Process for preparing aminothiol ester compounds and salts thereof

Abstract

A process for preparing aminothiol ester compounds and salts thereof. The present invention relates to a process for preparing compounds of formula (I), (I) comprising the following steps: a) reacting a compound of formula (II) with an inorganic acid or an organic acid, (II) b) reacting the compound obtained in step a) with a base; c) reacting the compound obtained in step b) with CO.sub.2; d) reacting the compound obtained in step c) with an alkyl chloroformate, a reagent capable of forming, with the compound obtained in step c), an acid halide, or a reagent capable of forming, with the compound obtained in step c), a mixed anhydride; e) reacting the compound obtained in step d) with an SMe anion precursor compound. ##STR00001##

Claims

1. A method for the preparation of compounds of formula (1) ##STR00014## in which X.sup.1 and X.sup.2, which are identical or different, are chosen from C.sub.1 to C.sub.7 alkyls, phenyl, benzyl, or X.sup.1 and X.sup.2 form with the nitrogen atom, which carries them, a heterocycle wherein the method comprises the following steps: a) reaction of a compound of formula (II) with an inorganic acid or an organic acid ##STR00015## b) reaction of the compound obtained in step a) with a base; c) reaction of the compound obtained in step b) with CO.sub.2; d) reaction of the compound obtained in step c) with an alkyl chloroformate, a reagent capable of forming, with the compound obtained in step c), an acid halide or a reagent capable of forming, with the compound obtained in step c), a mixed anhydride; and e) reaction of the compound obtained in step d) with an SMe.sup. anion precursor compound.

2. The method according to claim 1, wherein the compound of formula (II) is obtained by a step a1) of reaction of 3-chloro-3-methylbut-1-yne with X.sup.1X.sup.2NH in an aqueous medium.

3. The method according to claim 2, wherein the compound obtained in step a1) is purified by one or more filtrations.

4. The method according to claim 2, wherein the 3-chloro-3-methylbut-1-yne is obtained by a step a0) of reaction of 2-methylbut-3-yn-2-ol with hydrochloric acid in the presence of a copper catalyst.

5. The method according to claim 1, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.

6. The method according to claim 1, wherein the base of step b) has a pKa greater than 25.

7. The method according to claim 1, wherein step d) is implemented with: an alkyl chloroformate having a 1-6 carbon alkyl, which may comprise at least one double bond; or a reagent capable of forming with the compound obtained in stage c) a mixed anhydride chosen from acid chlorides; or a reagent capable of forming with the compound obtained in stage c) an acid halide selected from the group consisting of SOCl.sub.2, COCl.sub.2, PCl.sub.3, PCl.sub.5, PBr.sub.3 and PPh.sub.3Br.sub.2.

8. The method according to claim 1, wherein the SMe.sup. anion precursor compounds are selected from the group consisting of salts of formula XSMe, wherein X represents an alkali metal or alkaline earth metal, the methyl mercaptan, and (SMe).sub.2.

9. The method for preparing a salt of a compound of formula (1) as described in claim 1, comprising the steps of: i) preparation of the compound of formula (1) according to the method of claim 1; ii) reaction of the compound obtained in step i) with the acid corresponding to the desired salt.

10. The method according to claim 1, wherein X.sup.1 or X.sup.2, which are identical, represent a methyl.

11. The method according to claim 9, wherein said salt is fumaric, wherein said compound of formula (1) has X.sup.1 and X.sup.2, identical, representing a methyl, and in which the acid used in step ii) is fumaric acid.

12. The method according to claim 6, wherein the base implemented in step b) is chosen from bases based on lithium or magnesium.

13. The method according to claim 8, wherein the alkyl chloroformate is selected from the group consisting of methyl, ethyl, isoprenyl, isobutyl or isobutyl chloroformate.

14. The method according to claim 3, wherein the compound obtained in step a1) is purified in a succession of 2 to 10 filtrations.

15. The method according to claim 5, wherein the acid is hydrochloric acid.

16. The method according to claim 7, wherein the reagent capable of forming with the compound obtained in stage c) is pivaloyl chloride.

