Method of obtaining pyripyropene derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining pyripyropene derivatives, namely a compound of formula C: , where R represents a linear chain, a branched chain or cyclic C2-6alkylcarbonyl, on condition that, when an alkyl fragment in an alkylcarbonyl group represents a branched chain or a cyclic group, R represents C3-6alkylcarbonyl, including: selective acylation of hydroxyl groups in 1-position and 11-position of a compound B1, represented by formula B1: with an acylating agent in one-three stages in the presence or absence of a base. (i) compound C is obtained by acylation of hydroxyl groups in 1-position and 11-position of the compound B1 in one stage; (ii) method, including obtaining the compound C by acylation in two stages, consisting of stages: acylation of the hydroxyl group in 11-position of the compound B1 with the acylating agent with obtaining the compound B2, represented by formula B2: , where R is determined in formula C; and additional acylation of the hydroxyl group in 1-position of the compound B2; or (iii) method, including obtaining the compound C by acylation in three stages, consisting of stages: acylation of the hydroxyl group in 11-position of the compound B1 with obtaining the compound B2, represented by formula B2: , where R is determined in the formula C; transfer of acyl in 11-position of the compound B2 to hydroxyl in 1-position with obtaining the compound B3, represented by formula B3: , where R is such as determined in the formula C; and acylation of hydroxyl group in 11-position of the compound B3.

EFFECT: increased output.

16 cl, 1 dwg, 3 tbl, 22 ex

CROSS-REFERENCE TO RELATED APPLICATION

This patent application is an application requesting the priority of the prior patent applications of Japanese patent application Japan No. 116305/2009 (filing date: may 13, 2009) and the patent application of Japan No. 44416/2010 (filing date: March 1, 2010). Full disclosure of the prior applications are incorporated herein by reference.

BACKGROUND of INVENTION

The technical field to which the invention relates.

The present invention relates to a method for producing derivatives of peripherin applicable as a means of pest control, and more specifically, to obtain derivatives of peripherin who have acyloxy in its 1-position and the 11-position and the hydroxyl at the 7-position.

PRIOR art

Derivatives peripherin with acyloxy in its 1-position and the 11-position and the hydroxyl at the 7-position, are compounds that are effective against pests, as described in WO 2006/129714.

WO 2006/129714 and laid claim to the Japan patent No. 259569/1996 disclose a method of obtaining derivatives of peripherin with acyloxy in its 1-position and the 11-position and the hydroxyl at the 7-position. In accordance with the production method, the derivatives of peripherin purified or separated from the noreste products obtained by selective hydrolysis of acyloxy using 1,7,11-trisiloxane as the source connection.

Additionally, tiled patent application of Japan No. 259569/1996 describes the use of a combination of protective groups for the synthesis of derivatives of peripherin. Journal of Antibiotics Vol. 49, No. 11, p. 1149 (1996), Bioorganic Medicinal Chemistry Letter, Vol. 5, No. 22, p. 2683 (1995), and laid out in the patent application of Japan No. 269065/1996 disclose an example of a synthesis, in which introducing the acyl in the 7-position through the use of protective groups.

WO 2009/022702 discloses a method of obtaining 1,11-diacyl-7-diacetylpyridine of 1,7,11-tridecemlineatus using protective group.

Derivatives peripherin with acyloxy in the 1-position and the 11-position and the hydroxyl at the 7-position up to this time had been through a number of stages using a non-selective hydrolysis 1,7,11-trisiloxane and using protective groups. Accordingly, upon receipt of derivative peripherin on an industrial scale, are desirable for additional improvement of the effectiveness in obtaining, for example, through the reduction of production costs, improvement, output, simplifying purification and separation or reduction in the number of stages.

SUMMARY of the INVENTION

The authors of the present invention succeeded in obtaining races is nativeimage applicable 1,11-dellaccademia through an accelerated way through the selective acylation, either direct or sequential, hydroxyl at the 1-position and an 11-position tridecylamine (published patent application of Japan No. 259569/1996 and Journal of Technical Disclosure No. 500997/2008), easily obtained from peripherin (natural substances) and its analog (Pure Appl. Chem., vol. 71, No. 6, pp.1059-1064, 1999; WO 94/09147; lined patent application of Japan No. 239385/1996, laid claim to the Japan patent No. 259569/1996, Bioorganic Medicinal Chemistry Letter, Vol. 5, No. 22, p. 2683 (1995); and WO 2004/060065), which led to completion of the present invention.

1. In accordance with the present invention, provided is a method of obtaining compound C represented by the formula C:

Chemical formula 1

where R is a straight chain, branched chain or cyclic C2-alkylsulphonyl, provided that when the alkyl fragment in alkylcarboxylic group is a branched chain or a cyclic group, R represents C3-alkylsulphonyl, including:

selective acylation, through one-three stages of hydroxyl groups in the 1-position and the 11-position of compound B1 represented by the formula B1:

Chemical formula 2

allermuir agent in the presence or absence of a base.

2. In accordance with the present invention provides a method, in accordance with the above paragraph 1., different is eat, connection C acelerou from compound B1 through a single stage. That is, in accordance with this embodiment, in the method, in accordance with the above paragraph 1., connection C get through acylation of hydroxyl groups in the 1-position and the 11-position of compound B1 in only one stage.

3. In accordance with the present invention provides a method in accordance with the above paragraph 1., characterized in that the acylation carried out two stages, consisting of the steps:

acylation of the hydroxyl group at the 11-position of compound B1 allermuir agent to obtain compounds B2 represented by the formula B2:

Chemical formula 3

where R is as defined in formula C in the above paragraph 1.;

and

additional acylation of the hydroxyl group in 1-position of compound B2. That is, in accordance with this embodiment, in the method in accordance with the above paragraph 1., connection C get through acylation through two stages, consisting of stages: acylation of the hydroxyl group at the 11-position of compound B1 allermuir agent to obtain compounds B2; and additional acylation of the hydroxyl group in 1-position of compound B2.

4. In accordance with another aspect of us is Vashego of the invention, given the method in accordance with the above paragraph 1., characterized in that the acylation is carried out in three stages, consisting of stages: acylation of the hydroxyl group at the 11-position of compound B1 with obtaining compounds B2; transferring acyl 11-position of the compound B2 to the hydroxyl at the 1-position obtaining connection B3 represented by the formula B3:

Chemical formula 4

where R is as defined in formula C, in the above paragraph 1.; and

acylation of the hydroxyl group at the 11-position of the compound B3. That is, in accordance with this embodiment, in the method in accordance with the above paragraph 1., the connection to get through three stages, consisting of the steps:

acylation of the hydroxyl group at the 11-position of compound B1 with obtaining compounds B2; transferring acyl 11-position of the compound B2 to the hydroxyl at the 1-position obtaining connection B3; and acylation of the hydroxyl group at the 11-position of the compound B3.

5. Additionally, in accordance with the present invention provides a method in accordance with any of the above paragraphs 1. to 4., includes, as the stage of obtaining the compound B1, the hydrolysis of acyl groups in the 1-position, 7-position and the 11-position of compound A1 represented by the formula Al in the presence of the first:

Chemical formula 5

where A1, A7 and A11, which may be identical or different, represent acetyl or propionyl. That is, in accordance with this embodiment, the method in accordance with the above paragraphs 1. to 4., additionally includes, as the stage of obtaining the compound B1, the hydrolysis of acyl groups in the 1-position, 7-position and the 11-position of compound A1 in the presence of a base.

6. In accordance with another another aspect of the present invention, provided is a method of obtaining compound C, which includes stage: acylation of hydroxyl groups in the 1-position, 11-position and 7-position of compound B1 with obtaining connection B4 represented by the formula B4:

Chemical formula 6

where R is as defined above; and then selective diallylamine hydroxyl group at the 7-position.

In accordance with an additional aspect of the present invention provides a method for isolation and purification of crystals MES compound C obtained by a method in accordance with any of the above paragraphs 1. to 5., includes: adding a suitable solvent to the crude product of compound C obtained by concentrating the reaction solution, from which containing a series connection C, obtained through any of the above paragraphs 1. to 5., under reduced pressure; the concentration of an ethyl acetate extract of the reaction solution containing the compound C obtained by a method in accordance with any of the above paragraphs 1. to 5.; or more add the selected solvent to the concentrate to precipitate crystals MES connection C.

