CA1218378A - Preparation of novel 1-[2-carbethoxy 4- benzalkylamido phenoxy]3-amino 2-propanols useful in therapeutics - Google Patents
Preparation of novel 1-[2-carbethoxy 4- benzalkylamido phenoxy]3-amino 2-propanols useful in therapeuticsInfo
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- CA1218378A CA1218378A CA000449516A CA449516A CA1218378A CA 1218378 A CA1218378 A CA 1218378A CA 000449516 A CA000449516 A CA 000449516A CA 449516 A CA449516 A CA 449516A CA 1218378 A CA1218378 A CA 1218378A
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- benzamido
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
PATENT APPLICATION
entitled: Preparation of novel 1-[2-carbethoxy 4-benzalkylamido phenoxy]
3-amino 2-propanols useful in therapeutics ABSTRACT OF THE DISCLOSURE
Process for preparing compounds of formula:
entitled: Preparation of novel 1-[2-carbethoxy 4-benzalkylamido phenoxy]
3-amino 2-propanols useful in therapeutics ABSTRACT OF THE DISCLOSURE
Process for preparing compounds of formula:
Description
--I--The present invention relates to the preparation of novel derivatives of ~-benzalkylamido 2-carbalkoxy phenoxy amino-propanol of general forrnula (I) and ~o their acid addition salts. The derivatives in question present a highly original and very surprizing pharmacological profile since they are 5 endowed with diuretic properties associated, for certain, with ,B ~ blocking properties.
The present invention also relates to the process for preparing the novel intermediate compounds allowing synthesis of said products.
The novel compounds according to the invention belong to the group 10 constituted by the products of general formula (1) and their non-toxic acid addition salts COO Rl R ~ 2)n CONH~OCH2_1CH-CH2-NH R2 R' (I) In formula (1):
20 - R and R' may each designate an atom of hydrogen, an atom of halogen for examPle fluorine, a nitro group or alkyl or alkoxy radicals with Cl-C5, branched or not, or a SCH3 or ~3 grouF~;
- Rl represents a lower alkyl radical with I to 5 carbon atoms, branched or not, advantageously the ethyl radical;
25 - R2 represents a lower alkyl radical with I to 5 carbon atoms, straight or branched, and preferably the isopropyl radical or the terbutyl radical;
- n designates an integer less than 5, and preferably equal to 0 or 1.
The compounds according to the invention are synthesized by action of an NH2-R2 base (R2 being defined as hereinabove) on a compound of 30 formula (Il) without solvent or in a conventional organic solvent such as alcohols, at a temperature of between 20C and 150C.
8~78 ,COO ~
R ~3 (CH2~--CONH~ ~oc~2--C~H2 R' (Il) In formula (Il), R, R', Rl and n are defined as hereinabove.
The compounds of formula (Il) are generally obtained by reaction of a phenol of general formula (111) with an excess of epihalohydrin, particularly 10 epichlorohydrin or epibrornohydrin, in the presence of a catalyst such as benzyltrimethylammonium chloride, at a temperature ranging from ilOC
to 130C. This process yields perfectly crystallized compounds with better yields than the processes evoked hereinafter. The compounds of formula (Il) may also be obtained by reaction of the phenol of general formula (III) 15 with any epihalohydrin according to the conventional processes. The phenol of formula (111) will then be metalled by conventional metallation agents such as potassium hydroxide, sodium hydroxide, an alcoholate or sodium hydride in a dilute alcoholic, alcohoîic solvent or dimethylformamide (DMF) at a temperature of between 20C and 150C. However, these processes yield 20 products which are less well defined.
COO Rl R~(C~2) -- CO~H ~ OH
R' (111) In formula (III), R, R', Rl and n are defined as hereinabove.
The compounds of formula (III) are obtained in accordance with known processes of preparation consisting either in reacting the chloride 30 of the corresponding arylalkanoic acid with a 4-amino 2-carbalkoxy phenol in the presence of a base such as triethylamine in a solvent such as acetone or benzene, or in esterifying the corresponding acid (IV) in a sulfuric acid-alcohol medium.
.
~2~ 37~
~C~OH
R~_(CH2) -- CO~ OH
~, (IV) In formula (IV), R, R' and n are defined as hereinabove.
The addition salts of the compounds of formula (I) may be obtained by reaction of these compounds with an inorganic or organic acid in accordance 10 with a method known per se. Among the acids which may be used to this end, particular mention will be made of hydrochloric, hydrobromic, acetic, p-toluene sulfonic, methane sulfonic, oxalic, succinic, maleic, fumaric, cinna-mic, malic, aspartic, glutamic, ascorbic, N-acetyl aspartic, N-acetyl glutamic acids.
The novel compounds according to the invention are endowed with remarkable pharmacological properties and may be used in therapeutics for the treatment of hypertension since, most surprizingly, they present diuretic properties with, for certain of the products, /~1 blocking properties, and low toxicity. These remarkable characteristics seem to be due to the presence 20 in the molecules of the ester function in ortho position and of the amide function in para position.
In human therapeutics, the compounds of formula (I) and their non-toxic acid addition salts may be administered in particular by the oral route.
In that case, the use of gelatin-capsules or of tablets containing from 50 25 to 300 mg of active ingredient in association with a physiologically acceptable excipient is recommended. The compounds claimed present -the advantage of rendering treatment easier. On the other hand, with respect to the l3_ blocking/diuretic associations used in the treatment of hypertension~ the cornpounds of formula (I) have the advantage of single pharmacokinetics.
30 Angor pectoris and arrhythmia will be mentioned as other possible examples of indications.
Other features and advantages of the invention will appear more clearly on reading the following non-limiting examples of preparation given by way of illustration.
~ 8;37~3 The forrnulae corresponding to the Examples are given in the single Table at the end of the specification.
Example 1: 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula ll R = Fluorine in 4 position Rl C2H5 R' = H n = 0 In a flask, the rnixture of 34 g of 2-carbethoxy 4-(4-fluoro benzamido) phenol and 150 ml of epic:hlorohydrin is heated to 110C. 2.7 g of benzyltrimethyl ammonium chloride are then introduced. The reaction mixture is heated to reflux for 1/2 hr. then cooled. Once the temperature has dropped to 50C, 150 ml of water are added and the mixture is stirred well. The organic phase is decanted and the aqueous phase extracted twice with 50 ml ether. The organic phases are dried over magnesium sulfate then concentrated in vacuo.
The crude residue obtained crystallizes in 200 ml of ether to yield 22 g of 1-[2-carbethoxy 4-~4-fluoro benzamido) phenoxyi 2,3-epoxy propane melting at 115C.
Example 2: 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = Fluorine in 3 position Rl C2H5 R' = H n = 0 The rnodus operandi is identical to the one described in Example 1. From 50 g of 2-carbethoxy 4-(3-fluoro benzamido) phenol, 4 g of benzyltri-methylammonium chloride and 250 ml of epichlorohydrin, 24 g of 1-[2-carb-ethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane melting at 100C
are obtained.
Example 3: 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = fluorine in 2 position Rl C2H5 R' = H n = 0 The modus operandi is the same as the one described in Example 1. From 36 g of 2-carbethoxy 4-(2-fluoro benzamido~ phenol, 3 g of benzyltri-methylammonium chloride and 185 ml of epichlorohydrin, 14 g of 1-[2-carbethoxy 4-(2-fluoro benzarnido) phenoxy] 2,3-epoxy propane melting at 89C are obtained.
Example 4: 1-[2-carbethoxy 4-~4-fluoro benzamido) phenoxy] 3-terbutylamino _.
The present invention also relates to the process for preparing the novel intermediate compounds allowing synthesis of said products.
The novel compounds according to the invention belong to the group 10 constituted by the products of general formula (1) and their non-toxic acid addition salts COO Rl R ~ 2)n CONH~OCH2_1CH-CH2-NH R2 R' (I) In formula (1):
20 - R and R' may each designate an atom of hydrogen, an atom of halogen for examPle fluorine, a nitro group or alkyl or alkoxy radicals with Cl-C5, branched or not, or a SCH3 or ~3 grouF~;
- Rl represents a lower alkyl radical with I to 5 carbon atoms, branched or not, advantageously the ethyl radical;
25 - R2 represents a lower alkyl radical with I to 5 carbon atoms, straight or branched, and preferably the isopropyl radical or the terbutyl radical;
- n designates an integer less than 5, and preferably equal to 0 or 1.
The compounds according to the invention are synthesized by action of an NH2-R2 base (R2 being defined as hereinabove) on a compound of 30 formula (Il) without solvent or in a conventional organic solvent such as alcohols, at a temperature of between 20C and 150C.
8~78 ,COO ~
R ~3 (CH2~--CONH~ ~oc~2--C~H2 R' (Il) In formula (Il), R, R', Rl and n are defined as hereinabove.
