CH681302A5 - Optically active 2-oxetanone prepn. - by cyclo:addn. of carbonyl cpds. and ketone(s) obtd. by dehydrochloridation of carboxylic acid chloride(s) using catalytic amts. of optically active amine(s) - Google Patents

Abstract

The prepn. of optically active 2-oxetanone derivs. of formula (I) comprises cycloaddition of ketones of formula R3R4C=C=O (III) (which have been obtd. insitu by dehydrochlorination of carboxylic acid chlorides of formula R3R4CH-COCl (II)) and carbonyl cpds. of formula R1R2C=O (IV) in the presence of optically active tert. amines used in an amt. which is less than the stoichiometrically necessary amt., the rest being made up with an optically inactive tert. amine. R1= CXR5R6, X= F, Cl or Br. R5 and R6= each H, F, Cl, Br or opt. halosubstd. alkyl; R2= H, 1-6C alkyl or a gp. R1; R3 and R4= each H, F, Cl, Br, opt. susbtd. alkyl or opt. substd. aryl; or R3= MeO or phthalimido and R4= H; provided that R1=R2 and R3=R4 do not occur simultaneously. USE/ADVANTAGE - (I) are valuable chiral building blocks which can be converted into a wide variety of optically pure prods. The use of the optically inactive tert-amine in the presence of a catalytic amt. of optically active tert. amine (known as a catalyst for the enantiomer selective cycloaddition and for the conversion of (II) into (III)) enables (I) to be prepd. in good yields and optical purity. Using optically active tert. amine alone would be too expensive for use on a commercial scale.

Description

Optically active 2-oxetanones are valuable chiral building blocks because, as beta-lactones, they represent reactive compounds which can be converted into a wide variety of products by hydrolysis or reactions with a large number of reagents (see e.g. HE Zaugg, Org.Reactions, Vol. 8 , Pp. 305-363 (1954)). These reactions are mostly stereospecific, so that optically pure products are finally obtained from optically pure 2-oxetanones.

A suitable reaction for the preparation of numerous substituted 2-oxetanones is the cycloaddition of ketenes and carbonyl compounds. In particular, activated carbonyl compounds, such as alpha-halogen aldehydes and alpha-halogen ketones, for example chloral, react with ketenes in the presence of catalysts to form the corresponding substituted 2-oxetanones (DE-PS 1 136 323; WT Brady and L. Smith, J. Org. Chem . 36, 1637 (1971)). If optically active amines, such as, for example, quinidine or cinchonine, are used as catalysts, it is possible to carry out the cycloaddition of unsymmetrical carbonyl compounds enantioselectively, so that the 2-oxetanone formed is also optically active. The optical purities that can be achieved are quite considerable here (H. Wynberg and E. G. J. Staring, J. Am. Chem. Soc. 104, 166 (1982)).

It is also known that the ketenes for the cycloaddition with activated carbonyl compounds can also be prepared in situ by reacting carboxylic acid chlorides with tertiary amines (DE-PS 1 214 211). In this way, ketenes that are unstable or otherwise difficult to obtain in pure form can also be converted. If optically active amines are used to produce ketene, optically active 2-oxetanones can also be produced accordingly (D. Borrmann and R. Wegler, Chem. Ber. 100, 1575 (1967)). However, the latter process has the disadvantage that the optically active amine has to be used in a stoichiometric amount, which is generally much too expensive for industrial use.

The object of the present invention was to provide a process which enables the enantioselective cycloaddition of ketenes and carbonyl compounds in the presence of catalytic amounts of an optically active auxiliary substance without the ketene having to be used as such.

According to the invention, this object is achieved by the method according to claim 1.

It has surprisingly been found that it is possible, by using an optically inactive tertiary amine in the presence of catalytic amounts of an optically active tertiary amine, which is known per se as a catalyst for the cycloaddition of ketenes and carbonyl compounds, even when the ketene is prepared in situ to produce optically active 2-oxetanones in good yields and optical purities from the corresponding carboxylic acid chloride.

