JPS6019752A - Norpinane derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is tetrahydropyran-2-yloxymethyl, hydroxymethyl, formyl, etc.; two R<2>'s are are H or methyl; R<3> is 2-5C acyl or benzoyl; R<4> is single bond or 1-5C alkylene; R<5> is 1-8C alkyl, 4-7C cycloalkyl which may be substituted with at least one 1-8C alkyl, etc.; when R<4> is single bond, R<5> is not phenoxy or phenylthio). EXAMPLE:( 2alpha,3beta )-2-( 2-Hydroxy )ethyl-3-{N-[(2beta-acetoxy-3-phenyl)-propyl]-N- acetylamino}-6,6-dimethylnorpinane. USE:Useful as an important intermediate for a 13-azathromboxanemimic compound useful as a drug. PREPARATION:The compound of formula III is prepared by the oxidation reaction of the compound of formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel norpinane derivatives. More specifically, the present invention relates to norpinane derivatives that are important intermediates in the production of 16-azathromboxane-like compounds useful as pharmaceuticals.

As a 13-azathromboxane analogue compound.

(5zi5αβ)-9,11-methano-1 represented by the following formula
0,10-dimethyl-16-aza-15-hydroxy-
A compound in which the basic structure is 11α-carbatrombo-5-enoic acid and its 15th and lower positions are modified, G5C; a compound in which the vinylene group between 6 and 6 is replaced with an ethylene group, and the dimethyl group at the 10th position is removed.1. Also known are compounds and 1-alpha compounds in which a carboxylic acid at the 1-position is esterified. These series of compounds are known as Thrombogyza 7 A2 (t
, bromboyane A2, hereinafter abbreviated as TXA2. ), it has an antagonistic effect on inflammation, hypertension, thrombosis, stroke, asthma, etc. in mammals including humans.
It is useful for the prevention and treatment of myocardial infarction, angina pectoris, cerebral infarction, and acute cardiac death.
No. 6 and No. 58-13551 regarding sand molds). Furthermore, recent research has shown that the configuration at position 15 is α-
It has been found that compounds with the β-configuration (Sunawa\15, C-40H) exhibit stronger pharmacological effects than compounds with the C-40H configuration (that is, 1). .

Two synthetic routes are known for the production of compounds similar to No. 16-Azato-1 Convoxane, which are described in &411, the above-mentioned published specification. That is, the formula (where T
HP represents a tetrahydropyran-2-yl group, and both R2 represent a hydrogen atom or a methyl group. )
A method of first introducing the upper side chain (α-side chain) and then introducing the lower side chain (ω-side wall) using a 6-amizurpinane product conductor shown as a starting intermediate; Introduction of ω-side chain 1-1 Next, the amine group at the 16th position and the hydroxyl group at the 15th position are modified in the form of a cyclic carbamate, and then the α-side chain is introduced, followed by a cyclic carf ζ which is a pupil-retentive group. Methods of removing mate are known.

However, in method (1), formula (1) (Ill
The number of steps required to reach the target compound from the compound represented by is large (approximately 10 steps, depending on the target compound).

), the overall yield is very low (for example, in the case of a compound represented by the general formula (Il) in which the lower position of the 15th position is substituted with a benzyl group and the hydroxyl group at the 15th position is attached in the β-configuration, ) and (11115), even if you want to obtain only those with the hydroxyl group in the α-configuration or β-configuration, separation of the 15th position can only be performed in the final step, which is very uneconomical and It has the disadvantage of being inefficient,
In addition, in method (1), depending on the target compound, the hydroxyl group at position 15 is likely to be dehydrated during protection with a cyclic carbamate and during removal, and is not general as a retaining Hψ group. In addition to this, it also has the disadvantage of easily causing other side reactions (11), which inevitably leads to low yields. In this way, it can be said that both manufacturing methods are inappropriate for industrial production of Okawa 411.

The present inventors have improved such drawbacks by reducing the number of steps, separating the 15α-isomer and the 15β isomer in the initial stage 1':4' of the synthesis, making it difficult for side reactions to occur, and achieving a high As a result of repeated research to find an intermediate that can industrially produce the desired 16-azathromboxane analog compound in high yield, a series of compounds 71F shown below were found.
The present invention was completed by discovering that the object could be achieved.