The compounds of formula (Il) are generally obtained by reaction of a phenol of general formula (111) with an excess of epihalohydrin, particularly 10 epichlorohydrin or epibrornohydrin, in the presence of a catalyst such as benzyltrimethylammonium chloride, at a temperature ranging from ilOC
to 130C. This process yields perfectly crystallized compounds with better yields than the processes evoked hereinafter. The compounds of formula (Il) may also be obtained by reaction of the phenol of general formula (III) 15 with any epihalohydrin according to the conventional processes. The phenol of formula (111) will then be metalled by conventional metallation agents such as potassium hydroxide, sodium hydroxide, an alcoholate or sodium hydride in a dilute alcoholic, alcohoîic solvent or dimethylformamide (DMF) at a temperature of between 20C and 150C. However, these processes yield 20 products which are less well defined.
COO Rl R~(C~2) -- CO~H ~ OH
R' (111) In formula (III), R, R', Rl and n are defined as hereinabove.
The compounds of formula (III) are obtained in accordance with known processes of preparation consisting either in reacting the chloride 30 of the corresponding arylalkanoic acid with a 4-amino 2-carbalkoxy phenol in the presence of a base such as triethylamine in a solvent such as acetone or benzene, or in esterifying the corresponding acid (IV) in a sulfuric acid-alcohol medium.
.
~2~ 37~
~C~OH
R~_(CH2) -- CO~ OH
~, (IV) In formula (IV), R, R' and n are defined as hereinabove.
The addition salts of the compounds of formula (I) may be obtained by reaction of these compounds with an inorganic or organic acid in accordance 10 with a method known per se. Among the acids which may be used to this end, particular mention will be made of hydrochloric, hydrobromic, acetic, p-toluene sulfonic, methane sulfonic, oxalic, succinic, maleic, fumaric, cinna-mic, malic, aspartic, glutamic, ascorbic, N-acetyl aspartic, N-acetyl glutamic acids.
The novel compounds according to the invention are endowed with remarkable pharmacological properties and may be used in therapeutics for the treatment of hypertension since, most surprizingly, they present diuretic properties with, for certain of the products, /~1 blocking properties, and low toxicity. These remarkable characteristics seem to be due to the presence 20 in the molecules of the ester function in ortho position and of the amide function in para position.
In human therapeutics, the compounds of formula (I) and their non-toxic acid addition salts may be administered in particular by the oral route.
In that case, the use of gelatin-capsules or of tablets containing from 50 25 to 300 mg of active ingredient in association with a physiologically acceptable excipient is recommended. The compounds claimed present -the advantage of rendering treatment easier. On the other hand, with respect to the l3_ blocking/diuretic associations used in the treatment of hypertension~ the cornpounds of formula (I) have the advantage of single pharmacokinetics.
30 Angor pectoris and arrhythmia will be mentioned as other possible examples of indications.
Other features and advantages of the invention will appear more clearly on reading the following non-limiting examples of preparation given by way of illustration.
~ 8;37~3 The forrnulae corresponding to the Examples are given in the single Table at the end of the specification.
Example 1: 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula ll R = Fluorine in 4 position Rl C2H5 R' = H n = 0 In a flask, the rnixture of 34 g of 2-carbethoxy 4-(4-fluoro benzamido) phenol and 150 ml of epic:hlorohydrin is heated to 110C. 2.7 g of benzyltrimethyl ammonium chloride are then introduced. The reaction mixture is heated to reflux for 1/2 hr. then cooled. Once the temperature has dropped to 50C, 150 ml of water are added and the mixture is stirred well. The organic phase is decanted and the aqueous phase extracted twice with 50 ml ether. The organic phases are dried over magnesium sulfate then concentrated in vacuo.
The crude residue obtained crystallizes in 200 ml of ether to yield 22 g of 1-[2-carbethoxy 4-~4-fluoro benzamido) phenoxyi 2,3-epoxy propane melting at 115C.
Example 2: 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = Fluorine in 3 position Rl C2H5 R' = H n = 0 The rnodus operandi is identical to the one described in Example 1. From 50 g of 2-carbethoxy 4-(3-fluoro benzamido) phenol, 4 g of benzyltri-methylammonium chloride and 250 ml of epichlorohydrin, 24 g of 1-[2-carb-ethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane melting at 100C
are obtained.
Example 3: 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = fluorine in 2 position Rl C2H5 R' = H n = 0 The modus operandi is the same as the one described in Example 1. From 36 g of 2-carbethoxy 4-(2-fluoro benzamido~ phenol, 3 g of benzyltri-methylammonium chloride and 185 ml of epichlorohydrin, 14 g of 1-[2-carbethoxy 4-(2-fluoro benzarnido) phenoxy] 2,3-epoxy propane melting at 89C are obtained.
Example 4: 1-[2-carbethoxy 4-~4-fluoro benzamido) phenoxy] 3-terbutylamino _.
2-propanol ~21~33~
Formula I R = fluorine in 4 position Rl = C2H5 R2=-C-CH3 1~3 R' = H n = 0 T~le mixture of 11 g of the product of Example 1, 20 ml of terbutyl-amine and 60 ml of ethanol is heated to 60C for 8 hrs., then concentrated 5 in vacuo. The residue is taken up in 3 ml of acetic acid in 200 ml of water and 200 ml of isopropyl acetate. The mixture is stirred well and the isopropyl acetate eliminated by decantation. The aqueous phase is then neutralized by ammonia then extracted 3 times with 50 ml of methylene chloride. After drying over magnesium sulfate and concentration in vacuo oI the organic - 10 phase, a residue is obtained which crystallizes in ether. Recrystallization in isopropyl acetate yields 8 g of 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy]
Formula I R = fluorine in 4 position Rl = C2H5 R2=-C-CH3 1~3 R' = H n = 0 T~le mixture of 11 g of the product of Example 1, 20 ml of terbutyl-amine and 60 ml of ethanol is heated to 60C for 8 hrs., then concentrated 5 in vacuo. The residue is taken up in 3 ml of acetic acid in 200 ml of water and 200 ml of isopropyl acetate. The mixture is stirred well and the isopropyl acetate eliminated by decantation. The aqueous phase is then neutralized by ammonia then extracted 3 times with 50 ml of methylene chloride. After drying over magnesium sulfate and concentration in vacuo oI the organic - 10 phase, a residue is obtained which crystallizes in ether. Recrystallization in isopropyl acetate yields 8 g of 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol in the form of white crystals melting at 130C.
Example 5: 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol 15 Formula I R = fluorine in 4 position Rl=C2H5 R2= -CH
R' = H n = 0 The modus operandi is identical to the one described in Example
Example 5: 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol 15 Formula I R = fluorine in 4 position Rl=C2H5 R2= -CH
R' = H n = 0 The modus operandi is identical to the one described in Example
4 but using isopropylamine in place of terbutylamine. From 11 g of the product of Example 1, a crude product is obtained whichSrecrystallized in isopropyl 20 acetate, yields 6 g of 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-iso-propylamino 2-propanol in the form of white crystals melting at 117C.
Example 6: 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = fluorine in 3 position Rl=C2H5 R2=-C-CH3 R' = H n = 0 The modus operandi is the same as the one described in Example 4. From 14 g of the product of Example 2 and from 80 ml of terbutylamine, 7 g of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting at 114C are obtained after :~Z~8~371~
recrystallization in isopropyl acetate.
Example 7: Hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy~
3-isopropylamino 2-propanol ~ C H 3 Formula I R = fluorine in 3 position Rl=C2~15 R2=-CH
R' = H n = 0 The modus operandi is the same as the one described in Example 4 but from 8 g of the product of Example 2 and 30 ml of isopropylamine, and a white product is obtained which crystallizes in ether. By dissolving this product in acetone (200 ml) and by adding hydrochloric ether up to pil 10 2, the expected hydrochloride precipitates. After washing with acetone and drying, 3 g of hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxyl 3-isopropylamine 2-propanol in the form of white crystals meltin~ at 182C
are thus obtained.
Example 8: 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino 15 2-propanol ~H3 Formula I R = fluorine in 2 position Rl=C2H5 R2=-C-CH3 R' = H n = 0 The modus operandi is the same as the one described in Exannple 4. Starting frorn 12 g of the product of Example 3, 3.5 g of 1-[2-carbethoxy 20 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at 124C.
Example 9: Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido~ pllenoxy]
3-isopropylamino 2-propanol ,CH3 Formula I R = fluorine in 2 position Rl=C2H5 R2=-CH~
R' = H n = 0 The modus operandi is the same as the one described in Example 7 but from 14 g of the product of Example 3. 2 g of hydrochloride of 1-[2-carb-ethoxy 4-12-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol are thus obtained, in the form of white crystals melting at 188~C.
~L2~83~
7_ _xample 10 ~ 2-carbethoxy 4-benzamido phenoxy] 2,3-epoxy propane ~orrnul~ 11 R - R' = H Rl C2 5 n = 0 The modus operandi is identical to that described in Example I but from 42 g-of 2-carbethoxy 4-benzamido phenol, 257 ml of epichlorohydrin and 3.5 g of benzyltrimethylarnmonium chloride; 23 g of 1-(2-carbethoxy 4-benzamido phenoxy) 2,3-epoxy propane are obtained in the form of white crystals melting at 12~C.
r ~ple 11: 1-[2-carbethoxy 4-benzamido phenoxy] 3-terbutylamino 2-propanol 10 l~ormula I R = R' = H Rl C2H5 C,H3 n = 0 R = -C-CH3 ~H3 The modus operandi is the same as that described in Example 4.
