DE2214474A1 - 1-Benzyl-substituted tetrahydro-2 (1H> pyrimidones and process for their preparation - Google Patents

Description

DR. ING. F. WUESTHOFF DR. E. τ. PECH ^ IANN DR. ING. D. BKHRENS DIPL. ING. R. G OETZ PATENT LAWYERS

22H474

8 MUNICH SWEEPER HATE TIHTO »(0811) 60 30 TKLXX 3 S-Ii 070

TELKORAKUK I MOIICTPiTIST

1A-4-1 193

Description of the patent application

MORTON-NORWICH PRODUCTS, INC. 17 Eaton Avenue, Norvd.cn, New York 13815, U.S.A.

concerning:

"In the 1-position benzy _n l3ubstituierte l'etrah.ydro-2 (1H) -pyrimidone and methods for their Herstellun g"

The invention relates to those which are benzyl-substituted in the 1-position Tetrahydro-2 (iH) -pyrimidone of the general formula:

(D

209841/1194

wherein H, if it is in the 4-position, is a lower alkyl group, hydrogen, a carbomethoxy, carboxy, carboxyamido, dimethylamine or aminomethyl group or, if it is in the 3-position, a trifluoromethyl group, while R,. stands for a phenyl radical or hydrogen, but where R and R. do not mean hydrogen at the same time.

The compounds of the invention have one on the Central nervous system attacking pharmacological activity. In animals they show when administered orally ant! convulsive effect and act as a tranquilizer. Their anticonvulsant effect can be demonstrated by the suppression of van induced by pentylenetetrazole Cramps in mice. An oral dose of 200 mg / kg of one of the compounds according to the invention suppresses in mice, who received 45 mg / kg pentylenetetrazole intravenously, the convulsive effect of pentylenetetrazole. Also an oral dose of 200 to 1600 mg / kg of these compounds has Mice have a sedative effect that results from muscle relaxation and decreased spontaneous activity.

Intermediate products in the preparation of the compounds according to formula I are compounds of the general Formula:

O = C

209841/1194

wherein R and R ,. have the same meaning as in formula I.

The preparation of the compounds according to the invention takes place according to the following scheme:

O = C.

.HCl

ArCHoX O = C

In this scheme, E and R have _x . the above meaning, Ar is an optionally substituted phenyl radical and X is a halogen atom. The process is carried out in the presence of solvents which are inert towards the reactants, such as methanol or dimethylformamide. Additives which promote the reaction, such as potassium carbonate and alkali iodides, are advantageous in that they cause the condensation between the hydroxypyniridine and the optionally substituted benzyl halide. The hydrogenation is preferably effected with the aid of platinum oxide or palladium on carbon in catalytic amounts.

209841/1 194

The examples explain the process according to the invention in more detail.

B is ρ i el 1

The preparation of methyl p- / ~ "(hexahydro-2-oxo ~ 1-pyrimidinyl) methyl__7benzoate took place in the following steps: A. Methyl p - / "(2-oxo-i-pyrimidinyl) methyl 7benzoate

74 g (0.56 mol) of 2-hydroxypyriinidine hydrochloride in 800 ml of methanol were treated with 152 g (1.12 mol) £ ₂ ^C0 3> 46 g (0.28 mol) KI and 127 g (0.56 mol) Methyl p-bromomethyl benzoate. The reaction mixture was refluxed with stirring for 24 hours and filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in 500 ml of water and extracted with CHCl 2. The CHCl ₇ extract was dried over MgSO ^ overnight, filtered and evaporated to dryness. 46 g of ester were obtained as a light yellow pesticide with a melting point of 170 ° to 179 °; yield

The aqueous phase from the extraction was adjusted to a pH of 3 to 4 with 100 ml of concentrated hydrochloric acid and gave 74 g of ceric acid with a melting point of 242 to 249 °; Yield 57 % «

The ester was recrystallized from 500 ml of acetonitrile and then melted at 188-189 ° C; Total yield 28 s (20%).

