CA2065014A1 - 7-7-dimethylnorbornane derivatives - Google Patents
7-7-dimethylnorbornane derivativesInfo
- Publication number
- CA2065014A1 CA2065014A1 CA002065014A CA2065014A CA2065014A1 CA 2065014 A1 CA2065014 A1 CA 2065014A1 CA 002065014 A CA002065014 A CA 002065014A CA 2065014 A CA2065014 A CA 2065014A CA 2065014 A1 CA2065014 A1 CA 2065014A1
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- Prior art keywords
- exo
- alanine
- alpha
- dimethylnorbornyl
- lower alkyl
- Prior art date
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
- C07K5/06113—Asp- or Asn-amino acid
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
- B01J21/02—Boron or aluminium; Oxides or hydroxides thereof
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
- B01J23/20—Vanadium, niobium or tantalum
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
- B01J27/053—Sulfates
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
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- C07C47/105—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing rings
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention discloses 7,7-dimethylnorbor- nane derivatives useful as intermediates for the production of various synthetic perfumes and high intensity sweeteners.
2R-exo-7,7-Dimethylnorbornyl acetaldehyde, 3-(2R-exo-7,7-dimethylnorbornyl)-2-amino-propionitrile,3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin and N-acyl-3-(2R-exo-7,7-dimethylnorbornyl) alanines are disclosed. The present invention describes a process for making 7,7-dimethylnorbornane derivatives, 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl esters and alpha-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl esters. A process for making alpha-fenchene, a process for making alpha-fenchyl alcohol and a process for making an optically active 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its lower alkyl ester are also disclosed. Dehydration and rearrangement catalysts are also disclosed.
2R-exo-7,7-Dimethylnorbornyl acetaldehyde, 3-(2R-exo-7,7-dimethylnorbornyl)-2-amino-propionitrile,3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin and N-acyl-3-(2R-exo-7,7-dimethylnorbornyl) alanines are disclosed. The present invention describes a process for making 7,7-dimethylnorbornane derivatives, 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl esters and alpha-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl esters. A process for making alpha-fenchene, a process for making alpha-fenchyl alcohol and a process for making an optically active 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its lower alkyl ester are also disclosed. Dehydration and rearrangement catalysts are also disclosed.
Description
WO91/02711 PCT/~S90/04~2' -l- 2 ~
7,7-DIMETHYLNORBORNANE DERIVATIVES
BACKGROUND AND SUMMARY
This invention relates to novel nor~ornane derivatives and processes for their preparation and conversion o~ such derivatives to high intensity artificial sweeteners. In addition, this invention also relates to novel catalysts for the preparation of fenchyl alcohol and alpha-fenchene.
The novel norbornane derivatives of this invention are more speci~ically represented by formula (I) as follows:
I~-`Y (~
wh e r e i n Y i s -CHO, .
C H o r ~<QN H
wherein R is hydrogen or a lower alkyl group of one to three :
carbons and wherein R' is hydrogen or a lower alkyl group of one to three carbons. The compounds of f ormula (I) are very useful as intermediates for the production of high intensity sweQteners, particularly L-aspartyl-3-(7,7-dimethylnorbornyl)-L-alanine derivatives of the following formula:
.. : : . . . : - .
';~' ~ ~ '. ' ' . . ' ' .
.: .
W091/02~11 PCT/US~/W722 6 ~4 /
~ ~C 11 - H - C - C 11 - C r 2 ~ C O O ~ ( l V ) :' wherein R is a lower alkyl group of one to three carbons.
Such high intensity sweeteners are described in U.S. Patent ~o. 4,788,069.
In U.S. Patent No. 4,78~,069 the preparation of sweetener (IV) involves the synthesis of the amino acid I-2 and the amino ester I-3, the later being prepared from the former via esterification with methanolic hydrochloric acid.
~ ~ C - ~U~ 1 -2 , R
., Tws methods are di3clo~ed for the preparation of I-2 and related bicyclic amino acids. In the first, alpha-fenchene is converted to the corresponding 7,7-dimethylnorbornyl-2-methanol u~ing diborane and hydrogen peroxide. This intermediate is then converted to the tosylate and condensed with sodium dimethylmalonate to give a norbornyl malonic acid diester. To finally arrive at amino acid I-2, three :, . ~ . , . " . . . . . .
- . , ~ , .
wos~ l PCT/US~/~722 3206~01~
additional steps, bromination, hydrolysis and amination, are required. The overall process known in the art is very expensive and give~ only low yields of the I-2. In the second method, alpha-fenchene is treated with 9-bcrabicyclo~3.3.1]nonane and the resulting hydroboration product condensed with methyl-N-(diphenylmethylene)-2-acetoxyglycinate to give an adduct which can be hydrolyzed to I-3 with dilute acid. This method, although much simpler than the first, involves the use of very expensive reagents and would not be economical on an industrial scale.
The present invention overcomes the disadvantageR of the prior art by converting alpha-fenchene directly to the novel aldehyde I-1 either via reductive carbonylation or via the Vilsmeier reaction and catalytic hydrogenation. See Reaction Schemes A and B. The novel norbornyl aldehyde I-l can b~
readily converted to amino acid I-2 via I-4 (the Strecker reaction) or via I-5 (the hydantoin procedure~. In both cases yields are high and reagent costs low.
The present invention provides a process for ~aXing 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alXyl esters represented by the following formula:
. . _ , , :.
[~ / ;H C-CH -Cll 2-COOII ( I V ) ~ `' wherein R represents a lower alkyl group of 1 to 3 carbon atoms comprising the steps of: (a) rearranging (-)-~n~-2-.,' . , ~- : . .:
:: . . - , . - :
.. . . .
: : :
.
~ '' . ` . . .
WO91~02~1l PCT/US~/~722 ~ 4-pinanol to form (+)-alpha-fenchyl alcohol; (b) dehydrating (+)-alpha-fenchyl alcohol to form (+)-alpha-fenchene;
(c) converting the (+)-alpha-fenchene to 2R-exo-7,7-dimethylnor~ornyl acetaldehyde; (d) converting 2R-exo-7,7-dimethylnorbornyl acetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine (e) resolving 3-(2R-exo-7,7-dimethylnorbornyl)-D,L- alanine to produce 3~(2R-exo-7,7-dimethylnorbornyl)-L- alanine; and (f) esterifying 3-(2R-exo-7,7-dimethylnor- bornyl)-L-alanineto form 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester. In the above process step (d) may comprise converting the acetaldehyde to an aminonitrile and hydrolyzing the nitrile to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
Alternatively, in the above process step (d) may comprise converting the acetaldehyde to a hydantoin and hydrolyzing the hydantoin to for~ 3-(2R-exo-7,7-dimethyl- norbornyl)-D,L-alanine. In the above process the step of resolving ~ay occur after the step of esterifying.
In step (a) (+)-alpha-fenchyl alcohol is produced by reacting (-)-trans-2-pinanol with a catalyst selected from the group of aluminum phosphate, niobium oxide and nickel sulfate.
General methods of producing alpha-fenchyl alcohol include, for example, (1) the Wagner-Meerwein type rearrangement reaction of alpha- or ~eta-pinene with mineral acids or organic acids [G. G. Henderson et al., J. Chem. Soc., 125, 107-13 (1924)], (2) the reduction of fenchone with various reducing agents, for example metallic sodium and alcohol tW. Huckel et al., Chem. Ber. 90, 2025 (1957); P.
Teisseire et al., ~echerches, 19, 232 (1974)] and (3) the rearrangement o~ n~-2-pinanol with perchloric acid or acetic anhydride t~. Indyk et al., J. Chem. Soc. Perkin II, :' ?
- :
O9l/02,lI pCT/~S~/~7~7 _5_ 2 0 ~ S 0 ~ ~
3113 (1974), W. D. Burrows et al., J. Am. Chem. Soc. 81, 245 (1959)~.
In the Wagner-Meerwein type reaction in method (1), the selectivity of alpha-fenchyl alcohol or alpha-fenchyl alcohol derivative is 10% or less, and it is dif~icult for this method to give alpha-fenchyl alcohol at a high selectivity. In method (2), the production of fenchone itssl~ is complex [G.
~uchbauer et al~, Liebigs. Ann. Chem., 2093 tl981)]. Method (3) is not economically feasible because it requires acetic anhydride or a large amount of solvent and the product i obtained as alpha- fenchyl acetate.
The present invention overcomes the problems of the prior art and provides an economical industrial method of producing alpha-fenchyl alcohol from trans-2-pinanol as a starting material.
In step (b) above, (+)-alpha-fenchyl alcohol is converted to (+)-alpha-fenchene by heating in the presence of a specially prepared aluminum oxide catalyst disclosed herein.
one prior process for producing alpha-fenchene comprises solvolyzing fenchyl tosylate with acetic acid in the presence of an excess of sodium acetate thereby giving alpha fenchene in a selectivity of 90% [W. Hueckel et al., Liebigs Ann. Chem.
664, 31 (1963)]. However, this process is economically and industrially disadvantageous because tosylation of -fenchyl alchol requires a large amount of pyridine and a long period of reaction ~me and the solvolysis requires a large amount of acetic acic As a method of dehydrating and rearranging fenchyl alcohol to alpha-fenchene, the use of potassium sulfate [W. ~ueckel et al., Liebigs Ann. Chem., 687~ 40 (1965)], the use of aluminum phosphate tD. Tishchenko et al., Zhur. Obshchei Khim., ~, 1824-29 (1952)], and the use of kaolin or zinc chloride [E. Pulkkinen, Suomen Kemistilehti, - .
. :, : . . :-:- . -, :
WO 91/0271 I j~,~,, P/~/I~Sgo/04722 ~Q~, 239 (1957)] are known. In all o~ these methods, theselectivity and yields of alpha-fenchene are about 20 to 30%, and are not industrially satisfactory.
The present invention overcomes the above disadvantages of the prior art and provides a co,~ ercial process utilizin~ a solid acid catalyst and heat to convert renchyl alcohol to alpha-fenchene with high selectivity and high yield.
The present invention also discloses a process for purifying (+)-alpha-fenchyl alcohoI, which comprises crystallizing alpha-fenchyl alcohol in a hydrocarbon solvent at low temperatures.
In steps (c) through (f) described above the intermediate (+)-alpha-fenchene is converted to amino acid ester I-3 via the novel intermediates I-l, I-4, and I-5 using procedures described in the literature. See Reaction Schemes A and B and the specification below.
The present invention also provides a proces~ for producing alpha-L-aspartyl-3-(2R-exo-7,7-dimethylnor~or- nyl)-L-alanine lower alkyl ester represented by the following formula:
- .
\~ '~
~\\C H -11 H - C - C H - C H 2 - C O O H ( I V ) ~:
wherein R is a lower alkyl group of one to three carbon atoms comprising the steps of: (a) coupling 3-(2R-exo-7,7-,: : :: ~ - . .
7,7-DIMETHYLNORBORNANE DERIVATIVES
BACKGROUND AND SUMMARY
This invention relates to novel nor~ornane derivatives and processes for their preparation and conversion o~ such derivatives to high intensity artificial sweeteners. In addition, this invention also relates to novel catalysts for the preparation of fenchyl alcohol and alpha-fenchene.
The novel norbornane derivatives of this invention are more speci~ically represented by formula (I) as follows:
I~-`Y (~
wh e r e i n Y i s -CHO, .
C H o r ~<QN H
wherein R is hydrogen or a lower alkyl group of one to three :
carbons and wherein R' is hydrogen or a lower alkyl group of one to three carbons. The compounds of f ormula (I) are very useful as intermediates for the production of high intensity sweQteners, particularly L-aspartyl-3-(7,7-dimethylnorbornyl)-L-alanine derivatives of the following formula:
.. : : . . . : - .
';~' ~ ~ '. ' ' . . ' ' .
.: .
W091/02~11 PCT/US~/W722 6 ~4 /
~ ~C 11 - H - C - C 11 - C r 2 ~ C O O ~ ( l V ) :' wherein R is a lower alkyl group of one to three carbons.
Such high intensity sweeteners are described in U.S. Patent ~o. 4,788,069.
In U.S. Patent No. 4,78~,069 the preparation of sweetener (IV) involves the synthesis of the amino acid I-2 and the amino ester I-3, the later being prepared from the former via esterification with methanolic hydrochloric acid.
~ ~ C - ~U~ 1 -2 , R
., Tws methods are di3clo~ed for the preparation of I-2 and related bicyclic amino acids. In the first, alpha-fenchene is converted to the corresponding 7,7-dimethylnorbornyl-2-methanol u~ing diborane and hydrogen peroxide. This intermediate is then converted to the tosylate and condensed with sodium dimethylmalonate to give a norbornyl malonic acid diester. To finally arrive at amino acid I-2, three :, . ~ . , . " . . . . . .
- . , ~ , .
wos~ l PCT/US~/~722 3206~01~
additional steps, bromination, hydrolysis and amination, are required. The overall process known in the art is very expensive and give~ only low yields of the I-2. In the second method, alpha-fenchene is treated with 9-bcrabicyclo~3.3.1]nonane and the resulting hydroboration product condensed with methyl-N-(diphenylmethylene)-2-acetoxyglycinate to give an adduct which can be hydrolyzed to I-3 with dilute acid. This method, although much simpler than the first, involves the use of very expensive reagents and would not be economical on an industrial scale.
The present invention overcomes the disadvantageR of the prior art by converting alpha-fenchene directly to the novel aldehyde I-1 either via reductive carbonylation or via the Vilsmeier reaction and catalytic hydrogenation. See Reaction Schemes A and B. The novel norbornyl aldehyde I-l can b~
readily converted to amino acid I-2 via I-4 (the Strecker reaction) or via I-5 (the hydantoin procedure~. In both cases yields are high and reagent costs low.
The present invention provides a process for ~aXing 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alXyl esters represented by the following formula:
. . _ , , :.
[~ / ;H C-CH -Cll 2-COOII ( I V ) ~ `' wherein R represents a lower alkyl group of 1 to 3 carbon atoms comprising the steps of: (a) rearranging (-)-~n~-2-.,' . , ~- : . .:
:: . . - , . - :
.. . . .
: : :
.
~ '' . ` . . .
WO91~02~1l PCT/US~/~722 ~ 4-pinanol to form (+)-alpha-fenchyl alcohol; (b) dehydrating (+)-alpha-fenchyl alcohol to form (+)-alpha-fenchene;
(c) converting the (+)-alpha-fenchene to 2R-exo-7,7-dimethylnor~ornyl acetaldehyde; (d) converting 2R-exo-7,7-dimethylnorbornyl acetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine (e) resolving 3-(2R-exo-7,7-dimethylnorbornyl)-D,L- alanine to produce 3~(2R-exo-7,7-dimethylnorbornyl)-L- alanine; and (f) esterifying 3-(2R-exo-7,7-dimethylnor- bornyl)-L-alanineto form 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester. In the above process step (d) may comprise converting the acetaldehyde to an aminonitrile and hydrolyzing the nitrile to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
Alternatively, in the above process step (d) may comprise converting the acetaldehyde to a hydantoin and hydrolyzing the hydantoin to for~ 3-(2R-exo-7,7-dimethyl- norbornyl)-D,L-alanine. In the above process the step of resolving ~ay occur after the step of esterifying.
In step (a) (+)-alpha-fenchyl alcohol is produced by reacting (-)-trans-2-pinanol with a catalyst selected from the group of aluminum phosphate, niobium oxide and nickel sulfate.
General methods of producing alpha-fenchyl alcohol include, for example, (1) the Wagner-Meerwein type rearrangement reaction of alpha- or ~eta-pinene with mineral acids or organic acids [G. G. Henderson et al., J. Chem. Soc., 125, 107-13 (1924)], (2) the reduction of fenchone with various reducing agents, for example metallic sodium and alcohol tW. Huckel et al., Chem. Ber. 90, 2025 (1957); P.
Teisseire et al., ~echerches, 19, 232 (1974)] and (3) the rearrangement o~ n~-2-pinanol with perchloric acid or acetic anhydride t~. Indyk et al., J. Chem. Soc. Perkin II, :' ?
- :
O9l/02,lI pCT/~S~/~7~7 _5_ 2 0 ~ S 0 ~ ~
3113 (1974), W. D. Burrows et al., J. Am. Chem. Soc. 81, 245 (1959)~.
In the Wagner-Meerwein type reaction in method (1), the selectivity of alpha-fenchyl alcohol or alpha-fenchyl alcohol derivative is 10% or less, and it is dif~icult for this method to give alpha-fenchyl alcohol at a high selectivity. In method (2), the production of fenchone itssl~ is complex [G.
~uchbauer et al~, Liebigs. Ann. Chem., 2093 tl981)]. Method (3) is not economically feasible because it requires acetic anhydride or a large amount of solvent and the product i obtained as alpha- fenchyl acetate.
The present invention overcomes the problems of the prior art and provides an economical industrial method of producing alpha-fenchyl alcohol from trans-2-pinanol as a starting material.
In step (b) above, (+)-alpha-fenchyl alcohol is converted to (+)-alpha-fenchene by heating in the presence of a specially prepared aluminum oxide catalyst disclosed herein.
one prior process for producing alpha-fenchene comprises solvolyzing fenchyl tosylate with acetic acid in the presence of an excess of sodium acetate thereby giving alpha fenchene in a selectivity of 90% [W. Hueckel et al., Liebigs Ann. Chem.
664, 31 (1963)]. However, this process is economically and industrially disadvantageous because tosylation of -fenchyl alchol requires a large amount of pyridine and a long period of reaction ~me and the solvolysis requires a large amount of acetic acic As a method of dehydrating and rearranging fenchyl alcohol to alpha-fenchene, the use of potassium sulfate [W. ~ueckel et al., Liebigs Ann. Chem., 687~ 40 (1965)], the use of aluminum phosphate tD. Tishchenko et al., Zhur. Obshchei Khim., ~, 1824-29 (1952)], and the use of kaolin or zinc chloride [E. Pulkkinen, Suomen Kemistilehti, - .
. :, : . . :-:- . -, :
WO 91/0271 I j~,~,, P/~/I~Sgo/04722 ~Q~, 239 (1957)] are known. In all o~ these methods, theselectivity and yields of alpha-fenchene are about 20 to 30%, and are not industrially satisfactory.
The present invention overcomes the above disadvantages of the prior art and provides a co,~ ercial process utilizin~ a solid acid catalyst and heat to convert renchyl alcohol to alpha-fenchene with high selectivity and high yield.
The present invention also discloses a process for purifying (+)-alpha-fenchyl alcohoI, which comprises crystallizing alpha-fenchyl alcohol in a hydrocarbon solvent at low temperatures.
In steps (c) through (f) described above the intermediate (+)-alpha-fenchene is converted to amino acid ester I-3 via the novel intermediates I-l, I-4, and I-5 using procedures described in the literature. See Reaction Schemes A and B and the specification below.
The present invention also provides a proces~ for producing alpha-L-aspartyl-3-(2R-exo-7,7-dimethylnor~or- nyl)-L-alanine lower alkyl ester represented by the following formula:
- .
\~ '~
~\\C H -11 H - C - C H - C H 2 - C O O H ( I V ) ~:
wherein R is a lower alkyl group of one to three carbon atoms comprising the steps of: (a) coupling 3-(2R-exo-7,7-,: : :: ~ - . .
2~11 PCT/~S~/~722 2~.)014 dimethylnorbornyl)-L-alanine lower alkyl ester with an N-protected aspartic acid anhydride to produce an N-protected-(alpha/beta~-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkylester; (b) deprotecting the N-protected-(alpha/beta)-L-aspartyl-3-(2R-exo-7,7-di~ethylnorbornyl)L-alaninelower alkyl ester to produce a mixture of alpha and beta-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl estçrs; and (c) separating the alpha-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester from the mixture. The step of deprotecting may occur after the step of separating. An N-protected aspartic acid havin~ a beta-ester protecting group may be utilized for the N-protected aspartic acid anhydride.
~ he present invention also discloses a process for producing an optically active 3-(2R-exo-7,7-dlmethylnor-bornyl)-L-alanine or its lower alkyl ester, which comprises treating an N-acyl-3-(2R-exo-7,7-dimethyl~or- bornyl)-D,L-alanine or its lower alkyl ester with an acylase in an aqueous medium, and recovering the resulting 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its lower alkyl ester.
In the present invention, the term "lower" used to qualify a group or a compound includes methyl, ethyl, n-propyl, and isopropyl groups.
An advantage o~ the present invention is to provide the novel 7,7-dimethylnorbornane derivatives of-formula (I) which are use~ul as synthesis intermediates for the preparation of L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine derivativ~ of formula (IV), particularly the compound of formula (IV-l, R-CH3), which are useful as sweeteners having high sweetening power.
Another advantage of the present invention is to provide a process for producing the L-aspartyl-3-(7,7-:~ ' . .
: , , ., - ::
- . : .
.
091~0271~ 4 PCT/US~/~722 dimethyl~orbornyl)-L-alanine derivatives of formula (IV) useful as sweeteners from the novel 7,7-dimethylnorbor- nane derivatives of ~ormula (I).
Another advantag~ of the present invention is to provide novel catalysts use~ul in the preparation of fenchyl alcohol and alpha-fenchene.
In summary the present inventio~ discloses compounds repre~ented by the following formula:
I~Y ( 1 w h ~ r e i n Y i s - C H O , .
NH2 NHCR'~ r C N C O O R H N~
wherein R is hydrogen or a lower alkyl group of one to three car~ons and wherein R' is hydrogen or a lower al~yl group of one to three carbons. The present invention discloses 2R-exo-7,7-dimethylnorbornyl acetaldehyde, 3-(2R-exo-7,7-dimethylnorbornyl)-2-aminopropionitrile and 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin. A compound compri~ing N-acyl-3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine, wherein acyl is acetyl, propionyl, butyryl or chloroacetyl is disclosed in the present invention. ~pecifically, N-acetyl-, WO91/02~11 PCT/~'S~/~722 20~:~014 _9_ 3-(2R-exo-7,7-dimethyl-norbornyl)-D,L-alanine and N-chloroacotyl-3-(2R-exo-7,7- dlmethylnorbornyl)-D,L-alanine are disclosed.
A fenchyl alcohol dehydration catalyst selected ~rom the group consisting of calcined aluminum oxide is disclosed;
specifically, the dehydration catalyst comprising calcined aluminum oxide having Hammett acidity function of -5.6cHS-3.0 is described. Finally, there is also disclosed a catalyst for producing alpha-fenchyl alcohol from trans-2-pinanol, selected from the group aluminum phosphate, niobium oxide and nickel sulfate.
The compounds of formula (I) in accordance with this invention [the compounds of formulae (I-l), (I-2) and (I-33 in the following reaction scheme] may be produced by a synthetic route summarized in the following reaction Scheme A.
