JP3491296B2 - Optically active 1,5-disubstituted-2,4-O-isopropylidene-2,4-dihydroxypentane and process for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [0001] The present invention relates to a hypercholesterolemia
HMG-CoA reductase inhibitor known as a therapeutic agent for
Novel optical activity suitable for use as an intermediate for the synthesis of harmful agents
And a method for producing the same. [0002] 2. Description of the Related Art HMG-CoA reductase inhibitors are highly
Although it is attracting attention as a treatment for sterolemia,
Active analogues of the pharmacological activity of kuno analogs
Has been done. U.S.A. S. Pat. N
o. 4681893 (Bruce D. Roth et al.)
A pyrrole derivative of the following formula (7) is disclosed. Embedded image U.S. S. Pat. No. 5003080 (Dona
ld. E. FIG. Butler et al.) Effective production of the above (7)
A law is disclosed. In this prior document, the following equation (8)
By treating the compound of (9) with 10% hydrochloric acid,
It has been shown that the compound of (7) can be easily synthesized.
You. The one synthetic fragment (9) is a nitrile compound
(10) is catalytically reduced at 0 to 70 ° C.
Is shown. Embedded image + Embedded image → Embedded image Embedded image → Embedded image [0003] However, this prior art
Production of nitrile compound (10) disclosed in literature
The law is not industrially superior. Ie disclosed
The production method of the nitrile compound (10) includes the following steps.
ing. First, 1,6-heptadien-4-ol (1
1) Create alkyl lithium, iodine and carbon dioxide sequentially
To generate iodide (12) in the reaction system
Potassium, alkaline earth metal hydroxide or carbonate
This is treated to give an epoxide (13). Alkaline to this
Acting on metal cyanide to open the oxirane ring, then
Ketalization is performed to obtain (14). No more -20 ° C
Ozone oxidation at -78 ° C to give aldehyde (15)
After that, the carboxylic acid (1
6). 1,8-diazabicyclo [5,4,0]-
To alkyl halides in the presence of 7-undecene (DBU)
Further esterification gives ester (17). Embedded image → Embedded image → Embedded image → Embedded image → Embedded image → Embedded image→ Embedded image [0004] However, in the manufacture of (12), handling is difficult.
That you must use a new alkyl lithium,
In the production of (15), ozone oxidation is performed at low temperature (not -20 ° C).
-78 ° C), for the production of (16)
Use Jones reagent containing harmful chromic acid
There are many industrial disadvantages. And the book
Separation of erythro and threo forms is possible with synthetic route
Even if it is possible, it is impossible to synthesize optically active substances
The final product (7) synthesized by this route is racemic
is there. Physiological activity as HMG-CoA reductase inhibitor
One pyrrole derivative is a 2R-trans form shown in (7).
Only, and the optical isomer has no activity. U.S. Pat. S. Pat. No. 5003080
Also describes the synthesis of optically active forms. Sand
The optically active nitrile compound (10) is synthesized by the following route.
Is done. A method known from isoascorbic acid (18)
Carboxylic acid (19) derived from
Add carbon using sol and malonic acid half ester (20)
And deprotected to give alcohol (21). This one
At -78 ° C to -110 ° C, preferably -100 ° C.
℃, triethylborane or methoxydiethylbora
Followed by stereoselective reduction with sodium borohydride.
Hydroxyl group protected with acetonide after diol (22)
Optically active nitrile compound (10) can be obtained.
You. Embedded image → Embedded image → Embedded image → Embedded image → Embedded image → Embedded image However, isoascorbic acid (18)
That the conversion to rubonic acid (19) requires multiple steps;
Cole (21) reduction requires cryogenic temperature (high temperature
Does not exhibit stereoselectivity), and industrially advantageous
Not a law. Hence optically active nitrilation
Compound (10), or equivalent to (10), or (1)
0) a novel optically active compound easily derivable to
Industrially advantageous under mild reaction conditions, easily derived to (10)
There is a need for a new method for producing optically active compounds
You. The inventors have worked diligently to solve such problems.
As a result, Pi, one of the HMG-CoA reductase inhibitors,
Optically active nitrile which is a raw material for the synthesis of the roll derivative (7)
Equivalent to the compound (10) or easily induced to the compound (10)
New and useful new optically active compounds, optically active
Erythro-1-alkanoyloxy-2,4-O-iso
Propylidene-2,4-dihydroxy-5-substituted penta
Compound (1) and compound (1) of the present invention can be conveniently and conveniently used.
A manufacturing method was found and the present invention was completed.