That is, the present invention relates to the general formula [wherein R1 is a tetrahydropyran-2-yloxymethyl group, a human 90oxymethyl group, a formyl group, or the formula -X-(CH2)rL-GOOH (wherein X is yx-
GH= represents a group represented by ci (represents a - group or a -CH2CH2- group, n represents an integer from 1 to 6) 1-1 Both R's represent a hydrogen atom or both represent a methyl group , R3 represents a straight or branched acyl group or benzoyl group having 2 to 5 carbon atoms, and R
4 represents a single bond or a straight chain or branched alkylene group having 1 to 5 carbon atoms, R5 is a straight chain or branched alkyl group having 1 to 8 carbon atoms, and is unsubstituted or has at least one carbon number. Represents a cycloalkyl group having 4 to 7 carbon atoms or an atom or a sulfur atom substituted with a linear or branched alkyl group of 1 to B, R is a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon number It represents a linear or branched alkyl group having 1 to 5 carbon atoms, a trihalomethyl group, an alkoxy group having 1 to 5 carbon atoms, an amino group, or a mono- or dialkylamino group having 1 to 5 carbon atoms. ) represents a group represented by However, when L R4 represents a single bond, R5 does not represent a substituted or unsubstituted phenoxy group or phenylthio group. ] This relates to a norpinane derivative represented by the following.

The present invention relates to a compound represented by the general formula (11), i.e., an optically active "natural type" or its enantiomer, or a mixture thereof; Regarding.

In the structural formulas of this specification, including the claims, dotted lines indicate that the group to which they are attached is behind the plane, i.e., in the α-configuration, in accordance with generally accepted nomenclature rules; indicates that the group attached to it is in front of the plane, ie, in the β-configuration, and the wavy line indicates that the group attached to it is in the α- or β-configuration or a mixture thereof.

As will be apparent to those skilled in the art, the compound represented by the general formula (till) has at least two asymmetric centers, and these two asymmetric centers are located at the 2-position and the 61-carbon atom of norpinane. Furthermore, R3, R4, R5 or 1 (6
When the alkyl group and alkylene group represented by h represent a branched chain, other asymmetric centers may occur. As is well known, the presence of asymmetric centers gives rise to isomers. However, the compound represented by the general formula (+111) has a configuration ↑4 such that the substituents on the carbon atoms at the 2nd and 6th positions of the norpinane ring are troughed.

Therefore, the 2nd and 6th positions of the compound represented by the general formula (III)
Isomers in which the substituent attached to the carbon atom in position ) has a lance configuration, and mixtures thereof are included within the scope of the compound represented by the general formula (ffl).

In the general formula (1111V, the formula -x, -(C■12')n in -COOH represented by R1
Examples of the - group include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene groups, and a preferred group is trimethylene.

In general formula (1), examples of the acyl group or benzoyl group having 2 to 5 carbon atoms represented by R3 include acetyl, propionyl, butyryl, valeryl groups and their isomers, and benzoyl group, but the preferred group is acetyl It is the basis.

In the general formula (letter), the alkylene group having 1 to 5 carbon atoms represented by 114 is methylene and ethylene.

Trimethylene, te)ramethylene, pentamethylene groups and isomers thereof are mentioned, and 1. /1 (4 is a single bond, methylene or ethylene group.

In the general formula (13), preferable groups of the alkyl group having 1 to 8 carbon atoms represented by R5 are methyl, ethyl, propyl, 1
-Methylpropyl, 2-methylpropyl, methyl, 1-
Methylbutyl, 2-methylbutyl, pentyl, and i-.methyl are methyl, 2-methylpentyl, hexyl, 1-methylhexyl, and 2-methylbexyl groups.

The preferred cycloalkyl group having 4 to 8 carbon atoms which is unsubstituted or substituted with at least υ· straight chain or branched alkyl groups having 1 to 8 carbon atoms represented by R5 is cyclobutyl. , 1-propylcyclobutyl, 1-butylcyclobutyl, 1-pentylcyclobutyl, cyclopentyl, 6-ethylcyclopentyl, 3-7'ropylcyclobentyl, 6-butylcyclopentyl, 3-te
rt-Butylcyclopentyl, cyclohexyl, 3-ethylcyclo-\xyl, 3-isopropylcyclohexyl, 4-methylcyclohegycyl, 4-ethylcyclohexyl, 4-propylcyclohexyl, 4-tert -
7'Tylcyclohexyl and cycloheptyl group R6 have the same meanings as above. ) Preferred groups include phenyl, phenoxy, phenylthio groups, and those groups in which one carbon atom of the benzene ring has a chlorine atom, a fluorine atom, a hydroxyl group, or a linear or branched chain having 1 to 5 carbon atoms. Chain alkyl group, trifluoromethyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino,
Or a group having a diethylamino group.

