WO2012002203A1 - β-アミノカルボニル化合物の製法 - Google Patents
β-アミノカルボニル化合物の製法 Download PDFInfo
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- WO2012002203A1 WO2012002203A1 PCT/JP2011/064220 JP2011064220W WO2012002203A1 WO 2012002203 A1 WO2012002203 A1 WO 2012002203A1 JP 2011064220 W JP2011064220 W JP 2011064220W WO 2012002203 A1 WO2012002203 A1 WO 2012002203A1
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- aminocarbonyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/60—Preparation of compounds containing amino groups bound to a carbon skeleton by condensation or addition reactions, e.g. Mannich reaction, addition of ammonia or amines to alkenes or to alkynes or addition of compounds containing an active hydrogen atom to Schiff's bases, quinone imines, or aziranes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to a process for producing a ⁇ -aminocarbonyl compound.
- the Mannich-type reaction in which a carbonyl compound is directly added to aldimine is one of carbon-carbon bond formation reactions important for organic synthesis because the product becomes an optically active ⁇ -aminocarbonyl compound.
- Non-Patent Documents 1 to 6 only a few examples of the reaction of adding malonic acid diester to aldimine are known (Non-Patent Documents 1 to 6), and are difficult to develop despite being an important reaction. It is said that.
- hetero Diels-Alder reaction and Bayer-bilger oxidation reaction are known as reactions using a magnesium complex of BINOL (1,1'-bi-2-naphthol) as a catalyst (Non-patent Documents 7 and 8).
- Non-Patent Documents 1 to 6 described above Mannich-type reactions in which malonic acid diesters are added to aldimine using a catalyst have been reported. However, the reaction time is long or the enantiomeric excess is low. There is a problem that it is necessary to use a catalyst having a complicated structure.
- Non-Patent Documents 7 and 8 report a reaction using a BINOL magnesium complex as a catalyst, but no attempt has been made to use it as a Mannich-type reaction catalyst.
- the present invention has been made in order to solve such problems.
- a Mannich-type reaction between aldimine and malonic acid diester using a catalyst having a simple structure, ⁇ -amino acid with a high enantiomeric excess is obtained.
- the main purpose is to obtain a carbonyl compound in a high yield.
- the present inventors have already reported a chiral lithium binaphtholate catalyst as a Mannich-type reaction catalyst for direct addition of a carbonyl compound to aldimine.
- This catalyst is a compound in which the carbonyl compound is a malonic diester. In some cases it was not applicable.
- a chiral magnesium binaphtholate catalyst was examined. As a result, it was found that the product was obtained with a high enantiomeric excess and a high yield. It came to.
- the production method of the ⁇ -aminocarbonyl compound of the present invention is such that nitrogen is protected in the presence of optically active BINOL and 1 to 2 moles of dialkylmagnesium (the two alkyl groups are the same or different) with respect to the BINOL.
- An optically active ⁇ -aminocarbonyl compound is obtained by a Mannich-type reaction between the aldimine thus obtained and malonic acid diesters.
- an optically active ⁇ -aminocarbonyl compound can be obtained with a high enantiomeric excess and a high yield.
- a magnesium binaphtholate complex corresponding to optically active BINOL is generated in the system, and this serves as a catalyst to proceed with an asymmetric Mannich type reaction.
- This catalyst has a simple structure in which magnesium is coordinated to BINOL, and can be easily prepared in the system using, for example, a commercially available reagent.
- the presumed reaction mechanism is shown in the following formula.
- the reaction between tert-butylbenzylidene carbamate and dimethyl malonate was exemplified.
- the asymmetric Mannich type reaction is presumed to proceed via, for example, a form such as Bronsted acid-Bronsted base shown on the left side or Lewis acid-Bronsted base shown on the right side.
- the production method of the ⁇ -aminocarbonyl compound of the present invention is such that nitrogen is protected in the presence of optically active BINOL and 1 to 2 moles of dialkylmagnesium (the two alkyl groups are the same or different) with respect to the BINOL.
- An optically active ⁇ -aminocarbonyl compound is obtained by a Mannich-type reaction between the aldimine thus obtained and malonic acid diesters.