As is clear from the above description, the purpose of the present invention is to
To provide a novel compound and a method for producing the compound
It is. [0007] Means for Solving the Problems The first aspect of the present invention is as follows. General formula Embedded image (However, in the above formula, R¹ Represents a halogen atom or a cyano group
Then R^Two Represents an alkyl group having 1 to 6 carbon atoms. )so
Represented optically active erythro-1-alkanoyloxy-
2,4-O-isopropylidene-2,4-dihydroxy
-5-substituted pentane. The second aspect of the present invention formula Embedded image Meso-1,2,4,5-pentanetetrao represented by
Ester in the presence of lipase formula Embedded image (However, in the above formula, R^Three Is an alkyl having 1 to 10 carbons
Represents a group. ) -Meso-1,5-dialkanoyl represented by
Digit after oxy-2,4-dihydroxypentane
The rule formula Embedded image (However, in the above formula, R^Three Is an alkyl having 1 to 10 carbons
Represents a group. A) meso-1,5-dialkanoyl
Oxy-2,4-O-isopropylidene-2,4-dihi
Dealkanoylation after conversion to droxypentane formula Embedded image Meso-2,4-O-isopropylidene-1 represented by
Lipase after 2,4,5-pentanetetraol
Act on esters in the presence of formula Embedded image (However, in the above formula, R^Two Is an alkyl having 1 to 10 carbons
Represents a group. ) An optically active erythro-1-alka represented by
Noyloxy-2,4-O-isopropylidene-1,
2,5-pentanetriol and then halogenation General formula Embedded image (However, in the above formula, R¹ Is a halogen atom, R^Two Is 1 carbon
And 6 to 6 alkyl groups. )
Litro-1-alkanoyloxy-2,4-O-isoprop
Lopylidene-2,4-dihydroxy-5-halogenopene
And then cyanation formula Embedded image (However, in the above formula, R¹ Represents a cyano group;^Two Is the carbon number
And represents 1 to 6 alkyl groups. Optical activity represented by)
Erythro-1-alkanoyloxy-2,4-O-iso
Propylidene-2,4-dihydroxy-5-cyanopen
It is characterized by a tongue. General formula Embedded image (However, in the above formula, R¹ Represents a halogen atom or a cyano group
Then R^Two Represents an alkyl group having 1 to 6 carbon atoms. )so
Represented optically active erythro-1-alkanoyloxy-
2,4-O-isopropylidene-2,4-dihydroxy
This is a method for producing -5-substituted pentanes. In addition, the present invention
Three is formula Embedded image Meso-2,4-O-isopropylidene-1 represented by
2,4,5-pentanetetraol in the presence of lipase
It is characterized by acting an ester. formula Embedded image(However, in the above formula, R^Two Is an alkyl group having 1 to 6 carbon atoms
Is shown. ) An optically active erythro-1-alkano represented by
Iloxy-2,4-O-isopropylidene-1,2,
This is a method for producing 5-pentanetriol. In addition, the present invention
The fourth is formula Embedded image Meso-1,2,4,5-pentanetetrao represented by
Lipase in the presence of lipase
I do. formula Embedded image (However, in the above formula, R^Three Is an alkyl having 1 to 10 carbons
Represents a group. A) meso-1,5-dialkanoyl
A process for producing oxy-2,4-dihydroxypentane.
You. Further, the fifth aspect of the present invention is as follows. Embedded image Meso-1,2,4,5-pentanetetrao represented by
Ester in the presence of lipase Embedded image (However, in the above formula, R^Three Is an alkyl having 1 to 10 carbons
Represents a group. A) meso-1,5-dialkanoyl
Digit after oxy-2,4-dihydroxypentane
The rule Embedded image (However, in the above formula, R^Three Is an alkyl having 1 to 10 carbons
Represents a group. A) meso-1,5-dialkanoyl
Oxy-2,4-0-isopropylidene-2,4-dihi
Dealkanoylation after conversion to droxypentane Embedded image Meso-2,4-0-isopropylidene-1 represented by
Lipase after 2,4,5-pentanetetraol
Act on esters in the presence of Embedded image (However, in the above formula, R^Two Is an alkyl group having 1 to 6 carbon atoms
Is shown. ) An optically active erythro-1-alkano represented by
Iloxy-2,4-0-isopropylidene-1,2,
Halogenation after conversion to 5-pentanetriol Embedded image (However, in the above formula, R¹ Is a halogen atom, R^Two Is 1 carbon
And 6 to 6 alkyl groups. Optical activity represented by)
Erythro-1-alkanoyloxy-2,4-0-iso
Propylidene-2,4-dihydroxy-5-halogenope
And then cyanation Embedded image (However, in the above formula, R¹ Is a halogen atom, R^Two Is 1 carbon
And 6 to 6 alkyl groups. Optical activity represented by)
Erythro-1-alkanoyloxy-2,4-0-iso
Propylidene-2,4-dihydroxy-5-cyanopen
And then convert the cyano group to an alkoxycarbonyl group.
Characterized by replacing Embedded image (However, in the above formula, R^Four Is an alkyl group having 1 to 6 carbon atoms
Is shown. ) Optically active erythro-3,5-0
-Isopropylidene-3,5,6-trihydroxyhexyl
Sanoate manufacturing method. In the compound of the formula (1), R¹ But shea
A alkanoyloxy group at position 1 in the molecule;
It has a cyano group at the 5-position. The 5-position cyano group is an organic compound
Chemically equivalent to a carboxyl group, if necessary
For example, as in the seventh embodiment, a normal organic chemical technique is used.
