The method of producing binarydigit

 

(57) Abstract:

The invention relates to a method of transforming bonarparte ormula I binarydigit formula II

< / BR>
which is a known intermediate compound in the synthesis of progesterone. The method is carried out by oxidation of I with sodium hypochlorite in the presence of catalytic amount of 4-substituted derivative of 2,2,6,6-tetramethylpiperidine-1-oxyl in the presence of sodium bicarbonate and potassium bromide at pH of 8.5 to 10.5 at a temperature of from -10 to 15oC and with the stoichiometric quantity of sodium hypochlorite. The method allows to achieve high selectivity and allows to carry out the process continuously. 15 C.p. f-crystals.

The invention relates to a method of transforming bonarparte formula I in binarydigit formula II, which is a known intermediate compound in the synthesis of progesterone.

Oxidation of bonarparte (I) in binarydigit (II) is a well-known process.

Famous is 4-hydroxy-TAMRA (4-hydroxy-2,2,6,6 - tetramethylpiperidine-1-oxyl), see Synthesis, 190-202 and L-414 (1971).

In the journal J. Org. Chem., v. 52, 2559 (1987) described a two-phase oxidation of primary alcohols and secondary alcohols to aldehydes one-1-oxyl, with the use of bromide of potassium and 0.35 M solution of sodium hypochlorite at a pH of 8.5, supported buffer solution of sodium bicarbonate.

In the journal J. Org. Chem., v. 56, 6110 (1991) described the use of stoichiometric quantities oxammonium salts generated during the processing of TEMPO (2,2,6,6-tetramethylpiperidine-1 - oxyl or 4-acetylamino-TAMRA (4-acetylamino-2,2,6,6 - tetramethylpiperidine-1-oxyl) organic sulfonic acids, for selective oxidation of primary alcohols and secondary alcohols to aldehydes or ketones, respectively.

In the journal J. Amer. Chem. Soc., v. 106, 3374 (1984) described the use of TEMPO (2,2,6,6-Tetra-methylpiperidin-1 - oxyl or 4-hydroxy-TAMRA (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) for the catalytic oxidation of primary alcohols and secondary alcohols to aldehydes or ketones, respectively, oxygen and salts of divalent copper.

In U.S. patent N 5136102 described using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl or 4-substituted derivatives of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and promesapanama salt for catalytic oxidation of secondary alcohols to ketones nitric acid and oxygen.

In U.S. patent N 5155278 described using TEMPO (2,2,6,6-tetramethylene primary alcohols to aldehydes under the influence of nitric acid and oxygen.

In U.S. patent N 5155279 described using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl or 4-substituted derivatives of TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) for the catalytic selective oxidation of primary alcohols to aldehydes under the influence of nitric acid in the absence of oxygen.

In U.S. patent N 5155280 described using TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl or 4-substituted derivatives of TEMPO (2,2,6, 6-tetramethylpiperidine-1-oxyl) and nitrosodialkylamines salt of an alkali metal for the catalytic selective oxidation of primary alcohols to aldehydes by the action of oxygen in the absence of nitric acid.

In the Japan patent N J5 6152498 described the oxidation of bonarparte in binarydigit using dimethyl sulfide and N-chlorosuccinimide or chlorine.

Described is a method of obtaining binarydigit formula II

< / BR>
which includes: 1) formation of a mixture of (a) bonarparte formula I

< / BR>
b) a catalytic amount of 4-hydroxy-2,2,6,6 - tetramethylpiperidine-1-oxyl in the range of pH from about 8.5 to about 10.5 and at a temperature range of approximately -10 to approximately 15oC and (2) contacting the mixture of stage (1) with the stoichiometric quantity of hypochlorite (see diagram A is use progesterone and hydrocortisone, see journal, J. Amer. Chem. Soc., v. 74, 5933 (1952).