In the general formula (11), preferable R1 is tetrahyl-"
They are a ropyran-2-yloxymethyl group, a hydroxymethyl group, a formyl group, and a (Z)-5-carboxy-inter-1-enyl group. Preferred R4-R5 groups are benzyl groups, phenoxymethyl groups, phenylthiomethyl groups, and a chlorine atom on one carbon atom of the phenyl ring of these groups. It is a group having a linear or branched alkyl group or a trifluoromethyl group having 1 to 5 carbon atoms.Furthermore, in the general formula (1), the preferred t2 configuration of the carbon atom attached to 0F (3 groups is β -The arrangement.

According to the present invention, the norpinane derivative represented by the general formula ([1) is produced by a series of reactions shown in the following scheme. In the scheme, 1 ( is a straight or branched chain having 2 to 5 carbon atoms. represents an acyl group, anzoyl group, or an isoptoxica A.bonyl group, and the other symbols have the same meanings as above.The compound of the present invention represented by the general formula (ml) is represented by the general formula (IA) in the diagram.

(IB), (C), (ID) and (ME).

Examples of the acyl group or benzoyl group having 2 to 5 carbon atoms represented by f(7 include acetyl, propionyl, notyryl, valeryl group and isomers thereof, benzoyl group and isobutoxycarbonyl group, and preferred R7
is an acetyl group, an imbutyryl group, a pinozeta-royl group or an imbutoxycarbonyl group.

Figure Formula % Formula % () () Each reaction shown in the diagram is carried out by a known method, and most of the reactions are performed in JP-A-57-108046 and JP-A-57-108046.
It is described in detail in the specification of No. 13551. Briefly explaining each step, step [a) is a combination of a compound represented by the general formula (IV) and the general formula (Vll) (VIID (IX) (wherein, or mesyl group, and R4 and R5 have the same meanings as above).

This reaction is well known and is carried out in an inert organic solvent, such as methanol, a lower alkanol such as ethanol, methylene chloride, or chloroform, from 0° C. to the reflux temperature of the solvent.

If desired, the general formula (vID, (VID)
Or, by using an optically active form of the compound represented by (I)r) (those in which the asymmetric carbon marked with * is in the S-configuration or R-configuration), the hydroxyl group is in the α-configuration or β-configuration. The compound represented by the general formula (Vl) can be stereoselectively obtained. This eliminates the need for separation in subsequent steps, which is economical and leads to improved yield.

Step (b) is a reaction that forms an amide bond.

Amirization is carried out by combining an amine represented by the general formula (IV) with the general formula (
In the formula, all symbols have the same meanings as above. ) in an inert organic solvent such as a lower alkanol such as methanol or ethanol, diethyl ether, tetrahydrofuran, 1.2-
ethers such as dimethoxyethane or dioxane,
Hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as methylene chloride, acetonitrile, N,
The reaction is carried out in N-dimethylformamide or hexamethylphosphatamide (HMPA), or a mixed solvent of two or more thereof at room temperature or, if necessary, by heating or cooling.

Examples of reactive derivatives of acid of general formula (X) include acid halides such as acid chloride or acid bromide, pivaloyl chloride, isoptyryl chloride or mixtures with isobutyl chloroformate. Examples include acid anhydrides or active esters with dicyclohexylcarbodiimibi (DOG). When producing a reactive derivative of the acid represented by the general formula (X), it is desirable to protect the hydroxyl group at the α-position of the acid with a suitable protecting group. For example, in the case of an active ester with an acid halide and DOG, any group may be used as long as it can be easily removed in the next two steps without affecting other functional groups; It is convenient to protect with groups.

When a mixed acid anhydride is used, the acyl group corresponding to the acid chloride used will inevitably be used to protect the pupils.

Preferably, the reaction is carried out using a mixed acid anhydride obtained by reacting an acid represented by general formula (Xi) with pivaloyl chloride at 0°C in the presence of a base such as triethylamine in 90% tetrahydrofuran. To the solution, a solution of the amine represented by the general formula (IV) in tetrahyl-''roalane was added dropwise.
．． , the reaction is carried out at room temperature.

If desired, α represented by general formula (X) may be used as a starting material.
- By using an optically active form of oxyacid, the general formula (V) in which the OR" group is in the α-configuration or β-configuration and -(
The compound represented by can be stereoselectively obtained. This eliminates the need for separation in subsequent steps, which is economical and leads to improved yield.

