JPH0383936A - 7, 7-dimethylnorvolnane derivative - Google Patents

Abstract

NEW MATERIAL: A compd. of formula I, (where Y is CHO or formula II-IV; R and R' are each H or 1-3C alkyl).

EXAMPLE: 2R-Exo-7,7-dimethylnorbornyl acetoaldehyde.

USE: As an intermediate of synthetic perfumes or high strength sweeteners.

PROCESS: The compd. of formula I, shown as the example, is obtd. by dehydration-isomerizing (+)-α-phenthyl alcohol to obtain (+)-α-phenthiene, allowing it to undergo a Bismayor reaction to obtain 7,7-dimethyl-2- formylmethylnorbornane and stereoselectively reducing it. A compd. of formula VL, (where R is H or 1-3C alkyl), useful as the intermediate of an L-aspartyl-7,7- dimethylnorbornyl alanine derivative (high strength sweetener) of formula V, (where R is 1-3C alkyl), is obtd. from the compd. of formula I, shown as the example, through the compd. of formula I, (where Y is formula II or IV), in a high yield and at low cost.

COPYRIGHT: (C)1991,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel norbornane derivatives, processes for their preparation and the conversion of such derivatives into high-intensity artificial sweeteners.

Furthermore, the present invention also relates to novel catalysts for the production of fenthyl alcohol and tr-fenchen.

SUMMARY OF THE INVENTION The present invention discloses 7,7-dimethylnorbornane derivatives useful as intermediates for the production of various synthetic flavors and high-intensity sweeteners.

2R-exo-7,7-dimethylnorbornylacetaldehyde, 3-(2R-exo-7,7-dimethylnorbornyl)-2-aminopropionitrile, 3-(2R
-Equin-7,7-dimethylnorbornyl)alaninehydantoin and N-acyl-3-(2R-exo-7,
7-dimethylnorbornyl)alanine is disclosed. The present invention provides 7,7-dimethylnorbornane derivatives, 3-(2
R-echin-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester and a-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester. The manufacturing method will be explained. σ− Method of manufacturing Fenchen, α−
Method for producing fenthyl alcohol and optically active 3
-(2R-exo-7,7-dimethylnorbornyl)-
Also disclosed is a method of producing L-alanine or its lower alkyl ester. Dehydration and rearrangement catalysts are also disclosed.

More specifically, the novel norbornane derivatives of the present invention have the following formula (I), where Y is hydrogen or a lower alkyl group having 1-3 carbon atoms, and R / is hydrogen or I having 1-3 carbon atoms; is a lower alkyl group. Compounds of formula (I) are high-intensity sweeteners, in particular L-aspartyl-7,7-dimethylnorbor of the formula OOR, where R is a lower alkyl group having 1-3 carbons. It is very useful as an intermediate for producing nilalanine derivatives. Such high-intensity sweeteners are described in U.S. Patent No. 4.78.
No. 8,069.

In U.S. Pat. No. 4.788.069, Sweet Law
The production of V') consists of amino al-2 and amino ester I
-3, the latter being prepared from the former by esterification with methanolic hydrochloric acid.

Two methods for the production of I-2 and related bicyclic amino acids are disclosed. In the first method, α-fenchen is converted to the corresponding 7,7-dimethylnorbornyl-2-methanol using diporane and hydrogen peroxide. This intermediate is then converted to the tosylate and condensed with sodium dimethylmalonate to yield the norbornylmalonic acid diester. Finally amino acid I-2
To reach , three additional steps are required: bromination, hydrolysis and amination. The overall process known in the art is very expensive and provides only low yields of I-2. In the second method, α-fenchene is treated with 9-borabicyclo[3,3,1]nonane, and the resulting doroborated compound is converted into methyl-N-(diphenylmethylene)-2-acetoxyglycylamide. Condensation with nate gives an adduct, which can be hydrolyzed with dilute acid to give I-3. Although this method is much simpler than the first method, it involves the use of very expensive reagents and would not be economical on an industrial scale.

The present invention overcomes the shortcomings of the prior art by directly converting 6-fenchene to the novel aldehyde I-1 via reductive carbonylation or Vilsmeier reaction and catalytic hydrogenation. See Reaction Schemes A and B. The novel norbornyl aldehyde I-1 can be synthesized by l-4 (Strecker reaction) or l-5 (
It can be easily converted to amino acids 1-2 via the hydantoin method). In both cases, yields are high and reagent costs are low.

The present invention provides (+)-α-phentyl alcohol by rearranging (aX-)-trans-2-pinanol.
FiQjE L , (bX 10) -a -7 Enthyl alcohol is dehydrated to form (+)-, -fenchen, and (C) this (+)-α-fenchen is converted to 2R-exo-7.

Converted to 7-dimethylnorbornylacetaldehyde,
(d) Converting 2R-exo-7,7-dimethylnorbornylacetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine,
e) Add 3-(2 R-exo-7,7-dimethylnorbornyl)-D,L-alanine to 3-(2 R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
-exo-7,7-dimethylnorbornyl)-L-alanine, (f) 3 -(2 R-exo-7,
7-dimethylnorbornyl)-L-alanine to form a 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, In the formula, R represents a lower alkyl group having 1-3 carbon atoms, 3-(2 R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester Provides a method for manufacturing. In the above method step (d) converts the acetaldehyde to aminonitrile and hydrolyzes the nitrile to form 3-(2R-
It may be removed by forming exo-7,7-dimethylnorbornyl)-D,L-alanine. Alternatively, in the above method, step (d) converts the acetaldehyde to hydantoin and hydrolyzes the hydantoin to form 3-(2R-exo-7,7-dimethylnorbornyl)-, L- Arani. There may be more than just forming a ring. In the above method, the step of resolution can be performed after the step of esterification.

In process ffl(a), (+)-a-phentyl alcohol is prepared by reacting (-)-1-lance-2-pinanol with a catalyst selected from the group of aluminum phosphate, niobium oxide and nickel sulfate. Manufactured.

Common methods for producing a-phentyl alcohol include, for example, (1) Wagner-Maelvein type rearrangement reaction of α- or β-pinene with an inorganic or organic acid [G.G. Henderson et al., Journal On Chemical Science, 125.107 13 (1924) (G.
G., Henderson et al.

J, Chem, Soc, 125.107-13
(1924))], (2) Reduction of the 7-ention with various reducing agents, such as metallic sodium and alcohols [W Hützkel et al., Hemische Berichte, 9
0, 2025 (1957) (W, Huckel e
Lat, Chem, Ber, 90°2025X
1957)) ; B Teilsseir et al., Teilsseir, 19.232 (1974) (P, Teilsseir
s etal, Recherches, 19.2
32 (1974))] and (3) Rearrangement of trans-2-pinanol with perchloric acid or acetic anhydride [H., Indyke et al., Journal on Chemical Society, Perkin ■, 3113 (1974XH, Indy
K et al., J. Chem.

Soc, Perkin II, 3113 (19
74)); W e day Preuss et al., Journal.
On the American Chemical Society, 81
245, (1959XW, D, Burrows
et al., J. Am. Chem. Soc.

81245, (1959))].

In the Wagner-Meerwein type reaction of method (1), the selectivity of σ-phentyl alcohol or a-7-ethyl alcohol derivative is 10% or less, and it is difficult to obtain a high selectivity with this method. It is difficult. In method (2), the production of the fenchon itself is complicated [G. Brafbaraer et al., Liebig's Annalen der Hemi-2093 (1981) (G, B
uchbauer etal, Liebigs,
Ann, Chew, 2093 (1981)].

Process (3) is not economically viable as it requires acetic anhydride or large amounts of solvent and the product is obtained as σ-7 ethyl acetate.

The present invention overcomes the problems of the prior art and provides an economical industrial process for producing alpha-7 ethyl alcohol from trans-2-pinanol as a starting material.

In step (b) above, the (+)-, -7 ethyl alcohol is converted to (+) by heating in the presence of the specifically prepared aluminum oxide catalyst disclosed herein.
)-α-fenchen.

According to one conventional method of producing α-fenchene, fentyltosylate is solvolyzed with acetic acid in the presence of excess sodium acetate to obtain 6
- Fenchen is obtained [W.Hickel et al.
Liebigs Annaren der Hemi-664,3
1 (1963Xw.

Hueckel et al., Liebigs A.
nn, Chem, 6664+31 (1963))
]. However, this method is economically and industrially disadvantageous since tosylation of 7-ethyl alcohol requires large amounts of pyridine and long reaction times, and solvolysis requires large amounts of acetic acid. As a method for dehydrating and rearranging fenthyl alcohol to obtain σ-fenchen, use of potassium sulfate [W. W. Wickel et al., Rihichs Annaren der Hemi-68, 40
(1965) (W, Hueckel et al.
, Liebigs Ann, CheIll, 68
7.40 (1965)], the use of aluminum phosphate [Dey-Tichenko et al.
5hchenko et al, Zhur, 0b
shchi Khim, 22.1587 (1952
))] and the use of kaolin or zinc chloride [E. Pulkinen, Suomen Chemistry-30A1239 (
1957) (E, Pulkkinen, Suome
n Kemistilehti, 30A, 239 (
1957))] is known. For both of these methods, the selectivity and yield of α-fenchene is around 20-30
%, which is not industrially satisfactory.

The present invention overcomes the above drawbacks of the prior art and provides a commercial method for converting 7-ethyl alcohol to α-fenchene with high selectivity and high yield using solid acid catalyst and heating. do.

The present invention consists of crystallizing α-7 ethyl alcohol in a hydrocarbon solvent at low temperature.
A method for purifying ethyl alcohol is also disclosed.

In the above steps (C) to (f), the intermediate (+)-
a-Fengchene is converted to the amino acid ester I-3 via novel intermediates I-1, 1-4 and I-5 by methods described in the literature. See Schemes A and B and explanation below.

The present invention relates to the coupling of (a) 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester with N-protected aspartic anhydride.
-B11(a,β)-L-aspartyl-3-(2R-
(b) This N-protection (ff1 β)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester is formed; The protecting group of the lower alkyl ester of a- and β-L-
(C) forming a mixture of aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester; and (C) producing a -L-aspartyl-3-(2R-exo-7 , 7-dimethylnorbornyl)-L-alanine lower alkyl ester, in which R represents a lower alkyl group having 1-3 carbon atoms. Also provided is a method for producing σ-L-aspartyl-(2R-exo7,7-dimethylnorbornyl)-L-alanine lower alkyl ester. The step of removing the protecting group may be performed after the separation step. N-protected aspartic acid with a β-ester protecting group may be used in place of N-protected aspartic anhydride.

The present invention provides N-acyl-3-(2R-exo-7,7-
dimethylnorbornyl)-D,L-alanine or its lower alkyl ester is treated with acylase in an aqueous medium and the resulting 3-(2R-4xo-7,7-';
Optically active 3-alanine or its lower alkyl ester
(2R-exo-7,7-dimethylnorbornyl)-L
- A method for producing alanine or its lower alkyl ester is also disclosed.

