Method for the preparation of naproxen chloride

The invention relates to a method for the preparation of 2-(6'-methoxy-2'-naphthyl)propionic acid chloride (naproxen chloride) using phosgene, and a method for the preparation of esters and amides derived from the thus prepared naproxen chloride.

Esters and amides derived from 2-(6'-methoxy-2'-naphthyl)propionic acid are known in the literature and are useful as drugs against inflammation, pain and pyrexia. US Patent 4,048,330 and WO 2009/000723 A disclose methods for the preparation of 2-(6'- methoxy-2'-naphthyl)propionic acid chlorides using thionyl chloride, and derivates there from.

Since the 2-(6'-methoxy-2'-naphthyl)propionic acid derivatives are used as drugs, a high degree of purity is desired and mandatory. The analysis of products prepared by the known methods using thionyl chloride shows impurities. There was a need for an improved process which provides products with higher purity. Surprisingly, by the disclosed process the problem can be solved. Halogen in the following means F, CI, Br or I; alkyl comprises linear or branched alkyl; if not otherwise stated.

Subject of the invention is a method for the preparation of a compound of formula (I),

characterized by a reaction (A) of a compound of formula (II) with a compound (PhosA),

the compound (PhosA) is selected from the group consisting of phosgene, diphosgene,

triphosgene and reagent (A),

reagent (A) is a compound of formula (PhosAl).

(PhosAl)

Compound of formula (II) is called naproxen, compound of formula (I) is called naproxen chloride.

The method allows the preparation of both enantiomers individually and of a racemic mixture of the enantiomers of compound of formula (I). What is formed depends on which compound of formula (II) is used.

Preferably, compound of formula (II) is a compound of formula (Il-down),

Preferably, compound of formula (I) is a compound of formula (I-down).

Preferably, compound of formula (I-down) is prepared by reaction (A) by using compound of formula (II-down).

The compound of formula (PhosAl) is a known compound and is made by a reaction of phosgene with dimethylformamide.

Preferably, the compound (PhosA) is selected from the group consisting of monophosgene, diphosgene, triphosgene and compound of formula (PhosAl).

The compound (PhosA) and the compound of formula (II) are known compounds and can be prepared by known methods.

Preferably the reaction (A) is carried out in the presence of a catalyst (A), the catalyst (A) being a compound of formula (III),

O

^H - ^R4 (in)

R5

wherein

R4 and R5 are identical or different and independently from each other selected from the group consisting of hydrogen and C1.4 alkyl.

More preferably, R4 and R5 are identical or different and are independently from each other

C alkyl.

Even more preferably, R4 and R5 are identical and are methyl or ethyl.

Preferably the reaction time in reaction (A) is of from 5 min to 24 h, more preferably of from 10 min to 16 h, even more preferably of from 15 min to 8 h. Preferably the reaction (A) is carried out in a solvent (A), the solvent (A) being selected from the group consisting of dichloromethane, chlorobenzene, toluene, acetonitrile, dioxane, tetrahydrofurane (THF) and ethylacetate;

more preferably of dichloromethane, chlorobenzene, toluene, acetonitrile, dioxane and ethylacetate;

even more preferably of dichloromethane, chlorobenzene and ethylacetate;

especially, solvent (A) is dichloromethane.

Preferably the reaction (A) is carried out at a pressure of from atmospheric pressure to 15 atm. More preferably the reaction (A) is carried out at atmospheric pressure.

Preferably the reaction (A) is carried out at a temperature of from -10 to 150 °C, more preferably of from -5 to 60 °C, even more preferably of from 0 to 40 °C. Preferably, the amount of solvent (A) is of from 0.1 to 10.0 fold, more preferably of from 1.0 to 6.0 fold, even more preferably of from 2.0 to 4.0 fold, of the weight of compound of formula (II).

Preferably, of from 1.0 to 6.0 mol-equivalents, more preferably of from 1.0 to 4.0 mol- equivalents, even more preferably of from 1.3 to 2.0 mol-equivalents, of compound (PhosA) are used, with the mol-equivalents being based on the moles used of compound of formula (II).

If a catalyst (A) is used, then preferably, of from 0.01 to 1.50 mol-equivalents, more preferably of from 0.01 to 1.00 mol-equivalents, even more preferably of from 0.02 to 0.50 mol-equivalents, of catalyst (A) are used, with the mol-equivalents being based on the moles used of compound of formula (II).