Starting from 10 g of the product of Example 10 and 50 ml of terbutylamine, 3.5 g of 1-[2-carbethoxy 4-benzamido phenoxy] 3-terbutylamino 2-propanol 15 are obtained, in the form of white crystals melting at 120C.
Example 12: 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = CH3 in 4 position R' = H
Rl 2 5 n = 0 The modus operandi is identical to that described in Example 1.
From 27 g of 2-carbethoxy 4-(4-methyl benzamido) phenol, 40 ml of epichloro-hydrin and 2.3 g of benzyltrimethylammonium chloride, 13.1 g of 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of white crystals melting at 117C.
25 Example 13: 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = CH3 in 4 position Rl C2H5 Cl H3 R' = H R2 = -C-CH3 n = 0 The modus operandi is the same as that described in Example 4, but starting from 11 g of the product of Example 12 and 60 ml of terbutylamine;
~2~837~3 6.6 g of 1-~2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained in the form of ~vhite crystals melting at 140C.
_xam le 14: !-L2-carbethoxy 4-~4-methyl benzamiclo) phenoxy] 3-isopropylamino 2-propanol Formula I R = CH3 in 4 position Rl 2 5 R' = H R2 = -CH C~3 n = 0 CH3 The modus operandi is the same as the one described in Example 4, bu~ replacing the -terbutylamine by isopropylarmine. Starting frorrl 15 g of the product of Example 12 and 70 ml of isopropylamine, ~ ~ of 1-[2-carb-ethoxy 4-(4-methyl benzamido phenoxy] 3-isopropylamino 2-propanol are ob-tained in the form of white crystals melting at 114C.
Exampl_: 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = OCH3 in 4 position Rl C2H5 R' = H n = 0 The modus operandi is identical to that described in Example 1, but from 13.1 g of 2-carbethoxy 4-(4-methoxy benzoamido~ phenol, 66 ml of epichlorohydrin and I g of benzyltrimethylammonium chloride; 8.6 g of 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane are obtained in the forrn of white crystals melting at 126C.
Example 16: 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxyl 3-terbutylamino 2-propanol Formula I R = OCH3 in 4 position Rl C2H5 $H3 R' = H R2 = -C-CH3 n = 0 CH3 The modus operandi is the same as the one described in Example 4. From 8~6 g of the product of Example 15 and 20 ml of terbutylamine,
Example 6: 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = fluorine in 3 position Rl=C2H5 R2=-C-CH3 R' = H n = 0 The modus operandi is the same as the one described in Example 4. From 14 g of the product of Example 2 and from 80 ml of terbutylamine, 7 g of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting at 114C are obtained after :~Z~8~371~
recrystallization in isopropyl acetate.
Example 7: Hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy~
3-isopropylamino 2-propanol ~ C H 3 Formula I R = fluorine in 3 position Rl=C2~15 R2=-CH
R' = H n = 0 The modus operandi is the same as the one described in Example 4 but from 8 g of the product of Example 2 and 30 ml of isopropylamine, and a white product is obtained which crystallizes in ether. By dissolving this product in acetone (200 ml) and by adding hydrochloric ether up to pil 10 2, the expected hydrochloride precipitates. After washing with acetone and drying, 3 g of hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxyl 3-isopropylamine 2-propanol in the form of white crystals meltin~ at 182C
are thus obtained.
Example 8: 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino 15 2-propanol ~H3 Formula I R = fluorine in 2 position Rl=C2H5 R2=-C-CH3 R' = H n = 0 The modus operandi is the same as the one described in Exannple 4. Starting frorn 12 g of the product of Example 3, 3.5 g of 1-[2-carbethoxy 20 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at 124C.
Example 9: Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido~ pllenoxy]
3-isopropylamino 2-propanol ,CH3 Formula I R = fluorine in 2 position Rl=C2H5 R2=-CH~
R' = H n = 0 The modus operandi is the same as the one described in Example 7 but from 14 g of the product of Example 3. 2 g of hydrochloride of 1-[2-carb-ethoxy 4-12-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol are thus obtained, in the form of white crystals melting at 188~C.
~L2~83~
7_ _xample 10 ~ 2-carbethoxy 4-benzamido phenoxy] 2,3-epoxy propane ~orrnul~ 11 R - R' = H Rl C2 5 n = 0 The modus operandi is identical to that described in Example I but from 42 g-of 2-carbethoxy 4-benzamido phenol, 257 ml of epichlorohydrin and 3.5 g of benzyltrimethylarnmonium chloride; 23 g of 1-(2-carbethoxy 4-benzamido phenoxy) 2,3-epoxy propane are obtained in the form of white crystals melting at 12~C.
r ~ple 11: 1-[2-carbethoxy 4-benzamido phenoxy] 3-terbutylamino 2-propanol 10 l~ormula I R = R' = H Rl C2H5 C,H3 n = 0 R = -C-CH3 ~H3 The modus operandi is the same as that described in Example 4.
Starting from 10 g of the product of Example 10 and 50 ml of terbutylamine, 3.5 g of 1-[2-carbethoxy 4-benzamido phenoxy] 3-terbutylamino 2-propanol 15 are obtained, in the form of white crystals melting at 120C.
Example 12: 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = CH3 in 4 position R' = H
Rl 2 5 n = 0 The modus operandi is identical to that described in Example 1.
From 27 g of 2-carbethoxy 4-(4-methyl benzamido) phenol, 40 ml of epichloro-hydrin and 2.3 g of benzyltrimethylammonium chloride, 13.1 g of 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of white crystals melting at 117C.
25 Example 13: 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = CH3 in 4 position Rl C2H5 Cl H3 R' = H R2 = -C-CH3 n = 0 The modus operandi is the same as that described in Example 4, but starting from 11 g of the product of Example 12 and 60 ml of terbutylamine;
~2~837~3 6.6 g of 1-~2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained in the form of ~vhite crystals melting at 140C.
_xam le 14: !-L2-carbethoxy 4-~4-methyl benzamiclo) phenoxy] 3-isopropylamino 2-propanol Formula I R = CH3 in 4 position Rl 2 5 R' = H R2 = -CH C~3 n = 0 CH3 The modus operandi is the same as the one described in Example 4, bu~ replacing the -terbutylamine by isopropylarmine. Starting frorrl 15 g of the product of Example 12 and 70 ml of isopropylamine, ~ ~ of 1-[2-carb-ethoxy 4-(4-methyl benzamido phenoxy] 3-isopropylamino 2-propanol are ob-tained in the form of white crystals melting at 114C.
Exampl_: 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = OCH3 in 4 position Rl C2H5 R' = H n = 0 The modus operandi is identical to that described in Example 1, but from 13.1 g of 2-carbethoxy 4-(4-methoxy benzoamido~ phenol, 66 ml of epichlorohydrin and I g of benzyltrimethylammonium chloride; 8.6 g of 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane are obtained in the forrn of white crystals melting at 126C.
Example 16: 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxyl 3-terbutylamino 2-propanol Formula I R = OCH3 in 4 position Rl C2H5 $H3 R' = H R2 = -C-CH3 n = 0 CH3 The modus operandi is the same as the one described in Example 4. From 8~6 g of the product of Example 15 and 20 ml of terbutylamine,
5.2 g of 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at 124C.
30 Exam~: 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutyl-amino 2-propanol ~11 83~7~3 Formula I R = fluorine in 2 position ~1'3 ~1 = C2HS
R' = fluorme in 4 position R2 = -C-CH3 n = 0 ~H3 This product is synthesized in the same rnanner. From 1-[2-carbethoxy 5 4-(2,4-difluoro benzamido) phenoxy] 2,3-epoxy propane and terbutylamine, 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxyJ 3-terbutylamino 2-propanol is obtained in accordance with the modi operandi previously described ~.P 138-140C.
Example 18: 1-[2-carbethoxy 4-(4-fluoro benzacetamido) phenoxyl 3-terbutyl-_ _ amino 2-propanol 10 Forrnula I R = fluorine in 4 position Rl C2H5 l H3 R' = H R2 = -C-CH3 n = 0 CH3 In thc same manner, 1-[2-carbethoxy 4-(4-fluoro benzacetamido) phenoxy] 3-terbutylamino 2-propanol is obtained from 1-[2-carbethoxy 4-(4-15 fluoro benzacetamido) phenoxy] 2,3-epoxy propane and terbutylamine in accor-dance with a modus operandi identical to those described previously M.P 109C.
Example 19: 1-[2-carbethoxy 4-(4-chloro benzamido phenoxy] 2,3-epoxy propane Formula 11 R = Cl in 4 position Rl C2H5 R' = H n = 0 The modus operandi is identical to that described in Example 1.
