparation of 2,6-diisopropyl-4-morpholinomethylaniline 2,6-diisopropylaniline (35.45 g, 0.4 g
20 mol), 37% aqueous formaldehyde (16.2)
ml, 0.20 mol), morpholine (17.42 g,
0.20 mol), acetic acid (6.00 g, 0.10 mol)
l) and a solution of ethanol (25 ml) were reacted under the same 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, a solution of hydrogen chloride (0.20 mol) in ethanol was added. Filtration and drying were performed using the hydrochloride salt of the title compound (4
7.58 g (76.0%). This salt (20.0
g, 0.6 mol) was dissolved in acetone and treated with solid potassium bicarbonate. Filtration and evaporation of the solvent gave the title compound (16.27 g, 92.2%). Elemental analysis: C ₁₇ H ₂₈ N ₂ O Calculated: C 73.87; H 10.21; N 10.13 Measured: C 74.04; H 10.31; N 10.17

Example 5 Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropylbenzyl) -6-methylthiopyrimidine 2,4-diamino-6 in ethylene glycol (50 ml) at 114 ° C. Methylthiopyrimidine (1.5
6 g, 10.0 mmol) and ethylene glycol (2
V (R ₄ = H, R ₅ = R ₆ = CHMe ₂ , 5 ml)
NR ₇ R ₈ = morpholino, 3.32 g, 12.0 mmol
l) and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) were added. Temperature 1
Maintained between 25 ° C and 140 ° C for 3 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 (3.44 g, 90.
(0%) was dissolved in methanol, treated with activated charcoal, filtered and evaporated until crystallization began. The sludge was diluted with isopropanol, filtered and dried to give the purified hydrochloride of the title compound (2.58 g, 68%).

The title compound is hydrochloride (1.67 g, 4.
Aqueous solution of concentrated ammonium hydroxide (6 m
1) was obtained. Filtration and drying
This gave the title compound (1.38 g, 91.4%). ¹ H
NMR (CDCl ₃ ): δ 1.30 (d, 12, CH
₃ ), 2.60 (s, 3, SCH ₃ ), 3.0 (m,
2, CH), 3.6 (broad s, 2, ArNH ₂ ),
_{3.35 (s, 2, ArCH 2} ), 4.7 ( broad _{s, 4, NH 2),} 7.0 (s, 2, ArH). In a similar manner, VI (R ₉ = SCH ₃ , 1.56 g, 10.0
mmol) with V (R ₄ = H, R ₅ = R ₆ = CHMe ₂ ,
NR ₇ R ₈ = piperidino, 3.29 g, 12.0 mmol
1) to give the title compound (1.41 g, 41%)
I got Under the same conditions, VI (R ₉ = SC
H ₃ , 1.56 g, 10.0 mmol) was converted to V (R ₄ =
_{H, R 5 = R 6 =} CHMe 2, R 7 = R 8 = CH 3,
(2.81 g, 12.0 mmol) to give the title compound (0.97 g, 28.4%).

Example 6 Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropylbenzyl) pyrimidine Methyl cellosolve (10 ml) and water (0.5 ml)
VII (R ₄ = H, R ₅ = R ₆ = CHMe ₂ , R ₉
= SCH ₃ , 0.50 g, 1.45 mmol) was refluxed with T-1 Raney nickel (3 g) 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 1
77-180 ° C.

EXAMPLE 7 2,4-Diamino-5- (4-amino-3,5-diiso
Preparation of propylbenzyl) -6-hydroxypyrimidine VI.H in ethylene glycol (75 ml)_TwoO (R
₉= OH, 1.44 g, 10.0 mmol), V (R_Four
= H, R_Five= R₆= CHMe_Two), NR₇R₈= Morpho
Reno, 3.32 g, 12.0 mmol) and p-tolu
Ensulfonate monohydrate (0.19 g, 1.0 m
mol) solution at 133-138 ° C. for 4.5 hours
did. The solvent is distilled off under vacuum and 3N hydrochloric acid (20 m
l) was added to the residue. The resulting hydrochloride is isolated and dissolved in water.
And neutralized by the addition of concentrated ammonium hydroxide.
Gave the title compound (2.36 g, 74.9%). table
The title compound was purified by recrystallization from ethanol
(1.44 g, 45.7%). ¹1 H NMR (DMSO
-D₆): Δ 1.05 (d, 6, CH_Three), 2.90
((M, 2, CH), 3.30 (s, 2, ArC
H_Two), 4.15 (broad s, 2, ArNH_Two),
5.45 (broad s, 2, NH_Two), 4.15 (Bro
Mode s, 2, NH_Two), 6.80 (s, 2, ArH),
9.90 (s, 1, OH). The title compound is, for example, English
As described in U.S. Pat. No. 1,542,804, methanes
VII (R₉= OSO_TwoMe)
VII (R
₉= H) by a continuous reaction to obtain VII (R ₉= H)
Can be converted.

