Synthesis of mono-chlorinated acetophenone

Abstract

The present invention relates to the improved synthesis of chlorinated acetophenones (CAP) of formula (I). Particularly, the invention shows a way how to reduce the use of chlorinated solvents and the formation of chlorinated volatile by-products in the synthesis. ##STR00001##

Claims

1. A process for manufacturing a compound of formula (I) ##STR00016## wherein a compound of formula II is chlorinated with sulfuryl chloride to form the compound of formula I according to the following scheme: ##STR00017## wherein R.sub.1 and R.sub.2 are independently H or OH or a substituted C1-C4 alkyl, and wherein the reaction is conducted in the presence of toluene at a temperature higher than 20° C.

2. A process according to claim 1, wherein R.sub.1 is 3-OH and R.sub.2 is H, so that the compound of formula II is 3-hydroxyacetophenone.

3. A process according to claim 1, wherein the reaction furthermore comprises the presence of an aliphatic alcohol.

4. A process according to claim 3, wherein the aliphatic alcohol is selected from methanol, ethanol, 1-propanol, and 1-butanol.

5. A process according to claim 3, wherein the aliphatic alcohol is methanol.

6. A process according to claim 3, wherein the aliphatic alcohol is present in an amount of less than 1.0 molar equivalents compared to formula (II).

7. A process according to claim 3, wherein the amount of the aliphatic alcohol is from 0.1 to 0.5 molar equivalents compared to formula (II).

8. A process according to claim 3, wherein the amount of the aliphatic alcohol is 0.2 molar equivalents compared to formula (II).

9. A process according to claim 1 wherein the temperature is more than 30° C.

10. A process according to claim 9, wherein the temperature is between 38° C. and 42° C.

11. A process for the preparation of ephedrine comprising: preparation of 3-hydroxychloroacetopheoneone (I) with R.sub.1=H and R.sub.2=3-OH according to claim 1; asymmetric reduction of the carbonyl functionality to the respective alcohol (III), and conversion of the chloride to the methylamine to form ephedrine (IV) ##STR00018##

12. A process according to claim 2, wherein the reaction furthermore comprises the presence of an aliphatic alcohol.

13. A process according to claim 12, wherein the aliphatic alcohol is selected from methanol, ethanol, 1-propanol, and 1-butanol.

14. A process according to claim 13, wherein the aliphatic alcohol is methanol.

15. A process according to claim 12, wherein the aliphatic alcohol is present in an amount of less than 1.0 molar equivalents compared to formula (II).

16. A process according to claim 15, wherein the amount of the aliphatic alcohol is from 0.1 to 0.5 molar equivalents compared to formula (II).

17. A process according to claim 16, wherein the amount of the aliphatic alcohol is 0.2 molar equivalents compared to formula (II).

18. A process according to claim 2, wherein the temperature is more than 30° C.

19. A process according to claim 18, wherein the temperature is between 38° C. and 42° C.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) According to the above mentioned reasons, the invention discloses a process for the preparation of monochlorinated substituted acetophenones, from the corresponding acetophenone, preferably 3-hydroxyacetophenone, in the presence of toluene as depicted in FIG. 9, wherein R.sub.1 and R.sub.2 may be independently H or OH or a substituted C1-C4 alkyl

(2) ##STR00014##

(3) This solves the problem of chlorinated solvents like dichloromethane in the reaction. It further results in better quality of the reaction product in terms of side products in the isolated chlorinated product. It further allows using an aliphatic alcohol as moderator in an amount of less than equimolar amount, which also solves the problem of reducing the amount of chlorinated hydrocarbons in the reaction mixture and the waste products.

(4) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of an aliphatic alcohol in the amount of less than 1 molar equivalent compared to the substituted acetophenone used.

(5) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of an aliphatic alcohol in the amount of 0.1 to less than 1 molar equivalent compared to the substituted acetophenone used.

(6) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of an aliphatic alcohol in the amount of 0.1 to 0.5 molar equivalent compared to the substituted acetophenone used.

(7) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of an aliphatic alcohol in the amount of 0.1 to 0.3 molar equivalent compared to the substituted acetophenone used.

