WO2010041739A1 - 光学活性ビニルシクロプロパンカルボン酸誘導体及び光学活性ビニルシクプロパンアミノ酸誘導体の製造方法 - Google Patents
光学活性ビニルシクロプロパンカルボン酸誘導体及び光学活性ビニルシクプロパンアミノ酸誘導体の製造方法 Download PDFInfo
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- 0 *N(*)C(*I)[Al] Chemical compound *N(*)C(*I)[Al] 0.000 description 1
- HHODZWNOSJWRQU-UHFFFAOYSA-N CNC(C1)(C1C=C)C(O)=O Chemical compound CNC(C1)(C1C=C)C(O)=O HHODZWNOSJWRQU-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- the present invention relates to a method for producing an optically active vinylcyclopropanecarboxylic acid derivative and an optically active vinylcyclopropane amino acid derivative useful as pharmaceuticals, particularly as an intermediate for hepatitis C drugs.
- Non-patent Document 1 Method of synthesizing racemic vinylcyclopropanemalonic acid diester by reaction of malonic acid diester with 1,4-dibromo-2-butene and then cleaving it with lipase
- Patent Document 1 2) Method of optical resolution by reacting racemic vinylcyclopropanedicarboxylic acid with an optically active amine to form a diastereomeric salt
- the method 1) since the selectivity at the time of enzyme division is low and the reaction activity is also low, a large amount of enzyme must be used. Furthermore, it is not preferable as an industrial production method because an enzyme derived from pig is required. Further, the method 2) has a problem in that since a cyclocyclopropanedicarboxylic acid is a highly water-soluble compound, a large amount of an organic solvent is required during the extraction operation, and the productivity is low. In addition, the resolution efficiency when optically resolving racemic vinylcyclopropanedicarboxylic acid is as low as 78% ee or less, and in order to satisfy the pharmaceutical intermediate standard that generally requires high optical purity, the purification load in the subsequent process is high. It has the problem of becoming high.
- amino acid derivatives and amino alcohol derivatives are used as amine resolution agents, but this synthesis is complicated and inefficient. Furthermore, among the amino acids that are the raw materials for these resolving agents, compounds having a natural configuration are relatively easy to obtain, but it is difficult and expensive to obtain a compound having the opposite configuration, Depending on the desired configuration of the vinylcyclopropanedicarboxylic acid, the production cost of the resolving agent is very high.
- Patent Document 1 Non-Patent Document 1
- An object of the present invention is to provide a method for obtaining an optically active vinylcyclopropanecarboxylic acid derivative having high optical purity at low cost and safely. Furthermore, it is to provide a vinylcyclopropane amino acid having high optical purity at low cost and safety.
- the present invention is a method for producing an optically active vinylcyclopropanecarboxylic acid derivative, which is represented by the general formula (1):
- R is NH 2 , a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a substituted or unsubstituted aryloxy group having 6 to 10 carbon atoms, or a substituted or unsubstituted group having 7 to 11 carbon atoms.
- An aralkyloxy group, M represents hydrogen or a metal
- * 1, * 2 represents an asymmetric carbon
- an optically active amine is reacted with a racemic vinylcyclopropanecarboxylic acid derivative.
- an optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt an optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt.
- R 1 represents an alkyl group having 1 to 3 carbon atoms
- R 2 represents a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms, or hydrogen.
- Ar represents a substituted or unsubstituted aralkyl group having 6 to 10 carbon atoms.
- R represents an unsubstituted aryl group, R, * 1, * 2 are the same as above, * 3 represents an asymmetric carbon.
- the present inventors have conducted intensive studies on a method of converting to a vinylcyclopropane amino acid derivative using a vinylcyclopropanecarboxylic acid derivative, and as a result, without using a Curtius rearrangement that is not suitable for industrial production. It was found that a compound was obtained.
- the present invention has the general formula (6):
- R 5 represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms, or a metal.
- * 4 represents an asymmetric carbon.
- a salt thereof is reacted with a halogenating agent in the presence of a base.
- R 4 is a substituted or unsubstituted alkyloxycarbonyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyloxycarbonyl group having 7 to 12 carbon atoms, a substituted or unsubstituted group having 2 to 12 carbon atoms.
- a vinylcyclopropane amino acid derivative (6) produced by the above method. It is related with the method characterized by protecting the amino group.
- the vinylcyclopropanecarboxylic acid derivative having high optical purity can be obtained at low cost by the method according to the present invention.
- an optically active vinylcyclopropane amino acid having high optical purity can be obtained easily and inexpensively.
- a diastereomeric salt of an optically active vinylcyclopropanecarboxylic acid derivative and an amine is sometimes referred to as an optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomeric salt.
- M represents hydrogen or a metal.
- the metal include alkali metals such as lithium, sodium and potassium; alkaline earth metals such as magnesium and calcium. Of these, sodium, potassium and hydrogen are preferable, and hydrogen is more preferable.
- M When M is hydrogen, ie carboxylic acid, it may be in the form of an amine salt.
- the amine used for forming the amine salt is not particularly limited, but trimethylamine, triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, N.I.
- R is NH 2 , a substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, a substituted or unsubstituted aryloxy group having 6 to 10 carbon atoms, or a substituted or unsubstituted group having 7 to 11 carbon atoms, or Represents an unsubstituted aralkyloxy group.
- Examples of the substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group.
- Examples of the substituted or unsubstituted aryloxy group having 6 to 10 carbon atoms include a phenoxy group and a p-methoxyphenoxy group.
- Examples of the substituted or unsubstituted aralkyloxy group having 7 to 11 carbon atoms include benzyloxy group and p-methoxybenzyloxy group.
- substituents examples include an alkyl group, an aryl group, an aralkyl group, an amino group, a nitro group, a sulfonyl group, a halogen atom, a hydroxyl group, an acyloxy group, and an alkoxy group.
- NH 2 , a methoxy group, an ethoxy group, and a benzyloxy group are preferable, NH 2 and a methoxy group are more preferable, and NH 2 is most preferable.
- * 1 and * 2 represent asymmetric carbon.
- * 1 and * 2 may be either (R) -isomer or (S) -isomer. Since the compound (1) is a racemate, the four optical isomers (1R, 2R), (1R, 2S), (1S, 2R), and (1S, 2S) may be mixed evenly. , (1R, 2R), (1S, 2S) may be excessive, or (1R, 2S), (1S, 2R) may be excessive. In particular, it is preferable that the enantiomers (1R, 2R) and (1S, 2S) useful as pharmaceutical intermediates are excessive.
