HU202478B - Process for producing cis- and trans-2-(aminomethyl)-cycloalkanols - Google Patents

Abstract

Prepn. of cis- and trans-2-(amino-ethyl)1-cycloalkanols of general formula (I), where n = 1, 2 or 3; R = hydrogen atoms, 1-4C straight or branched chain alkyl gp., respectively, a substd. benzyl gp.; 5-6C (substd.) cyclo-alkyl gp., 2'-adamantyl gp.; in this case a substd. phenyl-gp. - Acid adducts of (1) may be prepd. for pharmaceutical use.

Description

The present invention relates to a process for the preparation of cis or trans isomers of 2- (aminomethyl) -2-cycloalkanols of formula (I).

The compounds of formula I are known compounds having antiarrhythmic activity

According to our invention, we do so

(a) catalytically reducing a trans cyano derivative of formula (Π) in the presence of an amine of formula (V) to produce trans isomers of compounds of formula (I), or

b) for the preparation of a compound of formula I wherein R is a substituent other than hydrogen, a cis or transamino alcohol of formula ΙΠ wherein n is as defined above and an oxo compound of formula IV: wherein

Y is a reaction mixture obtained by reacting a group obtained by removing hydrogen from one of the above R substituents in an inert solvent with NaBH 4, or

c) reacting an allyl derivative of formula VII with thionyl chloride to prepare the cis isomers of a compound of formula I wherein R is not hydrogen.

In the formulas, n is 1, 2 or 3,

R is hydrogen, C 1 -C 4 straight or branched alkyl, benzyl optionally substituted by halogen, C 5 -C 6 optionally substituted by C 1 -C 6 alkyl, cycloalkyl, 2-adamantyl,

Y is a group obtained by removing hydrogen from a substituent R other than hydrogen,

R ¹ is C 1 -C 4 alkanoyl or benzoyl.

Several methods are known in the literature for the preparation of compounds of formula I: Tetrahedron 40, 2053 (1984) and 35,799 (1979); Synthesis 1981,628; Acta Chim. Hung. 70, 271 (1971) and 74,479 (1972) and 64,183 (1970).

These methods are characterized by starting from the appropriate amides or oxazinyl derivatives and using expensive and industrially hazardous LiAlH4 as reducing agents, and in many cases the isomers have to be resolved in a complicated manner due to the non-stereospecific nature of the reaction used.

However, the methods of the invention are stereospecific methods without L1AIH4.

The starting materials used in process (a) according to the invention are Zhur. Org. Kbim. 1977, 327. The procedure described therein was also applied to cyclopentane oxide.

In the process (a) according to the invention, a catalyst containing nickel or palladium is preferably used for the reduction.

Variant b) of our process is suitable for the preparation of both cis and trans compounds in good yield.

The starting material for the process is a mixture of an amino alcohol of formula (ΙΠ) and an oxo compound of formula (TV) in an inert solvent, preferably a C 1 -C 4 alcohol. NaBH4 is then added to the mixture according to the process of the present invention.

Analogous to process c) according to the invention the conversion of N-substituted derivatives of the compounds ^(L is hydrogen (VB R) formula) was known (Tetrahedron, 35 799 (1979), and the reaction proceeds via an intermediate of formula (IX).

However, for the N-substituted derivatives, the analogous reaction was not expected to take place, as it would presumably be possible to carry out the reaction via previously unknown compounds of formula VIII.

The starting compounds of formula (VII) may be prepared in a manner known per se by acylation of a cis derivative of an amino alcohol of formula (ΕΠ).

The invention is illustrated by the following examples, without limiting the scope thereof.

Example 1 trans-2-cyano-cyclopentanol g (2 mol) of sodium cyanide dissolved in 700 ml of water and ^this at a temperature below -10 C with constant stirring for 30 minutes 140 ml of 20% strength hydrochloric acid and 42 g (0 (5 moles) of epoxy-cyclopentane was added dropwise and the reaction mixture was left to shake several times a day for one week. Slowly add approx. Dry ice (150 g) was added and the reaction mixture was evaporated to dryness. To the residue was added chloroform (600 mL) and after standing overnight, the inorganic material was filtered off and washed with chloroform (2 x 200 mL). After drying and evaporating the filtrate, the crude product was distilled in vacuo (43.3 g, 78%).