Can be easily converted to a carboxyl group.
You. In addition, alkanoyloxy group under mild conditions,
Treated with alcohol and sodium carbonate in alcohol
Is easily converted to a hydroxyl group.
Further, in the embodiment, the same relaxation as shown in the fifth and sixth stages is performed.
Can be converted to a cyano group under mild conditions. That is, the present invention (1)
The compound of the formula is one of the HMG-CoA reductase inhibitors
Optically active nitrile, a raw material for the synthesis of pyrrole derivative (7)
Equivalent to tolyl compound (10) or easy to (10)
It can be said that it can be guided to. Further shown in the examples
As described above, according to the method of the present invention, the stereochemistry is (2S, 4S,
It is possible to produce S) form (1) with good optical purity
However, this is a combination of the bioactive pyrrole derivative (7).
This is a preferred solid as a raw material. In the compound of formula (1) of the present invention, R¹ Is halo
Geno is meso-1,2,4,5-pentane
In five steps from tetraol (2), the compound of formula (1)
Of which R¹ Is a cyano group is produced in 6 steps.
Further, erythro-3,5-O-isopropylidene-3,
5,6-trihydroxyhexanoate (1 ') has 7 levels
Manufactured in. Next, each step of the present invention will be described in detail.
You. (First step) meso-1,5-dialkanoyl
Production of oxy-2,4-dihydroxypentane (3). The first reaction is meso-1,2,4,5-pentanetetra
Stir the mixture of all (2), lipase and ester
By transesterifying only the hydroxyl groups at the 1,5 position
Done. In this case, the transesterification reaction is only the primary hydroxyl group
And selectively esterify only positions 1 and 5.
Can be. Only primary hydroxyl groups can be used for lipase.
Any that can be selectively esterified
Can be used. Ripper to use in this case
Although commercially available suffices are sufficient, for example, Lipper
Zeap (origin Aspergillus niger, Amano Pharmaceutical),
Pase M (origin Mucor Javanics, Amano Pharmaceutical),
Lipase P (Origin Pseudomonas sp., Amano
Pharmaceuticals), Lipase PS (Origin Pseudomonas sp.)
, Amano Pharmaceutical), Lipase CES (Origin Pseudomona)
Species, Amano Pharmaceuticals), Lipase CE (Origin HI)
Umicola Ranuginosa, Amano Pharmaceutical), Lipase II (Origin)
Porcine pancreas, sigma, lipase VIII (origin)
Geotricum Candidom, Sigma), Lipase X (K
Source Rhizopus delerma, sigma), lipase
Mobacterium biscosum, oriental brewing), paratase
A (Origin Aspergillus niger, Novo industry
-), Lipase (origin Rhizopus Niveus, from Nagase)
Industry), lipase B (source Pseudomonas furaj,
Polo beer) can be used. The amount of ester used is
2 to 3 molar equivalents to (2) may be used, but primary hydroxyl
Reaction rate of transesterification reaction on secondary hydroxyl group
It is much faster than
Can be used. As ester to use
Is alkyl acetate, alkyl propionate, butanoic acid
Kill, alkyl pentanoate, alkyl hexanoate, hept
Fatty acid esters such as alkyl tanates or vinyl acetate
, Vinyl propionate, vinyl butanoate, pentanoic acid
Vinyl, vinyl hexanoate, vinyl heptanoate, lauri
Vinyl esters such as vinyl acid, triacetin, trib
Triglycerides such as tillin and tricaproin are preferably used.
Can be used. In this case, the stereoselectivity depends on the alkyl chain length.
Since there is no dependency, use an ester of any chain length.
Both are possible. Although no special reaction solvent is required (2)
Has low solubility in esters.
It is preferred to use a co-solvent such as mide as appropriate. Anti
After completion of the reaction, take out the target product (3) from the reaction system as follows.
It can be done easily. That is, lipa in suspension
The filtrate was concentrated after filtration of the crude
(3) is obtained. This is the next reaction without purification
Can be used for The filtered lipase is reused as it is
it can. The reaction temperature is sufficient at room temperature, and the reaction time is one.
The chair is 50 hours. (Second stage) meso-1,5-dialkanoyl
Oxy-2,4-O-isopropylidene-2,4-dihi
Production of droxypentane (4). The second stage reaction is meso-1,5-dialkanoyl in the presence of an acid catalyst.