Step [C] is a reaction in which the amide is reduced and the R7 group is removed at the same time. A suitable reduction is carried out in an inert organic solvent, for example a hydrocarbon such as benzene or toluene, an ether such as tetrahydroalane or 1,2-dimethoxyethane, or a mixture of two or more thereof, with a reducing agent,
For example, diisobutylaluminum high l-”ride (D
IBAL), lithium aluminum hydride (
LAH) or diborane [J, Org, Ghem,
, Vol. 38, No. 5, p. 912 (1973)] from 0°C to the reflux temperature of the solvent.
Preferably it is carried out using LAH in tetrahydrofuran or DIBAL in toluene at room temperature.

Second, step [d] is a reaction in which amine groups and hydroxyl groups are protected with acyl groups. Such acylation reactions are known, but are preferably carried out in the presence of a tertiary amine such as pyridine or triethylamine in an inert organic solvent such as methylene chloride or without a corresponding acyl chloride at a temperature below 50°C. , benzoyl chloride or an acid anhydride.

If the product represented by the general formula (HA) thus obtained is a mixture of those in which the OR3 group is in the α-configuration and the β-configuration, if desired, conventional separation means, e.g. The isomers can be separated using a thin layer of silica gel, a column, high performance liquid chromatography, or the like.

In this way, 15α and 15β are integrated at the very early stage of synthesis.
By separating the two components, only the desired isomer needs to be reacted in subsequent steps, which is very economical and efficient.

Step [θ] is carried out by a hydrolysis reaction under acidic conditions. Preferred hydrolysis methods include a mixture of dilute hydrochloric acid and methanol, acetic acid, a mixture of water and tetrahydrofuran, phosphoric acid,
The reaction is carried out using a mixture of water and tetrahydrofuran, or a mixture of P-).luenesulfonic acid and methanol at room temperature or under heating.

Step [f] is a reaction of oxidizing to a formyl group, which is a hydroxymethyl group. This type of oxidation reaction is well known, for example, in "Organic Synthetic Chemistry 1 Synthesis Edition I" edited by Tetsuji Kametani published by Nankodo.
Pages J176-206 (August 1, 1976), or (h) Jot>n Wiley & 5ons, I
Published by nc, Inc. (USA) [Compendi, um of
Organic 5ynthetic Method
sl Volume 1 (1971),! See section 48 or 168 of Volume 2 (1974) and Volume 3 (1977).
．． <Described. Oxidation under mild neutral conditions is particularly preferred, for example with chromium trioxide-pyridine complexes (e.g. Collins reagent), Jones reagent or chromic acid solutions (
(manufactured from chromium trioxide, manganese sulfate, sulfuric acid and water),
Oxalic acid chloride and dimethyl sulfoxide [Swan (
(Swern) oxidation], but Collins oxidation, Jones oxidation or Swann oxidation are preferred. Collins oxidation +j, chloroform, methylene chloride,
It is carried out at a temperature of 0° C. from an indoor source of a halogenated hydrocarbon such as carbon tetrachloride. Jones oxidation is usually performed at temperatures below room temperature. Swan oxidation is performed by reacting in a halogenated hydrocarbon such as chloroform or methylene chloride at -50°C to -78°C, and then treating with triethylamine.
L is carried out.

Step [g) is a Wittig reaction. Favorable Wina
The reaction can be carried out using an inert organic solvent, such as ethers such as tetrahydrofuran, hydrocarbons such as benzene, toluene, and glycylene, halogenated hydrocarbons such as methylene chloride, dimethyl sulfoxide, dimethylformamide, or two or more thereof. in a mixed solvent, preferably in toluene, from 0°C to the reflux temperature of the solvent to form a compound of the general formula (where xl represents a halogen atom, preferably a bromine atom, and R9 is unsubstituted or has 1 to 4 carbon atoms).
represents a phenyl group substituted with an alkyl group, or an alkyl group having 1 to 6 carbon atoms, preferably a phenyl group, a butyl group or a hexyl group, and ru represents the same meaning as above. ) is carried out using a ylide of a phosphonium compound shown in The ylide is prepared by adding a compound represented by the general formula (XI) to a suitable base, such as methyllithium, lithium diisopropylamide, dimsyl sodium, sodium methoxylζpotassium! 4-1-zotogiside, triethylamine, preferably 1-< is carrum QrHj.

-obtained by reaction in the presence of butoxide or dimsyl sodium.

Step [h] is carried out by subjecting the product to a hydrogenation reaction in a lower alkanol such as methanol or ethanol in the presence of a hydrogenation catalyst such as palladium on carbon, palladium black, or platinum dioxide.