In the present invention, the term "lower" used to define groups or compounds includes methyl, ethyl, N-propyl and isopropyl groups.

An advantage of the present invention is for the preparation of formula % 7.7-dimethylnorbornyl)-L-alanine derivatives useful as high-intensity sweeteners, particularly compounds of formula (IV-1,R-CHs). The novel 7,7. of formula (1) is useful as a composite field.
- dimethylnorbornane derivatives.

Another advantage of the present invention is that from the novel 7,7° dimethylnorbornane derivatives of formula (I), formula (IV) is useful as a sweetener.
) L-aspartyl-3-(7,7-dimethylnorbornyl)-L-alanine derivative is provided.

Another advantage of the present invention is that it provides a novel catalyst useful in the production of 7-ethyl alcohol and σ-fenchen.

In summary, the present invention provides the following formula: where Y is , R is hydrogen or a lower alkyl group having 1-3 carbon atoms, and R/ is hydrogen or a lower alkyl group having 1-3 carbon atoms. Discloses a compound represented by, which is a lower alkyl group having The present invention provides 2R-exo-7,7-dimethylnorbornylacetaldehyde, 3-(2R-exo-7,
7-dimethylnorbornyl)-2-aminopropionitrile and 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin are disclosed. Disclosed in the present invention are compounds consisting of N-acyl-3-(2R-exo-7,7-dimethylnorbornyl)-D%L-alanine, where acyl is acetyl, propionyl, butyryl or chloroacetyl. . In particular, N-acetyl-
3-(2R-exo-7,7-'; methylnorbornyl)-, L-alanine and N-chloroacetyl-3-(
2R-exo-7,7-dimethylnorbornyl)-D,
L-alanine is disclosed.

A fenthyl alcohol dehydration catalyst selected from the group consisting of calcined aluminum oxide is disclosed in the present invention. In particular, a dehydration catalyst is disclosed comprising calcined aluminum oxide having a Hammett acidity function of 5.6<Ho≦-3.0. Finally, a catalyst for the production of a-7 ethyl alcohol from trans-2-pinanol selected from the group of aluminum phosphate, niobium oxide and nickel arsenate is also disclosed.

Compounds of formula (I) according to the present invention [Compounds 1 of formulas (I-1), (I-2) and (t-3) in the following reaction formula are
It can be produced by the synthetic route summarized in Reaction Scheme A below.

Reaction formula A trans-2-pinanol ay entitol α-Fengchen fhiFll+(+-1) (+-3) (+-2) In the above reaction formula A, R is a lower alkyl group represent.

In the above reaction formula A, σ-7 ethyl alcohol is
By heating trans-2-pinanol to a temperature of 60-150°C in the presence of one or more catalysts selected from aluminum phosphate, niobium oxide and nickel oxide, high conversion and high selectivity can be achieved. Manufactured.

This method will be explained in detail below. The trans-2-pinanol used as starting material in this process is usually obtained by subjecting nobinone (obtained by oxidation of β-pinene with ozone or potassium permanganate) to a Grignard reaction with methylmagnesium halide [W-Hüggal et al. , Liebig's Annalen der Hemi-16
25, 12, (1959) (W, Huckel et
al., Liebigs, Ann, Chem.
, 625.12. (1959))] or catalytic reduction of σ- or β-pinene to form binane, which is oxidized with oxygen and further reduced [Niss, G.-Trainor et al., Journal on Organic Chemistry, 45.900 (1980) (S, G,
Traynor et al., J. Org.
Chem, 45°900 (1980)].

The aluminum phosphate used as a catalyst in the present invention includes hydrated aluminum nitrate, hydrated aluminum sulfate,
Hydrolyzing hydrated aluminum chloride or sodium aluminate with an aqueous solution of a nonmetallic alkali, i.e., ammonia or urea, adding an equivalent amount of orthophosphoric acid to the resulting aluminum hydroxide for precipitation, and precipitating the resulting hydrated aluminum phosphate. It can be obtained by calcination at a temperature of 300-800°C, preferably 300°C, for about 3 hours.

The niobium oxide used as catalyst in the process of the invention can contain water. Niobium oxide and its hydrates (so-called niobic acid) can generally be produced by precipitation from a solution of a niobium compound such as niobium chloride or niobium oxalate under the action of an alkali. The resulting precipitate usually contains a significant amount of water, which can be almost completely dehydrated by heating above 200°C. Niobic acid obtained by precipitation from solution can be used as is or after calcination at 500° C. or lower as niobium oxide.

Another catalyst, nickel sulfate, can be produced by calcination of commercially available nickel sulfate aqueous products.

Treatment of trans-2-pinanol in the presence of a catalyst is
It can be carried out at a temperature of 60-150°C, preferably 65-75°C.

A suitable amount of catalyst used is about 1-10% by weight based on trans-2-pinanol.

The reaction in the present invention is usually carried out without using a solvent. In terms of separation of the desired compound from the reaction products, the conversion of trans-2-pinanol is preferably at least 90%.

After the reaction, the reaction mixture is filtered to remove the catalyst and the residue is distilled in a conventional manner. Alternatively, the reaction mixture can be distilled directly without separating the catalyst.

The starting trans-2-pinanol contains (+) and (-) isomers, and its optical purity can be determined by its specific optical rotation. The present inventor prepared trans-2-pinanol in the presence of pyridine with N-carbobenzyloxy-(D
)- or (L)-alanoyl chloride, the N-protecting group was removed from the reaction product, and its optical purity was determined by gas chromatography [the gas chromatography column was, for example, a PEG-HT capillary tube. , diameter 0.25 mm, length 25 m, manufactured by Gascro Industries Co., Ltd.
). The a7 ethyl alcohol obtained by the method of the present invention also includes (+) and (-) isomers. Any one of these forms can be obtained using either the (+) or (-) form of trans-2-pinanol as a starting material. For example, as a starting material the Liebig's Annalen der Hemi-1625,12,
(-)-trans- obtained by the method of (1959)
When carrying out the process of the invention by using 2-pinanol, (+)-α-phentyl alcohol is obtained without racemization.

The process of the present invention can economically provide σ-7 ethyl alcohol useful as a raw material for flavorings or as a sweetener intermediate as described above.

In Reaction Formula A above, fenthyl alcohol is heated in the presence of a solid acid catalyst to simultaneously perform dehydration and isomerization to selectively produce a-fenchene.

According to the invention, aluminum oxide has been found to be particularly suitable as solid acid catalyst for use in this reaction.

Particularly preferred are hydrolyzed aluminum nitrate, hydrated aluminum rLate, hydrated aluminum chloride or sodium aluminate with an aqueous solution of a non-metallic alkali such as ammonia or urea, and the resulting aluminum hydroxide is calcined. Prepared aluminum oxide.

More specifically, this aluminum oxide is hydrolyzed by dispersing a 10% by weight aqueous solution of aluminum nitrate aqueous solution in 28% 8% ammonia at room temperature, and the resulting aluminum hydroxide precipitate is filtered out according to a conventional method. Collect,
It is obtained by calcining the resulting aluminum hydroxide at a temperature of about 400-600°C, preferably about 500°C, for about 3 hours. The acid strength of aluminum oxide prepared under these conditions is expressed as Hammett's acidity function:
．． 6<Ha≦−3,0. This is a solid acid of medium acidity.

For conversion to 7-enethiene, the solid acid is generally 0.1-1% based on the weight of the starting fenthyl alcohol.
It can be used in amounts of 0%, preferably 1-5%.

The reaction temperature is usually 150-250°C, especially 195-20°C.
It is in the range of 0°C. If the reaction temperature is too low, the reaction rate will be slow. Reaction times vary depending on the 67-ethyl alcohol used, but periods of about 1-24 hours are usually sufficient.

In the above reaction, the presence of water in the reaction system is undesirable, and the reaction is preferably carried out in a reactor equipped with a water removal device such as a Dean-Stark device. Usually, this reaction can be carried out without the use of a solvent.

After the reaction, with or without prior separation of the catalyst, the reaction mixture is distilled and, if necessary, rectified in a rectification column.

The starting 7-ethyl alcohol may be either σ-phentyl alcohol or β-7-ethyl alcohol. α-7 Enthyl alcohol is readily available commercially or can be prepared from trans-2-pinanol as described above.

β-7 ethyl alcohol can be obtained by catalytic reduction of fernchion, converting the resulting mixture of α- and β-7 ethyl alcohol into crystalline p-nitrobenzoate, repeatedly recrystallizing and hydrolyzing the purified product. High purity can be obtained by

Alternatively, α under hydrogen pressure in the presence of a copper-chromium catalyst
- By epimerizing 7-ethyl alcohol,
A mixture of α-fentyl alcohol and β-fentyl alcohol can be obtained.

In particular, L-aspartyl-3 of the formula (IV-1, R-CH)
-(2R-equin-7,7dimethylnorbornyl)-L
In the production of -alanine methyl ester, preference is given to using (+)-y-7 ethyl alcohol as starting material. (+)-α-7 ethyl alcohol can be obtained, for example, by crystallizing commercially available α-7 ethyl alcohol in a hydrocarbon type organic solvent at low temperature.
, e can be isolated and purified with high optical purity.

Commercially available α-7 ethyl alcohol is generally a mixture of the (+)-α- and (-)-α-isomers in a weight ratio of 80:20 to 70:30. n-pentane, n-hexane, inhexane, n-hebutane, n-
By crystallizing commercially available alpha-7 ethyl alcohol in an aliphatic hydrocarbon solvent such as octane and isooctane (preferably n-heptane or n-octane).
High purity (+)-α-isomers are obtained, for example optical purity of 94% e, e or higher.

The crystallization process involves dissolving α-7 ethyl alcohol in the above solvent at room temperature or slightly elevated temperature, and heating the solution at about -10°C to 160°C, preferably -35°C to -60°C.
'C! This can be done by cooling to a temperature of

A single crystallization gives a product with sufficient optical purity, but repeating the crystallization two or three times gives a product with very high optical purity.

The optical purity of purified <+>-α-7 ethyl alcohol can be determined by its specific optical rotation. The present inventor has discovered that L-alanine or D of σ-phentyl alcohols
- Gas chromatography of alanine ester (column, for example, manufactured by Gas Chloé Industry Co., Ltd., with a diameter of 0.2
The optical purity of α-7 ethyl alcohols was measured using a PEG-HT capillary (5 mn+, 25 cm long). Samples were prepared using a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in the presence of N,N-dimethylaminopyridine. Condensing ethyl alcohol with N-carbobenzyloxy-(D)-alanine or (L)-alanine or using the dehydrating agents mentioned above to convert a-phentyl alcohol to N-butoxycarbonyl-(D)-alanine. Alternatively, it was prepared by condensation with (L)-alanine.

The amino protecting group is then removed by hydrogenation (N-carbobenzyloxy group) or acid treatment (Nt-butoxycarbonyl group) before GC analysis.