17. The method according to claim 12, wherein the base implemented in step b) is butyllithium or hexyllithium.

18. The method according to claim 13, wherein the alkyl chloroformate is isobutyl chloroformate.

19. The method according to claim 8, wherein the SMe.sup. anion precursor compound is NaSMe.

Description

EXAMPLE 1: PREPARATION OF S-METHYL 4-(DIMETHYLAMINO)-4-METHYLPENT-2-YNETHIOATE (DIMATE) AND FUMARATE THEREOF

(1) 1. Step a0)

(2) 226.4 g of CaCl.sub.2 (2.040 mol), 219.70 g of CaCl.sub.2 (1.634 mol) and 2.40 g of Cu (0.0384 mol) are added to a flask. The mixture is placed at 20 C. 1770 ml of HCl (57.8 mol) are added in 30 minutes. The reaction mixture is stirred for 1 hour at 20 C. 300 g of 2-methyl-3-butyn-2-ol (4 mol) are added over 45 minutes at 20 C. After 2 h30 at 20 C. and return to room temperature (20-25 C.), the mixture is left to settle, then the phases are separated and the organic phases are washed 6 times with 140 ml of 37% HCl, then with water. The organic phases are then combined and dried over K.sub.2CO.sub.3 and then distilled over K.sub.2CO.sub.3 at 40-45 C., 350 mbar. 268 g of 3-chloro-3-methylbut-1-yne are obtained (yield 60%).

(3) 2. Step a1)

(4) 268 g of the compound obtained in step a0) (2.61 mol) are added to a flask with 476 ml of dimethylamine (40% by weight in aqueous solution) (9.41 mol). After 16 hours of reaction at room temperature, the reaction medium is filtered, the filtrate obtained is mixed and then filtered and this step is repeated 2 more times. 156.5 g of the amine are obtained (yield 53.8%).

(5) 3. Step a)

(6) 156.5 g of the amine obtained in step a1) are dissolved in 7 volumes of dioxane and 3 volumes of dioxane HCl 6.5M. At the end of the reaction at ambient temperature, the salt is filtered and washed with dioxane and then recrystallized from an EtOH/AcOEt mixture (70/30 8 volumes). 146 g of the amine salt are obtained (yield of 37.8%).

(7) 4. Stages b), c), d) and e)

(8) 500 mg of the salt obtained in step a) (0.003386 mol) is introduced, under a nitrogen atmosphere, into a flask with 5 ml of tetrahydrofuran (0.06 mol). The reaction mixture is cooled to 78 C. 3 ml of a 2.5M solution of n-BuLi in hexane are added. The reaction mixture is allowed to reach 0 C. 1 g of CO.sub.2 (0.03 mol) is added (by bubbling) at 0 C. The reaction mixture is allowed to reach room temperature (20-25 C.). The reaction mixture is then cooled to 0 C. and 0.486 ml of isobutyl chloroformate (0.00372 mol) are added. The reaction mixture is allowed to reach room temperature (20-25 C.). 0.285 g of NaSMe (0.00406 mol) are added. After 20 min at room temperature (20-25 C.), water and ethyl acetate are added. The aqueous phases are extracted with ethyl acetate and the organic phases are washed with saturated NaCl solution, dried over MgSO.sub.4 and concentrated to give a yellow oil (600 mg). The product obtained is purified on silica gel with a 9/1 to 7/3 cyclohexane/AcOEt eluent and the dimate is obtained (157 mg) in the form of a colorless oil (yield 25.02%).

(9) 5. Step ii)

(10) 11.4 g of fumaric acid (0.09821 mol) are dissolved in 450 ml of ethanol (7.7 mol) at room temperature, a sonication that may achieve total solubilization. This solution is added dropwise to a solution of 19.2 g of dimate (0.1036 mol) in 250 ml of ether (2.4 mol). After 30 minutes, the resulting mixture is filtered, washed with ether (50 ml), dried under vacuum and the dimate fumarate is obtained as a white solid (19.1 g, 64.5% yield).