Aceto in oxy-2,4-dihydroxypentane (3)
Act on 2,2-dimethoxypropane
It is performed by Mineral acids such as sulfuric acid and hydrochloric acid as acid catalysts,
such as p-toluenesulfonic acid and camphorsulfonic acid;
Rufonic acid and acidic ion exchange resins can be suitably used. Anti
The reaction temperature is preferably around room temperature. Perform the reaction without solvent
However, when the solubility of (3) is low,
It is preferable to carry out the reaction by adding lumamide as appropriate. (Third stage) Meso 2,4-O-isopropyl
Riden-1,2,4,5-pentanetetraol (5)
Manufacturing of. The third reaction is carried out under neutral or basic conditions.
-Dialkanoyloxy-2,4-O-isopropylide
Deacetylation of 2,4-dihydroxypentane (4)
This is done by converting For example, methanol, ethanol
Natocarbonate in polar solvents such as ethanol, isopropanol and water
Lium, potassium carbonate, calcium carbonate, barium carbonate
, Potassium hydroxide, sodium hydroxide, calcium hydroxide
And barium hydroxide, etc.
You. Solvents such as diethyl ether and tetrahydrofuran
Lithium aluminum hydride, lithium borohydride in medium
And reducing agents such as sodium borohydride
It can also be performed by dealkanoylation. (Fourth step) Optically active erythro 1-alka
Noyloxy-2,4-O-isopropylidene-1,
Production of 2,5-pentantriol (6). The reaction of the fourth step is meso 2,4-O-isopropylidene.
-1,2,4,5-pentanetetraol (5), Lipa
-The mixture of the ester and the ester was stirred to remove the hydroxyl group at the 1,5 position.
By transesterifying only one of them
You. In this case, the transesterification proceeds stereoselectively and
(6) is obtained. The lipase used is (5)
Only one of the hydroxyl groups at positions 1 and 5 of the
Any type of material that can be
But can be used. The lipase used in this case is commercially available.
Is sufficient, for example, lipase AP (origin
Aspergillus niger, Amano Pharmaceutical), Lipase M (KI
Source Mucor Javanics, Amano Pharmaceutical), Lipase P
(Origin Pseudomonas sp., Amano Pharmaceutical)
Pase PS (Original Pseudomonas sp., Amano
Pharmaceuticals), Lipase CES (Original Pseudomonas sp.)
Seeds, Amano Pharmaceutical), Lipase CE (Origin Humicola)
Ranuginosa, Amano Pharmaceutical), Lipase II (origin porsimpa)
Nucleus, Sigma), Lipase VIII (origin Geotric)
Mu Candidom, Sigma), Lipase X (Origin Rhizopus)
  Delerma, sigma), lipase (origin chromobacteria)
Um Biscosme, Toyo Brewery, Paratase A (Origin
Spergillus niger, Novo industry), lipase
(Origin Rhizopus Niveus, Nagase Sangyo), Lipase B
(Origin Pseudomonas Frazi, Sapporo Beer)
Can be used. Particularly preferably, lipa derived from Pseudomonas sp.
Is The amount of ester used is 1 to (5)
To 2 molar equivalents, but stereoselection of transesterification
It is safe to use a large excess of ester
Absent. Ester used is alkyl acetate, propyl
Alkyl onates, alkyl butanoates, alkyl pentanoates
, Alkyl hexanoate, alkyl heptanoate, etc.
Acid esters or vinyl acetate, vinyl propionate
, Vinyl butanoate, vinyl pentanoate, hexanoate
Nyl, vinyl ester of vinyl heptanoate, triaceti
, Tributyrin, tricaproin, etc.
Can be suitably used. Stereoselectivity depends on alkyl chain length
Longer-chain esters can be used because there is no dependence
It is possible. Although a reaction solvent is not particularly required,
If the solubility in steal is low, dimethylforma
It is preferred to use a co-solvent such as mide as appropriate. Anti
After completion of the reaction, take out the target product (6) from the reaction system as follows.
It can be done easily. That is, lipa in suspension
The filtrate is concentrated after filtration of the lysate (6).
Is obtained. The lipase filtered off can be reused as it is
Wear. The reaction temperature is sufficient at room temperature, and the reaction time is 0.5
Or 50 hours. (Fifth Step) Optically Active Erythro-1-Alka
Noyloxy-2,4-O-isopropylidene-2,4
-Dihydroxy-5-halogenopentane ((1)
Wherein R1 is a halogen atom. )Manufacturing of. The reaction in the fifth step is carried out under neutral or basic conditions under an optically active area.
Toro-1-alkanoyloxy-2,4-O-isopro
Pyridene-1,2,5-pentanetriol (6)
It is performed by the formation of a log. For example, Trifeni
(6) is heated under reflux in carbon tetrachloride in the presence of luphosphine
In the presence of triphenylphosphine
Treatment with N-chlorosuccinimide in dichloromethane
More chloride (R in (1)¹ Is a chlorine atom
of. ) Can be manufactured. 1 equivalent of triphenylphos
More than 1 equivalent of (6) in dichloromethane in the presence of phen
N-chlorosuccinimide or 2 to 3 equivalents of carbon tetrabromide
The bromide ((1) is treated with R¹
Is a bromine atom. ) Can be manufactured. Also imidazo
In the presence of (6) triphenylphosphine and iodine
By reacting with iodine, the iodide ((1)
¹ Is an iodine atom. ) Can be manufactured. Iodide
Treats chlorides and bromides with sodium iodide in acetone.
