JPH11158115A - Deuterated ester compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new deuterated ester compound useful as an intermediate for the production of 2,2-dideutero-5-aminolevulinic acid by introducing deuterium using inexpensive heavy water but not using a large excess amount of it. SOLUTION: This compound shown by the formula [R<1> is a 1-4C alkyl; R<2> forms a single bond together with R<3> ; R<4> is H] is obtained by the reaction of an allylmalonic acid ester with 1.0-1.5 equivalent(s) of a base (e.g. sodium hydroxicle, n-butyl lithium) in an appropriate solvent at -50 to 100 deg.C, followed by the reaction with 1.0-5 equivalent(s), preferably 1.0-2 equivalent(s), of heavy acetic acid prepared by adding 1/2 equivalent of heave water to acetic acid anhydride and stirring the mixture.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an MR (magnetic resonance)
The present invention relates to an important intermediate in a novel method for producing 2,2-dideutero-5-aminolevulinic acid, which is useful as a PDT (photodynamic therapy) agent having a diagnostic function, and a method for producing the intermediate.

[0002]

2. Description of the Related Art
As a method for producing 2-dideutero-5-aminolevulinic acid, the present inventors have proposed a method in which 5,5-dimethoxy-2-piperidone is deuterated and then hydrolyzed (WO
However, in the present method, deuteration is carried out through an equilibrium reaction between a compound serving as a deuterium source and 5,5-dimethoxy-2-piperidone. In order to obtain 2-dideutero-5-aminolevulinic acid, there was a serious disadvantage that a large excess of expensive deuterium source compounds had to be used. on the other hand,
2,2-dideutero-5-aminolevulinic acid is obtained by the same route as the present inventors producing 2,2-dideutero-5-aminolevulinic acid (JP-A-9-67323).
However, it should be able to be manufactured.
2-dideuter-4-pentenoic acid ester (in the present application, among compounds represented by the following general formula (II), R ² , R ³ =
A single bond, a compound represented by R ⁴ = hydrogen atom). Recently, the synthesis of 2,2-dideutero-4-pentenoic acid was reported (J. Amev. Chem. So.
o. , 118 , 2634 (1996)), but also in this synthesis method, the deuterium atom introduction reaction has a large excess (about 100).
Heavy water). An object of the present invention is to use heavy water, which is available at the lowest cost, as a deuterium source compound, and to use a low-cost 2,2-dideutero-5-aminolevulinic acid through a reaction of introducing a deuterium atom without using a large excess thereof. It is to provide a simple manufacturing method.

[0003]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have replaced active hydrogen of easily available allyl malonic ester with deuterium,
Then, 2,2-dideutero-4-pentenoic acid ester is deoxidized in the presence of heavy water, that is, a method in which deuteration can be performed using 1.5 molar equivalents of heavy water in a stoichiometric manner. They have found that they can be easily produced at a hydrogenation rate, and have reached the present invention. That is, the gist of the present invention is represented by the following general formula (I)

[0004]

Embedded image (In the formula, R ¹ represents an alkyl group of C ₁ ~C _4, R ²
Represents an amino group, an azido group, or a phthalimide group, or R ² may form a single bond or an epoxy ring together with R ³ . R ³ represents a hydroxyl group which may be protected by a substituted silyl group. R ⁴ represents a hydrogen atom or, together with R ³ , represents an oxo group. )) Or a salt thereof, or a hydrate or solvate thereof, and a compound represented by the above general formula (I), which is decarboxylated in the presence of heavy water. The following general formula (I
I)

[0005]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). In the present invention, in the above general formula (II),
R ¹ is a hydrogen atom, R ² is an amino group, and R ³ and R ⁴ together represent an oxo group, that is, a method for producing 2,2-dideutero-5-aminolevulinic acid is the most preferred embodiment. .

[0007]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. In the above definition, examples of the C ₁ -C ₄ alkyl group for R ¹ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a t-butyl group.
Examples of the substituted silyl group for protecting the hydroxyl group in R ³ include:
Examples include a trimethylsilyl group, a triethylsilyl group, and a t-butyldimethylsilyl group. Hereinafter, specific examples of preferred compounds represented by the general formula (I) are shown in the following Tables.
1, -2, -3, -4, -5, -6 and -7. (1) When R ² and R ³ together represent a single bond

[0008]

[Table 1]

(2) When R ² and R ³ together form an epoxy ring

[0010]

[Table 2]

(3) When R ² represents an azide group a) When R ³ represents a hydroxyl group which may be protected by a substituted silyl group (in this case, R ⁴ = hydrogen atom)