In accordance with another aspect of the present invention provides a method for isolation and purification of crystals MES connection C, which includes the stages of: (a) extraction of the reaction solution containing the compound C, an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, and concentration of the extract after or without drying; (b) evaporation of the reaction solution containing the compound C to dryness to obtain the crude product, and then dissolving the crude product in an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, methanol and ethanol at on the th temperature or heating; or (c) evaporation of the reaction solution containing the compound C to dryness to obtain the crude product, dissolving the crude product in an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, methanol and ethanol at room temperature or under heating, and adding a weak solvent selected from the group consisting of heptane, hexane and cyclohexane, to the solution. In a preferred embodiment of the present invention, the specified stage (a) must be a stage (a') extraction of the reaction solution containing the compound C, ethyl acetate, and concentration of the extract after or without dehydration. In yet another preferred embodiment of the present invention, the specified stage (b) must be a stage (b') evaporation of the reaction solution containing the compound C to dryness to obtain the crude product, and then dissolving the crude product in ethyl acetate at room temperature or under heating. In yet another preferred embodiment of the present invention, the specified stage (c) must be a stage (c') evaporation of the reaction solution containing the compound C to dryness to obtain the crude product, dissolving the crude product in ethyl acetate at room temperature or under heating, and adding hexane to the solution.

In accordance with another another aspect of the present invention, provided is a method of obtaining compound C from compound B1 in accordance with any of the above paragraphs 1. to 5., which includes the extraction and cleaning compound C by crystallization from the reaction solution containing the compound C. that is, in accordance with this embodiment, the method in accordance with any of the above paragraphs 1. to 5. additionally includes the extraction and cleaning compound C by crystallization from the reaction solution containing the compound C. In accordance with the present invention, derivatives of peripherin who have acyloxy in the 1-position and the 11-position and the hydroxyl at the 7-position, and are applicable as a means of destruction of agricultural insect pests can be efficiently obtained in a short way.

BRIEF DESCRIPTION of DRAWINGS

Fig.1 is a powder roentgenogram measured for crystals of an ethyl acetate MES 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A.

DETAILED description of the INVENTION

The way to obtain

The term"alkyl", as used herein, as a substituent or part of a substituent means alkyl, that is straight chain, branched chain or cyclic group, or type combinations thereof, unless otherwise specified.

The symbol "Ca-b", attached to the Deputy, as used herein, means that the number of carbon atoms contained in the Deputy, as used herein, is from a to b. Additionally, the "Ca-b" in "Ca-b" means that the number of carbon atoms in the alkyl fragment, excluding the carbon atom in the carbonyl fragment is from a to b.

Specific examples Ramazanova, branched chain or cyclic C2-alkylsulphonyl represented by R, provided that when the alkyl fragment in alkylcarboxylic group is a branched chain or a cyclic group, R represents C3-alkylsulphonyl include cyclopropanecarbonyl and propionyl.

In accordance with another preferred embodiment of the present invention, in the method in accordance with any of the above paragraphs 1. to 5., the acylation is carried out in the absence of base.

In accordance with a preferred embodiment of the present invention, in the method in accordance with any of the above paragraphs 1. to 5., the base line is used in the acylation of the hydroxyl at the 1-position and the 11-position of the compound B1, represents a 2,4,6-kallidin or 2,6-lutidine.

In accordance with another preferred embodiment of the present invention, in the method in accordance with the above paragraph 2., allerease agent is used in amount of from 2.0 to 5.0 equivalents in the calculation of the junction B1.

In accordance with an additional preferred embodiment of the present invention, the method in accordance with the above paragraph 3., characterized in that the solvent used at the stage of obtaining compounds B2, is different from the solvent used at the stage of additional acylation of the hydroxyl at the 1-position of compound B2.

In accordance with another preferred embodiment of the present invention, a method, in accordance with the above paragraph 4., characterized in that a step for connection B3 from compound B2 is carried out in the presence of a base.

In accordance with another preferred embodiment of the present invention, the method in accordance with the above paragraph 4., characterized in that a step for connection B3 from compound B2 is carried out in the presence of 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) as the base.

In accordance with an additional preferred embodiment of this image is to be placed, C2-alkylsulphonyl represented by R is a cyclic C3-alkylcarboxylic, more preferably, cyclopropanecarbonyl.

In accordance with a preferred embodiment of the present invention, in the method in accordance with the above paragraph 3., the base is used at the stage of obtaining compounds B2 and receive additional acylation of the hydroxyl at the 1-position of compound B2, the amount of base used at the stage of obtaining compounds B2, is from 1.0 to 3.0 equivalents, based on compound B1, the total amount of the base used at the stage of obtaining compounds B2 and base applied at the stage of additional acylation of the hydroxyl at the 1-position of compound B2 is from 2.0 to 4.5 equivalents, more preferably from 2.0 to 3.0 equivalents.

In accordance with a preferred embodiment of the present invention, in the method in accordance with any of the above paragraphs 1. to 4., allerease agent is used in amount of from 2.0 to 5.0 equivalents in the calculation of the junction B1.

In accordance with a preferred embodiment of the present invention, in the method, in accordance with the above paragraph 3., allerease agent is used at the stage of obtaining compounds B2 and receive additional acylation of hydroxy is and in the 1-position of compound B2, the number Alliluyeva agent used at the stage of obtaining compounds B2, is from 1.0 to 3.5 equivalents in the calculation of the junction B1, the total number Alliluyeva agent applied at the stage of obtaining compounds B2 and Alliluyeva agent applied at the stage of additional acylation of the hydroxyl at the 1-position of compound B2 is from 2.0 to 4.5 equivalents.

In accordance with another preferred embodiment of the present invention, provided the use of compound B2 as an intermediate connection when the connection C of compound B1. That is, in the embodiment, provided the use of compound B2 when the connection is C.

In accordance with another preferred embodiment of the present invention, provided the use of compounds B2 and B3 in connection as an intermediate connection when the connection C of compound B1. That is, in this embodiment, is provided the use of compound B3 when the connection is C.

The present invention will be described in more detail in accordance with the following schema.

Chemical formula 7

where A1, A7, A11 and R are as defined above.

The product obtained at each stage of the scheme, may also skin is sterile without further processing or selection to the next stage.

1-1: connection B1 from compound A1

Compound A1 can be obtained by a method described, for example, Pure Appl. Chem., vol. 71, No. 6, pp. 1059-1064, 1999.; posted the application on the Japan patent No. 239385/1996 posted the application on the Japan patent No. 184158/1994, WO 2004/060065 Posted the application on the Japan patent No. 259569/1996 or Bioorganic Medicinal Chemistry Letter, vol. 5, No. 22, p. 2683.

When the connection A1 as the initial connection is peripherin a, peripherin And may be one obtained by a method described in Journal of Synthetic Organic Chemistry (1998), Vol. 56, No. 6, p. 478-488 or WO 94/09147.

Compound B1 can also be derived, obtained by the method described, for example, posted in the patent application of Japan No. 259569/1996 or Journal of Technical Disclosure No. 50997/2008.

The method described in WO 2009/022702, may be mentioned as a method of obtaining compounds of B1 from compound A1 and compound B1 can be obtained by hydrolysis of the acyl in the 1-position, 7-position, and the 11-position of compound A1 in the presence of a base.

More specifically, the solvents applicable in this invention include alcohol solvents having from 1 to 4 carbon atoms, such as methanol; solvent of ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar organic solvents, such as N,N-dimetil is mamid, dimethyl sulfoxide, N,N-dimethylacetamide, and acetonitrile; halogenated solvents such as dichloromethane and chloroform; or water; and mixed solvents composed of two or more of these solvents.

Grounds applicable in this invention include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; alkaline earth metal alkoxides; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine and guanidine. Preferred are 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

The amount used of the base is preferably from 0.01 to 4.5 equivalents in the calculation of the amount of compound A1. The reaction temperature is preferably from -20°C to 50°C. the reaction Time is preferably from 0.5 hour to 72 hours.

2-1: Getting with the unity C from compound B1

(1) the stage of obtaining compounds of C directly from compound B1

The solvents applicable in the production method of compound C from compound B1 in the above paragraph 2., include solvents from ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazine and N,N-dimethyl-2-imidazolidinone; halogenated solvents such as dichloromethane and chloroform; or an aromatic hydrocarbon solvents such as toluene; and mixed solvents composed of two or more of these solvents. Preferred are aprotic polar organic solvents. More preferred are N-methyl-2-pyrrolidinone and N,N-dimethyl-2-imidazolidinone. Especially preferred is N-methyl-2 pyrrolidinone.

The method in accordance with the above paragraph 2., preferably carried out in the absence of base. However, when the method is carried out in the presence of a base, examples of the applicable bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, guide the ID of potassium, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, and barium hydroxide; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, kallidin, 2,2'-bipyridyl, triphenylamine, quinoline, N,N-dimethylaniline, and N,N-diethylaniline. Preferred are pyridine, 2,6-lutidine, 2,4,6-kallidin, 2,2'-bipyridyl, triphenylamine, N,N-dimethylaniline, N,N-diethylaniline, etc., More preferred are 2,6-lutidine, 2,4,6-kallidin, triphenylamine, N,N-dimethylaniline, and N,N-diethylaniline. Especially preferred are 2,6-lutidine and 2,4,6-kallidin.

When using the base, the amount of base is preferably from 2.0 to 4.5 equivalents, more preferably from 2.0 to 3.0 equivalents, based on the amount of compound B1.