In the above dehydroisomerization reaction involving 7-ethyl alcohol, the reaction rate of β-7-ethyl alcohol is faster than that of its α-epimer. The reaction with β-7 ethyl alcohol is generally complete within 3 hours to form α-fenchen with about 80% selectivity. On the other hand, when et-7 ethyl alcohol is used as the starting material, the selectivity for α-fenchene after 16 hours is about 59%. When using a mixture of α- and β-7 ethyl alcohols (σ/β-6/4), the selectivity for a-fenchen increases to 65%.

The a-7 enethiene thus obtained is subjected to the Vilsmeier reaction.
n), 7,7-dimethyl-2-formylmethylene norbornane is formed. Stereoselective reduction of this product yields 2R-exo-7,7-dimethylnorbornylacetaldehyde (I-1).

The σ-Fenchen Weilsmeyer reaction is, for example,
C. Uts et al., Hemitssie Berichte, 100115
36 ('l 967) (C, Jutzetal,, Ch.
em, Ber, 100.1536 (1967)]
This can be carried out by the known method described in . for example,
α-fenchen with phosgene or thionyl chloride and N,
From N-disubstituted formamides such as N-methylformanilide, preferably at least 1 equivalent of N with phosphorus oxychloride.
, N-dimethylformamide to Vilsmeyer's reagent prepared at room temperature. This mixture was heated at 50-90℃.
Dehydro (z-1) is usually obtained as an E-/Z- mixture.

The resulting 7,7-dimethyl-2-formylmethylene-norbornane [dehydro(I-1)] was reduced to form the formula (
2R-exo-7,7-dimethylnorbornylacetaldehyde of I-1) is obtained. Reduction of dehydro (I-1) can be carried out by catalytic hydrogenation using hydrogen in the presence of a noble metal catalyst such as palladium on carbon.

As a result, the compound of formula (■-1) is obtained with an exoselectivity of about 95% or more.

Alternatively, σ-fenchene can be directly converted to acetaldehyde by an oxo reaction using various rhodium complex catalysts.

According to this method, the selectivity for the echen form of formula (I-1) is slightly inferior to that of the method using dehydro (I-1).

The oxo reaction of σ-fenchen is, for example, double-
Hinol et al., Tetrahedron Letters, 907, l.
976 (W. Himmele et al.
Tetrahedron 1etters, 907+
1976) and J.
) and K. Bruns, US Pat. No. 4,334,100. For example, σ-fenchen is combined with a rhodium complex catalyst, e.g. Eva, a rhodium carbonyl complex, e.g. Rh@(co)+i, RhCI(COX
pph") tCIn the formula, pph 3 is triphenylphosphine'i-Table t), RhH(Co)(pph")
1, [Rh(COD)Xl x (COD represents Schiff 0.?ctadienyl, X represents halogen, acetate)
or about 25 to about 150 in the presence of Rh(COD)(acac) (acac represents acetylacetonate).
Hydroformylation is carried out with a gaseous mixture of carbon monoxide and hydrogen at a temperature of from about 30 DEG to about 150 DEG C. under a gas pressure of "Kg/cm".

The resulting 2R-exo-7,7-dimethylnorbornylacetaldehyde of formula (I-1) is then synthesized by Strecker's amino acid synthesis method [for example, J. ”
, Volume 1, pp. 698-700 (1961XJ, P, G
reenstein & M, Winitz.

“Chemistry of the Am1no A
c1ds″, Vol, I, pg-698-
700 (1961); Earl Gardley, Canadian Journal on Research, 24B, 301 (
1946) (R, Gardry, Can, J.
Res,, 24B.

301 (1946)] with ammonia or ammonium chloride and hydrogen cyanide or an alkali cyanide. The resulting 3-(2R-exo-
7,7-dimethylnorbornyl)-2-aminopropionitrile (I-4) is hydrolyzed under acidic conditions with mineral acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid. , 3-(2R-exo-7,7- of formula (I-2)
dimethylnorbornyl)-L-alanine is obtained.

The Strecker reaction can be carried out in an alcoholic solution or mixed alcoholic-aqueous solution using ammonia gas or ammonium hydroxide solution. Cyanide can be supplied as a salt to Li, Na or
Li and Na salts with good solubility are preferred. Reaction temperatures of O-30°C can be used and times can be adjusted accordingly. After removing the solvent by evaporation, the residue is treated with a strong base (such as NaOH, KOH or Na, CO, etc.) and the aminonitrile is extracted with ether, toluene or any suitable organic solvent that does not react with amino groups. .

The hydrolysis of the resulting 3-(2R-exo-7,7-dimethylnorbornyl)-2-aminopropionitrile is as follows:
This is best accomplished by refluxing for 18 hours in about ION of HCI solution. Lower acid concentrations can be used, but longer reaction times are required. By heating at elevated temperatures in an autoclave, shorter reaction times can be achieved. Other acids such as hydrobromic acid or sulfuric acid can also be used. Hydrochloric acid is particularly useful in that the product is obtained as the hydrochloride salt by direct crystallization from the cooled and concentrated reaction mixture.

Other methods of producing amino acids of formula (1-2) involve the production of intermediate hydantoins. In this method, the formula (
I-1) 2R-exo-7,7-dimethylnorbornylacetaldehyde is reacted with an alkali metal cyanide and ammonium carbonate [Buchererberg reaction (B
tl cherer-Berg rectton) - E. Barb, Chemical Reviews, April 4, 403, (
1950) (E, Wade, Chem, Rev.
.

46, 403. (1950))]. The resulting hydantoin (IV) was then treated with an aqueous strong base [N ao H,
B a(OH)! ] to produce amino acids (I
-2) is obtained.

In a typical method, 1 mole of the above aldehyde is
2-5 mol (N Ha)z in aqueous ethanolic solution
50-70 °C with cOs and 1.1 mol NaCN
Heat for 8-24 hours. The mixture was cooled, concentrated and p
Acidification of H5 precipitates the product (I-5) as a white solid.

Hydrolysis of (I-5) to amino acid (1-2) is as follows: 1.
5 M Ba(OH)! This is accomplished by refluxing the solution for 72 hours.

3-(2R-exo-7,7-dimethylnorbornyl)alanine of formula (I-2) produced as described above is generally obtained as a mixture of D-form and L-form. Therefore, this mixture must be optically resolved to recover the L form as a sweetener intermediate.

Optical resolution can be performed before or after esterifying the compound of formula (I-2).

Esterification of the compound of formula (I-2) can be carried out by reacting it with a lower alkanol having 1-3 carbon atoms.

For example, esterification of formula (1-2) with methanol is carried out by heating and refluxing a solution of the amino acid dissolved in a methanolic hydrogen chloride solution for 18 hours. Evaporation of the solvent yields the amino ester hydrochloride.

This aqueous solution of the hydrochloride salt is then diluted with a suitable base (KOH,
The free base (I-3, R-CHI
) is obtained. Evaporation of the extract yields the pure amino ester (■-3, R=CH,).

3-(2R-exo-7,7-dimethylnorbornyl)
-D,L-alanine (I-2) or its lower alkyl ester (I-3) can be optically resolved by a known method such as using D-271 tartaric acid or an enzyme.

(1) Optical resolution with D-5 talic acid is performed in methanol with D-5
- A 1:1 mixture of tartaric acid and the amino ester is added to D-
3-(2R-
Exo-7,7-dimethylnorbornyl)-D,L-alanine lower alkyl ester. The solution is then cooled to induce crystallization. Two further recrystallizations yield a material with >95% ee.

If possible, the alcohol used for crystallization should be (I-3
) should be the same as that represented by the R group of
Transesterification is then avoided.

(2) Optical resolution by enzymatic method N-acylation of the compound of formula (I2 or !-3) by a known method (for example, N-acetylation or N-chloroacetylation), and this acylation in an aqueous medium. Let acylase act on the compound. As a result, N-
The L form of acyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine or its ester is selectively deacetylated,
, 7-dimethylnorbornyl)-L-alanine or its ester is obtained.

Acylase that can be used in the above enzymatic reaction is
Any type of amino acid may be used as long as it can selectively hydrolyze L-type N-acylamino acids [e.g., Ai Shibata et al., K. Mosbach, et al.
ed., Methods in Enzymology, Volume 44, 7.
46-59, (1976) (1, Chibata, e.
tal,,in K,Mo5bach.

ed, Methods in Enzymolog
y, Vol. 44.746-5L (1976)]. This acylase can be of animal, vegetable or microbial origin. Since the acylase reaction is generally carried out in weak alkaline conditions, the acylase reaction is approximately 6
It is preferable to have an optimum pH of −9. Acylase is, for example, Aspergillus spp.
) or molds such as Penicillium, Pseudomonas
bacteria such as Streptomyces (omonas), Streptomyces (
Acylase can be obtained by culturing microorganisms such as bacteria such as Streptomyces and collecting acylase from the culture. For example, acylase ■ (manufactured by Sigma Chemical Company) and acylase "Amano" (manufactured by Amano Pharmaceutical Co., Ltd.) [Aspergillus viruleus (Aspergillus
derived from P. gillus, welleus) is commercially available.

N-acyl-3-(2
R-equin-7,7-dimethylnorbornyl)-D,L
-Deacylation of alanine (I-6) or its ester can be carried out in the same manner as a normal enzymatic reaction. For example, the N-acyl compound is dissolved or dispersed in an aqueous medium. The pH of this medium is adjusted to the optimum pH for acylase using an alkali such as sodium hydroxide or sodium carbonate. If desired, an enzyme stabilizer such as cobalt chloride hexahydrate may be added at a cobalt ion concentration of 1.0-'-10''''2M.
Add so that The reaction is carried out at a temperature range of about 35-40°C for several hours to more than 10 hours.

After the above reaction, the pH of the reaction mixture is adjusted to an acidic pH of, for example, about 1 to about 2, and unreacted N-acyl-3-(2R-
Exo-7,7-dimethylnorbornyl)alanine or its ester is separated and recovered using a solvent such as ethyl acetate, methylene chloride or chloroform. #
In the case of (I-2), the aqueous layer is adjusted to a pH of about 3-5 with aqueous ammonia. The desired 3-(2R-exo-7°7-dimethylnorbornyl)-L-alanine precipitates as crystals. The crystals are separated and purified by conventional methods, for example by treatment with activated carbon in hot water. White purified 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine can be recovered in this way. In the case of ester (I-3, R-CH3), the product was prepared by adjusting the aqueous layer to pH 8-9 (instead of 3-5) and extracting with a solvent such as ethyl acetate, chloroform or methylene chloride. isolate. Evaporation of the solvent yields 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester as a liquid.

The purified 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its ester is subjected to N-trifluoroacetylation and optionally esterification, and then transferred to a specially processed capillary (G- It has substantially 100% optical purity as determined by gas chromatography using a 800 column (manufactured by Japan Chemical Inspection Association).

Unreacted N-acyl-3-(2R-exo-7゜7-dimethylnorbornyl)-D-alanine or its ester is racemized by a known method, for example, by treating it with acetic anhydride. The racemate can be converted to 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its ester by subjecting it to an acylase reaction again.