[0012]

[Table 3]

B) when R ³ together with R ⁴ represents an oxo group

[0014]

[Table 4]

(4) When R ² represents a phthalimide group a) When R ³ represents a hydroxyl group which may be protected by a substituted silyl group (in this case, R ⁴ = hydrogen atom)

[0016]

[Table 5]

B) when R ³ together with R ⁴ represents an oxo group

[0018]

[Table 6]

(5) R ² represents an amino group, and R ³ represents R
^{When 4} represents an oxo group

[0020]

[Table 7]

In Tables 1 to 7, -Me represents a methyl group, -Et represents an ethyl group, and -tBu represents a t-butyl group. As the salts for the compound represented by the above general formula (I), pharmaceutically acceptable salts are preferable, and for example, inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate are preferred. Salts and organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, camphorsulfonate, etc. . Since the compounds of the above general formula (I) and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the scope of the present invention. Examples of the solvent for the solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, and methylene chloride.

The method for producing the compound of the present invention will be described.
In the general formula (I), the compound in which R ² and R ³ together represent a single bond is a compound in which an active methine hydrogen atom of an allyl malonic ester is substituted with a deuterium atom;
Allylmalonate is converted to tetrahydrofuran (TH
F), diethyl ether, dimethylformamide (DM
F) In a suitable solvent such as -50 ° C to 100 ° C, preferably -10 ° C to 20 ° C, 1.0 to 1.5 equivalents of an active methine hydrogen atom such as sodium hydride or n-butyllithium is hydrogenated. Gas, a heavy acetic acid which can be easily prepared by reacting a base which is withdrawn as an inert substance such as butane, and then adding 1/2 equivalent of heavy water to acetic anhydride and stirring,
It can be produced by reacting 1.0 to 5 equivalents, preferably 1.0 to 2 equivalents. Some allyl malonic esters are commercially available, and can be easily prepared by an allylation reaction of the malonic ester.

From the compound represented by the general formula (I) wherein R ² and R ³ together represent a single bond, from 0.01 to 20 equivalents of lithium chloride, sodium chloride and sodium cyanide in dimethylformamide Inorganic salts, such as
And 1.0 to 10 equivalents, preferably 1.0 to 2.
The compound can be converted to the compound represented by the above general formula (II) by heating under reflux for 30 minutes to 2 days, preferably 1 hour to 6 hours in the presence of 0 equivalent of heavy water.

The above-prepared R ² and R ³ together represent a single bond, that is, they are used to epoxidize an isolated double bond from a compound represented by the general formula (I) having a double bond. Method, for example, a method of reacting an oxidizing agent such as an organic peracid, an alkyl hydroperoxide, or hydrogen peroxide, or an N-halocarboxylic acid amide such as N-bromosuccinimide in a water-containing organic solvent,
In the general formula (I), a compound in which R ² and R ³ form an epoxy ring via an oxygen atom can be produced by a method of treating the resulting halohydrin with a base or the like. Peracetic acid, m-chloroperbenzoic acid and the like are used as the organic peracid,
0.1 to 10 equivalents, preferably 1 to 1.5 equivalents of this in a suitable organic solvent such as methylene chloride and chloroform,
It is allowed to act at 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 hour to 10 days, preferably 5 hours to 3 days. When an alkyl hydroperoxide or hydrogen peroxide is used, a metal oxide complex such as titanium, aluminum, vanadium, or molybdenum is used as a catalyst.

In the general formula (I) which can be produced by the above-mentioned method, a method of opening an epoxy ring with an azide anion from a compound in which R ² and R ³ are bonded via an oxygen atom to form an epoxy ring. For example, a method of reacting ammonium azide in an alcohol solvent (J. Org. Ch.
em. , 50 , 1556 (1985)) in an acetonitrile solvent in the presence of a metal salt such as lithium perchlorate.
Method of reacting sodium azide (Tetrahed
ron Letters, 31 , 5641 (1990)
Azide compounds such as trimethylsilyl azide and tri-n-butylstannyl azide without a catalyst (Tetr
ahedron Letters, 30 , 4153 (1
989)) or in the presence of a catalyst (Tetrahe
dron: Asymmetry, 2 , 437 (199
Compounds in which R ² is an azide group and R ³ is a hydroxyl group or a hydroxyl group protected by a substituted silyl group in the general formula (I) can be produced by a method or the like which acts 1). Instead of trimethylsilyl azide and tri-n-butylstannyl azide, for example, t-butyldimethylsilyl azide, t-butyl
If butyldimethylstannyl azide is used, the hydroxyl group becomes t
The compound protected with -butyldimethylsilyl group can be produced. Similarly, in the general formula (I), a compound in which R ² and R ³ are bonded via an oxygen atom to form an epoxy ring is reacted with potassium phthalimide or the like (Tetrahedron Lett., 23 , 169).
7 (1982)), R in general formula (I)
^A compound in which ² is a phthalimide group and R ³ is a hydroxyl group can be produced.