From 32 g of 2-carbethoxy 4-(4-chloro benzamido~ phenol, 140 ml of epichloro-hydrin and 3 g of benzyltrimethylammonium chloride, 13.2 g oi 1-[2-carbethoxy 4-(4-chloro benzamido) phenoxy] 2,3-epoxy propane are obtained, used as such for subsequent synthesis.
25 Example 20: 1-[2-carbethoxy 4-(4-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol ~ormula I R = Cl in 4 position Rl = C2H5 R2 = -C-CH3 R' = H n = 0 The modus operandi is the same as that described in Example 4 30 but, from 13 g of 1-[2-carbethoxy 4-(4.-chloro benzamido) phenoxy] 2,3-epoxy propane prepared in Example 19, 3.6 g of 1-[2-carbethoxy 4-(4-chloro benz-arnido) phenoxy] 3-terbutylamino 2-propanol in the form of crystals mel~ing L8~8 at 134C are obtained aIter recrystallization in isopropanol.
Example 21: 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxyi 2,3-epoxy propane Formula 11 R = CH3 in 3 position Rl C2H5 R' = H n = 0 According to the modus operandi of Example 1, hut starting from Il g of 2-carbethoxy 4-(3-methyl benzamido) phenol, 20 cm2 of epichlorohydrin and I g of benzyltrimethylammonium chloride, 15 g of 1-[2-carbethoxy 4-(3-methyl benzarnido) phenoxy] 2,3-epoxy propane are obtained, in the form of oil, used as such.
Example 22: 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = CH3 in 3 position Rl=C2H5 R2=~C~CH3 R' = }1 n = 0 CH3 According to the modus operandi of Example 4, from 15 g of the epoxicle prepared in Example 21, 8.6 g of 1-[2-carbethoxy 4-(3-methyl benzamido)phenoxy] 3--terbutylarnino 2-propanol are obtained, in the form of white crystals melting at 109C.
Example 23: 1-[2-carbethoxy 4-(3-methoxy benz~rudo ) phenoxy] 2,3-epoxy 20 propane Formula 11 R = MeO in 3 position Rl C2H5 R' = H n = 0 According to the modus operandi of Example 1, but from 16.4 g of 2-carbethoxy 4-(3-methoxy benzamido ) phenol, 50 ml of epichlorohydrin 25 and 1.5 g of benzyltrimethylammonium chloride, 14.5 g of 1-[2-carbethoxy 4-(3-methoxy benz~ido) phenoxy] 2.3-epoxy propane are obtained, in the form of crystals melting at 90C.
_ample 24: 1-[2-carbethoxy 4-(3-methoxy benzalrido ) phenoxy] 3-terbutyl-arnino 2-propanol ,CH3 30 Formula I E~ = MeO in 3 position Rl=C2H5 R2=-C-CH3 R' = H n = 0 CH3 According to the modus operandi of Example 4, but from 14.5 g of the epoxide prepared in Example 23, 2.6 g of 1-[2-carbethoxy 4-(3-methoxy 12~8~378 benzamido ) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at 94C.
Example 25: 1-[2-carbethoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane Formula 11 . R = CH3 in 2 position Rl C2H5 R' = H n = 0 After having prepared the sodium salt of 20 g of 2-carbethoxy 4-(2-methyl benzamido) phenol in ethanol in the presence of the stoichiometric quantity of sodium hydroxide in pastille form, 50 ml of epichlorohydrin are 10 added with stirring and the mixture is taken to reflux for 8 hours. The reaction rnixture is cooled then concentrated in vacuo. The residue obtained is taken up in methylene chloride and washed with water. The organic solution is dried over magnesiurn sulfate, filtered, then concentrated in vacuo. The residuehardens in isopropyl ether. By taking up the solid obtained in a mixture of 15 100 ml of ethyl ether and 10 ml of isopropyl acetate, ~, g of 1-[2-carbe~hoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of pink crystals melting at 94"C.
Example 26: 1-[2-carbethoxy 4-~2-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol C, H3 20 Formula I R = CH3 in 2 position R = C2H5 R2 = -C-CH3 R' = H n = 0 According to the modus operandi of Example 4, starting from 13 g of the epoxide prepared in Example 25, 1.2 g of 1-[2-carbethoxy 4-(2-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol is obtained, in the form 25 of white crystals melting at 126C.
Example 27: 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = CH3S in 4 position Rl C2H5 R' = H n = 0 According to the modus operandi of Example 25, but from 40 g of 2-carbethoxy 4-(4-methylthio benzamido phenol and 80 ml of epichloro-hydrin, 20 g of 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy3 2,3-epoxy propane are obtained, in the form of white crystals melting at 105C.
~2~ 378 Example 2~ [2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-terbutyl-amino 2-propanol Fornlula I R = CH3S in 4 position Rl = C2H5 R2 = -C-CH3 R' = H n = 0 ~ccording to the modus operandi of Example 4, starting from 12 g of the epoxide prepared in Example 27 and terbutylamine, 6 g of a crude product are obtained which, recrystallized in isopropyl acetate, yields 3.5 g of 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting at 142C.
10 Example 29: 1-[2-carbethoxy 4-~3-chloro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = Cl in 3 position Rl C2H5 R' = H n = 0 The modus operandi is identical to that of Example 1. From 7 g of 2-carbethoxy 4-(3-chloro benzamido) phenol, 30 ml of epichlorohydlin 15 and 0.7 g of benzyltrimethylammonium chloride, 4 g of 1-[2-carbethoxy 4-(3-chloro benzamido~ phenoxy] 2,3-epoxy propane are obtained in the form of white crystals melting at 95~C.
Example 30: 1-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol Cl H3 20 Formula I R = Cl in 3 position Rl = C2H5 R2 = -C-CH3 R' = H n = 0 According to the modus operandi described in Example 4, 13 g of the epoxide of Example 29 yield 2 g of 1-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting 25 at 107C.
Example 31: Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol Formula R = fluorine in 2 position Rl C2H5 R' = H . CH3 n = 0 R2 =-C-CH3 hydrochloride CH3 ~Z1~33 ,7~3 f\ solution oi 4.5 g of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol prepared in Example 8~ In 50 ml of absolute ethanol, is acidified to pll 2 by hydrochloric ether. The solvent is evaporated to dryness in vacuo, and the residue is taken up in ether.
After draining of the precipitate obtained and washing with ether, 4.6 g of hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylarnirlo 2-propanol, melting at 168C, are obtained in this way.
Example 32: 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxyl 2,3-epoxy propane Formula 11: R = CF3 in 4 position Rl C2H5 R' = H n = 0 According to the modus operandi described in Example 25 but from 20 g of 2-carbethoxy 4-(4-trifluoromethyl benzamido) phenol and 50 ml of epichlorohydrirl, 7 g of 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 2,3-epoxy propane in the forrn of an oil are obtained, used as such for the following.
Example 33: 1-L2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula 1: R = CF3 in 4 position Rl C2H5 2 0 R ' = H 2 ~ 3 n = 0 CH3 According to the modus operandi described in Example 4, starting from 13 g of the epoxide prepared in Example 32, and 50 ml of terbutylamine, 1.5 g of 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 3-terbutyl-amino 2-propanol melting at 155C is obtained a~ter crystallization in ether and washing with isopropyl acetate.
Example 34: 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane Formula 11: R = OCH3 in 2 position Rl = C2H5 R' = H n = 0 According to the modus operandi described in Example 1, but from 8.5 g of 2-carbethoxy 4-(4-methoxy benzamido phenol, 50 ml of epichlorohydrin and 600 mg of benzyltrimethyl ammonium chloride, 3.5 g of 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane, crystallized in isopropyl 1~3L8~78 ether and melting at 70C are obtained.
Example 35: 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-terbutyl-amino 2-propanol Formula 1: R = OCH3 in 2 position Rl C2~5 R'. = H ICH3 N = 0 R2 = -C-CH3 According to the modus operandi described in Example 4, but from 3.5 g of the epoxide prepared in Example 34 and 50 ml of terbutylamine, 1.2 g of 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-terbutylamino 10 2-propanol, crystallized in pentane and melting at 107C, is obtained.
Example 36: 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 2,3-epoxy propane Forrmula 11: R = Cl in 2 position Rl C2H5 R' = H n = 0 A solution of 10 g (0.03 mole) of 2-carbethoxy 4-(2-chloro benzamido) 15 phenol and 2 g of ~5/O potassium hydroxide (0.03 mole), in 200 ml oi ethanol and 30 ml of DMF, is added dropwise over 4.7 crn3 (0.06 mole) of epichloro-hydrin in 50 ml of ethanol.
This solution is stirred for 3 hrs. at ambient temperature, then for I hour at 50, and allowed to stand overnight. It is then concentrated, diluted 20 with water and extracted with ether. After drying and evaporation of the ether, 4 g of an oil are obtained, used as such for the following.
