WO2015154637A1 - Method for preparing silodosin intermediate - Google Patents

Abstract

A method for preparing silodosin intermediate is disclosed. Said intermediate has the structure of (M), wherein R is benzyl or benzoyl. Said preparation method has the characteristics of short reaction route, simple operation, low cost, high yield, stable process, etc. The method is suitable for industrial production, and has extra-high industrial application value. Intermediate compounds for preparing the intermediate represented by M are also disclosed.

Description

Method for preparing silodosin intermediate Technical field

The invention belongs to the technical field of medicine, and in particular relates to a method for preparing an intermediate of silodosin and a novel intermediate compound involved in the method.

Background technique

Benign prostatic hyperplasia (BPH) is a common and frequently-occurring disease in middle-aged and elderly men. Currently, the drugs used to treat BPH are mainly divided into two categories: α1 adrenergic receptor (α-AR) antagonist and 5α reductase inhibitor. Among them, α-AR antagonists are characterized by fast, safe and efficient. Silodosin is an alpha-AR antagonist of BPH for the treatment of dysuria caused by benign prostatic hyperplasia.

Silodosin has a selective inhibitory effect on urethral smooth muscle contraction, and reduces intraurethral pressure, but has no significant effect on blood pressure, and has few side effects, and thus can be used for treating benign prostatic hyperplasia. At present, there are many synthetic methods for silodosin, but there is a lack of a simple process, high yield, and suitable for industrial large-scale production.

The optically active R-compound of formula M below is a key intermediate in the preparation of silodosin.

JP2002265444 reports the preparation of the R-compound (R ₁ = benzyl) represented by the formula M. This method yields the desired product by resolution of the intermediate carboxylic acid of the synthesis. The method has long synthesis route, low resolution, and the resolving agent used is not easy to obtain.

JP2001199956 reports a process for the preparation of the R-compound (R ₁ = benzoyl) represented by the formula M, which passes the compound II

Asymmetric reductive amination with L-phenylglycinol gives the desired product. The method uses L-phenylglycinol, reductive amination to obtain a mixture of diastereomers of the following formula III (diastereomer ratio 3.8:1),

Then, in the presence of Pd/C, catalytic hydrogenation, removal of the phenylethyl alcohol fraction, and finally optical purification with L-tartaric acid yields a single R-compound represented by formula M (R ₁ = benzoyl). This method uses the more expensive reagents L-phenylglycinol and L-tartaric acid.

JP2006188470 reports the preparation of the R-compound (R ₁ = benzyl) represented by the formula M, but in this method, several steps are carried out by column chromatography, which is not suitable for industrial production.

As a key intermediate for the preparation of silodosin, a compound of the formula M has been used to prepare sirolimus which has been reported in JP2001199956, JP2006188470, WO2011124704.

Summary of the invention

The present invention has been proposed in the synthesis of silodosin based on the prior art, since the preparation of the key intermediate, optically active compound M, generally complicates the synthesis process and is costly.

It is an object of the present invention to provide a novel synthesis method of a silodosin intermediate for the above disadvantages. The method can improve the industrial production feasibility of synthesizing the compound, reducing the risk and cost.

One aspect of the present invention provides a method for preparing a compound of Formula M, which in turn comprises the following five steps:

The method specifically includes the following steps:

1) Compound of formula 1

a compound of formula 2 in the presence of an alkaline reagent under basic conditions

Reaction to obtain a compound of formula 3

2) reacting the compound of the formula 3 with phosphorus oxychloride and N,N-dimethylformamide to obtain a compound of the formula 4

3) reacting the compound of the formula 4 with hydroxylamine hydrochloride to obtain a compound of the formula 5

4) Compound of formula 6

An organozinc reagent is prepared by reacting with zinc powder, and the organozinc reagent is reacted with a compound of formula 5 under the catalysis of a palladium catalyst and an organic ligand to obtain a compound of formula 7

5) subjecting the compound of the formula 7 to a deprotection reaction under acidic conditions to obtain the compound of the formula M;

Wherein R represents a benzyl group or a benzoyl group.