;: 0 9 8 k 1 / Ί 1 9 U

22UA74

B. Methyl-p - ^ (hexahydro-2-oxo-1-pyriiaidinyl) methyl) _7 ~ benzoate

Of the substance obtained under A, 18 g (0.074 mol) together with 150 ml of methanol and 0.2 g of PtÖ £ in a Introduced pressure vessel of 0.5 1 and at a pressure

ο
of 8 kg / cm of hydrogenation. The water absorption was 10. ^ (theory? 13 #) in 0 _$ 6 hours. The reaction mixture was then diluted with 100 ml of methanol, heated , decolorized and filtered. The KJ.trat was evaporated under reduced pressure and gave 18 g of a light yellow solid with a melting point of 176 ° to 179 °? Yield 100%.

The product was recrystallized from 1.2 1 acetonitrile umkristallisi @ rt ₉ washed with acetonitrile and ether and dried; Jp. 177 to 180 °; Yield; 10 g (56%).

Analysis for C ^,

O , 89 6th H N , 29 about « 62 8 87 6th , 50 11 , 39 found 62 , 48 11

Example 2

The preparation of p- / ~ (hexahydro-2-oxo-1-pyrimidinyl) -methyl_7benzamide took place in the following steps: A. p- / ~ (2-Oxo-i-pyrimidinyl) iaethyl 7benzamide

A solution of 26 g (0.11 mol) of the compound A from Example 1 in 790 ml of methanol and 910 ml of concentrated ammonium hydroxide was stored for 4 days at room temperature stirred and then filtered. The white crystalline solid was washed with water and air-dried

209841/1194

22HA74

netj pp 252-254 °; Yield 8g (32%). .

The filtrate was evaporated to dryness and gave 16 g of a light yellow solid with a melting point of 241 up to 244 °; Yield 64%.

B. p- / ~ (Hexahydro-2-oxo-1-pyrimidinyl) methyl 7benzamide

In a pressure vessel of 0.5 1, 24 g (0.1 mol) of the above substance A, 150 ml of methanol and 0.5 g

ο PtO ₂ subjected to hydrogenation under a pressure of 2.8 kg / cm. The hydrogen uptake was 17 # (theory: 18 / $ in 4 hours. The reaction mixture was heated, decolored and filtered. The filtrate was evaporated under reduced pressure and gave 24 g of a white crystalline body with a melting point of 184 ° to 187 °; yield 100%. .

The product was _{recrystallized from 3 5} 7 1 acetonitrile, washed with acetonitrile and ether and dried; Mp 194-210 °; Yield 18g (75%).

Analysis for ^ p1552

found

B e is ρ i el '*>

σ , 78 6th H N 02 61 , 05 6th , 48 18 63 62 , 67 17,

The preparation of 1-diphenylethyl-3,4,5,6-tetrahydro-2 (1H) pyriinidone took place in the following steps: A. 1 ~ Diphenylmethyl-2 (1H) pyrimidone

93 6 (0.7 mol) 2-hydroxypyrimidine hydrochloride in 450 ml

209841/1194

Dimethylformamide was treated with 194 g (1.4 mol) of K ₂ GO ₅ , 58 g (0.55 mol) of EJ and 142 g (0.7 mol) of benzhydryl chloride with vigorous stirring. The reaction mixture was heated to 100 ° within half an hour and then kept at 110 ° for 5 hours. The hot slurry was poured into 5 liters of ice water, stirred for 2 hours and filtered. The white crystalline solid was washed with water and air dried. Mp 186-194 °; Yield 65 6 (36%).

The product was recrystallized from 200 ml acetonitrile, washed with acetonitrile and ether and dried} mp. 198 to 200 °; Yield 28g (15%).