The group R may be introduced in the 1-position and an 11-position using ROH, RCl, (R)2O or mixed acid anhydride, preferably RCl or (R)2O, as Alliluyeva agent corresponding to R. consider the Reaction may be carried out in the presence or absence of a base or using a condensing agent such as dicyclohexylcarbodiimide, hydrochloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, piperidinomethyl, diimides indicolite, 1,3,5-trichlorosilane, 1,3,5-trichlorobenzoic anhydride, PyBop or PyBrop. Preferably, the reaction is carried out using RCl or (R)2O in the presence or absence of a base.

More preferred alleluya agents include cyclopropanecarboxylate, butyrylcholine, and anhydride cyclopropanecarbonyl acid.

The number used Alliluyeva agent is preferably from 2.0 to 5.0 equivalents, more preferably from 2.2 to 4.5 equivalents, based on the amount of compound B1. This number is used immediately or two-five divided parts.

The reaction temperature is preferably from -20°C to 50°C, more preferably from -10°C to 50°C, even more preferably from -10°C to room temperature. The reaction time is preferably from 0.1 hour up to 7 days, more preferably from 3 hours to 4 days.

In accordance with this method, compound C can be obtained from compound B1 through a single stage when the output of not less than 40%.

(2) the stage of obtaining compounds of B2 from compound B1

The solvents applicable in the method of obtaining compounds of B2 from compound B1 in the above paragraph 3., or 4., include solvents from ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar organic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazine and N,N-dimethyl-2-imidazolidinone; halogenated solvents such as dichloromethane and chloroform; or an aromatic hydrocarbon solvents such as toluene; and mixed solvents composed of two or more of these solvents. Preferred are aprotic polar organic solvents. Especially preferred is N-methyl-2-pyrrolidinone.

The reaction can be carried out without the use of reason. However, when using the base, applicable examples of the bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, kallidin, 2,2'-bipyridyl, triphenylamine, quinoline, N,N-dimethylaniline and N,N-diethylaniline. Preferred are pyridine, 2,6-lutidine, 2,4,6-kallidin, 2,2'-bipyridyl, triphenylamine, N,N-dimethylaniline, N,N-diethylaniline, etc., More preferred are triethylamine, 2,6-lutidine, ,4,6-kallidin, triphenylamine, N,N-dimethylaniline and N,N-diethylaniline. Especially preferred are triethylamine, 2,6-lutidine.

ROH, RCl, (R)2O or mixed acid anhydride, preferably RCl or (R)2O, is used as Alliluyeva agent for introduction as group R. the Reaction may be carried out in the presence or absence of a base or using a condensing agent such as dicyclohexylcarbodiimide, hydrochloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, piperidinomethyl, diimidazole, 1,3,5-trichlorosilane, 1,3,5-trichlorobenzaldehyde, PyBop or PyBrop. Preferably, the reaction is carried out using RCl or (R)2O in the presence or absence of a base.

More preferred alleluya agents include cyclopropanecarboxylate and anhydride cyclopropanecarbonyl acid.

The number used Alliluyeva agent is preferably from 1.0 to 3.5 equivalents, more preferably from 1.1 to 3.0 equivalents, based on the amount of compound B1.

When using the base, the amount of base is preferably from 1.0 to 3.0 equivalents, more preferably from 1.1 to 2.5 equivalents, based on the amount of compound B1.

The reaction temperature is preferably from -20°C to 50°C, more preferably from -10° to 50°C. The reaction time is preferably from 0.1 hour up to 7 days, more preferably from 45 min to 48 hours.

(3) the stage of obtaining compounds of C from compound B2

The solvents applicable in the production method of compound C from compound B2 in the above paragraph 3., include solvents from ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazine and N,N-dimethyl-2-imidazolidinone; halogenated solvents such as dichloromethane and chloroform; or an aromatic hydrocarbon solvents such as toluene; and mixed solvents composed of two or more of these solvents. Preferred are aprotic polar organic solvents. Especially preferred is N-methyl-2-pyrrolidinone.

The reaction can be carried out without the use of reason. However, when using the base, applicable examples of the bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, GI is roxid lithium and barium hydroxide; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, kallidin, 2,2'-bipyridyl, triphenylamine, quinoline, N,N-dimethylaniline, and N,N-diethylaniline. Preferred are pyridine, 2,6-lutidine, 2,4,6-kallidin, 2,2'-bipyridyl, triphenylamine, N,N-dimethylaniline, N,N-diethylaniline, etc., More preferred are triethylamine, 2,6-lutidine, 2,4,6-kallidin, triphenylamine, N,N-dimethylaniline and N,N-diethylaniline. Especially preferred are triethylamine, 2,6-lutidine.

ROH, RCl, (R)2O or mixed acid anhydride, preferably RCl or (R)2O, is used as Alliluyeva agent for introduction as group R. the Reaction may be carried out in the presence or absence of a base or using a condensing agent such as dicyclohexylcarbodiimide, hydrochloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, piperidinomethyl, diimidazole, 1,3,5-trichlorosilane, 1,3,5-trichlorobenzoic anhydride, PyBop or PyBrop. Preferably, the reaction is carried out using RCl or (R)2O in the presence or absence of a base.

More preferred alleluya agents include cyclopropanecarboxylate and anhydride cyclopropanecarbonyl acid.

When the application is Aut base, the amount of base is preferably from 0.1 to 5.0 equivalents, more preferably from 0.1 to 3.0 equivalents in the calculation of the amount of compound B2. In a more preferred embodiment, the total number of evidence used at this stage and at the stage described in the above paragraph (2) is from 2.0 to 4.5 equivalents, more preferably from 2.0 to 3.0 equivalents.

The number Alliluyeva agent is preferably from 1.0 to 3.0 equivalents in the calculation of the number of connections B1, more preferably from 2.0 to 4.5 equivalents total Alliluyeva agent used at this stage and at the stage described in the above paragraph (2).

The reaction temperature is preferably from -20°C to 60°C. the reaction Time is preferably from 0.1 hour up to 7 days.

This stage can also be carried out continuously without selection of the product obtained at the stage described in the above paragraph (2).

(4) the stage of obtaining compounds of B3 from compound B2

The solvents applicable in the production method of compound B3 from compound B2 in the above paragraph 4., include solvents from ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar organic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazine and N,N-dimethyl-2-imidazolidinone; halogenated solvents such as dichloromethane and chloroform; or an aromatic hydrocarbon solvents such as toluene, chlorobenzene and dichlorobenzene; and mixed solvents composed of two or more of these solvents. Preferred are aprotic polar organic solvents.

Grounds applicable in this invention include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, barium hydroxide, and tert-piperonyl potassium; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, kallidin, quinoline, N,N-dimethylaniline, N,N-diethylaniline, fosfates. Preferred are potassium carbonate, cesium carbonate, tert-piperonyl potassium, 1,8-diazabicyclo[5.4.0]undeca-7-ene and 1,5-diazabicyclo[4.3.0]Nona-5-ene, etc., More preferred are 1,8-diazabicyclo[5.4.0]undeca-7-ene and 1,5-diazabicyclo[4.3.0]Nona-5-ene.

The number of used basis of the Oia is preferably from 0.1 to 3.0 equivalents, more preferably from 0.1 to 2.0 equivalents, based on the number of connections B2.

The reaction temperature is preferably from 0°C to 150°C. the reaction Time is preferably from 0.1 hour up to 7 days.

(5) the stage of obtaining a connection from the connection B3

The solvents applicable in the production method of compound C from compound B3 in the above paragraph 4., include solvents from ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone, N-methyl-2-piperazine and N,N-dimethyl-2-imidazolidinone; halogenated solvents such as dichloromethane and chloroform; or an aromatic hydrocarbon solvents such as toluene; and mixed solvents composed of two or more of these solvents. Preferred are aprotic polar organic solvents. Especially preferred is N-methyl-2-pyrrolidinone.

The reaction can be carried out without the use of reason. However, when using the base, applicable examples of the bases include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, GI is roxid potassium, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide, and barium hydroxide; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, guanidine, lutidine, kallidin, 2,2'-bipyridyl, triphenylamine, quinoline, N,N-dimethylaniline and N,N-diethylaniline. Preferred are pyridine, 2,6-lutidine, 2,4,6-kallidin, 2,2'-bipyridyl, triphenylamine, N,N-dimethylaniline, N,N-diethylaniline, etc., More preferred are 2,6-lutidine, 2,4,6-kallidin, triphenylamine, N,N-dimethylaniline, and N,N-diethylaniline.

ROH, RCl, (R)2O or mixed acid anhydride, preferably RCl or (R)2O, is used as Alliluyeva agent for introducing R as a group. The reaction may be carried out in the presence or absence of a base or using a condensing agent such as dicyclohexylcarbodiimide, hydrochloride, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, carbonyldiimidazole, piperidinomethyl, diimidazole, 1,3,5-trichlorosilane, 1,3,5-trichlorobenzaldehyde, PyBop or PyBrop. Preferably, the reaction is carried out using RCl or (R)2O in the presence or absence of a base.