~ . ., .: , : .. . . . -WO 91/02~ PCr/US90/~47~2 Re~ç~t ion Scheme A
_ , OH _ _ ~
l~orncrl20110n OH l~m~rlZO~lon 1rcnr-2-pino~ol -~-nchol Vil~rnoior roogcn~ ~ ~
-lonchono doh~dro (1-l) ( 1-1 ) ~=
~N ~
~0; /a~OH)2 t 5 t o r i f i c a t i o n ~, ~N R 2 ( 1-2) ''' : :- . :, . : :.
- :: . ... .
~ ;- :. . ::
.
WO9l/02/ll PCT/~S~/~22 206;,~14 In the abcve Reaction Scheme A, alpha-fenchyl alcohol is prepared in a high conversion and at a high ~electivity by heating tr~n~-2-pinanol to a temperature of 60 to 150C in the presence of one or more catalysts selected from aluminum phosphate, nio~ium oxide and nic~el sul~ate.
This method will be doscribed below in detail. ~ns-2-pinanol used as a starting material in this method can usually be obtained by subjectin~ nopinone (obtained by oxidation of beta-pinene with ozone or potassium permanganate) to Grignard reaction with a methyl magnesium halide tW. Huckel et al., Liebigs, Ann. Chem., 625, 12, (1959)], or by catalytically reducing alpha- or beta-pinene to form pinane, oxidizing it with oxygen and reducing it further ~S. G. Traynor et al., J. Org. Chem., 45, 900 (1980).
Aluminu~ phosphate used as the catalyst in this invention can be obtained by hydrolyzing hydrous aluminum nitrate, hydrous aluminum sulfate, hydrous aluminum chloride or sodium aluminate with an aqueous solution o~ ~ nonmetallic alkali, i.e. ammonia or urea, adding an equivalent weight of ortho-phosphoric acid to the re~ulting aluminum hydroxids to permit precipitation, and calcining the resulting hydrous aluminum phosphate at a temperature of 300 to 800C, preferably 300C, for about 3 hours.
Niobium oxide used as the catalyst in the method of this invention may contain water. Niobium oxide and its hydrate (so-called niobic acid) may generally be produced by precipitation from a solution of a niobium compound such as niobium chloride or niobiuo oxalate by the action of an alkali. U~ually, the resulting precipitate contains a considerable amount of water, but it can be dehydrated almost completely by heating to more than 200C. Niobic acid : , : ::: .:. . : . . .
:. ; . : :: :
. . .
.
WO91/02711 PCT/~S~W72' 6~ 4 -12-obtained by precipitation Erom solution can be used as such or after calcination at soooc or below, as niobium oxide.
Nickel sulfate as another catalyst can be prepared by calcination of a commercially available nickel sul~ate hydrate.
The treatment of trans-2-pinanol in the presence of the catalyst may be carried out at a temperature of 60 to 150C, preferably 65 to ~5C.
The suitable amount of the catalyst used is about l to 10% by weight based on the ~n~-2-pinanol. The reaction in this invention is usually performed without solvent. In view of the separation of the desired compound from the reaction products, the conversion o~ trans-2-pinanol is preferably at least 90%.
After the reaction, tha reaction mixture is filtered to remove the catalyst, and the residue distilled in a customary manner. Alternatively, the reaction mixture may be directly distilled without separation of the catalyst.
The starting trans-2-pinanol includes a (~)-form and a (-)-form, and its optical purity can be determlned by its specific rotation. The present inventors condensed trans-2-pinanol with N-carbobenzyloxy-(D)- or (L)-alanoyl chloride in the presence of pyridine, removed the N-protecting group from the reaction product, and measured its optical purity by gas chromatography ~the gas chromatographic column is, for example, a PEG-HT capillary, 0.25 mm. in diameter, 25 m. in length; made ~y Gasukuro Kogyo Co., Ltd.,). Alpha-fenchyl alcohol obtained by the method of this invention also includes a (+)-form and a (-)-form. The use of either the (+)-form or (-)-form of ~rans-2-pinanol can give either one of theise forms. For example, if the method of this invention is carried out by using t-)-trans-2-pinanol obtained by the ,~, "
. . . ~ : ~ , . . . .
~() (!1~)!~1 I PCr/l:S90/W/2Z
2 0 6 ,~
method of the above-cited Liebigs Ann. Chem., 62S, 12, (1959) as the starting material, (+)-alpha-fenchyl alcohol is obtained without racemization.
The method of this invention can economically give alpha-f~nchyl alcohol useful as a material for a perfume or as a sweetener intermediate as described below.
In the above Reaction Scheme A, fenchyl alcohol is heated in the presence of a ~olid acid catalyst to per~orm a dehydration and isomerization reaction simultaneously to selectively produce alpha-fenchene.
It has now been found in accordanc~ with this invention that aluminum oxide is especially suitable as the solid acid catalyst used in this reaction. Especially suitable is aluminum oxide prspared by hydrolyzing hydrous aluminum nitrate, hydrous aluminum sulfate, hydrous aluminum chloride or sodium aluminate with an aqueous solution of a non-metallic alkali such as ammonia or urea and calcining the resulting aluminum hydroxide. More specifically, thi~ aluminum oxide is obtained by dispersing a lOS by weight aqueous solution of aluminum nitrate hydrate in 28% aqueous ammonia at room temperature to hydrolyze it, separating and recovering the resulting aluminum hydroxide precipitate by filtration in a customary manner, and calcining the resulting aluminu~
hydroxide at a te~perature range of from about 400 to 600C, preferably about 500C, for about 3 hours. The acid strength of the aluminum oxide prepared under these conditions, expressed by the Ham~ett acidity function, is -5.6<~os-3Ø
It is a solid acid o~ a medium acidity.
For the conversion to fenchene the solid acid can generally be used in an amount of 0.1 to 19%, preferably 1 to 5~, based on the weight of the starting fenchyl alcohol.
..... ~ .~ ~- , . . .
: ~ , . , {
,, .
- ~: ,. .
.: . . . ~ . .
'~ ' , . . , : ' ~ . -PCT/~'S~/~72' The reaction temperature is usually in a range from about 150 to 250C, particularly 195 to 2000C. If the reaction temperature is too low, the rate o~ the reaction becomes slow.
The reaction time varies with the ~enchyl alcohol used, but usually a period of time ranging from about 1 to 24 hours suffices.
The presence of water in the reaction system in the above reaction is undesirable, and it is preferred to carry out the reaction in a reactor equipped with a water removing device such as the Dean-Stark device. Usually, the reaction can be carried out without using a solvent.
After the reaction, the reaction mixture is distilled with or without prior separation of the catalyst, and as required, rectified in a rectification column.
The starting fenchyl alcohol may be either alpha-fenchyl alcohol or beta-fenchyl alcohol. Alphafenchyl alcohol can be obtained commercially or prepared from trans-2-pinanol as described above. Beta-fenchyl alcohol can be obtained in a high purity by catalytically reducing fenchone, converting the resulting mixture of alpha- and beta-fenchyl alcohols into their crystalline p-nitrobenzoates, recrystallizing repeatedly, and hydrolyzing the purified product.
Alternatively, a mixture of alpha-fenchyl alcohol and beta-fenchyl alcohol may be obtained by epimerizing alpha-fenchyl alcohol under hydrogen pressure in the presence of a copper-chromiu~ catalyst.
In the production of L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl~-L-alanine methyl ester of formula (IV-1, R=CH3) in particular, the use of (+)-alpha-fenchyl alcohol as the starting material is preferred. ~he (+)-alpha-fenchyl alcohol may be isolated and purified in a high optical purity of, for exa~ple, about 94~ e.e. by crystallizing commercial .. . .
, . .- . . - ~
, . , . . - ~ , . , . -~.-- .. .. . - ~ . . , : .
\~)9lJ0~~ll PCT/~S~/W722 2~6~
alpha-fenchyl alcohol in a hydrocarbon type organic sol-ent at low temperatures.
The commercially available alpha-fenchyl alcohol is generally a mixture of the (+)-alpha-isomer and the (-)-alpha-isomer in a weight ratio of from 80:20 to 70:30.
C.ystallization of the commercial alpha-fenchyl alcohol in an aliphatic hydrocarbon solvent such as n-pentane, n-hexane, isohexane, n-heptane, n-octane and isooctane ~preferably n-heptane or n-octane) gives the (+)-alpha-isomer of high purity, for example an optical purity of 94 S e.e. or more.
The crystallization treatment can be carried out by dissolving the alpha-fenchyl alcohol in the solvent at roo~
temperature or at a slightly elevated temperature and cooling the solution to a temperature of about -10 to -60C, preferably -35 to -60C.
A product having a sufficient optical purity may be obtained by one crystallization, but by repeating the crystallization two or three times, a product of a very high optical purity can be obtained.
The optical purity of the purified (+)-alpha- fenchyl alcohol can be determined by its specific rotation. The present inventors measured the optical purity of the alpha-fenchyl alcohols by gas chromatography of their L-alanine or D-alanine esters (the col o may be, for example, PEG-HT
capillary, 0.25 mm in diameter and 25 m in length, made by Gasukuro ~ogyo K. R.). ~he sample wa prep~red by condensing alpha-fenchyl alcohol with N-carbobenzyloxy-(D) or (L)-alanine using a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3- (3-dimethylamino- propyl)carbodiimide hydrochloride in the presence of N,N-dimethylaminopyridine, or by condensing alpha- fenchyl alcohol with N-butoxycarbonyl-(D) or (L)-aianine using the above dehydrating agent.
..... . ... . . .
: ,, '' ~ , ~ , :: - . , .
WO9l/02,lI PCT/~'S~/~722 ~Q~ -16-The amino protecting groups are then removed by hydrogenation (the N-carbobenzyloxy group) or acid treatment (the N-t-butoxycarbonyl group) prior to G.C. analysis.
In the above dehydration-isomerization reaction o~
fenchyl alcohol to alpha-fenchene, the rate of the reaction of beta-fenchyl alcohol is faster than that o~ its alpha-epimer.
The reaction with beta-fenchyl alcohol generally comes to completion within 3 hours, and alpha-fenchene forms with a selectivity of about 80~. On the other hand, when alpha-fenchyl alcohol is used as the starting material, the selectivity for alpha-fenchene after 16 hours is about 59%.
When a mixture of alpha- and beta-fenchyl alcohols (alpha/beta s 6/4) is used, the selectivity for alpha-fenchene i~
increased to 65~.
The alpha-fenchene so obtained is subjected to the Vilsmeier reaction to form 7,7-dimethyl-2-~ormyl-methylenenorbornane. Stereoselective reduction~ of this product yields 2R-exo-7,7-dimethylnorbornyl acetaldehyde (I-1) .
Tha Vilsmeier reaction of alpha-fenchene can be carried out by a known method described, for example, in C. Jutz et al., Chem. Ber. 100, 1536 (1967). For example, alpha-fenchene is added to the Vilsmeier reagent prepared at room temperature from phosgene or thionyl chloride and an N,N-disubstituted formamide such ac N-methylformanilide;
preferably from phosphoru3 oxychloride and more than one equivalent of N,N-dimethylformamide. The mixture i8 reacted at a temperature of 50 to gooc to give dehydro~ 1) as an E-/Z- mixture.
The resulting 7,7-dimethyl-2-formylmethylenenorbornane [dehydro-(I-1)] is reduced to give 2R-exo-7,7-dimethyl-norbornyl acetaldehyde of for~ula (I-1). Reduction of ~,. . . : : ;i .;, . . .
.: .^~ .: . , . . . . . . . .
~09l/02~ll PCT/US~/W~22 2 ~
dehydro~ 1) may be carried out by a catalytic hydrogenation method using hydrogen in the presence of a noble metal catalyst such as palladium on carbon. As a result, the compound of formula (I-l) can be obtained with an exo-selectivity of as high as or greater than about 95S.
As an alternative, alpha-fenchene may be directly converted to 7,7-dimethylnorbornyl-2-acetaldehyde of formula (I-l) by oxo reaction using various rhodium complex catalysts.
According to this method, the selectivity of the exo-form of formula (I-l) is somewhat inferior to that in the method which goes through dehydro-(I-l).
The oxo reaction of alpha-fenchene may be carried out in the same way as an ordinary oxo reaction described, for example, in W. Himmele et al., Tetrahedron Letters, 907, 1976 and J. Hagen and K. Bruns, U.S. Patent No. 4,334,100. For example, alpha-fenchene is hydroformylated with a gaseous mixture of carbon monoxide and hydrogen a~ a temperature of about 30 to about 150C under a gas pressure of about ~5 to about 150 kg/cm2 in the presence of a rhodium complex catalyst, for example a rhodium carbonyl complex such as Rh6(CO)16, RhCl(CO)(pph3)2 (pph3 stand for triphenylphosphine), RhH(CO)(pph3)3, [Rh(COD)X~2 ~COD stands for cyclooctadienyl and X i5 halogen, acetate) or Rh(COD)(acac) (acac stands for acetyl acetonate).
The resulting 2R-exo-7,7-dimethylnorbprnyl acetaldehyde of formula (I-1) is then reacted wi~h ammonia or ammonium chlorido and hydrogen cyanide or an alkali cyanide in accordance with Strecker'samino acid synthesis method [see, for example, J.P. Green~tein & M. Winitz, "Chemistry of the Amino Acids," Vol. I, pg. 698-700 (1961); R. Gardry, Can. J.
Res., ~, 301 (1946)]. The resulting 3~(2R-exo-7,7-dimethylnorbornyl) -2-amino propionitrile (I-4) is hydrolyzed ~.
; -091/0271l 6~4 PCT/US~/~22 under acidic conditions created by a mineral acid such as hydrochloric acid, hydrobromic acid or hydriodic acid to give 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine of formula (I-2).
The Strecker reaction can be conducted in alcoholic or mixed alcoholic-aqueous solution using ammonia gas or ammonium hydroxide solution. The cyanide can be supplied as the Li, Na or K salt, the more soluble Li and Na salts being preferred.
Reaction temperatures of 0 to 30OC may be employed, the time being adjusted accordingly. After removal of the solvent by evaporation the residue is treated with a strong base (such as NaOH, KOH or Na2CO3) and the aminonitrile extracted with ether, toluene, or any suitable organic solvent which does n~t react with the amino function.
Hydrolysis of the resulting 3-(2R-exo-7,7-dimethyl-norbornyl~-2-amino propionitrile is best achieved by refluxing in approximately 10 ~ HCl solution for 18 hours. ~Lower acid concentrations may be used, but longer reaction times are required. Shorter reaction times may be achieved by heating at elevated temperatures in an autoclave. Other acids may also be employed such as hydrobromic or sulfuric.
Hydrochloric i5 particularly useful in that the product can be obtained as the hydrochloride by direct crystallization from the cooled, concentrated reaction mixture.
An alternative method for producing the amino acid of formula (I-2) involves preparation of an intermediate hydantoin. In this procedure, the 2R-exo-7,7-dimethyl-norbornyl acetaldehyde of formula (I-l) i~ reacted with an alkali metal cyanide and ammonium carbonate. ~8~cherer-Berg reaction - SQe H. R. Henze and R. J. Speer, J. Am. Chem. Soc., 64, 522-3 (1942) and E. Wade, Chem. Rev., 46, 441-4, (`1950)].
,~.. .. .. ~ . ..... . .
, . . : .. -: ~ : . . . ~ ' . - ' . .:
~91102~11 PCT/~S~/~722 -19- 20~ 14 The resultinq hydantoin (I-5) is then hydrolyzed with a strong aqueous base [NaOH, ~a(0~)2] to afford the amino acid (I-2).
In a typical procedure, one mole of the aldehyde is heated at 50-70C for 8-24 hours with 2-5 moles of (NH4)2C03 and l.l moles of NaCN in an aqueous ethanolic solution. The mixture is cooled, concentrated and acidi~ied to pH ~~ 5 to precipitate the product (I-5) as a white solid.
Hydrolysis of (I-5) to the amino acid (I-2) is then achieved by refluxing in 1.5 M Ba(OH)2 solution for 72 hours.
The 3-(2R-exo-7,7-dimethylnorbornyl)alanine of formula (I-2) produced as above is generally obtained as a mixture of the D-form and L-form. The mixture must, therefore, be optically r solved and the L-form suitable a a sweetener intermediate recovered.
Optical resolution may be carried out before or after the compound of formula (I-2) is esterified.
Esterification of the compound of formula (I-2) can be carried out by reacting it with a lower aikanol having from one to three carbon atoms.
For example, esterification of (1-2) with methanol is readily achieved by heating a solution of the amino acid in methanolic hydrogen chloride solution for 18 hours at reflux.
Evaporation of the solvent af~ords the amino ester hydrochloride. The free base (I-3, R'CH3) is then obtained by neutrali~ing an aqueous solution of the hydrochloride with a suitabl~ base (~OH, NaOH, Na2CO3) and extracting the product into ether, toluene or other organic solvents which are not base-sensitive. Evaporation of the extract gives the pure amino e~ter (I-3, R - CH3).
Optical resolution of 3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine (I-2) or its lower alkyl ester (I-3) may be ..... . -: . ,, ; , .
, ~
6 PCT/~S~/W722 carried out by known methods such as using D-tartaric acid or an enzyme.
(1) Optical resolution with D-tartaric acid is practiced on the 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine lower alXyl ester by heating a one to one mixture of D-tartaric acid and the amino ester in methanol until the D-ta.taric acid goes into solution. The solution is then cooled to induce crystallization. Two further recrystallizations gives matçrial of >95% ee.
If possible, the alcohol used for the crystallizations should be the same as that represented by the R group of (I-3) so that trans-esterification is avoided.
(2) Optical resolution by the enzy~e method.
The compound of formula (I-2 or I-3) is N-acylated ~for example, N-acetylated or N-chloroacetylated) in a known manner and acylase is caused to act on the acylated compound in an aqueous medium. A~ a re~ult, the L-for~ of N-acyl~3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine or its ester i8 selectively deacetylated to give 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its ester.
The acylase that can be used in the enzyme reaction may be of any type which has the ability to hydrolyze the L-form of an N-acylamino acid selectively tsee for example I. Chibata, et al., in K. ~osbach, ed., Methods in Enzvmo}ocv, Vol. 44, 746-59, (1976)]. It may be originated from an animal source, a plant source or a microorganism source. Since the acyla~e reaction $s qenerally carried out in weak alkalinity, the acylase preferably has an optimal pH in the range of from about 6 to 9. ~he acylase may be obtained by culturing a microorganism, for example a mold of the genus Aspergillus or Penicillium, a bacterium of the genus Pseudomonas, or an actinomyces of the genus Streptomyces, and recovering the .
,. . ~ , : . . .
~ . , .: . . . -:- ~ ~ ;. : . . ' - :
:: . . . : . . : , : . :
, w091/02~1I PCT/~S~/W722 2~ 01~
acylase from the culture. For example, Acylase I (Sigma Chemical company) and Acylase "Amano" (Amano Pharmaceutical Co., Ltd.; derived from As~erqill~s welleus~ are co~mercially available.
Deacylation of the N-acyl-3-(2R-exo-7,7-dimethylnor-bornyl)-D,L-alanine (I-6) or its ester using such an acylase may be carried out in the same way as in an ordinary enzy~e reaction. For exampl~, the N-acyl compound is dissolved or dispersed in an aqueous medium. ~he pH of the medium is adjusted to the optimal pH of the acylase with an alXali such as sodium hydroxide or sodium carbonate. If desired, an enzyme stabilizer such as cobalt chloride hexahydrate is added so that the cobalt ion concentration becomes 10-6 to 1o~2M.
The reaction is carried out at a temperature range of from about 35 to 40C for several hours to more than 10 hours.
After the reaction, the pH of the reaction mixture is adjusted to an acidic pH, for example about 1 to about 2, and the unreacted N-acyl-3-(2R-exo-7,7-dimethylnorbor- nyl)alanine or its ester is separated and recovered usinq a solvent such as ethyl acetate, methylene chloride or chloroform. In the case of the acid (I-2) the aqueous layer is adjusted to a pH
range of from about 3 to 5 with aqueous ammonia. The desired 3-(2R-exo-7,7-di~ethylnor- bornyl)-L-alanine precipitates as crystals. ~he crystals are separated and purified by a customary method, for example by treat~ent with activated car~on in hot water. White purified 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine can thus be recovered. In the case of the ester (I-3, R=CH3) the aqueous layer is adjusted to pH 8-9 (instead of 3-5) and the product isolated by extraction with a solvent such as ethyl acetate, chloroform or methylene chloride. Evaporation of the solvent gives 3-(2R-.~, . ~, . . .
:
.
WO ~1/02~ PCT/I S90/04~22 exo- 7,7-di~ethylnorbornyl)-L-alanine methyl ester as a liquid.
The purified 3-~2R-exo-7,7-dimethylnor~ornyl)-L- alanine or its ester has an optical purity, determined by gas chromatography using a specially worked capillary (G-800 column made by Chemical Inspection & Testing Institute) after N-trifluoroacetylation and as required esterification, of substantially 100%.
~ he unreacted N-acyl-3-(2R-exo-7,7-dimethyl- norbornyl)-D-alanine or its ester ~ay be converted to 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its ester by a Xnown method, for example, by treating it with acetic anhydride to racemize it, and subjecting the racemate again to the acylase reaction.
The N-acyl derivative of (I-2) used in the above enzymatic resolution procedure can in principle also bQ
prepared by the direct amido carbonylation of either alpha-fenchene or the 7,7-dimethylnorbornyl-2-acetalde- hy~de O
(I-l) using CO/H2, R-C-NH2 and a catalyst. ~The amido-carbonylation reaction -- see I. Ojima, J. Mol. Catal., 37, 25-44 (1986); P. Magnus and M. Slater, Tet. Let., 28, 2829 (1987~; K. Izawa, Svn Ora. Chem. J~., 46, 218 (1988) and Japanese Patent No. 61/236760.
Typical condition require the alkene (or aldehyde), a combined cobalt-rhodium catalyst, carbon monoxide, acetamide, hydrogen (500-2000 p5i) and a temperature of 80-150C for 1-10 hours.
A third method of resolving the amino acid of Formula (I-2) can also ~e envisioned, which involves treating the hydantoin (I-5) with a microbial enzyme capable o~ selective hydrolysis of the hydantoin ring to afford the L-amino acid.
Although most hydantoinase enzymes give the D-amino acid as .. .
::. : - : .
.:: . : : . . -,: .
. .
. , -, . ~
WO 9 1 /027 1 I Pcl /us9o/w722 2 o ~ 4 the only product, the enzyme isolated from ~3C~ brevis has been found to give the desired L-isomer in the case of valine hydantoin. [(See A. Yamashiro et al., Aaric. ~iol. Chem., 52, 2851-2856 and 2857-2863, (1988).]
Treatment of hydantoin (I-5) with the enzyme and reaction conditions described by Yamashiro et al., hould give 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine (I-2).
The compound of formula (1-2 or 1-3) produced as above is useful as an intermediate for production of the compound of formula (IV) which is useful as a non-nutritive sweetener.
