WO2003035605A1

WO2003035605A1 - Novel compounds and process for their production

Info

Publication number: WO2003035605A1
Application number: PCT/JP2002/011054
Authority: WO
Inventors: Hisao Nemoto
Original assignee: Techno Network Shikoku Co., Ltd.; Eisai Co., Ltd.
Priority date: 2001-10-24
Filing date: 2002-10-24
Publication date: 2003-05-01
Also published as: JP4163113B2; JPWO2003035605A1

Abstract

Compounds represented by the general formula: RO-CH(CN)2 (wherein R is a monovalent organic group), which are useful as carbon-addition reagent, can be produced efficiently and in a high yield. Specifically, a process for production of compounds represented by the general formula (2): (2) (wherein R is a monovalent organic or organometallic group), characterized by adding peracetic acid to a compound represented by the general formula: (1) (wherein R” is alkyl or aryl), stirring the resulting mixture to conduct oxidative cleavage, and adding a hydroxyl-protecting reagent to the obtained crude product to protect the hydroxyl group.

Description

Statement ^

Novel compound and method for producing the same

Technical field

The present invention relates to a compound useful as a carbon addition reagent, and a method for efficiently producing the compound. Conventional technology

The compounds represented by the following general formulas react with various electrophiles to arrange an acyl cyanide functional group together with a one-carbon enrichment, and also react with various nucleophiles. It is known to have high applicability to compound synthesis (Hisao Nemoto; Yasufumi Kubota; Yoshinori Yamamoto, J. Org. Chem., 55, 4515-4516, 1990.),

R0-CH (CN) ₂

(Wherein, R represents R′R ² R ³ Si—, R′0-CR ² R ³ — (R ² and R ³ are monovalent hydrocarbon groups).) As a carbon addition reagent for the above compound Is represented by the following formula, as described in the above-mentioned paper.

'— SiR ¹ R ² R ³

R =

■ c-one o- c-

Recently, the following reaction formula was also announced.

On the other hand, a method for synthesizing such a compound represented by RO—CH (CN) ₂ is also described in the above-mentioned paper, and the following six-step synthesis reaction is required.

However, the above synthesis method requires as many as six steps, includes a step requiring a reaction time of 2 weeks or more (fifth step), and requires an expensive condensing agent (sixth step). There was a problem that the total yield was not sufficient (about 10%), and improvement was required.

Further, those obtained by the above synthesis method are limited to those in which R is an organic silicon type (RiR ³ Si—) or a monoalkoxyalkyl group type (O—CR ² R ³ —). For example, compounds in which R is an alkanoyl group (R'CO-) are expected to have other applications than those of the above-mentioned organosilicon type or 1-alkoxyalkyl group type, but such compounds are still provided. Not. For example, if an alkanoyl group-type compound is to be produced by the above synthesis reaction, the above synthesis reaction involves a process using ammonia in the fifth step, and the R'CO bond is cleaved by the decomposition of the processing compound, resulting in extremely difficult synthesis. Is expected Disclosure of the present invention

The present invention has been made in view of the above problems of the related art, and has as its object to provide a method for efficiently producing a compound useful as a carbon addition reagent represented by the above general formula, and to provide a novel carbon addition reagent compound. And

The present inventors have conducted intensive studies to achieve such an object, and as a result, have found a method for obtaining the above compound in a two-step reaction step by a specific method, and have completed the present invention.

That is, the present invention provides a compound represented by the following general formula (1)

R "(HO) C = C (CN) ₂ (1)

(In the formula, R ″ represents an alkyl group or an aryl group.)

Oxidative cleavage reaction is carried out by adding peracetic acid to the crude product, and a hydroxyl group in the obtained crude product is subjected to a protection reaction by adding a protecting reagent to the resulting compound to obtain a compound represented by the following general formula (2). Production method,

RO-CH (CN) ₂ (2)

(In the formula, R represents a monovalent organic group or an organic metal group.)

And a novel compound represented by the following general formula (3).

R'COO-CH (CN) ₂ (3)

(In the formula, R ¹ represents a monovalent hydrocarbon group.)