More preferred alleluya agents include cyclopropanecarbonitrile anhydride and cyclopropan Borovoy acid.

When using the base, the amount of base is preferably from 1.0 to 3.0 equivalents in the calculation of the amount of compound B2.

The number used Alliluyeva agent is preferably from 1.0 to 2.5 equivalents in the calculation of the amount of compound B1.

The reaction temperature is preferably from -20°C to 60°C.

The reaction time is preferably from 0.1 hour up to 7 days.

(6) cleaning Method and highlight the connection C of the crude product

The method of obtaining compounds of C by crystallization preferably mentioned as a method of cleaning and highlight the connection C of the reaction solution or the crude product of compound C obtained in the way described in the above paragraph (1), (3) or (5). Crystals can be obtained in the form of crystals of MES containing solvent included in the crystal lattice. Alternatively, the connection C that does not contain any solvent or water, can be obtained by drying the crystals MES or by precipitation, for example, by dissolving crystals of MES in methanol and adding water to the solution, collecting the precipitates by filtration, and drying the collected precipitation by heating under reduced pressure.

In accordance with the preferred domestic is to obtain crystals of compound C, provides a method that includes extraction of the reaction solution containing the compound C obtained by a method in accordance with any of the above paragraphs 1. to 5., organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane and simple ester, the concentration of the extract after or without drying and, in this state, ensuring the flow of crystallization, or a method, which includes evaporation of the reaction solution containing the compound C to dryness to obtain the crude product, dissolving the crude product in an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, ether, methanol, and ethanol, at room temperature or heating, and adding a weak solvent selected from the group consisting of heptane, hexane and cyclohexane, the solution to cause crystallization. A simple ether used in the method, preferably selected from diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane.

A more specific example of the method of producing crystals of compound C includes: either the stage of adding solvent to the reaction solution, the Alenia solvent by distillation to obtain crude product, and adding ethyl acetate to the crude product, or the stage of concentration of an ethyl acetate extract of the reaction solution; and the selection of an ethyl acetate solvate crystals after storage at room temperature or optionally after heating. If necessary, pentane, hexane or cyclohexane, preferably hexane, is added to an ethyl acetate extract or concentrate of an ethyl acetate extract to obtain an ethyl acetate solvate of crystals. Compound C can be obtained by dissolving an ethyl acetate solvate of crystals in methanol, adding water to the solution, collecting the resulting precipitation through filtering, and drying the collected precipitation by heating under reduced pressure.

2-2:Getting connection C from compound B1 through connection B4

The stage of obtaining compounds from compound B4 B1 in the way specified in the above paragraph 6., can also be carried out in the absence of solvent. However, when the stage is carried out in the presence of a solvent, examples of applicable solvents include ketone solvents such as acetone and diethylketone; solvents from ethers, such as diethyl ether, diisopropylether and tetrahydrofuran; ester solvents such as ethyl acetate and butyl acetate; aprotic polar is s organic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, N-methyl-2-pyrrolidinone and N-methyl-2-piperazinone; halogenated hydrocarbon solvents such as dichloromethane and chloroform; or an aromatic hydrocarbon solvents such as toluene; and mixed solvents composed of two or more such solvents.

ROH, RCl, (R)2O, or a mixed acid anhydride may be mentioned as Alliluyeva agent, for the introduction of group R. Allerease agent is preferably a RCl or (R)2O. The reaction may be carried out in the presence or absence of a base or using a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, carbonyldiimidazole, piperidinomethyl, diimidazole, 1,3,5-trichlorosilane, 1,3,5-trichlorobenzoic anhydride, PyBop or PyBrop.

Grounds applicable in this invention include sodium carbonate, potassium carbonate, sodium hydride, tert-piperonyl potassium, sodium methoxide, ethoxide sodium, pyridine, lutidine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine and diisopropylethylamine.

The reaction temperature is preferably from -20°C to 50°C. the reaction Time is preferably from 0.5 hour to 48 hours.

The solvents applicable at the stage of obtaining the connection C from compound B4, in the way specified in the above paragraph 6., include alcohol solvents having from 1 to 4 carbon atoms, such as methanol; solvent of ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar organic solvents, such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetonitrile, N-methyl-2-pyrrolidinone and N-methyl-2-piperazinone; halogenated solvents such as dichloromethane and chloroform; or water; and mixed solvents composed of two or more of these solvents.

Grounds applicable in this invention include inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium; alkaline earth metal alkoxides; and organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine and guanidine. Preferred are 1,8-di is sabillo[5.4.0]undeca-7-ene, 1,5-diazabicyclo[4.3.0]Nona-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.

The amount used of the base is preferably from 0.01 to 24 equivalents calculated from the number of compound B4. The reaction temperature is preferably from -20°C to 50°C. the reaction time is preferably from 0.5 hour to 14 days.

EXAMPLES

The present invention is additionally illustrated by the following examples, which do not imply limitation of the invention.

Purity described in the Experimental examples, the mean percentage area of the substances measured under the following HPLC conditions, unless otherwise indicated.

The measurement conditions for HPLC

Column: Inertsil ODS-2 or ODS-4 (5 μm); 4.6 mm in diameter × 150 mm

(ODS-2 was used in examples 1-13 and ODS-4 was used in examples 14-20)

The column temperature: 30°C

Mobile phase: Water-acetonitrile

Conditions mobile phase: As shown in table 1 below

Volumetric flow rate: 1.0 ml/min

The wavelength of detection: UV at 320 nm

Example 1

Synthesis_11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (1,00 g)synthesized in accordance with the method described in WO2006/129714, suspended in 5 ml of N-methyl-2-pyrrolidinone, to the suspension was added with 0.55 ml (2.2 equivalents) of 2,6-lutidine, and 0.44 ml (2.2 equivalent) cyclopropanecarbonitrile was added dropwise to the suspension at room temperature. After one hour of adding dropwise, the reaction solution was added dropwise to 200 ml of water. The mixture was stirred for 5 hours, and the resulting precipitate is then collected by filtration, washed with water and dried to obtain 0,816 g powder consisting mainly of 11-O-cyclopropane arbonyl-1,7,11-tridecemlineatus A. Separately, to the filtrate was added 25 g of sodium chloride, and the mixture was extracted with 20 ml ethyl acetate. An ethyl acetate layer was washed with water, the ethyl acetate was removed by distillation, and the residue was dried to obtain 0.27 g of foamy substance consisting mainly of 11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. Powder and frothy substance were combined together, followed by chromatography on silica gel (100 ml of silica gel C-60 production Merck Ltd.; the ethyl acetate-methanol (50:1 (vol./vol.); the volume flow rate of 10 ml/min) to give 532 mg of 11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 46,3%) (purity: 95.6%of).

FAB-MS; m/z 526 (M+H)⁺;¹H-NMR (CDCl₃) δto 2.15 (1H, dt, J=3,4, 9.5 Hz), 2,42 (1H, user.C), 2,96 (1H, s)to 3.41 (1H, DD, J=5,1, 11,0 Hz in), 3.75 (1H, d, J=11,9 Hz), 3,83 (1H, DD, J=4,9, to 11.9 Hz), the 4.29 (1H, d, J=11.7 Hz), 5,00 (1H, d, J=3.2 Hz), of 6.52 (1H, s), 7,42 (1H, DD, J=4,9, 8.1 Hz), 8,11 (1H, dt, J=2,0, 8,3 Hz), 8,69 (1H, DD, J=1,3, 4,8 Hz), of 9.00 (1H, d, J=1.7 Hz)

Example 2

Synthesis of 11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (1,00 g) suspended in 5 ml of N-methyl-2-pyrrolidinone, and 0.50 ml (2.0 equivalent) of 2,6-lutidine was added to the suspension, and 0.33 ml (1.7 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension at room temperature. After 45 min pocataligo added, the reaction solution was added dropwise to 100 ml of water. Thereto was added chloridate (5 g), and the mixture was stirred over night. The resulting precipitate is then collected by filtration, washed with water, and dried to obtain 1,053 g powder consisting mainly of 11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. Powder (526 mg; half the quantity) was purified by chromatography on silica gel (100 ml of silica gel C-60N (40-50 microns) production KANTO CHEMICAL CO., INC.; the ethyl acetate-methanol (50:1 (vol./vol.); the volume flow rate of 5 ml/min) to give 366 mg of 11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 63,7%) (purity: 95,1%).