It can also be manufactured by processing. More optically active elite
B-1-Alkanoyloxy-2,4-O-isopropyl
Sulphide-1,2,5-pentanetriol (6)
It is also possible to halogenate after it has been converted to a phonate.
is there. (Sixth Step) Optically Active Erythro-1-Alka
Noyloxy-2,4-O-isopropylidene-2,4
-Dihydroxy-5-cyanopentane (in (1)
R¹Is a cyano atom. )Manufacturing of. The sixth reaction is dimethylformamide or dimethylformamide.
Optically active erythro-1-alkanoy in rusulfoxide
Luoxy-2,4-O-isopropylidene-2,4-di
Hydroxy-5-halogenopentane (R in (1)
¹ Is a halogen atom. ) To sodium cyanide
, Potassium cyanide and copper cyanide
It is done. Optically active erythro-1-alkanoylo
Xy-2,4-O-isopropylidene-2,4-dihydride
When roxy-5-halogenopentane is iodide
The reaction proceeds at room temperature, but heats chlorides and bromides.
There is a need to. Further, optically active erythro-1-alkano
Yloxy-2,4-O-isopropylidene-dihydro
Xy-5-cyanopentane (R in formula (1)¹ But shea
Erythro-3,5-
O-isopropylidene-3,5,6-trihydroxy
It can be induced to xanoate (1 '). Ie cyanide
(R in (1)¹ Is a cyano atom)
The carboxylic acid obtained by hydrolysis under neutral conditions to the presence of DBU
By esterification with an alkyl halide below,
In addition, cyanide is dried with diisobutyl aluminum hydride.
After reducing by DIBAL, in alcohol
To work with pyridium dichloromate (PDC)
(1 ′) can be manufactured. Mesow 1, which is the starting material,
About the synthesis of 2,4,5-pentanetetraol (2)
To synthesize adonitol as a raw material (Zhuo-F
eng XIE et al. Chem. Phar
m. Bull. ,37(6), 1650 (198
9)) 1,2-O-isopropylidene-1,2,4-
Method for synthesizing butanetriol as a raw material (Johann
  Mulzer et al. , Liebigs An
n. Chem. , 947, (1991)).
It can be manufactured by the method described in the literature. Optically active erythro-1-alkanoyl oxo
C-2,4-O-isopropylidene-1,2,5-pen
For the production of tantriol (6), Zhuo-Fe
An alternative synthesis is reported by ngXIE et al.
(Zhuo-Feng XIE et al., Che.
m. Pharm. Bull. ,37(6), 1650
(1989)). Meso 1,2,4,5-pentanedet
Selective preservation of hydroxyl groups at positions 1 and 5 of laol by acetyl groups
Protection, protection by acetonide at position 2 and 4, followed by the resulting dia
By asymmetric hydrolysis of acetate with lipase (6)
Are synthesized. However, the hydroxyl groups at the 1,5 position by acetic anhydride
Selective protection for selective protection by acetyl group yields 61%
And low. Alkanoyl at the 1,5-position hydroxyl group in the present invention
The yield of protection by oxy groups was 75%. Also,
Optical activity obtained by asymmetric hydrolysis with pase
Litro-1-alkanoyloxy-2,4-O-isoprop
Stereochemistry of lopylidene-1,2,5-pentanetriol
Is the enantiomer of the desired compound (2R, 4R)
This is not an industrially useful method. In addition to lipase
Asymmetric hydrolysis in water must be performed in water,
Since it is not soluble, a large amount of reaction solvent is required. Also underwater
Recovery of lipase from soil cannot be reused. [0017] The novel compound of the present invention optically active erythro-
1-alkanoyloxy-2,4-O-isopropylide
2-, 4-dihydroxy-5-substituted pentane (1) is
Pyrrole induction, one of HMG-CoA reductase inhibitors
Optically active nitrile compound as raw material for synthesis of conductor (7)
Equivalent to (10) or easily derivable to (10)
It is a compound. Also, the novel compound of the present invention, optically active erythro
-1-alkanoyloxy-2,4-O-isopropyl
Den-2,4-dihydroxy-5-substituted pentanes (1)
Is a pillow which is the aforementioned HMG-CoA reductase inhibitor
Active Nitrilation as a Raw Material for the Synthesis of the Derivative (7)
In addition to the compound (10),
It can be suitably used as a raw material for synthesis. The following is an example
I do. Embedded image Novel compound of the present invention optically active erythro-1-alkanoy
Luoxy-2,4-O-isopropylidene-2,4-di
Hydroxy-5-cyanopentane (R in formula (1)¹
Is a cyano atom. ) Hydrolyzes the cyano group
(1 '), then easily lactonized by acid treatment
Give the croton (22). This is HMG-CoA
Compactin known as one of the former enzyme inhibitors
(23) (AG Brown et al., JC).
hem. Soc. Perkin Trans. I, 11
65 (1976)), mevinolin (24) (AWA
lberts et al. Proc. Natn. A
cad. Sci. U. S. A.77, 3957 (198
It is possible to provide the lactone site of 0)). Ma
Pyridi, also an HMG-CoA reductase inhibitor
Derivative (25) (Eur. Pat. Appl., EP
356778) as a raw material for the synthesis of the novel compound of the present invention.