- the optically active BINOL used in the process for producing the ⁇ -aminocarbonyl compound of the present invention ie, 1,1′-bi-2-naphthol
- this BINOL reacts with a magnesium source, a magnesium binaphtholate complex is formed, and this complex is considered to function as a catalyst for an asymmetric Mannich type reaction. Therefore, the amount of BINOL used is closely related to the amount of catalyst used.
- the amount of BINOL used is not particularly limited, but is preferably 1 to 20 mol%, more preferably 2.5 to 10 mol%, based on the reaction substrate (for example, aldimine). However, depending on the structure of the reaction substrate and the structure of the catalyst, good results may be obtained even if this value is exceeded.
- dialkylmagnesium In the process for producing a ⁇ -aminocarbonyl compound of the present invention, 1 to 2 moles of dialkylmagnesium is used with respect to BINOL, but usually 1 mole of dialkylmagnesium is used and good results are obtained.
- the reaction substrate has a hetero atom (group) such as an alkoxy group
- the amount exceeds 1 mole, for example, 1.2 to 2.0 moles, and further 1.5 to 2.0 moles.
- a molar amount and specifically, it is preferable to use a 1.5-fold or 2-fold mole. This is presumably because magnesium is coordinated to the oxygen atom of the alkoxy group in the reaction substrate, and the amount of magnesium forming the catalyst is reduced.
- dialkylmagnesium may be the same or different.
- dialkylmagnesium is not particularly limited.
- Me 2 Mg, Et 2 Mg, n-Pr 2 Mg, i-Pr 2 Mg, n-Bu 2 Mg, i-Bu 2 Mg, sec- Examples include Bu 2 Mg and tert-Bu 2 Mg.
- n-Bu 2 Mg is preferable in consideration of easy availability.
- aldimines used for Mannich type reaction are R 1 —CH ⁇ NR 2 (R 1 is an aryl group or an ester group, R 2 is tert-butoxycarbonyl (Boc), benzyl)
- R 1 is an aryl group or an ester group
- R 2 is tert-butoxycarbonyl (Boc)
- benzyl A compound represented by oxycarbonyl (Cbz) or 2,2,2-trichloroethoxycarbonyl (Troc)) is preferable.
- examples of the aryl group include aromatic hydrocarbon groups such as a phenyl group, a naphthyl group, a phenanthryl group, and an anthranyl group, and aromatic heterocyclic groups such as a furyl group, a thienyl group, and a pyridyl group.
- aromatic hydrocarbon groups such as a phenyl group, a naphthyl group, a phenanthryl group, and an anthranyl group
- aromatic heterocyclic groups such as a furyl group, a thienyl group, and a pyridyl group.
- substituent in this case include an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an alkoxy group, and a halogen.
- examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group.
- examples of the alkenyl group include a vinyl group, an allyl group, a butenyl group, and a styryl group.
- examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
- Examples of the aryl group include a phenyl group, a biphenyl group, a naphthyl group, and a binaphthyl group.
- Examples of the alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.
- Examples of the halogen include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a chlorine atom or a bromine atom is preferable.
- ester groups include methoxycarbonyl group, ethoxycarbonyl group, n-propylcarbonyl group, isopropylcarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, phenoxycarbonyl Groups and the like.
- R 2 is a protecting group.
- Boc is used as the protecting group, deprotection is possible under strongly acidic conditions such as trifluoroacetic acid or hydrochloric acid-ethyl acetate solution.
- Cbz is used, palladium is removed. Deprotection is possible by a hydrogenation reaction or birch reduction using a catalyst.
- R 2 is preferably the above-described protecting group, but may be an aryl group such as a phenyl group, a 2-methoxyphenyl group, a 4-methoxyphenyl group, or a naphthyl group.
- the malonic acid diesters used in the production method of the ⁇ -aminocarbonyl derivative of the present invention are represented by CHX (CO 2 R 3 ) 2 (X is a hydrogen atom or a halogen atom, R 3 is alkyl, allyl, benzyl or aryl). It is preferable that it is a compound.
- diallyl malonate, dibenzyl malonate, diphenyl malonate, etc. one in which one of the two hydrogen atoms at the ⁇ -position is substituted with a halogen atom can be mentioned.