Further, the present invention provides a compound represented by the following general formula (1):

(1)

(Wherein, R "is a hydrogen atom, CI_ ₃ alkyl group, C ₆ - ₁₄ Ariru showing a Teroariru group to group or 5-1 4 membered..) Is performed in the peracetic acid addition and stirred oxidative cleavage reaction, The present invention further provides a method for producing a compound represented by the following general formula (2), which comprises reacting a hydroxyl group in the obtained crude product with a protecting reagent to carry out a protection reaction.

RO-CH (CN) ₂ (2)

(Wherein, R represents R iRSRSS i, shaku ^1. CR ² R ³ — or I ^ CO—. R ¹ R ² and R ³ are each independently a hydrogen atom, an alkyl group, C ₆ - ₁₄ show a Teroari Ichiru group to § Li Ichiru group or 5-14 membered).

R "is preferably a methyl group. R is an acetyl group, n C ^ Hs ₃ —CO—, a benzoyl group, a t-butyldimethylsilyl group or a compound represented by the formula

It is preferably a group represented by The present invention provides a compound represented by the following general formula (3).

R ¹ C 00- CH (CN) ₂ (3)

(Wherein, R ¹ represents a hydrogen atom, CI- ₃ alkyl group, C ₆ -.. Shows the Teroariru group to ₁₄ Ariru group or 5-1 4 membered) In the above compounds, scale ^1. . One is preferably an acetyl group, nCnH—CO— or a benzoyl group. DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the present invention will be described in detail. In the present invention, the target compound represented by the following general formula (2) can be efficiently and efficiently obtained in two steps by using R ″ (HO) C = C (CN) ₂ as a starting material. It is characterized by being manufactured.

RO-CH (CN), (2)

In the above formula, R represents a monovalent organic group or an organometallic group, and more specifically, R i Si-, R'0-CR ² R ^3- , or ^ CO— (R ', R ² R ³ is a monovalent hydrocarbon group such as an alkyl group and an aryl group), but is not limited thereto. The reaction formula in the production method of the present invention is represented as follows.

R in the general formula is the starting material in the production method of the present invention (1) "(HO) OC (CN smell Te, R" represents an alkyl group or Ariru group, from easy availability, CH _3, Eta ₅ It is preferable to use, and particularly preferably. Regardless of which R "is used, the reaction mechanism itself is the same,

H ₃ C (HO) C = C (CN), Sci, Papers Inst, Phys, C em, Res, (Tokyo) 1962,

The synthesis method is described in Vol. 56, pp. 216-217, and the present invention will be described below with reference to an example using this as a starting material.

In the present invention, first, an aqueous solution of HC (H0) C = C (CN), or an organic solvent such as methanol Add peracetic acid slightly more than 1 to 5 molar equivalents (more preferably 1.2 to 4 molar equivalents) and stir for 2 to 10 hours (more preferably 2 to 4 hours). This oxidative cleavage reaction may be performed at room temperature.

Next, a compound (protecting reagent) corresponding to a desired R such as acetyl chloride, benzoyl chloride, dodecanol chloride, tert-butychlorodimethylsilane, ethyl vinyl ether, and pyridines are formed in the obtained crude product. Add an auxiliary agent that activates the reaction while capturing hydrogen halide etc. in the neutralization reaction, and at about 0 ° C to 100 ° C (more preferably around room temperature), depending on the protective reagent and auxiliary agent. The reaction may be carried out for several minutes to several tens of hours.

After completion of the reaction, the desired product can be obtained by performing appropriate known purification as necessary.

