TW499410B - Chiral ligand and method for preparing cyanohydrins from aldehydes - Google Patents

Abstract

A chiral ligand of the formula (II) or formula (II'), was synthesized. The chiral ligand (II) or formula (II') can chelate to metals to form a catalytic complex to catalyze the addition of trimethylsilyl cyanide to aldehydes to give optically active cyanohydrin, individually.

Description

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 499410

The present invention relates to a novel chiral ligand, and the present invention also relates to an organometallic catalyst containing a novel palm auxiliary group. The organometallic catalyst can catalyze trimethylsilyl cyanide, so that The cyano groups are added to the aldehydes to obtain optically active cyanohydrins. 1 Purely optically active cyanohydrins are a very important intermediate in chemical synthesis, which can be easily converted into "-ammoniolide U-hydroxy acids) and" _hydroxyaldehyde b- hydroxy aldehydes), i-hydroxy ketones), 0-hydroxy amines), and a-arnino acid derivatives. '' Light cyanide chemical synthesis method has been invented for hundreds of years, but the produced compound is a meso compound. Compared with the use of valence, the preparation of optically active hydroxycyanide can generally be divided into four categories: the first category It is catalyzed by enzymes, the second is catalyzed by palm polymer, the third is catalyzed by organic metal, and the fourth is catalyzed by moon. Organic metal-catalyzed methods have been developed in recent years, but they are not complete so far. ~ The use of organometallic catalysts formed by palm auxiliary groups and metals to catalyze the reaction of the addition of trimethylsilyl cyanide to aldehydes to obtain optically active hydroxycyanines. However, they all have their disadvantages. Existing, for example: some catalysts The paper size of this catalyst applies to China National Standard (CNS) A4 specification mm) -1 ~-

Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 499410 V. Description of the invention (> Two pairs of non-fragrant cyclic aldehydes have better selectivity, but the choice of aromatic cyclic aldehydes is poor, and (2) some catalyst encounters When the acid is destroyed, there is no way to recover it. (3) Some catalysts need to use equivalent catalysts instead of catalytic ones. Mr. Wang Bingjun, one of the four people in Bengi, filed a patent application No. 871 of the Republic of China No. 12176 "Palm Auxiliary Group, Organic Metal Catalyst Containing It and Its Application", this patent application provides a compound

Compound (I) and compound (I,) can be used to form organometallic catalysts with metals, catalyze trimethylsilyl cyanide, and add cyano groups to aldehydes to obtain Different optically active sheep 1 cyanohydrins. The palmitious auxiliary group of compound ⑴ or compound (1,) only needs a catalytic amount to catalyze the synthesis of cyanocyanine to cyanide, and has good selectivity for all aldehydes. Although compound (I) or compound (1,) has a good selectivity for fatty aldehydes, it is still difficult to reach a high level of more than 90% in mirror image (e.e_; enantiomeric excess). SUMMARY OF THE INVENTION The present invention provides a new class of palmitoyl groups related to the following compound (Π).

A7 V. Description of Invention B7

(II) The formation of the palm auxiliary auxiliary group invented with titanium tetraisopropoxide [Ti (oipr) 4] 'was made with a rat's nail; Gu Dan, and in the presence of molecular sieves 4 A 2, It is used to catalyze the addition of cyano group J on trimethylsilyl cyanide to obtain optically active sheep to cyanocyanine and recover the used palm auxiliary group. The palm auxiliary group of the present invention is a Novel auxiliary group, this novel auxiliary group / and the catalytic amount can catalyze the synthesis of sheep to cyanocyanine; the most special is that it has very high selectivity for fatty aldehydes, which can reach the mirror image transcendence (ee; enantiomeric excess) 90 The above high level.

The present invention also relates to a novel diastereoisomer compound (II) of the compound (II). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

A7 V. Description of the invention (present) The synthesis and application of the novel palmitic auxiliary compound (II,) of the present invention are roughly the same as those of human 6 (11). Anyone who is familiar with this technology can use this technology. The state-of-the-art book discloses the synthesis and application of the compound, and learns the synthesis and application of the compound (IΓ), which will not be described here-redundant description. Man J1 is a preferred embodiment. The synthesis of the novel palmitoyl compound (II) of the present invention is based on ketopmic acid chlride as the starting material and trans- (1R, 2 ^ 4,2 dibenzyl It is obtained by the action of trans- (lR, 2R) -1,2-diphenyl ethylene diamine after reduction of the carbonyl group of the product. The novel palm auxiliary compound (π) of the present invention is used to synthesize sheep to cyanide The reaction is roughly as follows: A palm auxiliary compound and molecular sieves (molecular sieves 4 A.) powder and titanium tetraisopropoxide [Ti ((ypr) 4]) are stirred in the presence of a dichloromethane solvent. Hours, then add trimethyl dream to stir at ▲ temperature for half an hour, and then reduce the temperature to, add aldehydes. 'After the reaction is completed, add 1N hydrochloric acid (HC1) and stir; stir, then extract with dichloromethane The saturated salt solution was salted out, and the sodium sulfate was dried and concentrated. The crude product printed by the employees' cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs was used to separate the crude product and purified by column chromatography. The specific description does not limit the scope of the present invention. Preparation Example] Preparation of compound (21) (lR, 2R) -1,2-N, N, _bis [(lS, 4R) -7,7-dimethyl_2- This paper is in accordance with China National Standard (CNS) A4 specifications ( 210 X 297 诿 love) 499410 A7 ___B7__ 5. Description of the invention (S) oxo-bicyclo [2.2.1] heptylcarboxyl] diphenyl ethylene diamine (2 1) (111, 21〇-1, 2-team: ^ '-double [(13,41〇-7,7-dimethyl-2-keto-bisfluoren [2.2.1] heptylmethylfluorenyl] diphenylethylenediamine (21)

