JP2703048B2 - Production method of proline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL APPLICATION The present invention relates to asymmetric phosphine ligands (K. Achiwa, J. Am. Ch.
em. Soc., 1976, 98 p8265), γ-amino-β-hydroxybutyric acid (T. Shibata, K. Iino and Y. Sugimura, Heterocycl)
es, 1986 24 p1331), carbapenem (P. Renand and DS
eebach, Synthesis, 1986 p424; J. Hausler, Monatsh. Che
m., 1987, 118 p865) are important intermediates for synthesizing useful compounds such as angiotensin converting enzyme inhibitors (EMSmith et al, J. Med. Chem., 1988, 31 , p875) (2S, 4
The present invention relates to a highly stereoselective process for producing R) -4-hydroxyproline and a compound represented by the general formula (I) which is a precursor of this compound.

[Problems to be solved by the prior art and the invention]

Conventionally, the following structural formula (III) (2S, 4R) -4-hydroxyproline represented by
Although it was obtained from a natural product through a complicated process, its isolation and purification are extremely difficult, so that it cannot be said that it is an industrially satisfactory production method.

Further, (2S, 4R) -4 represented by the structural formula (III)
Although various attempts have been made to produce -hydroxyproline by means of chemical synthesis, this compound is difficult to asymmetrically induce to the 2- and 4-positions of the pyrrolidine ring, so that it is effective for chemical synthesis to achieve high stereoselection. Production method has not been established yet.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve such problems, and as a result, using the compound represented by the general formula (II) as a starting material, it is easy to industrialize, has high yield, and has high purity (2S, 4).
R) -4-Hydroxyproline and its precursor, a compound represented by the general formula (I), have been found to be highly stereoselective.

That is, the present invention provides a compound represented by the general formula (II): Wherein R ₁ is a hydroxyl-protecting group and R ₂ is aryl or alkyl. The compound represented by the formula (I) is cyclized by treating it with iodine. (Wherein R ₁ and R ₂ are as described above).

The synthesis of (2S, 4R) -4-hydroxyproline from this compound can be achieved by protecting the N-position of this compound with the compound of formula (IV) (Wherein R ₁ and R ₂ are as described above, and R ₃ is a protecting group at the N-position). Then, the protecting group at the 2-position of the compound is removed. Equation (V) (Wherein R ₂ and R ₃ are as described above). The compound is then subjected to an oxidation reaction to obtain a compound of the formula (VI) (Wherein R ₂ and R ₃ are as described above), and then saponified to obtain a compound of the formula (VII) (Wherein R ₃ is as defined above), followed by deprotection at the N-position, thus giving (2S, 4R) -4 of formula (III)
-Hydroxyproline is produced.

In the compounds of the above formulas (I) and (II), examples of the hydroxyl-protecting group include a benzyl group and a benzyl group in which hydrogen of a phenyl group is substituted by lower alkyl or lower alkoxy. is there. In the compound of the formula (IV), examples of the N-position protecting group include a t-butoxycarbonyl group.

In the present invention, the reaction of treating a compound of formula (II) with iodine to obtain a compound of formula (I) comprises converting iodine to a compound of formula (II)
1 to 5 moles, preferably 3 moles, of the compound of the formula (1), is mixed with an aprotic solvent such as dioxane, tetrahydrofuran, dimethoxyethane, diethylene glycol diethyl ether and the like in a mixed solvent of water with -10.
The reaction is carried out at a reaction temperature of 1010 ° C., preferably -2 to 2 ° C., for 5 to 20 hours (the reaction is completed in about 10 hours). The obtained compound of the formula (I) is isolated and purified, or used crude in the next reaction step.

The following reaction for introducing a protecting group at the N-position of a compound of the formula (I) to obtain a compound of the formula (IV) is carried out by using a base such as a nitrogen-containing organic base such as triethylamine, tributylamine, pyridine, quinoline or dimethylaniline. In the presence, for example, using di-t-butyl dicarbonate, for example, in a halogen-based solvent such as dichloromethane, chloroform, dichloroethane, and trichlene at a reaction temperature of 0 to 40 ° C, preferably 10 to 30 ° C for 5 to 20 hours ( The reaction is completed in about 10 to 15 hours.)

The following reaction for removing the protecting group at the 2-position of the compound of the formula (IV) to obtain the compound of the formula (V) is carried out in the presence of a hydrogenation catalyst such as a palladium hydroxide-carbon catalyst in the presence of a solvent such as methanol or ethanol. At a reaction temperature of 10-30 ° C,
The reaction is carried out by adding hydrogen under normal pressure or under pressure for 10 to 30 hours (the reaction is terminated after 15 to 20 hours when hydrogen is absorbed).