The sweetener compound of formula (IV) can be produced from the compound of formula (I-3) by a synthesis route summarized in the following Reaction Scheme B.
. . .
:.... . , :. , . . ., :
:-, . .. , . .. , : , .
: . ... . : : .
: . .. . . :~:
WO 91/02711 Pcr/~sso/o4722 6~ 4 -24-Reaction Scheme ~
_ _ ~ `
\/
,NH2 +
COOR l-H
~1-3) (Il) NH-Z
(l-form) ~ .
~\CH-NH-C-CH2-CH i ~\CH-NH-C-CH-CHl-COOH
COOR COOH (111 olpho) -:~
(111 b-t~) ~limln3tlon o~ tho , omino prot~cting group : -/ \CH-NH-C-CH-CHl-COOH
COOR ( V ) - _ _ _ __ ~.
: . :, . . ~ . . -.: . .
~, ' ~ ' " '"- ~ ' ' : ' :' :: ..
~ )91/02~1l PCT/US90/~722 20~3014 In the above scheme, Z represents a protective group for the amino function. (See M. Bodansky, "Principles of Peptide Syntnesis," Springer-Verlag, Berlin, (1984) pp. 90-102) and R is as defined above. Typical examples of Z include the allyloxy carbonyl [I. Ninomi et al, Tet.
Let., 26, 2449 (1985); O. Dangles et al., J. Ora. Chem., 52, 4984-93 (1987)], the formyl (U.S. Patent No~.:
~ he present invention also discloses a process for producing an optically active 3-(2R-exo-7,7-dlmethylnor-bornyl)-L-alanine or its lower alkyl ester, which comprises treating an N-acyl-3-(2R-exo-7,7-dimethyl~or- bornyl)-D,L-alanine or its lower alkyl ester with an acylase in an aqueous medium, and recovering the resulting 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its lower alkyl ester.
In the present invention, the term "lower" used to qualify a group or a compound includes methyl, ethyl, n-propyl, and isopropyl groups.
An advantage o~ the present invention is to provide the novel 7,7-dimethylnorbornane derivatives of-formula (I) which are use~ul as synthesis intermediates for the preparation of L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine derivativ~ of formula (IV), particularly the compound of formula (IV-l, R-CH3), which are useful as sweeteners having high sweetening power.
Another advantage of the present invention is to provide a process for producing the L-aspartyl-3-(7,7-:~ ' . .
: , , ., - ::
- . : .
.
091~0271~ 4 PCT/US~/~722 dimethyl~orbornyl)-L-alanine derivatives of formula (IV) useful as sweeteners from the novel 7,7-dimethylnorbor- nane derivatives of ~ormula (I).
Another advantag~ of the present invention is to provide novel catalysts use~ul in the preparation of fenchyl alcohol and alpha-fenchene.
In summary the present inventio~ discloses compounds repre~ented by the following formula:
I~Y ( 1 w h ~ r e i n Y i s - C H O , .
NH2 NHCR'~ r C N C O O R H N~
wherein R is hydrogen or a lower alkyl group of one to three car~ons and wherein R' is hydrogen or a lower al~yl group of one to three carbons. The present invention discloses 2R-exo-7,7-dimethylnorbornyl acetaldehyde, 3-(2R-exo-7,7-dimethylnorbornyl)-2-aminopropionitrile and 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin. A compound compri~ing N-acyl-3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine, wherein acyl is acetyl, propionyl, butyryl or chloroacetyl is disclosed in the present invention. ~pecifically, N-acetyl-, WO91/02~11 PCT/~'S~/~722 20~:~014 _9_ 3-(2R-exo-7,7-dimethyl-norbornyl)-D,L-alanine and N-chloroacotyl-3-(2R-exo-7,7- dlmethylnorbornyl)-D,L-alanine are disclosed.
A fenchyl alcohol dehydration catalyst selected ~rom the group consisting of calcined aluminum oxide is disclosed;
specifically, the dehydration catalyst comprising calcined aluminum oxide having Hammett acidity function of -5.6cHS-3.0 is described. Finally, there is also disclosed a catalyst for producing alpha-fenchyl alcohol from trans-2-pinanol, selected from the group aluminum phosphate, niobium oxide and nickel sulfate.
The compounds of formula (I) in accordance with this invention [the compounds of formulae (I-l), (I-2) and (I-33 in the following reaction scheme] may be produced by a synthetic route summarized in the following reaction Scheme A.
~ . ., .: , : .. . . . -WO 91/02~ PCr/US90/~47~2 Re~ç~t ion Scheme A
_ , OH _ _ ~
l~orncrl20110n OH l~m~rlZO~lon 1rcnr-2-pino~ol -~-nchol Vil~rnoior roogcn~ ~ ~
-lonchono doh~dro (1-l) ( 1-1 ) ~=
~N ~
~0; /a~OH)2 t 5 t o r i f i c a t i o n ~, ~N R 2 ( 1-2) ''' : :- . :, . : :.
- :: . ... .
~ ;- :. . ::
.
WO9l/02/ll PCT/~S~/~22 206;,~14 In the abcve Reaction Scheme A, alpha-fenchyl alcohol is prepared in a high conversion and at a high ~electivity by heating tr~n~-2-pinanol to a temperature of 60 to 150C in the presence of one or more catalysts selected from aluminum phosphate, nio~ium oxide and nic~el sul~ate.
This method will be doscribed below in detail. ~ns-2-pinanol used as a starting material in this method can usually be obtained by subjectin~ nopinone (obtained by oxidation of beta-pinene with ozone or potassium permanganate) to Grignard reaction with a methyl magnesium halide tW. Huckel et al., Liebigs, Ann. Chem., 625, 12, (1959)], or by catalytically reducing alpha- or beta-pinene to form pinane, oxidizing it with oxygen and reducing it further ~S. G. Traynor et al., J. Org. Chem., 45, 900 (1980).
Aluminu~ phosphate used as the catalyst in this invention can be obtained by hydrolyzing hydrous aluminum nitrate, hydrous aluminum sulfate, hydrous aluminum chloride or sodium aluminate with an aqueous solution o~ ~ nonmetallic alkali, i.e. ammonia or urea, adding an equivalent weight of ortho-phosphoric acid to the re~ulting aluminum hydroxids to permit precipitation, and calcining the resulting hydrous aluminum phosphate at a temperature of 300 to 800C, preferably 300C, for about 3 hours.
Niobium oxide used as the catalyst in the method of this invention may contain water. Niobium oxide and its hydrate (so-called niobic acid) may generally be produced by precipitation from a solution of a niobium compound such as niobium chloride or niobiuo oxalate by the action of an alkali. U~ually, the resulting precipitate contains a considerable amount of water, but it can be dehydrated almost completely by heating to more than 200C. Niobic acid : , : ::: .:. . : . . .
:. ; . : :: :
. . .
.
WO91/02711 PCT/~S~W72' 6~ 4 -12-obtained by precipitation Erom solution can be used as such or after calcination at soooc or below, as niobium oxide.
Nickel sulfate as another catalyst can be prepared by calcination of a commercially available nickel sul~ate hydrate.
The treatment of trans-2-pinanol in the presence of the catalyst may be carried out at a temperature of 60 to 150C, preferably 65 to ~5C.
The suitable amount of the catalyst used is about l to 10% by weight based on the ~n~-2-pinanol. The reaction in this invention is usually performed without solvent. In view of the separation of the desired compound from the reaction products, the conversion o~ trans-2-pinanol is preferably at least 90%.
After the reaction, tha reaction mixture is filtered to remove the catalyst, and the residue distilled in a customary manner. Alternatively, the reaction mixture may be directly distilled without separation of the catalyst.
The starting trans-2-pinanol includes a (~)-form and a (-)-form, and its optical purity can be determlned by its specific rotation. The present inventors condensed trans-2-pinanol with N-carbobenzyloxy-(D)- or (L)-alanoyl chloride in the presence of pyridine, removed the N-protecting group from the reaction product, and measured its optical purity by gas chromatography ~the gas chromatographic column is, for example, a PEG-HT capillary, 0.25 mm. in diameter, 25 m. in length; made ~y Gasukuro Kogyo Co., Ltd.,). Alpha-fenchyl alcohol obtained by the method of this invention also includes a (+)-form and a (-)-form. The use of either the (+)-form or (-)-form of ~rans-2-pinanol can give either one of theise forms. For example, if the method of this invention is carried out by using t-)-trans-2-pinanol obtained by the ,~, "
. . . ~ : ~ , . . . .
~() (!1~)!~1 I PCr/l:S90/W/2Z
2 0 6 ,~
method of the above-cited Liebigs Ann. Chem., 62S, 12, (1959) as the starting material, (+)-alpha-fenchyl alcohol is obtained without racemization.
The method of this invention can economically give alpha-f~nchyl alcohol useful as a material for a perfume or as a sweetener intermediate as described below.
In the above Reaction Scheme A, fenchyl alcohol is heated in the presence of a ~olid acid catalyst to per~orm a dehydration and isomerization reaction simultaneously to selectively produce alpha-fenchene.
It has now been found in accordanc~ with this invention that aluminum oxide is especially suitable as the solid acid catalyst used in this reaction. Especially suitable is aluminum oxide prspared by hydrolyzing hydrous aluminum nitrate, hydrous aluminum sulfate, hydrous aluminum chloride or sodium aluminate with an aqueous solution of a non-metallic alkali such as ammonia or urea and calcining the resulting aluminum hydroxide. More specifically, thi~ aluminum oxide is obtained by dispersing a lOS by weight aqueous solution of aluminum nitrate hydrate in 28% aqueous ammonia at room temperature to hydrolyze it, separating and recovering the resulting aluminum hydroxide precipitate by filtration in a customary manner, and calcining the resulting aluminu~
hydroxide at a te~perature range of from about 400 to 600C, preferably about 500C, for about 3 hours. The acid strength of the aluminum oxide prepared under these conditions, expressed by the Ham~ett acidity function, is -5.6<~os-3Ø
It is a solid acid o~ a medium acidity.
For the conversion to fenchene the solid acid can generally be used in an amount of 0.1 to 19%, preferably 1 to 5~, based on the weight of the starting fenchyl alcohol.
..... ~ .~ ~- , . . .
: ~ , . , {
,, .
- ~: ,. .
.: . . . ~ . .
'~ ' , . . , : ' ~ . -PCT/~'S~/~72' The reaction temperature is usually in a range from about 150 to 250C, particularly 195 to 2000C. If the reaction temperature is too low, the rate o~ the reaction becomes slow.
The reaction time varies with the ~enchyl alcohol used, but usually a period of time ranging from about 1 to 24 hours suffices.
The presence of water in the reaction system in the above reaction is undesirable, and it is preferred to carry out the reaction in a reactor equipped with a water removing device such as the Dean-Stark device. Usually, the reaction can be carried out without using a solvent.
After the reaction, the reaction mixture is distilled with or without prior separation of the catalyst, and as required, rectified in a rectification column.
The starting fenchyl alcohol may be either alpha-fenchyl alcohol or beta-fenchyl alcohol. Alphafenchyl alcohol can be obtained commercially or prepared from trans-2-pinanol as described above. Beta-fenchyl alcohol can be obtained in a high purity by catalytically reducing fenchone, converting the resulting mixture of alpha- and beta-fenchyl alcohols into their crystalline p-nitrobenzoates, recrystallizing repeatedly, and hydrolyzing the purified product.
Alternatively, a mixture of alpha-fenchyl alcohol and beta-fenchyl alcohol may be obtained by epimerizing alpha-fenchyl alcohol under hydrogen pressure in the presence of a copper-chromiu~ catalyst.
In the production of L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl~-L-alanine methyl ester of formula (IV-1, R=CH3) in particular, the use of (+)-alpha-fenchyl alcohol as the starting material is preferred. ~he (+)-alpha-fenchyl alcohol may be isolated and purified in a high optical purity of, for exa~ple, about 94~ e.e. by crystallizing commercial .. . .
, . .- . . - ~
, . , . . - ~ , . , . -~.-- .. .. . - ~ . . , : .
\~)9lJ0~~ll PCT/~S~/W722 2~6~
alpha-fenchyl alcohol in a hydrocarbon type organic sol-ent at low temperatures.
The commercially available alpha-fenchyl alcohol is generally a mixture of the (+)-alpha-isomer and the (-)-alpha-isomer in a weight ratio of from 80:20 to 70:30.
C.ystallization of the commercial alpha-fenchyl alcohol in an aliphatic hydrocarbon solvent such as n-pentane, n-hexane, isohexane, n-heptane, n-octane and isooctane ~preferably n-heptane or n-octane) gives the (+)-alpha-isomer of high purity, for example an optical purity of 94 S e.e. or more.
The crystallization treatment can be carried out by dissolving the alpha-fenchyl alcohol in the solvent at roo~
temperature or at a slightly elevated temperature and cooling the solution to a temperature of about -10 to -60C, preferably -35 to -60C.
A product having a sufficient optical purity may be obtained by one crystallization, but by repeating the crystallization two or three times, a product of a very high optical purity can be obtained.
The optical purity of the purified (+)-alpha- fenchyl alcohol can be determined by its specific rotation. The present inventors measured the optical purity of the alpha-fenchyl alcohols by gas chromatography of their L-alanine or D-alanine esters (the col o may be, for example, PEG-HT
capillary, 0.25 mm in diameter and 25 m in length, made by Gasukuro ~ogyo K. R.). ~he sample wa prep~red by condensing alpha-fenchyl alcohol with N-carbobenzyloxy-(D) or (L)-alanine using a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3- (3-dimethylamino- propyl)carbodiimide hydrochloride in the presence of N,N-dimethylaminopyridine, or by condensing alpha- fenchyl alcohol with N-butoxycarbonyl-(D) or (L)-aianine using the above dehydrating agent.
..... . ... . . .
: ,, '' ~ , ~ , :: - . , .
WO9l/02,lI PCT/~'S~/~722 ~Q~ -16-The amino protecting groups are then removed by hydrogenation (the N-carbobenzyloxy group) or acid treatment (the N-t-butoxycarbonyl group) prior to G.C. analysis.
In the above dehydration-isomerization reaction o~
fenchyl alcohol to alpha-fenchene, the rate of the reaction of beta-fenchyl alcohol is faster than that o~ its alpha-epimer.
The reaction with beta-fenchyl alcohol generally comes to completion within 3 hours, and alpha-fenchene forms with a selectivity of about 80~. On the other hand, when alpha-fenchyl alcohol is used as the starting material, the selectivity for alpha-fenchene after 16 hours is about 59%.
When a mixture of alpha- and beta-fenchyl alcohols (alpha/beta s 6/4) is used, the selectivity for alpha-fenchene i~
increased to 65~.
The alpha-fenchene so obtained is subjected to the Vilsmeier reaction to form 7,7-dimethyl-2-~ormyl-methylenenorbornane. Stereoselective reduction~ of this product yields 2R-exo-7,7-dimethylnorbornyl acetaldehyde (I-1) .
Tha Vilsmeier reaction of alpha-fenchene can be carried out by a known method described, for example, in C. Jutz et al., Chem. Ber. 100, 1536 (1967). For example, alpha-fenchene is added to the Vilsmeier reagent prepared at room temperature from phosgene or thionyl chloride and an N,N-disubstituted formamide such ac N-methylformanilide;
preferably from phosphoru3 oxychloride and more than one equivalent of N,N-dimethylformamide. The mixture i8 reacted at a temperature of 50 to gooc to give dehydro~ 1) as an E-/Z- mixture.
The resulting 7,7-dimethyl-2-formylmethylenenorbornane [dehydro-(I-1)] is reduced to give 2R-exo-7,7-dimethyl-norbornyl acetaldehyde of for~ula (I-1). Reduction of ~,. . . : : ;i .;, . . .
.: .^~ .: . , . . . . . . . .
~09l/02~ll PCT/US~/W~22 2 ~
dehydro~ 1) may be carried out by a catalytic hydrogenation method using hydrogen in the presence of a noble metal catalyst such as palladium on carbon. As a result, the compound of formula (I-l) can be obtained with an exo-selectivity of as high as or greater than about 95S.
As an alternative, alpha-fenchene may be directly converted to 7,7-dimethylnorbornyl-2-acetaldehyde of formula (I-l) by oxo reaction using various rhodium complex catalysts.
According to this method, the selectivity of the exo-form of formula (I-l) is somewhat inferior to that in the method which goes through dehydro-(I-l).
The oxo reaction of alpha-fenchene may be carried out in the same way as an ordinary oxo reaction described, for example, in W. Himmele et al., Tetrahedron Letters, 907, 1976 and J. Hagen and K. Bruns, U.S. Patent No. 4,334,100. For example, alpha-fenchene is hydroformylated with a gaseous mixture of carbon monoxide and hydrogen a~ a temperature of about 30 to about 150C under a gas pressure of about ~5 to about 150 kg/cm2 in the presence of a rhodium complex catalyst, for example a rhodium carbonyl complex such as Rh6(CO)16, RhCl(CO)(pph3)2 (pph3 stand for triphenylphosphine), RhH(CO)(pph3)3, [Rh(COD)X~2 ~COD stands for cyclooctadienyl and X i5 halogen, acetate) or Rh(COD)(acac) (acac stands for acetyl acetonate).
The resulting 2R-exo-7,7-dimethylnorbprnyl acetaldehyde of formula (I-1) is then reacted wi~h ammonia or ammonium chlorido and hydrogen cyanide or an alkali cyanide in accordance with Strecker'samino acid synthesis method [see, for example, J.P. Green~tein & M. Winitz, "Chemistry of the Amino Acids," Vol. I, pg. 698-700 (1961); R. Gardry, Can. J.
Res., ~, 301 (1946)]. The resulting 3~(2R-exo-7,7-dimethylnorbornyl) -2-amino propionitrile (I-4) is hydrolyzed ~.
; -091/0271l 6~4 PCT/US~/~22 under acidic conditions created by a mineral acid such as hydrochloric acid, hydrobromic acid or hydriodic acid to give 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine of formula (I-2).
The Strecker reaction can be conducted in alcoholic or mixed alcoholic-aqueous solution using ammonia gas or ammonium hydroxide solution. The cyanide can be supplied as the Li, Na or K salt, the more soluble Li and Na salts being preferred.
Reaction temperatures of 0 to 30OC may be employed, the time being adjusted accordingly. After removal of the solvent by evaporation the residue is treated with a strong base (such as NaOH, KOH or Na2CO3) and the aminonitrile extracted with ether, toluene, or any suitable organic solvent which does n~t react with the amino function.
Hydrolysis of the resulting 3-(2R-exo-7,7-dimethyl-norbornyl~-2-amino propionitrile is best achieved by refluxing in approximately 10 ~ HCl solution for 18 hours. ~Lower acid concentrations may be used, but longer reaction times are required. Shorter reaction times may be achieved by heating at elevated temperatures in an autoclave. Other acids may also be employed such as hydrobromic or sulfuric.
Hydrochloric i5 particularly useful in that the product can be obtained as the hydrochloride by direct crystallization from the cooled, concentrated reaction mixture.
An alternative method for producing the amino acid of formula (I-2) involves preparation of an intermediate hydantoin. In this procedure, the 2R-exo-7,7-dimethyl-norbornyl acetaldehyde of formula (I-l) i~ reacted with an alkali metal cyanide and ammonium carbonate. ~8~cherer-Berg reaction - SQe H. R. Henze and R. J. Speer, J. Am. Chem. Soc., 64, 522-3 (1942) and E. Wade, Chem. Rev., 46, 441-4, (`1950)].
,~.. .. .. ~ . ..... . .
, . . : .. -: ~ : . . . ~ ' . - ' . .:
~91102~11 PCT/~S~/~722 -19- 20~ 14 The resultinq hydantoin (I-5) is then hydrolyzed with a strong aqueous base [NaOH, ~a(0~)2] to afford the amino acid (I-2).
In a typical procedure, one mole of the aldehyde is heated at 50-70C for 8-24 hours with 2-5 moles of (NH4)2C03 and l.l moles of NaCN in an aqueous ethanolic solution. The mixture is cooled, concentrated and acidi~ied to pH ~~ 5 to precipitate the product (I-5) as a white solid.
Hydrolysis of (I-5) to the amino acid (I-2) is then achieved by refluxing in 1.5 M Ba(OH)2 solution for 72 hours.
The 3-(2R-exo-7,7-dimethylnorbornyl)alanine of formula (I-2) produced as above is generally obtained as a mixture of the D-form and L-form. The mixture must, therefore, be optically r solved and the L-form suitable a a sweetener intermediate recovered.
Optical resolution may be carried out before or after the compound of formula (I-2) is esterified.
Esterification of the compound of formula (I-2) can be carried out by reacting it with a lower aikanol having from one to three carbon atoms.
For example, esterification of (1-2) with methanol is readily achieved by heating a solution of the amino acid in methanolic hydrogen chloride solution for 18 hours at reflux.
Evaporation of the solvent af~ords the amino ester hydrochloride. The free base (I-3, R'CH3) is then obtained by neutrali~ing an aqueous solution of the hydrochloride with a suitabl~ base (~OH, NaOH, Na2CO3) and extracting the product into ether, toluene or other organic solvents which are not base-sensitive. Evaporation of the extract gives the pure amino e~ter (I-3, R - CH3).
Optical resolution of 3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine (I-2) or its lower alkyl ester (I-3) may be ..... . -: . ,, ; , .
, ~
6 PCT/~S~/W722 carried out by known methods such as using D-tartaric acid or an enzyme.
(1) Optical resolution with D-tartaric acid is practiced on the 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine lower alXyl ester by heating a one to one mixture of D-tartaric acid and the amino ester in methanol until the D-ta.taric acid goes into solution. The solution is then cooled to induce crystallization. Two further recrystallizations gives matçrial of >95% ee.
If possible, the alcohol used for the crystallizations should be the same as that represented by the R group of (I-3) so that trans-esterification is avoided.
(2) Optical resolution by the enzy~e method.
The compound of formula (I-2 or I-3) is N-acylated ~for example, N-acetylated or N-chloroacetylated) in a known manner and acylase is caused to act on the acylated compound in an aqueous medium. A~ a re~ult, the L-for~ of N-acyl~3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine or its ester i8 selectively deacetylated to give 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its ester.
The acylase that can be used in the enzyme reaction may be of any type which has the ability to hydrolyze the L-form of an N-acylamino acid selectively tsee for example I. Chibata, et al., in K. ~osbach, ed., Methods in Enzvmo}ocv, Vol. 44, 746-59, (1976)]. It may be originated from an animal source, a plant source or a microorganism source. Since the acyla~e reaction $s qenerally carried out in weak alkalinity, the acylase preferably has an optimal pH in the range of from about 6 to 9. ~he acylase may be obtained by culturing a microorganism, for example a mold of the genus Aspergillus or Penicillium, a bacterium of the genus Pseudomonas, or an actinomyces of the genus Streptomyces, and recovering the .
,. . ~ , : . . .