The term “. ^ 3. Alkyl group” as used herein refers to a monovalent group derived from an aliphatic hydrocarbon having 1 to 30 carbon atoms by removing one hydrogen atom. 1-30 straight or branched alkyl groups are meant. In the “(: ₃₀ alkyl group)”, “dialkyl group” is preferable. The “u alkyl group” is specifically, for example, a methyl group, an ethyl group, a monopropyl group, a 2-propyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a monobutyl group, _Ndenyl group (η〇 ^ Η ₂₃ ―) and the like. The “C 6-14 aryl group” represented in the present specification means an aromatic hydrocarbon cyclic group having _{6 to} ₁₄ carbon atoms. The rather preferable in the "C ₆ _ ₁₄ Ariru group" is a "C ₆ _ ₁₀ Ariru group". This particular 'specifically the "C ₆ _ ₁₀ Ariru group" for example, phenyl group, 1 one naphthyl, 2-naphthyl group. The “5- to 14-membered heteroaryl group” represented in the present specification means that the number of atoms constituting the ring of the cyclic group is 5 to 14, and one of the atoms constituting the ring of the cyclic group is 1 Means an aromatic cyclic group containing a plurality of heteroatoms. The “5- to 14-membered heteroaryl group” is preferably a “5- to 10-membered heteroaryl group”.

The “5- to 10-membered heteroaryl group” means a monovalent group derived from the “5- to 10-membered aromatic heterocycle” by removing one hydrogen atom at an arbitrary position. This “5- to 10-membered aromatic heterocycle” means that the number of atoms constituting the ring of the cyclic group is 5 to 10, and one to a plurality of atoms constitute the ring of the cyclic group. And an aromatic ring containing a hetero atom of, for example, a pyridine ring, a thiophene ring, a furan ring, a pyrrolyl ring and the like. As used herein, the term "protecting reagent" refers to a reagent generally used for adding a protecting group to a hydroxyl group, and specifically includes, for example, acetyl chloride, benzoyl chloride, dodecanoyl chloride, and the like. Acid anhydrides such as acetic anhydride; vinyl ether compounds such as ethyl vinyl ether; and silylating reagents such as tert-butylcyclodimethyldimethylsilane. Preferable examples of the "protecting reagent" include, for example, acetyl chloride, benzoyl chloride, dodecanoyl chloride, ethyl vinyl ether and t-butylchlorodimethylsilane. As used herein, the term "protection reaction" refers to a reaction in which a compound having a hydroxyl group is reacted with a protective reagent under appropriate conditions to introduce a protective group into the hydroxyl group. In this reaction, a protecting group can be introduced into a hydroxyl group under conditions generally used for introducing a protecting group, depending on the protecting reagent used in the reaction. For example, during the reaction, a base or an acid can be added. Examples of the base include imidazole, pyridine, 4-dimethylaminopyridine (DMAP) and the like, and examples of the acid include 4-toluenesulfonic acid. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.

Example 1 (Synthesis experimental section of CH ₃ C00_CH (CN))

H ₃ C (HO) C = C (CN) ₂ (202 mg, 1.87 t ol) in aqueous solution (4 mL) with peracetic acid (3% of 9% acetic acid solution, 3.74 t ol) at room temperature And stirred at room temperature for 4 hours. The resulting reaction solution was mixed with acetyl chloride (12 mL, 12.7 rol), 4- (N, N-dimethylamino) pyridine (23 mg, 0.19 mmol) and stirred at room temperature for 5 minutes. The mixture was concentrated under reduced pressure to a volume of about 1 mL, and the residue was purified by silica gel column chromatography using an eluent of hexane Z ethyl acetate = 6: 1 by volume. Yield 146 mg (1.18 mmol, 63% yield). NMR (300 negation _{z, CDC1 3): 52.29 (} s, 3H), 6.10 (s, 1H);, 3 C NMR (75MHz, CDC1 3):. Δ 167.1, 109.2, 47.5, 19.7; IR (neat): 2261, 1784 cm Example 2 (Synthesis experiment section of C ₆ H ₅ C00_CH (CN) ₂ )

_ Me _ _T PhCOCl (1.0

ΓΝ, eq)

./ CH ₃ CO ₃ H (3.8 eq) _Py (ii _eq )