The compound represented by the general formula (IV) used as a starting material is disclosed in JP-A-57-108046 and JP-A-58-1355.
It is a known compound described in the specification of No. 1. General formula (
The compounds represented by (2), (VIID, (IX), (X) and Off) are known per se or can be easily produced by known methods.

By subjecting the R group of the compounds represented by the general formulas (ID) and (IE) obtained by the present invention to a known deacylation reaction, for example, by using an aqueous solution of sodium hydroxide in methanol, the desired It can be converted into a 16-adithromboxane analog compound represented by the general formula (in which all symbols have the same meanings as above). The general formula (Xf
Since the compound represented by l) has an antagonistic effect on TXA2, it is useful for the prevention and treatment of inflammation, hypertension, thrombosis, stroke, asthma, myocardial hard water, angina pectoris, cerebral infarction, and acute cardiac death.

Use of the intermediate of the present invention is advantageous over conventional methods in the following respects.

(1) From a compound represented by general formula (IV) to general formula (
The number of steps leading to the compound represented by Xll) can be reduced (it can be produced in 6 to 8 steps).
The OH form and the 15β-OH form can be separated.

Further, by using a compound represented by the optically active general formula (■), (Vl), (W) or (Xi), only one of them can be selectively obtained.

By using an acyl group (particularly an acetyl group) as the holding group represented by 31R3, each reaction step can be carried out in high yield without side reactions.

(4) From the above, the total yield from the compound represented by the general formula (IV) to the compound represented by the general formula (Xll) was improved to 15-20%. This is about 6 times the yield of the conventional method.

(5) The manufacturing method is suitable for industrial six-layer production.

Hereinafter, the present invention will be explained in detail with reference to five examples and examples.
The present invention is not limited to these examples. In addition, [TLcJ, [NMRJ, JI] in Reference Examples and Examples
RJ and [kAass J stand for "thin layer chromatography", "nuclear magnetic resonance spectroscopy", "Sekiyu 1 absorption suite", and "mass spectrometry", respectively. The solvent in parentheses listed in the section for separation by chromatography indicates the elution solvent or developing solvent used. Unless otherwise specified, I)1 is measured by liquid film method1. , NMR was measured using deuterated chloroform (CI) (E63) solution.

Reference example 1 (2α, 3β)-2-[2-(tetrahydropyran-2
-yloxy)ethyl]-3-(N-((2αβ-hydroxy-3-phenyl)propyl]amine) -6,6
-S'-fkNorbinane Under argon atmosphere, (2α, 6β)-2-[2-(tetrahuman90pyran-2-yloxy)ethyl]-5-j
Mino-6,6-dimethylnorpinane (JP-A-58-13
Compounds described in b-groove side 8 of the specification of No. 551) 31.
7. ! After refluxing a mixture of i', 1-phenyl-2,3-epoxypropane 15.9 g and methanol 3QQ*/ for 24 hours, the reaction mixture was concentrated under reduced pressure to obtain a crude product having the following physical properties. Approximately 48 g of the title compound was obtained.

TI, C (chloroform:methanol = 10:1):R
f = 0.64 and 0,27° Example 1 (2α, 6β)-2-(2-(tetrahydropyran-2
-yloxy)ethyl)-3-(N-((2α-acetoxy-6-phenyl)furopi,l]-N-acetyl aξ
) S-6,6-dimethylnorpinane and the corresponding 2β-
After stirring a mixture of about 489 crude 2αβ-hydroxy acetogyrosine (produced in μ groove side 1), 1501Rt of acetic anhydride, and 150 ml of pyridine at room temperature for 16 hours, the reaction mixture was concentrated under reduced pressure (1~). Toluene was added and concentrated under reduced pressure at low temperature to obtain the crude title compound (a mixture of 2α-acetoxy and 2β-acetoxy). The obtained crude product was purified by silica gel column chromatography (FL-hexane:ethyl acetate=2=1, then 1:1),
The title compound (2α-acetoxy form) having the following physical properties:
19.1 and 20.1 g of the corresponding 2β-acetoxy compound were obtained.

(1) 2α-acetoxy form 'I' LG (Syc-o-hex?7': u-acid dif; 1:1): Rf "" 0.56 pNM
R: a=7.4-7.1 (5H, m), 5.4-5.
1 (IH, 771), 4.6-4.3(1)Lm),
4.5-4.1 (IH, m), 1.3-1.2 (
3H, 711), 1.1-1.0 (3H, m); IR Niji=2920.1760.1645.1250,102
0.740.690 side.