Preferably compound of formula (I) is isolated by standard procedures such as filtration and subsequent drying.

Preferably before a filtration, a precipitation is done by adding a precipitating solvent to the reaction mixture, preferably the precipitating solvent is selected from the group consisting of C5-8 alkane, Ci_4 alkyl C5-8 cycloalkane and mixtures thereof; more preferably of pentane, hexane, heptane, cyclopentane, cyclohexane, cycloheptane, C14 alkylcyclopentane, Ci-4 alkylcyclohexane, C alkylcycloheptane and mixtures thereof; with the C alkyl being preferably methyl or ethyl.

Especially the precipitating solvent is n-hexane, methylcyclohexane or mixtures thereof. Further subject of the invention is a method for the preparation of a compound of formula (IV),

wherein

X is ORl or N(R2)R3 ;

Rl is selected from the group consisting of C _1-10 alkyl, phenyl and benzyl, with Rl being unsubstituted or substituted by 1 , 2 or 3 substituents selected from the group consisting of halogene, CM alkoxy and nitro;

R2 and R3 are identical or different and are independently from each other selected from the group consisting of hydrogen, Ci-io alkyl, phenyl and benzyl, with R2 and R3 being independently from each other unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of halogene, CM alkoxy and nitro; characterized by two steps, the first step being the reaction (A) as defined above,

the second step being a reaction (B) of the compound of formula (I), which has been prepared in the first step, with a compound of formula (V),

X

H

(V) wherein the X in formula (V) has the same definition as and is identical with the X in formula (IV). Preferably, Rl is selected from the group consisting of C1.4 alkyl, phenyl and benzyl, with Rl being unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, Br and C _{1 -2} alkoxy.

Preferably, R2 and R3 are identical or different and independently from each other selected from the group consisting of hydrogen, C alkyl, phenyl and benzyl, with R2 and R3 being independently from each other unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, Br and C _1-2 alkoxy

More preferably, Rl is selected from the group consisting of methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, phenyl and benzyl, with Rl being unsubstituted or substituted by 1 substituent selected from the group consisting of F, CI and methoxy.

More preferably, R2 and R3 are identical or different and independently from each other selected from the group consisting of hydrogen, C _1-3 alkyl, phenyl and benzyl, the R2 and R3 being unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, CI, Br and C _{1 -2} alkoxy.

Even more preferably, Rl is selected from the group consisting of ethyl, 3-chloro-l-propyl, iso-propyl and benzyl.

Even more preferably, R2 is hydrogen and R3 is benzyl; or R2 and R3 are iso-propyl.

Preferably, compound of formula (IV) is a compound of formula (IV-down),

Preferably, compound of formula (IV-down) is prepared by using compound of formula (II- down) in the first step of the reaction sequence, i .e. in the reaction (A).

Preferably the reaction time in reaction (B) is of from 5 min to 30 h, more preferably of from 10 min to 24 h, even more preferably of from 30 min to 20 h. Preferably the reaction (B) is carried out in a solvent (B), the solvent (B) being selected from the group consisting of dichloromethane, chlorobenzene, toluene, acetonitrile, dioxane, tetrahydrofurane (THF) and ethylacetate;

more preferably of dichloromethane, chlorobenzene, toluene, acetonitrile, dioxane and ethylacetate;

even more preferably of dichloromethane, chlorobenzene and ethylacetate;

especially, solvent (B) is dichloromethane.

Preferably the reaction (B) is carried out at atmospheric pressure.

Preferably the reaction (B) is carried out at a temperature of from 0 to 200 °C, more preferably of from 5 to 100 °C, even more preferably of from 10 to 50 °C.

Preferably, the amount of solvent (B) is of 0.1 to 10.0 fold, more preferably of from 1.0 to 6.0 fold, even more preferably of from 2.0 to 4.0 fold, of the weight of compound of formula (II).

Preferably, of from 0.8 to 5.0 mol-equivalents, more preferably of from 0.9 to 3.0 mol- equivalents, even more preferably of from 1.0 to 2.0 mol-equivalents, of compound of formula (V) are used, with the mol-equivalents being based on the moles used of compound of formula (II).