(8) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of an aliphatic alcohol in the amount of 0.2 molar equivalent compared to the substituted acetophenone used.

(9) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of a moderator selected from methanol, ethanol, n-propanol and n-butanol in the amount of less than 1 molar equivalent compared to the substituted acetophenone used.

(10) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of a moderator selected from methanol, ethanol, n-propanol and n-butanol in the amount of 0.1 to less than 1 molar equivalent compared to the substituted acetophenone used.

(11) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of a moderator selected from methanol, ethanol, n-propanol and n-butanol in the amount of 0.1 to 0.5 molar equivalent compared to the substituted acetophenone used.

(12) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of a moderator selected from methanol, ethanol, n-propanol and n-butanol in the amount of 0.1 to 0.3 molar equivalent compared to the substituted acetophenone used.

(13) In a further embodiment of the invention, the reaction is performed in the presence of toluene and in the presence of a moderator selected from methanol, ethanol, n-propanol and n-butanol in the amount of 0.2 molar equivalent compared to the substituted acetophenone used.

(14) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of a moderator selected from methanol and n-butanol in the amount of less than 1 molar equivalent compared to the substituted acetophenone used.

(15) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of a moderator selected from methanol and n-butanol in the amount of 0.1 to less than 1 molar equivalent compared to the substituted acetophenone used.

(16) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of a moderator selected from methanol and n-butanol in the amount of 0.1 to 0.5 molar equivalent compared to the substituted acetophenone used.

(17) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of a moderator selected from methanol and n-butanol in the amount of 0.1 to 0.3 molar equivalent compared to the substituted acetophenone used.

(18) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of a moderator selected from methanol and n-butanol in the amount of 0.2 molar equivalent compared to the substituted acetophenone used.

(19) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of methanol as a moderator in the amount of less than 1 molar equivalent compared to the substituted acetophenone used.

(20) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of methanol as a moderator in the amount of 0.1 to less than 1 molar equivalent compared to the substituted acetophenone used.

(21) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of methanol as a moderator in the amount of 0.1 to 0.5 molar equivalent compared to the substituted acetophenone used.

(22) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of methanol as a moderator in the amount of 0.1 to 0.3 molar equivalent compared to the substituted acetophenone used.

(23) In a further embodiment of the invention, the reaction is performed in the presence of toluene as the solvent and in the presence of methanol as a moderator in the amount of 0.2 molar equivalent compared to the substituted acetophenone used.

(24) The chlorinated acetophenone as produced by the before mentioned embodiments may be used for the manufacture of active pharmaceutical ingredients. For example it may be used for the synthesis of ephedrine:

(25) ##STR00015##

(26) With employing the new way of manufacture of compound (I) in the synthesis of ephedrine, no need of purification in the last step is necessary. Due to the low impurity content of compound (I) when manufactured by the process as described and claimed in this invention, the entire process is more efficient, more cost effective and produces less chlorinated volatile impurities in the process.

EXAMPLES

(27) Wherever the unit of a measurement is characterized as “HPLC-result” or “area %” or “a %”, the result of a H PLC-analysis of a solution in isopropanol is stated.

(28) The value “Yield” refers to the isolated material. The H PLC-analysis shows the quality of the reaction product.

(29) Where the amount of solvent is stated in volumes (vol), it is the volume in ml calculated on the starting material in g. 60 g Hydroxyacetophenone in 120 ml toluene is equivalent to a toluene volume of 2.

(30) Where equivalents are given, the equivalents are molar equivalents calculated on the starting material.

(31) IT means inner reactor temperature. JT means jacket temperature.

Example 1

(32) Compatibility testing of solvents with sulfuryl chloride

(33) 60 ml of the solvent is stirred and sulfuryl chloride is added. The solution is monitored visually and the temperature is checked continuously. Results see Table 9

Example 2

(34) Solubility of the Starting Material in the Solvent

(35) To 1 g of HAP is added 5 ml of solvent. The mixture is stirred in a water bath at 20° C. The solvent is further slowly added under stirring until a clear solution appears.