Example 3

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (1,00 g) suspended in 5 ml of N-methyl-2-pyrrolidinone, 0,76 ml (2.6 equivalents) of 2,4,6-collidine was added to the suspension, and the mixture was added dropwise to 0,50 ml (2.5 equivalent) cyclopropanecarbonitrile at room temperature. Provided the reaction for 8.5 hours. The reaction solution was then added dropwise to 200 ml of water. The mixture was stirred overnight and the resulting precipitate is then collected by filtration and dried to obtain 1,135 g powder consisting mainly of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. Separately, 25 g of sodium chloride was added to the filtrate, and the mixture was extracted with 20 ml ethyl is Zetta. An ethyl acetate layer was washed with water, the ethyl acetate was removed by distillation, and the residue was dried to obtain 0.12 g of foamy substance consisting mainly of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. Powder and frothy substance were combined together, followed by chromatography on silica gel (150 ml of silica gel C-60 production Merck Ltd.; only ethyl acetate; the volume flow rate of 10 ml/min) to obtain 743 mg 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 57,2%) (purity: 80,8%). For compounds thus obtained, measured FAB-MS and 1H-NMR, and as a result, it was found that the data were consistent with data for the connection 261, described in W02006/129714.

FAB-MS ; m/z 594 (M+H)⁺;¹H-NMR (CDCl₃) δof 3.75 (1H, d, J=12.0 Hz), with 3.79 (1H, DD, J=4,6, 11.7 Hz), a 3.87 (1H, d, J=11.7 Hz), 4,82 (1H, DD, J=4,9, 11.2 Hz), 4,99 (1H, s), of 6.52 (1H, s), 7,42 (1H, DD, J=4,8, 7.9 Hz), 8,10 (1H, d, J=7.8 Hz), 8,69 (1H, d, J=3,9 Hz), of 9.00 (1H, s)

Example 4

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (1,00 g) suspended in 4 ml of N-methyl-2-pyrrolidinone, 0.75 ml (3.0 equivalents) of 2,6-lutidine was added to the suspension, and 0.54 ml (2,7 5 equivalent) cyclopropanecarbonitrile was added dropwise to the suspension at room temperature. Provided the reaction for three hours. The reaction solution was added a cap on the nm to 100 ml of water. The mixture was stirred for two hours and then added 10 g of sodium chloride. The mixture then was stirred overnight and the resulting precipitate was collected by filtration, washed with water, and dried to obtain 1,276 g powder consisting mainly of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A, thus obtained, was purified by chromatography on silica gel (silica gel C-60 production Merck Ltd.; 50 ml for the first time, 150 ml of the collected basic fractions for the second time, and only ethyl acetate; the volume flow rate of 5 ml/min) to give 576 mg 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 44,4%) (purity: 88,6%) and 115 mg (yield: 8,8%) (purity: 74,9%).

Example 5

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (500 mg) suspended in 2.5 ml N-methyl-2-pyrrolidinone and 0.25 ml (2.5 equivalent) cyclopropanecarbonitrile was added dropwise to the suspension at room temperature. Provided the reaction within 24 hours. The reaction solution was added dropwise to 50 ml of water. The mixture was brought to pH 7.5 by adding 8% aqueous sodium bicarbonate. To it was then added sodium chloride (5 g)and the mixture was stirred over night. Polucen the th resulting precipitate is then collected by filtration and washed with water to obtain a powder. The powder was dried to obtain 604 mg powderconsisting mainly of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A, thus obtained, was purified by chromatography on silica gel (100 ml of silica gel C-60N production KANTO CHEMICAL CO., INC.; only ethyl acetate; the volume flow rate of 5 ml/min) to give 338 mg 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 52,0%) (purity: 93,2%).

Example 6

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (500 mg) suspended in 2.5 ml N-methyl-2-pyrrolidinone, the suspension was cooled to 0°C, and 0.15 ml (1.5 equivalents) of cyclopropanecarbonitrile was added to it dropwise. The mixture was stirred at 0°C for 20 h, and 0.1 ml (1.0 equivalent) of cyclopropanecarbonitrile then added additionally. The mixture was stirred for 66 hours, and 0.1 ml (1.0 equivalent) of cyclopropanecarbonitrile was further added in addition. The mixture was stirred for 95 hours and added dropwise to 50 ml of ice water. The mixture was brought to pH 7.5 by adding 8% aqueous sodium bicarbonate. Then thereto was added sodium chloride (5 g)and the mixture was stirred. The resulting precipitate is then collected by filtration and washed with water. The filtrate ex who was regionali with ethyl acetate, and an ethyl acetate layer was then washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue and the precipitate were combined together, followed by purification by chromatography on silica gel (150 ml of silica gel C-60N production KANTO CHEMICAL CO., INC.; only ethyl acetate; the volume flow rate of 5 ml/min) to give 396 mg 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 60,9%) (purity: 95.3 per cent).

Example 7

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

11-O-Cyclopropanecarbonyl-1,7,11-tridecemlineatus A (200 mg, purity: 95.6%of)obtained in Example 1, suspended in 1.0 ml of N-methyl-2-pyrrolidinone, and 0.06 ml (1.5 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension at room temperature. Provided the reaction for 21.5 hours, and 20 ml of water was added to the reaction solution. The mixture was brought to pH 7.5 by adding 8% aqueous sodium bicarbonate, and 10 ml of ethyl acetate and thereto was added 3 g of sodium chloride. The mixture was extracted and then washed with water. Ethyl acetate (10 ml) was then added to the aqueous layer and the mixture was extracted. The extract is then washed with water and combined with an ethyl acetate layer obtained above. The ethyl acetate was removed by paragons is under reduced pressure to obtain a powder (295 mg) consisting basically, 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. the Powder was purified by chromatography on silica gel (100 ml of silica gel C-60N production KANTO CHEMICAL CO., INC.; only ethyl acetate; the volume flow rate of 5 ml/min) to give 119 mg 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (output: 55,0%) (purity: 96.5 percent).

Example 8

Synthesis 1,7,11-three-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (500 mg) suspended in 2.5 ml N-methyl-2-pyrrolidinone, of 0.44 ml (5 EQ) of pyridine was added to the suspension, and 0.45 ml (4.5 EQ) of cyclopropanecarbonitrile was added dropwise to the suspension at room temperature. Provided the reaction for 1.5 hours. The reaction solution was added dropwiseto 50 ml of water. The mixture was stirred for three hours, and then thereto was added 5 g of sodium chloride. Then, the reaction solution was stirred for 1.5 hours, and the resulting precipitate is then collected by filtration and washed with water. The powder thus obtained was dried to obtain 721 mg 1,7,11-three-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A powder (yield: 99.4 per cent) (purity: 89,6%). For compounds, thus obtained, was measured by FAB-MS and 1H-NMR, and as a result, it was found that the data corresponded to the connection 218, described the WO 2006/129714.

FAB-MS; m/z 662 (M+H)+;¹H-NMR (CDC1₃) δ2,89 (1H, s), and 3.72 (1H, d, J=11.7 Hz), 3,82 (1H, d, J=11.7 Hz), 4,79 (1H, DD, J=4,9, and 11.5 Hz), free 5.01 (1H, user.C)5,02 (1H, DD, J=4,9, 11.2 Hz), 6,46 (1H, s), 7,41 (1H, DD, J=4,8, 7.9 Hz), 8,10 (1H, dt, J=1,7, 6.4 Hz), 8,69 (1H, user.C)of 9.02 (1H, s)

Example 9

Synthesis of 1,11-O-dicyclopropyl-1,7,11-tridecemlineatus A

1,7,11-O-Tricyclodecane-1,7,11-tridecemlineatus A (1.0 g)synthesized in example 8, was dissolved in 95% aqueous solution of methanol (30 ml), and thereto was added tert-piperonyl potassium (85 mg) was added at room temperature. The mixture was stirred at this temperature for 16 h and then was added acetic acid. The methanol was removed by distillation under reduced pressure, and the residue was extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure to get crude product 1,11-O-dicyclopropyl-1,7,11-tridecemlineatus A (724 mg, purity: 50%). The crude product was purified by column chromatography on silica gel (Merck silica gel 60F254 0.5 mm; hexane:acetone = 10:5,5)with the receipt of 1,11-O-dicyclopropyl-1,7,11-tridecemlineatus A (370 mg, yield: 41%).

Example 10

Synthesis of 1,11-O-dicyclopropyl-1,7,11-tridactylidae the foam a method using a crystallization)

1,7,11-0-tricyclodecane-1,7,11-tridecemlineatus A (4 g)synthesized in example 8, was dissolved by heating in methanol (100 ml), and thereto was added potassium carbonate (420 mg) at room temperature. The mixture was stirred at this temperature for 6 hours, thereto was added acetic acid (370 mg) and water (100 ml)and the mixture was allowed to stand for 23 hours. Precipitated starting material was removed by filtration, then was added water (50 ml)and the mixture was allowed to stand for 20 hours. The methanol was removed by distillation under reduced pressure, and the residue was allowed to stand for 7 hours. As a result, 1,11-O-dicyclopropyl-1,7,11-tridecemlineatus A was precipitated, and the precipitated 1,11-O-dicyclopropyl-1,7,11-tridecemlineatus A was collected by filtration (900 mg, yield: 25,1%, purity: 81%).