(11) Compound Obtained at the End of Step e) (DIMATE)

(12) .sup.1H NMR (300 MHz, CDCl.sub.3): =1.42 (s, 6H, (CH.sub.3).sub.2), 2.31 (s, 6H, N(CH.sub.3).sub.2), 2.39 ppm (s, 3H, CH.sub.3S).

(13) .sup.1H NMR (300 MHz, DMSO-d.sub.6): =1.35 (s, 6H, (CH.sub.3).sub.2), 2.20 (s, 6H, N(CH3h), 2.39 ppm (s, 3H, CH3S).

(14) .sup.13C NMR (75 MHz, CDCl.sub.3): 0=12.1 (CH.sub.3S) 27.5 ((CH.sub.3).sub.2), 40.0 (N(CH.sub.3).sub.2), 54.7 (C), 81.5 (C), 94.7 (C), 175.8 (COS) ppm

(15) Compound Obtained at the End of Step ii) (DIMATE FUMARATE):

(16) .sup.1H NMR (300 MHz, DMSO-d.sub.6): =1.36 (s, 6H, (CH.sub.3).sub.2), 2.21 (s, 6H, N(CH.sub.3).sub.2), 2.39 (s, 3H, CH.sub.3S), 6.63 (s, 2H, CH), 13.12 ppm (s, 2H, CO.sub.2H).

(17) .sup.1H NMR (300 MHz, D.sub.2O): =1.79 (s, 6H, (CH.sub.3).sub.2), 2.46 (s, 3H, CH.sub.3S), 2.98 (s, 6H, N(CH.sub.3).sub.2), 6.68 ppm (s, 2H, CH).

(18) .sup.13C NMR (75 MHz, DMSO-d.sub.6): =12.3 (CH.sub.3S), 27.2 ((CH.sub.3).sub.2), 39.8 (N(CH.sub.3).sub.2), 54.7 (C), 81.2 (C), 95.4 (C), 134.1 (CH), 166.1 (CO.sub.2H), 175.8 (COS) ppm

EXAMPLE 2: PREPARATION OF S-METHYL-4-[HEPTYL (METHYL) AMINO]-4-METHYL-PENT-2-YNETHIOATE

(19) The procedure detailed in steps a0) to e) is repeated using the following amine (compound of formula II): N-(1,1-dimethylprop-2-ynyl)-N-methyl-heptan-1-amine. To N-methylheptan-1-amine (3.84 g, 29.7 mmol) dissolved in THF (50 mL) are added successively at room temperature (20-25 C.) diisopropylamine (4.3 mL, 24.7 mmol), Cu (0.150 g, 2.4 mmol), CuCl (0.150 g, 1.5 mmol) and then 3-chloro-3-methylbut-1-yne (2.54 g, 24.8 mmol) (obtained as mentioned in Example 1). The reaction medium is stirred for 16 hours. After addition of 25 mL of water and decantation, the aqueous phase is extracted with ethyl acetate (330 mL). The combined organic phases are washed successively with 10% aqueous NH.sub.4OH (25 mL) and a saturated aqueous solution of NaCl (25 mL). After drying over Na.sub.2SO.sub.4, concentration on a rotary evaporator, the residue is purified by vacuum distillation in a Kugelrohr apparatus (18 Torr, oven temperature: 100 to 150 C.). 2.10 g of N-(1,1-dimethylprop-2-ynyl)-N-methyl-heptan-1-amine are obtained in the form of a colorless oil, yield 43%.

(20) Molecular weight=195.35

(21) Chemical formula=C13H25N.

(22) .sup.1H NMR (300 MHz, DMSO) 3.08 (s, 1H), 2.37-2.28 (m, 2H), 2.13 (s, 3H), 1.39-1.18 (m, 10H), 1.27 (s, 6H), 0.91-0.80 (m, 3H).