B. 1-Diphenylmethyl-3 »4,5 _} 6-tetrahydro-2 (iH) -pyrimidone

15 g (0.057 mol) θ-irae «1-Diphenylmethyl-2 (iH) pyrimidon $, 150 ml of methanol and 0.6 g of PtO ₉ were in a pressure

Subjected vessel of 0.5 1 at 3 kg / cm pressure of hydrogenation. The hydrogen consumption was 136 τ £ (theory:.. 144 ^ j Qin 1.5 hours, the Reduktionsgeaiscii was diluted with 250 ml acetonitrile, heated, decolorized and filtered Evaporation of the filtrate to dryness under reduced pressure erhäeLt 15 g of a non-white crystalline solid (yield 100%).

The product was recrystallized from 800 ml of acetonitrile, washed with acetonitrile and ether and dried and then ijchjüolz at 217 to 221 °; Yield 12g (80 %).

■ i J ¹ J 8 A Ί / Ί 1

C. , 66 H N ber. 76 , 90 6.81 10.52 found 76 6.82 10.70

Analysis for

Example 4

The preparation of 1- (p-octylbenzyl) -3,4,5,6-tetrahydro-2 (iH) pyrimidone took place in the following stages:

A. p-Octylbenzyl alcohol

59 g (0.25 mol) of p-octyl benzoic acid in 750 ml of hexane under a stream of dry nitrogen for half an hour under vigorous stirring at 15 to 20 ⁰ C treated with 610 ml DiBaIH (0.756 mol) in 270 ml of hexane. The reaction mixture was kept at 10 to 1.3 hours, then treated with a solution of 130 ml of methanol in 210 ml of water at 15 "to 25 ° and then with 156 ml of HCl at 15 to 25 ° and finally with 240 ml of water. the separated organic layer was dried overnight over MgSO ^ and filtered. the JFiItrat gave after evaporation to dryness 41 g (25 ⁰ Zo) of a light-colored semi-solid product.

B. p-Octylbenzyl chloride

41 g (0.19 mol) of the substance obtained above under A in 300 ml of chloroform were _{treated at -10 to 0 ° with 69 ml (118 g, 0.95 mol) of SOCl 2} , whereupon the mixture was treated within half an hour Allowed to warm to 20 C and refluxed it for a further 1.2 hours. After evaporation under reduced pressure, the solution gave 44 g of p-octylbenzyl chloride (yield 98%).

C. 1- (p-Octylbenzyl) -2 (iH) -pyrimidone

23ι9 g (0 »18 mol) of 2-hydroxypyrimidine hydrochloride in 600 ml of methanol were treated with 38.2 g (0.36 mol) of Na ₂ CO ₅ , 13i5 g (0.09 mol) of NaI and 43.5 S (0, 18 mol) of substance B. The reaction mixture was refluxed for 20 hours and then evaporated to dryness under reduced pressure. The residue was stirred with 500 ml of water and 800 ml of chloroform. The chloroform extract was washed with 300 ml of water, dried over MgSO ^ for 2 hours and filtered. After evaporation to dryness under reduced pressure, the filtrate gave 48 g of a cream-colored solid with a melting point of 105 ° to 112 ° (yield 89%).

The crude product was recrystallized from 150 ml of acetonitrile and then melted at 118 to 120 °; yield 34 g (63%).

D. 1- (p-Octylbenzyl) -3,4,5,6-tetrahydro-2 (iH) pyrimidone

20 g (0.067 mol) of substance C, 150 ml of methanol and 0.3 g of FtOo were in a pressure vessel of 0.5 l subjected to hydrogenation at a pressure of 2.3 kg / cm. The theoretical amount of hydrogen was absorbed within 22 hours. The reduction mixture was then filtered and evaporated to dryness. The residue was taken up in 35 ml of acetonitrile, cooled, filtered and washed with acetonitrile and ether. After drying, 14.9 g of a white crystalline remained Solid left that melted at 87-90 °} yield 74%.