The following reaction for oxidizing the compound of the formula (V) to obtain the compound of the formula (VI) is carried out using sodium periodate in the presence of ruthenium chloride in a solvent such as carbon tetrachloride-acetonitrile in an appropriate ratio. -10 to 30 ° C in an aqueous solvent
At a reaction temperature of 20 minutes to 1 hour (the reaction is completed in about 30 minutes).

The following reaction for hydrolyzing the compound of the formula (VI) to obtain the compound of the formula (VII) is carried out using potassium carbonate or sodium carbonate in a solvent such as methanol or ethanol at a reaction temperature of 10 to 30 ° C. For 30 minutes to 2 hours (the reaction is completed in about 1 hour).

The final step of deprotecting the compound of formula (VII) to obtain (2S, 4R) -4-hydroxyproline of formula (I) is carried out, for example, by heating in dioxane and an aqueous HCl solution under reflux.

The compound of the formula (II) (R ₁ = benzyl) which is a raw material of the present invention can be prepared by the following method (Synthesi
s 139 (1987). ).

(In the scheme, Bn is a benzyl group and Ph is a phenyl group.) That is, the (S) -O-benzylglycidol of the formula (VIII) is reacted with sodium acetylide in dimethyl sulfoxide to give a compound of the formula (IX) To give a compound of formula (X), which is then half-reduced in ethyl acetate at room temperature in the presence of a Pd / CaCO ₃ catalyst to give a compound of formula (X),
-15 in tetrahydrofuran in the presence of diisopropylazodicarboxylate and triphenylphosphine
At -25 ° C, the compound of formula (XI) is reacted with phthalimide to form a compound of formula (XI). The compound is heated under reflux with hydrazine in ethanol for about 6 hours to obtain a compound of formula (XII). Is reacted with benzoyl chloride in methylene chloride in the presence of triethylamine to give (S) -N-benzoyl-1-benzyloxy-pent-4-en-2-ylamine of formula (II).

〔Example〕

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 (S) -N-benzoyl-1-benzyloxypent-
4-en-2-ylamine a) (S) -1-benzyloxypent-4-en-2
-Il phthalimide S.Takano, Y.Sekiguchi, N.Sato, K.Ogasawara, Synthesi
(R) -1- synthesized according to the method described in s, 1987, 139.
4.82 g of benzyloxy-2-hydroxy-4-pentene
(25.1 mmol), 7.24 g of triphenylphosphine (27.6 mmo)
l) and a solution of 4.06 g (27.6 mmol) of phthalimide in 200 ml of tetrahydrofuran were cooled to −20 ° C. and 5.43 ml (27.6 mmol) of diisopropylazodicarboxylate were added thereto.
Was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 10 hours. Subsequently, the temperature was returned to room temperature, 40 g of silica gel for column was added, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 300 g of silica gel (solvent, ethyl ether: n-hexane = 1: 7), The title compound was obtained as a colorless oil.

Yield 5.90 g (73.0%) IR: ▲ ν ^neat _max ▼ (cm ⁻¹ ) 1775, 1710 NMR: δ (ppm) 2.30 to 2.95 (2H, m), 3.60 to 4.10 (2H,
m), 4.45-4.80 (3H, m), 4.90-5.15 (2H, m), 5.50
6.06.00 (1H, m), 7.75 (5H, s), 7.60 to 7.90 (4H, m).

^{MS: m / e321 (M +} ), 91 (100%) Elemental analysis (as _{C 20 H 19 NO 3) C} % H% N% Calculated: 74.75 5.96 4.36 Found: 74.87 6.02 4.41 b) (S ) -1-benzyloxypent-4-ene-2
-Ylamine To a solution of 5.0 g (15.6 mmol) of the compound obtained in a) above in ethanol (100 ml) was added 90% hydrazine monohydrate.
1.01 ml (18.7 mmol) was added, and the mixture was heated under reflux for 6 hours. After air cooling, the solvent was distilled off under reduced pressure, and the residue was washed with chloroform and then passed through celite. The solvent was distilled off under reduced pressure to obtain 2.90 g of a crude amine (title compound) as a pale yellow oil. Then, the product was distilled using a Kugelrohr to obtain a colorless oily product.

Yield 2.57 g (87%) Boiling point 120-125 ゜ (0.5 mmHg) IR: δ 1.60 (2H, s), 1.85-2.45 (2H, m), 2.90-3.5
5 (3H, m), 4.55 (2H, s), 4.95 to 5.25 (2H, m), 5.55
6.06.05 (1H, m), 7.30 (5H, s).