- a racemic vinylcyclopropanecarboxylic acid derivative represented by the above formula (1) for example, when R is an alkoxy group, an aryloxy group or an aralkyloxy group, a racemic vinylcyclopropanemalon is used. There is a method of hydrolyzing an acid diester, whereby the compound can be synthesized easily and in a high yield.
- racemic vinylcyclopropanemalonic acid diester is amidated with ammonia according to, for example, Synthetic Communications, 1994, 24, 1477, and then hydrolyzed so that R is an NH 2 group. Can be synthesized in high yield.
- racemic vinylcyclopropanemalonic acid diester can be conveniently and easily reacted by reacting 1,4-dihalo-2-butene with malonic acid diester in the presence of a base in accordance with, for example, Journal of Organic Chemistry, 2004, 69, 2427. It can be synthesized in high yield.
- optically active amine for example, the general formula (2):
- optically active amine derivatives derived from natural products such as cinchonidine, cinchonine, quinine, and quinidine; amino acids such as lysine, prolinamide derivatives, proline benzyl ester, alaninol, and phenylglycinol Derivatives; 2-amino-1,2-diphenylethanol, 2-amino-1,2-diphenylamine and the like.
- the optically active 1-arylethylamine derivative represented by the above formula (2) is preferable because both the (R) -isomer and (S) -isomer are industrially available in large quantities.
- R 1 represents an alkyl group having 1 to 3 carbon atoms.
- the alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, and a propyl group. Among these, a methyl group is preferable because it can be obtained at low cost.
- R 2 represents a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms or hydrogen. Examples of the substituent include the same as those described for R.
- Examples of the substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms include benzyl group, p-methoxybenzyl group, m-methoxybenzyl group, o-methoxybenzyl group, 2,3-dimethoxybenzyl group, p-chloro group.
- Ar represents a substituted or unsubstituted aryl group having 6 to 10 carbon atoms.
- substituent include the same as those described for R.
- Examples of the substituted or unsubstituted aryl group having 6 to 10 carbon atoms include phenyl group, o-methylphenyl group, m-methylphenyl group, p-methylphenyl group, 2,3-dimethylphenyl group, and o-methoxyphenyl.
- a phenyl group, a p-methylphenyl group, a p-chlorophenyl group, a p-methoxyphenyl group, a 1-naphthyl group, and a 2-naphthyl group are preferable. More preferred are a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
- R 1 is preferably a methyl group
- R 2 is a benzyl group, a p-methylbenzyl group, an m-methylbenzyl group, an o-methylbenzyl group, 2 , 3-dimethylbenzyl group, p-chlorobenzyl group, m-chlorobenzyl group, o-chlorobenzyl group, 3,4-dichlorobenzyl group, 3,5-dichlorobenzyl group, p-nitrobenzyl group, m-nitro Benzyl group, o-nitrobenzyl group, hydrogen
- Ar is any of phenyl group, p-methylphenyl group, p-chlorophenyl group, p-methoxyphenyl group, 1-naphthyl group, 2-naphthyl group It is a combination.
- R 1 is a methyl group
- R 2 is any one of a benzyl group, an o-chlorobenzyl group, a p-chlorobenzyl group, an m-chlorobenzyl group, and hydrogen
- Ar is a phenyl group
- R 1 is a methyl group
- R 2 is a benzyl group
- Ar is a combination of a phenyl group, R 1 is a methyl group
- R 2 is a p-chlorobenzyl group
- Ar is a phenyl group
- R 1 is a methyl group
- R 2 is a m-chlorobenzyl group
- Ar is a phenyl group
- R 1 is a methyl group
- R 2 is an o-chlorobenzyl group
- Ar is a phenyl group
- R 1 is a methyl group
- R 2 is hydrogen
- Ar is a phenyl group
- R 1 is a methyl group
- R 2 is hydrogen
- Ar is a 1-naphthyl group combination, It is.
- * 3 represents an asymmetric carbon. * 3 may be (R) -isomer or (S) -isomer.
- the optically active amine used may be in the form of a free amine or an amine salt. It does not specifically limit as a form of amine salt, For example, hydrochloride, a sulfate, carbonate etc. are mentioned. Among these, a free amine form and a hydrochloride form are preferable, and a free amine form is more preferable.
- the optically active amine is usually used in an amount of 0.1 equivalent or more, preferably 0.3 to 2.0 equivalents, more preferably 0.000 equivalents relative to the vinylcyclopropanecarboxylic acid derivative (1). 3 to 1.5 equivalents, more preferably 0.4 to 1.5 equivalents, particularly preferably 0.5 to 1.1 equivalents, most preferably 0.6 to 1.0 equivalents. .
- the solvent used in the reaction is not particularly limited, and examples thereof include aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, hexamethylphosphoric triamide; Hydrocarbon solvents such as hexamethylbenzene, toluene, n-hexane, cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran (THF), diisopropyl ether, methyl tert-butyl ether, dimethoxyethane; chlorobenzene, methylene chloride, chloroform, 1 Halogen solvents such as 1,1,1-trichloroethane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile and butyronitrile; methanol, ethanol, isopropanol, butano
- acetone, toluene, methyl tert-butyl ether, ethyl acetate, acetonitrile, methanol, ethanol, and isopropanol are preferable, and acetone, toluene, ethyl acetate, acetonitrile, and isopropanol are more preferable.
- the amount of the solvent to be used is 1 to 200 times by weight, preferably 1 to 50 times by weight with respect to the compound (1).
- the reaction temperature is usually in the range of 0 to 120 ° C. Preferably it is in the range of 10 to 100 ° C, more preferably in the range of 10 to 80 ° C.
- the vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt obtained as described above is further subjected to a crystallization step to perform optical resolution.
- the temperature at the time of crystallization is usually in the range of ⁇ 50 to 70 ° C., preferably ⁇ 20 to 50 ° C. More preferably, it is ⁇ 10 to 50 ° C.
- the stirring power requirement per unit volume of the crystallization typically from about 0.01 kW / m 3 or higher, preferably 0.1 kW / m 3 or more, more preferably 0.2 kW / m 3 or more flow is preferred. If the above fluidity is obtained, it is not always necessary to use a stirring blade. For example, a method by circulating liquid may be used.