In principle, the N-acyl derivative (I-2) used in the enzymatic resolution method described above can be converted to σ-fenchen or 7.7- Dimethylnorbornylacetaldehyde (1
It can also be produced by direct amide carbonylation of -1). [Amidocarbonylation reaction (The a
midocarbonylation reactio
n) --Ai Ojima, Journal on Molecular Catalysis (1, Ojima, J, Mo1.
CataJ, ), 37°25-44 (1986);
P. Magnus and M. Slater, Tetrahedron Letters (P. Magnus and M., 5)
later, Tet, Let, ), ■, 2829
(1987); Kei Izawa, Journal of Organic Synthetic Chemistry (K,
Izawa, J., Syn, Org., Chev.
n, Jp), 46.218 (1988) and Japanese Patent No. 61.236.960 (10/22/1986)
reference].

In typical conditions, the alkene (or aldehyde),
Combined cobalt-rhodium catalyst, acetamide, hydrogen (500-2000 psi) and 1-
It takes 10 hours.

A third method of resolving the amino acid of formula (I-2) can also be considered. This method involves treating hydantoin (I-5) with a microbial enzyme capable of selectively hydrolyzing the hydantoin ring to obtain L-amino acids. Most hydantoinase enzymes (hydantoin)
Bacillus enzyme) gives D-amino acids as the only product;

An enzyme isolated from Bacillus brevis was found to give the desired L isomer in the case of valinehydantoin. [A. Yamashiro et al., Agricultural Chemistry]
al. , Agric.

Biol. Chem. ), 5212851-285
6 and 2857-2863, (1988) Reference 1.

Treatment of hydantoins (1-5) with the enzymes mentioned above and according to the reaction conditions described by Yamashiro et al.
R-exo-7,7-dimethylnorbornyl)-L-
will give alanine (I-2).

The compounds of formula (I-2 or Ni-3) prepared as described above are useful as intermediates for the production of compounds of formula (IV) useful as non-nutritive sweeteners. Expression (■)
Sweetener compounds can be prepared from compounds of formula (1-3) by the synthetic route summarized in Scheme B below.

Reaction formula B In the above reaction formula, Z represents a protecting group for the amino group [M. Buttonski, “Principle of Peptide Synthesis”, Springer-Fenollerlag, Berlin, (1984) 90
-page 102 (M. Bodansky, “Princ
iplesof Peptide Synthesis
“, Springer-Verlag, Berfi
n, (1984) pp. 90-102) Reference 1,
R is as described above. Typical examples of Z include allyloxycarbonyl [Ai Ninomii et al., Tetrahedron Letters (+.
al. , Tet.

Let), ■, 2449 (1987); J. Dangles et at., J. Or.
g. Chem), 52, 4984-93 (1987)
], formyl [U.S. Pat. Nos. 4,684.745, 3,879,372 and 3.933.781),
t-Butoxycarbonyl [Da Chee Witschak et al.
Journal of Medicinal Chemistry (D.
T. Witiak et al. , J. Mad
．． Chem), 14, 24-30 (1971)] and carbobenzyloxy [U.S. Pat. No. 4.508.912
No.: EP by T. Yukawa etc.
227,301, July 1, 1987 1 is included.

The latter are particularly useful in that they can be easily removed by catalytic hydrogenation.

In Reaction Scheme B, a compound of formula (I-3, L form) is reacted with N-protected L-aspartic anhydride in an aprotic solvent to form the desired σ-(N-protected-L -aspartyl)-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine alkyl ester (I[I
g) is obtained. In addition, a small amount (lO-20%) of β-(N-
Protected-L-aspartyl)-3-(2R-exo-7,
7-dimethylnorbornyl)-L-alanine alkyl ester (mβ) is also produced. The amount of by-product (■β) formed in the reaction is z! Carbobenzyloxy (-C
BZ) can be controlled by changing the reaction conditions as shown in Table 5.

Phenylalanine methyl ester and (II) (Z-CB
Similar solvent effects on the coupling of Z) were reported by Yang and Su [Journal of Organic Chemistry (J, Org, C
hem), 1 Sat., 5186-91 (1986)] and Yukawa et al.
, P. 227.301; July 1, 1987).

The undesired product (■β) can be removed by partitioning between a suitable organic solvent and an aqueous buffer of appropriate pH (III
) can be separated from Previous reports of this type of isolation [W.
Young, Journal on the Chemical Industry 4- (W, J, LeQuesne and G, T,
Young, J., Chen+, 5oc), 24-
28 (1954) and D. D. John and G. Chi. Young, Journal on the Chemical Society (W, D, John and G.
T, Young, J, Chem, 5oc), 2
870 (1954)], α/β−N−force α/β
-N-carbobenzyloxyaspartylglycinel,
a/β-N-carbobenzyloxyaspartyltyrosine methyl ester, σ/β-N-carbobenzyloxyaspartylglutamate diethyl ester, and α
/β-N-carpobenzyloxyasbartylvaline has been isolated by extraction of an ethyl acetate solution with aqueous sodium carbonate (concentration and pH not specified).

In another example, σ- and β-NCBZ-aspartylphenylalanine-7 have been separated by extracting the β-isomer from ethyl acetate using a pH buffer of 7 [JJ-Dahlmans et al. J. J. Dahlmans
et al. U.S. Pat. No. 3,808.190 (19
Apr. 30, 1974), the purity of the separated isomers is not indicated.

We have found that in the case of (II[σ) and (■β) (Z-CBZ), the pH of the aqueous phase must be carefully controlled (see Table 6). Furthermore, the choice of organic phase is also important. Good separation is achieved with ether and toluene. Only moderate partitioning is achieved with ethyl acetate, and no total heat separation is achieved with hexane or butanol.

On a manufacturing scale, the crude coupling mixture (■σ/β−
a/β-5/1, Z-CBZ) in 1% toluene solution at p
H5.5, O. Yields of 50-70% and 93-98% were obtained by extracting with 1M phosphate buffer three times.
(I[Ig) was obtained with a purity of The rest (■β) is (IV
) is removed during crystallization.

Removal of the CBZ group from (naa) using palladium on activated carbon as a catalyst in methanolic solution 2-3
kg/cm". The catalyst is removed by filtration through celite and the filtrate is evaporated to give the crude (IV). The sweetener (IV) is chloroform-
Purified by crystallization from hexane.

Furthermore, we obtained the initial (■σ - ■β) mixture (9/1, mσ/■
It has also been found that pure (TV) can be obtained from β).

This method consists of (III tt
)/(I[rβ) ratio is high (II[a/IIIβ〉8/
l) It is most effective in cases.

A similar separation of σ-N-aspartylphenylalanine methyl ester from the β-isomer by crystallization from water or water-alcohol mixtures was described by Y. Ariyoshi et al.
Ariyoshi et al) (U.S. Patent Nos. 3 and 7)
No. 86.039, January 15, 1974).

Another coupling method that avoids the formation of mixed products of 0- and β-dipeptides is to combine (1-3, R-CHz) with an aspartic acid derivative (V) in which two groups are protected, where X -benzyl or di-butyl, and Y is carbobenzyloxy or t-butoxycarbonyl (t-BO
C). (M. Podansky, “Principle of Peptide Synthetic Leather”, Springer Verlag, Berlin, 1984, p. 70-79.9O-102
). The coupling reaction is performed by treating the free carboxyl of the aspartic acid moiety with a leaving group activated by treating it with p-nitrophenol/DCC, N-hydroxysuccinimide/DCC, inbutylchloroformate/N-methylmorpholine, etc. This can be done by first converting and then adding (I-3, R-CH3). Alternatively, in an organic solvent from -20°C to 30°C.
This can be done using DCC at a temperature of . [M.
Bo Dansky, Quote (loc.

cit), pp. 9-58; U.S. Patent No. 4.788,069
No. and J.W. Tsang et al., Journal of Medicinal Chemistry (J, LTsang et al.
et al, J, Med, Chem), 1U, 16
63-1668 (1984)]. The resulting intermediate was then subjected to standard hydrogenation conditions for -C', Y-CBZ and X-benzyl (P d/C, MeOH, Hx pressure 10
-50 psig) by deprotonation by catalytic hydrogenation to (IV). Y-t-B
In the case of OC and is obtained after neutralization of the resulting salt.

The invention will be explained in more detail by the following examples.

Example 1 Conversion of trans-2-pinanol to alpha-7 ethyl alcohol.

Manufacture of Catalysts Catalysts A, B and C used in the following experiments were manufactured as follows.

Catalyst A Commercially available reagent, aluminum nitrate nonahydrate [AI(N
O3) 3・9H20: Junsei Kagaku Co., Ltd. product 1150g
was dissolved in 800 mQ of water. To this solution was added 27 ml of 85% phosphoric acid (product of Nacalai Tesque), and while stirring the mixture at room temperature, 24 ml of 10% aqueous ammonia was added.
The pH was adjusted to 7 by slow dropwise addition of 0 m Powder it in a mortar to obtain a powder with dimensions smaller than 50 mesh.

Catalyst B Hydrous niobium hydroxide [Nb2O5, XH! 01Companhia Brasileira de Metalungia e Mineraheo
Metalungias Hineraq Ao) was pulverized to less than 40 mesh.

Catalyst C Nickel sulfate hexahydrate (NiS O4-6HtOs, a product of Nacalai Tesque) was calcined at 250-350°C for 3 hours to reduce its size to less than 40 meshes.

Experiment I Catalyst A was calcined at 300° C. for 3 hours and used in this example.

Trans-2-pinanol (a product of Glidco Organics) in a four-loaf flask equipped with a stirrer, thermometer, and reflux condenser.
35 g (0,227 mol) and 2.0 g of catalyst were charged and it was reacted at 75° C. for 16 hours with stirring.

The reaction product was crudely distilled to obtain 29.1 g of an oily product.

Gas chromatography analysis shows that the conversion rate is 98.2% and the selectivity for α-7 ethyl alcohol is 48.1%.
It was shown that

The reaction product is rectified to obtain α-phentyl alcohol15.
3 g (42.9% of theoretical yield, 98.3% purity) were obtained.

Experiment 2 Trans-2-pinanol (product of Glidco Organics) in a four-loaf flask equipped with a stirrer, thermometer, and reflux condenser.
35 g (0,227 mol) and catalyst B2. Og was charged and reacted at 75°C for 63 hours. The reaction products were treated as described in Example 1 and analyzed by gas chromatography. The conversion rate was 99.3%, and the selectivity for α-7 ethyl alcohol was 52.3%.

Experiment 3 Trans-2-pinanol [a product of Glidco Organics] in a four-necked 7-flask equipped with a stirrer, thermometer, and reflux condenser.
35 g (0,227 mol) and 2.0 g of catalyst were charged and reacted at 75° C. for 200 hours. The conversion rate is 51.
0%, and the selectivity for α-7 ethyl alcohol is 40
．． It was 6%.