Ma, ss: s/t = 485 (M), 4
25.401.384° (il 2β-acetoxy form TIjC (cyclohexane:ethyl acetate-1:1)
:Rf=0.26'.

NMR: δ=7.4-7.1 (5H, 711), 5.
7-5.2 (IH, m), 4.6-4.4 (IH,
m), 1.3-1.1 (3H, m), 1.1-0.9
(3H, m); Engineering R Niji = 2920.1735.1640.1230.
1025.750.700c1n-'; Mass: s/g = 485 (M”), 425
．． 401.684゜Example 2 (2α, 6β)-2-(2-human°roxy)ethyl-3
-(N-[(2β-acetoxy-6-phenyl)furovir]-N-acetylamino+-6,6-dimethylnorpinane 2-(te)rahij-90pyran-2-yloxy dissolved in 2001 nl of methanol ) ethyl form (produced in Example 1) 20.1 P-) luenesulfonic acid.
615 m9 of monohydrate was added and stirred at room temperature for 4 hours. After adding 5 ytrl of triethylamine Q to the reaction mixture and concentrating under reduced pressure, the resulting residue was diluted with ethyl acetate 1~, washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Approximately 17.9% of the title compound having the following physical properties was obtained.

TLC (cyclohexane: ethyl acetate = 1:2): R
f=0.17; NMR: δ-7,25 (5H, #), 5
．． 7-5.4 (I H, blasphemous), 4.5-4.0 (I
H, m), 1.3-1.1 (3H, m), 1.1-0
．． 9 (3I (, inertia); 工Rniji=3400.1730.1620,1230.
750.700cm+ Maso:yx/g=401 (M, 658.34
1゜Example 6 (2α, 6β)-2-formylmethyl-3-(N-[(
2β-acetoxy3-phenyl)-furovir]-N-
-y cetyl amino I-6,6-dimethylnorpinane Under argon atmosphere, 4.75 ml of oxalyl chloride dissolved in 100 ffle of methylene chloride 1K, N,N-dimethylsulfoxyl' dissolved in 20 me of methylene chloride
7.7 Add TR1 dropwise while stirring at -78℃,
After 5 minutes, 1 of the crude 2-hydroxyethyl derivative (prepared in Example 2) was dissolved in 33 m, 1 of methylene chloride.
6.7. ! i' was added dropwise and stirred at the same temperature for 20 minutes, followed by dropwise addition of 23.2 In/l-ethylamine, and then the temperature was raised to 0° C. over 60 minutes. Add ice water to the reaction mixture, stir for 20 minutes, and then extract with diethyl ether. The extract was washed successively with water, 1N hydrochloric acid, water, saturated carbonated water solution, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude title compound 16 having the following physical properties. .28g was obtained.

TLC (cyclohexane:ethyl acetate=1:2):
Rf=0.40°NMR: δ=9.8 9.5(, IH
, m), 7.4-7.1 (5H, tJ, 5.5-5.
1 (IH, m), 4.5-4.1 (1H, m)
, 1.3-11 (31:T, m), 1.1-0
．． 9 (3H, m):IR Niji=292[:l, 1Z6
0.1630, 1370.123[].

1030.750.695 an-';Ma s s
: m7g = 399 (M"-), 371.65
6.339. .

Example 4 (2α, 6β) ・-2-((Z)-6~carboxy-
2-hexenyl)-3-(N-1:'(2β-acetoxy-6-phenyl)propyl)-tq-acetylamino+-6,6-dimethylnorbinotuargon atmosphere, 4
-Carboxybutyltriphenylphosphonium puromite"a,o,y,potassium tart-butoxy)'3.
2. 1 and dry toluene at 80°
After stirring at C for 1 hour, the mixture was cooled to room temperature. 6.6 g of 2-formylmethyl compound (produced in Example 3) dissolved in 2 Qinl of dry L. toluene was added at once at room temperature, and the mixture was stirred at the same temperature for 2 hours. In reaction 67, the combined solution was poured into cold 2N hydrochloric acid with stirring and extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain about 10 g of the crude title compound having the following physical properties.