Example 37: 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol and hydrochloride Formula I = R = Cl in 2 posi-tion Rl C2H5 ~' = H ICH3 n = 0 R2 = -C-CH3 According to the modus operandi described in Example 4, but starting from 4 g of the epoxide prepared in Example 36, 2.5 g of 1-12-carbethoxy 4-(2-chloro benzamido) phenoxy3 3-terbutylamino 2-propanol, crystallized 30 in an acetone-ether mixture and melting at 113-115C, are obtained.
Preparation of the hydrochloride
30 Exam~: 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutyl-amino 2-propanol ~11 83~7~3 Formula I R = fluorine in 2 position ~1'3 ~1 = C2HS
R' = fluorme in 4 position R2 = -C-CH3 n = 0 ~H3 This product is synthesized in the same rnanner. From 1-[2-carbethoxy 5 4-(2,4-difluoro benzamido) phenoxy] 2,3-epoxy propane and terbutylamine, 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxyJ 3-terbutylamino 2-propanol is obtained in accordance with the modi operandi previously described ~.P 138-140C.
Example 18: 1-[2-carbethoxy 4-(4-fluoro benzacetamido) phenoxyl 3-terbutyl-_ _ amino 2-propanol 10 Forrnula I R = fluorine in 4 position Rl C2H5 l H3 R' = H R2 = -C-CH3 n = 0 CH3 In thc same manner, 1-[2-carbethoxy 4-(4-fluoro benzacetamido) phenoxy] 3-terbutylamino 2-propanol is obtained from 1-[2-carbethoxy 4-(4-15 fluoro benzacetamido) phenoxy] 2,3-epoxy propane and terbutylamine in accor-dance with a modus operandi identical to those described previously M.P 109C.
Example 19: 1-[2-carbethoxy 4-(4-chloro benzamido phenoxy] 2,3-epoxy propane Formula 11 R = Cl in 4 position Rl C2H5 R' = H n = 0 The modus operandi is identical to that described in Example 1.
From 32 g of 2-carbethoxy 4-(4-chloro benzamido~ phenol, 140 ml of epichloro-hydrin and 3 g of benzyltrimethylammonium chloride, 13.2 g oi 1-[2-carbethoxy 4-(4-chloro benzamido) phenoxy] 2,3-epoxy propane are obtained, used as such for subsequent synthesis.
25 Example 20: 1-[2-carbethoxy 4-(4-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol ~ormula I R = Cl in 4 position Rl = C2H5 R2 = -C-CH3 R' = H n = 0 The modus operandi is the same as that described in Example 4 30 but, from 13 g of 1-[2-carbethoxy 4-(4.-chloro benzamido) phenoxy] 2,3-epoxy propane prepared in Example 19, 3.6 g of 1-[2-carbethoxy 4-(4-chloro benz-arnido) phenoxy] 3-terbutylamino 2-propanol in the form of crystals mel~ing L8~8 at 134C are obtained aIter recrystallization in isopropanol.
Example 21: 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxyi 2,3-epoxy propane Formula 11 R = CH3 in 3 position Rl C2H5 R' = H n = 0 According to the modus operandi of Example 1, hut starting from Il g of 2-carbethoxy 4-(3-methyl benzamido) phenol, 20 cm2 of epichlorohydrin and I g of benzyltrimethylammonium chloride, 15 g of 1-[2-carbethoxy 4-(3-methyl benzarnido) phenoxy] 2,3-epoxy propane are obtained, in the form of oil, used as such.
Example 22: 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = CH3 in 3 position Rl=C2H5 R2=~C~CH3 R' = }1 n = 0 CH3 According to the modus operandi of Example 4, from 15 g of the epoxicle prepared in Example 21, 8.6 g of 1-[2-carbethoxy 4-(3-methyl benzamido)phenoxy] 3--terbutylarnino 2-propanol are obtained, in the form of white crystals melting at 109C.
Example 23: 1-[2-carbethoxy 4-(3-methoxy benz~rudo ) phenoxy] 2,3-epoxy 20 propane Formula 11 R = MeO in 3 position Rl C2H5 R' = H n = 0 According to the modus operandi of Example 1, but from 16.4 g of 2-carbethoxy 4-(3-methoxy benzamido ) phenol, 50 ml of epichlorohydrin 25 and 1.5 g of benzyltrimethylammonium chloride, 14.5 g of 1-[2-carbethoxy 4-(3-methoxy benz~ido) phenoxy] 2.3-epoxy propane are obtained, in the form of crystals melting at 90C.
_ample 24: 1-[2-carbethoxy 4-(3-methoxy benzalrido ) phenoxy] 3-terbutyl-arnino 2-propanol ,CH3 30 Formula I E~ = MeO in 3 position Rl=C2H5 R2=-C-CH3 R' = H n = 0 CH3 According to the modus operandi of Example 4, but from 14.5 g of the epoxide prepared in Example 23, 2.6 g of 1-[2-carbethoxy 4-(3-methoxy 12~8~378 benzamido ) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at 94C.
Example 25: 1-[2-carbethoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane Formula 11 . R = CH3 in 2 position Rl C2H5 R' = H n = 0 After having prepared the sodium salt of 20 g of 2-carbethoxy 4-(2-methyl benzamido) phenol in ethanol in the presence of the stoichiometric quantity of sodium hydroxide in pastille form, 50 ml of epichlorohydrin are 10 added with stirring and the mixture is taken to reflux for 8 hours. The reaction rnixture is cooled then concentrated in vacuo. The residue obtained is taken up in methylene chloride and washed with water. The organic solution is dried over magnesiurn sulfate, filtered, then concentrated in vacuo. The residuehardens in isopropyl ether. By taking up the solid obtained in a mixture of 15 100 ml of ethyl ether and 10 ml of isopropyl acetate, ~, g of 1-[2-carbe~hoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of pink crystals melting at 94"C.
Example 26: 1-[2-carbethoxy 4-~2-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol C, H3 20 Formula I R = CH3 in 2 position R = C2H5 R2 = -C-CH3 R' = H n = 0 According to the modus operandi of Example 4, starting from 13 g of the epoxide prepared in Example 25, 1.2 g of 1-[2-carbethoxy 4-(2-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol is obtained, in the form 25 of white crystals melting at 126C.
Example 27: 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = CH3S in 4 position Rl C2H5 R' = H n = 0 According to the modus operandi of Example 25, but from 40 g of 2-carbethoxy 4-(4-methylthio benzamido phenol and 80 ml of epichloro-hydrin, 20 g of 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy3 2,3-epoxy propane are obtained, in the form of white crystals melting at 105C.
~2~ 378 Example 2~ [2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-terbutyl-amino 2-propanol Fornlula I R = CH3S in 4 position Rl = C2H5 R2 = -C-CH3 R' = H n = 0 ~ccording to the modus operandi of Example 4, starting from 12 g of the epoxide prepared in Example 27 and terbutylamine, 6 g of a crude product are obtained which, recrystallized in isopropyl acetate, yields 3.5 g of 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting at 142C.
10 Example 29: 1-[2-carbethoxy 4-~3-chloro benzamido) phenoxy] 2,3-epoxy propane Formula 11 R = Cl in 3 position Rl C2H5 R' = H n = 0 The modus operandi is identical to that of Example 1. From 7 g of 2-carbethoxy 4-(3-chloro benzamido) phenol, 30 ml of epichlorohydlin 15 and 0.7 g of benzyltrimethylammonium chloride, 4 g of 1-[2-carbethoxy 4-(3-chloro benzamido~ phenoxy] 2,3-epoxy propane are obtained in the form of white crystals melting at 95~C.
Example 30: 1-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol Cl H3 20 Formula I R = Cl in 3 position Rl = C2H5 R2 = -C-CH3 R' = H n = 0 According to the modus operandi described in Example 4, 13 g of the epoxide of Example 29 yield 2 g of 1-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting 25 at 107C.
Example 31: Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol Formula R = fluorine in 2 position Rl C2H5 R' = H . CH3 n = 0 R2 =-C-CH3 hydrochloride CH3 ~Z1~33 ,7~3 f\ solution oi 4.5 g of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylamino 2-propanol prepared in Example 8~ In 50 ml of absolute ethanol, is acidified to pll 2 by hydrochloric ether. The solvent is evaporated to dryness in vacuo, and the residue is taken up in ether.
After draining of the precipitate obtained and washing with ether, 4.6 g of hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-terbutylarnirlo 2-propanol, melting at 168C, are obtained in this way.
Example 32: 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxyl 2,3-epoxy propane Formula 11: R = CF3 in 4 position Rl C2H5 R' = H n = 0 According to the modus operandi described in Example 25 but from 20 g of 2-carbethoxy 4-(4-trifluoromethyl benzamido) phenol and 50 ml of epichlorohydrirl, 7 g of 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 2,3-epoxy propane in the forrn of an oil are obtained, used as such for the following.
Example 33: 1-L2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula 1: R = CF3 in 4 position Rl C2H5 2 0 R ' = H 2 ~ 3 n = 0 CH3 According to the modus operandi described in Example 4, starting from 13 g of the epoxide prepared in Example 32, and 50 ml of terbutylamine, 1.5 g of 1-[2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 3-terbutyl-amino 2-propanol melting at 155C is obtained a~ter crystallization in ether and washing with isopropyl acetate.