Example 11

Synthesis_______11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (4,53 g) suspended 22.5 g of N-methyl-2-pyrrolidinone, and to the suspension was added 1.51 g (1.51 equivalent) of triethylamine and 2.25 g of anhydride (1.47 equivalent)cyclopropanecarbonyl acid, and the mixture was heated under stirring at 60°C for 23 hours. Then, the heated mixture was concentrated under reduced pressure with a bath temperature of equal to 70°C. Water (10 ml) was added to the oil, the floor is obtained thereby for curing. The solid is washed with three times 10 ml of water and collected by filtration. The powder thus obtained was washed in 5 mlwater and dried under reduced pressure at 40°C for one day with the 11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (4,73 g, output: 91,4%, purity: 76,2%).

Example 12

Synthesis of 1-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

11-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (199,7 mg, purity: 95.6%of)obtained in the same way as in example 1, suspended in 2.0 ml of chlorobenzene. DBU (0,02 ml, about 0.4 equivalent) was added to the suspension, and the mixture was heated under stirring at 80°C for 9 hours. Then, the reaction solution was gradually cooled to room temperature and was stirred at room temperature for two days. Thereto was added ethyl acetate (20 ml) and 5 ml of water, and the organic layer was separated and concentrated under reduced pressure. The crystals were besieged in such a state that the chlorobenzene remained in the system. Accordingly, the crystals were collected by filtration and washed with toluene. The crystals were dried under reduced pressure at 60°C overnight to obtain 1-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (153,4 mg, yield: 76,8%, purity: 94.5%of).

Example 13

Synthesis of 1,11-di-O-cyclopropanecarbonyl the-1,7,11-tridecemlineatus A

1-O-Cyclopropanecarbonyl-1,7,11-tridecemlineatus A (500 mg) suspended in 3.0 ml of N-methyl-2-pyrrolidinone, and the suspension was added dropwise to 0.10 ml (1.0 equivalent) of cyclopropanecarbonitrile at 0°C. was Provided by the reaction in one day, and it was added to 0.025 ml (0.25 equivalent) of cyclopropanecarbonitrile. Then after 41 hours from the addition of cyclopropanecarbonitrile, 1.0 ml of N-methyl-2-pyrrolidinone and 0.025 ml (0.25 equivalent) of cyclopropanecarbonitrile was added to the reaction solution, and provide a reaction for 65 hours. The reaction solution was then poured into 30 ml of ice water and 50 ml of ethyl acetate. The mixture was neutralized with 8% aqueous sodium bicarbonate, to it was added 3 g of sodium chloride, and the mixture was stirred, followed by separation. The organic layer was washed twice with 10 ml water, and the solvent was removed by distillation under reduced pressure. Powder (678 mg)thus obtained was subjected to chromatography on silica gel (silica gel C-60 (80 ml) production by Merck Ltd.; the ethyl acetate-methanol (50:1 (vol./about.)) to retrieve 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (479 mg, yield: 83,3%, purity: 95.2 per cent) and 51 mg (10,2%) of 1-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A.

Example 14

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridea ethylpyridine A (1,00 g) suspended in 7.0 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to 0°C, and 0.4 ml (2.0 equivalent) of cyclopropanecarbonitrile was added dropwise to the suspension.

Then, 0.1 ml (0.5 equivalent) of cyclopropanecarbonitrile was additionally added thereto dropwise at 0°C, after passing each period, equal to 7 hours, 23 hours and 26 hours from completion pocataligo add. 4 days after adding dropwise, the reaction solution was poured into 50 ml of ethyl acetate and 50 ml of water with ice. Next, the mixture was neutralized 0.7 g of sodium bicarbonate and to it was added 8% aqueous sodium bicarbonate and 5.0 g of sodium chloride. The mixture was stirred and gave her the opportunity to settle, followed by separation. The organic layer was washed twice with 20 ml water and concentrated under reduced pressure. Ethyl acetate (8.0 ml) was added to a foamy powder, thus obtained mixture was heated to 60°C, and thereto were added to 8.0 ml of n-hexane. The mixture was cooled to 50°C, and added a very small amount of the seed crystals. After deposition of crystals was added 2.0 ml of n-hexane, and the mixture was stirred over night. The crystals were collected by filtration, and the collected crystals were washed with 10 ml n-hexane-ethyl acetate (1:1 (vol./vol.)). The crystals thus obtained were dried overnight at 60°C with getting 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (787 mg, yield: 60,5%, purity: 87,5%)

Example 15

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (10.0 g) suspended in 40.0 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to 0°C, and 3.0 ml (1.5 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension.

Then, thereto was further added cyclopropanecarbonyl dropwise at 0°C after completion of each period equal to 6 hours (2.0 ml, 1.0 equivalent), 24 hours (1.0 ml, 0.5 equivalent), 32 hours (0,50 ml, 0.25 equivalent), and 48 hours (1.0 ml, 0.5 equivalent) from complete pocataligo add. Additionally, was added N-methyl-2-pyrrolidinone after passing 6 hours (20,0 ml) and 48 hours (10.0 ml) from complete pocataligo add. 96 hours pocataligo added, the reaction solution was poured into 100 ml ethyl acetate and 200 ml of ice water and stirred, followed by separation.

Ethyl acetate (170 ml) was added to the aqueous layer, the mixture is then neutralized to 10.1 g of sodium bicarbonate, and thereto were added to 20.0 g of sodium chloride. The mixture was stirred and gave her the opportunity to settle with the subsequent separation. The organic layer was washed once with 50 ml of 5% saline solution and twice with 30 ml of water and concentrated under reduced pressure. Ethyl acetate was added to the residue to volume equal to 110 ml of the Mixture was then heated to 60°C IR was added to 100.0 ml of n-hexane. The mixture was cooled to 50°C, and added a very small amount of the seed crystals. After a three-hour deposition of crystals was added 20 ml of n-hexane, and the mixture was stirred for two days. The crystals were collected by filtration, and the collected crystals were washed with 50 ml of a mixture n-hexane-ethyl acetate (1:1 (vol./vol.)). The crystals thus obtained were dried at 60°C for one day with getting 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (8,83 g, mass: 67,9%, purity: 86,4%).

Then, the weight to 8.70 g from 8,83 g of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A was dissolved in of 43.5 ml of methanol, and 29.0 ml of water was added thereto at room temperature. As a result, the solution became milky and, therefore, it was heated to 30°C. To it was added methanol (1.0 ml) and added a very small amount of the seed crystals. After deposition of crystals, a mixed solution consisting of 15.0 ml of water and 3.0 ml of methanol, was added in two divided portions. The mixture was stirred at room temperature overnight and was filtered. The crystals are washed with a mixed solution consisting of 16.0 ml of water and 4.0 ml of methanol. The crystals were dried at 80°C under reduced pressure to get 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (6,22 g, the mass output: 48,5%, purity: 94.5%of).

Example 16

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (10.0 g) suspended in 40.0 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to 0°C, and to the suspension was added dropwise to 7.0 ml (3.5 equivalents) of cyclopropanecarbonitrile.

Then, provided the reaction at 0°C for 53 hours, and the reaction solution was poured into 50 ml of ethyl acetate and 80 ml of water with ice. The mixture was stirred at 7°C or below, with further separation. Ethyl acetate (ml) was added to the aqueous layer and the mixture was stirred, followed by separation. Ethyl acetate (100 ml) was added to the water layer thus obtained and the mixture is neutralized 72 ml of 1N. sodium hydroxide and a small amount of 8% aqueous sodium bicarbonate. Sodium chloride (15.0 g) was added to the mixture at 10 to 15°C, and the mixture was stirred, and she was given the opportunity to settle with the subsequent separation. The organic layer was washed once with 30 ml of a 5% salt solution and twice with 30 ml water, and the mixture was concentrated under reduced pressure. Ethyl acetate (20 ml) was added to the residue, and the mixture was heated to 60°C, and thereto was added 14 ml of n-hexane. As a result, the solution became milky, and, therefore, 4,0 ml of ethyl acetate was added for dissolution. The solution is then cooled to 50°C, and added a very small amount of the seed crystals. After passing 1.5 h the owls from deposition of crystals, added 10 ml of n-hexane, and the mixture was stirred over night. The crystals were collected by filtration and washed with 30 ml of a mixture n-hexane-ethyl acetate (1:1 (vol./vol.)). The crystals were dried at 80°C for two days with getting 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (8,48 g, mass: 65,2%, purity: of 83.4%).