']'LC (chloroform:methanol-10:1)
:Rf=0.40° Reference example 2 (5Z, 15β) -9,11-methano-10,10-
Dimethyl-16-aza-15-hydroxy-16-phenyl-17,18,19゜20-tetratrue 11α-
About 10 g of carbatronpo-5-enoic acid acetate (produced in Example 4) dissolved in 35 ml of methanol,
Add 5 ml of 2N aqueous sodium hydroxide solution to 80
Stir at ℃ for 2 hours. After the reaction mixture was concentrated under reduced pressure to remove ethanol, water was added, the pH was adjusted to 6 to 7 with acetic acid, and the mixture was extracted with chloroform. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol = 10[]:2.then 1
00:5) to obtain 6 g of a yellow solid. The obtained solid was made cloudy with 7 ml of methanol, 35 ml of diethyl ether was added, and the mixture was stirred for 2 hours under water cooling. The obtained crystals were washed with diethyl:[-thyl 1-1 and dried under reduced pressure to obtain 1.52 g of the title compound (white crystals) having the following physical properties.

Melting point: 174°C; TLC (chloroformnia '7//'=10:1):
Rf=0.14 sNMR: δ=7.3-7.1 (5H
, m), 5.5-5.3 (2H, nt), 4.2-3.
9 (I H, m), 1.21 (3H, s), 0.89
(611, J) ; IR (KBr method) Niji = 3170.292o, 1665
．． 156o, 1395.740,695cm-';M
ass: ra/a = 399 (M”), 308
, 303, 278° Reference Example 6 (2α, 3β)-2-[2-(tetrahydropyran-2
-yloxy)ethyl]-3-(N~[(2α-piparoyloxy-3-phenyl)propionylcoamino-
6,6-Dimethylnorbinane was added to the solution of the mixed acid anhydride of pivaloyl chloride and (2R)-2-hy)roxy-6-7-phenylpropionic acid (produced by the method described below), dried. (2α, 3β)-21:2-tetrahydropyran-2-yloxy)ethyl]-6-amino-6,6-dimethylnorpinane dissolved in tetrahydropyran 2d (JP-A-58-135
Compound described in Reference Example 8 of Specification No. 51) 320m
g was added dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with diethyl ether (1 to 1), washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (luhexane:ethyl acetate-5:1) to obtain the title compound 5001n9 having the following physical properties.

TLC (cyclohexane:ethyl acetate-4:1) diRf
=0.25° The mixed acid anhydride solution used in the above reaction was prepared as follows.

111 for 160mg of water! Add 22g of D-phenylalanine to 22g of diluted D-phenylalanine while stirring 2N acid 5Q+nl and water (nitrous acid dissolved in 50rnl) IJum 11.
The mixture was added dropwise at 0° C. for 1.5 hours, and stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals.

The obtained crystals were washed with 11-hexane and dried under reduced pressure to obtain (2R)-2-hydroxy-6- having the following physical properties.
Phenylpropionic acid (white crystals) 16.19 was obtained.

Melting point: 120°C.

Under an argon atmosphere, 332m? of (2R)-2-hydroxy-6-phenylpropionic acid obtained above? , triethylamine 55/μl and dry tetrahydropyran 6
ml of the mixed solution was stirred at 0° C., and 590 μe of pivaloyl chloride was added thereto dropwise. 1-1 The mixture was stirred at room temperature for 1 hour to obtain a solution of the desired mixed acid anhydride.

Groove side 4 (2α, 6β)-2-[2-(te)rahito9ppyran-2-yloxy)ethyl]-3-(N-[:(2β-
hydroxy-6-phenyl)propylcoamino+-6,
6-dimethylnorpinane Dry under argon atmosphere, 4ml 1kc of tetrahydrofuran
9 1-damides (produced in Reference Example 3) 100
8 m9 of lithium aluminum Hi-TriPyro was added to (2) at room temperature, and the mixture was stirred at 60°C for 20 hours. After decomposing the excess reducing agent with ethyl acetate and neutralizing with 2N hydrochloric acid, the crystals were separated. The e solution was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain about 80 μl of the crude title compound having the following physical properties.

TLC (chloroformimethanol = 10:1): Rf
=0.27゜Example 5 (2α, 3β)-2-[2-(tetrahydropyran-2
Crude 2β-hydroxy From about 801n9 of the compound (produced in Reference Example 4), the title compound 60■ having the following physical properties was obtained.

TLC (cyclohexane: ethyl acetate = 1:1): Rf
=0.26゜From the compound obtained in Example 5, the desired (5Z, 15β)-9,11-methano −
10,10-dimethyl-13-aza-15-hydroxy-16-phenyl-17,18,19,20-tetratrue 11α-carbatronp-5-enoic acid was obtained.