^{MS: m / e191 (M +} ), 91 (100%) Elemental analysis (C ₁₂ as _{H 17 NO) C% H%} N% Calculated: 75.35 8.96 7.32 Found: 74.95 9.10 7.19 c) (S ) - N-benzoyl-1-benzyloxypent-4-en-2-ylamine To a solution of 2.2 g (11.5 mmol) of the compound obtained in b) in methylene chloride (20 ml) was added 1.76 ml of triethylamine at 0 ° C.
(12.7 mmol) and 1.4 ml (12.1 mmol) of benzoyl chloride
Was added dropwise and stirred for 10 minutes. After returning to room temperature, 10 ml of methylene chloride was added, and the organic layer was washed with water and a saturated aqueous solution of NaCl, and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using 120 g of silica gel (eluent: ethyl ether-n-hexane) to give 3.25 g (100 g) of the title compound as a colorless solid.
I got This solid was recrystallized from ethyl ether-n-hexane to give colorless needles.

Yield: 3.09 g (95%), melting point: 64 to 66 ° C [α] _D = 29.5 ゜ (c = 1.01, CHCl ₃ ) IR: ▲ ν ^neat _max ▼ (cm ^-1 ) 1650 NMR: δ (ppm) 2.40 to 2.55 (2H, bt, J = 7Hz), 3.40 ~
3.75 (2H, m), 4.10 to 4.50 (1H, m), 4.55 (2H, s), 5.
00-5.20 (2H, m), 5.60-6.05 (1H, m), 6.40 (1H, b
m), 7.30 (5H, s), 7.25-7.50 (3H, m), 7.60-7.80
(2H, m).

^{MS: m / e295 (M +} ), 105 (100%) Elemental analysis (as _{C 19 H 21 NO 2) C} % H% N% Calculated: 77.26 7.17 4.75 Found: 77.23 7.18 4.75 Example 2 (2S A) (2S, 4R) -4-benzoyloxy-2-benzyloxymethyl-pyrrolidine (S) -N-benzoyl-1-benzyloxypent-4 obtained in Example 1 -487 mg of en-2-ylamine
(1.72 mmol) tetrahydrofuran-water (1: 1 v / v, 5 ml)
1.32 g (5.16 mmo) of iodine was added to the solution at 0 ° C under a stream of argon.
l) was added and the mixture was stirred at the same temperature for 9 hours. After adding 5 ml of a saturated aqueous solution of NaHCO ₃ to the reaction solution, a 10% aqueous solution of Na ₂ S ₂ O ₃ was added until the color of iodine disappeared. After liquid separation, the organic layer was washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. One part of the obtained crude product was subjected to column chromatography using silica gel to obtain the title compound as a colorless oil.

〔[Α] ²⁴ _D ▼ = + 33.6 ゜ (c = 2.0, CHCl ₃ ) IR: νν ^neat _max ▼ (cm ⁻¹ ) 1710, 3400 NMR (CDCl ₃ ): δ (ppm) 1.7-2.2 (2H , m), 2.30 (1
H, s, exchangeable with D ₂ O), 2.95-3.70 (5H, m),
4.55 (2H, s), 5.30-5.60 (1H, m), 7.20-7.70 (8H,
m), 7.90-8.16 (2H, m).

MS: m / e 311 (M ⁺ ) b) (2S, 4R) -N-[(1,1-dimethylethoxy) carbonyl] -4-benzoyloxy-2-benzyloxymethyl-proline Repeat step a) above. (However, the column chromatography on silica gel was omitted) (2S, 4
The crude product of R) -4-benzoyloxy-2-benzyloxymethyl-pyrrolidine was dissolved in 5 ml of methylene chloride and 0.12 ml (0.86 mmol) of triethylamine and di-t
394 mg (1.81 mmol) of -butyl dicarbonate was added, and the mixture was stirred at room temperature for 12 hours. After washing with a 5% aqueous HCl solution, a saturated aqueous NaCl solution, a saturated aqueous NaHCO ₃ solution, and a saturated aqueous NaCl solution, the mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting brown oil (890 mg) was subjected to column chromatography using 32 g of silica gel to give the title compound as a colorless oil.

Yield 549 mg (77.6%) ▲ [α] ²⁴ _D ▼ = -49.7 ゜ (c = 2.05, CHCl ₃ ) IR: ▲ ν ^neat _max ▼ (cm ^-1 ) 1710, 1680 NMR (CDCl ₃ ): δ (ppm) 1.46 (9H, s), 2.10-2.45
(2H, m), 3.50-3.85 (4H, bm), 4.00-4.30 (1H, b
m), 4.55 (2H, s), 5.40-5.65 (1H, m), 7.25-7.70
(8H, m), 7.90-8.10 (2H, m).