Experiment 4-16 Same as Experiment 1-3, α-phentyl alcohol was produced from trans-2-pinanol using catalyst A, B or C prepared as described above at the calcination temperature and reaction temperature listed in Table 1. was manufactured. The results are shown in Table 1. In these examples, PEG-HT capillaries, 0.25 diameter
mm x length 25cm.

Shimadzu GC-9A (manufactured by Gascro Industries Co., Ltd.)
Gas chromatography was performed using a chromatography system (manufactured by Shimadzu Corporation). Column temperature was 100'c.

Table 1 Example 2 Purification of (+)-a-7 Enthyl Alcohol Commercially available α-7 Enthyl Alcohol ([α]X-+10.
0@(c=5, ethanol), melting point 43.2°C170
9.2 g) was dissolved in 355 g of n-hebutane and the solution was cooled to about -33°C. The precipitated crystals were separated by filtration, and the first collection of crystals was 793°6 g ([σ] sealed - +
11.6", melting point 45.2°) was obtained.

The residue (228.9 g) remaining after evaporating the filtrate was
-Dissolved in 160 g of hebutane and cooled the solution to -50°C. Filter the precipitate to obtain a second collection of crystals 128.6
g ([α]+IO, 2°, melting point 43°2°) was obtained. These crystals were of the same quality as the starting material. This was dissolved again in 64 g of n-hebutane, and this solution was
Cooled to ℃. The precipitated crystals were separated by filtration to give crystals ([α]il?-+ll.

5°, melting point 45.1°C) was obtained. These crystals were combined with the first crystals (total of 587.6 g) and dissolved in 411 g of n-hebutane. This solution is about -3
Cooled to 5°C. The precipitated crystals are separated by filtration to obtain second crystals ([α] = +11.9@, melting point 45.7°C)
416.1g was obtained. This second crystal collection (416
, 2 g) was dissolved in 310 g of n-hebutane, and the solution was cooled to -31'C. The precipitated crystals were separated by filtration to form a third crystal ([σ]16-+12.2°, melting point 46
．． 4° C.) 278.9 g was obtained.

The mother liquor of the second crystal and the mother liquor of the third crystal were combined, and the solvent was recovered to obtain 298.7 g of crystal ([σ] +9.84@). The obtained crystal was subjected to three cycles of crystallization in the same manner as described above to obtain a fourth crystal ([σ]
. 84.2 g of melting point 46.1'0) was obtained. The third and fourth crystals were combined to give 363.2 g of the desired (+)-a-phentyl alcohol with a yield of 51.2%.

The optical purity of the obtained crystals was measured by the following method.

The results are shown in the table below.

Table 2 Starting materials +10.0” 81 1st
Crystal +11.6' 89.9 2nd
Crystal +11.6” 92.1vg
3rd crystal +12.2' 94.8 4th crystal +12.1@94.6 Measurement of optical fiber density N-carbobenzyloxy-L-alanine (0°31g
, 1.4 mmol), N,N dimethylaminopyridine (
0.01 g (0.1 mmol) of DMAP) and 0-2 g (1.28 mmol) of fenthyl alcohol were dissolved in 2 mQ of methylene chloride. l under cooling in a stream of nitrogen.
-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) 0.27 g (1.4 mmol) was added to this solution and reacted for about 30 minutes. The temperature was returned to room temperature and the reaction was carried out for about 1 hour. Methylene chloride was added to the reaction solution to bring the total volume of the reaction mixture to 1Or12.

This was combined with a 10% aqueous solution of citric acid, 4 ml of sodium carbonate.
% aqueous solution and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.

The solvent was evaporated below 40°C. Dilute the residue with methanol 5
r12 and reduced with hydrogen under atmospheric pressure in the presence of 20 mg of palladium black. The solution was analyzed by gas chromatography under the following conditions.

Column: PFG-HT, diameter 0.25IIIfl + length 25m Introducing temperature: 200℃, Column temperature: Approximately 100-200"O range, 3℃/min, Retention time: Approximately 11-12 minutes range, Separation Coefficient: 1.02 Example 3 Production of α-fenchen from 7-ethyl alcohol 1, Production of aluminum oxide catalyst (a) Catalyst A Aluminum nitrate nonahydrate [AI(NOx)s
9H,0: Junsei Kagaku Co., Ltd. - grade] 200g water 2Q
t: Dissolved. Add this solution to 500 g of 28% ammonia water.
It was slowly added dropwise to the inside while stirring.

The purified aluminum hydroxide was aged overnight, filtered, washed with water, and dried at 60"O for 24 hours to obtain 43 g of aluminum hydroxide. This was powdered in a mortar and heated in an electric furnace for 50 g.
After firing at 00℃ for 3 hours, white powdered aluminum oxide 2
8.4g was obtained. The Hammett acidity function H of this product is 5.6<H.

≦-3,0.

(b) Catalyst B Aluminum sulfate 14-18 hydrate [Al2(SO4
)3-14-18 Hto: Manufactured by Junsei Kagaku Co., Ltd.-
1200 g of grade was dissolved in water 2I2. Aqueous ammonia (10% by weight) was added dropwise to this solution until the pH of the solution became 8. The resulting aluminum hydroxide was thoroughly washed with a large amount of water and dried at about 60° C. for 24 hours. The dried product was powdered in a mortar and calcined in an electric furnace at 500° C. for 3 hours to obtain 70 g of aluminum oxide as a white powder. The Hammett acidity function H of this product is −5,6<Ho≦−
It was 3.0.

(c) Catalyst C Aluminum chloride hexahydrate (AlCl2.6H,O: - grade manufactured by Junsei Kagaku Co., Ltd.) 2001 was dissolved in water 212. The mixture was then treated in the same manner as in the production of catalyst B to obtain 60 g of aluminum oxide. The Hammett acidity function of this product was -5,6<HO≦-3,0.

(d) Catalyst D 200 g of sodium aluminate (NaAIO=, xH, O: - grade manufactured by Hanui Tesque Co., Ltd.) was dissolved in 2Q of water.

While stirring, this solution was added to hydrochloric acid (250 g/3Q) to adjust the pH of this solution to approximately 8. The precipitate was filtered off and
Dry at ℃ for 12 hours and add 500m+2 of 14% ammonia water.
Washed 5 times with The washed product was dried at 60°C for 24 hours, turned into powder in a mortar, and calcined in an electric furnace at 500°C for 3 hours to obtain 5 g of aluminum oxide as a white powder.
I got it. The Hammett acidity function of this product is −5,6<
Ho≦−3.0.

2. Preparation of (+)-r-fenchen (a) In a three-necked flask equipped with a Dean-Staaf apparatus, a stirrer, a temperature system, and a reflux condenser, 100 g of α-7 ethyl alcohol (0.65 mol, purity 98 .7
%) and 5 g (5% by weight) of catalyst A were charged and the mixture was heated with stirring at a temperature of about 195-200° C. for 10 hours. The reaction mixture was then crudely distilled to give an oily product 95
．． 8g was obtained. Analysis by gas chromatography is
This oily product was shown to consist of 72% of the 7-ene'A compound (59% α-fenchene) and 28% of unreacted fenthyl alcohol. The oily product was rectified to obtain 34.4 g (+)-α-fenchen (yield 54°1
%, purity 98.7%; experiment number l) was obtained.

Boiling point: 157-158°O (730mmHg) ([a]
萱-+36.27@ni-to)'HN MR (CD
Cls): 0.97 and 0.98 (3H,s each), 1.20-1.
34 (2H, m), 1.65 (lH, t), 1.79-
1.96 (3H, +++), 2.03 (IH, d), 2
．． 41 (IH, d), 4.60 and 4.81 (each IH,
s) Mass spectrum (m/e): 136 (M+), 121, 107.93.79.53.
41.39°(b), Catalyst (A) (5%) was mixed with (+)-α-7 ethyl alcohol and (+)-β-7 ethyl alcohol (,/
β-674) was added to the mixture. This mixture was added to the above (a
) to give an oily product. Analysis by gas chromatography revealed that this product was a 7-fenchen isomer [65% (+)-σ-fenchen] 9
5% (Experiment No. 2).

(c) Catalyst A (5% by weight) was added to (+)-β-7 ethyl alcohol (95% purity). The mixture was heated with about agitation at a temperature of about 195-200° C. for 3 hours and then crudely distilled. Gas chromatographic analysis of the distillate revealed that the product was a 7-ethylene isomer [(+
)-a-Feng Chen contained 80% and 198% (Experiment No. 3).

(d) Catalyst B, C or D was used to produce (+)-α-phentylalcoholne. The results are shown in Table 3 below (experiment number 4-6)
.

(e) Instead of catalyst A used in (a) above, Hammett's acidity function was +1.5<Ho≦+3.3 and +3.3(H
o≦+4.8 (Test Nos. 7 and 8), a commercially available aluminum oxide catalyst and a catalyst obtained by calcining nickel sulfate hexahydrate at about 400°C for about 3 hours (Test No. 1)
0), aluminum sulfate (test number 11), a catalyst obtained by calcining aluminum phosphate at about 500°C for about 3 hours (test number 12), aluminum silicate (test number 13), alum (test number 14) ) or acidic clay (Test No. 15), the method (a) above was repeated. The results are shown in Table 3.

Fenchen analysis was performed using Shimadzu GC-9A (manufactured by Shimadzu Corporation) gas chromatography with 0 as a column.
Using VIOI silica capillary (diameter 0.25 mw +, length 25 m III) (manufactured by Gascro Industries Co., Ltd.),
The measurement temperature was about 70°C.

Example 4 Preparation of 7.7-dimethyl-2-formylmethylene norbornane
50 g of (+)-α-fenchen obtained as described in Example 1 above to a solution prepared by adding 92.5 m<2 (1.19 mol) over a period of about 1 hour.
(0,368 mol) was added dropwise under nitrogen at 50-60°C over about 1 hour. This mixture was allowed to react for 2 hours.

This reaction solution was mixed with an 800 lO% aqueous solution of sodium carbonate.
mg and extracted twice with 300+yl toluene. The toluene extracts were combined, washed with water and the solvent was evaporated. Fractional distillation under reduced pressure yielded 50.5 g of the title compound (
Yield 71%) was obtained.

Boiling point = 76-80 °C/l + smHg' H-NMR (CD Cl s solvent, TMS internal standard, δ): E 0.98 and 1.08 (each 3 H*s, CH3),
5.94 (18,d, J=7.9Hz, olefinic H
) and 9.79 (lu, d, J=7.9Hz, CHO)
.

Z integral 0.97 and 1.08 (each 3 H*s*CHs
), 5.86 (IH, d, J = 8.4 Hz, olefinic H), 9.84 (IH, d, J = 8.3 Hz.

CHO).