- a halogen atom a chlorine atom or a bromine atom is preferable.
- the reaction solvent is not particularly limited, but it is preferable to use an aromatic solvent, a halogenated hydrocarbon solvent, or an ether solvent.
- aromatic solvent include toluene and xylene.
- halogenated hydrocarbon solvent include methylene chloride, 1,1-dichloroethane, 1,2-dichloroethane, and the like.
- ether solvent include diethyl ether. Of these, toluene is preferred.
- the reaction temperature is not particularly limited, but is preferably ⁇ 60 ° C. to 50 ° C., more preferably ⁇ 40 ° C. to 30 ° C. (room temperature).
- the reaction time may be a time until the reaction substrate disappears or the reaction stops, but is usually set within a range of several minutes to several hours.
- a dehydrating agent such as magnesium sulfate or molecular sieves may be added to the reaction system.
- Example 1 To a Schlenk reaction vessel purged with nitrogen, 100 mg of magnesium sulfate was added, and dried with a heat gun for about 3 to 5 minutes under reduced pressure ( ⁇ 5 Torr). The reaction vessel was dissipated to room temperature while being decompressed, and nitrogen was introduced. Thereafter, (R) -BINOL (7.1 mg, 0.025 mmol) and toluene (3 mL) were added to the reaction vessel and stirred well. The mixture was cooled to ⁇ 20 ° C., n-Bu 2 Mg (1.0 M heptane solution, 25.0 ⁇ L, 0.025 mmol) was added, and the mixture was stirred at ⁇ 20 ° C. for 5 minutes.
- the obtained product is easily converted into an optically active ⁇ -lactam useful as an intermediate for pharmaceuticals and agricultural chemicals by treatment with hydrochloric acid and then treatment with LDA as shown in the following formula. I was able to.
- Example 2 Asymmetric Mannich reaction between dimethyl malonate and various aldimines shown in Table 1 was carried out in the same manner as in Example 1. The results are shown in Table 1. In any of Examples 2-9, the product was obtained with a very high enantiomeric excess. The numerical values in [] in the column of yield and enantiomeric excess in Example 5 are the results when 5 mol% (R) -BINOL and 7.5 mol% n-Bu 2 Mg are used. . In Example 5, 5 mol% of (R) -BINOL and 5 mol% of n-Bu 2 Mg were used in comparison with 5 mol% of (R) -BINOL and 5 mol% of n-Bu 2 Mg.
- Example 10 to 14 An asymmetric Mannich type reaction between tert-butylbenzylidene carbamate and various malonic acid diesters shown in Table 2 was carried out in the same manner as in Example 1. The results are shown in Table 2. In any of Examples 10 to 14, the product was obtained with very high yield and enantiomeric excess. The numerical values in [] in the column of yield and enantiomeric excess in Example 14 are the results when 2.5 mol% (R) -BINOL and 3.75 mol% n-Bu 2 Mg are used. Indicates.
- Example 15 In Example 15, as shown in the following formula, an asymmetric Mannich reaction between an aldimine derived from glyoxal having a 4-methoxyphenyl group on nitrogen and dimethyl malonate having a bromine atom at the ⁇ -position was carried out. And performed in the same manner. Also in this case, a relatively good result was obtained as shown in the following formula.
- Example 16 and 17 and Comparative Examples 1 to 6 An asymmetric Mannich reaction between tert-butylbenzylidene carbamate and dimethyl malonate was carried out according to Example 1 under the reaction conditions shown in Table 3 in the presence of (R) -BINOL and MX shown in Table 3. The results are shown in Table 3. As is apparent from Table 3, Comparative Example 1 using only (R) -BINOL, Comparative Examples 2 and 4 using (R) -BINOL and n-BuLi, (R) -BINOL and n-BuLi In Comparative Examples 3 and 5 in which t-BuOH was used, the reaction proceeded in some cases, but in all cases, the enantiomeric excess was low.