Mp: 89-92 ° C at 400 Pa; nfl = 1.4690; IR 2235 cm ^-1 (C sN).

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Analysis calculated for C 6 H 8 NO (111.14): C, 64.84; H, 8.16; N, 12.60.

Found: C, 64.73; H, 8.31; N, 12.72.

Example 2 Trans-2-cyano-1-cyclohexanol

Epoxycyclohexane prepared according to Example 1. Yield: 52.6 g (84%), m.p. 102-106 ° C (400Pa; m.p. 48-49 ° C; IR 2240 cm -1) (C a N). Literature (Boiko, 1P., And Zhur. Org. Khim., 1977.327): 56%, m.p. 48-49 ° C.

Example 3 Trans-2- (aminomethyl) -1-cyclopentanol

Trans-2-cyano-1-cyclopenol (22.2 g, 0.2 mole) was dissolved in 150 ml of methanol and 100 ml of methanol containing 25% dry ammonia gas and 10 g of Raney nickel anhydrous in methanol were added. Subsequently, the mixture was reduced in an autoclave for 1.5 hours under hydrogen pressure of 2 MPa at 80 ° C. After removal of the catalyst, methanol was evaporated and the desired 1,3-amino alcohol was distilled in vacuo. Yield 21.4 g (92%), bp .: 79 to 83 ⁰ C / 400 Pa Literature (Bemáth G., et al, Acta Chim Hung 74.479 (1972) bp.. 8587.5 ° C / 530Pa

Example 4 Trans-2- (aminomethyl) -1-cyclohexanol

Prepared from trans-2-cyano-1-cyclohexanol according to Example 3. Yield 90%, bp 78-80 ° C / 400 Pa. Literature (G. Bemáth et al., Acta Chim. 64, 183 (1970) bp 85-89 ° C / 4-500 Pa).

Example 5

JV-methyl-trans-methyl-2Vamino / -l-cyclohexanol

Trans-2-cyano-1-cyclohexanol (0.05 mol, 6.25 g) was dissolved in methanol (150 ml) and 40% aqueous methylamine (20 ml) and palladium on charcoal (0.3 g) were added at 50 ° C. Hydrogen was reduced in an autoclave at 5 x ^{10 6} H 2 for 2 hours. After filtering off the catalyst the solution is evaporated to dryness under reduced pressure to afford the title compound pure aminoalcohol (separated hockey installments picrate, mp.. 171-173 ⁰ C. Literature (Gera L "et al, Acta Chim Hung 105.293 (1980)) pikrátop : 170-174 ° C.

Example 6

N-cyclohexyl-trans-2-aminomethyl / -1-cyclohexanol

A mixture of 0.2 mole (25 g) of trans-2-cyano-1-cyclohexanol and 0.4 mole (39.6 g) of cyclohexylamine in 250 ml of methanol in the presence of 1 g of palladium on charcoal at 50 ° C, ^{It was} reduced in an autoclave at ⁶ Pa hydrogen pressure. After the calculated amount of hydrogen the catalyst is filtered off, the solvent and the excess of amine was evaporated in vacuo and the residue quickly crystallized, mp 58-60 ⁰ C (n-hexane) yield 94%. The physical data for your hydrochloride are given in the table

Example 7

JV-benzene-trans-2 - / - aminomethyl / -l-cyclohexanol

A mixture of 0.02 mol (2.5 g) of trans-2-cyano-1-cyclohexanol and 0.04 mol (4.28 g) of benzylamine in 80 ml of methanol in the presence of 0.2 g of palladium-on-charcoal C, 5x10 ⁶ Pa hydrogen pressure was reduced after filtering off the catalyst the solvent was evaporated and the residue 6,25xl0 ² Pa to fractional distillation of the resulting amino alcohol fraction was deposited on hydrochloride with ethanolic hydrogen chloride for 2 hours. Yield 51%, m.p. 135-136 ° C (ethanol-ether). Literature (G. Bemáth et al., Acta Chim. Hung. 70, 271 (1971)), mp 136-137 ° C.