Mass spectrum (m/e): E 150.125.109.107.82.81 (standard)
, 79.67 and 41°2 integral 165 (M"+1), 164 (M"), 149.121
(Standard), 93.91, 79.77.41 and 39° Example 5 Preparation of 2R-exo-7,7-dimethylnorbornylacetaldehyde (a) In an autoclave of l a, the method described in Example 3 above was added. 20 g (0.12 mol) of 7,7-dimethyl-2-formylmethylene-norbornane, n-
Hebutane 200mM and 5% palladium-carbon 0.5g
The reaction was carried out at room temperature under a hydrogen pressure of 2 kg/cm''. After the reaction, the catalyst was filtered and the solvent was evaporated. The residue was distilled under reduced pressure to obtain 19.7 g of the title compound (yield 9).
7.3%).

The exo/endo ratio of this compound was found to be 98:2 by 'H-NMR measurement.

Boiling point: 54-55℃ 10.2m+wHg'H-NMR (
CDCI, solvent, TMS internal standard, δ) Exo unitary 0.97 and 1.08 (3H, s, CH3 each), 2.6
0(2H, a, d, a.

J=2. L 9.6.5.9Hz; CH, CHO)) and 9-71 (IH, t.

J=7.9Hz; CHO).

Sanotsu Enji 1.02 and 1.08 (each 3 H + s + CHs
), 9.76 (IH, t, J-7, 9Hz, CHO).

Mass spectrum (m/e): 166 (M+), 151,133.123.122 (reference), 107.95.8179.69.67.55.4
1 (b) In a 200 mQ autoclave, 5.0 (+)-α-fenchen obtained as described in Example 3 was added.
g (0,037 mol), rhodium (I) chloride-1
, 5-cyclooctadiene dimer 45.3 mg (0,
18 mol), triphenylphosphine 95 mg (0,3
6 mmol), triethylamine 0.5 mg and benzene 25 m (2), synthetic leather gas pressure of 80 kg/cm'' (-carbon oxide pressure 40 kg/cm'', hydrogen pressure 40 kg/c)
The reaction was carried out at 90°C for 16 hours at 90°C (I).The solvent was evaporated and the residue was fractionated under reduced pressure to give 5.7 g of an exo/endo mixture of 7.7-dimethylnorbornyl-2-acetaldehyde. (yield 93.4%).The (2R)-exo/(2S)-endo ratio of this product was determined by 'H-NMR.
It was determined that the time was 85:15.

(c) By carrying out the okyne reaction as described in (b) above under the conditions shown in Table 4, 7,7 with the (2R)-niquine/(2S)-endo ratio shown in Table 4 -dimethylnorbornyl-2-acetaldehyde was obtained.

Table 4 Present C0D-1,5-cyclooctadiene Example 6 Production of 3-(2R-exo-7,7,-dimethylnorbornyl)2-D,L-aminopropionitrile Add ammonia gas to 400 mff of methanol 15 at 5℃
It went through for a minute. Add 17. sodium cyanide to the resulting solution.
5g (0,357 mol), ammonium chloride 17.8g
(0,333 mol) and (2R-exo-7,7,-dimethylnorbornyl)acetaldehyde 52.0 g (0
, 313 mol) was added. The reaction mixture was left at room temperature overnight and the methanol was evaporated under reduced pressure. To this residue was added 750 mQ of a 2% aqueous solution of sodium carbonate and the mixture was extracted twice with 350 mff of ether. The extracted ether layer was washed with water, then IN hydrochloric acid 300m
Extracted twice with 12. The extracted hydrochloric acid layer was neutralized with sodium carbonate, and further extracted three times with 300 mQ of ether.

The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give 3-(2R-Equin-7.7.-
Dimethylnorbornyl)-2-D,L-aminopropionitrile was obtained with a yield of 95.5%.

'H-NMRCCDC 1M solvent, TMS internal standard, δ)
= 1.07 and 1.11 (3H% 8% CH3 each) and 4.38-4.49, CN (as lH,In, CHX aminopropionitrile hydrochloride) -exo-7,7-dimethylnorbornyl)
Production of -D,L-alanine/hydrochlorideTo 200 mQ of water and 900 mQ of concentrated hydrochloric acid, 52.0 g of 3-(2R-equin-7.7.-dimethylnorbornyl)-2-D,L-aminopropionitrile ( 0°271 mol) was added and the mixture was heated under reflux for 18 hours. The reaction solution was concentrated under reduced pressure and then cooled. Amino acid hydrochloride was precipitated. This was left at 5°C overnight, washed with 600mQ of ether, and 63.2g of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride was dissolved at 94°1%.
was obtained in a yield of .

'HN M R (CD C1s solvent, TMS internal standard, δ): 1.02 and 1.11 (3H, S, CH3 each)
Amino acids were prepared by neutralization of the hydrochloride salts and precipitation at pH 4.0. Melting point: 216-218°C, IR: 340
0,2930.1610,1495.1395.133
0 and l l 00 cm-' Example 8 Optical resolution of 3-(2R-exo-7,7,-dimethylnorbornyl)-D,L-alanine methyl ester by tartaric acid method 3-(2R- exo-7,
7,-dimethylnorbornyl)-D,L-alanine methyl ester (3-(2R-
exo-7,7,-dimethylnorbornyl)-〇,L-
A solution of 25.7 g of D-(-)-tartaric acid in 500 ml of methanol was added to a solution of 36.5 g (prepared from alanine). Dilute this solution with methanol to 180%
0mff, and then heated to reflux to dissolve the precipitate that had formed. Crystallization was achieved by standing this thick solution overnight at about 21'O. Filtered, washed with 50 mQ of methanol and dried in vacuo to obtain 24.1 g.

The above obtained material was recrystallized from 850ml of methanol to obtain 13.1g. Add this to 450ml of methanol
2 to give 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester.
8.8 g of 〇-tartrate was obtained. Melting point: 160'O (decomposed), [σ]W −+ 36.4” (c −0,5, Me
OH).

Example 9 Synthetic leather 3-(2R-
exo-7,7,-dimethylnorbornyl)-D,L-
Alanine hydrochloride (60 g, 0.242 mol) in NaOH
was dissolved in 300 ml of a 10% aqueous solution of and then 32 g (0,314 mol) of acetic anhydride were added dropwise at 35-40°C. After the addition, the mixture was allowed to react for 30 minutes. The reaction solution was cooled to 5-10°C and adjusted to pH 3 with 6N hydrochloric acid.

The precipitated crude crystals were filtered, washed with water and dried. The crude crystals were recrystallized from ethyl acetate and n-hexane to obtain 60 g (yield 97.6%) of the title compound.

Melting point: 170-171'0 [σIW-+36.6°(C-1, methanol)'H-
NMR (CD, OD solvent, TMS internal standard, δ): 0.
98 and 1.09 (3 H% Ss CH3 each), 1.
98(3H,s,NHCOCHs) and 4.31 Example 1O Optical resolution of N-acetyl-3-(2R-equin-7.7.-dimethylnorbornyl))-D,L-alanine 450 mQ of water; 28.8 g of disodium hydrogen phosphate.

Cobalt chloride hexahydrate and N-acetyl-3-(2R-
exo-7,7,-dimethylnorbornyl)-D,L-
A 4N aqueous solution of NaOH was added to a slurry made from 60 g (0,236 mol) of alanine, and the pH was adjusted to MA to 8.
．． It was set to 0. Phosphate buffer (pH 8,0) 12m+2
Acylase inside (Amano Pharmaceutical Co., Ltd. III) 1.12g
solution was added and the mixture was stirred at 37-39°C for 20 hours. The reaction solution was adjusted to pH 1.4 with concentrated hydrochloric acid and washed three times with 200 ml of ethyl acetate. The aqueous layer was adjusted to pH 3.0 with aqueous ammonia. The precipitated crude crystals were separated by filtration. The resulting crude crystals (18.3 g) were dissolved in 800 rrl of hot water and treated with 1.8 g of activated carbon to obtain 17.7 g of 3-(2R-exo-7,7,-dimethylnorbornyl)-L-alanine ( A yield of 71.1%) was obtained.

Melting point: 224-226℃ [αlt? -1,49.5@(c-1, methanol)'H
-NMR (CD, OD solvent, TMS internal standard, δ): 0.99 and 1.11 (3H, s, CHs each) and 3.44 3-47 (IH, m% CHCow)NH
.

Separately, concentrate the ethyl acetate washing solution to obtain crude crystals (34°8 g).
I got it. The crude crystals were recrystallized from ethyl acetate and n-hexane, and N-acetyl-3-(2R-exo-7,
7,-dimethylnorbornyl)-〇-alanine 26.6
g (yield: 88.7%).

Example 11 N-acetyl-3-(2R-exo-7,7.-dimethylnorbornylation) N-acetyl-3-(2R-exo-7,7.-dimethylnorbornylation obtained in Example 1O) )-D-Arania 10 g (0.039 mol) was dissolved in 50 mff of acetic acid and 1.0 g of acetic anhydride and reacted at 100°C for 16 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting crude crystals were dissolved in 35 ml of ethyl acetate and washed with water. The ethyl acetate layer was crystallized by the addition of n-hexane to give N with a specific optical rotation of +35.5" (c=1, methanol). -acetyl-3 -(2 R-exo-7
, 7,-dimethylnorbornyl)-D,L-alanine 6
-8gtt gain f:.

Example 12 N-chloroacetyl-3-(2R-exo-7.

Synthetic skin of 7,-dimethylnorbornyl)-D,L-alanine 3-(2R-exo-7,7,-dimethylnorbornyl)-D,L-alanine Log (47.4 mmol)
was suspended in 120 mQ of ethyl acetate, and 35.36 g (47.4 mmol) of chloroacetyl chloride was added.

The mixture was heated under reflux for 1 hour.

After cooling, unreacted amino acids were separated by filtration and ethyl acetate was evaporated. The obtained crude crystals were recrystallized from ether and n-hexane to obtain 10.1 g (yield 63%) of the title compound.

Melting point: 149-150°C [a]t? -+2 2.2° (c-1, methanol)'
H N M R ( C D s O D solvent, T
MS internal standard, δ): 0, 98 and 1.09 (3 HSs, CHs each), 4.

07 (2H1d, J = IO-7Hz%NHCOC
HzCI), 4.3 6-4-4 4(l H.rn,
CHCO*H Example 13 N-chloroacetyl-3-(2R-equin-7.

7, -Dimethylnorbornyl)-D,L-alanine Optical resolution 300 m of water, 24.1 g of disodium hydrogen phosphate, 25.5 mg of cobalt chloride hexahydrate, and N-chloroacetyl-3 -(2 R-exo -7,7,-dimethylnorbornyl)-D,L-alanine 50. Og(0.173
The pH was adjusted to 8.0 by adding a 4N aqueous solution of NaOH. A solution of 0.85 g of acylase (manufactured by Amano Pharmaceutical Co., Ltd.) in 5 mQ of 0.5 M phosphate buffer (pH 8-0) was added, and the mixture was stirred at 37-39°C for 16 hours. . The reaction solution was adjusted to pH 1.7 with concentrated hydrochloric acid and washed twice with 350 m2 of ethyl acetate. The aqueous layer was adjusted to pH approximately 3.0 with aqueous ammonia. The precipitated crude crystals were separated by filtration. The obtained crude crystals (io.3 g) were soaked in hot water 8
00ml and treated with 1.4g of activated carbon to obtain 3-
(2 R-exo-7,7.