Optically active erythro-1-alkanoyloxy-2,4-
O-isopropylidene-2,4-dihydroxy-5-cy
Anopentane (R in (1)¹ Is a cyano atom
thing. ) Is useful. Embedded imageThat is, deprotection of the 1-position alkanoyloxy group
To aldehyde (26) by oxidation and protection, then pyridine
Introduce the skeleton and further hydrolyze, deacetonide, ester
Producing (25) by converting the moiety to a metal salt
it can. Further, in the present invention, such a useful new
An optically active compound can be produced by a simple method. Next
The effects of the method of the present invention will be listed. Special regioselectivity of esterification in the first stage
Only primary hydroxyl groups can be esterified without using conditions. Esterification by lipase in the first and third stages
Because it can be performed in organic solvents, it is an enzymatic reaction
The reaction can be performed at a high substrate concentration. Esterification by lipase in the first and third stages
Because it can be performed in an organic solvent, recovery and re-use of lipase after use
Easy to use. Stereoselection of lipase esterification in the fourth stage
Highly pure, optically pure compound in one enzymatic reaction
You can get things. The reaction conditions at each stage are very mild. Other than the sixth row
All of the step reactions can be performed at room temperature. High yield of each step (first stage 75%, second stage 63%,
Third stage quantitative, fourth stage 70%, fifth stage 77%, sixth stage 5
5%, total yield 14%). Embodiment Hereinafter, the present invention will be more specifically described by representative examples.
Will be described. (First stage) Meso 1,5-diacetoxy
Production of 2,4-dihydroxypentane (3). Meso 1,2,4,5-pentanetetraol (2) 2
5.7 g (0.19 mol), Lipase PS (Amano Pharmaceutical Co., Ltd.)
9g, vinyl acetate 48.7g (0.57m
), Dimethylformamide (DMF) mixture at room temperature
For 28 hours. Filter and filter out lipase PS
The residue was washed with 50 ml of ethyl acetate. For filtrate and washing
The used ethyl acetate was combined and concentrated under reduced pressure. As a residual
1,5-diacetoxy-2,4-dimethol
25.2 g of hydroxypentane (3) (75% yield)
Obtained. This product can be used as a second stage raw material without purification.
Used. (Second stage) Meso 1,5-diacetoxy-
2,4-O-isopropylidene-2,4-dihydroxy
Production of pentane (4). Meso 1,5-diacetoxy-2,4-di obtained in the first step
25.2 g of hydroxypentane (3) (0.14
2) 400 ml of 2,2-dimethoxypropane, DMF
P-Toluenesulfonic acid was added to a 200 ml mixture under ice cooling.
Add 2.5 g (0.013 mol) of monohydrate and add 22 g at room temperature.
Time stirred. 20 g of sodium bicarbonate under ice-cooling
After stirring for 1 hour, add saturated aqueous sodium hydrogen carbonate
300 ml of the solution were added. Extract with 300 ml of ethyl acetate
The organic layer was washed twice with 200 ml of water, and then sulfuric anhydride was added.
Dried over magnesium. Ethyl acetate is distilled off under reduced pressure
The residue is subjected to silica gel column chromatography (elution solvent
Toluene: ethyl acetate (8: 1), Rf value 2.0)
1,5-diacetoxy crude as a yellow oil
-2,4-O-isopropylidene-2,4-dihydroxy
Cipentane (4) was obtained. Furthermore, n-heptane 100m
recrystallized from 1 to give meso-1,5-diacetoxy as colorless needles.
C-2,4-O-isopropylidene-2,4-dihydro
Xypentane (4) 22.8 g (63% yield) was obtained. 50.7-53.5 [deg.] C.¹  H-NMR (90 MHz, CDCl_Three ) Δ (pp
m): 1.36-1.68 (3H, m), 1.43 (3
H, s), 1.46 (3H, s), 2.09 (6H,
s), 4.01-4.21 (6H, m)¹³ C-NMR (90 MHz, CDCl_Three ) Δ (pp
m): 19.5, 20.5, 29.0, 29.5, 6
7.5, 99.5, 171.0 MS m / z: 245 (M⁺ -15), 203, 187 (Third stage) Meso 2,4-O-isopropyl
Riden-1,2,4,5-pentanetetraol (5)
Manufacturing of. Meso 1,5-diacetoxy-2,4-0 obtained in the second stage
-Isopropylidene-2,4-dihydroxypentane
(4) 15.2 g (0.6 mol) of THF 250 ml
4.6 g of lithium aluminum hydride (0.1 g
2 mol), dropwise added to a suspension of 125 ml of THF at 0 ° C or lower.