The optically inactive amines used are advantageously those with a total of at least 6 carbon atoms, preferably trialkylamines with at most one methyl group on the nitrogen atom, where the alkyl groups can also be branched or cyclic, or two alkyl groups through an alkanediyl group, which with the nitrogen an optionally alkyl-substituted piperidine or pyrrolidine ring forms, can be replaced. Amines with one or two secondary carbon atoms on the nitrogen, for example dicyclohexylmethylamine or diethylisopropylamine, or amines with three alkyl groups of medium chain length, such as tri-n-butylamine, i.e. tertiary amines which have a certain steric hindrance, are particularly preferred. However, the steric hindrance must not be too great, because otherwise the chemical yield can be severely impaired.

On the other hand, triethylamine, for example, can be used as the base, the optical yield being lower for the same amount of optically active catalyst. However, this decrease can only be partially compensated for by increasing the amount of catalyst, for example from 0.5 to 1 mol% to 2 to 5 mol%.

The optically active amines used are preferably the cinchona alkaloids known for high asymmetric induction, such as quinidine and quinine or their derivatives, in particular the O-acyl derivatives such as O-benzoylquinine or O-acetylquinidine.

The amounts of the optically inactive amine and the optically active amine are expediently chosen so that together they give the amount stoichiometrically required for the elimination of hydrogen chloride from the carboxylic acid chloride or a slight excess, the optically active amine preferably in a proportion of 0.1 to 10 Mol% is present. Proportions of from 0.5 to 5 mol% of optically active amine are particularly preferred.

In principle, any carboxylic acid chloride can be used as the carboxylic acid chloride which has at least one hydrogen atom on the alpha carbon atom and which can be converted into the corresponding ketene with a tertiary amine, i.e. not only acetyl chloride, but also chlorides of higher alkanoic acids, arylacetic acid chlorides, such as phenylacetyl chloride, or else Carboxylic acid chlorides with heteroatoms on the alpha carbon atom, for example chloroacetyl chloride, methoxyacetyl chloride or phthalimidoacetyl chloride (N-phthaloylglycine chloride). If the alpha carbon atom in the acid chloride is a chiral or prochiral center, this forms a (second) center of chirality in 2-oxetanone, so that diastereomer pairs can also occur.

An aldehyde or ketone with at least one halogen atom in the alpha position to the carbonyl group can be used as the activated carbonyl compound. Multiply halogenated compounds, such as, for example, chloral (trichloroacetaldehyde) or 1,1,1-trichloroacetone, are particularly preferred.

The cycloaddition is expediently carried out in a solvent which is inert towards ketenes and acid chlorides, such as, for example, diethyl ether, tetrahydrofuran, ethyl acetate, acetone, acetonitrile, dichloromethane, hexane or toluene. Particularly good results were achieved with the first three solvents mentioned. In suitable cases, an excess of the carbonyl compound can also serve as a solvent.

The reaction temperature is expediently between -30 and +40 ° C., preferably between -10 and +20 ° C.

Either the two amines used, i.e. the optically inactive amine and the catalytic amount of optically active amine, presented in part of the solvent and the carboxylic acid chloride and the carbonyl compound are added simultaneously but separately with the remaining solvent, or only a solution of the optically active amine is presented and the optically inactive amine is added separately, but at the same time as the other reactants. It is also possible to initially charge the optically active amine with the carbonyl compound and to add solutions of the carboxylic acid chloride and the optically inactive amine at the same time.

The reaction mixture can be worked up by methods known per se.

The following examples illustrate the implementation of the process according to the invention.

example 1

(R) -4-trichloromethyl-2-oxetanone

15.17 g of diethyl isopropylamine (98% strength, 115 mmol) and 0.16 g of quinidine (0.5 mmol) were dissolved in 65 ml of diethyl ether and the mixture was cooled to -11 ° C. 14.89 g of chloral (99%, 100 mmol) in 45 ml of diethyl ether and 7.85 g of acetyl chloride (100 mmol) in 45 ml of diethyl ether were metered into this solution within 1 h.

The reaction mixture was stirred for a further 2 h at -11 ° C. and then extracted twice with 50 ml of 1N hydrochloric acid each time. The organic phase was dried over sodium sulfate and the solvent was distilled off.