In some embodiments, the steps 1) to 5) are each carried out in an organic solvent, and the organic solvents in the steps 1) to 5) are each independently selected from the group consisting of C ₁ -C ₄ lower alcohols, toluene, and A group consisting of toluene, glacial acetic acid, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, trifluoroacetic acid, ethyl acetate, N,N-dimethylformamide, and combinations thereof.

In some embodiments, the alkaline agent in step 1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium iodide, sodium hydrogencarbonate, diisopropylethylenediamine, pyridine, choline. A group consisting of a reagent and triethylamine.

In some embodiments, the palladium catalyst in step 4) is selected from the group consisting of palladium acetate, tetrakis(triphenylphosphine)palladium, palladium chloride, [1,1'-bis(diphenylphosphine) dioxin Iron] palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloride Methyl chloride complex, bis(tricyclohexylphosphine)palladium dichloride, bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylideneacetone)palladium(0), tris(dibenzylidene) Acetone) dipalladium chloroform adduct, di(acetylacetonate)palladium(II), palladium hydroxide carbon, palladium carbon, (1,5-cyclooctadiene) palladium dichloride, di(acetonitrile) dichloride A group consisting of palladium (II), bis(benzonitrile) palladium dichloride (II), and combinations thereof.

In some embodiments, the organic ligand in step 4) is selected from the group consisting of triphenylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, 4,5-bisdiphenylphosphine-9,9 - dimethylxanthene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, Di-tert-butylcyclohexylphosphine, tri(o-tolyl)phosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 1,2,3,4,5 -pentaphenyl-1'-(di-tert-butylphosphine)ferrocene, 1,1'-bis(diphenylphosphino)ferrocene, 2-di-tert-butylphosphine-2',4',6 a group consisting of '-triisopropylbiphenyl and combinations thereof.

In some embodiments, the acidic condition in step 5) is obtained by adding an acid or a hydrogen chloride gas, wherein the acid is selected from the group consisting of concentrated hydrochloric acid, trifluoroacetic acid, acetic acid or formic acid, wherein the concentrated hydrochloric acid is a volume concentration. It is 37% hydrochloric acid.

Preferably, the palladium catalyst in the step 4) is selected from the group consisting of palladium acetate, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium chloroform adduct or di(acetyl). Acetone) Palladium (II).

Preferably, the palladium catalyst in the step 4) is bis(acetylacetonate)palladium(II).

Preferably, the organic ligand in the step 4) is selected from the group consisting of tri-tert-butylphosphine, 2-dicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl, 2-bicyclic ring Hexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene Or 4,5-bisdiphenylphosphino-9,9-dimethyloxazepine.

Preferably, the organic ligand in the step 4) is 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene.

In some embodiments, the reaction temperature of the step 1), the step 2) and the step 3) is 50 to 200 ° C, the reaction time is 1 to 10 h, preferably the reaction temperature is 60 to 150 ° C, and the reaction time is It is 3 to 8 hours.

In some embodiments, the reaction temperature of the step 4) and the step 5) is -20 to 50 ° C, the reaction time is 1 to 10 h, preferably the reaction temperature is -10 to 30 ° C, and the reaction time is 1 to 5 h. .

One aspect of the present invention provides novel intermediate compounds involved in the above preparation methods:

One aspect of the present invention provides a method of preparing a compound of Formula 6, comprising the steps of:

The method specifically includes the following steps:

1) A compound represented by the formula SLD-9C is reacted with thionyl chloride for 3 to 10 hours under an organic solvent-containing reflux condition to obtain a compound represented by the formula SLD-8C.

2) The compound represented by the formula SLD-8C is reacted with di-tert-butyl dicarbonate in an organic solvent under basic conditions for 3-7 hours to obtain a compound represented by SLD-7C.

3) The compound represented by the formula SLD-7C is reacted with sodium borohydride in an organic solvent under basic conditions to obtain a compound represented by the formula SLD-6C.