- Comparative Example 7 In Comparative Example 7, 2.5 mol% each of (R) -BINOL and n-Bu 2 Mg having a 3,4,5-trifluorophenyl group introduced at the 3,3 ′ position were used, and the reaction time was 2 hours. The reaction was performed in the same manner as in Example 1 except that. As a result, the corresponding ⁇ -aminocarbonyl compound was hardly obtained. Further, when n-Bu 2 Mg was doubled, that is, increased to 5 mol% and the reaction time was increased to 5 hours, the corresponding ⁇ -aminocarbonyl compound was obtained in a yield of 88%, but the enantiomeric excess was 35% It was only ee. From this, it was found that in order to obtain the desired product with a high enantiomeric excess, the substituent at the 3,3 ′ position of (R) -BINOL is unnecessary.
- the present invention can be used in the pharmaceutical and chemical industries, and can be used, for example, in the production of various ⁇ -aminocarbonyl compounds used as intermediates for pharmaceuticals, agricultural chemicals, cosmetics and the like.
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Abstract
Description
窒素置換したシュレンク反応容器に、硫酸マグネシウム100mgを加えて、減圧下(<5Torr)、ヒートガンで3~5分程度加熱乾燥した。その反応容器を減圧のまま室温まで放熱し、窒素導入した。その後、その反応容器に(R)-BINOL(7.1mg,0.025mmol)、トルエン(3mL)を加え、よく撹拌した。この混合液を-20℃に冷却し、n-Bu2Mg(1.0Mヘプタン溶液、25.0μL、0.025mmol)を加え、-20℃で5分間撹拌した。次いで、マロン酸ジメチル(62.9μL,0.55mmol)を加え、-20℃で5分間撹拌した。最後に、アルジミンとしてtert-ブチルベンジリデンカーバメート(102.6mg,0.50mmol)を加えて、-20℃で3時間撹拌した。反応終了をTLCで確認し、1M塩化水素-メタノール溶液(2mL)を加えて反応を停止した。反応混液に酢酸エチル(10mL)と水(5mL)を加え、通常の分液処理を行った。水層からさらに酢酸エチル抽出(10mL×2回)を行った。抽出した有機層は飽和塩化ナトリウム水溶液(10mL)で洗浄し、硫酸ナトリウムで乾燥後、ろ過、濃縮した。濃縮物をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1~2:1)に展開して生成物を分取し、純生成物を収率>99%(169mg)で得た。更に、キラルカラムAD-Hを充填した高速液体クロマトグラフィー(ヘキサン:イソプロパノール=9:1,1.0mL/min)により、生成物の鏡像体過剰率を92%ee(R)と決定した。この実施例1では、(R)-BINOLとn-Bu2Mgの両方とも、アルジミンに対して5mol%使用した。
マロン酸ジメチルと表1に示す各種のアルジミン類との不斉マンニッヒ型反応を、実施例1と同様にして行った。その結果を表1に示す。実施例2~9のいずれにおいても、非常に高い鏡像体過剰率で生成物が得られた。なお、実施例5の収率及び鏡像体過剰率の欄の[ ]内の数値は、5mol%の(R)-BINOLと7.5mol%のn-Bu2Mgを用いた場合の結果を示す。実施例5では、5mol%の(R)-BINOLと5mol%のn-Bu2Mgを用いた場合に比べて、5mol%の(R)-BINOLと7.5mol%のn-Bu2Mgを用いた場合の方が好結果となった。その理由は、前者ではアルジミンのメトキシ基の酸素原子にマグネシウムがキレートして触媒種が減少したのに対し、後者ではn-Bu2Mgを増量したことによりそのような触媒種の減少を防止できたためと考えられる。この結果から、アルジミンの構造によっては、(R)-BINOLの使用量よりもn-Bu2Mgの使用量を多くすることが好ましいことがあることがわかった。
1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 3.64 (s, 3H), 3.75 (s, 3H), 3.93 (brs,1H), 5.49 (brs, 1H), 6.16 (brs, 1H), 7.23-7.34 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 28.2 (3C), 52.5, 52.8, 53.3, 56.6, 79.7, 126.1 (2C), 127.6, 128.6 (2C), 139.3, 155.1, 167.5, 168.3. M.p. 95-97℃. IR (KBr) 3375, 2982, 2954, 1737, 1689, 1521, 1294, 1245, 1173, 1011, 705 cm-1. [α]D 27 = -14.8 (c 1.0, CHCl3, 92% ee(R)) HRMS (FAB+) calcd for C17H23NNaO6 [M+Na]+ 360.1423, found 360.1419. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 21.4 min (minor, S), 29.0 min (major, R).