HO CN ^MeOH , ^rt , ^{4 h} CH ₃ CN, 0 V mm

To a methanol solution (10 mL) of H ₃ C (HO) C, C (CN) ₂ (208 mg, 1.93 minol), add peracetic acid (5 mL of a 9% acetic acid solution, equivalent to 6.04 ol) at room temperature. Stirred for hours. To the reaction mixture was further added peracetic acid (1 mL of a 9% acetic acid solution, about 1.24 liters) at room temperature, and stirring was continued at room temperature for 2 hours. The obtained reaction solution was concentrated under reduced pressure while keeping the temperature at 35 ° C. or lower, and the residue was dissolved in 5 mL of acetonitrile. Benzoyl chloride (271 mg, 1.93 IMO1) and pyridine (168 mg, 0.17 mL, 2.13 dragonol) were added dropwise to this solution at 0 ° C, and the mixture was stirred at 0 ° C for 5 minutes, and then acetonitrile was removed under reduced pressure. The residue was diluted with 30 mL of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times with 15 mL), and a saturated saline solution (1 time with 15 mL), dried over magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. Purification was performed by chromatography using an eluate having a hexane / ethyl acetate = 6: 1 volume ratio. Yield 197 mg (1.06 mmol, 55% yield). 'H NMR (300 MHz, CDCL ₃ ): δ 6.35 (s, 1H), 7.50 (t, 2H, J = 7.6Hz), 7.68 (t, 1H, J = 7.3Hz), 8.05 (d, 2H, J = 7.9Hz)

_{13 C NMR (75MHz, CDC1 3} ): δ 162.9, 135.1, 130.3, 128.9, 125.7, 109.5, 48.2 IR (KBr): 3067, 2944, 2256, 1737, 1601, 1584 cm one '.

Example 3

_{_{C u H 23 COCl (1.2 eq}} )

Me CN

CH3CO3H (2.0 eq) DMAP (0.1 eq)

»

HO CN MeOH, rt, 3h CH ₃ CN, 0, 5 min

To a solution of H ₃ C (HO) C = C (CN) ₂ (208 mg, 1.93 ol) in methanol (10 mL) was added peracetic acid (5 mL of a 9% acetic acid solution, equivalent to 6.04 iMiol) at room temperature. Stirred for hours. To the reaction mixture was further added peracetic acid (equivalent to 1111.24 mmol of a 9% acetic acid solution) at room temperature, and stirring was continued at room temperature for 2 hours. The obtained reaction solution was concentrated under reduced pressure while keeping the temperature at 35 ° C. or lower, and the residue was dissolved in 5 mL of acetonitrile. To this solution was added dropwise dodecanoyl chloride (507 mg, 2.32 alcohol) at 0 ° C, 4- (N, N-dimethylamino) pyridine (23 mg, 0.19 mmol) was added, and the mixture was stirred at 0 for 5 minutes and then under reduced pressure. The acetonitrile was removed, the residue was diluted in 30 mL of ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution (15 mL).

3 times), wash with saturated saline (once with 1511 ^), dry with sulfuric acid, reduce The mixture was concentrated under reduced pressure, and purified by silica gel column chromatography using an eluent of hexane / ethyl acetate = 6: 1 by volume. Yield 281 mg (l.06 marl ol, 55% yield). _{Ή NMR (300MHz, CDC1 3)} : δ 0.88 (t, 3H, J = 6.84Hz), 1.103-1.416 (m, 16H), 1.574- 1.731 (m, 2H), 2.49 (t, 3H, J = 7.57) , 6.115 (s, 1H); I3 C NMR (75MHz, CDC1 3): <5170.0, 109.4, 47.6, 32.8, 31.8, 29.5, 29.4, 29.2, 29.0, 28.7, 24.2, 22.6, 14.0; IR (neat): 2261, 1785 ¹ .

Example 4 (Synthesis experiment section of TBSO-CH (CN) ₂ )