The compounds of formula (V) are known compounds and can be prepared by known methods. Preferably, the compound of formula (IV) is isolated by standard procedures such as washing the reaction mixture, evaporation of the reaction solvent and subsequent drying.

Preferably, the washing of the reaction mixture is done with aqueous sodium carbonate or with water or with both. Preferably reaction (A) and reaction (B) are done consecutively without isolating the compound of formula (I), preferably solvent (A) and solvent (B) are identical.

More preferably reaction (A) and reaction (B) are done in one pot, and solvent (A) and solvent (B) are identical. Surprisingly, the use of the compound (PhosA) instead of thionyl chloride provides higher purities, i.e. less by products in the reaction (A). A one pot synthesis of compound of formula (IV) starting from the compound of formula (II) thereby also enjoys this benefit, and this is important for the production of pharmacologically used compounds of formula (IV).

Also the yields can be improved by using phosgene and its derivatives instead of thionyl chloride.

Furthermore, when an entiomerically pure compound of formula (II) is used as starting material, the use of phosgene allows for the production of enantiomerically pure compounds of formula (I) and (IV), i.e. no racemization occurs.

Examples

List of Abbreviations and Raw materials

DCM dichloromethane

DMF dimethylform amide

eq. molar equivalent to the respective reagent of the reference example

NMR Nuclear Magnetic Resonance

HPLC High Pressure Liquid Chromatography

IPC In Process Control

RRT relative retention time: the retention time was expressed relative to the

respective reaction product, if not otherwise stated

THF tetrahydrofurane

Compound of formula (II-down) was used in commercial quality

Method Description

HPLC Method 1): Determination of conversion rate and purity

The conversion rate, also called "conversion" or "conv" in the following, and the purity, both given in the below examples, were determined according to the following method:

Waters Symmetry CI 8, 250.0 x 4.6mm, 5pm, temperature 40°C

Flow: 0.8 mL/min

Mobile phase A: acetonitrile

Mobile phase B: buffer

Buffer: 0.33% (v/v) AcOH in water, pH adjusted with 25 wt% aq. NaOH to 4.0

Run time: 30 min

Gradient composition: 67% mobile phase A and 33% mobile phase B

Detection at 232 nm

Sample preparation

A specific amount of sample of 50 mg was dissolved in 50 mL acetonitrile.

Injection volume was 1 μL.

HPLC Method 2): Determination of enantiomeric purity

The enantiomeric purity, given in the below examples, was determined according to the following method:

Regis (S,S)-WHELK-0-l (5pm), Ι ΟθΑ, 250 x 4.6mm I.D., temperature 25°C Flow: 2.0 mL/min

Eluent: 850 mL of methanol and 150 mL of water.

Run time: 20 min

Gradient composition: 100% eluent

Detection at 232 nm

Sample preparation

A specific amount of sample in the range of 70 to 90 mg was dissolved in ca. 50 mL MeOH. To 1 mL of the prepared solution 19 mL of eluent were added. Injection volume was 10 μL.

Yields in examples 1 to 22 are crude yields without considering purity. Yields in examples 23 to 29 were calculated having taken into consideration the purity.

LOD-method (Loss on Drying-method)

A small portion (1 to 5 g) of the wet cake, which was obtained after filtration, was taken and dried under nitrogen over night. The thereby determined dry content was used to calculate the dry content of the wet cake.

Example 1

To a suspension of compound of formula (II-down) (30.5 g, 132.4 mmol), DCM as solvent (78 ml) and DMF as catalyst (0.51 g, 7.0 mmol) at 20 to 25°C, phosgene as chlorination agent (25.6 g / 258.8 mmol) was added in 20 min. The mixture was stirred at 20 to 25°C for 1.5 h (conversion 99%). The DCM was distilled off at an inner temperature of 35 to 40°C until having a final volume of ca. 50 mL. The resulting suspension was cooled to 5 to 10°C in ca. 1 h. n-Hexane (252 ml) was added in the process of the cooling. After stirring for another 2 h the solid was filtered off under Nitrogen. The filtrate was washed with n-Hexane (2 times with 32mL each). 29.1 g of compound of formula (I-down) (118 mmol) were obtained based on LOD-method.

Yield: 89% yield

Purity: 99.2%.