Example 8

JV-isopropyl-trans-2- / amino methyl / -l-cyclohexanol

The physical data of the hydrochloride of trans-2-cyano-1-cyclohexanol with isopropylamine (87% yield) in the reaction time of Example 6 are shown in the table.

Example 9

N - (n-butyl) -trans-2- (aminomethyl) -1-cyclohexanol

Prepared from Example 6 from trans-2-cyano-1-cyclohexanol with n-butylamine for 1.5 hours. Yield 83%, physical data for hydrochloride are given in the table

Example 10

Prepared from Example 6 from trans-2-cyano-1-cyclopentanol with n-butylamine in the same manner as in Example 6. Yield 87%, physical data for hydrochloride are shown in the table

Example 11

N-isopropy-trans-2- (aminomethyl) -1-cyclopentanol

Prepared from Example 6 from trans-2-cyano-1-cyclopentanol with isopropylamine for 1 hour. Yield 91%, physical data for hydrochloride are given in the table.

Example 12

N-cyclopentyl-trans-2- (aminomethyl) -1-cyclohexanol

Trans-2-aminomethyl-1-cyclohexanol (0.02 mol, 2.6 g) in ethanol (30 ml) was stirred with cyclopentanone (0.025 mol, 2.1 g) for 30 minutes, and the reaction mixture was cooled to 0 ° C and 0.025 mol ( Sodium tetrahydroborate (III) (0.95 g) was added. After stirring for 10 minutes, water (30 ml) was added to the reaction mixture and the ethanol was evaporated in vacuo and the residue was extracted with benzene (4 x 30 ml). After drying and evaporation, the crude product was distilled in vacuo. The hydrochloride of the product was separated with hydrochloric ethanol. Physical data for the hydrochloride salt are given in the table

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Example 13

N-cyclohexyl-trans-27-aminomethyl / -1-cyclohexanol

Example 12 was prepared from trans-27aminomethyl-1-cyclohexanol by cyclohexanone. Yield 90%. Its hydrochloride does not give melting point depression a

Hydrochloride of the compound prepared according to Example 6.

Example 14

N-isopropyl-trans-2- (aminomethyl) -1-cyclohexanol

Example 12 was prepared from trans-2- (aminomethyl) -1-cyclohexanol with acetone. Yield 81%. Its hydrochloride does not give melting point depression with the hydrochloride of the amino alcohol prepared in Example 8.

Example 75

N-cyclohexyl-cis-2- (aminomethyl) -1-cyclohexanol

A12. Prepared from cis-27-aminomethyl-1-cyclohexanol according to example 3c with cyclohexone. 74-75 ° C (diisopropyl ether), 89% yield. The physical data for your hydrochloride are given in the table

Example 16

N- (2'-adamantyl) -trans-2- (aminomethyl) -1-cyclohexanol

Example 12 was prepared from trans-27aminomethyl-N-1-cyclohexanol after reduction with adamantanone for 60 minutes at room temperature. Yield 77%. 173-175 ° C (diisopropyl ether). The physical data for your hydrochloride are given in the table

77. p & da

N-cyclopentyl-trans-2- (aminomethyl) -1-cyclopentanol

Trans-2-aminomethylcyclopentanol prepared according to Example 12 was cyclopentanone. Yield 80%. The physical data for your hydrochloride are given in the table

Example 18

N-cyclohexyl-trans-2- (aminomethyl) -1-cyclopentanol

Prepared from trans-2-aminomethyl-1-cyclopentanol according to Example 12 with cyclohexanone. Mp 71-73 ⁰ C (diisopropyl ether), yield 87%. The physical data for your hydrochloride are given in the table