Example 34: 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane Formula 11: R = OCH3 in 2 position Rl = C2H5 R' = H n = 0 According to the modus operandi described in Example 1, but from 8.5 g of 2-carbethoxy 4-(4-methoxy benzamido phenol, 50 ml of epichlorohydrin and 600 mg of benzyltrimethyl ammonium chloride, 3.5 g of 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane, crystallized in isopropyl 1~3L8~78 ether and melting at 70C are obtained.
Example 35: 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-terbutyl-amino 2-propanol Formula 1: R = OCH3 in 2 position Rl C2~5 R'. = H ICH3 N = 0 R2 = -C-CH3 According to the modus operandi described in Example 4, but from 3.5 g of the epoxide prepared in Example 34 and 50 ml of terbutylamine, 1.2 g of 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-terbutylamino 10 2-propanol, crystallized in pentane and melting at 107C, is obtained.
Example 36: 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 2,3-epoxy propane Forrmula 11: R = Cl in 2 position Rl C2H5 R' = H n = 0 A solution of 10 g (0.03 mole) of 2-carbethoxy 4-(2-chloro benzamido) 15 phenol and 2 g of ~5/O potassium hydroxide (0.03 mole), in 200 ml oi ethanol and 30 ml of DMF, is added dropwise over 4.7 crn3 (0.06 mole) of epichloro-hydrin in 50 ml of ethanol.
This solution is stirred for 3 hrs. at ambient temperature, then for I hour at 50, and allowed to stand overnight. It is then concentrated, diluted 20 with water and extracted with ether. After drying and evaporation of the ether, 4 g of an oil are obtained, used as such for the following.
Example 37: 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol and hydrochloride Formula I = R = Cl in 2 posi-tion Rl C2H5 ~' = H ICH3 n = 0 R2 = -C-CH3 According to the modus operandi described in Example 4, but starting from 4 g of the epoxide prepared in Example 36, 2.5 g of 1-12-carbethoxy 4-(2-chloro benzamido) phenoxy3 3-terbutylamino 2-propanol, crystallized 30 in an acetone-ether mixture and melting at 113-115C, are obtained.
Preparation of the hydrochloride
6 g of 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-terbutyl-~2~837i~3 amino 2-propanol are dissolved in 50 ml of acetone, and the solution is acidi-fied to pH 2 by hydrochloric ether.
4.5 g of hydrochloride of 1-[2-carbethoxy (4-(2-chloro benzamido) phenoxy] 3-terbutylamino 2 propanol in the form of crystals melting at 158-161 5 are obtained in this way.
Example 38: Hydrochloride of 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I = R = fluorine in 2 position Rl C2H5 R' = fluorine in 4 position CH3 n = O R2 = -C-CH3 hydrochloride CH3 A solution of 25 g of 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutylamino 2-propanol prepared in Example 17 in 100 ml of ethanol is acidified to pH 2 by hydrochloric ether. The precipitate formed 15 is drained, washed with ether.
24 g of crude hydrochloride are thus obtained, which, crystallized in acetonitrile, yield 22 g of hydrochloride of 1-t2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy~ 3-terbutylamino 2-propanol in the form of white crystals melting at 151-152~C.
1~8378 T A B L E
Example 1 : F_ ~ CONH ~ \ T
Example 2 : ~ CONH_ ~ OCH2-CH-CH2 Example 3 : ~ CONH_ ~ _OCH2-C\ /H2 Example 4 : F ~ CONH_ ~ CH2 ICH 2 j 3 Example 5 : F ~ CONH ~ OCII2-~U-CH2-NH-CU
Example 6 : ~ CONH ~ 2 1 2 1 3 Example 7 : ~ CONH. ~ CH2-CH-CH2-NH-CH-CH3, HCl ~ COO C2H5 7H3 Example 8 : ~ ~ _ CONH _ ~ OCH2-CIH CH2 NH I 3 Example 9 : ~ CONH ~ OCH2-CH-CH2-NH-CH;CH3, HCl _l7 _ Exanple 10 ~ CON~H ~OC~12-CH-CH2 Ex~mple 11 : ~ CO~ 2 1 2 1 3 Exa,npLe 12 : CH3 ~ CONH_ ~ 2 \ 5 2 Example 13 : CH3 ~ ~ CONH_ ~ 2 1 2 1 3 Example14 : CH3 ~ CONH_~ 2 1 2 f 3 ExamplelS : CH30- ~ CONH ~ 2 \O/ 2 Exanplel6 : CH30 ~ CONH ~ OCH2-CH-cH2 NH l C 3 Example 17 : F~ CONH~ 2 1 2 1 3 Exa,nplel8 :F ~ CH2 _ CONH _ ~ _OCH2-1H-CH2-NH I CH3 ~2~83t~8 Ex ~ple 19 C1~3COl~T.l--(~O-CH2 CH--CH2 Example 20 C1~CONH~ -CH2--ICH-CH~l--Cl--CH3 CH3 COO-~2~5 Ex ample 21 ~CONH~O-CH2--CH--C~H2 CH3 COO-C H fH3 Ex ample 22 ~ ONH-- ~ -C~2--1CH-CH2 Nl~~~Cl~~CH3 CH COO-C~H5 Example 23 ~ ONH- ~ -CH2 CH~-CH2 CH3 C00-C2H- fH3 ~ CO~H_ ~ O-CH2 ,CH-CH ~N~--G--CH3 Example 24 \~/ \J OH C~3 :~Z~378 Example 25 ~ CO~H~_O-CH2 C~a~CH2 ~xa~ple 26 ~CONH~ O c,~ ~ 3 CO~-C2H5 E:~ample 27 Cll3 S { ~ COli'.~ O-CH2 C\ ~CH2 CO~-C2H5 3 Example 28 C113 S~ CO.NI~ CH--CH----CH~H_ ~3CH3 C ,COO-C H5 Example 29 ~3 CONH~30-C'.12 CE~\ /C. 2 Cl~ COO-C2H5 1~11,3 Ex anple 30 ~CO~IH ~ ~f ~ 1 3 ~83~7~3 F ÇOO~t ample 31 ~ CONH ~ ~ O C!l ~ H-CH ~.~ ~ CH3, HCl COOEt Example 32 F3C ~ CONH ~ O CH2 C - CH2 Ex ample 33 F3C ~ ONH ~ o~ CH3 O~e COO_t Example 34 ~ONH ~ O-CH2--C\~CH2 O!le COOE t Exa.nple 35 ~ ONH ~ ~H2 b~-CH2 ~ CH3 Cl ,COOE t Ex aDple 36 ~ C-NH ~ O C~,~2-CH-CH2 .
~83~8 C 1 COOEt Exa~ple 37 : ~C_NH~O-CH2-CH-CH2-NH +, HCl F ÇOOE t Exa~ple 38: F~C-~H~O-CH2-CH CH2-NH+, HCl
4.5 g of hydrochloride of 1-[2-carbethoxy (4-(2-chloro benzamido) phenoxy] 3-terbutylamino 2 propanol in the form of crystals melting at 158-161 5 are obtained in this way.
Example 38: Hydrochloride of 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I = R = fluorine in 2 position Rl C2H5 R' = fluorine in 4 position CH3 n = O R2 = -C-CH3 hydrochloride CH3 A solution of 25 g of 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutylamino 2-propanol prepared in Example 17 in 100 ml of ethanol is acidified to pH 2 by hydrochloric ether. The precipitate formed 15 is drained, washed with ether.
24 g of crude hydrochloride are thus obtained, which, crystallized in acetonitrile, yield 22 g of hydrochloride of 1-t2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy~ 3-terbutylamino 2-propanol in the form of white crystals melting at 151-152~C.