(36) The amount of used solvent is noted.

Example 3 (Comparative Example)

(37) General procedure for the chlorination of 3-hydroxyacetophenon in dichloromethane 450 g of 3-hydroxyacetophenone are mixed with 1 l dichloromethane and 400 ml methanol. The mixture is cooled to 5-15° C.

(38) While stirring 300 g of sulfuryl chloride are added within approx. 2 h, the temperature is kept between 10 to 15° C. A second portion of 300 g of sulfuryl chloride is added within approx. 2 h, the temperature is allowed to rise up to 17-22° C. After addition the mixture is stirred at least 30 minutes at 17-22° C. 50 ml water are added within approx. 1 h. The temperature is kept between 20 to 30° C. 75 ml water are added within approx. 3 h. The temperature is kept between 20 to 30° C. The layers are separated. The aqueous layer is washed with dichloromethane.

(39) The organic layers are combined. The extract aqueous layer is disposed off.

(40) Dichloromethane is distilled off from the organic layer at a maximum of 65° C. until the distillation stagnates. The pressure is reduced for further concentration. The distillate from the concentration is distilled again and may be reused.

(41) Quality of HCAP solution in 2-propanol is as follows:

(42) TABLE-US-00009 3-Hydroxyacetophenon 1-3 area % 2-Chlor-1-(2-chlor-3-hydroxyphenyl)-ethanone 1-2 area % 2-Chlor-1-(3-hydroxy-4-chlor-phenyl)-ethanone 1-2 area % 2-Chlor-1-(2-chlor-5-hydroxyphenyl)-ethanone 2-4 area % 2,2-Dichlor-1-(3-hydroxyphenyl)-ethanone 4-6 area % 2-Chlor-1-(3-hydroxyphenyl)-ethanone 85-90 area % 

Example 4

(43) General Procedure for the Chlorination of 3-Hydroxyacetophenone (HAP)

(44) The results of different experiments are shown in Table 5 and Table 6. If changes to the general procedure were made, this also is disclosed in the tables. This might be with regards to the solvent volume for HAP, the solvent volume as diluent for sulfuryl chloride, the alcohol volume, the temperature, the equivalents of sulfuryl chloride or the addition time of the sulfuryl chloride.

(45) 11.3 g HAP is dissolved in the solvent mixture (6 vol of the solvent and 2 vol of the aliphatic alcohol) and the mixture is kept at 18° C. 15 g SO.sub.2Cl.sub.2 is added to the mixture under stirring over a period of 30 minutes keeping a temperature of between 18 and 23° C.

(46) The mixture is stirred for another 60 minutes and 50 ml water is added. The organic phase is separated and analyzed.

Example 5

(47) General Procedure for the Chlorination of 3-Hydroxyacetophenone in Toluene and n-Butanol

(48) The results of different experiments are shown in Table 7 and Table 10. If changes to the general procedure were made, this also is disclosed in the tables. This might be with regards to the toluene volume for HAP, the toluene volume as diluent for sulfuryl chloride, the butanol volume, the temperature, the equivalents of sulfuryl chloride or the addition time of the sulfuryl chloride.

(49) 10.0 g of HAP (0.073 mol), 5.48 g (1 eq.) of n-Butanol and 17.4 g of toluene are charged to the jacketed reactor under nitrogen. The mixture temperature is kept with jacket temperature (JT) 20° C. Subsequently, 13.3 g sulfuryl dichloride (1.3 eq.), dissolved in 13.3 g (1 Vol) of toluene is added dropwise over 30 minutes, keeping the IT at 20° C. After addition of the sulfuryl chloride, the mixture is stirred for 60 minutes at IT 20° C. Afterwards, the suspension is cooled to IT 0-5° C. within ca. 20 minutes and stirred at this temperature for ca. 60 minutes. The product is filtered and washed with 20 ml toluene in 2 portions. The filter cake is dried over night at 40° C.