Crude product: yield 16.61 g, content (GC) 86% (corresponds to 75.4% of theory)

[alpha] 20-578 = -10.5 DEG (c = 1, cyclohexane)

For purification, 9.4 g of crude product were distilled at 0.1 mbar in a Kugelrohr apparatus.

8.10 g of distillate with a content of 94.0% (GC) and [alpha] 20-578 = -12.9 ° (c = 1, cyclohexane) were obtained, which, based on the total amount, corresponds to a yield of 71.0% and corresponds to an optical purity of 88%.

Example 2

(R) -4-trichloromethyl-2-oxetanone

The procedure was as described in Example 1, except that triethylamine (10.62 g, 105 mmol) was used instead of diethylisopropylamine.

Crude product: yield 18.20 g, content (GC) 84.9% (corresponds to 81.6% of theory)

[alpha] 20-578 = -3.8 ° (c = 1, cyclohexane)>

After the distillation, the content was 95.0% (GC) and the yield 74.5%, the rotation value [alpha] 20-578 = -4.8 ° (c = 1, cyclohexane) corresponded to an optical purity of 32%.

Example 3

(S) -4-trichloromethyl-2-oxetanone

15.17 g of diethyl isopropylamine (98%, 115 mmol) and 0.43 g of O-benzoylquinine (1 mmol) were dissolved in 50 ml of dichloromethane. The solution was cooled to -15 ° C. and 14.89 g of chloral (99% strength, 100 mmol) and 8.54 g of acetyl chloride (110 mmol) in 45 ml of dichloromethane each time were metered in over the course of 1 hour. The procedure described in Example 1 was continued. After the distillation, 12.3 g of crude product gave 6.40 g of distillate with a content (GC) of 96.6%, corresponding to a yield of 32.6%, based on chloral.

Rotation value: [alpha] 20_578 = +9.2 DEG (c = 1, cyclohexane)

The optical purity (ee) was determined to be 61% by derivatization with 1-phenylethylamine and HPLC analysis.

Examples 4-15

(R) -4-trichloromethyl-2-oxetanone

Analogously to Examples 1 to 3, chloral was reacted at -16 to -10 ° C. with acetyl chloride in the presence of quinidine and diethylisopropylamine (Examples 4-11) or triethylamine (Examples 12-15), the solvent and the amount of quinidine being varied .

Yield, content and optical purity of the distilled product and the variable parameters are summarized in Table 1. <TABLE> Columns = 6 Title: Table 1 Head Col 01 AL = L: Example No. Head Col 02 AL = L: Solvent Head Col 03 AL = L: Amine Head Col 04 AL = L: Quinidine amount re. on chloral [mol%] Head Col 05 AL = L: Yield rel. chloral [%] Head Col 06 AL = L: opt.cleanliness [% ee] 4 toluene Et2Pr <i> N 1.0 15 93 5 CH2Cl2 Et2Pr <i> N 1.0 57 66 6 THF Et2Pr <i> N 1.0 96.4 79 7 EtOAc Et2Pr <i> N 1 , 0 91.7 79 8 Et2O Et2Pr <i> N 5.0 62 90 9 Et2O Et2Pr <i> N 2.5 70 84 10 Et2O Et2Pr <i> N 1.0 57 86 11 Et2O Et2Pr <i> N 1 , 0 66 84 12 Et2O Et3N 5.0 59 71 13 Et2O Et3N 2.5 79 61 14 Et2O Et3N 2.0 90 68 15 Et2O Et3N 1.0 78 43 </TABLE>

Example 16

(R) -4-methyl-4-trichloromethyl-2-oxetanone

1.10 g of O-acetylquinidine (3 mmol) were dissolved in 49.92 g of 1,1,1-trichloroacetone (97%, 300 mmol) and the solution was cooled to -15.degree. While stirring, 13.19 g of diethylisopropylamine (98%, 100 mmol) and 7.85 g of acetyl chloride (100 mmol) were simultaneously added dropwise over the course of 50 minutes, a slurry-like suspension being formed. The mixture was stirred for a further 30 minutes, after 30 ml of dichloromethane had been added it was warmed to 20 ° C. and washed twice each time with 20 ml of 1N hydrochloric acid and deionized water.