- Crystallization method is not particularly limited, and any method may be used.
- a method of adding a suitable solvent and an optically active amine to the compound (1) and then heating to a homogeneous solution and then cooling and crystallizing may be used.
- the compound (1) may be dissolved or dissolved in a suitable solvent.
- a method of dispersing and adding an optically active amine thereto for crystallization may be used.
- a method may be used in which an optically active amine is dissolved or dispersed in a suitable solvent, and the compound (1) is added thereto for crystallization.
- operations such as seed crystal addition can be appropriately combined with the above-described method.
- the thus obtained crystal of the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt is subjected to solid-liquid separation by, for example, centrifugation, pressure filtration, vacuum filtration, etc., and if necessary, cake washing Can be obtained as a wet body. Further, dry crystals can be obtained by further drying under reduced pressure.
- the obtained crystal When used for the reaction in the next step, it may be used as a dry crystal or may be used as a wet body.
- the isolated optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt can be obtained as an optically active vinylcyclopropanecarboxylic acid derivative by subjecting it to a salt removal treatment.
- an extraction operation may be performed using water and an organic solvent in the presence of an acid or a base.
- the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt is extracted with an organic solvent-water mixture in the presence of an acid to form the optically active vinylcyclopropanecarboxylic acid derivative on the organic layer side.
- the optically active vinylcyclopropanecarboxylic acid derivative can be distributed to the aqueous layer side and the optically active amine can be distributed to the organic layer side to obtain. .
- the solvent used at the time of extraction is not particularly limited, and the solvents described above can be used as the reaction solvent. These may be used alone or in combination of two or more. Of these, hydrocarbon solvents, ether solvents, halogen solvents, and ester solvents are preferable, and toluene, methyl tert-butyl ether, chlorobenzene, methylene chloride, and ethyl acetate are more preferable.
- the amount of the solvent used is 1 to 200 times by weight, preferably 1 to 50 times by weight with respect to the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt.
- the amount of water used is 0.5 to 200 times by weight, preferably 0.5 to 50 times by weight with respect to the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt.
- the acid used is not particularly limited, and examples thereof include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid. These acids may be used alone or in combination. Of these, hydrochloric acid and sulfuric acid are preferred.
- the acid may be used in an equivalent amount or more with respect to the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt, preferably 0.5 to 200 equivalents, more preferably 0.5 to 50 equivalents, still more preferably. 1 to 10 equivalents, particularly preferably 1 to 5 equivalents.
- the base used may be an inorganic base or an organic base.
- the inorganic base include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, and barium hydroxide; carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate. .
- the organic base is not particularly limited, but a tertiary amine is preferable.
- the tertiary amine include trialkylamines having 1 to 12 carbon atoms such as trimethylamine, triethylamine, and ethyldiisopropylamine; N, N-dimethylaniline, N, N-diethylaniline, N.I.
- Tertiary amines consisting of alkyl groups having 1 to 4 carbon atoms such as N-dimethylaminopyridine and phenyl groups; nitrogen-containing organic bases such as pyridine, picoline, lutidine; N, N, N, N-tetramethyl-1, N, N, having 1 to 10 carbon atoms such as 2-ethylenediamine, N, N, N, N-tetramethyl-1,3-propanediamine, N, N, N, N-tetramethyl-1,6-hexanediamine Examples thereof include N, N-tetramethyl ⁇ , ⁇ -alkyldiamine.
- lithium hydroxide, sodium hydroxide, and potassium hydroxide are preferable because they are inexpensive and easily available.
- the base may be used in an amount of 1 equivalent or more with respect to the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt, preferably 1 to 200 equivalents, more preferably 1 to 50 equivalents, still more preferably. 1 to 10 equivalents, particularly preferably 1 to 5 equivalents.
- the temperature during the extraction operation is usually in the range of ⁇ 20 to 120 ° C., preferably ⁇ 20 to 90 ° C. More preferably, it is ⁇ 20 to 70 ° C.
- an optically active vinylcyclopropanecarboxylic acid derivative can be easily obtained with high optical purity as compared with the conventional method.
- optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomer salt represented by the formula (1) is a novel compound that has been found as a result of studies by the present inventors and has been developed as a pharmaceutical intermediate and has not been described in any literature. is there.
- R and M are the same as the formula (1).
- * 1 and * 2 represent asymmetric carbon.
- * 1 and * 2 may both be (R) -isomer or (S) -isomer.
- the optically active vinylcyclopropanecarboxylic acid derivative-amine diastereomeric salt is an optically active substance, any one of (1R, 2R), (1R, 2S), (1S, 2R), (1S, 2S) Is present in excess, but (1S, 2S) is preferably excess.
- * 3 represents an asymmetric carbon. * 3 may be (R) -isomer or (S) -isomer.
- a halogenating agent is reacted with a vinylcyclopropanamide carboxylic acid derivative (hereinafter referred to as compound (5)) or a salt thereof represented by the general formula (6):
- R 5 represents hydrogen, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms, or a metal.
- substituents include the same as those described for R.
- Examples of the substituted or unsubstituted alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, and an isopropyl group.
- Examples of the substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms include a benzyl group and a p-methoxybenzyl group.
- the metal examples include alkali metals such as lithium, sodium and potassium, and alkaline earth metals such as magnesium and calcium.
- R 5 is preferably hydrogen, a methyl group, an ethyl group, sodium, or potassium, and particularly preferably hydrogen.
- R 5 When R 5 is hydrogen, that is, carboxylic acid, it may be in the form of an amine salt.
- the amine that forms the amine salt is not particularly limited, but trimethylamine, triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, N.I.
- optically active amine for example, an optically active amine derivative derived from a natural product such as an optically active 1-arylethylamine derivative described in the above formula (2), cinchonidine, cinchonine, quinine, quinidine; lysine, prolinamide Derivatives, amino acid derivatives such as proline benzyl ester, alaninol, phenylglycinol; 2-amino-1,2-diphenylethanol, 2-amino-1,2-diphenylamine and the like.
- the optically active amine salt represented by the formula (2) is preferred.
- * 4 and * 5 represent asymmetric carbon.
- * 4 and * 5 may be either (R) -isomer or (S) -isomer.
- a racemate may be used or an optically active substance may be used, but an optically active substance is preferable.