~ . , .: . . . -:- ~ ~ ;. : . . ' - :
:: . . . : . . : , : . :
, w091/02~1I PCT/~S~/W722 2~ 01~
acylase from the culture. For example, Acylase I (Sigma Chemical company) and Acylase "Amano" (Amano Pharmaceutical Co., Ltd.; derived from As~erqill~s welleus~ are co~mercially available.
Deacylation of the N-acyl-3-(2R-exo-7,7-dimethylnor-bornyl)-D,L-alanine (I-6) or its ester using such an acylase may be carried out in the same way as in an ordinary enzy~e reaction. For exampl~, the N-acyl compound is dissolved or dispersed in an aqueous medium. ~he pH of the medium is adjusted to the optimal pH of the acylase with an alXali such as sodium hydroxide or sodium carbonate. If desired, an enzyme stabilizer such as cobalt chloride hexahydrate is added so that the cobalt ion concentration becomes 10-6 to 1o~2M.
The reaction is carried out at a temperature range of from about 35 to 40C for several hours to more than 10 hours.
After the reaction, the pH of the reaction mixture is adjusted to an acidic pH, for example about 1 to about 2, and the unreacted N-acyl-3-(2R-exo-7,7-dimethylnorbor- nyl)alanine or its ester is separated and recovered usinq a solvent such as ethyl acetate, methylene chloride or chloroform. In the case of the acid (I-2) the aqueous layer is adjusted to a pH
range of from about 3 to 5 with aqueous ammonia. The desired 3-(2R-exo-7,7-di~ethylnor- bornyl)-L-alanine precipitates as crystals. ~he crystals are separated and purified by a customary method, for example by treat~ent with activated car~on in hot water. White purified 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine can thus be recovered. In the case of the ester (I-3, R=CH3) the aqueous layer is adjusted to pH 8-9 (instead of 3-5) and the product isolated by extraction with a solvent such as ethyl acetate, chloroform or methylene chloride. Evaporation of the solvent gives 3-(2R-.~, . ~, . . .
:
.
WO ~1/02~ PCT/I S90/04~22 exo- 7,7-di~ethylnorbornyl)-L-alanine methyl ester as a liquid.
The purified 3-~2R-exo-7,7-dimethylnor~ornyl)-L- alanine or its ester has an optical purity, determined by gas chromatography using a specially worked capillary (G-800 column made by Chemical Inspection & Testing Institute) after N-trifluoroacetylation and as required esterification, of substantially 100%.
~ he unreacted N-acyl-3-(2R-exo-7,7-dimethyl- norbornyl)-D-alanine or its ester ~ay be converted to 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its ester by a Xnown method, for example, by treating it with acetic anhydride to racemize it, and subjecting the racemate again to the acylase reaction.
The N-acyl derivative of (I-2) used in the above enzymatic resolution procedure can in principle also bQ
prepared by the direct amido carbonylation of either alpha-fenchene or the 7,7-dimethylnorbornyl-2-acetalde- hy~de O
(I-l) using CO/H2, R-C-NH2 and a catalyst. ~The amido-carbonylation reaction -- see I. Ojima, J. Mol. Catal., 37, 25-44 (1986); P. Magnus and M. Slater, Tet. Let., 28, 2829 (1987~; K. Izawa, Svn Ora. Chem. J~., 46, 218 (1988) and Japanese Patent No. 61/236760.
Typical condition require the alkene (or aldehyde), a combined cobalt-rhodium catalyst, carbon monoxide, acetamide, hydrogen (500-2000 p5i) and a temperature of 80-150C for 1-10 hours.
A third method of resolving the amino acid of Formula (I-2) can also ~e envisioned, which involves treating the hydantoin (I-5) with a microbial enzyme capable o~ selective hydrolysis of the hydantoin ring to afford the L-amino acid.
Although most hydantoinase enzymes give the D-amino acid as .. .
::. : - : .
.:: . : : . . -,: .
. .
. , -, . ~
WO 9 1 /027 1 I Pcl /us9o/w722 2 o ~ 4 the only product, the enzyme isolated from ~3C~ brevis has been found to give the desired L-isomer in the case of valine hydantoin. [(See A. Yamashiro et al., Aaric. ~iol. Chem., 52, 2851-2856 and 2857-2863, (1988).]
Treatment of hydantoin (I-5) with the enzyme and reaction conditions described by Yamashiro et al., hould give 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine (I-2).
The compound of formula (1-2 or 1-3) produced as above is useful as an intermediate for production of the compound of formula (IV) which is useful as a non-nutritive sweetener.
The sweetener compound of formula (IV) can be produced from the compound of formula (I-3) by a synthesis route summarized in the following Reaction Scheme B.
. . .
:.... . , :. , . . ., :
:-, . .. , . .. , : , .
: . ... . : : .
: . .. . . :~:
WO 91/02711 Pcr/~sso/o4722 6~ 4 -24-Reaction Scheme ~
_ _ ~ `
\/
,NH2 +
COOR l-H
~1-3) (Il) NH-Z
(l-form) ~ .
~\CH-NH-C-CH2-CH i ~\CH-NH-C-CH-CHl-COOH
COOR COOH (111 olpho) -:~
(111 b-t~) ~limln3tlon o~ tho , omino prot~cting group : -/ \CH-NH-C-CH-CHl-COOH
COOR ( V ) - _ _ _ __ ~.
: . :, . . ~ . . -.: . .
~, ' ~ ' " '"- ~ ' ' : ' :' :: ..
~ )91/02~1l PCT/US90/~722 20~3014 In the above scheme, Z represents a protective group for the amino function. (See M. Bodansky, "Principles of Peptide Syntnesis," Springer-Verlag, Berlin, (1984) pp. 90-102) and R is as defined above. Typical examples of Z include the allyloxy carbonyl [I. Ninomi et al, Tet.
Let., 26, 2449 (1985); O. Dangles et al., J. Ora. Chem., 52, 4984-93 (1987)], the formyl (U.S. Patent No~.:
4,684,745, 3,879,372 and 3,933,781), the t-butoxycarbo-nyl, tD. T. Witiak et al., J. ~ed. Che~. 14, 24-30 t1971)]; and the carbobenzyloxy (U.S. Patent No. 4,508,912; EP 22730~; July 1, 1987). The latter is particularly useful in that it can be readily removed by catalytic hydrogenation.
In the Reaction Scheme B, the compound of formula (I-3,L-form) is reacted with an N-protected-L-aspartic acid anhydride in a non-protic solvent to yield the desired alpha-(~-protected-L-aspartyl)-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine alkyl ester (I~I alpha). In addition, a small (10-20%) amount of the beta-(N-protected-L-aspartyl)-3-(2R-exo-7,7- dimethylnorbornyl)-L-alanine alkyl ester (III beta) is also produced. The amount of by-product (III beta) formed in the reaction can be controlIed by variations of the reaction conditions as shown in Table 5 for Z = carbobenzyloxy (=CBZ).
Si~ilar solvent effects on the coupling of (II) (Z=CBZ) with phenylalanine methyi ester have been observed by Yang and Su tJ. Ora. Chç~, ~, 5186-91 (1986)] and T. Yukawa et al, EP 227301~.
The undesired (III beta) can be separated from ~III alpha) by partitioning between a suitable organic solvent and an aaueous buffer of the proper pH. In WO 91/0271 I PCI/I.'S90/04722 previous reports of this type of separation tw.
J. LeQuesne and G. T. '~oung, J. Chem. Soc., 24-28 (1952) and W. D. John and G. T. Young, J. Chem. Soc. 2870 (1954) ], alpha/beta-N carbobenzyloxyaspartylglycine m e t h y 1 e s t e r , a 1 p h a / ~ e t a - N -carbobenzyloxyaspartyltyrosine methyl ester, alpha/beta-N-carbobenzyloxyaspartylglutamic acid diethyl ester, and alpha/beta-N-carbobenzyloxyaspar- tyl-valine were separated by extraction of ethyl acetate solutions with aqueous sodium carbonate (concentration and pH
unspecified).
In a further example alpha and beta-NCBZ-aspartylphenylalanine methyl esters were separated by extraction of the beta- isomer from ethyl acetate using buffer of about pH 6-7 ~ t ~ S ~ Patent No. 3,808,190). No indication of the purity of the separated isomers was given.
We have folmd in the case of (III alpha) and (III beta) (Z=CBZ) that the pH of the aqueous pha~e mu t be carefully controll~d (See Table 6)o In addition, the choice of organic phase is also important. Good separation is achieved with ether and toluene, only modest partitioning with ethyl acetate and no separation at all with hexane or butanol.
on a preparative scale, the extraction of a 1%
toluene solution of the crude coupling mixture (III alpha/beta, alpha/beta~5/1, Z~CBZ) with three portions of p~ 6.5, 0.1 ~ phosphate buffer gives (III alpha) in 50-70% yield and a purity of 93-98%. The remaining (III beta) is removed during crystallization of (IV).
.~ '.:
' .: -WO 91/0271 ~ PCl/US90/1)4722 2 ~
Removal of the CBZ group from (III alpha) is readily achieved by hydrogenation at 2-3 kg./cm.2 using palladium on charcoal as catalyst in a methanol solution. ~he catalyst is removed by filtration through celite and the filtrate evaporated to give crude (IV). Sweetener (IV) is purified by crystallization ~rom chloroform-hexane.
In addition we have also ~ound that pure (IV) can be obtained from the original (III alpha-III beta) mixture (- 9/1, III alpha/III beta) by hydrogenation as mentioned and repeated crystallization from methanol-water as shown in Table 7. Tha procedure is most effective when the (III alpha)/(III beta) ratio from the coupling reaction is high (III alpha/III beta >8/1).
A similar separation of alpha-N-aspartylphenylala-nine methyl ester fro~ the beta- isomer by crystallization from water or water-alcohol mixtures has been described previously in U.S. Patent No. 3,786,039.
An alternate coupling procedure which avoids the above formation o~ a product mixture of alpha- and beta-dipeptides involves performing the reaction using (I-3, R=CH3) and a diprotected aspartic acid derivative (V~
;
.......... ,.. ~ ~ . : ;
Wo 9l/02711 PCT/US~/W122 _ N H Y ( V ) X O O C/ C O O H
where X = benzyl or t-butyl and Y = carbobenzyloxy or t-butoxycarbonyl. (t-BOC) [M. Bsdansky, "Principles o~
Peptide Synthesis,~ Springer-Verlag, Berlin, 70-79 and 90-102 (1984)~ The coupling reaction may be carried out by first converting the ~ree carboxyl of the aspartic acid moiety to an activat-d leaving group by treatment with i.e. p-nitrophenol/DCC, N-hydroxy~uccinimide/DCC, isobutylchoroformate/N-methylmorpholine, or the like, followed by the addition of (I-3, R~CH3). Alternatively, it may be performed using DCC in organic solvents at a temperature range of from about -20 to 30C. ~See M. Bodansky, loc. cit., pg. 9-58; U.S. Patent No.
4,788,069 and J. W. Tsang et al., J. Med Chem, 27, 1663-1668 (1984).] The resulting intermediates may then be converted to (IV) by deprotection employing catalytic hydrogenation under standard hydrogenation conditions (Pd/C, MeOH, H~ pressure 10-50 psig) for Y 3 CBZ and X ~
benzyl. In the cas- where Y ~ t-~OC and X ~ t-butyl, the deprotection may be carried out in organic solvents w09l/o'7ll PCT/~'S~/~2~
2o~t~vl 4 employing strang acids [HCl, trifluoracetic acid (TFA) or the like] with ~IV) being obtained ~ollowing neutralization of the resultant salt.
The following examples illustrate the present invention more specifically.
Conversion of trans-2-pinanol to alpha-~enchyl alcohol.
PreDaration of Catalvs~s Catalysts A, B and C used in the following Runs were prepared as follows:
Catalyst A
Commercial reagent, aluminum nitrate nonahydrate [Al(NO)3 9H20] (a product o~ Junsei Chemical Co., Ltd.), 150 g., was dissolved in 800 ml. of water, and 27 ml. of 8S% phosphoric aoid (a product of Nacalai Te~gue, Inc.) was added to the solution, and while the mixture was being stirred at room temperature 240 ml. of 10 % aqueous ammonia was slowly added dropwise to adjust its pH to 7.
The resulting precipitate was left to stand overnight, filtered, thoroughly washed with water, and dried at 60C
for 24 hours to give 65 g. of product. It was powdered in a mortar to give a powder having a size sma~ler than 40 mesh.
Catalvst B
Hydrous niobium hydroxide (Nb205-xH20, a product o~
Companhia Brasileira de Metalurgia E Mineraç~o) was pulverized to a size smaller than 40 mesh.
'. '-' ' ,, - '' .' . , - :
.: . . . .
WO 91/0271 I PCT/I,'S90/W7'2 Catalvst C
Nickel sulfate hexahydrate (NiSo4-6H2o, a product of Nacalai Tesque, Inc.) was calcined at 250C or 350C for 3 hours to reduce its size to smaller than 40 mesh.
Catalyst A was calcined at 300C for 3 hours, and used in this example.
A four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 35 g.
(0.227 mole) of trans-2-pinanol (a product of Glidco Organics) and 2.0 g. of the catalyst, and with stirring, it was reacted at 75C for 16 hours. The reaction product was coarsely distilled to give 29.1 g. of an oily product. Gas chromatographic analysis showed that the conversion was 98.2 S, and the selectivity of alpha-fenchyl alcohol was 48.1 %. The reaction product was rectified to give 15.3 g. (theoretical yield 42.9 ~;
purity 98.3 %) of alpha-fenchyl alcohol.
RU~ 2 A four-necked flaak equipped with a stirrer, a thermometer and a reflux condenser was charged with 35 g.
(0.227 mole) of trans-2-pinanol (a product of Glidco Organics) and 2.0 g. of catalyst B, and it was reacted at 75C for 63 hours. The reaction mixture was treated a~
in Example 1 and analyzed by gas chromatography. The conversion was 99.3 %, and the selectivity of alpha-fenchyl alcohol was 52.3 %.
Catalyst C was calcined at 250C for 3 hours, and used in this example.
A four-necked flask equipped with a stirrer, a thermometer and a re~lux condenser was charged with 35 g.
. ~ ~ . ....... . . . .............................. - . , .
, , : ... ,,.,., . :. . .
. . ~ .
WO 91/0271 I PC~ S90/0~722 -31- 205~V14 t0.227 mole) o~ trans-2-pinanol (a product of Glidco Or~anics) and 2.0 g. of the catalyst, and it was reacted at 75C for 20 hours. The conversion was 51.0 ~, and the selectivity of alpha-fenchyl alcohol was 40.6 %.
As in Runs 1 to 3, alpha-fenchyl alcohol was producsd from trans-2-pinanol using catalyst A, B or C
prepared as abo~e at the calcination temperatures and reaction temperatures indicated in Table 1. The results are shown in Table 1. In the examples, gas chromatographic analysis was carried out using a Shimadzu GC-9A (made by Shimadzu Seisakusho Ltd.) with a PEG-HT
capillary 0.25mm. in diameter X 25m. in length (made by Gasukuro Kagyo Co., Ltd.). The column temperature was 100C.
! ' . . ' .
''' ' ' .. ' ~" ~ , ' : ' :` ~ ' ' ~,. . ' . ' WO91/02711 PCT/US~/~22 2 a 6~ 4 -32-_ Calci- Reaction nation conditions Con- Selectivity tempera- version of ~-fenchyl Run Cata- ture (%)alcohol lyst (C) (%) ~emper- Time ature (hr) (C) _ 1 300 75 16 98.248.1 2 _ 75 63 99.352.3 3 C 250 75 20 51.0 40.6 _ _ _ 4 300 110 6 100 41.2 n 500 110 6 lOQ 36.0 _ . _ 6 n 800 110 3 100 35.0 7 _ 110 18 99.3 45.4 8 ~ 200 75 18 97 . 8 46.1 9 ~ 200 110 4 100 34.2 - 300 75 22 99.4 43.2 11 n 400 75 22 99.4 42.7 _ _ 12 500 75 19 98.5 41.7 :- .
13 n 600 75 20 34.1 40.0 .
14 C 2S0 110 18 100 24.8 350 75 18 23.9 34.4 16 3S0 110 15 97.3 20.3 - : . , .:
.
.
, .
`
WO9l/02~11 PCT/US90/~72~
2 0 ~
Example 2. Purification of (+)-alpha-fenchyl alcohol Commercial alpha-fenchyl alcohol (~]23D-+10.0(c-5, ethanol), mp. 43.2c; 709.2 g) was dissolved in ~55 g. of n-heptane, and the solution wa~ cooled to about -33C. The crystals that precipitated were separated by filtration to gi~e 493.6 g. of a first crop of crystals ([~]2~'+11.6, mp. 45.2) The residue (228.9 g.) left after evaporation of the filtrate was dissolved in 160 g. of n-heptane and the solution was cooled to -50C. The precipitate was filtered giving 128.6 g. of a second crop of crystals ([~]2~=+10.2, mp. 43.2C). These crystals were of the same quality aR the starting mat¢rial.
They were again dissolved in 64 g. of n-heptane, and the solution was cooled to about -33C. The crystals that precipitated were separated by filtration to obtain 94.0 g. of the crystals ([~]23=+11.5, mp. 45.1C~. These crystals were combined with the first crystals (total 587.6 g.) and dissolved in 411 g. of n-heptane. The solution was cooled to about -35C. The crystals that precipitated were separated by filtration to obtain 416.1 g. of second crystals ([~]a~=+11.9, mp. 45.7C). The second D
crop of crystals (416.2 g.) was dissolvQd in 310 g. of n-heptano, and the solution was cooled to -31C. The crystals that precipitated were separated by filtration to obtain 218.9 g. of third crystal3 ([~2~,+l2.2o~ mp. 46.4C) : ::
': : . . .. .
:.:: ~ ,: . - ~ : .
: ~ - - .. -WO91102~11 PCTtUS~/W,2 9 ~ 5 ~ ~
The mother liquors of the second crystals and third crystals were combined, and the solvent was reco~ered to yield 298.7 g. of crystals ([~]23=+9.84O). The resulting crystals were subjected to three cycles of crystallization in the same way as above to give 84.2 g. of fourth crystal~
([~]23=+l2.2, mp. 46.1C). The third crystals and fourth crystals were combined to obtain 363.2 g. of the desired t+)-alpha-fenchyl alcohol in a yield of 5l.2 %.
The optical purities of the resulting crystals were measured by the method described below. The results are tabulated below.
Ta~le,2 optical Specific purity rota,,~iQ~ (,% e-e- L
Starting +lO.0 81 material First crystals +ll.6 89.9 Second crystals +ll.6 92.l Third crystals +12.2 94.8 Fourth crystals +12.1 94.6 Mea~ur,ement of ~he O~ti~al P4~ity N-carbobenzyloxy-L-alanine (0.31 g.; 1.4 m~, O.Ol g.
(O.1 mM) of N,N-d$methylaminopyridine (DMAP) and 0.2 g. (l.28 mM) of fenchyl alcohol were dissolved in 2 ml. of methyl~ne chloride. In a stream of nitrogen under cooling, 0.27 g. (1.4 mM) of l-ethyl-3-(3-di- methylaminopropyl~carbodiimid-hydrochlorid~ (WSC) was added to the solution, and reacted for about 30 minutes. The temperature was returned to room ,i- , . .
~O9l/02~1l PCT/~'S~/~722 2 0 ~
temperature, and the reaction was carried out for about 1 hour. Methylene chloride was added to the reaction solution to adjust the total amount of the reaction mixture to 10 ml.
It was washed with a 10% aqueous solution of citric acid, a 4%
aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated at less than 40OC. ~he residue was dissolved in 5 ml. of methanol 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: PEG-HT, 0.25 mm. in diameter and 25 m. in length Introduction temperature: about 200C.
Column temperature: a range from about 100 -200C, 3oC/min.
Retention time: a range of about 11-12 min.
Separation coefficient: 1.02 Preparation of alpha-fenchene from fenchyl alcohol 1. Preparation of aluminum oxide catalysts ;~
(a) Catalyst A
Two hundred grams of aluminum nitrate nonahydrate [Al(N03)3~9H20; reagent first class produced by Junsei Chemical Co., Ltd.~ was dissolved in 2 liters of water. The solution was slowly added dropwise with stirring to 500 g. of 28%
agueous ammonia. After standing, the resulting aluminum hydroxide was aged overnight, filtered, washed with water, and dried at 60C for 24 hours to give 43 of aluminu~
hydroxide. It was powdered in a mortar anc calcinQd in an , , ,. : . , - . :
: . -: : .. .-: -. ~. - -- -: .: ~,- . : : - -, :, :: . , - ' -: , : . . :- , : - : ~ -W0~l/0271l PCT/~S~/W~22 ~e5~ 4 electric furnace at 5000C for 3 hours to give 28.4 g. of aluminum oxide as a white powder. The Hammett acidity function H~ of this product was -5.6<H S-3Ø
o (b) Catalyst B
Two hundred grams of aluminum sulfate 14- to 18-hydrate tA12(S0~)3-14-18 H20; r~agent first cla~s produced by Junsei Chemical Co., Ltd.~ was dissolved in 2 liters o~
water. Aqueous ammonia (10% by weight) W2S added dropwise to the solution until the solution reached pH 8. The resulting aluminum hydroxide was fully washed with a large amount of water, and dried at about 60C for 24 hours. The dried product was powdered in a mortar and then calcined in an electric furnace at 5000C for 3 hours to give 70 g. o~
aluminum oxide as a white powder. The Hammett acidity function Ho of the product was -5.6<Hos-3Ø
(c) Catalyst C
Two hundred grams of aluminum chloride hexa- hydrate [AlC13.6H20; reagent first class produced by Junsei Chemical Co., Ltd.] was dissolved in 2 liters of water, and then treated as in the preparation of catalyst B to give 62 g. of aluminum oxide. The Hammett acidity function of this product was -5.6<H S-3Ø
(d) Catalyst D
Two hundred grams of sodium aluminate [NaA102 xH20;
reagent first class produced by Nakarai Tesque Co., Ltd.]
wa~ dissolved in 2 liters of water. With stirring, the solution was added to an aqueous solution of hydrochloric acid (250 g/3 liters) to adjust the solution to about pH 8. The precipitate was ~eparated by filtration, dried .
:: , ,: :- : - . .
osl/o2~1l PCT/~'S~/W72 _37_ 2 0 S i 0 1 ~
at 60C for 12 hours, and washed five times with 500 ml.
of 14% aqueous ammonia. The washed product was dried at 60C for 24 hour~, powdered in a mortar, and calcined in an electric furnace at 500C for 3 hours to give 115 g. o~
aluminum oxide as a white powder. The Hammett acidity function of this product was -5.6~H~<-3Ø
2. Production of (+)-alpha-fenchene (a) A three-nec~ed flask equipped with a Dean-Stark device, a stirrer, a thermometer and a reflux condenser was charged with 100 g. (0.65 mole, purity 98.7%) of alpha-fenchyl alcohol and 5 g. (5% by weight) o~
catalyst A, and with stirring, the mixture was heated at a temperature range ~rom ab~ut 195 to 200C for 10 hours.
