JPS61293983A - 5n-acyltetrahydropterin compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<0> is H or formula II; R<1> is H, CH3, formula III, etc.; R<2> is H or CH3; R<3> is formula IV (R<4> is H, CH3, C6H5CH2, etc.), etc.]. EXAMPLE:N<2>-Isobutyryl-5,6,7,8-tetrahydro-6,7-dimethyl-5-succinylpterin. USE:Useful as various intermediates for pterin-related compounds, particularly providing various choices for setting reaction processes from the viewpoint of crystallinity or stability. The absorption in cells is increased. PREPARATION:A 2'-N-isobutyryl derivative expressed by formula V is hydrogenated in methanol solvent in the presence of a platinum catalyst to give a compound expressed by formula VI, which is then acylated with an acylating agent in a pyridine solution to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is based on the general formula (1): hail)
, R2 is -H or -CH, , R is -CH2CH2C
ONH-C)I-COOHMataha-CHR'-NOR@
(R'1i-H, -CH3, -C,H6C)12, IO
C, H, C)1. -1-CH, 5H1-CIl, 5CI
(,,-CH2C1(2SH.

-C1,CH2C001 (or -CH2C112C)
I2N11. , R5 is -H1-CI, ,C,H,CH2
-1lIOC,11,C1,-1CH,SCH,, -C
H2SH,,CH,CF12SH,-C112C)12
5N-7 siltetophhydropterin compound which is composed of cOO) 1*-CH2CH, Cl2NH2, R6 represents monolayer or C, H, C1, COO-).

[Jubei's technology] Pterin compounds represented by the formula (Z) are generally widely known in a negative sense due to their difficult to handle physical properties and, in particular, their insolubility in virtually all solvents. There is. In the search for freely soluble pterin, 7mi/
It was found that the solubility of these compounds was dramatically increased by 7-sylation of the substituent (Bikarel (
P, Karrer) Onigari R Schweitz 7-(R
, Schwyzer) Noherhechika Doumika Acta, 3
Volume 2, page 423, 1949, and D.F.T.
Lua (D, f, Wolf), 7-Lucy 7 Nkuson (R, C0^nderson), Eney Kauriki (E, ^.

Kaczka), Nisny Harris (S, ^ + Harri
s), G.E.7-S (1;, E, ^rth), P. L. Southwick (P, L, Southwick)
), R2M17 ingo and K. Folkers, Journal of American Chemical Society, 69@
, p. 2753, 1947), making cropping even easier.

Furthermore, these acylpterins represented by the general formula (3): (wherein R represents an alkyl group, an aryl group, or an aralkyl group) can be converted into pterins of the formula (2) by hydrolysis with a weak acid or a weak base. The system compound is generated again (M, Vis
Contini) and H.R.H.
H, R9 Weilenmann), Helvetica Chimica Acta, vol. 228, 21 f0H11958).

This simple N-acylation is also an effective tool for elucidating the chemistry of 5,6,7,8-tetrahydropterin, which has formula (4). The reduced pterin expressed by formula (4) is extremely unstable towards oxygen;
However, when the nitrogen atom at the 5th position is acylated, it is stable in the air and often crystalline.
Kuta, vol. 228, 21701. 1958, R. Brown, M. C.

Joseph), T, Leigb#
and M.Swain's Journal
Of Chemical Science, Perkin Tra
ns, 1.1003 pages, 1977, and Niss Niss Angry (S.

NJangu13') and M. Visconti's Helvetica Chimica Acta, Volume 65, Page 1090, 19
When Tetrahy l/r:I pterin is treated with a strong acylating agent such as trifluoroacetic anhydride, all four nucleophilic nitrogen atoms are acylated, giving the general formula (5): (wherein R1, R2, R3 and R4 represent -COCF), the tetrakis-()+7 fluoroacetyl) derivative (Ahlweber (R
When treated with a weak acylating agent such as acetic anhydride, N(
3) is not acylated, N(8) is partially acylated, and in general formula (5), R1, R3 and R4 are -C
OCH, and R2 is -H, and in general formula (5), R' and R
A mixture of bisacetyltetrahydropterin in which 3 is -COCH, and R2 and R4 are -H
(See R. Weber and M. Visconti, Helvetica Chimica Acta, Vol. 60, p. 152, 1977). From these studies, the ease of 7-silation of various nucleophilic nara atoms is N(5), 2-N, N(8),
The conclusion is that the order is N(3) (see R. Weber, M. Visconti, Helvetica Chimica Acta, Vol. 60, p. 152, 1977), which also means that 2-N, N(8) and This is also supported by the fact that the acyl substituent at N(3) is hydrolytically removed and the 5-acyl group remains unshadowed (7-Le Faber and M. Bisconti's Helvetica chimica acta, Volume 60, page 152,
1977, and M. Visconti and M.
CoHchi-GreuLer
), Helvetica Chimica Acta, vol. 54, p. 1125, 1971). If the hydrolysis conditions are made more severe, the 5-acyl group is also removed, and the tetrahydropterin compound of formula (4) is obtained again (N. 1982, and M. Bisconti and M. Fuguchi Breuter's Helvetica Chimica Acta, vol. 54, p. 1125, 197.
(see 1st year).