- the optically active substance is not particularly limited, and (1R, 2R), (1R, 2S), (1S, 2R), and (1S, 2S) may be used in any excess. Among these, (1S, 2S) is preferably excessive.
- an optically active cyclopropanamide carboxylic acid derivative-amine diastereomer salt that can be produced by the method described above may be used, or an optically active vinylcyclopropanamide carboxylic acid derivative may be obtained by subjecting it to a salt removal treatment. It may be obtained and used. Furthermore, you may use what was obtained by the other method.
- * 6 and * 7 represent asymmetric carbon.
- * 6 and * 7 may be either (R) -isomer or (S) -isomer.
- the 1-position display of the resulting compound (6) is opposite to that of the vinylcyclopropanamide carboxylic acid derivative (compound (5)). That is, (1S, 2R) compound (6) is produced from (1R, 2R) compound (5), and (1S, 2S) compound (6) is produced from (1R, 2S) compound (5). And (1S, 2R) compound (5) produces (1R, 2R) compound (6), and (1S, 2S) compound (5) produces (1R, 2S) compound (5). 6) is generated.
- a preferred configuration of compound (6) is (1R, 2S).
- the base used in this reaction may be an inorganic base or an organic base.
- the inorganic base include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, and barium hydroxide; carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate.
- the organic base is not particularly limited, but a tertiary amine is preferable.
- the tertiary amine include trialkylamines having 1 to 12 carbon atoms such as trimethylamine, triethylamine, and ethyldiisopropylamine; N, N-dimethylaniline, N, N-diethylaniline, N.I.
- Tertiary amines consisting of alkyl groups having 1 to 4 carbon atoms such as N-dimethylaminopyridine and phenyl groups; nitrogen-containing organic bases such as pyridine, picoline, lutidine; N, N, N, N-tetramethyl-1, N, N, having 1 to 10 carbon atoms such as 2-ethylenediamine, N, N, N, N-tetramethyl-1,3-propanediamine, N, N, N, N-tetramethyl-1,6-hexanediamine Examples thereof include N, N-tetramethyl ⁇ , ⁇ -alkyldiamine.
- lithium hydroxide, sodium hydroxide, and potassium hydroxide are preferable because they are inexpensive and easily available.
- the base may be used in an amount of 1 equivalent or more with respect to the compound (5), preferably 1 to 20 equivalents, and more preferably 1 to 10 equivalents.
- the base used in this reaction may be used without being diluted in water or an organic solvent, or may be used after being diluted.
- halogenating agent used in this reaction examples include sodium hypochlorite, potassium hypochlorite, sodium hypobromite, chlorine, bromine, iodine, N-chlorosuccinimide (NCS), N-bromosuccinimide ( NBS), N-iodosuccinimide (NIS), N-chloroisocyanuric acid and the like.
- sodium hypochlorite and sodium hypobromite are preferable, and sodium hypochlorite is more preferable.
- halogenating agents may be used as they are, or those diluted with water or an organic solvent may be used.
- an aqueous solution is usually used.
- the halogenating agent may be prepared in the system.
- a methanol solution of sodium hypobromite can be prepared by reacting bromine and sodium methoxide in a methanol solvent.
- the halogenating agent may be used in an amount of 1 equivalent or more, preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents, relative to compound (5).
- the amount of water used is 1 to 200 times the weight, preferably 1 to 50 times the weight of the compound (5).
- the presence of an organic solvent is preferable because the reaction may be accelerated.
- the solvent to be used is not particularly limited, and the solvents exemplified as the reaction reaction solvent in the description of the reaction between the compound (1) and the optically active amine can be used. These may be used alone or in combination of two or more. Of these, ether solvents, ester solvents, alcohol solvents, and water are preferable, and tetrahydrofuran (THF), ethyl acetate, methanol, ethanol, isopropanol, n-propanol, and water are more preferable.
- THF tetrahydrofuran
- the reaction temperature is usually within a range of ⁇ 30 to 120 ° C., preferably ⁇ 20 to 100 ° C. More preferably, it is ⁇ 20 to 80 ° C.
- the extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
- the target compound is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure.
- an acid such as hydrochloric acid or sulfuric acid may be added to the reaction solution, the system pH may be set to the isoelectric point of the amino acid, and the product may be obtained by filtration.
- the reaction solvent may be distilled off or replaced by an operation such as heating under reduced pressure, and then the same operation as described above may be performed.
- the target product thus obtained is almost pure, but purification may be carried out by a general method such as crystallization purification, fractional distillation, column chromatography, etc. to further increase the purity.
- the compound (6) synthesized in this way may be represented by the general formula (4):
- R 4 is a substituted or unsubstituted alkyloxycarbonyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyloxycarbonyl group having 7 to 12 carbon atoms, or a substituted group having 2 to 12 carbon atoms.
- an unsubstituted acyl group is represented. Examples of the substituent include the same as those described for R.
- Examples of the substituted or unsubstituted alkyloxycarbonyl group having 1 to 15 carbon atoms include t-butyloxycarbonyl group (Boc group), methoxycarbonyl group (Moc group), 9-fluorenylmethoxycarbonyl group (Fmoc group). Etc.
- Examples of the substituted or unsubstituted aralkyloxycarbonyl group having 7 to 12 carbon atoms include benzyloxycarbonyl group (Cbz group), p-methoxybenzyloxycarbonyl group and the like.
- Examples of the substituted or unsubstituted acyl group having 2 to 12 carbon atoms include an acetyl group and a benzoyl group.
- t-butyloxycarbonyl group (Boc group), methoxycarbonyl group (Moc group), 9-fluorenylmethoxycarbonyl group (Fmoc group), benzyloxycarbonyl group (Cbz group), and acetyl group are preferable. More preferred are t-butyloxycarbonyl group (Boc group) and benzyloxycarbonyl group (Cbz group).
- the method of deriving from compound (6) to compound (4) may be carried out under conditions for general protection. For example, it can be carried out according to the method described in Theodora W.Greene, Peter G.M.Wuts, Protectve Groups in Organic Chemistry (Third Edition)
- t-butyloxycarbonyl (Boc) can be protected by allowing t-butyl dicarbonate to act in a suitable solvent in the presence of a base, and benzyloxycarbonyl can be protected in a suitable solvent in the presence of a base.
- benzyloxycarbonyl (Cbz) protection can be performed.