The reaction mixture was then coarsely distilled to give 95.8 g. of an oily product. Gas chro~atographic analysis showed the oily product to consist of 72% o~ fenchene isomers (in which alpha-fenchene accounted for 59%~ and 28% of unreacted fenchyl alcohol. Rectification of the oily product gave 34.4 g. of (+)-alpha-fenchene (yield 54.1%; purity 98.7%; Run No.l).
Boiling point: 157-158C (730 mm Hg) (t~ '+36.27(neat) H-NMR (~DC~3) 0.97 and 0.98 (each 3H, s), 1.20 - 1.34 (2H, m), 1.65 (lH, t), 1.79 - 1.96 (3~, m) Z.03 (lH, d), 2.41 (lH, d) ,;, ,, ; , .. ' ' '. . ~ :
': " " , '' '' . ~ , ' . , ' ~ ~
: ' ' '- ' ' : ' ' : :
`~ 38-4.60 and 4.81 (each lH, s) Mass Spectrum (m/e):
136 (M+), 121, 107, 93, 79, 53, 41, 39.
(b) Catalyst A (5%) was added to a mixture of (+)-alpha-and (+)-beta-fenchyl alcohol (alpha-/ beta--6/4). The mixture was treated as in section (a) above to obtain an oily product. Gas chromatographic analysis showed the product to comprise 95% of fenchene isomers (in which (+)-alpha-fenchene accounted for 65%) (Run No.2).
(c) Catalyst A (5% by weight) was added to (+)-beta-fenchyl alcohol (purity 95%). ~he mixture was heated at a temperature range of from about 195 to 200C for 3 hours with stirring and then coarsely distilled. Gas chromatographic analysis of the distillate showed it to comprise 98% of fenchene isomers (in which (+)-alpha-fenchene accounted for 80%) (Run No.3).
(d) Using catalysts ~, C or D, (+)-alpha-fenchene was produced from (+)-alpha-fenchyl alcohol~ The results are shown in Table 3 below (Runs Nos. 4 to 6).
(e) The procedure as in (a) aboYe was repeated except that catalyst A was replaced by commercial aluminum oxide catalysts having a Hammett acidity function of +l.5<HoS+3. 3 and +3.3<Ho<+4.8.
(Runs Nos. 7 and 8), a catalyst obtained by calcining nickel sulfate hexahydrate at about 250C for 3 hours (Run No. 9), a catalyst obtained by calcining nickel sulfate hexahydrate at about 400C ~or about 3 hours (Run No. 10), aluminum sulfate (Run No. 11), a catalyst obtained by calcining aluminum phosphate at about 500C for about 3 hours (Run No.12), aluminum silicate (Run No. 13), alum " - . ,:
:- .. . , . :::
.,- :- .
.. . . ., .. : . . :
: :: :.
: - ~ : .: ~ : - , :-~0 91/02-1 I PCI/I S90/W7'' 2 ~
-3~-(Run No.14) or acid clay (Run No. 15). The results are also shown in Table 3.
. - . . . ~ ;... , :
W09l/027lI PCT/US~/W72' 2n~
vu~01440 ~able 3 __ Amount of the Reaction cata- conditions Total Alpha-Starting lyst fen- fen-Run Catalyst fenchyl based chene chene No. alcohol on tha selec- selec-fen- tivity tivity alhycl_ Temp. Time hol(C) (hr) (%) (%) (wt~) _ _ Catalyst A ~- 195-200 10 72 59 2 Catalyst A ~/B=6/4 5 195-20010 95 65 3 Catalyst A B- S 195-200 3 98 80 4 Catalyst B ~- 5 195-200 10 82 44 Catalyst C ~- 5 195-200 10 70 47 6 Catalyst D ~- 5 195-200 10 70 53 7 Active ~- 10195-200 16 20 36 alumina . .
8 Active ~- 10195-200 16 . 4 32 alumina _ 9 NiSo~-6H2o ~- 50 195-200 4 100 2 NiS04 CHa I ~- ¦50¦195-200¦ 4 ¦ 98 ¦ 10 ¦ 11 A12(SO~)3 ¦ ~ ¦ 50¦195-200l 4 1 88 1 6 12 A1106 ~- 50195-200 16 ~ 8 23 : . :: : :
:
:: :-. .-: :, ' -, ' `,, `
~ 91/0'71 I PCT/I~'S9~/W722 --41-- 3 t~ 1 ~
_ _ _ 13 Aluminum ~- 50 195-200 6 97 . 5 O
silicate 14 Alum ~ - 5 0 19 5 - 2 0 0 16 7 7 . 4 1 lS Ac id clay . 5 19 5-2 00 7 94 . 9 4 - :, . . ~ ,- . . - ~ . -. - - ~ .; , . . .
091/0271l Pcr~us~/~722 2 e 6~ 4 -42-The fenchenes were analyzed ~y gas chromatography using a gas chromatographic device ("Shimazu" GC-9A made by Shimazu Seisakusho Co., Ltd.~ using an OV-l silica capillary column (diameter O.25 mm., length 25 m.); made by Gasukuro Kogyo Co., Ltd.) at a temperature of about 700C.
Production of 7,7-dimethyl-2-formylmethylenenorbornane:
Fifty grams (0.368 mole) of (+)-alpha-fenchene obtained as in Example 3 was added dropwise under a nitrogen stream at 50 to 60C over about 1 hour to a solution which had been prepared by adding 38 ml. (0.415 mole) of POC13 to 92.5 ml.
(1.19 mole) of DMF over about 1 hour. The mixture was reacted for 2 hours. The reaction solution was poured into 800 ml. of a lOS aqueous solution of sodium carbonate, and extracted twice with 300 ml. of toluene. The combined toluene extracts were washed with water, and the solvent was evaporated.
Fractional distillation under reduced pressure gave 50.5 g.
(yield 71%) of the captioned compound.
Boiling point: 76 - aooc/l mm Hg ~H-NMR (CDC13 solvent, TMS internal standard, ~):
E-form 0.98 and 1.08 (each 3H, s, CH3), 5.94 (lH, d, J27.9 Hz, olefinic H) and 9.79 (lH, d, J=7.9 Hz, CHO).
Z-form 0.97 and 1.08 (each 3H, s, CH3), 5.86 (lH, d, J=8.4 Hz, olefinic H), 9.84 (lH, d, J=8.3 Hz, CHO).
, .
wO9~/U2~1l PCT/~'S~/~722 _43- 2~S~14 Mass Spectrum (m/e):
E-form 150, 125, 109, 107, 82, 81 (base), 79, 67 and 41.
Z-form 165 (M~+1), 164 (M~), 149, 121 (base), 93, 91, 19, 77, 41 and 39.
Production of 2R-exo-7,7-dimethylnorbornyl acetaldehyde:
(a) A 1 liter autoclave was charged with 20 g. (0.12 mole~ of 7,7-dimethyl-2-formylmethylenenorbornane obtained as in Example 4 above, 200 ml. of n-heptane and 0.5 q. of 5~
palladium-carbon, and the reaction was carried out at room temperature under a hydrogen pressure of 2 ~g./cm.2. After the reaction, the catalyst was filtered and the solvent was evaporated. The residue was distilled under reduced pressure to give 19.7 g. (yield 97.3%) of the captioned compound. The exo/endo ratio of this compound wa~ found to be 98:2 by measurement of lH-NMR.
Boiling point: 54 - 55C/0.2 mm ~g H-NMR (CDCl3 solvent, TMS internal standard, ~):
~o-form 0.97 and 1.08 (each 3H, s, CH3), 2.60 (2H, d, d, d, J=2.1, 9.6, 5.9 Hz; CH2CHO~) and 9.71 (lH, t, J=7.9Hz; CHO).
Endo-form 1.02 ?nd 1.08 (each 3H, s, CH3), 9.76 (lH, t, J=7.9 Hz, CHO).
~'O9l/0271l PCT/US~/W722 L~ Q ~ 4 Mass Spectrum (m/e): 166 (Ml), 151, 133, 123, 122 (base), 107, 95, 81, 79, 69, 67, 55, 41.
(b) A 200 ml. autoclave was charged with s.o g. (0.037 mole) of (+)-alpha-fenchene obtained as in Example 3, 45.3 ~g. (0.18 mmole) of the dimer of rhodium (I) chloride-1,5-cyclooctadiene, 95 mg. (0.36 mmole) of triphenylphospine, 0.5 ml. of triethylamine and 25 ml. of benzene, and the reaction was carried out at 90C for 16 hours under a synthesis gas pressure of 80 kg./cm.2 (carbon monoxide pressure 40 kg./cm.2;
hydrogen pressure 40 kg./cm.~). The solvent was evaporated, and the residue was fractionally distilled under reduced pressure to give 5.7 g. (yield 93.4~) of an exo/endo mixture of 7,7-dimethylnorbornyl-2-acetaldehyde. The (2R)-exo/(2S)-endo ratio of the product was determined to be 85:15 by lH-NMR.
(c) 7,7-Dimethylnorbornyl-2-acetaldehyde having the (2R)-exo/(2S)-endo ratios shown in Table 4 was obtained by carrying out the oxo reaction as in (b) above under the conditions shown in Table 4.
Table 4 _ Reaction conditions Yield Exo/endo Run Oxo reaction ratio No. catalyst t-mp. ti=e (~) 2 [CODRhC1)2-2pph3 50 64 35 ¦ 89/11 3 Rh6(co)16 1 70 1 18 1 ~0 1 66/34 4 ¦Rh6(CO~l6-2pph3 ¦ 70 1 17 1 81 ¦ 87113 *COD = 1,5-Cyclooctadiene .
~ ' ~ ' : ~ . - .
: ' Osl/o~-ll PCT/~'S~tW-22 _45_ 2 ~ ~ ~ 0 Production of 3-(2R-exo-7,7-dimethylnorbornyl) 2-D,L-amino propionitrile:
Ammonia gas was passed through 400 ml. of methanol at 5C
for lS minutes. To the resulting solution were added 17.5 g.
(0.357 mole) of sodium cyanide, 17.8 g. ~0.333 mole) of ammonium chloride and 52.0 g. (0.313 mole) of (2R-exo-7,7-dimethylnorbornyl) acetaldehyde. The reaction mixt~lre was stirred overnight at room temperature and the methanol was evaporated under reduced pressure. To the residue was added 750 ml. of a 2% aqueous solution of sodium carbonate, and the mixture was extrac ed with 350 ml. of ether twice. The extracted ether layers were washed with water, and then extracted with 300 ml. of 1 N hydrochloric acid twice. The extracted hydrochloric acid layers were neutralized with sodium carbonate and further extracted with 300 ml. of ether three times. The extracts were dried over anhydrous sodium sulfate and the solvent was evaporated to give 3-(2R-exo-7,~-dimethylnorbornyl)-2-D,L-amino propionitrile as a pale yellow oil in a yield of 95.5%.
lH-NMR (CD30D solvent, TMS internal standard, ~): 1.07 and 1.11 (each 3H, s, CH3) and 4.38 - 4.49 CN
(lH, m, C~< ) (as amino propionitrile hydrochloride) ;~
Production of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride:
:~:.:: . ~ . . .
:, - . . - ,, :
I I PCI / l,'S90/0472' ~Q6 ~ 46-52.0 g. (0.271 mole) of 3-(2R-exo-7,7-dimethylnorbornyl)-2-D,L-amino propionitrile was added to 200 ml. of water and 900 ml. of concentrated hydrochloric acid, and the mixture was heated under reflux for 18 hours. The reaction solution was concentrated under reduced pressure and then cooled. Amino acid hydrochloride precipitated. It was left to stand overnight at 5C, filtered, and washed with 600 ml. of ether to give 63.2 g. of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride in a yield of 94.1%.
1H-NMR (CD30D solvent, TMS internal standard, ~): 1.02 and 1.11 (each 3H, s, CH3) and 4.37-4.42 (lH, m, C~<
N
The amino acid was prepared by neutralization of the hydrochloride and precipitation at pH 4Ø Melting point:
216-218C, IR: 3400, 2930, 1610, 1495, 1395, 1330 and 1100 cm-1.
Optical resolution of 3-(2R-exo-7,7- dimethylnorbornyl)-D,L-alanine methyl ester by the tartaric acid method:
To a solution of 36.5 g. of 3-(2R-exo-7,7 dimethyl-norbornyl)-D,L-alanine methyl ester (prepared from 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine as described in Example 15) in 500 ml. of methanol was added a solution of 25.7 g. of D-(-)-tartaric acid in 500 ml. of methanol. The solution was diluted to 1800 ml. with methanol, then heated to reflux to dissolve the precipitate which had formed. Crystallization was obtained by allowing the hot solution to stand at about 21C overnight. Filtration, washing with 50 ml. of methanol and drying 1~ vacuo gave 24.1 g.
WO 91tO211 I PCl t~:S90/04~22 2 a ~
The above material was recrystallized from 850 ml. of methanol to give 13.1 g. This in turn was recrystallized from 450 ml. of methanol to afford 8.8 g. o~ 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester-D-tartrate salt.
Melting point: 160C (decompose) [~]20 - + 36.4 (c = 0.5, MeOH) D
Synthesis of N-acetyl-3-(2R-exo-7,7-dimethylnor~ornyl)-D,L-alanine:
3- (2R-exo-7, 7-dimethylnorbornyl) -D, L-alanine hydrochloride (60 g.; 0.242 mole) was dissolved in 300 ml. of a 10% aqu~ous solution of NaOH, and then 32 g. (0.314 mole) of acetic anhydride was added dropwise at 35 to 40C. After the addition, they were reacted for 30 minutes. The reaction solution was cooled to 5 to 10C, and adjusted to pH 3 with 6 N hydrochloric acid. The precipitated crude crvstals were filtered, washed with water and driOEd. The crude crystals were recrystallized from ethyl acetate and n-hexane to give 60 g. (yield 97.6%) of the captioned compound.
Melting point: 170 - 171C
[~]24 -~36.6 (c51, methanol) lH-NMR (CD3D solvQnt, TMS internal standard, ô):
0.98 and 1.09 (each 3H, s, C~I3), 1.98 t3H, s, NHCOC~3) and 4.31 - 4.39 (lH, m, C~<
NHAC
,., ., , .... . . ~. , :, .,: . . : i, : ,. : . .:
. - .:. .. : . . . . .
.:. . .: : : - : - :
W091/0271l PC~/~S90/W722 optical resolution of N-acetyl 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine:
A 4 N aqueous solution of NaOH was added to a slurry composed of 450 ml. of water, 28.8 g. of disodium hydrogen phoephate, 30 mg. of cobalt chloride hexahydr~te and 60 g.
(0.236 mole) of N-acetyl-3-(2R- exo-7,7-dimethylnorbornyl)-D,L-alanine to adjust the pH to 8Ø A solution of 1.12 g. of acylase (a product of Amano Pharmaceutical Co., Ltd.) in 12 ml. of phosphate buffer (pH 8.0~, was added and the mixtsre stirred at 37 to 390C for 20 hours. The reaction solution was adjusted to pH 1.4 with concentrated hydrochloric acid, and washed with 200 ml. of ethyl acetate three times. The aqueous layer was adjusted to pH 3.0 with aqueous ammonia. The crude crystals that precipitated were separated by filtration. ~he resulting crude crystals (18~3 g.) were dissolved in 800 ml.
of hot water, and treated with 1. 8 g. of activat~d carbon to give 17.7 g. (yield 71.1%) of 3-(iR-exo-7,7-dimethylnorbornyl)-L-alanine.
Melting point: 224 - 226C
t~]23 z+49.5 (csl, methanol) D
lH-NMR (CD30D solvent, TMS internal standard, ~):
0.99 and 1.11 (each 3H, s, CH3) and 3.44-3.47 (lH, m, C~-C02) Separately, the ethyl acetate washings were concentrated to give crude crystal3 (34.9 g.). The crude crystals were recrystallized from ethyl acetate and n-hexane to give 26.6 g.
(yield 88.7%) of N-acetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D-alanine having a specific rotation of +4.1 (c=1, methanol).
. ~ :
::~ ' . . . - . ' .
, .
O9l/0~7l1PCT/~S~/~7'~
_49_ 2 ~ 0 Racemization of N-acetyl-3-(2R-exo-7,7-dimethyl-norbornyl)-D-alanine:
Ten grams (0.039 mole) of N-acetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D-alanine obtained in Example 10 was dissolved in 50 ml. of acetic acid and 1.0 g. of acetic anhydride, and reacted at 100C 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 adding n-hexane to give 6.8 g. of N-acetyl-3-(2R-exo-7, 7-dimethylnor~ornyl)-D,L-alanine having a specific rotation of +35.50 (c=l, ~ethanol).
Synthesis of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine:
Ten grams (47.4 mmoles) of 3-(2R-exo-7,7-dimethyl-norbornyl)-D,L-alanine was suspended in 120 ml. of ethyl acetate, and 35.36 g. (47.4 mmoles) of chloroacetyl chloride was added. The mixture was heated under reflux for 1 hour.
After cooling, the unreacted amino acid was separated by filtration, and the ethyl acetate was evaporated. The resulting crude crystals were recrystallized from ether and n-hexane to give 10.1 g. (yield 63%) of the captioned compound.
... ...... ~.. .. .. . .
: - -. . : . ,: , :
: - . : ~ - -. -.. .
WO91/02~1l PCT/US~/W722 ~ Q -50-Melting point: 149 - 150C
[~]23 = ~22.2~ (c=1, methanol) D
lH-NMR ~CD30D solvent, TMS internal standard, ~):
0.98 and 1.09 (each 3~, s, CH3),4.07 (2H, d, J-10.7 Hz, NHCOC~2Cl), 4.36 - 4.44 (lH, m, C~Co2) NH--Optical resolution of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine:
A 4 ~ aqueous solution of NaOH was atded to a slurry composed of 300 ml. of water, 24.1 g. of disodium hydragen phosphate, 25.5 mg. of cobalt chloride hexahydrate and 50.0 9.
(0.173 mole~ of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl3-D,L- alanine to adjust the pH to 8Ø A
solution of 0.85 g. of acyla~e (a product ~ o~ Amano Pharmaceutical Co., Ltd.) in 42.5 ml. of 0.5 ~ phosphate buffer (pH 8.0), was added and the mixture stirred at 37 to 39C for 16 hours. The reaction soll~tion was adjusted to pH 1.7 with concentrated hydrochloric acid, and washed with 350 ml. of ethyl a~etate twice. The aqueous layer was adjusted to about pH 3.0 with aqueous ammonia. The crude crystals that precipit~ted were separated by filtration. The resulting crude cry~tals (10.3 g.) were dissolved in 800 ml.
of hot water, and treated with 1.4 g. of activated carbon to give 10.3 g. (yield 56.3%) of 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine.
Separately, the ethyl acetate washings were conc~ntrated, and the residue was recrystallized from ether and n-hexane to give 20.4 g. (yield 81.6%) of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D- alanine.
~: ' ' ., . ' :' ., . , : - :
- . '- : -.
~09l/0~1l PCT/~S~0/~
-51- 2 0 ~ 5 Melting point: 150 - 153C
23 ~ +14 . 1 ( c=l, methanol) Production of 3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine methyl ester:
Hydrogen chloride gas (12.S g.) was bubbled into 1 liter of methanol, and 52.0 g. (0.210 mole) of 3-(2R- exo-7,7-dimethylnorbornyl)-L-alanine hydrochloride was added. The mixture was heated under reflux for 18 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolYed in 750 ml. of water, and the pH of the solution was adjusted to about 8.5 with a 50% aqueous solution of NaOH under cooling. The reaction mixture was extracted with 250 ml. of ethyl acetate twice and dried over anhydrous sodium sulfate. The solvent was evaporated to give 47.2 g.
(yield 99.9%) of 3-(2R-exo-7,7-di~ethylnorbornyl)-L-alanine methyl ester as a pale yellow oil.
The product (45.0 g.; 0.2 mole) was dissolved in 80 ml.
of ethyl acetate and 13.2 g. (0.22 mole) of acetic acid was added under cooling and stirring. The crystals which precipitated were collected by filtration to give 48.8 g. of the acetic acid salt of the above-captioned compound having a melting point of 101 to 104C.
~ ..
Production of 3-(2R-exo-7,7-dimethylnorbornyl)-D, L-alanine methyl ester:
To a solution of 12.5 g. of hydrogen chloride gas in 1 liter of methanol was added 52.0 g. of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride. The olution was heated at reflux for 18 hours, then the product ~solated :: .. -, ,,~: , . .; ~ :
;: ,, - -: . . . .. , :: .
09l/027ll PCT/USsO~W72 2 ~ ~'i ~ ~ -52-as described in Example 14 to give the title compound t44-~ g.) as a pale yellow oil.
[~23, (as the hydrochloride) - +29.50 (C=1.2, methanol) Production of L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester:
24.9 g. (~.1 mole) of N-carbobenzyloxy-L-aspartic anhydride was suspended in S00 ml. of toluene, and the suspension was cooled to 5~C. With stirring, a suspension of 28.5 g. (0.1 mole) of 3-(2R-exo-7,7- dimethylnorbornyl)-L-alanine me~hyl ester acetate in 50 ml. of toluene was added.
The mixture was then stirrred overnight at 5C. The solution was subjected to a countercurrent distribution-type chromatographic device to obtain 33.5 g. (70.6 %) of N-(carbobenzyloxy -L-aspartyl)-3-(2R-exo-7,7-dim~thylnorbornyl)- ~-L-alanine methyl ester. In a l-liter autoclav2, 25.8 g. (54.4 mmoles) of N-(carbobenzyloxy-L-aspartyl)-3-(2R-exo- 7,7-dimethylnorbornyl)-L-alanine methyl ester was dissolved in 400 ml. of methanol, and catalytically reduced in the presence of 1.0 g. of 5% palladium carbon under a hydrogen pressure of 3 ~g./cm.2. After the decrease of the hydrogen pressure wa~
no longer observed, the catalyst was removed by ~iltration through Celite. The filtrate was concentrated under reduced pressure to give crude crystals. Recrystallization from chloro~orm/n-hexane gave 14.4 g. (yield 77.8%) o~ the desired L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine methyl ester.
Melting point: 148 - 148.2C
[~]23 = +30.50 (c=1, methanol) ., , .' ''' ' ' .