(Please read the precautions on the back before filling this page) -Installation—Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (21) Reversal (1R, 2R) _1,2-diphenylethylenediamine ( 50 mmole), triethylamine (100 mmole) and 100 mL of dichloromethane were placed in the reaction flask, and ketopinic acid chloride 100.5 mmole was dissolved in 200 mL of dichloromethane at 0 °. Slowly drip into the reaction flask at C, and finish dripping in about one hour; and continue stirring at room temperature for one hour, add 100 mL of deionized water and neutralize to neutrality, extract with dichloromethane X 2000 mL), The extract was washed with saturated brine (2 × 200 mL), and the organic layer was dried, filtered, and concentrated, and then purified by column chromatography to obtain a white solid compound (21) with a yield of 95%.

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499410 A7 __B7_ V. Description of the invention ("〇 Compound (21) spectral data: Proton nuclear magnetic resonance spectrum (400 MHZ, CDC13) d 8.84 (d, J = 6 Hz, 2H), 7.10 ~ 7.22 (m5 10H), 5.45 (dd, j = 2, 6Hz, 2Η), 2.39 ~ 2.48 (m, 2H), 2.40_2.49 (m, 4H), 1.96 ~ 2.08 (m, 6H), 1.46 ~ 1.60 (m, 2H) , 1.36 ~ 1.43 (m, 2H), 1.15 (s, 6H), 0.87 (s, 6H) 〇 Elemental analysis: Experiment 値 C: 75.53 Η: 7.46 N: 5.18 Theory 値 C: 75.47 Η: 7.43 N: 5.05 Implementation Example 1 Preparation of Compound (II).] (1 foot, 21〇-1, 2-team > ^ '_ bis [(18,211,41〇-7,7_dimethyl-2_hydroxy-bicyclo! 2,2,1] heptylformamidine] diphenylethylenediamine (II) * i (lR, 2R) -1,2-N, N, -bis [(lS, 2R, 4R) -7, 7_dimethyl-2-hydroxy-bicyclo [2? 2? L] heptyl carboxyl] diphenyl ethylene diamine (II) Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs

OH This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 centimeters) V. Description of the invention (;) L-Selectride tetrahydrofuran solution (18 mL) at -78 ° C and argon system ) Slowly drop into a tetrahydrofuran (5 mL) solution of the compound of formula (2 丨) (4 mm) and keep at _78 ° C for two hours, then return to room temperature and stir for one hour; under an ice bath Water (4-0 mL) was slowly added, and then ethanol (12 mL) and 3N aqueous sodium hydroxide solution (16 mL) were added, and a 30% aqueous solution of hydrogen peroxide was slowly added (rapid exotherm) until no more reaction ( (Approximately 12 liters, lasting about 30 minutes); add potassium carbonate solids until the aqueous layer is saturated, and extract the aqueous layer with dichloromethane; wash the organic layer with saturated brine, dry over sodium sulfate, filter, and concentrate to obtain one White solid compound (II), yield 95%. Compound (II) spectral data: Proton nuclear magnetic resonance spectrum (400 MHZ, CDC13) J 7.86 (d, J = 8 Hz, 2H), 7.16 (m, 6H), 7.03 (m, 4H), 5.39 (d, J = 8Hz, 2H), 5.29 (dd, J = 8, 4Hz, 2H), 3.89 (m, 2H), 2.46 (m, 2H), 1.94 (m, 4H), 1.75 (m, 4H), 1.06 (m, 4H), 0.97 (s, 6H), 0.80 (s, 6H) 〇 Carbon nuclear magnetic resonance spectrum (100 MHZ, CDC13) β 173.49 (C), 128_43 (2CH), 127.48 (CH), 126.94 (2CH) , 77_18 (CH), 59_19 (CH), 58.21 (C), 49.97 (C), 45.17 (CH), 40.94 (CH2), 28.81 (CH2), 26.26 (CH2), 20.62 (CH3), 20.47 (CH3) . Infrared spectrum (KBr) vmax (cm · 1): 3366, 293 6, 1642, 1545, 697 〇 Specific rotation: [oi] d26-170.52 (C0.52, CHCH3) The following application examples 1 to 2 use the present invention Synthesis of hydroxycyanine by the palm auxiliary compound (II). This paper size applies to China National Standard (CNS) A4 (210 X 297 cm) 499410 A7