- the compound (6) isolated by the above-described method may be used to induce the compound (4), or the compound (4) may be used as it is without using the reaction solution containing the compound (6) without performing the isolation operation. ).
- the mixture was stirred for 5 hours at an internal temperature of 24 ° C., and then ammonia gas (about 15 g, 0.88 mol) was introduced into the reaction solution over 1 hour while maintaining the internal temperature of 15 to 25 ° C.
- the mixture was stirred at an internal temperature of 25 ° C. for 15 hours, and then concentrated using a rotary evaporator until the total amount was about 142 g.
- Water (17.44 g) and a 30 wt% aqueous sodium hydroxide solution (12.17 g, 0.09 mmol) were added to the concentrate, and the mixture was stirred at an internal temperature of 40 ° C. for 4 hours.
- Example 2 (1S, 2S) -2-Vinyl-1-carbamoylcyclopropanecarboxylic acid (S) —N- (4-chlorobenzyl) -1-phenylethylamine salt production method Synthesized according to Production Example 2 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (1000 mg, 6.45 mmol), which is a 1: 1 mixture of 1S, 2S) -form and (1R, 2R) -form, was suspended in acetonitrile (10 mL), To this was added (S) —N- (4-chlorobenzyl) -1-phenylethylamine (1585 mg, 6.45 mmol) at room temperature.
- Example 4 Method for producing (1S, 2S) -2-vinyl-1-carbamoylcyclopropanecarboxylic acid
- Example 5 Production method of (1R, 2S) -2-vinyl-1- (t-butoxycarbonylamino) cyclopropanecarboxylic acid (1S, 2S) -2-vinyl-1-carbamoyl obtained in Example 4 Tetrahydrofuran (1 mL) was added to an aqueous solution containing sodium cyclopropanecarboxylate, and 11.7 wt% hypochlorous acid aqueous solution (957.1 mg, 1.50 mmol) was added at a bath temperature of 0 ° C. After stirring for 1 hour at the same temperature, stirring was further performed for 2 hours at a bath temperature of 60 ° C.
- reaction mixture was cooled to 26 ° C., and t-butyl dicarbonate (223.3 mg, 1.02 mmol) was added. After stirring for 3 hours at the same temperature, 1M hydrochloric acid was added until the pH in the system reached 3. Ethyl acetate (20 mL) was added, the organic layer was obtained by extraction operation, and the organic layer was washed with water (5 mL). The organic layer was concentrated using a rotary evaporator to obtain the title compound (acquired amount: 109 mg, yield: 70.0%).
- Example 7 Method for producing cis-2-vinyl-1-methoxycarbonylcyclopropanecarboxylic acid
- cis-2-vinyl-1-methoxycarbonylcyclopropanecarboxylic acid (R) -1- (1-Naphthyl) ethylamine salt 200 mg, 0.59 mmol
- toluene 2.5 mL
- water 2.5 mL
- 35 wt% aqueous sodium hydroxide solution 241.1 mg
- Example 8 Method for producing methyl cis-2-vinyl-1-carbamoylcyclopropanecarboxylate Triethylamine (89) was added to the toluene solution containing cis-2-vinyl-1-methoxycarbonylcyclopropanecarboxylic acid obtained in Example 7. .6 mg, 0.89 mmol) was added, and then pivaloyl chloride (74.7 mg, 0.62 mmol) was added at a bath temperature of 0 ° C. After stirring at the same temperature for 1 hour, 28 wt% aqueous ammonia (143.5 mg, 2.36 mmol) was added. The mixture was further stirred for 2 hours at a bath temperature of 24 ° C.
- Example 9 (1S, 2S) -2-Vinyl-1-carbamoylcyclopropanecarboxylic acid (S) -N- (2-chlorobenzyl) -1-phenylethylamine salt production method Synthesized according to Production Example 2 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (3000 mg, 19.34 mmol), which is a 1: 1 mixture of 1S, 2S) -form and (1R, 2R) -form, was suspended in ethyl acetate (21 g). To this was added (S) —N- (2-chlorobenzyl) -1-phenylethylamine (3802 mg, 15.47 mmol) at room temperature.
- Example 10 (1S, 2S) -2-Vinyl-1-carbamoylcyclopropanecarboxylic acid (S) -N- (2-chlorobenzyl) -1-phenylethylamine salt production method Synthesized according to Production Example 2 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (2000 mg, 12.89 mmol), which is a 1: 1 mixture of 1S, 2S) -form and (1R, 2R) -form, was suspended in ethyl acetate (21 g).
- Example 14 (1S, 2S) -2-Vinyl-1-carbamoylcyclopropanecarboxylic acid (S) -N- (2-chlorobenzyl) -1-phenylethylamine salt production method Synthesized according to Production Example 2 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (3000 mg, 19.34 mmol), which is a 1: 1 mixture of 1S, 2S) -form and (1R, 2R) -form, was suspended in acetone (21 g), (S) —N- (2-chlorobenzyl) -1-phenylethylamine (3.800 mg, 15.47 mmol) was added thereto at a bath temperature of 50 ° C.
- Example 15 (1S, 2S) -2-Vinyl-1-carbamoylcyclopropanecarboxylic acid (S) -N- (4-chlorobenzyl) -1-phenylethylamine salt production method Synthesized according to Production Example 2 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (1000 mg, 6.44 mmol), which is a 1: 1 mixture of 1S, 2S) -form and (1R, 2R) -form, was suspended in toluene (6.4 g).
- Example 16 (1S, 2S) -2-Vinyl-1-carbamoylcyclopropanecarboxylic acid (S) -N- (4-methylbenzyl) -1-phenylethylamine salt production method Synthesized according to Production Example 2 2-vinyl-1-carbamoylcyclopropanecarboxylic acid (1000 mg, 6.44 mmol), which is a 1: 1 mixture of 1S, 2S)-, (1R, 2R)-, was suspended in acetonitrile (7.0 g), To this was added (S) —N- (4-methylbenzyl) -1-phenylethylamine (1161 mg, 5.15 mmol) at a bath temperature of 30 ° C.