- , ~ ,.- . -WO91/0271l PCT/~S~/047Z2 2os~
lH NMR (CD30D sol~ent, TMS internal standard, ~):
0.98 and 1.10 (each 3H, s, CH3), 2.53 (lH, dd, J~9.7 and 16.0 Hz, CH2CO~H), 2.78 (lH, dd, J=4.7 and 17.1 Hz, CH2C02H), 4.09 (lH, q, J-4.64 Hz, -C~CH2COaH), 4.41 (lH, q, J-5.4Hz, C~CO~Me) NHCO
Production of (N-C8Z-L-aspartyl-beta-0-benzyl~-3-(2R- exo-7,7-dimethylnorbornyl)-L-alanine methyl ester:
43 g. of the 3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine methyl ester-D-tartrate was suspended in an excess of a 5%
NaaCO3 solution and stirred vigorously at 23C ~or 30 minutes to give the free a~ino ester. Thi~ mixture was extracted with 2 x 500 ml. of EtOAc and the combined EtOAc layers dried over MgS0~ (anh.). The EtOAc solution was filtered, the filtrate concentrated under reduced pressure and dried i~ vacuo to give 22.5 g. of ~ -the amino ester as a clear oil. [c]23 ~ 61.8 (c-2.2, dioxane).
The above 22.5 g. of amino ester was dissolved in 800 ml.
of dioxane under N~. This was followed by the addition of 35 g. o~ N-CBz-L-aspartic acid-B-benzyl ester, 24.8 g. of 1,3-dicyclohexylcar~odiimide and 12.4 g. of N-hydroxy-5-norbornene-2,3-dicarboximide. This mixture was then stirred overnight, during which time a solid precipitated.
The solid 1,3-dicyclohexylurea was removed by filtration and the filtrate concentrated under reduced pressure. The ~-residue was taken up in 1000 ml. of ether and washed with . . , . , ............ - .~ --. ~ : ~,, ' . :
: . .. , : :
wosl/027ll PCT/~S~/~7~2 ~ ~ S~3~ ~4 _54_ 2 x l000 ml. of 5~ citric acid, 2 x l000 ml. of 7% NaHCO3 and 200 ml. of saturated NaCl solution. The ether solution was then dried over MgSOq (anh.), filtered and the filtrate concentrated under reduced pressure.
The residue was chromatographed on silica gel using hexane with increasi~g amounts of EtOAc as the eluent. The progress of the column was monitored by TLC (silica gel-40%
EtOAc/Hexane) and the appropriate fractions combined to give, following concentration, 49.7 g. of the titled compound.
Melting point: 62-64C
t~]23 =+9 S (c=l, methanol) H-NMR (CDCl3 solvent, TMS internal standard, ~):
0.95 and 1.05 (each 3H, s, -CH3), 3.70 (3~, s, -OCH3), 5.15 (4H, s, -CH2-Ar), 7.35 (lOH, s, Ar) EXAMP~E 18 Production of L-aspartyl-3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine methyl ester:
To 8.6 g. of N-(~-benzyl-N-CBZ-L-aspartyl)-3-(2R-exo-7, 7-dimethylnorbornyl)-L-alanine methyl ester in 200 ml. of methanol was added 0.4 g. of 10% palladium/carbon. The mixture was hydrogenated at 3 kg./cm.2 H2 and room te~perature for 18 hours. The catalyst was then removed by filtration th~ough a short pad of celite and the filtrate evaporated to give 5.2 g. of th~ title compound as a clear gla~s. This was crystallized from chlorofor~/hexane to afford material comparable to that of Example 16 as determined by HPLC, IR and 3C NMR comparison.
Melting point: 144-146 C
~]23 , +29.2 ~c-l, methanol) ' .
WO 91/02?11 2 ~ PC~'/1,'590/1}4722 D
H NMR (CD30D solvent, TMS internal standard, ~):
l.o and 1.1 (each 3H, s, -CH3) 2.75 (lH, m, -CH2-C02H) 3.7S (3H, s, -OCH3) Purification of alpha-L-aspartyl-3-(2R-exo-7,7-dimethyl-nor~ornyl)-L-alanine methyl ester:
A 60.4 g. sample of ~ L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester (alpha/beta 390/10) was dissolved by heating in 900 ml. of a 1:2 methanol:water mixture. Cooling the solution afforded 51.2 g. of a white solid (alpha/beta = 94.6/5.4). Repeated crystallization from the same solvent mixture (15:1 vol./wt.) as shown in Table 7 gave IV (alpha/beta - 99.2/0.8).
Synthesis of 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin: -To a solution of 2 g. (12.2 mmole) of 2R-exo-7,7-dimethylnorbornyl acetaldehyde in 35 ml. of 60% EtOH-H20 was added 3.5 g. of ~N~)2C03 and the resulting slurry warmed to 55C. To this mixture was added 650 mg. (13.2 mmols) of NaCN
in 5 ~1. of H~0 and the resulting mixture heated at 60C
overnight under a reflux condenser. The condenser was removed and the solution warmed to 90C for three hours to drive off excess (NH~)2C03-Upon cooling to room temperature, 10 ml. of H20 was addedand the solution extracted with 20 ml. of hexane. The agueous phase was then acidified to pH 5 (to be carried out under a hood) with 1 N HCl to give a white solid precipitate. This ., WO9l/027ll PCT/~S~/W722 2~5~4 was removed by filtration and dried in vacuo to afford 3.1 g.
of the desired product.
Melting point: 178-183C;
IR: 3280, 2950, 1720, 1420, 1315 and 1190 cm. 1 H-NMR (Pyridine-d5, TMS, ~): 9.25-9.05 O , .
(lH, m, -NH-), 4.4 - 4.15 (lH, m, -C-CH-N), 2.4-1.3 I
(llH, m, -CH2-,-CH-), 1.1-0.8 (6H, s, -CH3) EXAMP~E 21 Hydrolysis of 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin:
A mixture of 500 mg. of 3-(2R-exo-7,7-dimethylnor-bornyl)alanine hydantoin (2.12 mmoles), 2.5 g. of barium hydroxide and 10 ml. of H~O was heated at reflux for 72 hours.
Upon cooling 20 ml. of H20 wa~ added and th~ mixture acidified to pH 2.0 with 1 ~ H25O~. The solid was removed by filtration and the filtrate adjusted to pH 4.0 with 1 N NaOH.
Concentration of the solution to -_ 10 ml. and cooling to 5C
gave a white solid. After drying n vacuo the yield was -83 ~g. (0.39 mmole, 19%) of 3-(2R-exo-7,7-dimethylnobornyl)-D,L-alanine. Nelting point: 217-219C;, IR: 3430, 2950, 1610, lS05, 1400, 1320 and 1100 cm~l.
; ` ' . ! . . ~ , . . .
., . ~ ' ' ' ' ' , ;
WO91102~11 PCT/~S90/W7~' _57_ 2 ~5 V l q ~able 5 "
SolventIII~/IIIB ~ielectric Constant Acetic Acid 4.5 6.15 Acetone 0.9 20.7 --Acetonitrile l.3 37.5 -Ethyl Acetate 3.6 6.02 Ethyl Ether * 7.7 (3.5) 4.34 Dioxane 2.2 2.~l Toluene* 8.6 2.38 Butyl Acetate 4.2 5.0l Carbon Tetrachloride * 5.0 2.24 Trichloroethylene 5.6 3.4 Tetrahydrofuran l.4 Chloroform 5.l 4.8l Diglyme 0.27 Hexane * l.5 l.89 Dimethylformamide 0.08 37.6 Cyclopentanone l.7 18.0 Xylene * 7.6 2.27 Butyl Ether * 6.8 3.0 * N-Carbobenzyloxyaspartic anhydride was insoluble (suspension) at 5C.
Reaction o~ one part N-carbobenzyloxy aspartic anhydride (II) with one part 3-(2R-exo-7,7-dimethyl- norbornyl)-L-alanine methyl ester acetic acid salt in lO0 parts solvent at 5C for 18 hours. Ratios of (III alpha)/(III beta) were determined by peak heights on HPLC using an Altex 5u C18 column :
. .
~ . ', . - : ~
- .
WO 91/02~1l PCT/US~/~722 2~Sv~
with 60~ acetonitrile/O.OSM KH2Po~, pH 4.0 as solvent and UV
detection at 210 nm.
Tabl* 6 III a III
pH 6.093/7 83/17 pH 6.587/13 17/83 pH 7.019/81 9/91 Partition of alpha- and beta-(N-carbobenzyloxy-L- -~ -aspartyl)-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester (III ~/B) between toluene and 0.1 ~ phosphate buffers at the pH indicated. The ratios indicate the percent in the toluene phase over the percent in the buffer phase. Values are for 100 mg. of compcund in 10 ml. of toluene and 10 ml. of buffer.
Table 7 A~ount of material ~ ratio 1. 1.482 89.9/10.1 2. 1.265 94.6/ 5.4 3. 1.129 97.1/ 2.9 4. 1.073 98.4/ 1.6 ~
S. 1.000 99.2/ 0.8 - ;
- - .. .. .
,, ~ . ,: .. -:, :.. :-: : . : , .
,. : :, . :, .
, : ~ .... . . . . .. .. .
WO91/02711 PCT/US~722 2 ~
Recrystallization of a mixture of ~IV alpha) and (IV beta) from 33% methanol-water. Alpha/beta ratios were determined by peak heights on HPLC using a unisil Q Cl8 column with 40%
acetonitrile/1% methanol/ 59S O.l ~ KH2P0~, pH-4.0 as solvent and W detection at 220 nm. (UNISIL Q Cl8: particle size 5~m, Gasukuto Kogyo Co. Ltd.) While specific embodiments of the invention have been shown and deccribed in detail to illustrate the application of the inventive principles, the invention may be embodied otherwise without departing from such principles.
,~ . ' ' ' , ' . . .
. ' . `~ ' .
" . "' ~ ', ` . ' ' ' ,. ',. ,, , ' .. '' ~. : ~' .: ' ', . , ~ , . , ' '
In the Reaction Scheme B, the compound of formula (I-3,L-form) is reacted with an N-protected-L-aspartic acid anhydride in a non-protic solvent to yield the desired alpha-(~-protected-L-aspartyl)-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine alkyl ester (I~I alpha). In addition, a small (10-20%) amount of the beta-(N-protected-L-aspartyl)-3-(2R-exo-7,7- dimethylnorbornyl)-L-alanine alkyl ester (III beta) is also produced. The amount of by-product (III beta) formed in the reaction can be controlIed by variations of the reaction conditions as shown in Table 5 for Z = carbobenzyloxy (=CBZ).
Si~ilar solvent effects on the coupling of (II) (Z=CBZ) with phenylalanine methyi ester have been observed by Yang and Su tJ. Ora. Chç~, ~, 5186-91 (1986)] and T. Yukawa et al, EP 227301~.
The undesired (III beta) can be separated from ~III alpha) by partitioning between a suitable organic solvent and an aaueous buffer of the proper pH. In WO 91/0271 I PCI/I.'S90/04722 previous reports of this type of separation tw.
J. LeQuesne and G. T. '~oung, J. Chem. Soc., 24-28 (1952) and W. D. John and G. T. Young, J. Chem. Soc. 2870 (1954) ], alpha/beta-N carbobenzyloxyaspartylglycine m e t h y 1 e s t e r , a 1 p h a / ~ e t a - N -carbobenzyloxyaspartyltyrosine methyl ester, alpha/beta-N-carbobenzyloxyaspartylglutamic acid diethyl ester, and alpha/beta-N-carbobenzyloxyaspar- tyl-valine were separated by extraction of ethyl acetate solutions with aqueous sodium carbonate (concentration and pH
unspecified).
In a further example alpha and beta-NCBZ-aspartylphenylalanine methyl esters were separated by extraction of the beta- isomer from ethyl acetate using buffer of about pH 6-7 ~ t ~ S ~ Patent No. 3,808,190). No indication of the purity of the separated isomers was given.
We have folmd in the case of (III alpha) and (III beta) (Z=CBZ) that the pH of the aqueous pha~e mu t be carefully controll~d (See Table 6)o In addition, the choice of organic phase is also important. Good separation is achieved with ether and toluene, only modest partitioning with ethyl acetate and no separation at all with hexane or butanol.
on a preparative scale, the extraction of a 1%
toluene solution of the crude coupling mixture (III alpha/beta, alpha/beta~5/1, Z~CBZ) with three portions of p~ 6.5, 0.1 ~ phosphate buffer gives (III alpha) in 50-70% yield and a purity of 93-98%. The remaining (III beta) is removed during crystallization of (IV).
.~ '.:
' .: -WO 91/0271 ~ PCl/US90/1)4722 2 ~
Removal of the CBZ group from (III alpha) is readily achieved by hydrogenation at 2-3 kg./cm.2 using palladium on charcoal as catalyst in a methanol solution. ~he catalyst is removed by filtration through celite and the filtrate evaporated to give crude (IV). Sweetener (IV) is purified by crystallization ~rom chloroform-hexane.
In addition we have also ~ound that pure (IV) can be obtained from the original (III alpha-III beta) mixture (- 9/1, III alpha/III beta) by hydrogenation as mentioned and repeated crystallization from methanol-water as shown in Table 7. Tha procedure is most effective when the (III alpha)/(III beta) ratio from the coupling reaction is high (III alpha/III beta >8/1).
A similar separation of alpha-N-aspartylphenylala-nine methyl ester fro~ the beta- isomer by crystallization from water or water-alcohol mixtures has been described previously in U.S. Patent No. 3,786,039.
An alternate coupling procedure which avoids the above formation o~ a product mixture of alpha- and beta-dipeptides involves performing the reaction using (I-3, R=CH3) and a diprotected aspartic acid derivative (V~
;
.......... ,.. ~ ~ . : ;
Wo 9l/02711 PCT/US~/W122 _ N H Y ( V ) X O O C/ C O O H
where X = benzyl or t-butyl and Y = carbobenzyloxy or t-butoxycarbonyl. (t-BOC) [M. Bsdansky, "Principles o~
Peptide Synthesis,~ Springer-Verlag, Berlin, 70-79 and 90-102 (1984)~ The coupling reaction may be carried out by first converting the ~ree carboxyl of the aspartic acid moiety to an activat-d leaving group by treatment with i.e. p-nitrophenol/DCC, N-hydroxy~uccinimide/DCC, isobutylchoroformate/N-methylmorpholine, or the like, followed by the addition of (I-3, R~CH3). Alternatively, it may be performed using DCC in organic solvents at a temperature range of from about -20 to 30C. ~See M. Bodansky, loc. cit., pg. 9-58; U.S. Patent No.
4,788,069 and J. W. Tsang et al., J. Med Chem, 27, 1663-1668 (1984).] The resulting intermediates may then be converted to (IV) by deprotection employing catalytic hydrogenation under standard hydrogenation conditions (Pd/C, MeOH, H~ pressure 10-50 psig) for Y 3 CBZ and X ~
benzyl. In the cas- where Y ~ t-~OC and X ~ t-butyl, the deprotection may be carried out in organic solvents w09l/o'7ll PCT/~'S~/~2~
2o~t~vl 4 employing strang acids [HCl, trifluoracetic acid (TFA) or the like] with ~IV) being obtained ~ollowing neutralization of the resultant salt.
The following examples illustrate the present invention more specifically.
Conversion of trans-2-pinanol to alpha-~enchyl alcohol.
PreDaration of Catalvs~s Catalysts A, B and C used in the following Runs were prepared as follows:
Catalyst A
Commercial reagent, aluminum nitrate nonahydrate [Al(NO)3 9H20] (a product o~ Junsei Chemical Co., Ltd.), 150 g., was dissolved in 800 ml. of water, and 27 ml. of 8S% phosphoric aoid (a product of Nacalai Te~gue, Inc.) was added to the solution, and while the mixture was being stirred at room temperature 240 ml. of 10 % aqueous ammonia was slowly added dropwise to adjust its pH to 7.
The resulting precipitate was left to stand overnight, filtered, thoroughly washed with water, and dried at 60C
for 24 hours to give 65 g. of product. It was powdered in a mortar to give a powder having a size sma~ler than 40 mesh.
Catalvst B
Hydrous niobium hydroxide (Nb205-xH20, a product o~
Companhia Brasileira de Metalurgia E Mineraç~o) was pulverized to a size smaller than 40 mesh.
'. '-' ' ,, - '' .' . , - :
.: . . . .
WO 91/0271 I PCT/I,'S90/W7'2 Catalvst C
Nickel sulfate hexahydrate (NiSo4-6H2o, a product of Nacalai Tesque, Inc.) was calcined at 250C or 350C for 3 hours to reduce its size to smaller than 40 mesh.
Catalyst A was calcined at 300C for 3 hours, and used in this example.
A four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 35 g.
(0.227 mole) of trans-2-pinanol (a product of Glidco Organics) and 2.0 g. of the catalyst, and with stirring, it was reacted at 75C for 16 hours. The reaction product was coarsely distilled to give 29.1 g. of an oily product. Gas chromatographic analysis showed that the conversion was 98.2 S, and the selectivity of alpha-fenchyl alcohol was 48.1 %. The reaction product was rectified to give 15.3 g. (theoretical yield 42.9 ~;
purity 98.3 %) of alpha-fenchyl alcohol.
RU~ 2 A four-necked flaak equipped with a stirrer, a thermometer and a reflux condenser was charged with 35 g.
(0.227 mole) of trans-2-pinanol (a product of Glidco Organics) and 2.0 g. of catalyst B, and it was reacted at 75C for 63 hours. The reaction mixture was treated a~
in Example 1 and analyzed by gas chromatography. The conversion was 99.3 %, and the selectivity of alpha-fenchyl alcohol was 52.3 %.
Catalyst C was calcined at 250C for 3 hours, and used in this example.
A four-necked flask equipped with a stirrer, a thermometer and a re~lux condenser was charged with 35 g.
. ~ ~ . ....... . . . .............................. - . , .
, , : ... ,,.,., . :. . .
. . ~ .
WO 91/0271 I PC~ S90/0~722 -31- 205~V14 t0.227 mole) o~ trans-2-pinanol (a product of Glidco Or~anics) and 2.0 g. of the catalyst, and it was reacted at 75C for 20 hours. The conversion was 51.0 ~, and the selectivity of alpha-fenchyl alcohol was 40.6 %.
As in Runs 1 to 3, alpha-fenchyl alcohol was producsd from trans-2-pinanol using catalyst A, B or C
prepared as abo~e at the calcination temperatures and reaction temperatures indicated in Table 1. The results are shown in Table 1. In the examples, gas chromatographic analysis was carried out using a Shimadzu GC-9A (made by Shimadzu Seisakusho Ltd.) with a PEG-HT
capillary 0.25mm. in diameter X 25m. in length (made by Gasukuro Kagyo Co., Ltd.). The column temperature was 100C.
! ' . . ' .
''' ' ' .. ' ~" ~ , ' : ' :` ~ ' ' ~,. . ' . ' WO91/02711 PCT/US~/~22 2 a 6~ 4 -32-_ Calci- Reaction nation conditions Con- Selectivity tempera- version of ~-fenchyl Run Cata- ture (%)alcohol lyst (C) (%) ~emper- Time ature (hr) (C) _ 1 300 75 16 98.248.1 2 _ 75 63 99.352.3 3 C 250 75 20 51.0 40.6 _ _ _ 4 300 110 6 100 41.2 n 500 110 6 lOQ 36.0 _ . _ 6 n 800 110 3 100 35.0 7 _ 110 18 99.3 45.4 8 ~ 200 75 18 97 . 8 46.1 9 ~ 200 110 4 100 34.2 - 300 75 22 99.4 43.2 11 n 400 75 22 99.4 42.7 _ _ 12 500 75 19 98.5 41.7 :- .
13 n 600 75 20 34.1 40.0 .
14 C 2S0 110 18 100 24.8 350 75 18 23.9 34.4 16 3S0 110 15 97.3 20.3 - : . , .:
.
.
, .
`
WO9l/02~11 PCT/US90/~72~
2 0 ~
Example 2. Purification of (+)-alpha-fenchyl alcohol Commercial alpha-fenchyl alcohol (~]23D-+10.0(c-5, ethanol), mp. 43.2c; 709.2 g) was dissolved in ~55 g. of n-heptane, and the solution wa~ cooled to about -33C. The crystals that precipitated were separated by filtration to gi~e 493.6 g. of a first crop of crystals ([~]2~'+11.6, mp. 45.2) The residue (228.9 g.) left after evaporation of the filtrate was dissolved in 160 g. of n-heptane and the solution was cooled to -50C. The precipitate was filtered giving 128.6 g. of a second crop of crystals ([~]2~=+10.2, mp. 43.2C). These crystals were of the same quality aR the starting mat¢rial.
They were again dissolved in 64 g. of n-heptane, and the solution was cooled to about -33C. The crystals that precipitated were separated by filtration to obtain 94.0 g. of the crystals ([~]23=+11.5, mp. 45.1C~. These crystals were combined with the first crystals (total 587.6 g.) and dissolved in 411 g. of n-heptane. The solution was cooled to about -35C. The crystals that precipitated were separated by filtration to obtain 416.1 g. of second crystals ([~]a~=+11.9, mp. 45.7C). The second D
crop of crystals (416.2 g.) was dissolvQd in 310 g. of n-heptano, and the solution was cooled to -31C. The crystals that precipitated were separated by filtration to obtain 218.9 g. of third crystal3 ([~2~,+l2.2o~ mp. 46.4C) : ::
': : . . .. .
:.:: ~ ,: . - ~ : .
: ~ - - .. -WO91102~11 PCTtUS~/W,2 9 ~ 5 ~ ~
The mother liquors of the second crystals and third crystals were combined, and the solvent was reco~ered to yield 298.7 g. of crystals ([~]23=+9.84O). The resulting crystals were subjected to three cycles of crystallization in the same way as above to give 84.2 g. of fourth crystal~
([~]23=+l2.2, mp. 46.1C). The third crystals and fourth crystals were combined to obtain 363.2 g. of the desired t+)-alpha-fenchyl alcohol in a yield of 5l.2 %.
The optical purities of the resulting crystals were measured by the method described below. The results are tabulated below.
Ta~le,2 optical Specific purity rota,,~iQ~ (,% e-e- L
Starting +lO.0 81 material First crystals +ll.6 89.9 Second crystals +ll.6 92.l Third crystals +12.2 94.8 Fourth crystals +12.1 94.6 Mea~ur,ement of ~he O~ti~al P4~ity N-carbobenzyloxy-L-alanine (0.31 g.; 1.4 m~, O.Ol g.
(O.1 mM) of N,N-d$methylaminopyridine (DMAP) and 0.2 g. (l.28 mM) of fenchyl alcohol were dissolved in 2 ml. of methyl~ne chloride. In a stream of nitrogen under cooling, 0.27 g. (1.4 mM) of l-ethyl-3-(3-di- methylaminopropyl~carbodiimid-hydrochlorid~ (WSC) was added to the solution, and reacted for about 30 minutes. The temperature was returned to room ,i- , . .
~O9l/02~1l PCT/~'S~/~722 2 0 ~
temperature, and the reaction was carried out for about 1 hour. Methylene chloride was added to the reaction solution to adjust the total amount of the reaction mixture to 10 ml.
It was washed with a 10% aqueous solution of citric acid, a 4%
aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated at less than 40OC. ~he residue was dissolved in 5 ml. of methanol 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: PEG-HT, 0.25 mm. in diameter and 25 m. in length Introduction temperature: about 200C.