Enantiomeric purity: 0.5 area% (R)-enantiomer (HPLC, method 2)

Comparative example 1

Example 8 of WO2009/000723 was repeated exactly as described. Yield obtained was 85 %.

Comparison of the impurity profile is given in table 1. Clearly, the method of instant invention provides higher purity. Table 1 shows area %, determined according to HPLC method 1. "n.o. " means "not observed".

Example 2

Example 1 was repeated with the differences given in table 2.

Examples 3, 4 and 5

Example 1 was repeated with the differences given in table 3, and the compound of formula (I-down) was not isolated, instead the reaction sequence ended after cooling to 20°C and before addition of n-Hexane.

Examples 6, 7, 8, 9, 10 and 11

Example 1 was repeated with the differences given in table 4. In examples 7 and 8, the compound of formula (I-down) was not isolated, instead the reaction sequence ended after cooling to 20 to 25°C and before addition of n-Hexane. In example 7, also the reaction temperature was changed as given in the table.

Examples 12, 13 and 14

Example 1 was repeated with the differences given in table 5. In examples 13 and 14, the compound of formula (I-down) was not isolated, instead the reaction sequence ended after cooling to 20 to 25°C and before addition of n-Hexane. Table 5

Ex Phosgene eq. DMF Conversion Reaction yield Purity R- eq. time Enantiomer

HPLC

12 1.50 0.10 96% 2 h 92% 99.0% 0.5%

13 1.25 0.10 69% 5 h - - -

14 3.00 1.00 >99% 1 h - - -

Examples 15 and 16

Example 1 was repeated with the differences given in table 6.

In example 16, the compound of formula (I-down) was not isolated, instead the reaction sequence ended after cooling to 20 to 25°C and before addition of n-Hexane.

Examples 17, 18, 19 and 20

Example 1 was repeated with the differences given in table 7.

In examples 17, 18, 19 and 20, the compound of formula (I-down) was not isolated, instead the reaction sequence ended after cooling to 20 to 25°C and before n-Hexane was added.

Example 21

Example 1 was repeated with the differences given in table 8.

In example 21, the compound of formula (I-down) was isolated using methyl cyclohexane instead of n-Hexane. Table 8

Ex DMF eq. Reaction time Conversion yield Purity

21 0.10 2 h 97% 80% 99.2%

Example 22

To a suspension of compound of formula (II-down) (30.5 g, 132.4 mmol), DCM as solvent (78 ml) and DMF as catalyst (0.51 g, 7.0 mmol) at 20°C, phosgene as chlonnation agent (25.6 g / 258.8 mmol) was added in 20 min. The mixture was stirred at 20°C for 3 h (conversion (1) 98%). The DCM was distilled off at an inner temperature of 35 to 40°C under pressure until having a final volume of ca. 50 mL. DCM (ca. 30 mL) was then added until having replaced the amount, which had been distilled off. The solution was cooled to 20°C and n-butanol (13.5 g, 193.4 mmol) was added. After a reaction time of 19 h (conversion (2) 99%) the mixture was cooled to 0 to 5°C and washed with 10% aq. sodium carbonate (3 times with 100 mL each) and with water (100 mL). The organic phase was distilled off until dryness and 35.5 g of compound of formula (1) (125 mmol) were obtained.

Yield 96%

Purity 98.8%

1H MR (500 MHz, CDC1 ₃ ): δ = 7.68 (m, 3H), 7.40 (dd, J = 8.5 and 1.8 Hz, 1H), 7.13 (m, 1H), 7.10 (d, J = 2.4 Hz, 1H), 4.07 (m, 2H), 3.90 (s, 3H), 3.84 (q, J = 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H), 1.53 (m, 2H), 1.28 (m, 2H), 0.85 (t, J = 7.5 Hz, 3H).

Examples 23, 24 and 25

Example 22 was repeated with the differences given in table 9 to produce different esters.

NMR data of compound of formula (2) obtained in example

1H MR (500 MHz, CDC1 ₃ ): δ = 7.69 (m, 2H), 7.64 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8 and 1.8 Hz, 1H), 7.13 (m, 1H), 7.10 (d, J = 2.5 Hz, 1H), 4.22 (m, 2H), 3.89 (s, 3H), 3.84 = 7.1 Hz, 1H), 3.43 (m, 2H), 2.00 (m, 2H), 1.57 (d, J = 7.1 Hz, 3H).