-dimethylnorbornyl)-L-alanine 10.3g (
A yield of 56.3% was obtained.

Separately, the ethyl acetate washings were concentrated and the residue was recrystallized from N-chloroacetate and n-hexane.
3-(2R-exo-7,7,-dimethylnorbornyl)-D-alanine 20.4 g (Yield IC8186
%) was obtained.

Melting point: 150-153°C [ff1i = +14.1' (C-1% methanol) Example 14 Production of 3-(2R-equin-7,7.-dimethylnorbornyl)-L-alanine methyl ester Methanol lI
Hydrogen chloride gas (12.5 g) was blown into 2, and 3-(
2R-exo-7,7,-dimethylnorbornyl)-L
-Alanine hydrochloride! 52.0 g (0,210 mol) was added. The mixture was heated under reflux for 18 hours. After cooling,
The solvent was evaporated under reduced pressure. The residue was dissolved in 750 ml of water and the pH of this solution was adjusted to approximately 8.5 with a 50% aqueous solution of NaOH under cooling. The reaction mixture was extracted twice with 250 m(+) ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated and the 3-(2R-exo-
47.2 g (yield 99.9%) of 7,7,-dimethylnorbornyl)-L-alanine methyl ester were obtained as a pale yellow oil.

The product (45-Og, 0.2 mol) was dissolved in 80 ml of ethyl acetate.
(2) and 13.2 g (0.22 mol) of acetic acid were added under cooling and stirring. 48.8g was obtained.

Example 15 Preparation of 3-(2R-exo-7,7,-dimethylnorbornyl)-D,L-alanine methyl ester To a solution of 12.5 g of hydrogen chloride gas in methanol la, 3-(2R
-exo-7,7,-dimethylnorbornyl)-D,L
- 52.0 g of alanine hydrochloride was added. Add this solution to 18
Heated at reflux for an hour and then isolated the product as described in Example 14 to give the title compound (44.9 g) as a pale yellow oil.

[α] (as hydrochloride) = +29.5' (c-1,
2, methanol) Example 16 Production of L-aspartyl-3-(2R-exo-7,7°-dimethylnorbornyl)-L-alanine methyl ester N-carbobenzyloxy-L-aspartic acid anhydride 24. 9 g (0.1 mol) was suspended in 500 mQ of toluene, and this suspension was cooled to 5°C.

While stirring, a suspension of 28.5 g (0.1 mol) of 3-(2R-exo-7,7,-'; methylnorbornyl)-L-alanine methyl ester acetate in 50 ml of toluene is added. Ta. The mixture was then left at 5°C overnight. This solution was applied to a countercurrent distribution chromatography device to obtain N-(carbobenzyloxy-L-aspartyl)-3-(2R-exo-7,7,-'; methylnorbornyl)-L-7 ranine methyl ester. 33.5g (
70.6%).

10 autoclaves, methanol 400mQ
N-(carbobenzyloxy-L-aspartyl')
-3-(2R-exo-7,7,-dimethylnorbornyl)-L-alanine methyl ester 25.8 g (54,
4 mmol) was dissolved and catalytically reduced in the presence of 1.0 g of 5% palladium on carbon under a hydrogen pressure of 3 kg/am''.

After the hydrogen pressure was no longer observed to decrease, the catalyst was removed by filtration through Celite. The filtrate was concentrated under reduced pressure to obtain crude crystals.

Recrystallization from chloroform/n-hexane yielded the desired L-aspartyl-3-(2R-exo-7,7,-
14.4 g (yield 77.8%) of L-alanine methyl ester (dimethylnorbornyl) was obtained.

Melting point: 148-148.2°C [g] U-+30.5' (c-1, methanol)'H
-NMR (CD, OD solvent, TMS internal standard, δ): 0.98 and 1.10 (each 3H%s, CH,), 2.5
3 (IHldd, J-9,7 and 16.0Hz.

CH, GO, H), 2.78 (l H, dd, J −
4,7 and 17.1 HzlCHzc OzH), 4.
09(l H,q.

J-4,64Hz, -CHCH,C02H), 4.41
(l H-q-J-5,4Hzs CdanCo, Me)H
CO Example 17 (N-CBZ-L-7 Spartyl-β-O-benzyl)
-Production of 3-(2R-exo-7,7,-dimethylnorbornyl)-L-alanine methyl ester 3-(2R-exo-7,7,-dimethylnorbornyl)-L-alanine methyl ester- D-Tartrate 43g
was suspended in excess 5% Na, Co3 solution and incubated at 23°C for 3
After stirring vigorously for 0 min, the free amino ester was obtained. The mixture was extracted with 2X500r+IEtOAc and the combined EtOAc layers were dried over Mg5o, (anhydrous). The EtOAc solution was filtered and the filtrate was concentrated under reduced pressure and dried in vacuo to yield 22.5 g of the amino ester as a clear oil. [α law +61.8” (c −2,2
, dioxane).

22.5 g of the above amino ester were dissolved in 800 ml of dioxane under N2. Subsequently, 35 g of N-CBZ-L-7 sppartic acid-β-benzyl ester, 24.8 g of 1,3-dicyclohexylcarbodiimide, and 12.4 g of N-hydroxy-5-norbornene-2,3-dicarboximide were added. Ta.

The mixture was then stirred overnight, during which time a solid precipitated.

Solid 1,3-dicyclohexylurea was removed by filtration, and the filtrate was concentrated under reduced pressure. Dilute the residue with ether 100
〇-Incorporate into 5% citric acid 2X100Orrl,
Wash with 7% NaHCOs2 x 1000 mQ and 200 mf1 of saturated NaCl solution. The ethereal solution was then dried over M g SO 4 (anhydrous), filtered, and the filtrate was concentrated under reduced pressure.

The residue was chromatographed on silica gel using increasing amounts of EtOAc and hexane as eluent. The progress of the column was monitored by TLC (silica gel-40%
EtOAc/hexanes) and the appropriate fractions were collected to give the title compound, 49.7 g, after concentration.

Melting point: 62-64°C [alf? -+9.5°(c-1, methanol)' H
NMR (CDCls solvent, TMS
Internal standard, δ): 0, 95 and 1, 0 5 (each 3 H 1S% C
H s), 3, 7 0 (3H, s, OCRl), 5
, 1 5 (4 H, s.

-CH, -Ar), 7, 3 5(l O H, s,
Ar) Example 18 L-aspartyl-3-(2 R-exo-7,7-
Preparation of N-(β-benzyl-NC) in 200 ml of methanol
BZ-L-aspartyl)-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester (8.6 g), 10% palladium/carbon 0.4
g was added. This mixture was heated to 3 kg/cm”Hz
and hydrogenated at room temperature for 18 hours. The catalyst was then removed by filtration through a short pad of Celite and the filtrate was evaporated to give 5.2 g of the title compound as a clear glass. This was crystallized from chloroform/hexane to give a material comparable to that of Example 15 as determined by HPLC, IR and CNMH comparison.

Melting point: 144-146℃ [αlt? =+2 9.2” (cm 1, methanol)'H-NMR (CD.OD solvent, TMS internal standard)
, δ): 1, 0 and 1.1 (each 3Hs Ss C H 3),
2,7 s(t H% Ill, CH*COzH
)3,7 5(3H% sl-QC)(,)Example 19 σ-L-aspartyl-3-(2R-exo-7,7-
Purification of a/β-L-aspartyl-3-(2R-exo-dimethylnorbornyl)-L-alanine methyl ester
60.4 g sample of 7,7-dimethylnorbornyl)-L-alanine methyl ester (σ/β-90/l O)
was dissolved by heating in 900 mff of a l:2 methanol:water mixture. The solution was cooled to yield 51.2 g of a white solid (α/β-94).

615, 4). The same solvent mixture as shown in Table 7 (1
5:l volume/weight) and then repeat the recrystallization from ■(α
/β-99.210.8) was obtained.

Example 20 Synthesis of 3-(2R-exo-7,7-dimethylnorbornyl)alaninehydantoin 2g of 2R-exo-7,7-dimethylnorbornylacetaldehyde in 60% E to H H so 35 mrl (NH4
) 3-5 g of 2COs were added and the resulting slurry was warmed to 55°C. Add s H2 to this mixture
650 mg (13-2 mmol) of NaCN in 0.5 mQ is added and the resulting mixture is placed under a reflux condenser for
Heated at 0°C overnight. The condenser was removed and the solution was warmed to 90 °C for 3 h to evaporate excess (NH4)2COs.

Upon cooling to room temperature, HzOIOm4 was added and the solution was extracted with 20 mQ hexane. The aqueous phase was then acidified with 1N HCl to pH 5 (should be done under 7-d) to obtain a white solid precipitate. This was removed by filtration and dried in vacuo to yield 3.1 g of the desired product.

Melting point: 178-183°C IR: 3280.2950.1720, 1420°13
15 and 1190 cm""'H-NMR (pyridine-d6, TMSl δ): 9.
25 9.05 (IH, ml-NH), 2-4-1.3
(11H1m, CHt-CH-), 1.1
0.8 (6H,s, CHs) Example 21 3-(2R-exo-7,7-dimethylnorbornyl)
Hydrolysis of alanine hydantoin 3-(2R-exo-
A mixture of 500 mg (2,12 mmol) 7,7-dimethylnorbornyl)alanine hydantoin 500B, 2.5 g barium hydroxide and Htol OmQ was heated under reflux for 72 hours.

Cool and add Hz020mQ and the mixture INHISO
4 to pH 2.0. Solids were removed by filtration and the filtrate was adjusted to pH 4.0 with 1N NaOH. The solution was concentrated to 1 onl and cooled to 5°C to yield a white solid. After drying in vacuo, the yield is 3-(2R-
Exo-7,7-dimethylnorbornyl)-D,L-alanine was 83 mg (0.39 mmol, 19%). Melting point: 217-219°C; IR: 3430.2950
．． 1610°1505.1400.1320 and l l
00cm-'Mixed layer acetic acidacetoneacetonitrileacetic acidethyl etherdioxanetoluenebutyl acetatecarbontetrachloridetrichloroethylenetetrahydro7ranechloroformdiglymehexanedimethylformamidecyclopentanonequinlene butyl etherTable 5 Red 1 4.5 0.9 1.3 3.6 * 7.7 (3,5) 2.2 pieces 8.6 4.2 pieces 5.0 5.6 1.4 5.1 0.27 pieces 1.5 0.08 1.7 pieces 7.6 pieces 6.8 a! Satomi 6.15 20.7 37.5 6.02 4.34 2.21 2.38 5.01 2.24 3.4 4.81 1.89 37.6 18.0 2.27 3.0 * N-carbobenzyloxyaspartic anhydride was insoluble (suspended) at 5°C.