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Abstract
Description
1)マロン酸ジエステルと1,4-ジブロモ-2-ブテンとの反応によりラセミ体のビニルシクロプロパンマロン酸ジエステルを合成した後、これをリパーゼにより分割する方法(非特許文献1)
2)ラセミ体のビニルシクロプロパンジカルボン酸を光学活性アミンと反応させ、ジアステレオマー塩とすることで光学分割を行う方法(特許文献1)
等が知られている。
R1がメチル基、R2がベンジル基、Arがフェニル基の組み合わせ、
R1がメチル基、R2がp-クロロベンジル基、Arがフェニル基の組み合わせ、
R1がメチル基、R2がm-クロロベンジル基、Arがフェニル基の組み合わせ、
R1がメチル基、R2がo-クロロベンジル基、Arがフェニル基の組み合わせ、
R1がメチル基、R2が水素、Arがフェニル基の組み合わせ、
R1がメチル基、R2が水素、Arが1-ナフチル基の組み合わせ、
である。
trans-1,4-ジブロモ-2-ブテン(25.00g,0.144mol)、マロン酸ジメチル(15.06g,0.144mol)のメタノール(150mL)溶液に対して、内温を1~5℃に保ちながら、28wt%ナトリウムメトキシド/メタノール溶液を30分間かけて滴下した。滴下終了後、内温24℃にて5時間の攪拌を行った。続いて反応液を冷却し、内温1~5℃を保ちながら、14%水酸化カリウム水溶液(36.02g,0.091mol)を30分間かけて滴下した。滴下終了後、内温24℃にて21時間の攪拌を行った後、ロータリーエバポレーターを用い、全量が約70gとなるまで濃縮を行った。濃縮液に水(45mL)、t-ブチルメチルエーテル(75mL)を添加したのち、系内のpHを2.5になるまで、濃塩酸を添加した。抽出操作により有機層を取得し、硫酸マグネシウムを用いて乾燥を行った後、ロータリーエバポレーターを用いて濃縮を行い、表題化合物を粗生成物として得た(粗収量:19.81g,粗収率:92.5%)。このときcis体とトランス体との生成比は83:17であった。
trans-1,4-ジブロモ-2-ブテン(25.00g,0.144mol)、マロン酸ジメチル(15.06g,0.144mol)のメタノール(150mL)溶液に対して、内温を1~5℃に保ちながら、28wt%ナトリウムメトキシド/メタノール溶液を30分間かけて滴下した。滴下終了後、内温24℃にて5時間の攪拌を行った後、内温15~25℃を保ちながら、1時間かけて反応液にアンモニアガス(約15g、0.88mol)を導入した。内温25℃にて15時間の攪拌を行い、続いてロータリーエバポレーターを用いて、全量が約142gとなるまで濃縮を行った。濃縮液に水(17.44g)及び30wt%水酸化ナトリウム水溶液(12.17g,0.09mmol)を添加し、内温40℃下、4時間の攪拌を行った。ロータリーエバポレーターを用いて、全量が約77gとなるまで濃縮を行い、水(105g)及びトルエン(30mL)を添加し、抽出操作により水層を取得した。系内のpHが3.0となるまで濃塩酸を添加し、析出した固体をろ過操作により取得後、乾燥を行い、表題化合物を得た(収量12.79g、収率:70%)。このときcis体とトランス体との生成比は2:98であった。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(500mg,3.22mmol)をアセトニトリル(5mL)に懸濁させ、これに(S)-N-ベンジル-1-フェニルエチルアミン(681mg,3.22mmol)を室温にて添加した。同温にて1時間の攪拌を行い、析出した結晶をろ過操作により取得した。0℃に冷却したアセトニトリル(1mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:416.9mg,収率:35.3%)。
1H NMR(400MHz,CDCl3/ppm):δ1.52(d,3H),1.79(dd,1H),1.92(dd,1H),2.43(ddd,1H),3.74(dd,2H),3.98(q,1H),5.07(dd,1H)、5.29(dd,1H)、5.80-5.89(m,1H)、6.04(br,2H)、6.20(br,1H)、7.24-7.41(m,10H)、9.21(br,1H)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(1000mg,6.45mmol)をアセトニトリル(10mL)に懸濁させ、これに(S)-N-(4-クロロベンジル)-1-フェニルエチルアミン(1585mg,6.45mmol)を室温にて添加した。同温にて1時間の攪拌を行い、析出した結晶をろ過操作により取得した。0℃に冷却したアセトニトリル(2mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:788.0mg,収率:30.5%)。
1H NMR(400MHz,CDCl3/ppm):δ1.53(d,3H),1.80(dd,1H),1.92(dd,1H),2.41(ddd,1H),3.71(dd,2H),3.97(q,1H),5.09(dd,1H)、5.31(dd,1H)、5.80-5.89(m,1H)、6.51(br,1H)、6.66(br,2H)、7.19-7.41(m,9H)、9.28(br,1H)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(200mg,1.29mmol)をアセトニトリル(2mL)に懸濁させ、これに(S)-N-(3,4-ジクロロフェニル)-1-フェニルエチルアミン(361.2mg,1.29mmol)を室温にて添加した。添加終了後、同温にて1時間の攪拌を行い、析出した結晶をろ過操作により取得した。0℃に冷却したアセトニトリル(1mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:131.4g,収率:23.5%)。
1H NMR(400MHz,CDCl3/ppm):δ1.51(d,3H),1.84(dd,1H),1.96(dd,1H),2.45(ddd,1H),3.68(dd,2H),3.94(q,1H),5.11(dd,1H)、5.32(dd,1H)、5.80-5.89(m,1H)、6.58(br,1H)、7.09(dd,1H)、7.26-7.52(m,8H)、9.11(br,1H)。
実施例1で得られた(1S,2S)-2-ビニル-1-カルバモイルシクロプロパンカルボン酸 (S)-N-ベンジル-1-フェニルエチルアミン塩(250mg,682mmol)をトルエン(2.5mL)、水(2.5mL)中に懸濁させ、攪拌下、30wt%水酸化ナトリウム水溶液(363.7mg)を添加した。静置後、分液操作により水層を取得した。
実施例4で取得した(1S,2S)-2-ビニル-1-カルバモイルシクロプロパンカルボン酸ナトリウムを含む水溶液にテトラヒドロフラン(1mL)を添加した後、バス温0℃下、11.7wt%次亜塩素酸水溶液(957.1mg,1.50mmol)を添加した。同温にて1時間の攪拌を行った後、バス温60℃下でさらに2時間の攪拌を行った。反応液を26℃まで冷却下のち、二炭酸t-ブチル(223.3mg,1.02mmol)を添加した。同温にて3時間の攪拌の後、系内のpHが3となるまで1M塩酸を添加した。酢酸エチル(20mL)を加え、抽出操作により有機層を取得後、有機層を水(5mL)で洗浄した。有機層をロータリーエバポレーターを用いて濃縮し、表題化合物を得た(取得量:109mg,収率:70.0%)。
1H NMR(400MHz,DMSO-d6/ppm):δ1.24(d,1H),1.37(s,9H),1.52(d,1H),2.06(ddd,1H)5.04(dd,1H)、5.23(dd,1H)、5.63-5.72(m,1H)。