An ethyl acetate solution obtained by post-processing, neutralized, washed with saturated salt solution and water and dried under reduced pressure. Separately, the filtrate obtained by collecting crystals, and washing was concentrated and dried. These two substances thus obtained were combined together (5,71 g)and the mixture was dissolved in methanol (30,0 ml). Then, 5,16 ml of 5N. the sodium hydroxide solution was added dropwise at room temperature. 5N solution of sodium hydroxide (2.0 ml) was then added dropwise after passing 1.5 hours from adding dropwise 5h. the sodium hydroxide solution. The mixture was stirred at room temperature for 18 hours, was filtered, and washed with 22 ml of a mixture of methanol-water (1:1 (vol./vol.)).

The crystals thus obtained were dried at 80°C within one day from receipt of source materials, i.e., 1,7,11-tridecemlineatus A (1,96 g extract: 19,6%, purity: 94.5%of).

When the extract was taken into account, the output 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridactylidae the and A was 81.0%.

Example 17

Synthesis of 1,1, l-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (10.0 g) suspended in 40.0 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to 3°C, and 7.0 ml (3.5 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension. Then provided the reaction at 0°C for 48 h, and the reaction solution was poured into 50 ml of ethyl acetate and 80 ml of water with ice. The mixture was stirred at 10°C or below, with further separation. Ethyl acetate (100 ml) was added to the aqueous layer, the mixture was neutralized with 25 ml 5N. sodium hydroxide and a small amount of 8% aqueous sodium bicarbonate, and thereto was added 8 g of sodium chloride at 10 to 15°C. the Mixture was stirred for dissolution, and she was given the opportunity to settle, followed by separation. The organic layer was washed once with 30 ml of a 5% salt solution and twice with 30 ml of water, concentrated to 40 ml under reduced pressure and stirred at room temperature for 5 hoursfor the deposition of crystals. Then, there was added 20 ml of n-hexane over a period of two hours, and the mixture was stirred over night. The crystals were filtered off and washed with 30 ml of a mixture n-hexane-ethyl acetate (1:1 (vol./vol.)). The crystals were dried at room temperature under reduced pressure for 30 min with getting 7,31 g of crystals 1,11-di-O-CEC is propananlol-1,7,11-tridecemlineatus A. NMR-spectrum (unit: Lambda-400, solvent: CDCl3, the ratio between the integral value for the two protons CH3COOCH₂CH3 at δ 4,12 and the integral value for a proton 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A) of the crystals thus obtained showed that the content of ethyl acetate was 0.96 mol calculated from 1.0 mole of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus And (mass output (in the form of an ethyl acetate MES): 49,1%, purity: 88,9%).

Diffraction x-ray powder crystals had the following values.

Diffraction x-ray powder

Device: RINT 2200 (production of Rigaku Denki Co., Ltd.)

Measuring conditions: x-ray source: CuKα/40 kV/20 mA, the gap for sample: 0,020°, scanning speed: 0,500°/min, the clearance scan: 2θ/θ, and the scanning range: from 3.0 to 40.0°. The characteristic peaks occurred at the following diffraction angles [2θ (°)].

The diffraction angles (2θ): 7,4±0,1°, 12,0±0,1°, 17,0±0,1°, 18,3±0,1°, and 19.1±0,1°.

Diffraction x-ray powder shown in Fig.1.

Example 18

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (10.0 g) suspended in 40.0 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to 0°C, and 3.0 ml (1.5 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension. the donkey passage of 4 hours from the addition dropwise, thereto was added dropwise cyclopropanecarbonitrile (2.0 ml (1.0 equivalent)at 0°C.

Provided the reaction at 0°C for 69 hours, and the reaction solution was then poured into 100 ml of ethyl acetate and 120 ml of ice water and stirred, followed by separation. Ethyl acetate (100 ml) was added to the aqueous layer, the mixture is then neutralized 9.5 g of sodium bicarbonate, and thereto was added 8.0 g of sodium chloride. The mixture was stirred and gave her the opportunity to settle with the subsequent separation. The organic layer was washed once with 30 ml of a 5% salt solution and twice with 30 ml water, and the mixture was concentrated under reduced pressure. Ethyl acetate (35,0 ml) was added to the residue, and the mixture is then stirred at room temperature for 1.5 hour. Then, thereto was added dropwise to 35.0 ml of n-hexane over a period of two hours. The mixture was stirred at room temperature overnight. Precipitated crystals were then collected by filtration, washed with 30 ml of a mixture n-hexane-ethyl acetate (1:1 (vol./vol.), and dried under reduced pressure for four hours with obtaining 9,39 g of crystals containing 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. the Crystals thus obtained were analyzed by the method described in example 17, and it was found that they contain 1 mol of ethyl acetate in the calculation of 1.0 mole of 1,11-and-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (mass output (in the form of an ethyl acetate MES): 63,0%) (purity: 85,5%).

Diffraction x-ray powder crystals corresponded shown in example 17.

An ethyl acetate MES (portion in 8.00 g in 9,39 g) 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A, thus obtained was dissolved in 16.0 ml of methanol. The solution was heated to 35°C, was added 10.0 ml of water. As a result, the solution became milky, and, therefore, were added 1.0 ml of methanol. After one hour from the addition of methanol, the mixture was cooled to 25°C, and a mixed solution consisting of a 16.8 ml of water and 7.2 ml of methanol was added thereto dropwise at 20 to 25°C for a period of two hours. The mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration and washed with a mixed solution consisting of 7,0 ml of water and 3.0 ml of methanol. The sample (500 mg) was extracted from the solid, thus obtained, and the remainder was dried at 80°C under reduced pressure obtaining of 5.68 g of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (6,01 g, taking into account the amount of extracted sample) (total mass output from 1,7,11-tridecemlineatus A: 54,2%) (purity: 92.3 per cent).

Example 19

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (20,0 g) suspended in 80,0 ml of N-methyl-2-pyrrolidinone, susp is SIU was cooled to -10°C and 12.0 ml (3.0 equivalent) cyclopropanecarbonitrile was added dropwise to the suspension. Provided the reaction at -10°C for 4 hours, and 4.0 ml (1.0 equivalent) of cyclopropanecarbonitrile was added thereto dropwise addition. Then provided the reaction at -10°C for 72 h, and the reaction solution was poured into 200 ml ethyl acetate and 180 ml of 8% aqueous sodium bicarbonate at 5°C or below. The mixture was neutralized with 20 ml of 8% aqueous sodium bicarbonate was then added 20 ml of 15% saturated salt solution, and the mixture was stirred at 10°C with subsequent separation. The organic layer was washed three times with 60 ml of water and concentrated to 60 ml under reduced pressure. Then thereto was added 100 ml of ethyl acetate, and the mixture was concentrated to 80 mlunder reduced pressure. The mixture was stirred at room temperature overnight, and the precipitated crystals were then collected by filtration and washed with a mixed solution consisting of 10 ml of n-hexane and 20 ml of ethyl acetate. The crystals thus obtained were dried under reduced pressure at 80°C overnight with getting 17,80 g of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. the Crystals were analyzed by the method described in Example 17, and it was found that they contain 0.75 mol of ethyl acetate in the calculation of 1.0 mole of 1,11-di-O-cyclopropanecarbonyl-1,7,1-tridecemlineatus A (mass yield: 61.8 percent (in the form of an ethyl acetate MES)) (purity: 87,5%).

Example 20

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (50.0 g) suspended in 200 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to -10°C, and 15.0 ml (1.5 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension. Then, cyclopropanecarboxylate was added dropwise to the mixture, in an amount equal to 15.0 ml (1.5 equivalent) 3 hours after adding dropwise, and a quantity of 10.0 ml (1.0 equivalent) 5 hours after adding dropwise at -10°C. was Provided by the reaction at -10°C for 72 hours. The reaction solution was then poured into 500 ml of ethyl acetate and 500 ml of 8% aqueous sodium bicarbonate at 5°C or below. The mixture was neutralized with a small amount of 8% aqueous sodium bicarbonate, and thereto was added 300 ml of 15% saturated salt solution at 10°C or above with further separation. The organic layer was washed three times with 100 ml of water and concentrated to 150 ml under reduced pressure. Then thereto was added 250 ml of ethyl acetate, and the mixture is again concentrated to 200 ml under reduced pressure.

Thereto was added ethyl acetate (50 ml)and the mixture was stirred at room temperature overnight. Precipitated crystalscollected by filtration and washed with 80 ml of ethyl acetate. The crystals thus obtained were dried under reduced pressure p and 50°C for two hours with obtaining 44,90 g of crystals, containing 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A. the Crystals were analyzed by the method described in example 17, and it was found that they contain 0,99 mol of ethyl acetate in the calculation of 1.0 mole of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (mass output: 60,2% (in the form of an ethyl acetate MES)) (purity: 87,5%).