Example 79

N-cyclohexyl-cis-2- (aminomethyl) -1-cyclopentanol

A12. prepared from cis-2- (aminomethyl) -1-cyclopentanol as described in Example 1 by cyclohexanone. M.p. 73-75 ° C (diisopropyl ether), 85% yield. The physical data for your hydrochloride are given in the table

Example 20

7β74-tert-Butyl-cyclohexyl-trans-27-aminomethyl--1-cyclohexanol

A12. prepared from trans-2- / aminomethyl / 1-cyclohexanol according to example 1b, with 4-tert-butylcyclohexanone. Ho4 zam 69%. The physical data for your hydrochloride are given in the table

Example 27

N-cyclopentyl trans-2- (aminomethyl) -1-cyclopeheptanol

Example 12 was prepared from trans-2- (aminomethyl) -1-cycloheptanol with cyclopentanone. Yield 74%. The physical data for your hydrochloride are given in the table

Example 22

N - (p-chlorobenzyl) -trans-2- (aminomethyl) -1-cyclohexanol

Example 12 was prepared from trans-2- (aminomethyl) -1-cyclohexanol with p-chlorobenzaldehyde. Yield: 68%. Hydrochloride m.p. 163-164 ° C. Literature (Phil. F., Bernáth G., Synthesis, 1981,628) m.p. 160-164 ° C.

Example 23

JV-cyclohexyl-cis-methyl-27amino / -l-cyclohexanol

The hydrochloride of the amino alcohol prepared in Example 14 (0.01 mol, 2.48 g) was benzoylated by the Schotten Baumann method with an excess of 10% benzoyl chloride (m.p. 152-155 ° C; petroleum ether) and the product was dissolved in 30 ml of chloroform without purification. and at 0 ° C, 3 ml of thionyl chloride was added with stirring over several minutes. After stirring at room temperature for 3 hours, the reaction mixture was evaporated and the resulting residue was refluxed with 50 ml of 10% aqueous hydrochloric acid for 4 hours. The benzoic acid precipitated after cooling, and the filtrate was evaporated. Trituration of the residue with acetonether gave the desired cis-amino alcohol hydrochloride (65% yield), which was identical to the product of Example 15.

Example 24

N-cyclohexyl-cis-2-aminomethyl-N-1-cyclohexanol

The amino alcohol prepared in Example 13 (0.01 mol, 2.11 g) was added to 10 ml of acetic anhydride with stirring, and after stirring for 1 hour, the reaction mixture was concentrated to dryness in vacuo. Thionyl chloride (3 mL) was added over a minute. After stirring at room temperature for 3 hours, the reaction mixture was evaporated and the resulting residue was refluxed with 50 ml of 10% aqueous hydrochloric acid for 4 hours and then evaporated. identical to the product prepared according to Example 15.

Example 25

N-cyclopentylcis-2- (aminomethyl) -1-cyclohexanol

Example 23 was prepared from N-cyclopentyl trans-2- (aminomethyl) -1-cyclohexanol (Example 12). Yield 67%, physical data for hydrochloride are given in the table

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Spreadsheet

Physical and analytical data for the hydrochlorides of V-substituted 2- (aminomethyl) -1-cycloalkanes