Example 8 Preparation of 2,4-diamino-5- (4-amino-3,5-diisopropylbenzyl) pyrimidine VI (R ₉ ＨH,
1.10 g, 10.0 mmol), V (R ₄ = H, R _{5
= R 6 = CHMe 2, NR} 7 R 8 = morpholino, 3.3
A solution of 2 g, 12.0 mmol) and p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) was heated at 150-160 ° C. for 5.5 hours. The solvent was distilled under vacuum and 3N hydrochloric acid (20 ml) was added to the residue. The resulting solution was washed with methylene chloride,
It then evaporated to an oil, which crystallized on standing. The crystals were triturated with isopropanol, filtered and dried to give the hydrochloride of the title compound (1.51 g, 45%).
It was recrystallized from ethanol (1.04 g, 68.
9%). Addition of 3N sodium hydroxide to an aqueous solution of the hydrochloride (0.74 g, 2.20 mmol) provided the title compound (0.50 g, 76%). ¹ H NMR (DM
_{SO-d 6): δ1.15 (} d, 12, CH 3), 2.
95 (m, 2, CH), 3.50 (s, 2, ArC
H _2), 4.50 (broad s, _2, ArNH 2),
6.15 (broad s, 2, NH ₂ ), 6.55 (broad s, 2, NH ₂ ), 6.80 (s, 2, ArH),
7.40 (s, 1, pyrimidine 5-H). Melting point 179-
182 ° C.

Example 9 Preparation of 5-dimethylaminomethyluracil hydrochloride Uracil (56.05 g, 0.50 mol) was added to water (1
Dimethylamine hydrochloride (81.55 g,
1.0 mol) and 37% aqueous formaldehyde (6
(1 ml, 1.0 mol) for 2 days. The solvent was evaporated and the product was triturated with methanol. After filtration and drying, the title compound was isolated (80.6 g, 7
8.3%). ¹ H NMR (DMSO-d ₆ + D
₂ O): δ 2.90 (s, 6, NMe ₂ ), 4.10
_{(S, 2, NCH 2)} , 7.95 (s, 1, uracil -
6H).

Example 10 5- (4-amino-3,5-diisopropylbenzyl)
Preparation of uracil 5-Dimethylaminomethyluracil hydrochloride (10.28 g, 50.0 mm) in ethylene glycol (75 ml)
ol) and 2,6-diisopropylaniline (10.
64 g, 60.0 mmol) in a mixture of 134-137.
Heated for 4.5 hours. After cooling, the title compound was filtered, washed with ethanol and dried (5.55)
g, 37%). A second group was obtained on standing from the mother liquor (3.24 g, 21.5%). The two groups were combined and recrystallized from methanol to give the purified title compound (5.84 g, 38.8%). Elemental analysis: C ₁₇ H ₂₃ N ₃ O ₂ Calculated: C 67.75; H 7.69; N 13.94 Measured: C 67.59; H 7.75; N 13.88 The title compound is, for example, British Patent No. 875 No. 562 or 1,132,082, or VII (R ₄ア ミ ノ H, R ₅₎ via successive halogenations and aminations as described in German Offenlegungsschrift 2,258,238.
= R ₆ = CHMe _2, it may be converted R ₉ = H) in.

EXAMPLE 11 Preparation of 2,4-diamino-5- (4-amino-3,5-dimethoxybenzyl) pyrimidine from 2,4-diamino-5-cyanopyrimidine in British Patent 1,413,472 2,4-diamino-5-hydroxymethylpyrimidine (4.30 g, 30.0 mmol), 2,6-dimethoxyaniline (5.05 g, 33.0 mmol) prepared as described, acetic acid (60 ml) and concentrated A mixture of hydrochloric acid (4.2 ml) was refluxed for 4.5 hours, cooled and filtered to give the hydrochloride salt of the title compound (7.13 g, 76.2%). The salt was dissolved in water and the solution was 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%). Elemental analysis: C ₁₃ H ₁₇ N ₅ O ₂ Calculated: C 56.72; H 6.22; N 25.44 Measured: C 56.63; H 6.29; N 25.39

Formula I prepared according to a variant (i) of the process
Other compounds of II are illustrated in Table 1.