NMR data of compound of formula (3) obtained in example

1H NMR (500 MHz, CDC1 ₃ ): δ = 7.69 (m, 2H), 7.66 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.6 and 1.8 Hz, 1H), 7.13 (m, 1H), 7.1 1 (d, J = 2.5 Hz, 1H), 5.00 (spt, J = 6.4 Hz, 1H), 3.91 (s, 3H), 3.80 (q, J = 7.0 Hz, 1H), 1.55 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H). NMR data of compound of formula (4) obtained in example 25:

1H MR (500 MHz, CDC1 ₃ ): δ = 7.65 (m, 3H), 7.39 (dd, J = 8.5 and 2.0 Hz, 1H), 7.19 - 7.29 (m, 5H), 7.12 (dd, J = 8.8 and 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 5.10 (AB system, J = 12.4 Hz, 2H), 3.89 (q, J = 7.1 Hz, 1H), 3.88 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H).

Example 26

Example 22 was repeated with the differences given in table 10 and the further difference, that during the washes performed after cooling the reaction mixture to 0-5°C a suspension appeared. The suspension was filtered off. The organic phase of the resulting mother liquor was evaporated and the solid obtained after evaporation was combined with the solid obtained after filtration. The combined solids consisted of compound of formula (5). Analysis and yield obtained are detailed in table 10.

NMR data of compound of formula (5) obtained in example

(5)

1H MR (500 MHz, CDC1 ₃ ): δ = 7.69 (m, 2H), 7.66 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.4 and 1.8 Hz, lH), 7.13 (m, 1H), 7.1 1 (d, J = 2.5 Hz, 1H), 4.13 (m, 2H), 3.90 (s, 3H), 3.83 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). Example 27

To a suspension of compound of formula (II-down) (30.5 g, 132.4 mmol), DCM as solvent (78 ml) and DMF as catalyst (0.51 g, 7.0 mmol) at 20°C, phosgene as chlorination agent (25.6 g, 258.8 mmol) was added in 20 min. The mixture was stirred at 20 to 25°C for 2.5 h (reaction time 1) (conversion (1) 98%). The DCM was distilled off at an inner temperature of 35 to 40°C under pressure until having a final volume of ca. 50 mL. DCM (ca. 30 mL) was then added until having replaced the amount distilled. The solution was cooled to 20°C and benzyl amine (28.8 g, 270 mmol) was added. After stirring for 18 h (reaction time 2) (conversion (2) 98%), the mixture was cooled to 0 to 5°C and washed with 10% aq. sodium carbonate (3 times with 100 mL each) and with water (100 mL). The organic phase was distilled off until dryness and 32.6 g of compound of formula (6) (101 mmol) were obtained.

Yield 76%

Purity 96%

1H MR (500 MHz, CDC1 ₃ ): δ = 7.70 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 9. 1 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.5 and 1.8 Hz, 1H), 7.23 (m, 3H), 7.13 (m, 4H), 5. 13 (br. s., 1H), 4.37 (m, 2H), 3.90 (s, 3H), 3.72 (q, J = 7.1 Hz, 1H), 1.62 (d, J = 7.1 Hz, 3H).

Example 28

Example 27 was repeated with the differences given in table 1 1 and the further difference, that after cooling to 0 to 5°C, the mixture was washed 6 times (100 mL each) with 10% aq. sodium carbonate instead of 3 times, and then 2 times (100 mL) with water each instead of 1 time. Table 11

Ex Amine Reaction Conv (1) Reaction Conv (2) yield Purity time 1 time 2

28 Diisopropyl- 1 h 99% 44 h 94% 75% 96% amine

NMR data of compound of formula (7) obtained in example

IH NMR (500 MHz, CDC1 ₃ ): δ = 7.68 (m, 2H), 7.59 (d, J = 1.8 Hz, IH), 7.35 (dd, J = 8.5 and 1.8 Hz, IH), 7.12 (m, IH), 7.10 (d, J = 2.5 Hz, IH), 4.09 (spt, J = 6.6 Hz, IH), 3.93 (q, J = 6.7 Hz, IH), 3.89 (s, 3H), 3.30 (m, IH), 1.46 (m, 6H), 1.40 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 0.52 (d, J = 6.6 Hz, 3H).