4) a compound represented by the formula SLD-6C is reacted with iodine in triphenylphosphine or an organic solvent to obtain a compound represented by the formula 6,

Those skilled in the art will appreciate that the above reaction conditions include the aforementioned reaction of the compound of the formula M. Conditions are not the only way to implement the technical solution of the present invention. Those skilled in the art can implement the technical solution of the present invention by modifying the reaction conditions according to actual needs without departing from the gist of the present invention.

An advantage of the present invention is that the compound of formula M synthesized by the process of the invention can be used as an intermediate compound for the synthesis of sirolimus. This method has the following advantages:

1. Shorten the reaction route and reduce production costs;

2. High purity and good yield;

3. The reaction conditions are mild, and the operation is simple and suitable for industrial production.

DRAWINGS

Figure 1 is a ¹ H NMR chart of the compound SLD-8C;

Figure 2 is a ¹ H NMR chart of the compound SLD-7C;

Figure 3 is a ¹ H NMR chart of the compound SLD-6C;

Figure 4 is a ¹ H NMR chart of Compound 6;

Figure 5 is a MS diagram of Compound 3-1;

Figure 6 is a MS diagram of Compound 3-2;

Figure 7 is a MS diagram of Compound 4-1;

Figure 8 is a MS diagram of Compound 4-2;

Figure 9 is a MS diagram of Compound 5-1;

Figure 10 is a MS diagram of Compound 5-2;

Figure 11 is a ¹ H NMR chart of Compound 7-1;

Figure 12 is a ¹ H NMR chart of Compound 7-2;

Figure 13 is a ¹ H NMR chart of Compound M-1;

Figure 14 is a ¹ H NMR chart of Compound M-2.

detailed description

The invention will now be described in connection with specific embodiments. It is to be understood that the following examples are illustrative of the invention and are not intended to limit the invention.

Example 1

1) Preparation of compound SLD-8C

Weigh 107g of SLD-9C (commercially available) into 2L three-necked flask, add 600mL of methanol, mechanically stir and add 131mL of thionyl chloride under ice water bath, and build a tail gas absorption device. After the completion of the drip, reflux reaction for 5-8h.

After the reaction was completely monitored by TLC, methanol was directly concentrated and evaporated, washed with 120 mL of 3 toluene, and concentrated toluene was evaporated. The oil was pumped for 24 hours to obtain 167 g of white solid SLD-8C. Yield: 99.6%.

¹ H-NMR (d ₆ -DMSO) δ: 8.71 (s, 1H); 8.52 (s, 2H); 3.71 to 4.05 (m, 1H); 3.36 to 3.46 (s, 3H); 1.19 to 1.62 (d, 3H).

See Figure 1 for the ¹ H NMR chart of the compound SLD-8C.

3) Preparation of compound SLD-7C

167 g of SLD-8C, 242 g of triethylamine were weighed, 1 L of dichloromethane was added to a 2 L three-necked flask, 313 g of di-tert-butyl dicarbonate was added dropwise, and 200 mL of dichloromethane was again added thereto, and reacted at room temperature for 5 hours.

After the reaction was completed by TLC, water was quenched, dichloromethane was separated, and extracted with dichloromethane (500 mL*2). The organic phase was combined, washed twice with water, dried over anhydrous sodium sulfate and evaporated. Red liquid 224 g SLD-7C, yield: 92.2%.

¹ H-NMR (d ₆ -DMSO) δ: 7.26 to 7.28 (d, 1H); 3.86 to 4.18 (m, 1H); 3.61 (s, 3H); 1.33 to 1.37 (s, 9H); 0.97 to 1.02 ( d, 3H).

See Figure 2 for the ¹ H NMR chart of the compound SLD-7C.

4) Preparation of compound SLD-6C

134g of calcium chloride was weighed and added to a 2L three-necked flask. 400mL of methanol and 500mL of tetrahydrofuran were added. After adding methanol, it was cooled in an ice water bath. After a little cold, 92g of sodium borohydride was added in batches. After stirring for 0.5h, 224g of SLD was added dropwise. -7C (dissolved in 200 mL of tetrahydrofuran), stirred at room temperature for 1 h, then slowly warmed to 70 ° C, and reacted for 15-20 h.