The organic phase was dried over sodium sulfate and the excess trichloroacetone was distilled off (bp = 131 ° C.). Crude product: Yield 8.54 g, content (GC) 74.7%

For purification, 7.50 g of crude product were distilled at 50 to 80 ° C./0.05 mbar in a Kugelrohr apparatus. The distillate (5.14 g) had a content (GC) of 92.2%, the yield, based on acetyl chloride, was accordingly 26.5%. The optical purity was determined to be 93.8% by means of HPLC after derivatization with 1-phenylethylamine.

Example 17

3-methyl-4-trichloromethyl-2-oxetanone

4.40 g of O-acetylquinidine (12 mmol) were dissolved in 390 ml of ethyl acetate. 91.01 g of diethylisopropylamine (98% strength, 690 mmol) in 270 ml of ethyl acetate and 56.70 g of propionyl chloride (98% strength, 600 mmol) and 89.34 g were added simultaneously at -15 ° C. with stirring within 1 h Chloral (99%, 600 mmol) in 270 ml of ethyl acetate was metered in and the reaction mixture was stirred at 20 ° C. for a further 5 h. The amine hydrochloride formed (47.3 g) was filtered off, the filtrate was concentrated to 2/3 of its volume and washed twice with 150 ml of 1N hydrochloric acid each time, once with 100 ml of 15% sodium chloride solution and once with 100 ml of saturated sodium hydrogen carbonate solution then dried over sodium sulfate.

After distilling off the solvent, 97.2 g of brown oil with a content (GC) of 35.7% trans isomer and 14.4% cis isomer, corresponding to an overall yield of 39.9%, were obtained.

The crude product was distilled at 0.2 mbar (top temperature 30-61 ° C.) and the distillate (50.1 g of yellow \ l) was fractionated at 0.04 mbar using a split tube column.

The isomer which passed first was identified as the trans isomer by <1> H-NMR (cf. W. T. Brady and L. Smith, l.c.).

[alpha] 20-578 = 39.5 DEG (c = 2, cyclohexane)

The trans isomer was identified as (3S, 4R) -3-methyl-4-trichloromethyl-2-oxetanone by correlation with the known (2S, 3S) -3-hydroxy-2-methylbutyric acid ethyl ester. The optical purity of the trans isomer was determined to be> 95% ee.

Example 18

trans -3-phthalimido-4-trichloromethyl-2-oxetanone

7.58 g of diethyl isopropylamine (98% strength, 59 mmol) and 0.37 g of O-acetylquinidine (1 mmol) were dissolved in 32.5 ml of ethyl acetate and the solution was cooled to -10.degree. 7.44 g of chloral (99%, 50 mmol) in 22.5 ml of ethyl acetate and 11.29 g of phthalimidoacetyl chloride (99%, 50 mmol) in 40 ml of ethyl acetate were metered in simultaneously within 1 h. The mixture (light yellow suspension) was stirred for a further 1 hour at -10 ° C. and 15 hours at 20 ° C., and finally diluted with 100 ml of ethyl acetate and filtered.

The filtrate was washed twice with 1N hydrochloric acid (25 ml each time) and saturated sodium hydrogen carbonate solution (50 ml each time) and dried over sodium sulfate. After the solvent had been distilled off, an oily residue remained, which was stirred with 50 ml of diethyl ether for 3 h. The precipitated crude product was filtered off and dried at 20 ° C./30 mbar.

Crude yield: 2.52 g.

For purification, the crude product was chromatographed over 110 g of silica gel 60 using ethyl acetate / cyclohexane (1: 3). 1.18 g of pure trans-3-phthalimido-4-trichloromethyl-2-oxetanone, corresponding to a yield of 7.1%, based on chloral, were isolated from the appropriate fractions.

M.p .: 184-217 ° C

[alpha] 20-578 = -12.3 DEG (c = 2, chloroform)

<1> H NMR (CDCl3, 300 MHz) delta 5.44 (d, J = 4.1 Hz, 1H) 5.91 (d, J = 4.1 Hz, 1H) 7.82-8.03 (AA min BB min, 4H)

The optical purity was determined to be 82% by means of HPLC after derivatization with 1-phenylethylamine.