1H NMR (400 MHz, CDCl3) δ 3.61 (s, 3H), 3.68 (s, 3H), 3.93 (brs, 1H), 5.07 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H), 5.55 (brs, 1H), 6.45 (brs, 1H), 7.10-7.55 (m, 10H). 13C NMR (100 MHz, CDCl3) δ 52.7, 53.0, 54.0, 56.6, 67.0, 126.3 (2C), 127.9, 128.1 (2C), 128.1 (2C), 128.5 (2C), 128.8, 128.8 (2C), 136.4, 139.1, 155.8, 167.4, 168.4. IR (neat) 3335, 4954, 1736, 1507, 1240, 1162, 1044 cm-1. [α]D 24 = +9.6 (c 1.0, CHCl3, 82% ee (R)) HRMS (FAB+) calcd for C20H21NNaO6 [M+Na]+ 394.1267, found 394.1261. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 46.8 min (minor, S), 67.0 min (major, R).
1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.65 (s, 3H), 3.75 (s, 3H), 3.88 (brs, 1H), 5.44 (brs, 1H), 6.16 (brs, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 28.2 (3C), 52.6, 52.7, 53.1, 56.5, 80.1, 127.7 (2C), 128.8 (2C), 133.6, 138.1, 155.1, 167.4, 168.3. IR (neat) 3421, 2978, 1717, 1491, 1244, 1161 cm-1. [α]D 23 = -10.0 (c 1.00, CHCl3, 93% ee (R)) HRMS (FAB+) calcd for C17H22ClNNaO6 [M+Na]+ 394.1033, found 394.1042. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 28.5 min (major, R), 35.6 min(minor, S).
1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.33 (s, 3H), 3.64 (s, 3H), 3.74 (s, 3H), 3.91 (brs, 1H), 5.45 (brs, 1H), 6.14 (brs, 1H), 7.02-7.13 (m, 3H), 7.20 (t,J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 21.6, 28.4 (3C), 52.6, 53.0, 53.4, 56.8, 79.8, 123.2, 127.0, 128.5, 128.6, 138.3, 139.4, 155.2, 167.7, 168.5. IR (neat) 3428, 2977, 1718, 1497, 1366, 1243, 1164, 1046 cm-1. [α]D 24 = -14.0 (c 1.00, CHCl3, 87% ee (R)). HRMS (FAB+) calcd for C18H25NNaO6 [M+Na]+ 374.1580,found 374.1574. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 17.9 min (minor, S), 25.8 min (major, R).
1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.65 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 3.88 (brs, 1H), 5.40 (brs, 1H), 6.10 (brs, 1H), 6.75-6.86 (m,3H). 13C NMR (100 MHz, CDCl3) δ 28.2 (3C), 52.7, 52.9, 53.3, 55.9, 56.0, 56.8, 79.8. 109.6, 111.1, 118.3, 132.1, 148.4, 148.9, 155.2, 167.6, 168.6. M.p. 96-97 °C. IR (KBr) 3373, 2976, 1717, 1517, 1259, 1163, 1026 cm-1. [α]D 23 = -2.4 (c 1.0, CHCl3, 90% ee (R)). HRMS (FAB+) calcd for C19H27NNaO8 [M+Na]+ 420.1634, found 420.1622. HPLC analysis; AD-H, n-hexane/i-PrOH = 4/1, 1.0 mL/min, tR =23.1 min (minor, S), 26.4 min (major, R).
1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.72 (s, 3H), 3.75 (s, 3H), 4.05 (brs, 1H), 5.54 (brs, 1H), 5.92 (brs, 1H), 6.22 (m, 1H), 6.30 (m, 1H), 7.31 (m, 1H).13C NMR (100 MHz, CDCl3) δ 28.3 (3C), 48.4, 52.7, 53.0, 54.1, 80.1, 106.8, 110.6, 142.1, 152.2, 155.1, 167.4, 168.3. IR (neat) 3428, 2978, 1719, 1497, 1367, 1248, 1165 cm-1. [α]D 24 = -3.6 (c 1.00, CHCl3, 90% ee (R)) HRMS (FAB+) calcd for C15H21NNaO7 [M+Na]+ 350.1216, found 350.1209. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 14.0 min (minor, S), 23.8 min (major, R).