製造例1に従い合成したラセミ体の2-ビニル-1-メトキシカルボニルシクロプロパンカルボン酸(cis-:trans=83:17混合物,250mg,1.47mmol)を酢酸エチル(2.50g)に懸濁させ、これに(R)-1-(1-ナフチル)エチルアミン(503.2mg,1.47mmol)を室温にて添加した。添加終了後、反応液は均一であったが、同温にて1時間の攪拌を行ったところ結晶化が確認された。バス温50℃下で、20分間攪拌したのち、室温で放置することにより、内温が30℃となるまで冷却を行った。結晶をろ過操作により取得し、酢酸エチル(1mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:241.5mg,収率:24.1%)。
(HPLC分析系)カラム:CHIRALCEL OF、溶離液:ヘキサン/イソプロパノール/トリフルオロ酢酸=90/10/0.1、流速:0.6mL/分、検出器:UV 210nm、カラムオーブン温度:30℃、保持時間:12.6分、18.7分
1H NMR(400MHz,DMSO-d6/ppm):δ1.18(dd,1H),1.31(dd,1H),1.67(d,3H)、2.13(ddd,1H),3.45(s,1H)、4.89-4.98(m,2H)、5.13-5.25(m,2H)、6.70(br,2H)、7.43-7.57(m,3H)、7.68(d,1H)、7.78(d,1H)、7.85-7.88(m,1H)、8.02(d,1H)。
実施例6で得られた(cis-2-ビニル-1-メトキシカルボニルシクロプロパンカルボン酸 (R)-1-(1-ナフチル)エチルアミン塩(200mg,0.59mmol)をトルエン(2.5mL)、水(2.5mL)中に懸濁させ、攪拌下、35wt%水酸化ナトリウム水溶液(241.1mg)を添加した。静置後、分液操作により有機層を取得した。有機層を濃縮し、トルエン(5mL)を用いて共沸脱水操作を2回実施した後、全量が2.5gとなるようにトルエンにて希釈を行った。
実施例7で取得したcis-2-ビニル-1-メトキシカルボニルシクロプロパンカルボン酸を含むトルエン溶液にトリエチルアミン(89.6mg,0.89mmol)を添加した後、バス温0℃下、塩化ピバロイル(74.7mg,0.62mmol)を添加した。同温にて1時間の攪拌を行った後、28wt%アンモニア水(143.5mg,2.36mmol)を添加した。バス温24℃下でさらに2時間の攪拌を行った。反応液に水(2.0mL)を添加し、抽出操作により有機層を取得した。有機層を無水硫酸ナトリウムにて乾燥後、ロータリーエバポレーターを用いて濃縮し、表題化合物を得た(取得量:55mg,収率:50.0%)。
1H NMR(400MHz,DMSO-d6/ppm):δ1.91(dd,1H),2.07(dd,1H),2.58(ddd,1H)3.74(s,3H)、5.18(dd,1H)、5.35(dd,1H)、)5.57-5.78(m,1H)、5.77(br,2H)、8.22(br,1H)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(3000mg,19.34mmol)を酢酸エチル(21g)に懸濁させ、これに(S)-N-(2-クロロベンジル)-1-フェニルエチルアミン(3802mg,15.47mmol)を室温にて添加した。同温にて3時間の攪拌を行い、析出した結晶をろ過操作により取得した。酢酸エチル(10mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:3194.8mg,収率:41.2%)。
1H NMR(400MHz,CDCl3/ppm):δ1.56(d,3H),1.80(dd,1H),1.93(dd,1H),2.46(ddd,1H),3.87(s,2H),4.03(q,1H),5.09(dd,1H)、5.30(dd,1H)、5.75(br,2H)、5.76-5.85(m,2H)、6.32(br,1H)、7.18-7.26(m,2H)、7.31-7.41(m,7H)),9.02(br,1H)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(2000mg,12.89mmol)を酢酸エチル(21g)に懸濁させ、これに(S)-N-(2-クロロベンジル)-1-フェニルエチルアミン(2220mg,9.02mmol)をバス温50℃下にて添加した。同温にて1時間の攪拌を行った後、バス温15℃下にてさらに17時間の攪拌を行った。析出した結晶をろ過操作により取得した。酢酸エチル(7.5mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:2000mg,収率:38.7%)。
製造例2に従い合成した(1S,2S)-体、(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(2000mg,12.89mmol)を酢酸エチル(21g)に懸濁させ、これに(S)-N-(2-クロロベンジル)-1-フェニルエチルアミン(1580mg,6.45mmol)をバス温20℃下にて添加した。同温にて1時間の攪拌を行った後、バス温20℃下にてさらに17時間の攪拌を行った。析出した結晶をろ過操作により取得した。酢酸エチル(7.5mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:2584mg,収率:50%)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(3000mg,19.34mmol)をアセトニトリル(21g)に懸濁させ、これに(S)-N-(2-クロロベンジル)-1-フェニルエチルアミン(3.800mg,15.47mmol)をバス温60℃下にて添加した。同温にて1時間の攪拌を行った後、バス温30℃下にてさらに2時間の攪拌を行った。析出した結晶をろ過操作により取得した。アセトニトリル(10mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:3470mg,収率:44.8%)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(3426.2mg,22.08mmol)をアセトニトリル(31g)に懸濁させ、これに(S)-N-(2-クロロベンジル)-1-フェニルエチルアミン(3.800mg,15.47mmol)をバス温70℃下にて添加した。同温にて1時間の攪拌を行った後、バス温40℃下にてさらに2時間の攪拌を行った。析出した結晶をろ過操作により取得した。アセトニトリル(10mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:3322mg,収率:37.5%)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(3000mg,19.34mmol)をアセトン(21g)に懸濁させ、これに(S)-N-(2-クロロベンジル)-1-フェニルエチルアミン(3.800mg,15.47mmol)をバス温50℃下にて添加した。同温にて1時間の攪拌を行った後、バス温20℃下にてさらに2時間の攪拌を行った。析出した結晶をろ過操作により取得した。アセトン(10mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:3017mg,収率:38.9%)。
製造例2に従い合成した(1S,2S)-体および(1R,2R)-体の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(1000mg,6.44mmol)をトルエン(6.4g)に懸濁させ、これに(S)-N-(4-クロロベンジル)-1-フェニルエチルアミン(1519mg,5.16mmol)をバス温50℃下にて添加した。同温にて1時間の攪拌を行った後、バス温0℃下にてさらに20時間の攪拌を行った。析出した結晶をろ過操作により取得した。アセトニトリル(2mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:503mg,収率:19.5%)。
製造例2に従い合成した(1S,2S)-、(1R,2R)-の1:1の混合物である2-ビニル-1-カルバモイルシクロプロパンカルボン酸(1000mg,6.44mmol)をアセトニトリル(7.0g)に懸濁させ、これに(S)-N-(4-メチルベンジル)-1-フェニルエチルアミン(1161mg,5.15mmol)をバス温30℃下にて添加した。同温にて15時間の攪拌を行った後、バス温0℃下にてさらに7時間の攪拌を行った。析出した結晶をろ過操作により取得した。アセトニトリル(2mL)にて洗浄を行った後、乾燥を行い、表題化合物を得た(取得量:287mg,収率:11.7%)。