After the reaction was completed by TLC, it was poured into a large amount of ice water and quenched, and the solid residue was filtered. The residue was washed three times with dichloromethane (500 mL*3), the organic layer was separated, and the aqueous layer was extracted with dichloromethane 1L*2. The layer was washed twice with water and dried over anhydrous sodium sulfate, and evaporated to give 185 g of white solid.

¹ H-NMR (d ₆ -DMSO) δ: 6.48 to 6.51 (d, 1H); 4.56 to 4.59 (m, 1H); 3.47 to 3.61 (m, 1H); 3.26 to 3.45 (m, 1H); 3.18 (m, 1H); 1.47 (s, 9H); 0.85 to 0.96 (d, 3H).

See Figure 3 for the ¹ H NMR chart of the compound SLD-6C.

5) Preparation of Compound 6

Weigh 187.6 g of triphenyl and 48.7 g of imidazole into a 2 L three-necked flask, add 1 L of dichloromethane, add 200 g of iodine in portions, keep the temperature below 30 ° C with an ice water bath, and add 125.3 g of SLD after stirring for 10 min. -6C was dissolved in 200 mL of dichloromethane, added dropwise to the reaction solution, and reacted at room temperature for 10-20 h after the completion of the dropwise addition.

After the reaction was completed by TLC, it was poured into water and quenched, and the organic layer was separated. The aqueous layer was extracted with 500 mL*2 dichloromethane. The organic layer was combined, washed twice, dried over anhydrous sodium sulfate and concentrated The crude product was obtained, crystallized from petroleum ether & methylene chloride to afford 60 g of white solids (yield: 29.4%).

¹ H-NMR (d ₆ -DMSO) δ: 6.96 (m, 1H); 3.46 to 3.51 (m, 1H); 3.19 to 3.31 (m, 2H); 1.39 to 1.48 (s, 9H); 0.99 to 1.12 ( d, 3H).

See Figure 4 for the ¹ H NMR chart of Compound 6.

6) Preparation of Compound 3-1

85 g of the compound 1, 80 g of the compound 2-1, 4 g of potassium iodide, and 98 g of K ₂ CO _{3 were} weighed and added to a three-necked flask containing 400 mL of DMF (N,N-dimethylformamide), and the mixture was heated to 120 ° C for 5 hours. After completion of the reaction, 800 mL of ethyl acetate and 200 mL of water were added, and ethyl acetate was washed with 300 mL of water, and washed four times, and dried, and the solvent was concentrated under reduced pressure, and purified by column chromatography to give 100 g of a yellow liquid (Compound 3-1). 67%.

In this step, the compound of the formula 2-1 is replaced with the compound of the formula 2-2, and the compound of the formula 3-2 is obtained by the same method.

See Figure 5 for the MS diagram of Compound 3-1;

See Figure 6 for the MS map of Compound 3-2.

7) Preparation of Compound 4-1

Weigh 30 g of phosphorus oxychloride, measure 250 mL of DMF, add to a 1 L three-necked flask, and replace with nitrogen three times. The temperature was raised to 80 ° C, and the reaction was carried out for 1 h, then 50 g of compound 3-1 was added, and the reaction was continued for 3 h. After the TCL detection reaction was completed, the reaction solution was added to an aqueous solution of sodium hydroxide, extracted with ethyl acetate, and dried, and the solvent was evaporated to vacuo. MS m/z: 373 (M ⁺ ), yield: 74.1%.

In this step, the compound of the formula 3-1 is replaced with the compound of the formula 3-2, and the compound of the formula 4-2 is obtained by the same method.

See Figure 7 for the MS diagram of Compound 4-1;

See Figure 8 for the MS map of Compound 4-2.