The present invention is accomplished by 1) formation of a mixture of bonarparte (I), catalytic amount of 4-hydroxy - TAMRA (2,2,6,6-tetramethylpiperidine-1-oxyl) in the range of pH from about 8.5 to about 10.5 and at a temperature range of about -10 to 15oC and 2) contacting the mixture of stage (1) with the stoichiometric quantity of hypochlorite. Preferably this reaction is carried out in the presence of bromide, preferably a catalytic amount of bromide. This mixture may be cooled at any time before adding the hypochlorite.

The current (effective) number of 4-hydroxy-2,2,6,6 - tetramethylpiperidine-1-oxyl range from approximately 0.025 mol.% up to about 15 mol.%; preferably, the number of 4-hydroxy - 2,2,6,6-tetramethylpiperidine-1-oxyl ranged from approximately 0.025 mol.% up to about 2.5 mol.%. An effective amount of bromide is from about 5 mol.% up to about 25 mol.%; preferably, the amount of bromide ranged from about 10 mol.% up to about 15 mol. %. The pH preferably is regulated through the use of bicarbonate. An effective amount of bicarbonate is from about 5 mol.% up to about 30 mol.%; p is a or bicarbonate is not essential, while these salts are soluble; the preferred cations are sodium, potassium and lithium, the preferred sodium or potassium. Effective solvents include dichloromethane, toluene, ethyl acetate, methyl tert-butyl ether, dichloromethane, o-dichlorobenzene, chlorobenzene and chloroform. The preferred solvent is methylene chloride. Although effective solvents are organic solvents which are not miscible with water, a small amount of water is effective and even preferred, as is well known to specialists in this field. In addition, the hypochlorite is added to the aqueous mixture. Preferably, the reaction temperature was in the range of from about -5oC to about 5oC. Preferably, the hypochlorite was added over a period of time from about 1 hour to about 6 hours Preferably, the amount of hypochlorite ranged from about 95 mol.% to about 120 mol. %. Preferably, after stage 2), the reaction mixture was rapidly cooled. Efficient coolers include bisulfite, thiosulfate, dimethyldisulfide, trimethylphosphate and triethyl phosphate. Preferably, the cooler was sodium thiosulfate or potassium.

How is ecialists in this area.

The reaction mixture is treated by methods known to experts in this field.

Binarydigit (II) can be converted into progesterone known methods, see journal, J. C. S. Chem. Comm., 314 (1969) and Tet. Lett., 985 (1969).

The following definitions and explanations are given for terms used throughout the volume of the document, including the description and the claims.

4-Hydroxy-TEMRO relates to 4-hydroxy-2,2,6,6 - tetramethylpiperidine-1-oxyl; TEMPO - 2,2,6,6-tetramethylpiperidine-1-oxyl.

It is assumed that no additional development, any specialist in this field will be able to fully implement the present invention, using the preceding description. The following detailed examples describe the preparation of various substances and/or performing the various processes of the invention, and they should be considered as merely illustrative and not limiting the preceding description in any way. Specialists in this field will be able to easily recognize the corresponding change techniques both in terms of reagents, and reaction conditions and techniques.

Example 1. Turning bonarparte (I) in binarydigit (II) if 1oC 4-Gidda potassium, 133 mg of sodium bicarbonate, 14 ml of dichloromethane and 2.2 ml of water is cooled to 1oC. Maintaining this temperature, add 6.3 ml of aqueous 14% solution of sodium hypochlorite for 5 hours the Reaction is finished, and add an aqueous solution of sodium thiosulfate, share two phases, and the product - binarydigit crystallizes when replacing dichloromethane in heptane. Get the desired compound with a melting point 153-154oC.

An NMR spectrum (CDCl3) : 9,56, 5,73, 2,2-2,5, 1,2-2,1, 1,20, 1,10, 0,79.

[]2D2= +of 83.4oC (methylene chloride, C = 1).

Example 2. Turning bonarparte (I) in binarydigit (II) if 10oC with 4-hydroxy-TAMRA.