Example 6

(50) General Procedure for the Chlorination of 3-Hydroxyacetophenon in Toluene without Moderator

(51) 10.01 g of HAP (0.073 mol), 17.40 g of toluene are charged to the jacketed reactor under nitrogen. The mixture is warmed up. Subsequently, 13.30 g sulfuryl dichloride (1.3 eq.), dissolved in 13.3 g (1 Vol) of toluene is added dropwise over 38 minutes, keeping the IT at 20° C. After addition of the sulfuryl chloride, the mixture is stirred for 60 minutes at IT 20° C.

(52) The solvents are distilled off and the product is washed with 20 ml toluene in 2 portions. The filter cake is dried over night at 40° C.

Example 7

(53) The results of different experiments are shown in Table 11. If changes to the general procedure were made, this also is disclosed in the table. This might be with regards to the toluene volume for HAP, the toluene volume as diluent for sulfuryl chloride, the methanol volume, the temperature, the equivalents of sulfuryl chloride or the addition time of the sulfuryl chloride.

(54) General procedure for the chlorination of 3-Hydroxyacetophenon in toluene and methanol 60.0 g of HAP (0.441 mol), 1.4 g (0.1 eq.) of methanol and 105.0 g of toluene (120 mL-2 Vol) are charged to the jacketed reactor under nitrogen. The mixture is warmed up with jacket temperature (JT) 40° C. Subsequently, 1.4 g (0.1 eq.) of methanol, dissolved in 26.2 g (0.5 Vol) of toluene, and 71.4 g of sulfuryl dichloride (1.17 eq.), dissolved in 70.6 g of toluene are added in parallel within ca. 70 minutes. At ca. 80% of the sulfuryl dichloride addition the gas flow increases and inner temperature (IT) is rising to 42° C. The mixture is stirred for 60 minutes at IT 40° C. Afterwards, the suspension is cooled to IT 20-25° C. within 20 minutes. The sandy suspension is stirred for 30 minutes, then cooled to IT 0-5° C. within ca. 20 minutes and stirred at this temperature for ca. 4 hours. The product is filtered and washed with 104.5 g toluene in 2 portions. The filter cake is dissolved with 140.3 g of isopropanol and the filter is rinsed with 20 g of isopropanol. The isopropanol is distilled of and the product is dried over night at 40° C.

(55) TABLE-US-00010 TABLE 9 Mi- DCM Tetraglyme THF Ether p-dioxane Methanol Ethanol Acetone Acetonitrile nutes T [° C.] T [° C.] T [° C.] T [° C.] T [° C.] T [° C.] T [° C.] T [° C.] T [° C.] 0 18 18 18 20 20 20 20.5 20.5 19 1 18 18 24 20 24 22 23.5 19 4 18.5 20 34 20 32 28 29 32 19 7 18.5 22 20.5 19 12 19 24 21 19 15 19 24 21.5 19 20 19 25 22.5 19 25 19 25 22.5 19 28 19.5 25.5 23 19 31 19.5 25 23 19 34 19.5 25 23.5 19 45 19.5 25 24 19 obser- None Slight Drastic Slight Drastic Drastic Drastic Drastic Yellowish va- gaseous gas gaseous gas gas gas gas imme- tions evolution, evo- evo- evo- evo- evo- evo- diately green lution lution lution lution lution lution yellowish and in- and in- and in- and in- and in- color. creasing creasing creasing creasing creasing temper- temper- temper- temper- temper- atue atue atue atue atue