1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.68 (s, 3H), 3.75 (s, 3H), 3.96 (brs, 1H), 5.55 (brs, 1H), 6.07 (brs, 1H), 7.00 (dd, J = 5.1, 1.2 Hz, 1H), 7.14 (dd,J = 3.0, 1.2 Hz, 1H), 7.28 (dd, J = 5.1, 3.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)δ 28.3 (3C), 50.0, 52.6, 52.9, 56.1, 79.8, 121.5, 126.0, 126.4, 140.7, 155.1,167.5, 168.5. IR (neat) 3423, 2977, 1736, 1498, 1366, 1245, 1165, 1046 cm-1. [α]D 24 = -3.6 (c 1.00, CHCl3, 95% ee (R)). HRMS (FAB+) calcd for C15H21NNaO6S [M+Na]+ 366.0987, found 366.0979. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 29.5 min (minor, S), 33.9 min (major, R).
1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.67 (s, 3H), 3.77 (s, 3H), 3.95 (brs, 1H), 5.53 (brs, 1H), 6.23 (brs, 1H), 7.28 (dd, J = 7.8, 4.8 Hz, 1H), 7.68 (dd,J = 7.8, 1.8 Hz, 1H), 8.53 (dd, J = 4.8, 1.8 Hz, 1H), 8.59 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 28.3 (3C), 51.6, 52.8, 53.1, 56.2, 80.3, 123.4, 134.2, 135.1,148.2, 149.1, 155.1, 167.2, 168.1. IR (neat) 3368, 2978, 1740, 1507, 1434, 1273, 1165, 1025 cm-1. [α]D 24 = -8.8 (c 1.00, CHCl3, 89% ee (R)). HRMS (FAB+) calcd for C16H22N2NaO6 [M+Na]+ 361.1376, found 361.1381. HPLC analysis; AD-H, n-hexane/i-PrOH = 4/1, 1.0 mL/min, tR = 18.7 min (minor, R), 25.0 min (major, S).
1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 3.55 (s, 3H), 3.82 (s, 3H), 4.09 (brs, 1H), 6.30 (brs, 1H), 6.60 (brs, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.50 (m, 2H), 7.58 (t, J = 6.9 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 28.4 (3C), 50.2, 52.5, 53.2, 55.4, 79.9, 122.2, 123.7, 125.2, 125.9, 126.9, 128.6, 129.2, 130.1, 133.9, 134.8, 155.2, 167.9, 168.7. IR (neat) 3421, 2977, 1717, 1496, 1366, 1245, 1163, 1055 cm-1. [α]D 23 = -34.4 (c 1.00, CHCl3, 88% ee (R)). HRMS (FAB+) calcd for C21H25NNaO6 [M+Na]+ 410.1580, found 410.1584. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 14.5 min (major, R), 17.1 min (minor, S).
tert-ブチルベンジリデンカーバメートと表2に示す各種のマロン酸ジエステル類との不斉マンニッヒ型反応を、実施例1と同様にして行った。その結果を表2に示す。実施例10~14のいずれにおいても、非常に高い収率、鏡像体過剰率で生成物が得られた。また、実施例14の収率及び鏡像体過剰率の欄の[ ]内の数値は、2.5mol%の(R)-BINOLと3.75mol%のn-Bu2Mgを用いた場合の結果を示す。
1H NMR (400 MHz, CDCl3) δ 0.79 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H),1.40 (s, 9H), 1.52 (m, 2H), 1.66 (m, 2H), 3.91 (brs, 1H), 3.99 (m, 2H), 4.10 (m, 2H), 5.49 (brs, 1H), 6.21 (brs, 1H), 7.20-7.34 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 10.2, 10.3, 21.7, 21.9, 28.3 (3C), 53.5, 57.0, 67.2, 67.6, 79.7, 126.3 (2C), 127.6, 128.6 (2C), 139.7, 155.1, 167.3, 168.3. IR (neat) 3430, 2971, 1724,1497, 1365, 1249, 1167, 1057 cm-1. [α]D 24 = -8.8 (c 1.0, CHCl3, 92% ee (R)). HRMS (FAB+) calcd for C21H31NNaO6 [M+Na]+ 416.2049, found 416.2062. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 14.3 min (minor, S), 19.2 min(major, R).