Column temperature: a range from about 100 -200C, 3oC/min.
Retention time: a range of about 11-12 min.
Separation coefficient: 1.02 Preparation of alpha-fenchene from fenchyl alcohol 1. Preparation of aluminum oxide catalysts ;~
(a) Catalyst A
Two hundred grams of aluminum nitrate nonahydrate [Al(N03)3~9H20; reagent first class produced by Junsei Chemical Co., Ltd.~ was dissolved in 2 liters of water. The solution was slowly added dropwise with stirring to 500 g. of 28%
agueous ammonia. After standing, the resulting aluminum hydroxide was aged overnight, filtered, washed with water, and dried at 60C for 24 hours to give 43 of aluminu~
hydroxide. It was powdered in a mortar anc calcinQd in an , , ,. : . , - . :
: . -: : .. .-: -. ~. - -- -: .: ~,- . : : - -, :, :: . , - ' -: , : . . :- , : - : ~ -W0~l/0271l PCT/~S~/W~22 ~e5~ 4 electric furnace at 5000C for 3 hours to give 28.4 g. of aluminum oxide as a white powder. The Hammett acidity function H~ of this product was -5.6<H S-3Ø
o (b) Catalyst B
Two hundred grams of aluminum sulfate 14- to 18-hydrate tA12(S0~)3-14-18 H20; r~agent first cla~s produced by Junsei Chemical Co., Ltd.~ was dissolved in 2 liters o~
water. Aqueous ammonia (10% by weight) W2S added dropwise to the solution until the solution reached pH 8. The resulting aluminum hydroxide was fully washed with a large amount of water, and dried at about 60C for 24 hours. The dried product was powdered in a mortar and then calcined in an electric furnace at 5000C for 3 hours to give 70 g. o~
aluminum oxide as a white powder. The Hammett acidity function Ho of the product was -5.6<Hos-3Ø
(c) Catalyst C
Two hundred grams of aluminum chloride hexa- hydrate [AlC13.6H20; reagent first class produced by Junsei Chemical Co., Ltd.] was dissolved in 2 liters of water, and then treated as in the preparation of catalyst B to give 62 g. of aluminum oxide. The Hammett acidity function of this product was -5.6<H S-3Ø
(d) Catalyst D
Two hundred grams of sodium aluminate [NaA102 xH20;
reagent first class produced by Nakarai Tesque Co., Ltd.]
wa~ dissolved in 2 liters of water. With stirring, the solution was added to an aqueous solution of hydrochloric acid (250 g/3 liters) to adjust the solution to about pH 8. The precipitate was ~eparated by filtration, dried .
:: , ,: :- : - . .
osl/o2~1l PCT/~'S~/W72 _37_ 2 0 S i 0 1 ~
at 60C for 12 hours, and washed five times with 500 ml.
of 14% aqueous ammonia. The washed product was dried at 60C for 24 hour~, powdered in a mortar, and calcined in an electric furnace at 500C for 3 hours to give 115 g. o~
aluminum oxide as a white powder. The Hammett acidity function of this product was -5.6~H~<-3Ø
2. Production of (+)-alpha-fenchene (a) A three-nec~ed flask equipped with a Dean-Stark device, a stirrer, a thermometer and a reflux condenser was charged with 100 g. (0.65 mole, purity 98.7%) of alpha-fenchyl alcohol and 5 g. (5% by weight) o~
catalyst A, and with stirring, the mixture was heated at a temperature range ~rom ab~ut 195 to 200C for 10 hours.
The reaction mixture was then coarsely distilled to give 95.8 g. of an oily product. Gas chro~atographic analysis showed the oily product to consist of 72% o~ fenchene isomers (in which alpha-fenchene accounted for 59%~ and 28% of unreacted fenchyl alcohol. Rectification of the oily product gave 34.4 g. of (+)-alpha-fenchene (yield 54.1%; purity 98.7%; Run No.l).
Boiling point: 157-158C (730 mm Hg) (t~ '+36.27(neat) H-NMR (~DC~3) 0.97 and 0.98 (each 3H, s), 1.20 - 1.34 (2H, m), 1.65 (lH, t), 1.79 - 1.96 (3~, m) Z.03 (lH, d), 2.41 (lH, d) ,;, ,, ; , .. ' ' '. . ~ :
': " " , '' '' . ~ , ' . , ' ~ ~
: ' ' '- ' ' : ' ' : :
`~ 38-4.60 and 4.81 (each lH, s) Mass Spectrum (m/e):
136 (M+), 121, 107, 93, 79, 53, 41, 39.
(b) Catalyst A (5%) was added to a mixture of (+)-alpha-and (+)-beta-fenchyl alcohol (alpha-/ beta--6/4). The mixture was treated as in section (a) above to obtain an oily product. Gas chromatographic analysis showed the product to comprise 95% of fenchene isomers (in which (+)-alpha-fenchene accounted for 65%) (Run No.2).
(c) Catalyst A (5% by weight) was added to (+)-beta-fenchyl alcohol (purity 95%). ~he mixture was heated at a temperature range of from about 195 to 200C for 3 hours with stirring and then coarsely distilled. Gas chromatographic analysis of the distillate showed it to comprise 98% of fenchene isomers (in which (+)-alpha-fenchene accounted for 80%) (Run No.3).
(d) Using catalysts ~, C or D, (+)-alpha-fenchene was produced from (+)-alpha-fenchyl alcohol~ The results are shown in Table 3 below (Runs Nos. 4 to 6).
(e) The procedure as in (a) aboYe was repeated except that catalyst A was replaced by commercial aluminum oxide catalysts having a Hammett acidity function of +l.5<HoS+3. 3 and +3.3<Ho<+4.8.
(Runs Nos. 7 and 8), a catalyst obtained by calcining nickel sulfate hexahydrate at about 250C for 3 hours (Run No. 9), a catalyst obtained by calcining nickel sulfate hexahydrate at about 400C ~or about 3 hours (Run No. 10), aluminum sulfate (Run No. 11), a catalyst obtained by calcining aluminum phosphate at about 500C for about 3 hours (Run No.12), aluminum silicate (Run No. 13), alum " - . ,:
:- .. . , . :::
.,- :- .
.. . . ., .. : . . :
: :: :.
: - ~ : .: ~ : - , :-~0 91/02-1 I PCI/I S90/W7'' 2 ~
-3~-(Run No.14) or acid clay (Run No. 15). The results are also shown in Table 3.
. - . . . ~ ;... , :
W09l/027lI PCT/US~/W72' 2n~
vu~01440 ~able 3 __ Amount of the Reaction cata- conditions Total Alpha-Starting lyst fen- fen-Run Catalyst fenchyl based chene chene No. alcohol on tha selec- selec-fen- tivity tivity alhycl_ Temp. Time hol(C) (hr) (%) (%) (wt~) _ _ Catalyst A ~- 195-200 10 72 59 2 Catalyst A ~/B=6/4 5 195-20010 95 65 3 Catalyst A B- S 195-200 3 98 80 4 Catalyst B ~- 5 195-200 10 82 44 Catalyst C ~- 5 195-200 10 70 47 6 Catalyst D ~- 5 195-200 10 70 53 7 Active ~- 10195-200 16 20 36 alumina . .
8 Active ~- 10195-200 16 . 4 32 alumina _ 9 NiSo~-6H2o ~- 50 195-200 4 100 2 NiS04 CHa I ~- ¦50¦195-200¦ 4 ¦ 98 ¦ 10 ¦ 11 A12(SO~)3 ¦ ~ ¦ 50¦195-200l 4 1 88 1 6 12 A1106 ~- 50195-200 16 ~ 8 23 : . :: : :
:
:: :-. .-: :, ' -, ' `,, `
~ 91/0'71 I PCT/I~'S9~/W722 --41-- 3 t~ 1 ~
_ _ _ 13 Aluminum ~- 50 195-200 6 97 . 5 O
silicate 14 Alum ~ - 5 0 19 5 - 2 0 0 16 7 7 . 4 1 lS Ac id clay . 5 19 5-2 00 7 94 . 9 4 - :, . . ~ ,- . . - ~ . -. - - ~ .; , . . .
091/0271l Pcr~us~/~722 2 e 6~ 4 -42-The fenchenes were analyzed ~y gas chromatography using a gas chromatographic device ("Shimazu" GC-9A made by Shimazu Seisakusho Co., Ltd.~ using an OV-l silica capillary column (diameter O.25 mm., length 25 m.); made by Gasukuro Kogyo Co., Ltd.) at a temperature of about 700C.
Production of 7,7-dimethyl-2-formylmethylenenorbornane:
Fifty grams (0.368 mole) of (+)-alpha-fenchene obtained as in Example 3 was added dropwise under a nitrogen stream at 50 to 60C over about 1 hour to a solution which had been prepared by adding 38 ml. (0.415 mole) of POC13 to 92.5 ml.
(1.19 mole) of DMF over about 1 hour. The mixture was reacted for 2 hours. The reaction solution was poured into 800 ml. of a lOS aqueous solution of sodium carbonate, and extracted twice with 300 ml. of toluene. The combined toluene extracts were washed with water, and the solvent was evaporated.
Fractional distillation under reduced pressure gave 50.5 g.
(yield 71%) of the captioned compound.
Boiling point: 76 - aooc/l mm Hg ~H-NMR (CDC13 solvent, TMS internal standard, ~):
E-form 0.98 and 1.08 (each 3H, s, CH3), 5.94 (lH, d, J27.9 Hz, olefinic H) and 9.79 (lH, d, J=7.9 Hz, CHO).
Z-form 0.97 and 1.08 (each 3H, s, CH3), 5.86 (lH, d, J=8.4 Hz, olefinic H), 9.84 (lH, d, J=8.3 Hz, CHO).
, .
wO9~/U2~1l PCT/~'S~/~722 _43- 2~S~14 Mass Spectrum (m/e):
E-form 150, 125, 109, 107, 82, 81 (base), 79, 67 and 41.
Z-form 165 (M~+1), 164 (M~), 149, 121 (base), 93, 91, 19, 77, 41 and 39.
Production of 2R-exo-7,7-dimethylnorbornyl acetaldehyde:
(a) A 1 liter autoclave was charged with 20 g. (0.12 mole~ of 7,7-dimethyl-2-formylmethylenenorbornane obtained as in Example 4 above, 200 ml. of n-heptane and 0.5 q. of 5~
palladium-carbon, and the reaction was carried out at room temperature under a hydrogen pressure of 2 ~g./cm.2. After the reaction, the catalyst was filtered and the solvent was evaporated. The residue was distilled under reduced pressure to give 19.7 g. (yield 97.3%) of the captioned compound. The exo/endo ratio of this compound wa~ found to be 98:2 by measurement of lH-NMR.
Boiling point: 54 - 55C/0.2 mm ~g H-NMR (CDCl3 solvent, TMS internal standard, ~):
~o-form 0.97 and 1.08 (each 3H, s, CH3), 2.60 (2H, d, d, d, J=2.1, 9.6, 5.9 Hz; CH2CHO~) and 9.71 (lH, t, J=7.9Hz; CHO).
Endo-form 1.02 ?nd 1.08 (each 3H, s, CH3), 9.76 (lH, t, J=7.9 Hz, CHO).
~'O9l/0271l PCT/US~/W722 L~ Q ~ 4 Mass Spectrum (m/e): 166 (Ml), 151, 133, 123, 122 (base), 107, 95, 81, 79, 69, 67, 55, 41.
(b) A 200 ml. autoclave was charged with s.o g. (0.037 mole) of (+)-alpha-fenchene obtained as in Example 3, 45.3 ~g. (0.18 mmole) of the dimer of rhodium (I) chloride-1,5-cyclooctadiene, 95 mg. (0.36 mmole) of triphenylphospine, 0.5 ml. of triethylamine and 25 ml. of benzene, and the reaction was carried out at 90C for 16 hours under a synthesis gas pressure of 80 kg./cm.2 (carbon monoxide pressure 40 kg./cm.2;
hydrogen pressure 40 kg./cm.~). The solvent was evaporated, and the residue was fractionally distilled under reduced pressure to give 5.7 g. (yield 93.4~) of an exo/endo mixture of 7,7-dimethylnorbornyl-2-acetaldehyde. The (2R)-exo/(2S)-endo ratio of the product was determined to be 85:15 by lH-NMR.
(c) 7,7-Dimethylnorbornyl-2-acetaldehyde having the (2R)-exo/(2S)-endo ratios shown in Table 4 was obtained by carrying out the oxo reaction as in (b) above under the conditions shown in Table 4.
Table 4 _ Reaction conditions Yield Exo/endo Run Oxo reaction ratio No. catalyst t-mp. ti=e (~) 2 [CODRhC1)2-2pph3 50 64 35 ¦ 89/11 3 Rh6(co)16 1 70 1 18 1 ~0 1 66/34 4 ¦Rh6(CO~l6-2pph3 ¦ 70 1 17 1 81 ¦ 87113 *COD = 1,5-Cyclooctadiene .
~ ' ~ ' : ~ . - .
: ' Osl/o~-ll PCT/~'S~tW-22 _45_ 2 ~ ~ ~ 0 Production of 3-(2R-exo-7,7-dimethylnorbornyl) 2-D,L-amino propionitrile:
Ammonia gas was passed through 400 ml. of methanol at 5C
for lS minutes. To the resulting solution were added 17.5 g.
(0.357 mole) of sodium cyanide, 17.8 g. ~0.333 mole) of ammonium chloride and 52.0 g. (0.313 mole) of (2R-exo-7,7-dimethylnorbornyl) acetaldehyde. The reaction mixt~lre was stirred overnight at room temperature and the methanol was evaporated under reduced pressure. To the residue was added 750 ml. of a 2% aqueous solution of sodium carbonate, and the mixture was extrac ed with 350 ml. of ether twice. The extracted ether layers were washed with water, and then extracted with 300 ml. of 1 N hydrochloric acid twice. The extracted hydrochloric acid layers were neutralized with sodium carbonate and further extracted with 300 ml. of ether three times. The extracts were dried over anhydrous sodium sulfate and the solvent was evaporated to give 3-(2R-exo-7,~-dimethylnorbornyl)-2-D,L-amino propionitrile as a pale yellow oil in a yield of 95.5%.
lH-NMR (CD30D solvent, TMS internal standard, ~): 1.07 and 1.11 (each 3H, s, CH3) and 4.38 - 4.49 CN
(lH, m, C~< ) (as amino propionitrile hydrochloride) ;~
Production of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride:
:~:.:: . ~ . . .
:, - . . - ,, :
I I PCI / l,'S90/0472' ~Q6 ~ 46-52.0 g. (0.271 mole) of 3-(2R-exo-7,7-dimethylnorbornyl)-2-D,L-amino propionitrile was added to 200 ml. of water and 900 ml. of concentrated hydrochloric acid, and the mixture was heated under reflux for 18 hours. The reaction solution was concentrated under reduced pressure and then cooled. Amino acid hydrochloride precipitated. It was left to stand overnight at 5C, filtered, and washed with 600 ml. of ether to give 63.2 g. of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride in a yield of 94.1%.
1H-NMR (CD30D solvent, TMS internal standard, ~): 1.02 and 1.11 (each 3H, s, CH3) and 4.37-4.42 (lH, m, C~<
N
The amino acid was prepared by neutralization of the hydrochloride and precipitation at pH 4Ø Melting point:
216-218C, IR: 3400, 2930, 1610, 1495, 1395, 1330 and 1100 cm-1.
Optical resolution of 3-(2R-exo-7,7- dimethylnorbornyl)-D,L-alanine methyl ester by the tartaric acid method:
To a solution of 36.5 g. of 3-(2R-exo-7,7 dimethyl-norbornyl)-D,L-alanine methyl ester (prepared from 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine as described in Example 15) in 500 ml. of methanol was added a solution of 25.7 g. of D-(-)-tartaric acid in 500 ml. of methanol. The solution was diluted to 1800 ml. with methanol, then heated to reflux to dissolve the precipitate which had formed. Crystallization was obtained by allowing the hot solution to stand at about 21C overnight. Filtration, washing with 50 ml. of methanol and drying 1~ vacuo gave 24.1 g.
WO 91tO211 I PCl t~:S90/04~22 2 a ~
The above material was recrystallized from 850 ml. of methanol to give 13.1 g. This in turn was recrystallized from 450 ml. of methanol to afford 8.8 g. o~ 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester-D-tartrate salt.
Melting point: 160C (decompose) [~]20 - + 36.4 (c = 0.5, MeOH) D
Synthesis of N-acetyl-3-(2R-exo-7,7-dimethylnor~ornyl)-D,L-alanine:
3- (2R-exo-7, 7-dimethylnorbornyl) -D, L-alanine hydrochloride (60 g.; 0.242 mole) was dissolved in 300 ml. of a 10% aqu~ous solution of NaOH, and then 32 g. (0.314 mole) of acetic anhydride was added dropwise at 35 to 40C. After the addition, they were reacted for 30 minutes. The reaction solution was cooled to 5 to 10C, and adjusted to pH 3 with 6 N hydrochloric acid. The precipitated crude crvstals were filtered, washed with water and driOEd. The crude crystals were recrystallized from ethyl acetate and n-hexane to give 60 g. (yield 97.6%) of the captioned compound.
Melting point: 170 - 171C
[~]24 -~36.6 (c51, methanol) lH-NMR (CD3D solvQnt, TMS internal standard, ô):
0.98 and 1.09 (each 3H, s, C~I3), 1.98 t3H, s, NHCOC~3) and 4.31 - 4.39 (lH, m, C~<
NHAC
,., ., , .... . . ~. , :, .,: . . : i, : ,. : . .:
. - .:. .. : . . . . .
.:. . .: : : - : - :
W091/0271l PC~/~S90/W722 optical resolution of N-acetyl 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine:
A 4 N aqueous solution of NaOH was added to a slurry composed of 450 ml. of water, 28.8 g. of disodium hydrogen phoephate, 30 mg. of cobalt chloride hexahydr~te and 60 g.
(0.236 mole) of N-acetyl-3-(2R- exo-7,7-dimethylnorbornyl)-D,L-alanine to adjust the pH to 8Ø A solution of 1.12 g. of acylase (a product of Amano Pharmaceutical Co., Ltd.) in 12 ml. of phosphate buffer (pH 8.0~, was added and the mixtsre stirred at 37 to 390C for 20 hours. The reaction solution was adjusted to pH 1.4 with concentrated hydrochloric acid, and washed with 200 ml. of ethyl acetate three times. The aqueous layer was adjusted to pH 3.0 with aqueous ammonia. The crude crystals that precipitated were separated by filtration. ~he resulting crude crystals (18~3 g.) were dissolved in 800 ml.
of hot water, and treated with 1. 8 g. of activat~d carbon to give 17.7 g. (yield 71.1%) of 3-(iR-exo-7,7-dimethylnorbornyl)-L-alanine.
Melting point: 224 - 226C
t~]23 z+49.5 (csl, methanol) D
lH-NMR (CD30D solvent, TMS internal standard, ~):
0.99 and 1.11 (each 3H, s, CH3) and 3.44-3.47 (lH, m, C~-C02) Separately, the ethyl acetate washings were concentrated to give crude crystal3 (34.9 g.). The crude crystals were recrystallized from ethyl acetate and n-hexane to give 26.6 g.
(yield 88.7%) of N-acetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D-alanine having a specific rotation of +4.1 (c=1, methanol).
. ~ :
::~ ' . . . - . ' .
, .
O9l/0~7l1PCT/~S~/~7'~
_49_ 2 ~ 0 Racemization of N-acetyl-3-(2R-exo-7,7-dimethyl-norbornyl)-D-alanine:
Ten grams (0.039 mole) of N-acetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D-alanine obtained in Example 10 was dissolved in 50 ml. of acetic acid and 1.0 g. of acetic anhydride, and reacted at 100C 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 adding n-hexane to give 6.8 g. of N-acetyl-3-(2R-exo-7, 7-dimethylnor~ornyl)-D,L-alanine having a specific rotation of +35.50 (c=l, ~ethanol).
Synthesis of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine:
Ten grams (47.4 mmoles) of 3-(2R-exo-7,7-dimethyl-norbornyl)-D,L-alanine was suspended in 120 ml. of ethyl acetate, and 35.36 g. (47.4 mmoles) of chloroacetyl chloride was added. The mixture was heated under reflux for 1 hour.
After cooling, the unreacted amino acid was separated by filtration, and the ethyl acetate was evaporated. The resulting crude crystals were recrystallized from ether and n-hexane to give 10.1 g. (yield 63%) of the captioned compound.
... ...... ~.. .. .. . .
: - -. . : . ,: , :
: - . : ~ - -. -.. .
WO91/02~1l PCT/US~/W722 ~ Q -50-Melting point: 149 - 150C
[~]23 = ~22.2~ (c=1, methanol) D
lH-NMR ~CD30D solvent, TMS internal standard, ~):
0.98 and 1.09 (each 3~, s, CH3),4.07 (2H, d, J-10.7 Hz, NHCOC~2Cl), 4.36 - 4.44 (lH, m, C~Co2) NH--Optical resolution of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine:
A 4 ~ aqueous solution of NaOH was atded to a slurry composed of 300 ml. of water, 24.1 g. of disodium hydragen phosphate, 25.5 mg. of cobalt chloride hexahydrate and 50.0 9.
(0.173 mole~ of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl3-D,L- alanine to adjust the pH to 8Ø A
solution of 0.85 g. of acyla~e (a product ~ o~ Amano Pharmaceutical Co., Ltd.) in 42.5 ml. of 0.5 ~ phosphate buffer (pH 8.0), was added and the mixture stirred at 37 to 39C for 16 hours. The reaction soll~tion was adjusted to pH 1.7 with concentrated hydrochloric acid, and washed with 350 ml. of ethyl a~etate twice. The aqueous layer was adjusted to about pH 3.0 with aqueous ammonia. The crude crystals that precipit~ted were separated by filtration. The resulting crude cry~tals (10.3 g.) were dissolved in 800 ml.
of hot water, and treated with 1.4 g. of activated carbon to give 10.3 g. (yield 56.3%) of 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine.
Separately, the ethyl acetate washings were conc~ntrated, and the residue was recrystallized from ether and n-hexane to give 20.4 g. (yield 81.6%) of N-chloroacetyl-3-(2R-exo-7,7-dimethylnorbornyl)-D- alanine.
~: ' ' ., . ' :' ., . , : - :
- . '- : -.
~09l/0~1l PCT/~S~0/~
-51- 2 0 ~ 5 Melting point: 150 - 153C
23 ~ +14 . 1 ( c=l, methanol) Production of 3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine methyl ester:
Hydrogen chloride gas (12.S g.) was bubbled into 1 liter of methanol, and 52.0 g. (0.210 mole) of 3-(2R- exo-7,7-dimethylnorbornyl)-L-alanine hydrochloride was added. The mixture was heated under reflux for 18 hours. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolYed in 750 ml. of water, and the pH of the solution was adjusted to about 8.5 with a 50% aqueous solution of NaOH under cooling. The reaction mixture was extracted with 250 ml. of ethyl acetate twice and dried over anhydrous sodium sulfate. The solvent was evaporated to give 47.2 g.