A method of oxidizing a secondary alcohol to a ketone from the compound represented by the general formula (I) in which R ² is an azide group or a phthalimide group and R ³ is a hydroxyl group produced by the above method, for example, (1) Jones reagent, chromium acetate such as pyridinium chlorochromate, (2) dimethylsulfoxide (DMSO) -sulfur trioxide-pyridine system, DM
DMSO oxidation using SO-trifluoroacetic anhydride system,
Alternatively, (3) a compound in which R ³ and R ⁴ together represent an oxo group, that is, a carbonyl compound, can be produced by hypohalous acid oxidation using sodium hypochlorite or calcium hypochlorite. In addition, depending on the oxidizing agent, for example, the carbonyl compound can be directly produced from a compound in which R ² is an azide group and R ³ is a hydroxyl group protected with a substituted silyl group by a Jones reagent without deprotection.

Further, the epoxidation of the aforementioned double bond,
A compound in which R ² and R ³ together represent a single bond in the general formula (I) without undergoing an epoxy ring cleavage by an azide, ie, a chromyl azide (Tet)
rahedron Lett. , 36 , 6751 (19
95)) in a suitable solvent such as methylene chloride to directly produce a compound represented by the general formula (I) wherein R ² represents an acid group and R ³ and R ⁴ represent an oxo group. .

R ² thus produced is an azide group,
General formula (I) wherein R ³ and R ⁴ together form an oxo group
When R ² is an azide group from the compound represented by, for example, using an alcohol corresponding to R ¹ as a solvent, one equivalent or more of a pharmacologically acceptable inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, or methanesulfonic acid, the presence of an organic acid such as p- toluenesulfonic acid, for example, palladium supported on activated carbon, palladium black, the presence of a catalytic hydrogenation reaction, such as platinum oxide catalyst, subjected to catalytic hydrogenation, R ² Is a compound represented by the general formula (I) wherein is an amino group. The reduction reaction is carried out using water as a solvent instead of alcohol, or the compound of general formula (I) in which R ² is an amino group once produced is acid-hydrolyzed to give 2,2
-Didutero-5-aminolevulinic acid can be produced.
The product is obtained as a salt of the acid used in the reaction. 2,2-
Didutero-5-aminolevulinic acid has the general formula (I)
Wherein R ² is a phthalimido group and R ³ and R ⁴ are together an oxo group by heating and hydrolyzing in the presence of a mineral acid such as hydrochloric acid or sulfuric acid.

[0029]

According to the present invention, a novel intermediate which can provide an inexpensive production method of 2,2-dideutero-5-aminolevulinic acid and a production method using the same can be obtained.

[0030]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to the following unless it exceeds the gist. Example 1

[0031]

Embedded image

60% sodium hydride (13.2 g,
0.33mol, n-hexane washing to remove oil
) In tetrahydrofuran (300 ml) suspension.
Under a nitrogen atmosphere, stir with stirring at about 20 ° C.
60 ml (0.30 mol) of lumalonate is slowly dropped
did. After dropping, continue stirring for 3 hours at room temperature.
After that, heavy water (D) was added to 24 ml (0.20 mol) of acetic anhydride.
(99.9%) 4.4 g (0.22 mol)
Stir the biacetic acid prepared by stirring at room temperature for 2 days.
Stir slowly through the stainless steel tube and add
Was. The reaction mixture was filtered by filtration in a nitrogen stream.
The solution was separated by filtration and washed with tetrahydrofuran. Reduce filtrate
The mixture was concentrated under reduced pressure, and diethyl ether and cold water were added to the residue.
Separate the organic layer into cold water and cold saturated aqueous sodium hydrogen carbonate
After washing with liquid and cold water in that order, dry (MgSO _Four), Filtration, thick
The residue that could be compacted was purified by distillation.