209841/1194

22HA74 - ίο -

CHN analysis for C ^ JL ^ ₂ ⁰ : calc. 75.4-5. 10.00 9.28

found 75.48 10.01 8.97

example

1- (m-Trif luorme thylbenzyl) -3,4,5,6-tetrahydro-2 (iH) -pyrimi do

A. 1- (m-Trifluoromethylbenzyl) -2- (iH) -pyrimidone

17.0 g (0.128 mol) of 2-hydroxypyrimidine hydrochloride in 75 ml of methanol were treated with 35.5 g (0.258 mol) of K ₂ CO ₅ , 10.6 g (0.064 mol) of EJ and 25.0 g (0.128 mol) α-Cülor-3-trifluoromethyltoluene. The reaction mixture was refluxed for 20 hours and evaporated to dryness under reduced pressure. The residue was taken up in 200 ml of water and extracted with 250 ml of chloroform. The chloroform extract was washed with water, over MgSO. dried and filtered. After evaporation under reduced pressure, the filtrate gave 31 g of a sticky white pesticide (yield 95%). The crude product was recrystallized in 50 ml of toluene and then melted at 85 to 88 °; Yield 12.9g (40%).

B. 1- (m-Trifluoromethylbenzyl) -3,4,5,6-tetrahydro-2 (iH) ~ pyrimidone

12.9 g (0.051 mol) of 1- (m-trifluoromethylben?, Yl) -2 (iH) -pyrimidone, 150 ml of methanol and 0.3 g of PtO ₀ were in a pressure vessel of 0.5 l at a pressure of 2 , 8 kg / cm ^t "of hydrogenation. The hydrogen uptake was 111 ^ (theory: 102 tf) in one hour. Bas Re-

209841/1194

221U74

The production mixture was heated, decolorized, filtered and evaporated to dryness under reduced pressure. This gave 12.9 g of an off-white solid which melted at 93 to 97 ° G; Yield 99 %.

the product has a melting point of 97 to 99 ° {Yield: 8.6 g

After recrystallization from 300 ml of acetonitrile, the pro * (66%).

Analysis for

C. , 81 H N , 85 ber. 55 , 86 5.07 10 , 91 found 55 5.07 10

Example 6

The production of 1 - (p-methylbenzyl) 3,4,5,6-tetra hydro-2 (iH) pyrimidone takes place via the following steps A. 1- (p-methylbenzyl-2 (iH) pyrimidone

39.9 g (0.3 mol) of 2-hydroxypyrimidine hydrochloride in 150 ml of methanol were treated with 82.9 g (0.6 mol) of K ₂ CO ₃ , 24.9 g (0.15 mol) of KI and 44.9 g (0.3 mole) of p-methylbenzyl chloride. The reaction mixture was stirred under reflux for 20 hours and then evaporated to dryness under reduced pressure. The residue was taken up in 500 ml of water and extracted _{with 1.7 l of CHOl 7.} The chloroform extracts were dried over MgSO 4 overnight, filtered and evaporated to dryness under reduced pressure.

37 g of crude product were obtained, which was recrystallized from 100 ml of acetonitrile and then melted at 148 ° to 150 °;

209841/1194

22U474

Yield 26g (43%).
B. 1- (p ~ methylbenzyl) -3,4,5,6-tetrahydro-2- (1H) pyrimidone

14 g (0.07 mol) of 1- (p-methylbenzyl) -2 (iH) pyrimidone / 150 ml of methanol and 0.3 g of PtO ₀ were hydrogenated in a pressure vessel of 0.5 l at 2.8 kg / cm subject. The hydrogen on would take was 163 ^ (theory 140 # in 3 hours, the reduction mixture was warmed, filtered and evaporated under reduced pressure to give then 14.0 of a non g off-white crystalline Peststoffs melting at 119 to 122 °; yield. 98%.

After recrystallization from 40 ml of acetonitrile, the product melted at 126 ° to 128 °; Yield 10.5g (73%).

CHN

Analysis for C ₁₂ H ₁₆ N ₂ O: calcd. 70.56 7.90 13.72

found 70.83 7.89 13.78

Example l '?