Claims (12)
- R1がメチル基である請求項2記載の製造方法。
- Arがフェニル基、1-ナフチル基、2-ナフチル基のいずれかである請求項2または3に記載の製造方法。
- RがNH2である請求項1~4のいずれかに記載の製造方法。
- R1がメチル基である請求項6記載の塩。
- Arがフェニル基、1-ナフチル基、2-ナフチル基の何れかである請求項6または7に記載の塩。
- RがNH2である請求項6~8のいずれかに記載の塩。
- ビニルシクロプロパンアミドカルボン酸誘導体が、請求項1~5いずれかに記載の製造方法にて製造した光学活性ビニルシクロプロパンアミドカルボン酸誘導体か又は光学活性ビニルシクロプロパンアミドカルボン酸誘導体-アミンジアステレオマー塩である請求項10または11に記載の製造方法。
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EP09819272A EP2345633A4 (en) | 2008-10-10 | 2009-10-09 | METHOD OF MAKING AN OPTICALLY ACTIVE VINYL-CYCLOPROPANE CARBOXYLIC ACID DERIVATIVE AND OPTICALLY ACTIVE VINYL-CYCLOPROPANE AMINO ACID DERIVATIVE |
JP2010532969A JPWO2010041739A1 (ja) | 2008-10-10 | 2009-10-09 | 光学活性ビニルシクロプロパンカルボン酸誘導体及び光学活性ビニルシクプロパンアミノ酸誘導体の製造方法 |
CN200980140185.3A CN102177132B (zh) | 2008-10-10 | 2009-10-09 | 光学活性乙烯基环丙烷羧酸衍生物及光学活性乙烯基环丙烷氨基酸衍生物的制造方法 |
US13/123,156 US20110245529A1 (en) | 2008-10-10 | 2009-10-09 | Method for producing optically active vinylcyclopropanecarboxylic acid derivative and optically active vinylcyclopropaneamino acid derivative |
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EP (1) | EP2345633A4 (ja) |
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Cited By (3)
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WO2011102388A1 (ja) * | 2010-02-16 | 2011-08-25 | 株式会社エーピーアイ コーポレーション | 1-アミノ-1-アルコキシカルボニル-2-ビニルシクロプロパンの製造方法 |
WO2012176715A1 (ja) | 2011-06-21 | 2012-12-27 | 三菱瓦斯化学株式会社 | 1-アミノ-2-ビニルシクロプロパンカルボン酸アミドおよびその塩、ならびにその製造方法 |
US10450291B2 (en) | 2015-06-29 | 2019-10-22 | Central Glass Company, Limited | Method for producing fluorine-containing cyclopropane carboxylic acid compound |
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CN103183603A (zh) * | 2011-12-30 | 2013-07-03 | 江苏天晟药业有限公司 | 藏红花酸有机胺盐及其制备方法 |
EP2802595B1 (en) | 2012-01-11 | 2016-01-06 | AbbVie Inc. | Processes for making hcv protease inhibitors |
EP3124469A4 (en) * | 2014-03-28 | 2017-11-08 | Kaneka Corporation | Process for producing 1-arylimino-2-vinylcyclopropanecarboxylic acid derivative |
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- 2009-10-09 EP EP09819272A patent/EP2345633A4/en not_active Withdrawn
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- 2009-10-09 CN CN200980140185.3A patent/CN102177132B/zh not_active Expired - Fee Related
- 2009-10-09 WO PCT/JP2009/067639 patent/WO2010041739A1/ja active Application Filing
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WO2011102388A1 (ja) * | 2010-02-16 | 2011-08-25 | 株式会社エーピーアイ コーポレーション | 1-アミノ-1-アルコキシカルボニル-2-ビニルシクロプロパンの製造方法 |
JP5613660B2 (ja) * | 2010-02-16 | 2014-10-29 | 株式会社エーピーアイ コーポレーション | 1−アミノ−1−アルコキシカルボニル−2−ビニルシクロプロパンの製造方法 |
US9061991B2 (en) | 2010-02-16 | 2015-06-23 | Api Corporation | Method for producing 1-amino-1-alkoxycarbonyl-2-vinylcyclopropane |
WO2012176715A1 (ja) | 2011-06-21 | 2012-12-27 | 三菱瓦斯化学株式会社 | 1-アミノ-2-ビニルシクロプロパンカルボン酸アミドおよびその塩、ならびにその製造方法 |
US10450291B2 (en) | 2015-06-29 | 2019-10-22 | Central Glass Company, Limited | Method for producing fluorine-containing cyclopropane carboxylic acid compound |
US10793540B2 (en) | 2015-06-29 | 2020-10-06 | Central Glass Company, Limited | Method for producing fluorine-containing cyclopropane carboxylic acid compound |
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US20110245529A1 (en) | 2011-10-06 |
EP2345633A4 (en) | 2012-05-16 |
CN102177132B (zh) | 2014-06-25 |
EP2345633A1 (en) | 2011-07-20 |
CN102177132A (zh) | 2011-09-07 |
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