AU595105B2 - Preparation 2,4-diamino-3-oxy-6-piperidyl pyrimidine - Google Patents

Description

AUSTRALIA

PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Form Short Title: Int. Cl: Application Number: Lodged: 5951 Complete Specification-Lodged: Accepted: Lapsed: Published: rt U I t St j o Priority: Related Art: [This documetnt conta:n i arnedrdments made u.

Section 49 and is corrcc t, printing.

TO BE COMPLETED BY APPLICANT Name of Applicant: FARMOS-YHTYMA OY Address of Applicant: TENGSTROMINKATU 6-8

TURKU

FINLAND

Actual Inventor: Address for Service: CLEMENT HACK CO., 601 St. Kilda Road, Melbourne, Victoria 3004, Australia.

*t Complete Specification for the invention entitled-PREPARATION S 2,4-DIAMINO-3-OXY-6-PIPERIDYL PYRIMIDINE The following statement is a full description of this invention including the best method of performing it known to me:- Farmos Group Ltd., P.O.Box 425, SF-20101 Turku, Finland A method for the preparation of a therapeutically active compound This invention relates to a method for the preparation of 2,4diamino-3-oxy-6-piperidylpyrimidine or minoxidil. Minoxidil, which has the formula

NH

2 N NH 2 I t is useful as an antihypertensive agent.

Methods for the preparation of minoxidil have been described for o I@ example in the German patent publication DOS 1620649, the US S* patents 3910928 and 3644364 and the British patent application GB 2032434A.

0 0 The British patent application GB 2032434A discloses inter alia on. a method for the preparation of minoxidil, where 6-hydroxy-2,4diaminopyrimidine is reacted with a sulfonyl halide to give a o compound according to formula (II) NH N I NH 2 N (II)

OSO

2

R

where R is a Cl-6 alkyl group or R is where X is CI_ 6 alkyl, halogen or nitro and n is Ct. 2 This compound is then reacted with a peracid, e.g. with mchloroperbenzoic acid to give a compound according to formula (III), where R is as above

(III)

which finally is reacted with piperidine to minoxidil.

The oxidation step can also be performed so that instead of using m-chloroperbenzoic acid as oxidizing agent magnesium monoperoxyphthalate (MMPP) hexahydrate, which has the formula C C

I',

C C 4 9C t I tC a C t o0 8r 1 0 00 0 o 80 S0 0 00 Mg 2 x 6 H 2 0 is used.

A compound of formula (III) is obtained as reaction product.

We have surprisingly found that compound (III) can be activated by reacting it with an acid halide (IV) or acid anhydride or alkylchloroformate (VI).

R-CO-Hal

R-CO-O-CO-R

Cl-COOR (R is as above, Hal halogen) The reaction product is a compound a mixture thereof

OH

Y-HN NH

ZN

OS0 2

R

(VII)

(IV)

(V)

(VI)

of formula (VII) or (VIII) or

(VIII)

(Y is COR or COOR and R is as above) UEPi 3depending on the reagent to be used.

The intermediates (VII) and (VIII) are novel compounds.

When compound (VII) or (VIII) or their mixture finally is reacted with piperidine, minoxidil is obtained at a substantially higher yield than when a compound of formula (III) is directly reacted with piperidine to minoxidil as disclosed in the British patent application GB 2032434A.

The compound of the general formula (III) is preferably reacted with an excess of acid halide, acid anhydride or alkyl chloroformate. According to a preferably method an excess of acetic cc Sacid anhydride is used either without any solvent or together with a solvent. Suitable solvents are for example alcohols as methanol or ethanol, ketones as methylethyl ketone or acetone, halogenated lower alkanes as dichlormethane, aromatic hydrocarbons as benzene or toluene, ethers as 1,4-dioxane, dimethyle formamide or tetrahydrofurane and organic acids as acetic acid.

The reaction can be carried out in the temperature range 0-100°C, preferably 20-50"C.

o a SThe compound of formula (VII) or (VIII) is preferably reacted with an excess of piperidine essentially in the same way as the o 0 compound (III) is reacted with piperidine according to the British patent application GB 2032434A.

a o As solvents can besides piperidine be used aromatic hydrocarbons 00 as benzene or toluene, halogenated lower alkanes as dichlormethane, alcohols as methanol or ethanol, ethers as 1,4-dioxane or tetrahydrofurane, ketones as acetone or methylethyl ketone.