1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 4.01 (brs, 1H), 5.04 (s, 2H), 5.12 (d, J = 12.0 Hz, 1H), 5.17 (d, J = 12.0 Hz, 1H), 5.56 (brs, 1H), 6.20 (brs, 1H), 7.06-7.12 (m, 2H), 7.20-7.36 (m, 13H). 13C NMR (100 MHz, CDCl3) δ 28.4 (3C), 53.4, 56.8, 67.3, 67.6, 79.7, 126.2 (2C), 127.6, 128.0, 128.2 (2C), 128.3, 128.4, 128.5 (2C), 128.6 (4C), 134.8, 134.9, 139.2, 139.3, 155.0, 166.8, 167.8. M.p. 105-106 °C. IR (KBr) 3429, 2977, 1720, 1496, 1366, 1251, 1163, 1026 cm-1. [α]D 22 = -15.2 (c 1.00, CHCl3, 91% ee (R)) HRMS (FAB+) calcd for C29H31NNaO6 [M+Na]+ 512.2049, found 512.2055. HPLC analysis; AS-H, n-hexane/i-PrOH = 39/1, 1.0 mL/min, tR = 28.1 min (major, R), 36.6 min (minor, S).
1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.97 (s, 1H), 4.53 (m, 2H), 4.64 (m, 2H), 5.15 (d, J = 16.2 Hz, 1H), 5.16 (d, J = 10.8 Hz, 1H), 5.24 (d, J = 10.8 Hz,1H), 5.32 (d, J = 16.2 Hz, 1H), 5.53 (brs, 1H), 5.74 (m, 1H), 5.88 (m, 1H), 6.20 (brs, 1H), 7.21-7.36 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 28.4 (3C), 53.5, 57.0, 66.2, 66.6, 79.8, 118.8, 119.1, 126.3 (2C), 127.6, 128.7 (2C), 131.2, 131.3, 139.4, 155.1, 166.8, 167.7. IR (neat) 3429, 2978, 1720, 1496, 1367, 1249, 1165 cm-1. [α]D 25 = -8.0 (c 0.5, CHCl3, 88% ee (R)) HRMS (FAB+) calcd for C21H27NNaO6 [M+Na]+ 412.1736, found 412.1737. HPLC analysis; AD-H, n-hexane/i-PrOH = 9/1, 1.0 mL/min, tR = 23.3 min (minor, S), 33.3 min (major, R).
1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.77 (s, 3H), 3.80 (s, 3H), 5.68 (d,J = 9.9 Hz, 1H), 5.97 (d, J = 9.9 Hz, 1H), 7.28-7.44 (m, 5H). 13C NMR (100 MHz, CDCl3) δ 28.3 (3C), 54.0, 54.1, 58.8, 73.4, 80.2, 128.2 (2C), 128.6, 128.8 (2C), 136.0, 154.3, 165.9, 166.1. IR (neat) 3439, 2978, 1719, 1494, 1367, 1255, 1166, 1022 cm-1. [α]D 23 = +3.2 (c 1.0, CHCl3, 97% ee (S)). HRMS (FAB+) calcd for C17H22ClNNaO6 [M+Na]+ 394.1033, found 394.1042. HPLC analysis; AD-H × 2, n-hexane/i-PrOH = 19/1, 0.5 mL/min, tR = 52.4 min (minor, R), 55.9 min (major, S).