(56) TABLE-US-00011 TABLE 10 Volumes Tol- uene n- (dil. of Bu- Tol- HPLC-results [a %] Exam- Re- SO.sub.2Cl.sub.2 SO.sub.2Cl.sub.2) tanol uene 3- core. core. core. Side yield ple marks* [eq.] [g] [eq.] [Vol] HAP HCAP 1 2 3 Chain [%] 5.8 1.3 n.a. 2 2 3.5 89.8 0.4 0.4 0.7 1.8 48.6 5.9 1.3 13.36 1.5 2 0.7 98.6 <0.05 0.2 0.2 0.3 65.3 5.10 1.3 13.3 1.0 2 2.0 97.5 <0.05 0.1 0.1 0.2 68.9 5.11 IT 1.3 13.28 0.5 2 2.5 96.5 <0.05 0.2 0.3 0.5 68.8 20° C. 5.12 IT 1.3 13.31 0.1 2 2.5 96.5 <0.05 0.2 0.3 0.5 69.3 20° C. 5.13 IT 1.3 13.29 0.1 2 1.5 97.7 <0.05 0.15 0.26 0.33 65.4 10° C. 5.14 IT 1.3 13.29 0.1 2 2.34 96.95 <0.05 0.09 0.21 0.42 68.9 30° C. 5.15 IT 1.3 13.33 0.1 2 0.07 98.22 n.d. 0.17 0.72 0.82 61.5 40° C. 5.16 IT 1.3 13.29 0.1 2 1.33 97.65 n.d. 0.10 0.35 0.56 67.4 30° C. Addi- tion over 3 hr 5.17 IT 20- 1.3 13.28 0.25 2 2.37 96.99 n.d. 0.10 0.15 0.39 70.8 30° C. 5.18 IT 1.15 11.42 0.1 2 1.52 97.09 0.02 0.17 0.55 0.65 61.0 30° C. Addi- tion over 3 h 5.19 IT 1.15 11.45 0.1 2 1.38 97.56 0.04 0.11 0.24 0.44 70.4 40° C. Addi- tion over 3 h 5.20 IT 1.15 11.44 0.2 2 2.03 97.56 n.d. 0.07 0.16 0.18 73.9 30° C. Addi- tion over 3 h 5.21 IT 1.15 11.4 0.2 2 2.19 97.34 n.d. 0.07 0.16 0.24 78.2 30° C. Addi- tion over 0.5 h 5.22 IT 1.15 11.44 0.2 3 1.81 97.61 n.d. 0.08 0.21 0.30 74.5 30° C. *Remarks contain differences to the standard procedure

(57) TABLE-US-00012 Volumes Tol- uene (dil. of) Meth- Tol- HPLC-results [a %] Exam- Re- SO.sub.2Cl.sub.2 SO.sub.2Cl.sub.2 anol uene 3- RRT RRT core. core. core. side- RRT yield ple marks* [eq.] [g] [eq.] [Vol] HAP 0.92 HCAP 1.01 1 2 3 chain 1.30 [%] 7.1 IT 10- 1.15 35.3 0.2 2 6.4 0.4 73.6 n.d. 3.4 0.4 3.5 1.7 0.3 62.2 12 °C. 7.2 IT 19- 1.15 35.3 0.2 2.5 0.63 n.d. 98.18 n.d. n.d. 0.10 0.32 0.63 0.08 78.5 22 °C. 7.3 IT 30- 1.16 — 0.2 2.5 0.3 n.d. 98.4 n.d. n.d. 0.1 0.3 0.8 n.d. 74 34 °C. 7.4 IT 35- 1.16 0.2 2.5 2.1 n.d. 97.1 n.d. n.d. 0.1 0.1 0.2 0.1 80.1 37 °C. 7.5 IT 38- 1.17 0.2 2.5 2.0 n.d. 97.5 n.d. 0.1 0.1 0.2 0.8 0.1 78.4 42 °C. 7.6 IT 38- 1.06 0.2 2.5 2.9 n.d. 95.5 n.d. 0.1 0.1 0.3 0.9 0.1 82 42 °C. 7.7 IT 38- 1.1 0.2 2.5 1.7 n.d. 97.8 n.d. 0.1 0.1 0.2 0.1 82 42 °C. 7.8 IT 38- 1.17 0.2 2.5 1.54 n.d. 97.81 n.d. n.d. 0.07 0.15 0.12 n.d. 80 42 °C. 7.9 IT 38- 1.15 0.2 2.5 1.8 n.d. 98.0 n.d. n.d. 0.05 0.08 0.08 n.d. 81 42 °C. 7.10 IT 38- 1.15 0.2 2.5 1.8 n.d. 98.0 n.d. n.d. 0.04 0.08 0.12 n.d. 82 42 °C. *Remarks contain differences to the standard procedure