The preparation of p - / "" (Hex & faydro-2-oxo-1 ~ pyrimidinyl) methyl_7-benzoesäare took place in the following stages:

25 S (0.15 Hol) p- / ~ ( _i ° -0xo-1-pyrimidinyl) methyl_7benzoic acid, 150 ml of methanol and 0.4 g of PtO ₀ were in a pressure vessel of 0.5; 1 subjected to hydrogenation at 2.8 kg / cm. The hydrogen uptake was 23 ¥ (theory: in 5> 5 hours. The reduction mixture was heated, decolorized, filtered * and evaporated to dryness under reduced pressure. The almost white pesticide was taken up in 500 ml of water. The pH of the solution was determined gutm rait 125 6 NaHCO, adjusted to 7 to 8,

2US841 / 1194

C. , 53 6th H N 96 ber. 61 , 64 6th , 02 11 80 found 61 , 02 11

- 13 -

whereby everything dissolved. The solution was filtered, the pH value was adjusted to 3 to 4 with 160 ml of acetic acid and afterwards. 1 hour of stirring filtered. The white crystalline solid was washed with 200 ml, first in air and then in an oven at 60 ^α 6 hours dried and then melted at 227 230 ⁰ Oj yield 25 g (72%).

Analysis for

Example 8

1- (p-aminomethylbenzyl) -3,4,5 »6-tetrahydro-2 (iH) -pyrimidone hydrochloride was prepared in the following stages:
A. 1- (p-Cyanobenzyl) -2 (iH) -pyrimidone

37 »5 g (0.28 mol) of 2-hydroxypyrimidine hydrochloride in 180 ml of dimethylformamide were treated with 78 g (0.57 mol) of K ₂ CO ₅ , 23.0 g (0.14 mol) of KI and 55 g (0, 28 moles) of a-bromo-p-toluene nitrile. The suspension was heated with stirring to 100 ° over the course of 0.2 hours, to 110 ° over the course of a further 0.2 hours and to 115 ° over the course of a further 0.2 hours and held there for 31/2 hours. After concentrating the reaction mixture under reduced pressure, a residue was obtained which was taken up in 200 ml of water and extracted with 500 ml of chloroform. The chloroform extract was washed with water, dried over MgSO ^ overnight, filtered and brought to dryness under reduced pressure.

2 0 9 8 A 1/1 1 9 4

22U474

vaporized there were 69 g of a light brown viscous get oil.

Recrystallization of the oil from 100 ml acetonitrile, Vaschen with acetonitrile and Ither and drying, to obtain a solid which melts at 184 to 187 ⁰ C. Yield 15 6 (25%).

B. 1- (p-Aminomethylbenzyl) -3,4,5,6-tetrahydro-2 (iH) -pyrimidone hydrochloride

11 g (0.052 mol of 1- (p-cyanobenzyl) -2 (iH) -pyrimidone in 150 ml of methanol were mixed with 10 g of 5 % Pd / C (50 % H ₀ O) and 10 ml of HCl in methanol, whereupon they at 2.8 kg / cm 2 were subjected to hydrogenation . The hydrogen uptake was 24 # (theory: 23 # 0 in hours. The reduction mixture was heated, decolorized and filtered. The filtrate was dissolved in HCl in

pH

Methanol adjusted to \ 3 to 4 and evaporated to dryness under reduced pressure.

12 g (92% yield) of a sticky crystalline solid were obtained which, after recrystallization from 55 ml of methanol, washing with methanol and ether and drying, melted at 258 ° to 261 °; Yield 2.7 g (21%).

By concentrating the filtrate from the recrystallization an additional 2.3 g (18%) of the desired product were obtained, which melted at 251 to 254 °. After recrystallization from methanol. (10 ml / g) had the product

209841/1194

a m.p. from 264 to 266 °,

Analysis for Ο _/ . _Ρ Η ^ ₇ Ν ^ Ο HCl: calc. '" ^{P found} :

example

σ , 35 H N , 4-3 56 , 44 7.09 16 , 29 56 7.16 16

The preparation of 1- (p-Dimethylaminobenzyl) -3,4-, 5,6-tetrahydro-2 (1H) pyrimidone took place in the following stages:

A, p-dimethylaminobenzyl chloride hydrochloride

To a solution of 15.2 g (0.1 mol) of p-dimethylaminobenzyl alcohol in 75 ml of chloroform, 22 ml (35.7 g, 0.30 Mol) thionyl chloride added. The solution was then stirred for a further 4-5 min at 5 °, 150 ml of toluene being added to it became. The supernatant liquid was poured off and the oil was washed twice with 100 ml of toluene each time.