51.7 g (86%). 94-5 ° C / 7 mmHg. ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.27
(6H, t, J = 7.1Hz , CH 2 C H 3), 2.6
3 (2H, d, J = 6.8Hz, C H 2 CH =), 4.
20 (4H, q, J = 7.1Hz, C H 2 CH 3),
5.08 (2H, m, -CH = C H 2), 5.78 (1
H, m, -C H = CH 2). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 13.9,
32.6, 51.2 (t, ¹ J (C, D) = 20.5H
z), 61.2, 117.3, 134.0, 168.
7. Example 2

[0034]

Embedded image

6.2 g of diester (30.8 mmol)
l), lithium chloride (dried at 150 ° C. under reduced pressure)
2.0 g (47.2 mmol), heavy water (D conversion> 99.
9%) A mixture of 2.0 ml (100 mmol) and 10 ml of dimethylformamide was heated and refluxed for 8 hours in a vessel equipped with a cooling tube through which ice water was flown under a nitrogen atmosphere, and then distilled at normal pressure to obtain a fraction up to 105 ° C. And the upper layer is washed with water (2
Times), dried (MgSO ₄ ), filtered and purified by distillation under reduced pressure to obtain 2.65 g (66%) of the target dideutero compound.

78-80 ° C./68 mmHg. ¹ H-NMR (CDCl ₃ , 300 MHz) δ 1.26
(3H, t, J = 7.0Hz , CH 2 C H 3), 2.3
6 (2H, d, J = 6.6 Hz, CH ₂ CD ₂ );
13 (2H, q, J = 7.0Hz, C H 2 CH 3),
5.03 (2H, m, CH ₂ =), 5.82 (1H,
_{m, -CH 2 = C H)} . ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 14.1,
28.6, 32.8 (pen, ¹ J (C, D) = 19.
5Hz), 60.1, 115.2, 136.6, 17
2.8. Example 3

[0037]

Embedded image

9.60 g (73.8 mmol) of olefin compound
l) To methylene chloride solution (100 ml) was added m-chloroperbenzoic acid (purity 55%, 25 g, 80 mmol) with stirring, and the mixture was allowed to stand at room temperature for 1 week. After adding an excess of an aqueous saturated sodium hydrogen carbonate solution and stirring vigorously, the separated organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution,
The residue obtained by successively washing with water, drying (MgSO ₄ ), filtration and concentration was subjected to SiO ₂ column chromatography purification (developing solution, n-hexane = ethyl acetate = 10: 1 → 6: 1). 6.82 g (63%) of the resulting epoxy compound was obtained.

[0039]¹H-NMR (CDCl_Three, 300MH
z) δ 1.26 (3H, t, J = 7.1 Hz, CH_TwoC
H _Three), 1.78 (1H, dd, J = 6.4, 14.3).
Hz, CH _aH_bCD_Two), 1.95 (1H, dd, J
= 4.7, 14.3 Hz, CH _a H _bCD_Two), 2.5
6 (1H, dd, J = 2.6, 4.9 Hz,H _aH_bC
= CH), 2.76 (1H, dd, J = 4.1, 4.9)
Hz, H _a H _bC = CH), 2.99 (1H, m, H_Two
C = CH).¹³ C-NMR (CDCl_Three, 75 MHz) δ 14.1,
27.4, 30.0 (pen,¹J (C, D) = 19.
5Hz), 46.9, 51.1, 60.4, 172.
7. Example 4

[0040]

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2.1 g of epoxy compound (16.1 mmo)
l), 4.3 ml of trimethylsilyl nitrile (32.2)
(mmol) of dimethylformamide (DMF, 3 ml) was heated under a nitrogen atmosphere for 50 hours at 85 ° C. After cooling to room temperature, excess reactant and DMF were distilled off under reduced pressure, and the residue was subjected to SiO ₂ column chromatography (developing solution). , N-hexane: ethyl acetate = 8: 1) to give 3.37 g (85%) of the desired azide.

[0042]¹H-NMR (CDCl_Three, 300MH
z) δ 0.11 (9H, s, SiMe _Three), 1.22
(3H, t, J = 7.1 Hz, CH_TwoCH _Three), 1.7
8 (1H, dd, J = 8.8 Hz, 14.3 Hz, CH
_aH_bCD_Two), 1.81 (1H, dd, J = 4.7,
14.3 Hz, CH _a H _bCD_Two), 3.13 (1H,
dd, J = 6.0, 12.5 Hz, CH _aH_bN_Three),
3.18 (1H, dd, J = 4.2, 12.5 Hz, C
H _a H _bN_Three), 3.82 (1H, m, CHOSi),
4.09 (2H, q, J = 7.1 Hz, CH _TwoC
H_Three).¹³ C-NMR (CDCl_Three, 75 MHz) δ0,14.
1,9.3 (pen,¹J (C, D) = 19.6H
z), 29.6, 56.5, 60.3, 70.4, 17
3.0. Example 5

[0043]

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3.3 g of trimethylsilyl ether compound (1
3.5 mmol) in acetone (40 ml) while stirring under ice-cooling with a Jones reagent (4).