Following the General method of example 1 and making non-critical changes to the method of example 1 is repeated with 10oC and get the desired connection.

Example 3. Turning bonarparte (I) in binarydigit (II) at -10oC with 4-hydroxy-TAMRA.

Following the General method of example 1 and making non-critical changes to the method of example 1 is repeated with -10oC and get the desired connection.

Example 4. Turning bonarparte (I) in binarydigit (II) if 1oC with 4-hydroxy-TAMRA.

Following the General methodology of parameterdependent-1-oxyl, and get the desired connection.

Example 5. Turning bonarparte (I) in binarydigit (II) if 1oC with 4-hydroxy-TAMRA.

Following the General method of example 1 and making non-critical changes to the method of example 1 is repeated, using 5 mg of 4-hydroxy - 2,2,6,6-tetramethylpiperidine-1-oxyl, and receive the requested connection.

Example 6. Turning bonarparte (I) in binarydigit (II) with 4-oxo-TAMRA.

A mixture of 6.6 g of bonarparte (I), 18 mg of 4-oxo-2,2,6,6 - tetramethylpiperidine-1-oxyl, 238 mg of potassium bromide, 180 mg of sodium bicarbonate, 30 ml of dichloromethane and 5 ml of water is cooled to 1oC. Then, to this mixture of 11.4 ml of water 14,6% sodium hypochlorite solution for 15 minutes At this reaction get the desired connection, but conversion of bonarparte is only 7% with selectivity to binarydigit 58%.

1. The method of producing binarydigit formula II

< / BR>
including the oxidation of bonarparte formula I

< / BR>
the hypochlorite in the presence of catalytic amount of 4-substituted derivative-2,2,6,6-tetramethylpiperidine-1-oxyl in the presence of bicarbonate and potassium bromide, characterized in that the contacting of a mixture of bonarparte and catalytic coricedin-1-oxyl is carried out at pH 8.5 - the 10.5 at a temperature of from -10 to 15oAnd with the stoichiometric quantity of hypochlorite.

2. The method according to p. 1, characterized in that a catalytic amount of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl is 0.025 to 15.0 mol.%.

3. The method according to p. 1, characterized in that kataliticheskoe the number of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl is 0.025 to 2.5 mol.%.

4. The method according to any of paragraphs.1 to 3, characterized in that the potassium bromide is used in catalytic amounts.

5. The method according to p. 4, characterized in that a catalytic amount of potassium bromide is 5 to 25 mol.%.

6. The method according to p. 5, characterized in that a catalytic amount of bromide of potassium is 10 - 15 mol.%.

7. The method according to any of paragraphs.1 - 6, characterized in that the amount of bicarbonate is 5 to 30 mol.%.

8. The method according to p. 7, characterized in that the amount of bicarbonate is 10 to 20 mol.%.

9. The method according to any of paragraphs.4 to 6, 7 and 8, characterized in that userpart formula I, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, bromide of potassium, and bicarbonate are all mixed together and then cooled to a temperature of from -10 to 15oC.

10. The method according to any of paragraphs.1 to 9, characterized testilomake ether, dichloromethane, o-dichlorobenzene, chlorobenzene and chloroform.

11. The method according to p. 10, wherein the solvent is methylene chloride.

12. The method according to any of paragraphs.1 - 11, characterized in that the temperature is from -5 to 5oC.

13. The method according to any of paragraphs.1 - 12, characterized in that the amount of hypochlorite is 95 - 120 mol.%.

14. The method according to any of paragraphs.1 - 12, characterized in that the reaction mixture is cooled rapidly after contacting this mixture with hypochlorite.

15. The method according to p. 14, characterized in that the reaction mixture is cooled chiller selected from bisulfite, thiosulfate, dimethyl sulfide, trimethyl phosphate and triethyl phosphate.

16. The method according to p. 15, characterized in that the cooler is sodium thiosulfate or potassium.

 

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