[Table 1]

5- (4-amino-3,5-dimethoxybenz)
5-((dimethylamino) methyl] uracil hydrochloride [Ross (B. Ro) in 50 ml of ethylene glycol under nitrogen ) -2,4- (1H, 3H) -pyrimidinedione under nitrogen.
th), JZ Strelitz and Hawkman (BS Hauckman), The Journal, Ob, The, Medical, Chemistry (J.
Med. Chem. ), 23 , 379 (1980)] 1
0.04 g (49 mmol) and 2,6-dimethoxyaniline [melting point: 73 to 74.5 ° C .; 2,6-dimethoxybenzoic acid to give an organic reaction (Org.
Reactions), 3 , 330 (1946)] 7.48 g (49 mmol) of the mixture was heated at 145 ° for 5 hours. The mixture was cooled and the precipitated solid was collected, suspended in 300 ml of boiling ethanol and collected to give 3.91 g (29%) of the title compound.
%); Melting point 243-245 [deg.] C (decomposition). Elemental _{analysis: C 13 H 15 N 3 O} 4 · 1/4 H 2 O Calculated: C55.41; H5.54; N14.91 measurements: C55.46; H5.54; N14.94 second 2.0 g (15%) were obtained by concentration of the ethanol extract.

5- (3,5-dimethoxy-4-dimethyl)
Aminobenzyl) -2,4- (1H, 3H) -pyrimidi
Njion 88% formic acid (70 ml) solution of 5- (4-amino-3,5
To a solution of -dimethoxybenzyl) 2,4- ( 1H , 3H ) -pyrimidinedione (5.4g, 19.5mmol) was added 37% formaldehyde (1.75g).
After refluxing for 18 hours, the reaction mixture was cooled and concentrated H
2 ml of Cl were added. The solution was evaporated and the residue was dissolved in 200 ml of water. Neutralization of this solution with 5N sodium hydroxide gave 5.25 g (89%) of the title compound; mp 228-230 ° C (dec). Elemental analysis: C ₁₅
H ₁₉ N ₃ O ₄ · 0.1H ₂ O Calculated: C55.66; H6.30; N13.68 Measured: C58.55; H6.30; N13.69

2,4-dichloro-5- (3,5-dimethoate
(X-4-dimethylaminobenzyl) pyrimidine phosphoryl chloride in 100 ml of 5- (3,5-dimethoxy-4-dimethylaminobenzyl) -2,4-
5.02 g of ( 1H , 3H ) -pyrimidinedione (1
6.4 mmol) was heated at reflux for 90 minutes.
Excess POCl ₃ was removed in vacuo, and the residue was dissolved in dichloromethane and washed with neutral aqueous sodium bicarbonate solution followed by water. The solution was dried over MgSO ₄ and then passed through a silica gel column, dichloromethane:
Eluted with methanol / 19: 1. The fractions containing the product were combined and concentrated to an oil; 3.75 g (67
%). The structure was confirmed by NMR.

2,4-diamino-5- (3,5-dimethoate
2,4 -dimethylaminobenzyl) pyrimidine 2,4 in 200 ml of ethanol saturated with ammonia
3.47 g of dichloro-5- (3,5-dimethoxy-4-dimethylaminobenzyl) pyrimidine (10.1 mm
ol) was heated in an autoclave at 150 ° for 8 hours. The solvent was removed in vacuo and the residue was triturated with water and collected. This was dissolved in dichloromethane: methanol / 4: 1, adsorbed on silica gel and placed on top of a silica gel column. Elution with the same solvent gave 2.27 g (74%) of the title compound. One part was converted to the dihydrochloride salt by recrystallization from 95% ethanol with concentrated HCl; mp 228-230 ° (dec). Elemental analysis: C ₁₅ H ₂₁ N ₅ O ₂ .2HCl.H ₂ O Calculated: C 45.69; H 6.39; N 17.76; C
117.98 Found: C 45.70; H 6.40; N 17.77; C
117.86

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Jillon Fletted Eday The Third, Chapel Hill, North Carolina, United States 127 Boxes, Route 6 (72) Inventor Thomas Lanii Henderson, Raleigh, North America, United States 181 Box, Routes 8

Claims (1)

(57) [Claims] 1. A compound of the formula (VIII) Wherein R ⁴ is selected from hydrogen and C _1-4 alkyl, and R ⁵ and R ⁶ are selected from halogen, C _1-4 alkyl and C _1-4 alkoxy and their acid additions salt.