1~8378 T A B L E
Example 1 : F_ ~ CONH ~ \ T
Example 2 : ~ CONH_ ~ OCH2-CH-CH2 Example 3 : ~ CONH_ ~ _OCH2-C\ /H2 Example 4 : F ~ CONH_ ~ CH2 ICH 2 j 3 Example 5 : F ~ CONH ~ OCII2-~U-CH2-NH-CU
Example 6 : ~ CONH ~ 2 1 2 1 3 Example 7 : ~ CONH. ~ CH2-CH-CH2-NH-CH-CH3, HCl ~ COO C2H5 7H3 Example 8 : ~ ~ _ CONH _ ~ OCH2-CIH CH2 NH I 3 Example 9 : ~ CONH ~ OCH2-CH-CH2-NH-CH;CH3, HCl _l7 _ Exanple 10 ~ CON~H ~OC~12-CH-CH2 Ex~mple 11 : ~ CO~ 2 1 2 1 3 Exa,npLe 12 : CH3 ~ CONH_ ~ 2 \ 5 2 Example 13 : CH3 ~ ~ CONH_ ~ 2 1 2 1 3 Example14 : CH3 ~ CONH_~ 2 1 2 f 3 ExamplelS : CH30- ~ CONH ~ 2 \O/ 2 Exanplel6 : CH30 ~ CONH ~ OCH2-CH-cH2 NH l C 3 Example 17 : F~ CONH~ 2 1 2 1 3 Exa,nplel8 :F ~ CH2 _ CONH _ ~ _OCH2-1H-CH2-NH I CH3 ~2~83t~8 Ex ~ple 19 C1~3COl~T.l--(~O-CH2 CH--CH2 Example 20 C1~CONH~ -CH2--ICH-CH~l--Cl--CH3 CH3 COO-~2~5 Ex ample 21 ~CONH~O-CH2--CH--C~H2 CH3 COO-C H fH3 Ex ample 22 ~ ONH-- ~ -C~2--1CH-CH2 Nl~~~Cl~~CH3 CH COO-C~H5 Example 23 ~ ONH- ~ -CH2 CH~-CH2 CH3 C00-C2H- fH3 ~ CO~H_ ~ O-CH2 ,CH-CH ~N~--G--CH3 Example 24 \~/ \J OH C~3 :~Z~378 Example 25 ~ CO~H~_O-CH2 C~a~CH2 ~xa~ple 26 ~CONH~ O c,~ ~ 3 CO~-C2H5 E:~ample 27 Cll3 S { ~ COli'.~ O-CH2 C\ ~CH2 CO~-C2H5 3 Example 28 C113 S~ CO.NI~ CH--CH----CH~H_ ~3CH3 C ,COO-C H5 Example 29 ~3 CONH~30-C'.12 CE~\ /C. 2 Cl~ COO-C2H5 1~11,3 Ex anple 30 ~CO~IH ~ ~f ~ 1 3 ~83~7~3 F ÇOO~t ample 31 ~ CONH ~ ~ O C!l ~ H-CH ~.~ ~ CH3, HCl COOEt Example 32 F3C ~ CONH ~ O CH2 C - CH2 Ex ample 33 F3C ~ ONH ~ o~ CH3 O~e COO_t Example 34 ~ONH ~ O-CH2--C\~CH2 O!le COOE t Exa.nple 35 ~ ONH ~ ~H2 b~-CH2 ~ CH3 Cl ,COOE t Ex aDple 36 ~ C-NH ~ O C~,~2-CH-CH2 .
~83~8 C 1 COOEt Exa~ple 37 : ~C_NH~O-CH2-CH-CH2-NH +, HCl F ÇOOE t Exa~ple 38: F~C-~H~O-CH2-CH CH2-NH+, HCl
Claims (79)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the for-mula (I) in which: R and R' each designate a hydrogen atom, a halo-gen atom, a nitro group or an alkyl or an alkoxy radical with 1 to 5 carbon atoms, or an-SCH3 or-CF3 group, R1 repre-sents a lower alkyl radical with 1 to 5 carbon atoms, R2 represents a lower alkyl radical with 1 to 5 carbon atoms, and n is an integer less than 5, or a pharmeceutically acceptable acid addition salt thereof said process comprising reacting a base of formula where R2 is as above with a compound of formula (II) (II) wherein R, R', R1 and n are as defined above at a tempera-ture of between 20°C and 150°C, and where the salt is re-k reacting the free base obtained with a suitable acid.
2. A process according to claim 1, in which the reaction is effected in the presence of a solvent.
3. The process of claim 1, wherein the compounds of formula II are obtained by reaction of a phenol of gen-eral formula (III) (III) R, R' and R1 being as defined in claim 1 with an excess of an epihalohydrin in the presence of a catalyst at a temperature of from 110°C to 130°C.
4. The process of claim 1, wherein R1 represents the ethyl group.
5. The process of claim 4, wherein R2 represents the isopropyl or tertbutyl radical.
6. The process of claim 5, wherein n is equal to 0 or 1.
7. A process of claim 6, wherein R is H and R' is F or R and R' are both F.
8. A compound of formula I given in claim 1, or a pharmaceutically acceptable acid addition salt thereof wherein R, R', R1, R2 and n are as in claim 1 whenever prepared or produced by the process claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
9. A compound of formula I given in claim 1, or a pharmaceutically acceptable acid addition salt thereof wherein R, R', R2 and n are as in claim 1 and R1 is ethyl whenever prepared or produced by the process claimed in claim 4, or an obvious chemical equivalent thereof.
10. A compound of formula I given in claim 1, or a pharmaceutically acceptable acid addition salt thereof wherein R, R' and n are as in claim 1, R1 is ethyl and R2 is isopropyl or tert-butyl whenever prepared or produced by the process claimed in claim 5, or an obvious chemical equi-valent thereof.
11. A compound of formula I given in claim 1, or a pharmaceutically acceptable acid addition salt thereof wherein R and R' are as in claim 1, n is 0 or 1, R1 is ethyl and R2 is isopropyl or tert-butyl whenever prepared or produced by the process claimed in claim 6 or an obvious chemical equivalent thereof.
12. A compound of formula I given in claim 1, or a pharmaceutically acceptable acid addition salt thereof wherein R1 is ethyl, R2 is isopropyl or tert-butyl, n is 0 or 1 and R and R' are as in claim 7 whenever prepared or produced by the process claimed in claim 7 or an obvious chemical equivalent thereof.
13. A process according to claim 1, in which R is fluorine in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
14. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2 car-bethoxy 4-(4-fluoro benzamido) phenoxy]2,3-epoxy propane.
15. 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol whenever prepared by the process claimed in claim 13 or 14 or an obvious chemical equivalent thereof.
16. A process according to claim 1, in which R is fluorine in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is isopropyl.
17. A process according to claim 1, which com-prises heating isopropyl amine in ethanol with l-[2-car-bethoxy 4-(4-fluoro benzamido) phenoxy]2,3-empoxy propane.
18. 1-[2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol whenever prepared or produced by the process claimed in claim 16 or 17 or an obvious chemical equivalent thereof.
19. A process according to claim 1, in which R is fluorine in the 3-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
20. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane.
21. 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 19 or 20 or an obvious chemical equivalent thereof.
22. A process according to claim 1, which com-prises heating isopropyl amine in ethanol with 1-[2-car-bethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane and the product obtained is treated with hydrochloric ether.
23. Hydrochloride of 1-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol whenever prepared or produced by the process claimed in claim 22 or an obvious chemical equivalent thereof.
24. A process according to claim 1, in which R is fluorine in the 2-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
25. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(2-fluoro benzamido) phenoxy] 2,3-epoxy propane.
26. 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 24 or 25 or an obvious chemical equivalent thereof.
27. A process according to claim 1, which com-prises heating isopropyl amine in ethanol with hydro-chloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy]
3-isopropylamino 2-propanol and the product obtained is treated with hydrochloric ether.
3-isopropylamino 2-propanol and the product obtained is treated with hydrochloric ether.
28. Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol whenever prepared or produced by -the process claimed in claim 27 or an obvious chemical equivalent thereof.
29. A process according to claim 1, in which R
and R' are hydrogen, R1 is ethyl, n is 0 and R2 is tert-butyl.
and R' are hydrogen, R1 is ethyl, n is 0 and R2 is tert-butyl.
30. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-benzamido phenoxy] 2,3-epoxy propane.
31. 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane whenever prepared or produced by the process claimed in claim 29 or 30 or an obvious chemical equivalent thereof.
32. A process according to claim 1, in which R is methyl in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
33. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane.
34. 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 32 or 33 or an obvious chemical equivalent thereof.
35. A process according to claim 1, in which R is methyl in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is isopropyl.
36. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-methyl benzamido) phenoxy] 2,3-epoxy propane.
37. 1-[2-carbethoxy 4-(4-methyl benzamido) phenoxy] 3-isopropylamino 2-propanol whenever prepared or produced by the process claimed in claim 35 or 36 or an obvious chemical equivalent thereof.
38. A process according to claim 1, in which R is methoxy in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
39. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane.
40. 1-[2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 38 or 39 or an obvious chemical equivalent thereof.
41. A process according to claim 1, in which R is fluorine in the 2-position, R' is fluorine in the 4-position, R1 is ethyl, n is 0 and R2 is tert-butyl.
42. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(2,4-difluoro benzamido) phenoxy] 2,3-epoxy pro-pane.
43. 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 41 or 42 or an obvious chemical equivalent thereof.
44. A process according to claim 1, in which R is fluorine in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
45. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-fluoro benzacetamido) phenoxy] 2,3-epoxy pro-pane.
46. 1-[2-carbethoxy 4-(4-fluoro benzacetamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 44 or 45 or an obvious chemical equivalent thereof.
47. A process according to claim 1, in which R is chlorine in the 4-position, R1 is ethyl, R2 is tert-butyl, R' is hydrogen and n is 0.
48. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-chloro benzamido) phenoxy] 2,3-epoxy propane.
49. 1-[2-carbethoxy 4-(4-chloro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 47 or 48 or an obvious chemical equivalent thereof.
50. A process according to claim 1, in which R is methyl in the 3-position, R1 is ethyl, R2 is tert-butyl R' is hydrogen and n is 0.
51. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(3-methyl benzamido) phenoxy] 2,3-epoxy propane.
52. 1-[2-carbethoxy 4-(3-methyl benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 50 and 51 or an obvious chemical equivalent thereof.
53. A process according to claim 1, in which R is methoxy in the 3-position, R1 is ethyl, R2 is tert-butyl, R' is hydrogen and n is 0.
54. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(3-methoxy benzamido) phenoxy] 2,3-epoxy propane.
55. 1-[2-carbethoxy 4-(3-methoxy benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 53 or 54 or an obvious chemical equivalent thereof.
56. A process according to claim 1, in which R is methyl in the 2-position, R1 is ethyl, R2 tert-butyl, R' is hydrogen and n is 0.
57. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(2-methyl benzamido) phenoxy] 2,3-epoxy propane.
58. 1-[2-carbethoxy 4-(2-methyl benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 56 or 57 or an obvious chemical equivalent thereof.
59. A process according to claim 1, in which R is CH3S-in the 4-position, R1 is ethyl, R2 is tert-butyl, R' is hydrogen and n is 0.
60. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy propane.
61. 1-[2-carbethoxy 4-(4-methylthio benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 59 or 60 or an obvious chemical equivalent thereof.
62. A process according to claim 1, in which R is chlorine in the 3-position, R1 is ethyl, R2 is tert-butyl, R' is hydrogen and n is 0.
63. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(3-chloro benzamido) phenoxy] 2,3-epoxy propane.
64. 1-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-tertbutylamino 2 propanol whenever prepared or produced by the process claimed in claim 62 or 63 or an obvious chemical equivalent thereof.
65. A process according to claim claim 25, in which the 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol obtained in absolute ethanol is acidified with hydrochloric ether.
66. Hydrochloride of 1-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 65 or an obvious chemical equivalent thereof.
67. A process according to claim 1, in which R is -CF3 in the 4-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
68. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 2,3-epoxy propane.
69. 1-[2-carbethoxy 4-(4-trifluoromethyl ben-zamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 67 or 68 or an obvious chemical equivalent thereof.
70. A process according to claim 1, in which R is methoxy in the 2-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
71. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(2-methoxy benzamido) phenoxy] 2,3-epoxy propane.
72. 1-[2-carbethoxy 4-(2-methoxy benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 70 or 71 or an obvious chemical equivalent thereof.
73. A process according to claim 1, in which R is chlorine in the 2-position, R1 is ethyl, R' is hydrogen, n is 0 and R2 is tert-butyl.
74. A process according to claim 1, which com-prises heating tert-butyl amine in ethanol with 1-[2-car-bethoxy 4-(2-chloro benzamido) phenoxy] 2,3-epoxy propane.
75. 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 73 or 74 or an obvious chemical equivalent thereof.
76. A process according to claim 74, in which the 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-tertbutyl-amino 2-propanol obtained, is disolved in acetone and the solution acidified by hydrochloric ether.
77. The hydrochloride of 1-[2-carbethoxy 4-(2-chloro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 76 or an obvious chemical equivalent thereof.
78. A process according to claim 42, in which the 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-tert-butylamino 2-propanol obtained in ethanol is acidified with hydrochloric ether.
79. The hydrochloride of 1-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-tertbutylamino 2-propanol whenever prepared or produced by the process claimed in claim 78 or an obvious chemical equivalent thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8304150A FR2542737B1 (en) | 1983-03-14 | 1983-03-14 | NOVELS (CARBETHOXY-2 BENZALKYLAMIDO-4 PHENOXY) -1 AMINO-3 PROPANOLS-2, THEIR PREPARATIONS AND THEIR THERAPEUTIC USES |
| FR8304150 | 1983-03-14 | ||
| FR8318509A FR2555169B2 (en) | 1983-11-21 | 1983-11-21 | NOVEL (CARBETHOXY-2 BENZALKYLAMIDO-4 PHENOXYL) -1 AMINO-3 PROPANOLS-2, THEIR PREPARATIONS AND THEIR THERAPEUTIC USES |
| FR8318509 | 1983-11-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1218378A true CA1218378A (en) | 1987-02-24 |
Family
ID=26223333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000449516A Expired CA1218378A (en) | 1983-03-14 | 1984-03-13 | Preparation of novel 1-[2-carbethoxy 4- benzalkylamido phenoxy]3-amino 2-propanols useful in therapeutics |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0122827B1 (en) |
| KR (1) | KR910002945B1 (en) |
| AT (1) | ATE20879T1 (en) |
| AU (1) | AU567332B2 (en) |
| CA (1) | CA1218378A (en) |
| DE (1) | DE3460323D1 (en) |
| DK (1) | DK117484A (en) |
| ES (1) | ES530503A0 (en) |
| GR (1) | GR81821B (en) |
| IE (1) | IE57094B1 (en) |
| PH (1) | PH19184A (en) |
| PT (1) | PT78238B (en) |
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| EP0617020A1 (en) * | 1992-04-02 | 1994-09-28 | Shudo, Koichi, Prof. Dr. | Carboxylic acid derivatives having retinoic acid-like activity |
| DE60013491T2 (en) * | 2000-04-19 | 2005-09-01 | Neurotech Co., Ltd., Suwon | COMPOUNDS, COMPOSITIONS AND METHOD FOR PREVENTING NEURODE GENERATION IN ACUTE OR CHRONIC INJURIES OF THE CENTRAL NERVOUS SYSTEM |
| US6964982B2 (en) | 2000-04-20 | 2005-11-15 | Neurotech Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
| EP1551793B1 (en) | 2002-06-19 | 2016-01-20 | AmKor Pharma, Inc. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
| ES2690205T3 (en) | 2006-04-13 | 2018-11-19 | Neurotech Pharmaceuticals Co., Ltd. | Pharmaceutical composition to treat or prevent inflammatory diseases |
| KR100852962B1 (en) | 2007-11-12 | 2008-08-20 | 주식회사 뉴로테크 | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts |
| US8596361B2 (en) | 2007-12-14 | 2013-12-03 | 3M Innovative Properties Company | Proppants and uses thereof |
| WO2009079315A2 (en) | 2007-12-14 | 2009-06-25 | 3M Innovative Properties Company | Fiber aggregate |
| BRPI0821118B1 (en) | 2007-12-14 | 2018-11-06 | Prad Research And Development Limited | method of completing a well, method of treating an underground formation intercepted by a well, using changeable additives, and method |
| KR101204108B1 (en) * | 2009-02-09 | 2012-11-22 | 주식회사 지엔티파마 | Medicinal use of 5-benzylaminosalicylic acid derivative or its salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3852468A (en) * | 1967-02-27 | 1974-12-03 | Ici Ltd | Alkanolamine derivatives as {62 -adrenergic blocking agents |
| MX158644A (en) * | 1982-07-20 | 1989-02-21 | Menarini Sas | PROCEDURE FOR PREPARING A DERIVATIVE 1-ALKYLAMINE-3- (4 (P-ALKYL OXYBENZAMIDE) -PHENOXY) -2PROPANOL |
-
1984
- 1984-02-28 DK DK117484A patent/DK117484A/en not_active Application Discontinuation
- 1984-03-05 IE IE528/84A patent/IE57094B1/en unknown
- 1984-03-12 EP EP84400490A patent/EP0122827B1/en not_active Expired
- 1984-03-12 AT AT84400490T patent/ATE20879T1/en active
- 1984-03-12 PT PT78238A patent/PT78238B/en not_active IP Right Cessation
- 1984-03-12 ES ES530503A patent/ES530503A0/en active Granted
- 1984-03-12 GR GR74075A patent/GR81821B/el unknown
- 1984-03-12 DE DE8484400490T patent/DE3460323D1/en not_active Expired
- 1984-03-13 AU AU25537/84A patent/AU567332B2/en not_active Ceased
- 1984-03-13 KR KR1019840001323A patent/KR910002945B1/en not_active IP Right Cessation
- 1984-03-13 CA CA000449516A patent/CA1218378A/en not_active Expired
- 1984-03-14 PH PH30393A patent/PH19184A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PH19184A (en) | 1986-01-23 |
| ATE20879T1 (en) | 1986-08-15 |
| DK117484D0 (en) | 1984-02-28 |
| KR910002945B1 (en) | 1991-05-11 |
| DK117484A (en) | 1984-09-15 |
| PT78238A (en) | 1984-04-01 |
| EP0122827B1 (en) | 1986-07-23 |
| AU2553784A (en) | 1984-09-20 |
| IE57094B1 (en) | 1992-04-22 |
| IE840528L (en) | 1984-09-14 |
| GR81821B (en) | 1984-12-12 |
| EP0122827A1 (en) | 1984-10-24 |
| KR840009078A (en) | 1984-12-24 |
| ES8504681A1 (en) | 1985-05-01 |
| DE3460323D1 (en) | 1986-08-28 |
| AU567332B2 (en) | 1987-11-19 |
| PT78238B (en) | 1986-04-24 |
| ES530503A0 (en) | 1985-05-01 |
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