Example 21

Synthesis of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A

1,7,11-Tridecemlineatus A (50.0 g) suspended in 200 ml of N-methyl-2-pyrrolidinone, the suspension was cooled to -10°C, and 15.0 ml (1.5 equivalents) of cyclopropanecarbonitrile was added dropwise to the suspension. Then, cyclopropanecarboxylate was added dropwise to the mixture, in an amount equal to 15.0 ml (1.5 equivalent) 3 hours after adding dropwise, and a quantity of 10.0 ml (1.0 equivalent) in 5 h after adding dropwise at -10°C. was Provided by the reaction at -10°C for 75 hours. The reaction solution is then poured into a mixed solution consisting of 500 ml of ethyl acetate, 500 ml of ice water, and 40.0 g of sodium bicarbonate at 5°C or below. The mixture was neutralized with a small amount of 8% aqueous sodium bicarbonate and 300 ml of 15% salt solution was added at 10°C or above, with further separation. The organic layer was washed three times with 150 ml of water and concentrated to 100 ml under reduced pressure, the NII. Then thereto was added 200 ml of ethyl acetate, and the mixture is again concentrated to 150 ml under reduced pressure. Additionally, then to it was added 50 ml of ethyl acetate, and the mixture was stirred at room temperature overnight. Precipitated crystals were collected by filtration and washed with 60 ml of ethyl acetate. The crystals thus obtained were dried under reduced pressure at 40°C for one hour and dried at room temperature for two hours with obtaining 49,10 g of crystals containing 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A (mass yield: 65.8 per cent (in the form of an ethyl acetate MES)) (purity: 84,7%).

The crystals were analyzed in the same manner as in example 17, and it was found that they contain 0.98 mol of ethyl acetate in the calculation of 1.0 mole of 1,11-di-O-cyclopropanecarbonyl-1,7,11-10 tridecemlineatus A.

A portion of the weight of 24.0 g of the crystals thus obtained, suspended in 48,0 ml of ethyl acetate, and the suspension was stirred at 70°C for one hour and stirred at room temperature overnight. Then, the reaction solution was filtered, followed by washing with 30 ml of ethyl acetate. The washed product was dried at room temperature for 5 hours to obtain 20,54 g of the product in question (the mass yield: 56.4% of (in the form of an ethyl acetate MES; total output from 1,7,11-thirty is acetylpiperidine A) (purity: 93,2%).

The crystals thus obtained, contains 1.00 mol of ethyl acetate in the calculation of 1.0 mole of 1,11-di-O-cyclopropanecarbonyl-1,7,11-tridecemlineatus A.

Example 22

1,11-O-dicyclopropyl-1,7,11-Trideceth-peripherin A was synthesized from 1,7,11-O-tricyclodecane-1,7,11-tridecemlineatus A synthesized in example 8, when the reagents, solvent, time and temperature conditions described in table 3 below. After completion of the reaction, the reaction solution was analyzed by high-performance liquid chromatography under the following analytical conditions to determine the number of 1,11-O-dicyclopropyl-1,7,11-tridecemlineatus A, obtained in the reaction solution. The results are shown in table 3.

Analytical conditions

Detector: the detector absorption in the ultraviolet range or the detector with photodiode matrix (wavelength dimension: 254 nm)

Column: CAPCELL PAK C18; 2.0 mm EXT. dia. × 150 mm inner diameter; 5 µm

The column temperature: 40°C

The mobile phase A: Water

The mobile phase B: Acetonitrile for liquid chromatography

The flow of mobile phase: Gradient of concentration is regulated by changing the relationship between mobile phase A and mobile phase B as follows.

Volumetric flow rate: 0.2 ml/min

Conditions for rolling the basics: As shown in table 2 below

1. The method of producing compound C represented by formula C:

where R is a straight chain, branched chain or cyclic C2-alkylsulphonyl, provided that when the alkyl fragment in alkylcarboxylic group is a branched chain or a cyclic group, R represents C3-alkylsulphonyl, including:
selective acylation of hydroxyl groups in the 1-position and the 11-position of compound B1 represented by the formula B1:

allermuir agent through one-three stages in the presence or absence of a base, and
(i) a connection to get through acylation of hydroxyl groups in the 1-position and the 11-position of compound B1 through one stage;
(ii) a method including receiving connection C via the
acylation through two stages, consisting of the steps:
acylation of g is drakeley group in the 11-position of compound B1 allermuir agent to obtain compounds B2, represented by the formula B2:

where R is defined in the formula C; and
additional acylation of the hydroxyl group in 1-position of compound B2; or
(iii) a method that includes receiving connection C via acylation through three stages, consisting of the steps:
acylation of the hydroxyl group at the 11-position of compound B1 with obtaining compounds B2 represented by the formula B2:

where R is defined in the formula C;
transferring acyl 11-position of the compound B2 to the hydroxyl at the 1-position obtaining connection B3 represented by the formula B3:

where R is as defined in formula C; and
acylation of the hydroxyl group at the 11-position connection
B3.

2. The method according to p. 1, where the connection to get through acylation of hydroxyl groups in the 1-position and the 11-position of compound B1 through one stage.

3. The method according to p. 1, which includes receiving connection via acylation through two stages, consisting of the steps:
acylation of the hydroxyl group at the 11-position of compound B1 allermuir agent to obtain compounds B2 represented by the formula B2:

where R is as defined in formula C in paragraph 1; and further acylation of the hydroxyl group in 1-position with the organisations B2.

4. The method according to p. 1, which includes receiving
connection C via acylation through three stages, consisting of the steps:
acylation of the hydroxyl group at the 11-position of compound B1 with obtaining compounds B2 represented by the formula B2:

where R is as defined in formula C, p. 1;
transferring acyl 11-position of the compound B2 to the hydroxyl at the 1-position obtaining connection B3 represented by the formula B3:

where R is as defined in formula C, paragraph 1; and acylation of the hydroxyl group at the 11-position of the compound B3.

5. The method according to p. 1, which additionally comprises, as a stage for obtaining compounds B1, hydrolysis of acyl groups in the 1-position, 7-position and the 11-position of compound A1 represented by formula A1:

where A1, A7 and A11, which may be identical or different, represent acetyl or propionyl in the presence of a base.

6. The method according to p. 1, where the acylation is carried out in the absence of base.

7. The method according to p. 1, where the base used in the acylation of the hydroxyl at the 1-position and/or 11-position of the compound B1, represents the 2,4,6 kallidin or 2,6-lutidine.

8. The method according to p. 3, where the base is used at the stage of obtaining compounds B2 and receive additional allir is of the hydroxyl at the 1-position of compound B2, the amount of base used at the stage of obtaining the compound B2 is from 1.0 to 3.0 equivalents, based on compound B1, the total amount of the base used at the stage of obtaining compounds B2, and bases used at the stage of additional acylation of the hydroxyl at the 1-position of compound B2 is from 2.0 to 4.5 equivalents.

9. The method according to p. 1, where allerease agent is used in amount of from 2.0 to 5.0 equivalents in the calculation of the junction B1.

10. The method according to p. 3, where allerease agent is used at the stage of obtaining compounds B2 and receive additional acylation of the hydroxyl at the 1-position of compound B2, the number Alliluyeva agent used at the stage of obtaining compounds B2, is from 1.0 to 3.5 equivalents in the calculation of the junction B1, the total number Alliluyeva agent applied at the stage of obtaining compounds B2, and Alliluyeva agent applied at the stage of additional acylation of the hydroxyl at the 1-position of compound B2 is from 2.0 to 4.5 equivalents.

11. The method according to p. 1, where R represents cyclopropanecarbonyl.

12. The method according to p. 4, where the stage of obtaining compounds of B3 from compound B2 is carried out in the presence of a base.

13. The method according to p. 1, which additionally includes the extraction and purification of compounds from the reaction solution containing Obedinenie With, by crystallization.

14. The method according to p. 1, further comprising the stage of:
(a) extraction of the reaction solution containing the compound With an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, and concentration of the extract after or without dehydration;
(b) evaporation of the reaction solution containing the compound With, to dryness to obtain the crude product, and then dissolving the crude product in an organic solvent,
selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, methanol, and ethanol, at room temperature or under heating, or
(c) evaporation of the reaction solution containing the compound With, to dryness to obtain the crude product, dissolving the crude product in an organic solvent selected from the group consisting of methyl acetate, ethyl acetate, butyl acetate, toluene, chlorobenzene, chloroform, dichloromethane, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, methanol, and ethanol, at room temperature or under heating, and EXT is the effect of a weak solvent, selected from the group consisting of heptane, hexane and cyclohexane, to the solution.

15. The use of compound B2 represented by the formula B2:

where R is as defined in formula C,
in obtaining the connection represented by the formula:

where R is a straight chain, branched chain or cyclic C2-alkylsulphonyl, provided that when the alkyl fragment in alkylcarboxylic group is a branched chain or a cyclic group, R represents C3-alkylsulphonyl.

16. The use of compound B3, represented by the formula B3:

in obtaining compound C represented by formula C:

where R is a straight chain, branched chain or cyclic C2-alkylsulphonyl, provided that when the alkyl fragment in alkylcarboxylic group is a branched chain or a cyclic group, R represents C3-alkylsulphonyl.