Example Formula Mp. * (° C) Molecular formula Móttömeg Analysis CalculatedVFound (%) C Η N IRKBr) (cm ^-1 ) 6th 13th Z ^ V ^ NH - ^^ - HCl xAoh 276-280 CuHzeCINO 247.81 63,00 63.16 10.57 10.60 5.65 5.44 3420 2920 1440 8th 14th - (· HCl 147-149 Ο, οΗζζΟΙΝΟ 207.74 57.81 57.88 10.67 10.84 6.74 6.83 3390-2920 1430 9th r ^^ Y ^ NHC ^ Hg HCl kX ₀ H 237-239 C ₂₄ H ₂₄ CINO 221.77 59.57 59.40 10.90 10.97 6.31 6.48 3355 2910 1430 10th Z ^ Y ^ NHC ^ Hg · HCl vAoh 267-269 Ο, οΗζζΟΝΟ 207.74 57.81 57.60 10.67 10.63 6.74 6.77 3410 2940 1430 11th Ζ ^ γ ^ ΝΗ— {· HCI 162-164 CeHaCINO 193.71 55.80 55.88 10.40 10.61 7.23 7.41 3365 2955 1435 12th ^ 'OH 234-237 C ₁₂ H ₂₄ CINO 233.78 61.75 61.71 10.34 10.44 5.99 6.91 3400 2920 1430 15th 23rd 24th  HCI 268-270 CnHzeCINO 247.81 63,00 63.20 10.57 10.60 5.65 5.83 33702930 1450 16th 02 ^ 215-220 C ₁₇ HjoCINO 299.88 68.08 68.16 10.08 10,31 4.67 4.69 32702920 1440 17th · HCl 257-260 Ο ,, ^ Η ΙΝΟ 219.75 60.12 60.17 10.09 10.16 6.37 6.18 3350 2950 1430 18th γ-γ ^ ΝΗ— · HCl \ - KoH 270-275 C _i2 H ₂₄ CINO 233.78 61.65 61.64 10.34 10.51 5.99 6.20 33502930 1430 19th NH— · HCl V-KOH 268-259 C _{) 2} H ₂₄ CINO 233.78 61.65 61.44 10.34 10.52 5.99 6.02 3330 2920 1440 20th - ^ ^ ~~ j ~ hct ^ OH 257-260 CuHmONO 303.91 67.18 66.82 11.27 10.80 4.61 4.78 33402930 1440 21st ZY ^ ^NH '\ J ^{, HCl} V /' / 0H 189-192 C aHaCINO 247.81 63,00 63.38 10.67 10.37 5.65 5.68 3385 2920 1440 25th CC ^NHH 0- ^HCl 165-167 C _{) 2} H ₂₄ CINO 233.78 61.65 61.71 10.34 10.65 5.99 6.18 3350 2920 1430

All the hydrochloride was recrystallized from ethanol ether.

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Example 26

N-Isopropyl-cis-2- (aminomethyl) -1-cyclohexanol Prepared according to the procedure of Example 23 from N-isopropyl-trans-2- (aminomethyl) -1-cyclohexanol (Examples 8, 14). . Yield 71%, m.p. 199-204 ° C. Literature (F. Fülöp, Bernát G „S Synthesis 1981,628) mp 201-203 ° C.

Example 27

The cis-cyclopentyl-2- / aminomethylphosphonic / -l-ciklopenttanol

Example 23 was prepared from N-cyclopentyl trans-2- (aminomethyl) -1-cyclopentanol (Example 17). Yield 67%. Hydrochloride m.p. 218-222 ° C. Literature (S. Fülöp, G. Bernáth, Synhesis 1981,628) mp 219-221 ° C.

Claims (1)

A process for the cis or trans isomers of 2-aminomethyl-1-cycloalkanols of formula I wherein n is 1,2 or 3 R is hydrogen, C 1 -C 4 straight or branched alkyl, benzyl optionally substituted by halogen, C 5 -C 6 optionally substituted C 1 -C 6 alkyl, cycloalkyl, 2-adamantyl, wherein the. for the preparation of the trans isomers of the compounds of formula (I) wherein R and n are as defined above, a compound of the formula (a) wherein n is the above trans catalytically reduced in the presence thereof, or b. for the preparation of compounds of formula (Ί) wherein R is other than hydrogen, a cis or transamino alcohol of formula (ΠΙ) wherein n is as defined above and an oxo compound of formula (IV) wherein Y is a reaction mixture obtained by reacting one of the aforementioned R substituents with a hydrogen group in an inert solvent. NaBH4, or c. a trans acyl derivative of formula (VQ) wherein R is as defined above for the preparation of cis isomers of compounds of formula (I) wherein R is other than hydrogen; R ¹ is a C 1 -C 4 alkanoyl group or a benzoyl group is reacted with trinyl chloride and then hydrolyzed by acid.