1H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 3.77 (s, 3H), 3.79 (s, 3H), 5.62 (d, J = 9.9 Hz, 1H), 6.16 (d, J = 9.9 Hz, 1H), 7.28-7.42 (m, 5H). 13C NMR (100 MHz,CDCl3) δ 28.3 (3C), 54.0, 54.2, 59.3, 64.4, 80.2, 128.2 (2C), 128.5, 128.9 (2C), 136.4, 154.4, 166.4, 166.7. IR (neat) 3439, 2978, 1715, 1317, 1245, 1165, 1037 cm-1. [α]D 24 = +24.8 (c 0.50, CHCl3, 96% ee (S)). HRMS (FAB+) calcd for C17H22BrNNaO6 [M+Na]+ 438.0528, found 438.0528. HPLC analysis; AD-H × 2, n-hexane/i-PrOH = 19/1, 0.5 mL/min, tR = 45.1 min (minor, R), 54.7 min (major, S).
実施例15では、下記式に示すように、窒素上に4-メトキシフェニル基を有するグリオキサール由来のアルジミンと、α位に臭素原子を有するマロン酸ジメチルとの不斉マンニッヒ型反応を、実施例1と同様にして行った。この場合も、下記式に示すように、比較的良好な結果が得られた。
tert-ブチルベンジリデンカーバメートとマロン酸ジメチルとの不斉マンニッヒ型反応を、(R)-BINOLと表3に示すMXとの存在下、表3に示す反応条件で実施例1に準じて行った。その結果を表3に示す。この表3から明らかなように、(R)-BINOLのみを用いた比較例1や(R)-BINOLとn-BuLiとを用いた比較例2,4、(R)-BINOLとn-BuLiとt-BuOHを用いた比較例3,5では、反応が進行するものもあったが、いずれも鏡像体過剰率が低かった。また、5mol%の(R)-BINOLと2.5mol%のn-Bu2Mgとを用いた比較例6(BINOL/Mgのモル比=1/0.5)では、ほとんど反応が進行しなかった。これに対して、5mol%の(R)-BINOLと5mol%のn-Bu2Mgとを用いた実施例16(BINOL/Mgのモル比=1/1)では、収率、鏡像体過剰率とも非常に高くなった。また、5mol%の(R)-BINOLと10mol%のn-Bu2Mgとを用いた実施例17(BINOL/Mgのモル比=1/2)では、実施例16と比べて収率は同等で、鏡像体過剰率はやや低下したものの十分高い値であった。
比較例7では、3,3’位に3,4,5-トリフルオロフェニル基を導入した(R)-BINOLとn-Bu2Mgとをそれぞれ2.5mol%用い、反応時間を2時間とした以外は、実施例1と同様にして反応を行った。そうしたところ、対応するβ-アミノカルボニル化合物はほとんど得られなかった。また、n-Bu2Mgを2倍つまり5mol%に増やし反応時間を5時間にしたところ、対応するβ-アミノカルボニル化合物は収率88%で得られたが、その鏡像体過剰率は35%eeに過ぎなかった。このことから、目的とする生成物を高い鏡像体過剰率で得るためには、(R)-BINOLの3,3’位の置換基は不要であることがわかった。
Claims (5)
- 光学活性なBINOLと、該BINOLに対して1~2倍モルのジアルキルマグネシウム(2つのアルキル基は同じか又は異なる)との存在下、窒素が保護されたアルジミン類とマロン酸ジエステル類とのマンニッヒ型反応により、光学活性なβ-アミノカルボニル化合物を得る、β-アミノカルボニル化合物の製法。
- 前記アルジミン類は、R1-CH=NR2(R1はアリール基又はエステル基、R2はtert-ブトキシカルボニル(Boc)、ベンジルオキシカルボニル(Cbz)、2,2,2-トリクロロエトキシカルボニル(Troc)、フェニル基、2-メトキシフェニル基、4-メトキシフェニル基又はナフチル基)で表される化合物である、請求項1記載のβ-アミノカルボニル化合物の製法。
- 前記マロン酸ジエステル類は、CHX(CO2R3)2(Xは水素原子又はハロゲン原子、R3はアルキル、アリル、ベンジル又はアリール)で表される化合物である、請求項1又は2に記載のβ-アミノカルボニル化合物の製法。
- 前記BINOLは、前記アルジミン類に対して2.5~10mol%使用する、請求項1~3のいずれか1項に記載のβ-アミノカルボニル化合物の製法。
- 反応溶媒として、芳香族系溶媒又はハロゲン化炭化水素系溶媒を使用する、請求項1~4のいずれか1項に記載のβ-アミノカルボニル化合物の製法。
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