B. 1- (p-Dimethylaminobenzyl) -2 (iH) pyrimidone

The toluene-insoluble residue of A was dissolved in 170 ml of methanol and the solution was cooled to 10 °, followed by 7.0 g of KI _5, 13.3 g (0.1 mol) of 2-hydroxypyrimidine hydrochloride and 4-1.4 with stirring - g (0.3 mol) of potassium carbonate were added. The mixture was stirred for 4-5 min at 10 to 15 ° and then for a further 2 1/2 hours at normal temperature.

The solvents were driven off in vacuo and the return

2 uy84 1/1194

221U74

stood for 30 min vigorously stirred with 30 ml of water. After filtering through a medium filter made of sintered Glass, washing 4 times with 50 ml each cold Water and drying in air gave 11.88 g of crude pyrimidone, read after recrystallization from absolute Ethanol melted at 173-175 °.

C. 1- (p-Dimethylaminobenzyl) -3,4,5,6-tetrahydro-2 (iH) -pyrimidone

11.88 g (0.052 mol) of the above substance B in 150 ml of methanol were shaken with hydrogen for 1 1/2 hours in the presence of 0.2 g of platinum oxide. Hydrogen uptake; 73 τ ^; Theory: 104 Φ . The catalyst was filtered off and washed 4 times with 15 ml of methanol each time. The filtrate and the washing liquid were evaporated to dryness together.

After recrystallization of the residue from 50 ml of acetonitrile 4.35 g of the above compound were obtained, which melted at 141 to 144 °; Yield 36%.

Analysis for

C. , 92 8th H ^- 18th N ber. 66 , 21 8th , 21 18th , 01 found 67 , 27 , 12

PATENT CLAIMS:

209841/1194

Claims (11)

PATENT CLAIMS 1-Benzyl-substituted tetrahydro-2 ("IH) -pyrimidones the general formula: (D wherein R, if it is in the 4-position, a lower alkyl group, a hydrogen atom, a carbomethoxy, Garb ^ oxy, carboxamido, dimethylamine or aminomethyl group or, if it is in the 3-position, a trifluoromethyl radical and R ^ stands for a phenyl radical or a hydrogen atom, but R and R ₇ J cannot simultaneously stand for hydrogen. 2) Compounds according to claim 1, characterized in that R is a 4-methyl group and R, - are hydrogen. 3) Compounds according to claim 1, characterized in that R is a 3-trifluoromethyl group and R. are hydrogen 4 ·) Compound according to claim 1, characterized in that R is a 4-octyl group and R ^ are hydrogen. 20984 1/1194 5) A compound according to claim 1, characterized in that g e k e η η shows that R is a hydrogen atom and R "j is a phenyl radical. 6) Compound according to claim 1, characterized in that R is a 4 ^ -Carboxymethoxy group and B ^ are hydrogen. 7) connection according to claim 1, characterized indicates that R is a 4-carboxy group and hydrogen. 8) Compound according to claim 1, characterized in that R is a 4-dimethylamino group and R ^ are hydrogen. 9) Compound according to claim 1, characterized in that R is a 4-carboxyamido group and Ry. Are hydrogen. 10) Compound according to claim 1, characterized in that R is a 4-aminomethyl group and Ryj are hydrogen. 11) Process for the preparation of the compounds according to claim 1 or according to one of claims 2 to 10, characterized in that first a compound of the formula: 20984 1/1194 O = C. ^(ΙΙ) wherein R and It. are those of the respective preceding claim have the corresponding meaning, and this intermediate in the presence of platinum oxide or hydrogenated palladium on carbon in a catalytic amount. 209841/1194