The reaction temperature depends on the solvent used and the desired reaction time. The reaction can be carried out at a temperature of 0-110°C.

=1 =11 4 99' 9" 9 99 Co 99 99 99 99 990 99 99.. CO 990 99 99 9 a 99 990 Example a) 2-imino-3-ac etyloxy-4-(N-acetylamino)-6-( p-tolylsulfonyloxy) pyr imidime g (0,0337 mol) of 2, 4-diamino-3-oxy-6-(p-tolylsulfonyloxy)pyrimidine and 100 ml of acetone are mixed and cooled to To this mixture a solution of 5,5 g (0,07 mol) acetyl chloride dissolved in 20 ml of acetone is added dropwise. The stirring is continued at 0-5'C for 5 hours. Then 180 ml of water are added dropwise to the mixture which is stirred for 0,5 h. The separated crystals are filtered off and the precipitate is washed with water and acetone. 8,9 g (69 of pure 2-imino--3-acetyloxy-4-(N-acetylamino)-6-(p-tolylsulfonyloxy)pyrimidine are obtained. M.p. 180-185*C.

b) 2-imino--3-acetyl"oxy-4-(N-ac etylamino)-6-(p-tolylsulfonyloxy) pyr imidime g (0,067 mol) of 2,4-diamino-3-oxy-6-(p-tolylsulfonyloxy)pyrimidine and 200 ml acetic ac id anhydride are heated at 40-60% for 5 h. Excess of acetic acid anhydride is distilled off at reduced pressure. To the residue are added 100 ml of water, the mixture is stirred at room temperature for 1 h after which the separated crystals are filtered off and the precipitate washed with water until the filtrate is neutral. 24,4 g (95 of pure 2-imino-3-acetyloxy-4-(N--acetylamino)-6-(p-tolylsulfonyloxy)pyrimidine are obtained, m.p. 180-185'C.

1 11-NMR (DMSo-d 6 int.std. ThIS): 2,21 r3 2,32 s (3H1); 2,43 s 7,50 d 7,70 s (111); 7,99 d 10,6 (2H) 2~ 0 0 c) 2,4-diamino-3-oxy-6-piperidylpyrimidine 24 g (0,063 mol) of the compound prepared in step a) or b) and 240 ml piperidine are refluxed by cooling for 3 h after which piperidine is distilled off at reduced pressure. To the residue are added 100 ml of a 5 aqueous solution of sodium hydroxide and the mixture is stirred for 0,5 h at room temperature. The separated crystals are filtered off and the precipitate is washed with water and toluene. 11,2 g (85 of pure decomposing 2,4-diamino-3-oxy-6-piperidylpyrimidine, m.p. 255-260*C are obtained.

t 0 1 t ct 0 C 0 t 00 0* o 00c 0 00 0 9 0 oo oa o a o a 0 06 o o o a 0 00

Claims (3)

1. A method for the preparation of 2,4-diamino-3-oxy-6- piperidylpyrimidine or minoxidil, where the compound .1~L in which R is a C 1 6 alkyl group or where X is C 1 6 alkyl, halogen or nitro and n is 0-5, is reacted with a 0 0 a 00 a) an acid halide RCOHal which formul ae R is as the compound or an acid anhydride RCO-0-GO-R in defined above and Hal is halogen, to RCO-HI 0-COR RCO-LN NH- .'N SO 2 R ;02R whereby any of which or their mixture piperidine to minoxidil is reacted with or b) an alkyl chloroforniate Ci-COOR, where R is as above, to the compound JS02R whereby any of which or their mixture is reacted with ,piperidine to minoxidil. aao ttg~t' Z2~C) o 7

2. A compound of the formula iS02R where Y is hydrogen or COR and R is the same as in Claim 1.

3. A compound of the formula o 00 *t o -y rN SO 2 R i Ol where Y is hydrogen or COOR and R is the same as in Claim 1. t e t 0 a oo a oo eo o 06 Q oo 0 e DATED THIS 24TH DAY OF MARCH 1988 FARMOS-YHTYMA OY By Its Patent Attorneys: CLEMENT HACK CO. Fellows Institute of Patent Attorneys of Australia