Then, the mixture was stirred at room temperature for 2 hours. Ethyl acetate 2 under ice cooling
5 ml, water 25 ml, 2N-sodium hydroxide aqueous solution 5
Then, the mixture was stirred at room temperature for 30 minutes. Precipitated
The crystals were filtered off and the filter was washed with 100 ml of THF. Filtration
The solution and THF used for washing are combined and concentrated under reduced pressure.
Was. The residue is purified by silica gel column chromatography (elution).
Solvent toluene: ethyl acetate (2: 1)) and colorless oil
2,4-O-isopropylidene-1, 2, 4,
11.5 g of 5-pentanetetraol (5) (yield determination)
Target).¹  H-NMR (90 MHz, CDCl_Three ) Δ (pp
m): 1.3-1.59 (3H, m), 1.43 (3
H, s), 1.47 (3H, s), 3.40 (2H, b
rs), 3.62 (4H, m), 4.00-4.20
(4H, m) (Fourth stage) (2R, 4S) -erythro-1
-Acetyloxy-2,4-O-isopropylidene-
Production of 1,2,5-pentanetriol (6). Meso 2,4-O-isopropylidene- obtained in the third step
8.2 g of 1,2,4,5-pentanetetraol (5)
(4.6 mmol), 100 ml of vinyl acetate, lipase
1 g of a mixture of PS (Amano Pharmaceutical Co., Ltd.) for 3 hours at room temperature
Stirred for 5 minutes. The lipase PS is filtered off and the filter
Washed with 10 ml of chill. Vinegar used for filtrate and washing
The ethyl acetate was combined and concentrated under reduced pressure. Silica gel residue
Ram chromatography (elution solvent: toluene: ethyl acetate
(2: 1), Rf 2.3.
R, 4S) -erythro-1-acetyloxy-2,4-
O-isopropylidene-1,2,5-pentanetrio
Thus, 7.1 g (yield 70%) of the compound (6) was obtained. [Α]_D ²⁷ + 4.7 ° (2.56, CHCl_Three )¹  H-NMR (90 MHz, CDCl_Three ) Δ (pp
m): 1.3-1.55 (2H, m), 1.43 (3
H, s), 1.47 (3H, s), 2.08 (3H,
s), 3.40 (1H, brs), 3.65 (2H,
m), 3.97-4.20 (4H, m) (2R, 4S) -erythro-1-acetyloxy obtained
C-2,4-O-isopropylidene-1,2,5-pen
The optical purity of tantriol (6) is as follows:
A (α-methoxy-α- (trifluoromethyl) phenyl
Acetic acid) to 400MHz-¹ H-NMR
Determined by (2R, 4S) -erythro-1-ace
Tyloxy-2,4-O-isopropylidene-1,2,
115 mg of 5-pentanetriol (6) (0.53
Rimole), R-α-methoxy-α- (trifluoromethyl
Phenylacetic chloride 199 mg (0.79 mmol
And a mixture of 3 ml of pyridine at room temperature for 12 hours.
did. Add water and extract with toluene.
Wash with aqueous solution of lithium and water and dry over anhydrous magnesium sulfate
Dried. After filtration on anhydrous magnesium sulfate, dissolution under reduced pressure
The solvent is distilled off, and the residue is subjected to silica gel column chromatography.
-(Eluent: toluene: ethyl acetate (3/1)
250 mg of a colored oily MTPA ester were obtained. NMR component
In the analysis, the observed peak at 3.56 ppm was a single peak.
Peak (6) was found to be optically pure
Was.¹  H-NMR (400 MHz, CDCl_Three ) Δ (pp
m): 1.29-1.32 (2H, m), 1.40 (3
H, s), 1.42 (3H, s), 2.07 (3H,
s), 3.56 (3H, s), 4.02-4.35 (6
H, m), 7.40-7.57 (5H, m) (Fifth stage) (2R, 4S) -erythro-1
-Acetyloxy-2,4-0-isopropylidene-
2,4-dihydroxy-5-bromopentane ((1)
Then R¹ Is a bromine atom. )Manufacturing of. (2R, 4S) -erythro-1-ace obtained in (fourth step)
Tyloxy-2,4-O-isopropylidene-1,2,
5.4 g of 5-pentanetriol (6) (0.025
To a mixture of 100 ml of dichloromethane
7.8 g (0.029 mol) of phenylphosphine, four odors
12.3 g (0.037 mol) of activated carbon were added at room temperature.
Stirred for hours. Add 2 ml of saturated sodium carbonate and add
After stirring for a minute, add anhydrous magnesium sulfate and dry.