Examples 19-22

(R) -4-trichloromethyl-2-oxetanone

Example 19 (general rule):

9.87 g of dicyclohexylmethylamine (50 mmol) and 0.09 g of O-acetylquinidine (0.25 mmol, approx. 0.5 mol% based on chloral) were dissolved in 30 ml of diethyl ether and the solution was brought to -12.degree cooled down. 6.55 g of chloral (44 mmol) and 3.49 g of acetyl chloride (44 mmol) in 20 ml of diethyl ether each were added dropwise over the course of 40 minutes, and the resulting white suspension was stirred for a further 4 hours at -10 ° C. and then analogous to the example 1 worked up.

Examples 20-22

The procedure was analogous to Example 19, but with tri-n-butylamine (Examples 20-21) or 1-ethylpiperidine (Example 22) as the base.

The results of Examples 19-22 are summarized in Table 2. The yields are based on the distilled product. <TABLE> Columns = 5 Title: Table 2 Head Col 01 AL = L: Example No. Head Col 02 AL = L: Amin Head Col 03 AL = L: O-acetylquinidine amount, re. on chloral [mol%] Head Col 04 AL = L: yield re. on chloral [%] Head Col 05 AL = L: opt. purity [% ee] 19 Me (C6H11) 2N 0.5 61.0 80 20 Bu <n> 3N 0.5 57.2 52 21 Bu <n> 3N 2.5 53.3 69 22 1-ethylpiperidine 0.5 32.6 38 </TABLE>

Claims (6)

1. Process for the preparation of optically active 2-oxetanones of the general formula wherein R 1 is a group -CXR 5 R 6 with X = fluorine, chlorine or bromine and R <5> and R <6> independently of one another are hydrogen, fluorine, chlorine, bromine or optionally halogen-substituted alkyl, R 2 is hydrogen, C1-C6-alkyl or one of the groups specified for R 1, and either R 3 and R 4 independently of one another are hydrogen, fluorine, chlorine, bromine, optionally substituted alkyl or optionally substituted aryl, or R 3 is methoxy or phthalimido and R 4 is hydrogen, provided that R 1 = R 2 and R 3 are not simultaneously R 4, by cycloaddition from in situ Dehydrochlorination of carboxylic acid chlorides of the general formula R <3> R <4> CH-COCl (2) obtained ketenes of the general formula R <3> R <4> C = C = O (3) and carbonyl compounds of the general formula R <1> R <2> C = O (4) in which R 1, R 2, R 3 and R 4 have the meanings given above, in the presence of optically active tertiary amines, characterized in that of the optically active tertiary amine less than the stoichiometrically required Amount is used and an additional non-optically active tertiary amine is present in at least the amount required to achieve the stoichiometric ratio. 2. The method according to claim 1, characterized in that an amine of the general formula is used as the non-optically active tertiary amine R <7> R <8> R <9> N (5) wherein R 7 is an unbranched alkyl group with 1 to 6 carbon atoms and R 8 and R 9 are independently straight-chain or branched alkyl groups with 2 to 6 carbon atoms or cycloalkyl groups with 3 to 6 carbon atoms in the ring or R 8 and R 9 together denote a 1,4- or 1,5-alkanediyl group optionally substituted by methyl groups and R 7, R 8 and R 9 together have at least 6 carbon atoms becomes. 3. The method according to claim 2, characterized in that an amine from the group diethyl-isopropylamine, tributylamine, dicyclohexyl-methylamine is used as the non-optically active tertiary amine. 4. The method according to any one of claims 1 to 3, characterized in that an optionally acylated cinchona alkaloid is used as the optically active tertiary amine. 5. The method according to any one of claims 1 to 4, characterized in that the optically active tertiary amine is used in an amount of 0.1 to 10 mol%, based on the carbonyl compound. 6. The method according to any one of claims 1 to 5, characterized in that chloral or 1,1,1-trichloroacetone is used as the carbonyl compound.