Claims (1)

[Claims] 1. General formula [In the formula, R1 is a tetrahydrobilan-2-yloxymethyl group, a hydroxymethyl group, a polmyl group, or
X-(Obairi-COOE((wherein, X is 2,5-OH=
It represents an OH- group or a -CF12CII2- group, and Oki represents an integer from 1 to O. ) represents the group shown. Both R2 represent a hydrogen atom or both represent a methyl group, R3 represents a straight or branched acyl group having 2 to 5 carbon atoms, or a benzoyl group, and R4 represents a single bond or a hydrogen atom having 1 to 5 carbon atoms. 5 represents a straight-chain or branched alkylene group, R5 is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, unsubstituted or at least one straight-chain or branched chain having 1 to 8 carbon atoms; It represents a cycloalkyl group having 4 to 7 carbon atoms substituted with a chain alkyl group, or a formula or a sulfur atom, and R is a hydrogen atom, a halogen atom, a hydroxyl group, or a straight or branched alkyl group having 1 to 5 carbon atoms. ,
It represents a trihalomethyl group, an alkoxy group having 1 to 5 carbon atoms, an amine group, or a mono- or dialkylamino group having 1 to 5 carbon atoms. ) represents a group represented by However, when R4 represents a single bond, R5t-1 does not represent a substituted or unsubstituted phenoxy group or phenylthio group. Norpinane derivative represented by ]. 2. The norpinane derivative according to claim 1, wherein R1 is a tetrahydrobilan-2-yloxymethyl group. 3. The norpinane derivative according to claim 1, wherein R1 is a hydroxymethyl group. 4. The norpinane derivative according to claim 1, wherein R1 is a formyl group. 5. The norpinane derivative according to claim 1, wherein R1 represents a group represented by the formula % (wherein X and L have the same meanings as in claim 1). 6. The norpinane derivative according to claim 5, wherein R1 is a (Z)-5-carboxylated ter-1-enyl group. 7. The norpinane derivative according to any one of claims 1 to 6, wherein both R2 are methyl groups. 8. The norpinane derivative according to any one of claims 1 to 7, wherein l'(" is an acetyl group. 9. R5 is the formula (wherein Z and R6 are The norpinane derivative according to any one of claims 1 to 8, which has the same meaning as described in claim 1.) 10. R'-R5 represents a benzyl group. 1. The norpinane derivative according to any one of claims 1 to 9. 11. In the general formula C, T HP represents a tetrahiviropicin-2-yl group. (7,]12 both represent a hydrogen atom or both represent a methyl group, R4 represents a single bond or a linear or branched alkylene group having 1 to 5 carbon atoms, L,
is a straight-chain or branched alkyl group having 1 to 8 carbon atoms; Represents a cycloalkyl atom, R6 is a hydrogen atom, ), a rogen atom, a hydroxyl group, a straight or branched alkyl group having 1 to 5 carbon atoms, a trihalomethyl group, an alkoxy group having 1 to 5 carbon atoms, an amine group , or a mono- or sialgylamino group having 1 to 5 carbon atoms. ) represents a group represented by However, when R4 represents a single bond, R5 does not represent a substituted or unsubstituted phenoxy group or phenylthio group. ] A general formula characterized by subjecting a compound represented by the above to an acylation reaction (wherein R3 represents a straight or branched acyl group having 2 to 5 carbon atoms or a benzoyl group, and other symbols are the same as those described above). has the same meaning as ). A method for producing a norpinane derivative. 12. A compound represented by the general formula (in which all symbols have the same meanings as described in claim 11) is subjected to a hydrolysis reaction under acidic conditions. 13. General formula (In the formula, all symbols have the same meanings as described in claim 11.) A method for producing a norpinane derivative represented by the general formula (in the formula, all symbols have the same meanings as above), characterized by subjecting the compound represented by the formula to an oxidation reaction.14. The symbol represents the same meaning as described in claim 11.) and the compound represented by (in the formula,
l represents a halogen atom, R9 represents an unsubstituted phenyl group or a phenyl group substituted with an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 6 carbon atoms, and 1 is an integer from 1 to represents. ) A method for producing a norpinane derivative represented by the general formula (in the formula, all symbols have the same meanings as above), characterized by subjecting ylide 9 of the phosphonium compound represented by the formula to a Wittig reaction. 15. Compound represented by the general formula (in the formula, R represents the same meaning as described in claim 14, and 1-1 and other symbols represent the same meaning as described in claim 11) A method for producing a norpinane derivative represented by the general formula (in the formula, No. 7312 of Sub-C has the same meaning as above), which comprises subjecting to a hydrogenation reaction.