Was. The solid is filtered off and the filter cake is washed with dichloromethane 20
Washed with ml. The dichloromethane was concentrated under reduced pressure. Remaining
The silica gel column chromatography (elution solvent
(Ruene: ethyl acetate (3: 1)).
R, 4S) -erythro-1-acetyloxy-2,4-
O-isopropylidene-2,4-dihydroxy-5-bu
Lomopentane (R in (1)¹ Is a bromine atom
of. 5.4 g (yield 77%).¹  H-NMR (90 MHz, CDCl_Three ) Δ (pp
m): 1.3-1.57 (2H, m), 1.44 (3
H, s), 1.48 (3H, s), 2.10 (3H,
s), 3.45 (2H, q), 3.97-4.29 (4
H, m) (Sixth stage) (2S, 4S) -erythro-1
-Acetyloxy-2,4-O-isopropylidene-
2,4-dihydroxy-5-cyanopentane ((1)
Then R¹ Is a cyano group. )Manufacturing of. (2R, 4S) -erythro-1-ace obtained in (fifth step)
Tyloxy-2,4-O-isopropylidene-2,4-
Dihydroxy-5-bromopentane ((1)
¹ Is a bromine atom. 4.8 g (0.017 m
), DMF 50 ml, sodium cyanide 1.7 g
(0.034 mol) at 70 ° C. for 1 hour
did. After cooling, add 50 ml of water and extract with 50 ml of ethyl acetate.
Issued. The organic layer is washed twice with 50 ml of water and then dried.
Dried over magnesium sulfate. Anhydrous magnesium sulfate
After filtration, ethyl acetate was concentrated under reduced pressure. Residue
Ricagel column chromatography (elution solvent
(5: 1)) to give a slightly yellow oil (2).
S, 4S) -erythro-1-acetyloxy-2,4-
O-isopropylidene-2,4-dihydroxy-5-cy
Anopentane (R in (1)¹ Is a cyano group
of. ) 2.1 g (55% yield).¹  H-NMR (400 MHz, CDCl_Three ) δ (ppm): 1.32-1.43 (1H, m);
66-1.70 (1H, m), 1.43 (3H, s),
1.47 (3H, s), 2.09 (3H, s), 2.5
3 (2H, q), 4.07 (2H, q), 4.08-
4.17 (2H, m).¹³ C-NMR (90 MHz, CDCl_Three ) δ (ppm): 19.4, 20.7, 24.8, 29.
5, 32.0, 64.6, 66.5, 66.6, 99.
3, 116.5, 170.6 (Seventh stage) (2R, 4S) -erythro-
3,5-O-isopropylidene-3,5,6-trihydride
Production of Roxyhexanoate (1 ') (2S, 4S) -erythro-1-ace obtained in (Stage 6)
Tyloxy-2,4-O-isopropylidene-2,4-
Dihydroxy-5-cyanopentane ((1)
¹ Is a cyano group) 2.0 g (0.0079
Diisobutyl) in a mixture of
24 ml of aluminum hydride was dropped at -70 ° C
Was. After stirring for 20 minutes, 5 ml of methanol and then a saturated salt
5 ml of an aqueous ammonium chloride solution was added. Diethyl ether
After adding 5 ml of water and filtering off the insoluble matter, the filtrate is concentrated.
(2R, 4S) -erythro-3,5-O-isopropyl
Den-3,5,6-trihydroxyhexanal 2.0
g was obtained. 2.0 g of the aldehyde obtained above (0.007
8 mol), 100 ml of DMF, 1.6 ml of methanol
Add pyridium dichromate (PDC) to the mixture and add 40
Minutes. Add a saturated aqueous sodium hydrogen carbonate solution under ice-cooling.
And extracted with ethyl acetate. After washing the organic layer with water
It was dried over magnesium sulfate. Concentrate the solvent under reduced pressure
After that, the residue was purified by silica gel column chromatography (solvent).
Solvent: toluene: ethyl acetate (1: 1)) and colorless oil
(2R, 4S) -erythro-3,5-O-isopro
Pyridene-3,5,6-trihydroxyhexanoate
1.57 g (yield 70%) of (1 ′) was obtained.¹  H-NMR (400 MHz, CDCl_Three ) δ (ppm): 1.29-1.53 (2H, m), 1.
39 (3H, s), 1.48 (3H, s), 1.58
(3H, brs), 2.49 (2H, ddd), 3.5
6 (2H, ddd), 3.69 (3H, s), 4.02
(1H, m), 4.34 (1H, m)

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C12P 41/00 C07D 319/06 CA / REGISTRY / BIOSIS / MEDLINE / WPIDS (STN)

Claims (1)

(57) [Claims] [Claim 1] The general formula: (However, in the above formula, R ¹ represents a halogen atom or a cyano group, and R ² represents an alkyl group having 1 to 6 carbon atoms.)
2,4-O-isopropylidene-2,4-dihydroxy-5-substituted pentanes.