MS: m / e411 (M ⁺ ), 68 (100%) c) (2S, 4R) -N-[(1,1-dimethylethoxy) carbonyl] -4-benzoyloxy-2-hydroxymethyl-pyrrolidine b 870 mg (2.11 mmol) of the compound obtained in
40% of 0% Pd (OH) ₂ (on carbon) is dissolved in 15 ml of methanol, and then 0.1 ml of chloroform is added.
Stirred at room temperature for 8 hours. Through celite,
The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using 25 g of silica gel to give the title compound as a colorless oil.

Yield 542 mg (80%) ▲ [α] ²⁴ _D ▼ = -53.7 ゜ (c = 1.17, CHCl ₃ ) IR: νν ^neat _max ▼ (cm ^-1 ) 3400, 1720, 1680 NMR (CDCl ₃ ): δ ( ppm) 1.46 (9H, s), 1.70-2.50
(3H, m), 3.50-3.90 (4H, m), 4.05-4.90 (1H, m),
5.40 to 5.55 (1H, m), 7.30 to 7.55 (3H, m), 7.90 to 8.10
(2H, m).

MS: m / e322 (M + 1), 68 (100%) d) (2S, 4R) -N-[(1,1-dimethylethoxy) carbonyl] -4-benzoyloxyproline 680 mg of the compound obtained by the above c) (2.12 mmol) in a solution of carbon tetrachloride-acetonitrile-water (1: 1: 1.5 v / v, 10.5 ml) under an argon stream at room temperature at room temperature.
g (6.36 mmol) and ruthenium chloride (RuCl ₃ .H ₂ O) 11 m
g (2.2% mol = 47 μmol) was added and stirred for 30 minutes. The reaction solution was extracted with 10 ml of methylene chloride, and the organic layer was washed with a saturated aqueous solution of NaCl and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 20 ml of a saturated aqueous solution of NaHCO ₃ and washed with 10 ml of diethyl ether. Water layer 10% HC
After adjusting the pH to 1 with an aqueous solution, the mixture was extracted with diethyl ether, washed with a saturated aqueous solution of NaCl, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless amorphous.

Yield: 530 mg (74.6%) IR: νν ^neat _max ▼ (cm ⁻¹ ) 3100, 1700 NMR (CDCl ₃ ): δ (ppm) 1.46 (9H, s), 2.40 to 2.65
(2H, m), 3.70-3.90 (2H, m), 4.35-4.70 (1H, m),
5.40-5.65 (1H, m), 7.30-7.60 (3H, m), 7.60-7.80
(1H, bs), 7.90-8.10 (2H, m).

MS: m / e335 (M ⁺ ), 57 (100%) e) (2S, 4R) -4-hydroxyproline Potassium carbonate was added to a solution of 550 mg (1.64 mmol) of the compound obtained in d) above in methanol (10 ml). 498mg (3.61mmo
l) and stirred at room temperature for 3 hours.
Distilled off. The residue was dissolved by adding 10 ml of water and washed with 10 ml of diethyl ether. The pH of the aqueous layer was carefully adjusted to about 2 by adding 10% aqueous HCl, and the mixture was extracted five times with 10 ml of methylene chloride. <Note 1> The solvent was distilled off under reduced pressure, and the resulting residue ((2S, 4R)-
N-[(1,1-dimethylethoxy) carbonyl] -4-
Hydroxyproline) was dissolved in 10 ml of dioxane, 10 ml of a 10% aqueous HCl solution was added thereto, and the mixture was heated under reflux for 30 minutes.
After air cooling, wash three times with 10 ml of diethyl ether <Note 2
> The aqueous layer was concentrated under reduced pressure. Dowex50 (H ⁺ type) 2
The column was subjected to ion exchange resin column chromatography using 0 cc (solvent: 0.23N NH ₄ OH) to give the target compound (2S, 4
180 mg (94%) of R) -4-hydroxyproline were obtained. This was recrystallized from (water-ethanol) to obtain a colorless plate crystal. Yield 125 mg (65%), mp 270-274 ° (decomposition), NMR (D ₂ O solvent), behavior on TLC, ninhydrin color development were completely consistent with the results of a standard sample of the compound.

<Note 1> Methyl benzoate and benzoic acid are produced under methanolysis conditions, but benzoic acid cannot be separated from the target compound (hydroxy acid).

<Note 2> Benzoic acid can be removed here.

Continuation of the front page (72) Inventor Yoshiharu Iwabuchi 1-4-5 Doi, Aoba-ku, Sendai-shi, Miyagi Dokokaikan (56) References JP-A-61-33166 (JP, A)

Claims (1)

(57) [Claims] 1. A compound of the general formula (II) Wherein R ₁ is a protecting group for a hydroxyl group and R ₂ is aryl or alkyl, and the compound represented by the general formula (I) (Wherein R ₁ and R ₂ are as described above).