To a methanol solution (10 mL) of H ₃ C (HO) C, C (CN) ₂ (208 mg, 1.93 t) was added peracetic acid (5 mL of a 9% acetic acid solution, equivalent to 6.04 mmol) at room temperature. Stirred for hours. To the reaction mixture was further added peracetic acid (1 mL of a 9% acetic acid solution, about 1.24 mmo) at room temperature, and stirring was continued at room temperature for 2 hours. The obtained reaction solution was concentrated under reduced pressure while keeping the temperature at 35 ° C. or lower, and the residue was dissolved in 5 mL of DMF (N, N-dimethylformamide). To this solution was added tert-butychlorodimethylsilane (436.3mg, 2.90 ol), imidazole (197.4mg, 2.90 mmol) was added at 0, and the mixture was stirred at 0 ° C for 5 minutes. Then, DMF was removed under reduced pressure, the residue was diluted with 30 mL of ethyl acetate, and a saturated aqueous solution of sodium hydrogen carbonate (3 times with 15 mL) was added. ), Washed with saturated saline solution (15 mL once), dried over magnesium sulfate, concentrated under reduced pressure, and silica gel column chromatography, using hexane Z ethyl acetate = 8: 1 by volume eluent. Purified. Yield 189.4 mg (0.97.ηπιο1, 50% yield). The physical physics is known in [Hi sao Nemo to; Yasufumi Kubota; Yoshinor i Yamamoto, J. Org. Chem., 55, 4515-4516, 1990.].

Example 5 (Synthesis experiment section of C ₃ C00-CH (CN) ₂ )

NC O O CN

H ₃ C (HO) C = C (CN) ₂ (208 mg, 1, 93 bandol) in methanol (lOmL) and peracetic acid (5 mL of 9% acetic acid solution, equivalent to 6.04 bandol) at room temperature And stirred at room temperature for 2 hours. To the reaction mixture was further added peracetic acid (9% acetic acid solution was 1111.24, 0 target) at room temperature, and stirring was continued at room temperature for 2 hours. The obtained reaction solution was concentrated under reduced pressure while keeping the temperature at 35 ° C. or lower, and the residue was dissolved in 5 mL of dichloromethane. After a catalytic amount of 4-toluenesulfonic acid (20 mg) was added to this solution, ethyl vinyl ether (278 mg, 3.86 bandol) was added dropwise at 0, and the mixture was stirred at 0 ° C for 30 minutes. The obtained reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate (50 mL), and extracted with ether (3 times with 30 mL). The collected organic layer was washed with a saturated saline solution (1 × 15 mL), dried over magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. Purification was performed by force gel column chromatography using an eluate having a hexane / ethyl acetate = 6: 1 volume ratio. Yield: 178.8 mg (l. 16 t ol, 60% yield). Physical data is known in [Hisao Nemoto; Yasufumi Kubota; Yoshinori Yamamoto, J. Org. Chem., 55, 4515-4516, 1990.].

Claims

The scope of the claims

1. A compound represented by the following general formula (1) R "(HO) C = C (CN) ₂ (1)

(In the formula, R ″ represents an alkyl group or an aryl group.)

Oxidative cleavage reaction is carried out by adding peracetic acid to the crude product, and a hydroxyl group in the obtained crude product is subjected to a protection reaction by adding a protecting reagent to the resulting compound to obtain a compound represented by the following general formula (2). Production method. RO-CH (CN) ₂ (2)

2. Compound (1) represented by the following general formula (1)

(Wherein, R "is a hydrogen atom. An alkyl group, ₍₆ _ ₁₄ Ariru group or 5-1 4 Indicates a heteroaryl group. ), Peroxidized cleavage reaction is carried out by adding peracetic acid to the resulting crude product, and then the protecting group is reacted by reacting a hydroxyl group in the obtained crude product with a protecting reagent to carry out a protecting reaction. A method for producing the compound shown.

RO- CH (CN) ₂ (2)

(Wherein, R represents RiRSRSS i-, I ^ O—CRSR ³ —, or R ¹ CO—. RR ² and R ³ each independently represent a hydrogen atom, an alkyl group, C ₆ — ₁₄ Represents a aryl group or a 5- to 14-membered heteroaryl group.)

3. The production method according to claim 2, wherein R "is a methyl group.

4. R is acetyl group, n CuH ^ —CO—, benzoyl group, t-butyldimethylsilyl group or formula

The method according to claim 2 or 3, which is a group represented by

5. A compound represented by the following general formula (3).

R ¹ COO-CH (CN) ₂ (3)

(Wherein, R ¹ represents a hydrogen atom, (I _{3 Q} alkyl group, C ₆ - shows a ₁₄ Ariru Teroariru group to group or 5-1 4-membered).

6. RiCO— is an acetyl group, n. The compound according to claim 5, which is 丄 —CO— or a benzoyl group.