(23) .sup.13C NMR (75 MHz, CDCl.sub.3) 086.29 (C), 70.72 (CH), 54.59 (C), 52.36 (CH.sub.2), 36.27 (CH.sub.3), 31.95 (CH.sub.2, 29.36 (CH.sub.2), 29.05 (CH.sub.2), 28.49 (CH.sub.3)), 27.61 (CH.sub.2), 22.69 (CH.sub.2), 14.14 (CH.sub.3).

(24) ESI-LRMS 196.0 [M+H].sup.+.

(25) The final product is obtained from 0.51 g (2.6 mmol) of N-(1,1-dimethylprop-2-ynyl)-N-methyl-heptan-1-amine with a yield of 25% in liquid form (free base) (0.176 g)

(26) Compound Obtained at the End of Step e) (S-methyl 4-[heptyl(methyl) amino]-4-methyl-pent-2-ynethioate)

(27) .sup.1H NMR (300 MHz, DMSO) 2.38 (s, 3H), 2.37 (t, J=7.0 Hz, 2H), 2.18 (s, 3H), 1.35 (s, 6H), 1.42-1.20 (m, 10H), 0.86 (t, J=6.7 Hz, 3H).

(28) .sup.13C NMR (75 MHz, CDCl.sub.3) 176.38 (C), 96.50 (C), 81.03 (C), 54.98 (C), 52.39 (CH.sub.2), 36.39, 31.85 (CH.sub.2), 29.25 (CH.sub.2), 28.79 (CH.sub.2), 27.81 (2CH.sub.3), 27.41 (CH.sub.2), 22.62 (CH.sub.2), 14.09 (CH.sub.3), 12.41 (CH.sub.3).

(29) ESI-LRMS 270.2 [M+H].sup.+.

EXAMPLE 3 PREPARATION OF S-METHYL 4-(DIHEPTYLAMINO)-4-METHYL-PENT-2-YNETHIOATE

(30) The method detailed in steps a0) to e) is repeated using the following amine (compound of formula II): N-(1,1-dimethylprop-2-ynyl)-N-heptyl-heptan-1-amine.

(31) To N-heptylheptan-1-amine (5.2 g, 24.4 mmol) dissolved in THF (41 mL) are added successively at room temperature (20-25 C.) diisopropylamine (3.54 mL, 20.3 mmol), Cu (0.120 g, 1.9 mmol), CuCl (0.120 g, 1.2 mmol) then 3-chloro-3-methylbut-1-yne (2.08 g, 20.3 mmol)) (obtained as mentioned in Example 1). The reaction medium is stirred for 16 hours. After addition of 25 mL of water and decantation, the aqueous phase is extracted with ethyl acetate (330 mL). The combined organic phases are washed successively with 10% aqueous NH.sub.4OH (25 mL) and a saturated aqueous solution of NaCl (25 mL). After drying over Na.sub.2SO.sub.4, concentration on a rotary evaporator, the residue is purified by vacuum distillation in a Kugelrohr apparatus (18 Torr, oven temperature: 100 to 150 C.). 1.50 g of N-(1,1-dimethylprop-2-ynyl)-N-heptyl-heptan-1-amine are obtained in the form of a colorless oil, yield 27%.

(32) The final product is obtained from 0.51 g (1.82 mmol) of N-(1,1-dimethylprop-2-ynyl)-N-heptyl-heptan-1-amine with a yield of 29% in the form of a liquid (base free) (0.187 g).

(33) Compound Obtained at the End of Step e) (S-methyl 4-(diheptylamino)-4-methyl-pent-2-ynethioate)

(34) .sup.13C NMR (75 MHz, CDCl.sub.3) 176.50 (C), 98.81 (C), 80.18 (C), 54.80 (C), 51.21 (CH.sub.2), 31.94 (CH.sub.2), 30.05 (CH.sub.2), 29.29 (CH.sub.2), 28.61 (CH.sub.3), 27.45 (CH.sub.2), 22.67 (CH.sub.2), 14.13 (CH.sub.3), 12.41 (CH.sub.3).

(35) ESI-LRMS 354.1 [M+H].sup.+.

(36) or compound.