In 100 parts of solvent, 1 part of N-carbobenzyloxyaspartic anhydride (If) and 3-(2R-exo-7,7
Reaction with 1 part of -'; methylnorbornyl)-L-alanine methyl ester acetate at 5°C for 18 hours. Cma)/
(ml) ratio of 60% γ-cetonitrile 10 as solvent
．． 05% KH! POI) Determined by peak height on HPLC using H4,0 on an Altex 5 μC1l column and UV detection between 210 and 210°C.

East-1 r! ! i 11 pH6,093/7 83/l 7pH6,58
7/13 17/83 pH 7,019/81 9/91 a- and β-N-(carbobenzyloxyaspartyl)-3-(2R -Ekin-7゜7-dimethylnorbornyl)-L-alanine methyl ester Cma/β
) distribution. The ratio indicates the percentage in the toluene phase relative to the percentage in the buffer phase. Values are for toluene lomQ and buffer 1
For 100+g of compound in 0 mff.

Table 7 Amount of substance ■ a/β ratio 1, 1.482 89.9/10.12
, 1.265 94.6/ 5.43,
1.129 97.1/ 2.94,
1.073 98.4/ 1.65, 1
．． 000 99.2/ Recrystallization of a mixture of (IVa) and (■β) from 0.833% methanol-water. The σ/β ratio is 40% acetonitrile/
1% methanol 159% 0.1MKHz PO pH-4
,0 using UNtsttQ Cl 8
HPLC peak height and 220n-
determined by UV detection at (UNISIL QC18:
While specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention, the invention may be modified without departing from such principles. It can be embodied as an embodiment.

The main features and aspects of the invention are as follows.

1. The following formula, where Y is , R is hydrogen or a lower alkyl group of 1-3 carbons, and R' is hydrogen or a lower alkyl group of 1-3 carbons, by Compound represented.

2゜ Y is The compound described in 1 above, which is -CHO thing.

3.Y is N The compound according to item 1 above.

4.Y is The compound according to item 1 above.

5゜ R' is -CH, or -CHIC The above which is 1 4. The compound described in 4.

6゜ Y is The compound according to item 1 above.

7. A 7-enthyl alcohol dehydration catalyst selected from the group consisting of calcined aluminum hydroxide.

8. The dehydration catalyst according to 7 above, comprising calcined aluminum hydroxide having a Hammett acidity of -5.6<Ho≦-3.0.

9, (a) (+)-σ-7 ethyl alcohol is dehydrated and isomerized to form (+)-σ-fenchene, (b) this (+)-α-fenchene is converted into 2R-exo-7 , 7-dimethylnorbornylacetaldehyde, (c) 2R-exo-7,7-dimethylnorbornylacetaldehyde is converted to 3-(2R-exo-7゜7-dimethylnorbornyl, (d) 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine is resolved to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
-exo-7,7-dimethylnorbornyl)-L-alanine is produced, (e) 3-(2R-exo-7,7-dimethyA//
3-(2) by esterifying lupornyl)-L-alanine
R-equin-7.7-'; methylnorbornyl)-L
3-(2R-exo-7, A method for producing 7-dimethylnorbornyl)-L-alanine lower alkyl ester.

1O0 step (C) converts the acetaldehyde to aminonitrile, and hydrolyzes this nitrile to form 3-(2
R-exo-7,7-dimethylnorbornyl)-D,L
- The method according to 9 above, comprising forming alanine.

11. Step (C) converts the acetaldehyde into hydantoin, and hydrolyzes this hydantoin to form 3-(
2R-exo-7,7-dimethylnorbornyl)-D,
10. The method according to 9 above, comprising forming L-alanine.

12, (a) (+)-σ-fenthyl alcohol is dehydrated and isomerized to form (+)-α-fenchene, (b) this (+)-σ-fenchene is converted into 2R-exo-7 , 7-dimethylnorbornylacetaldehyde, (c) 2R-exo-7,7-dimethylnorbornylacetaldehyde is converted to 3-(2R-exo-7゜7-dimethylnorbornyl, (d) Esterifying 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine to produce 3-
(2 R-exo-7,7-dimethylnorbornyl)-
(e) 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine lower alkyl ester is generated to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine lower alkyl ester; 7.7-dimethylnorbornyl)-L-alanine lower alkyl ester, in which R represents a lower alkyl group having 1-3 carbon atoms; A method for producing 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester.

13. Process. (C) converts the acetaldehyde to aminonitrile and hydrolyzes this nitrile to 3-(
2R-exo-7,7-dimethylnorbornyl)-D,
13. The method according to 12 above, which comprises forming L-alanine.

14. Step (c) converts the acetaldehyde to hydantoin, and hydrolyzes the hydantoin to form 3-
(2 R-exo-7,7-dimethylnorbornyl)-
13. The method according to item 12, comprising forming D,L-alanine.

15, (a) Coupling of 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester with N-protected aspartic anhydride to form N-protected (a1β)-L -Aspartyl-3-
(2 R-exo-7,7-dimethylnorbornyl)-
producing L-alanine lower alkyl ester; (b) protecting this N-protected Cas β)-L-aspartyl-3-(2 R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester; By removing the group, (σ,β)-L-aspartyl-3-
(2 R-exo-7,7-dimethylnorbornyl)-
(C) producing a mixture of L-alanine lower alkyl esters, and (C) producing a-L-aspartyl- from this mixture;
3-(2 R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, wherein R has l-3 carbon atoms. A method for producing a σ-L-aspartyl-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, which represents a lower alkyl group.

16. The method according to 15 above, wherein N-protected aspartic acid having a β-ester protecting group is used instead of N-protected aspartic anhydride.

17, (a) 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester is coupled with N-protected aspartic anhydride to form N
-protected (a,β)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, (b) from this mixture N-protected σ-L -Aspartyl-
3-(2R-exo-7,7-dimethylnorbornyl)
-L-alanine lower alkyl ester is separated, (C) this N-protected σ-L-aspartyl-3-(
2R-exo-7,7-dimethylnorbornyl)-L-
By removing the protecting group of alanine lower alkyl ester, α
-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, wherein R is l-3 carbon atoms. A method for producing α-L-aspartyl-(2R-exo7.7-dimethylnorbornyl)-L-alanine lower alkyl ester, which represents a lower alkyl group having .

18. A method for purifying (+)-a-phentyl alcohol comprising crystallizing σ-7 ethyl alcohol in a hydrocarbon solvent at low temperature.

19. The method according to 18 above, wherein the solvent is n-hebutane or n-octane and the temperature is in the range of 135°C to -60°C.

20. A method for producing α-fenchen, comprising heating fenthyl alcohol in the presence of an aluminum oxide catalyst.

21, the catalyst has a Hammett acidity function of −5,6 (H.

21. The method according to claim 20, wherein the calcined aluminum oxide has a temperature of -3,0.

22, N-acyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine or its lower alkyl ester is treated with acylase in an aqueous medium to obtain 3-(2R- the optically active 3-(2R-
A method for producing exo-7,7-dimethylnorbornyl)-L-alanine or a lower alkyl ester thereof.

23. The method according to 22 above, wherein N-acyl is selected from the group consisting of N-acetyl and N-chloroacetyl.

24, 2 above, where the acylase is aminoacylase I
The method described in 2.

60- in the presence of at least one catalyst selected from 25, aluminum phosphate, niobium oxide and nickel sulfate.
A process for producing 1-7 ethyl alcohol comprising reacting trans-2-pinanol at a temperature of 150<0>C.

Procedural amendment written by ω) December 5, 1999

Claims (1)

[Claims] 1. The following formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) In the formula, Y is -CHO, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Numerical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ where R is hydrogen or a lower alkyl group of 1-3 carbons, and R' is hydrogen or a lower alkyl group of 1-3 carbons. A compound represented by . 2. A fenthyl alcohol dehydration catalyst selected from the group consisting of calcined aluminum hydroxide. 3. (a) Dehydration of (+)-α-phentyl alcohol-
isomerize to form (+)-α-fenchen, (b) convert this (+)-α-fenchen into 2R-exo-
(c) 2R-exo-7,7-dimethylnorbornylacetaldehyde is converted to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L (d) 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine is resolved to 3-(2R-exo-7,7-dimethylnorbornyl). )-L-alanine is produced, and (e) 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine is esterified to produce 3-
(2R-exo-7,7-dimethylnorbornyl)-L
- The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R represents a lower alkyl group having 1-3 carbon atoms. A method for producing 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester. 4. (a) Dehydration of (+)-α-phentyl alcohol-
isomerize to form (+)-α-fenchen, (b) convert this (+)-α-fenchen into 2R-exo-
(c) 2R-exo-7,7-dimethylnorbornylacetaldehyde is converted to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L (d) Esterification of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine to 3-(2R-alanine).
-exo-7,7-dimethylnorbornyl)-D,L-
(e) 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine lower alkyl ester is generated to produce 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine lower alkyl ester. -dimethylnorbornyl)-L-alanine lower alkyl ester, the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R is a lower alkyl ester having 1 to 3 carbon atoms. A method for producing a 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, which represents an alkyl group. 5, (a) 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester with N-
Coupled with protected aspartic anhydride, N
-protection (α,β)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester is produced, (b) this N-protection (α,β) Upper-Aspartyl-3-
(2R-exo-7,7-dimethylnorbornyl)-
By removing the protecting group of alanine lower alkyl ester, (
α,β)-L-aspartyl-3-(2R-exo-7
(c) from this mixture α-L-aspartyl-3-(2
The following formula includes the step of separating R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R is 1-3 A method for producing α-L-aspartyl-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester, which represents a lower alkyl group having carbon atoms. 6, (a) 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester with N-
N-protected (α,β)-L-aspartyl-3-(2R-exo-
(b) From this mixture, N-protected α-L-aspartyl-
3-(2R-exo-7,7-dimethylnorbornyl)
-L-alanine lower alkyl ester is separated, (c) this N-protected α-L-aspartyl-3-(2R
-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester is removed, and α-L
-Aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester is produced by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R represents a lower alkyl group having 1-3 carbon atoms, α-L-aspartyl-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester represented by How to manufacture. 7. A method for purifying (+)-α-fentyl alcohol, comprising crystallizing α-fentyl alcohol in a hydrocarbon solvent at low temperature. 8. A method for producing α-fenchen, comprising heating fenthyl alcohol in the presence of an aluminum oxide catalyst. 9, N-acyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine or its lower alkyl ester is treated with acylase in an aqueous medium to obtain 3-(2R- the optically active 3-(2R-exo-7,7-dimethylnorbornyl)-L comprising recovering exo-7,7-dimethylnorbornyl)-L-alanine or a lower alkyl ester thereof. - A method for producing alanine or a lower alkyl ester thereof. 10, 60- in the presence of at least one catalyst selected from aluminum phosphate, niobium oxide and nickel sulfate.
A method for producing alpha-phentyl alcohol, comprising reacting trans-2-pinanol at a temperature of 150<0>C.