8) Preparation of Compound 5-1

40 g of Compound 4-1 was weighed into a 1 L single-mouth bottle, 500 mL of DMSO (dimethyl sulfoxide) and 15 g of hydroxylamine hydrochloride were added, and the temperature was raised to 100 ° C for 8 hours. After the reaction was completed by TLC, a large amount of water was added, and a large amount of solids were precipitated, which was filtered and subjected to column chromatography to obtain 30 g of a white solid. MS m/z: 370 (M ⁺ ), yield: 75%.

In this step, the compound of the formula 4-1 is replaced with the compound of the formula 4-2, and the compound of the formula 5-2 is obtained by the same method.

See Figure 9 for the MS map of Compound 5-1;

See Figure 10 for the MS map of Compound 5-2.

9) Preparation of Compound 7-1

21 g of Zn powder and 25 mL of dried tetrahydrofuran were weighed, the gas was replaced with nitrogen three times, stirred, and cooled to 0 ° C, and a mixed solution of 23 g of compound 6 and 25 mL of dried tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 1.5 h. 30 g of compound 5-1, 1.2 g of bis(acetylacetonate)palladium(II), 6.8 g of 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, nitrogen The gas was replaced three times and reacted at room temperature for 1.5 h. After the TCL detection reaction was completed, a large amount of water was added, and the solid was separated, filtered, ethyl acetate (25mL) and petroleum ether (80mL). 28 g of a white solid (Compound 7-1) were obtained in a yield: 75%.

¹ H-NMR (d ₆ -DMSO) δ: 7.981 (t, 2H); 7.645 (t, 1H); 7.499 (t, 2H); 7. s (s, 1H); 6.944 (s, 1H); , 1H); 4.369 (t, 2H); 3.670 (t, 2H); 3.557 (s, 2H); 2.913 (s, 2H); 2.506 to 2.467 (m, 2H); 2.093 to 1.984 (m, 2H); 1.317 (s, 9H); 1.0 (d, 3H).

In this step, the compound of the formula 5-1 is replaced with the compound of the formula 5-2, and the compound of the formula 7-2 is obtained by the same method.

¹ H-NMR (d ₆ -DMSO) δ: 7.265 to 7.336 (m, 5H); 7.030 (s, 1H); 6.934 (s, 1H); 6.765 to 6.702 (d, 1H); 3.484 to 3.575 (m, 7H); 2.866 to 2.924 (t, 2H); 2.494 to 2.506 (M, 2H); 1.832 to 1.879 (t, 2H); 1.324 (s, 9H); 0.981 to 1.002 (d, 3H).

The ¹ H NMR chart of Compound 7-1 is shown in Figure 11;

See Figure 12 for the ¹ H NMR chart of Compound 7-2.

10) Preparation of Compound M-1

28 g of compound 7-1 was weighed and added to 25 mL of trifluoroacetic acid, refluxed for 3 h, adjusted to pH = 10 with aqueous sodium hydroxide solution, extracted with ethanol, dried and dried. 21 g of a white solid (Compound M-1) was obtained in a yield: 96%.

¹ H-NMR (d ₆ -DMSO) δ: 8.003 (d, 2H); 7.705 (t, 1H); 7.499 (t, 2H); 7.050 (s, 1H); 6.955 (s, 1H); 4.369 (t) , 2H); 3.670 (t, 2H); 3.557 (s, 2H); 2.928 to 2.879 (m, 3H); 2.382 (d, 2H); 2.180 to 1.985 (m, 2H); 0.938 (d, 3H).

In this step, a compound of the formula 7-1 is replaced with a compound of the formula 7-2, and a compound of the formula M-2 is obtained by the same method.

¹ H-NMR (d ₆ -DMSO) δ: 7.2775 - 7.333 (m, 5H); 7.032 (s, 1H); 6.938 (s, 1H); 3.480 to 3.581 (m, 6H); 2.866 to 2.926 (t, 3H); 2.341 to 2.363 (d, 2H); 1.862 to 1.908 (t, 2H); 0.910 to 0.931 (d, 3H).