(yield 99.9%) of 3-(2R-exo-7,7-di~ethylnorbornyl)-L-alanine methyl ester as a pale yellow oil.
The product (45.0 g.; 0.2 mole) was dissolved in 80 ml.
of ethyl acetate and 13.2 g. (0.22 mole) of acetic acid was added under cooling and stirring. The crystals which precipitated were collected by filtration to give 48.8 g. of the acetic acid salt of the above-captioned compound having a melting point of 101 to 104C.
~ ..
Production of 3-(2R-exo-7,7-dimethylnorbornyl)-D, L-alanine methyl ester:
To a solution of 12.5 g. of hydrogen chloride gas in 1 liter of methanol was added 52.0 g. of 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine hydrochloride. The olution was heated at reflux for 18 hours, then the product ~solated :: .. -, ,,~: , . .; ~ :
;: ,, - -: . . . .. , :: .
09l/027ll PCT/USsO~W72 2 ~ ~'i ~ ~ -52-as described in Example 14 to give the title compound t44-~ g.) as a pale yellow oil.
[~23, (as the hydrochloride) - +29.50 (C=1.2, methanol) Production of L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester:
24.9 g. (~.1 mole) of N-carbobenzyloxy-L-aspartic anhydride was suspended in S00 ml. of toluene, and the suspension was cooled to 5~C. With stirring, a suspension of 28.5 g. (0.1 mole) of 3-(2R-exo-7,7- dimethylnorbornyl)-L-alanine me~hyl ester acetate in 50 ml. of toluene was added.
The mixture was then stirrred overnight at 5C. The solution was subjected to a countercurrent distribution-type chromatographic device to obtain 33.5 g. (70.6 %) of N-(carbobenzyloxy -L-aspartyl)-3-(2R-exo-7,7-dim~thylnorbornyl)- ~-L-alanine methyl ester. In a l-liter autoclav2, 25.8 g. (54.4 mmoles) of N-(carbobenzyloxy-L-aspartyl)-3-(2R-exo- 7,7-dimethylnorbornyl)-L-alanine methyl ester was dissolved in 400 ml. of methanol, and catalytically reduced in the presence of 1.0 g. of 5% palladium carbon under a hydrogen pressure of 3 ~g./cm.2. After the decrease of the hydrogen pressure wa~
no longer observed, the catalyst was removed by ~iltration through Celite. The filtrate was concentrated under reduced pressure to give crude crystals. Recrystallization from chloro~orm/n-hexane gave 14.4 g. (yield 77.8%) o~ the desired L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine methyl ester.
Melting point: 148 - 148.2C
[~]23 = +30.50 (c=1, methanol) ., , .' ''' ' ' .
- , ~ ,.- . -WO91/0271l PCT/~S~/047Z2 2os~
lH NMR (CD30D sol~ent, TMS internal standard, ~):
0.98 and 1.10 (each 3H, s, CH3), 2.53 (lH, dd, J~9.7 and 16.0 Hz, CH2CO~H), 2.78 (lH, dd, J=4.7 and 17.1 Hz, CH2C02H), 4.09 (lH, q, J-4.64 Hz, -C~CH2COaH), 4.41 (lH, q, J-5.4Hz, C~CO~Me) NHCO
Production of (N-C8Z-L-aspartyl-beta-0-benzyl~-3-(2R- exo-7,7-dimethylnorbornyl)-L-alanine methyl ester:
43 g. of the 3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine methyl ester-D-tartrate was suspended in an excess of a 5%
NaaCO3 solution and stirred vigorously at 23C ~or 30 minutes to give the free a~ino ester. Thi~ mixture was extracted with 2 x 500 ml. of EtOAc and the combined EtOAc layers dried over MgS0~ (anh.). The EtOAc solution was filtered, the filtrate concentrated under reduced pressure and dried i~ vacuo to give 22.5 g. of ~ -the amino ester as a clear oil. [c]23 ~ 61.8 (c-2.2, dioxane).
The above 22.5 g. of amino ester was dissolved in 800 ml.
of dioxane under N~. This was followed by the addition of 35 g. o~ N-CBz-L-aspartic acid-B-benzyl ester, 24.8 g. of 1,3-dicyclohexylcar~odiimide and 12.4 g. of N-hydroxy-5-norbornene-2,3-dicarboximide. This mixture was then stirred overnight, during which time a solid precipitated.
The solid 1,3-dicyclohexylurea was removed by filtration and the filtrate concentrated under reduced pressure. The ~-residue was taken up in 1000 ml. of ether and washed with . . , . , ............ - .~ --. ~ : ~,, ' . :
: . .. , : :
wosl/027ll PCT/~S~/~7~2 ~ ~ S~3~ ~4 _54_ 2 x l000 ml. of 5~ citric acid, 2 x l000 ml. of 7% NaHCO3 and 200 ml. of saturated NaCl solution. The ether solution was then dried over MgSOq (anh.), filtered and the filtrate concentrated under reduced pressure.
The residue was chromatographed on silica gel using hexane with increasi~g amounts of EtOAc as the eluent. The progress of the column was monitored by TLC (silica gel-40%
EtOAc/Hexane) and the appropriate fractions combined to give, following concentration, 49.7 g. of the titled compound.
Melting point: 62-64C
t~]23 =+9 S (c=l, methanol) H-NMR (CDCl3 solvent, TMS internal standard, ~):
0.95 and 1.05 (each 3H, s, -CH3), 3.70 (3~, s, -OCH3), 5.15 (4H, s, -CH2-Ar), 7.35 (lOH, s, Ar) EXAMP~E 18 Production of L-aspartyl-3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine methyl ester:
To 8.6 g. of N-(~-benzyl-N-CBZ-L-aspartyl)-3-(2R-exo-7, 7-dimethylnorbornyl)-L-alanine methyl ester in 200 ml. of methanol was added 0.4 g. of 10% palladium/carbon. The mixture was hydrogenated at 3 kg./cm.2 H2 and room te~perature for 18 hours. The catalyst was then removed by filtration th~ough a short pad of celite and the filtrate evaporated to give 5.2 g. of th~ title compound as a clear gla~s. This was crystallized from chlorofor~/hexane to afford material comparable to that of Example 16 as determined by HPLC, IR and 3C NMR comparison.
Melting point: 144-146 C
~]23 , +29.2 ~c-l, methanol) ' .
WO 91/02?11 2 ~ PC~'/1,'590/1}4722 D
H NMR (CD30D solvent, TMS internal standard, ~):
l.o and 1.1 (each 3H, s, -CH3) 2.75 (lH, m, -CH2-C02H) 3.7S (3H, s, -OCH3) Purification of alpha-L-aspartyl-3-(2R-exo-7,7-dimethyl-nor~ornyl)-L-alanine methyl ester:
A 60.4 g. sample of ~ L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester (alpha/beta 390/10) was dissolved by heating in 900 ml. of a 1:2 methanol:water mixture. Cooling the solution afforded 51.2 g. of a white solid (alpha/beta = 94.6/5.4). Repeated crystallization from the same solvent mixture (15:1 vol./wt.) as shown in Table 7 gave IV (alpha/beta - 99.2/0.8).
Synthesis of 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin: -To a solution of 2 g. (12.2 mmole) of 2R-exo-7,7-dimethylnorbornyl acetaldehyde in 35 ml. of 60% EtOH-H20 was added 3.5 g. of ~N~)2C03 and the resulting slurry warmed to 55C. To this mixture was added 650 mg. (13.2 mmols) of NaCN
in 5 ~1. of H~0 and the resulting mixture heated at 60C
overnight under a reflux condenser. The condenser was removed and the solution warmed to 90C for three hours to drive off excess (NH~)2C03-Upon cooling to room temperature, 10 ml. of H20 was addedand the solution extracted with 20 ml. of hexane. The agueous phase was then acidified to pH 5 (to be carried out under a hood) with 1 N HCl to give a white solid precipitate. This ., WO9l/027ll PCT/~S~/W722 2~5~4 was removed by filtration and dried in vacuo to afford 3.1 g.
of the desired product.
Melting point: 178-183C;
IR: 3280, 2950, 1720, 1420, 1315 and 1190 cm. 1 H-NMR (Pyridine-d5, TMS, ~): 9.25-9.05 O , .
(lH, m, -NH-), 4.4 - 4.15 (lH, m, -C-CH-N), 2.4-1.3 I
(llH, m, -CH2-,-CH-), 1.1-0.8 (6H, s, -CH3) EXAMP~E 21 Hydrolysis of 3-(2R-exo-7,7-dimethylnorbornyl)alanine hydantoin:
A mixture of 500 mg. of 3-(2R-exo-7,7-dimethylnor-bornyl)alanine hydantoin (2.12 mmoles), 2.5 g. of barium hydroxide and 10 ml. of H~O was heated at reflux for 72 hours.
Upon cooling 20 ml. of H20 wa~ added and th~ mixture acidified to pH 2.0 with 1 ~ H25O~. The solid was removed by filtration and the filtrate adjusted to pH 4.0 with 1 N NaOH.
Concentration of the solution to -_ 10 ml. and cooling to 5C
gave a white solid. After drying n vacuo the yield was -83 ~g. (0.39 mmole, 19%) of 3-(2R-exo-7,7-dimethylnobornyl)-D,L-alanine. Nelting point: 217-219C;, IR: 3430, 2950, 1610, lS05, 1400, 1320 and 1100 cm~l.
; ` ' . ! . . ~ , . . .
., . ~ ' ' ' ' ' , ;
WO91102~11 PCT/~S90/W7~' _57_ 2 ~5 V l q ~able 5 "
SolventIII~/IIIB ~ielectric Constant Acetic Acid 4.5 6.15 Acetone 0.9 20.7 --Acetonitrile l.3 37.5 -Ethyl Acetate 3.6 6.02 Ethyl Ether * 7.7 (3.5) 4.34 Dioxane 2.2 2.~l Toluene* 8.6 2.38 Butyl Acetate 4.2 5.0l Carbon Tetrachloride * 5.0 2.24 Trichloroethylene 5.6 3.4 Tetrahydrofuran l.4 Chloroform 5.l 4.8l Diglyme 0.27 Hexane * l.5 l.89 Dimethylformamide 0.08 37.6 Cyclopentanone l.7 18.0 Xylene * 7.6 2.27 Butyl Ether * 6.8 3.0 * N-Carbobenzyloxyaspartic anhydride was insoluble (suspension) at 5C.
Reaction o~ one part N-carbobenzyloxy aspartic anhydride (II) with one part 3-(2R-exo-7,7-dimethyl- norbornyl)-L-alanine methyl ester acetic acid salt in lO0 parts solvent at 5C for 18 hours. Ratios of (III alpha)/(III beta) were determined by peak heights on HPLC using an Altex 5u C18 column :
. .
~ . ', . - : ~
- .
WO 91/02~1l PCT/US~/~722 2~Sv~
with 60~ acetonitrile/O.OSM KH2Po~, pH 4.0 as solvent and UV
detection at 210 nm.
Tabl* 6 III a III
pH 6.093/7 83/17 pH 6.587/13 17/83 pH 7.019/81 9/91 Partition of alpha- and beta-(N-carbobenzyloxy-L- -~ -aspartyl)-3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine methyl ester (III ~/B) between toluene and 0.1 ~ phosphate buffers at the pH indicated. The ratios indicate the percent in the toluene phase over the percent in the buffer phase. Values are for 100 mg. of compcund in 10 ml. of toluene and 10 ml. of buffer.
Table 7 A~ount of material ~ ratio 1. 1.482 89.9/10.1 2. 1.265 94.6/ 5.4 3. 1.129 97.1/ 2.9 4. 1.073 98.4/ 1.6 ~
S. 1.000 99.2/ 0.8 - ;
- - .. .. .
,, ~ . ,: .. -:, :.. :-: : . : , .
,. : :, . :, .
, : ~ .... . . . . .. .. .
WO91/02711 PCT/US~722 2 ~
Recrystallization of a mixture of ~IV alpha) and (IV beta) from 33% methanol-water. Alpha/beta ratios were determined by peak heights on HPLC using a unisil Q Cl8 column with 40%
acetonitrile/1% methanol/ 59S O.l ~ KH2P0~, pH-4.0 as solvent and W detection at 220 nm. (UNISIL Q Cl8: particle size 5~m, Gasukuto Kogyo Co. Ltd.) While specific embodiments of the invention have been shown and deccribed in detail to illustrate the application of the inventive principles, the invention may be embodied otherwise without departing from such principles.
,~ . ' ' ' , ' . . .
. ' . `~ ' .
" . "' ~ ', ` . ' ' ' ,. ',. ,, , ' .. '' ~. : ~' .: ' ', . , ~ , . , ' '
Claims (25)
1. A compound represented by the following formula (I) wherein Y is -CHO, , or wherein R is hydrogen or a lower alkyl group of one to three carbons and wherein R' is hydrogen or a lower alkyl group of one to three carbons.
2. The compound recited in claim 1, wherein Y is -CHO.
3. The compound recited in claim 1, wherein Y is
4. The compound recited in claim 1, wherein Y is
5. The compound recited in claim 4, wherein R' is -CH3 or -CH2Cl.
6. The compound recited in claim 1, wherein Y is
7. A fenchyl alcohol dehydration catalyst comprising calcined aluminum hydroxide.
8. The dehydration catalyst recited in claim 7, comprising calcined aluminum hydroxide having Hammett acidlty of -5.6<H°?-3Ø
9. A process for making 3-(2R-exo-7,7-dimethyl-norbornane)-L-alanine lower alkyl ester represented by the following formula:
wherein R represents a lower alkyl group of one to three carbons comprising the steps of:
(a) dehydrating-isomerizing (+)-alpha-fenchyl alcohol to form (+)-alpha-fenchene;
(b) converting the (+)-alpha-fenchene to 2R-exo-7,7-dimethylnorbornyl acetaldehyde;
(c) converting 2R-exo-7,7-dimethylnorbornyl acetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L- alanine;
(d) resolving 3-(2R-exo-7,7-dimethylnor- bornyl)-D,L-alanine to produce 3-(2R-exo-7,7-dimethyl- norbornyl)-L-alanine; and (e) esterifying 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine to form 3-(2R-exo-7,7-dimethylnorbornyl)- L-alanine lower alkyl ester.
wherein R represents a lower alkyl group of one to three carbons comprising the steps of:
(a) dehydrating-isomerizing (+)-alpha-fenchyl alcohol to form (+)-alpha-fenchene;
(b) converting the (+)-alpha-fenchene to 2R-exo-7,7-dimethylnorbornyl acetaldehyde;
(c) converting 2R-exo-7,7-dimethylnorbornyl acetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L- alanine;
(d) resolving 3-(2R-exo-7,7-dimethylnor- bornyl)-D,L-alanine to produce 3-(2R-exo-7,7-dimethyl- norbornyl)-L-alanine; and (e) esterifying 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine to form 3-(2R-exo-7,7-dimethylnorbornyl)- L-alanine lower alkyl ester.
10. The process recited in claim 9, wherein step (c) comprises converting the acetaldehyde to an amino nitrile and hydrolyzing the nitrile to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
11. The process recited in claim 9, wherein step (c) comprises converting the acetaldehyde to a hydantoin and hydrolyzing the hydantoin to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
12. A process for making 3-(2R-exo-7,7-dimethyl-norbornane)-L-alanine lower alkyl ester represented by the following formula:
wherein R represents a lower alkyl group of one to three carbons comprising the steps of:
(a) dehydrating-isomerizing (+)-alpha-fenchyl alcohol to form (+)-alpha-fenchene;
(b) converting the (+)-alpha-fenchene to 2R-exo-7,7-dimethylnorbornyl acetaldehyde;
(c) converting 2R-exo-7,7-dimethylnorbornyl acetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L- alanine;
(d) esterifying 3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine to form 3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine lower alkyl ester; and (e) resolving 3-(2R-exo-7,7-dimethylnor- bornyl)-D, L-alanine lower alkyl ester to produce 3-(2R-exo-7,7-dimethyl- norbornyl)-L-alanine lower alkyl ester.
wherein R represents a lower alkyl group of one to three carbons comprising the steps of:
(a) dehydrating-isomerizing (+)-alpha-fenchyl alcohol to form (+)-alpha-fenchene;
(b) converting the (+)-alpha-fenchene to 2R-exo-7,7-dimethylnorbornyl acetaldehyde;
(c) converting 2R-exo-7,7-dimethylnorbornyl acetaldehyde to 3-(2R-exo-7,7-dimethylnorbornyl)-D,L- alanine;
(d) esterifying 3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine to form 3-(2R-exo-7,7-dimethylnorbor- nyl)-D,L-alanine lower alkyl ester; and (e) resolving 3-(2R-exo-7,7-dimethylnor- bornyl)-D, L-alanine lower alkyl ester to produce 3-(2R-exo-7,7-dimethyl- norbornyl)-L-alanine lower alkyl ester.
13. The process recited in claim 12, wherein step (c) comprises converting the acetaldehyde to an amino nitrile and hydrolyzing the nitrile to form 3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine.
14. The process recited in claim 12, wherein step (c) comprises converting the acetaldehyde to a hydantoin and hydrolyzing the hydantoin to form 3-(2R-exo-7,7-dimethylnorbornyl3-D,L-alanine.
15. A process for producinq alpha-L-aspartyl-(2R- exo-7,7-dimethylnorbornyl)-L-alanine lower alXyl ester represented by the following formula:
wherein R reprasents a lower alkyl group of one to three carbons comprising the steps of:
(a) coupling 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester with an N-protected aspartic acid anhydride to produce an N-protected (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dim-thylnorbornyl)-L- alanine lower alkyl ester;
(b) deprotecting the N-protected (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine lower alkyl ester to produce a mixture of (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester; and (c) separating the alpha-L-aspartyl-3- (2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester from the mixture.
wherein R reprasents a lower alkyl group of one to three carbons comprising the steps of:
(a) coupling 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester with an N-protected aspartic acid anhydride to produce an N-protected (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dim-thylnorbornyl)-L- alanine lower alkyl ester;
(b) deprotecting the N-protected (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine lower alkyl ester to produce a mixture of (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester; and (c) separating the alpha-L-aspartyl-3- (2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester from the mixture.
16. The process recited in claim 15 wherein an N-protected aspartic acid having a beta-ester protecting group is utilized for the N-protected aspartic acid anhydride.
17. A process for producing alpha-L-aspartyl-(2R- exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester represented by the following formula:
wherein R represents a lower alkyl group of one to three carbons comprising the steps of:
(a) coupling 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester with an N-protected aspartic acid anhydride to produce an N-protected (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine lower alkyl ester;
(b) separating the N-protected alpha-L-aspartyl-3- (2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester from the mixture; and (c) deprotecting the N-protected alpha-L-aspartyl-3- (2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester to produce alpha-L-aspartyl-3-(2R-exo-7,7- dimethylnorbornyl)-L-alanine lower alkyl ester.
wherein R represents a lower alkyl group of one to three carbons comprising the steps of:
(a) coupling 3-(2R-exo-7,7-dimethylnorbor- nyl)-L-alanine lower alkyl ester with an N-protected aspartic acid anhydride to produce an N-protected (alpha, beta)-L-aspartyl-3-(2R-exo-7,7-dimethylnorbornyl)-L- alanine lower alkyl ester;
(b) separating the N-protected alpha-L-aspartyl-3- (2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester from the mixture; and (c) deprotecting the N-protected alpha-L-aspartyl-3- (2R-exo-7,7-dimethylnorbornyl)-L-alanine lower alkyl ester to produce alpha-L-aspartyl-3-(2R-exo-7,7- dimethylnorbornyl)-L-alanine lower alkyl ester.
18. A process for purifying (+)-alpha-fenchyl alcohol, which comprises crystallizing alpha-fenchyl alcohol in a hydrocarbon solvent at low temperatures.
19. A process according to claim 18 in which the solvent is n-heptane or n-octane and the temperature range -35 to -60°C.
20. A process for producing alpha-fenchene, which comprises heating fenchyl alcohol in the presence of an aluminum oxide catalyst.
21. A process according to claim 20 where the catalyst is calcined aluminum oxide having a Hammett acidity function -5.6<H??-3Ø
22. A process for producing an optically active 3-(2R-exo-7,7-dimethylnorbornyl)-L-alanine or its lower alkyl ester, which comprises treating an N-acyl-3-(2R-exo-7,7-dimethylnorbornyl)-D,L-alanine or its lower alkyl ester with an acylase in an aqueous medium, and recovering the resulting 3-(2R-exo-7, 7-dimethylnorbornyl)-L-alanine or its lower alkyl ester.
23. The process recited in claim 22, wherein the N-acyl is selected from the group consisting of N-acetyl and N-chloroacetyl.
24. The process recited in claim 22, wherein the acylase is Amano acylase I.
25. A process for producing alpha-fenchyl alcohol, which comprises reacting trans-2-pinanol in the presence of at least one catalyst selected from the group consisting of aluminum phosphate, niobium oxide and nickel sulfate at a temperature of 60 to 150°C.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39658689A | 1989-08-21 | 1989-08-21 | |
| JP1213116A JPH0383936A (en) | 1989-08-21 | 1989-08-21 | 7, 7-dimethylnorvolnane derivative |
| US396,586 | 1989-08-21 | ||
| JP64/2131116 | 1989-08-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2065014A1 true CA2065014A1 (en) | 1991-02-22 |
Family
ID=26519616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065014A Abandoned CA2065014A1 (en) | 1989-08-21 | 1990-08-20 | 7-7-dimethylnorbornane derivatives |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU6293790A (en) |
| BR (1) | BR9007609A (en) |
| CA (1) | CA2065014A1 (en) |
| WO (1) | WO1991002711A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6740406B2 (en) * | 2000-12-15 | 2004-05-25 | Kimberly-Clark Worldwide, Inc. | Coated activated carbon |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4788069A (en) * | 1987-03-27 | 1988-11-29 | The Coca-Cola Company | Intensely sweet L-aspartyl-3-(bicycloalkyl)-L-alanine alkyl esters |
-
1990
- 1990-08-20 AU AU62937/90A patent/AU6293790A/en not_active Abandoned
- 1990-08-20 BR BR909007609A patent/BR9007609A/en not_active Application Discontinuation
- 1990-08-20 CA CA002065014A patent/CA2065014A1/en not_active Abandoned
- 1990-08-20 WO PCT/US1990/004722 patent/WO1991002711A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU6293790A (en) | 1991-04-03 |
| BR9007609A (en) | 1992-08-18 |
| WO1991002711A2 (en) | 1991-03-07 |
| WO1991002711A3 (en) | 1991-05-02 |
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