V. Description of the invention (“) Xiang JI Example 1 Preparation of 2-hydroxy-2-phenylethyridine from benzoaldehyde In the air system and at room temperature, the tetraisopropoxy number [TRcyPrhKO.iMSmL, 15 mol%) was added to the palm Auxiliary compound (π) (0.0897 g '16.5mol%) and molecular sieve powder sieves 4 A ° powder, 65mg, must be removed at 0.3 mmHg / 300 ° C for 24 hours before use in dichloromethane solution (2.5 mL) and mixed for 1 hour; then added trimethylsilyl cyanide (0.15 mL, 1.1 mmol) and stirred at room temperature for half an hour, and then the temperature was reduced to minus 78 ° C. 'Add benzoic acid (0.1 mL (1 mmol) for 48 hours (track the completion of the reaction by thin layer chromatography, ethyl acetate / n-hexane 1/5), add 1N hydrochloric acid (10mL) and warm to room temperature and stir for 6 hours. After filtration, the aqueous layer was extracted with methane extraction (10 mL × 2). The organic layer was washed with saturated brine (10 mL × 2), dried over sodium sulfate, filtered and concentrated to obtain a crude product, which was distilled under reduced pressure to obtain a pure optically active 2-Hydroxy-2-phenylethyrene's yield was 87%; e_e. (Enantiomeric excess) was 93.2%. The results are shown in Table 1. Office workers consumer cooperative print Application Example 2-3 substituted benzaldehyde of Example 1 was applied to different aldehydes react to different Hydroxyl cyanide, and the results are shown in Table I. This paper size applies to China National Standard (CNS) A4 specification (21 × 2971 public love) 499410 Α7 Β7 5. Description of the invention (?) Table 1

Application examples Yield of light cyano acids (%) ee (%) Configuration 1 benzaldehyde 2-benzyl-2-phenylethoxycyanene 87 93.2 S 2 cyclohexyl formaldehyde 2-carbothione-2 -Said Ethyl Green 90 90 S 3 Aldehyde 2-Hydroxyhexanine 92 97.4 S! &Quot;% Packing (Please read the precautions on the back before filling out this page) Comparative Examples 1 to 3 Repeat the previous Application Example 1 The same reaction steps from 3 to 3 are carried out, but the compound (II) is substituted with the compound (I) respectively. The results are shown in Table 2. Table II

Application Examples Aldehyde hydroxycyanide yield ee (%) Configuration (%) 1 benzaldehyde 2-hydroxy-2-phenylethoxycyanine 79 94 S 2 cyclohexyl formaldehyde 2-cyclohexyl-2-¾ Ethylpyrene 94 87.2 S 3 Carboxaldehyde 2-Hydroxyhexanoe 96 88.5 S

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. From the results of Tables 1 and 2, it can be clearly seen that the novel palm auxiliary compound (II) of the present invention and titanium tetraisopropoxide [Ti (〇 ipr) 4] The formed catalyst has better enantioselectivity when it is used in the reaction of synthesizing cyanol. That is, the catalyst formed by the novel palm auxiliary compound (II) and tetraisopropoxy titanium of the present invention is more selective than the palm auxiliary compound (I) and The catalyst formed by isopropoxyl is more excellent. This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 29ίbilli) 499410 A7 B7 V. Description of the invention (; 〇) In summary, the present invention can indeed achieve the purpose of the invention by the disclosed structure. New characteristics, progress, and industrial availability, but in line with the requirements of invention patents. However, what has been disclosed above is a preferred embodiment: Any local change or modification that is derived from the technical ideas of this case and is easy to be inferred by those familiar with the art, does not depart from the patent right of this case. " i Please read the notes on the back before filling in this page}

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Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is sized for China National Standard (CNS) A4 (210 X 2 oil 2 mm)

Claims (1)

499410 AS 1. A palm auxiliary group of the compound (II) or the compound (II,) shown below. Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, Cooperative Society ¾ 2. A private machine metal catalyst, which is composed of titanium tetraisopropoxide [1: 丨 (〇 卞 1 *) 4] and the first item in the scope of patent application Complexes formed by compound (11) or the palm auxiliary group of compound (11,). Two methods for preparing cyanohydrins from the like, are characterized by the use of an organometallic catalyst such as the item 2 of the patent application as a catalyst to catalyze the addition of cyano groups on trimethylsilyl cyanide It can be converted into aldehydes to obtain optically active hydroxycyanide. 4 · The method according to item 3 of the patent application range, wherein the addition reaction is performed in the presence of molecular sieves (molecular sieves 4 A. powder). 0 5 · For example, the method of claim 3, wherein the aldehyde refers to valeraldehyde. This paper size applies to China National Standard (CNS) A4 specifications (210 X 297). ^ -------- ^ --------- (Please read the precautions on the back before filling in this page)