The ¹ H NMR chart of Compound M-1 is shown in Figure 13;

See Figure 14 for the ¹ H NMR chart of Compound M-2.

Claims (14)

1. A method of preparing a compound of formula M,

   

   The method includes the following steps:

   1) Compound of formula 1

   

   a compound of formula 2 in the presence of an alkaline reagent under basic conditions

   

   Reaction to obtain a compound of formula 3

   

   2) reacting the compound of the formula 3 with phosphorus oxychloride and N,N-dimethylformamide to obtain a compound of the formula 4

   

   3) reacting the compound of the formula 4 with hydroxylamine hydrochloride to obtain a compound of the formula 5

   

   4) Compound of formula 6

   

   An organozinc reagent is prepared by reacting with zinc powder, and the organozinc reagent is reacted with a compound of formula 5 under the catalysis of a palladium catalyst and an organic ligand to obtain a compound of formula 7

   

   5) subjecting the compound of the formula 7 to a deprotection reaction under acidic conditions to obtain the compound of the formula M;

   Wherein R represents a benzyl group or a benzoyl group.
2. The method according to claim 1, wherein said steps 1) to 5) are each carried out in an organic solvent, and the organic solvents in said steps 1) to 5) are each independently selected from lower alcohols of C ₁ - C ₄ a group consisting of toluene, xylene, glacial acetic acid, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, trifluoroacetic acid, ethyl acetate, N,N-dimethylformamide, and combinations thereof .
3. The method of claim 1 wherein said alkaline agent in step 1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium iodide, sodium hydrogencarbonate, diisopropylethylenediamine, a group consisting of pyridine, choline reagent and triethylamine.
4. The method of claim 1 wherein said palladium catalyst in said step 4) is selected from the group consisting of palladium acetate, tetrakis(triphenylphosphine)palladium, palladium chloride, [1,1'-bis(diphenyl) Phosphine) ferrocene] palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocene palladium (II) dichloromethane complex, bis(tricyclohexylphosphine) palladium dichloride , bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium chloroform adduct, di(acetylacetonate)palladium (II), palladium hydroxide carbon, palladium carbon, (1,5-cyclooctadiene) palladium dichloride, di(acetonitrile) palladium (II) dichloride, bis(benzonitrile) palladium dichloride (II) ) and its combination of groups.
5. The method of claim 1 wherein said organic ligand in said step 4) is selected from the group consisting of triphenylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, 4,5-bisdiphenylphosphine. -9,9-Dimethyloxanthene, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy Biphenyl, di-tert-butylcyclohexylphosphine, tri(o-tolyl)phosphine, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 1,2,3 , 4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene, 1,1'-bis(diphenylphosphino)ferrocene, 2-di-tert-butylphosphine-2', A group consisting of 4',6'-triisopropylbiphenyl and combinations thereof.
6. The method according to claim 1, wherein said acidic condition in said step 5) is obtained by adding an acid or a hydrogen chloride gas, wherein said acid is selected from the group consisting of 37% hydrochloric acid, trifluoroacetic acid, acetic acid and formic acid. .
7. The method according to claim 4, wherein said palladium catalyst in said step 4) is selected from the group consisting of palladium acetate, bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium chloroform. A group consisting of an adduct and bis(acetylacetonate)palladium(II).
8. The method of claim 7 wherein said palladium catalyst in said step 4) is bis(acetylacetonate)palladium(II).
9. The method according to claim 5, wherein said organic ligand in said step 4) is selected from the group consisting of tri-tert-butylphosphine, 2-dicyclohexylphosphine-2', 4', 6'-triisopropyl Biphenyl, 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl, 1,2,3,4,5-pentaphenyl-1'-(di-tert A group consisting of butylphosphine) ferrocene and 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime.
10. The method according to claim 9, wherein said organic ligand in said step 4) is 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphine)ferrocene. .
11. A compound of the formula:

    
12. A compound of the formula:

    
13. A compound of the formula:

    
14. A compound of the formula:

    

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