[0] mmol /
6.6 ml) was added dropwise. After completion of the dropwise addition, the ice water bath was removed and stirring was continued for 7 hours. While cooling again in an ice-water bath, 2-propanol (2 ml) was added with stirring. Acetone is distilled off from the reaction mixture, and water and
Ethyl ether was added. The separated organic layer was washed with water (2
Times), washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, dried (MgSO ₄ ), filtered and concentrated to obtain a residue.
Purification by iO ₂ column chromatography (developing liquid n-hexane: ethyl acetate = 5: 1) gave 1.66 g (72%) of the desired ketone.

¹ H-NMR (CDCl ₃ , 300 MH
z) δ 1.26 (3H, t, J = 7.1 Hz, CH ₂ C
_{H 3), 2.71 (2H,} s, CH 2 CD 2), 4.0
3 (2H, s, CH ₂ N ₃ ), 4.14 (2H, q, J
_{= 7.1Hz, C H 2 CH 3} ). ¹³ C-NMR (CDCl ₃ , 75 MHz) δ 14.0,
27.3 (pen, ¹ J (C, D) = 19.5 Hz),
34.2, 57.4, 60.8, 172.2, 202.
9. Example 6

[0046]

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2.78 g of trimethylsilyl nitrile (2
Chromium oxide (25.7 g, 25.7 mmol) was added to a methylene chloride (32 ml) solution of the compound (4 mmol), and the mixture was stirred at room temperature for 3 hours.
7 mmol), and the mixture was further stirred for 24 hours. The filtrate from which the insoluble portion was removed by Celite filtration was concentrated, and the residue was
Purification was performed by O ₂ column chromatography (developing solution, n-hexane: ethyl acetate = 5: 1) to obtain 400 mg (27%) of the same ketone body as obtained in Example 5. Example 7

[0048]

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5.50 g (29.4 mmol) of azide compound
l) To a solution of concentrated hydrochloric acid (3 ml) in methanol (120 ml) was added 10% palladium / carbon (700 mg) under a nitrogen atmosphere, and the mixture was replaced with hydrogen gas and stirred vigorously at room temperature for 14 hours. The filtrate from which the catalyst was removed by filtration was concentrated, dissolved in 20 ml of a 1N aqueous hydrochloric acid solution, and allowed to stand at room temperature for 24 hours. Then, the mixture was concentrated under reduced pressure on a water bath at 40 ° C.
The operation of dissolving in 0 ml and leaving at room temperature for 5 hours was repeated twice, and then concentrated. The residue was dissolved in ethanol (12 ml), and ethyl ether (5 ml) was added. The generated crystals were collected by filtration, washed with a mixed solvent of ethanol and ethyl ether (2: 1), and dried to obtain 4.12 g of the desired amino acid hydrochloride. The filtrate was concentrated and recrystallized (ethanol: ethyl ether = 1: 1) to obtain 0.53 g of the desired product. The combined yield of the first and second crystals was 93%.

¹ H-NMR (D ₂ O, 500 MHz) δ
2.74 (2H, s, CH ₂ CD ₂ ), 3.99 (2
_{H, s, CH 2 N 3} ). ¹³ C-NMR (D ₂ O, 125 MHz, internal standard: dioxane) δ 27.3. (Pen, ¹ J (C, D) = 2
0.0 Hz), 34.7, 47.5, 177.2, 20
4.5.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code FI C07C247 / 04 C07C247 / 04 C07D303 / 40 C07D303 / 40 C07F7 / 18 C07F7 / 18NPTT // C07M 5: 00

Claims (3)

[Claims] 1. A compound represented by the following general formula (I) (In the formula, R ¹ represents an alkyl group of C ₁ ~C _4, R ²
Represents an amino group, an azido group, or a phthalimide group, or R ² may form a single bond or an epoxy ring together with R ³ . R ³ also represents a hydroxyl group which may be protected by a substituted silyl group. R ⁴ represents a hydrogen atom or, together with R ³ , represents an oxo group. Or a salt thereof, or a hydrate or solvate thereof. 2. A compound represented by the following general formula (II), wherein the compound represented by the general formula (I) is decarboxylated in the presence of heavy water. (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). 3. In the general formula (II), R ¹ is a hydrogen atom, R ²
Represents an amino group, and R ³ and R ⁴ together represent an oxo group.