2 (6): 2'-N-7 cetyl-6,7-nomethylpterin has been well known for a long time and has clearly better solubility than non-acylated compounds ( Be Anger (R, B.

^Bier) and W, V.

Curran's Journal of Authentic Chemistry, Vol. 26, p. 2129, 1961).

However, the compound of formula (6) is somewhat unstable to hydrolysis, and the acetyl group is partially cleaved in boiling water.

[Problems to be Solved by the Invention] When the present inventor produced a 2'-N-inbutyryl derivative represented by the formula (7), as expected, the 2'-N-inbutyryl derivative was found to be more resistant than the compound of the formula (6) in an organic solvent. It dissolved well. The compound of formula (7) also has the formula (6
) is more stable than the compound of formula (
It took four times as long as the compound 6).

Catalytic hydrogenation of the compound of formula (A) using a platinum catalyst in methanol solution yields 2'-N-imbutyryl-5,6,7,8-tetrahydro-6, which is of formula (8): , 7-methylpterin was converted, which was separated as an air-stable hydrochloride without losing the imbutyryl group, as measured by NMR spectroscopy! In fact, the 6- and 17-methyl groups in the compound of formula (8) were cis.

Acylation at the 5-position of the compound of formula (8) with various acylating agents in a bilion solution under mild conditions is selectively carried out, and some An interesting new 5-acyltetrahydrobuderine was introduced.

When the compound of formula (8) is acylated with succinic anhydride, the formula (
9): The basic pka of the compound of formula (9) from which the 5-succinyl derivative was obtained in good yield is -1°34±
It was measured as 0°03. The fact that the compound of formula (9) requires such low pH values for protonation excludes the possibility that this compound exists in the zwitterion form. A study of the hydrolysis reaction of the compound of formula (9) showed that the imbutyryl group was selectively removed in ammonium hydroxide at room temperature.

The reason for the difference in reactivity between the 2-ami7 group and the amide function in N(5) is due to the fact that 2-N conjugates with the carbonyl group at the 4-position to form a vinyl alcohol-like imide system. be. On the other hand, the amide functional group in N(5) cannot be conjugated with the 4-carbonyl group and is a simple amide as it is, which has high resistance to hydrolysis.

Therefore, the 2-N-inbutyryl substituent can be considered as a protecting group that improves solubility for the preparation of 5-7 siltetrahydropterin.

The compound of formula (9) has a free carboxyl group on the succinyl substituent, which the inventors utilized to bond the amino acid to the tetrahydropterin compound. Since the protecting group can be easily removed by hydrolysis, the carboxyl functional group is preserved as a benzyl ester, and J
amino acid ([7, Zerva
s), M. Winit, z., and Noei B. Greenstine (J. P. Greens).
22, p. 1515, 1957) was found to be most convenient. As a coupling agent, synchhexylcarboimide (Japanese) and Novi Hess (G.

N-Hydroxy-5-flubornene-2,3-nocarboximide (HONB) (M 7 ) / (H, Fujino
), Nis Kobayashi (S, Kobayash i)
, M Obayashi (M, 0bayash i),
Tee 7 kg (T, Fukuda), Niji Shinagawa (S, Shinagawa), and Oh Nijimura (0
The yield was optimized by adding an N-hydroxy-imide, such as NisbiN15bi, Chemical 7 Armasure Bulletin, Vol. 22, p. 1857, 1974). Hydrogen to a carboxylic acid represented by formula (12) of a compound represented by formula (11): (wherein R is a hydrogen atom or a furkyl group): (wherein R is the same as above) The chemical decomposition is rapidly carried out using a balanoum catalyst in a methanol solution, and finally the imbutyryl group is removed using ammonia in a methanol aqueous solution to obtain a compound of formula (13).

The inventors have also found that it is possible to condense an amino acid into the 5-position of the tetrahydropterin of formula (8) by acylation through the carboxyl function of the amino acid. To achieve this, the formula (1
4): (wherein, Activated by producing esters (M 7 Nono, Nis Kobayashi, M Obayashi, Tea 7 Kuda, Nis Shinagawa Ohage and Oh Nijimura Chemical 7γ-Mathewtical Pretan, 22
8. 1857 pages, 1974, and No Gubru
Anderson (GJ, ^r+derson), JETS4 Nv -? (J, E, Zimmeri*
ann) and F.M. Callahan (F.M., Ca.
Journal of the American Chemical Society, Volume 85, Page 3039, 1963.
(see year). When heated with the ester of formula (14) in biliran solution, 7-sylation occurs at N(5) to give tetrahydropterin of formula (15): (see No. E. Zimmerman and F. M. Callahan, T. Op. American Chemical Society, Vol. 85, p. 3039, 1963) is more suitable for this acylation, since in formula (14), ~5-Flubornene-2,3-nocarboximide ester (M 7 Nono, Nis Kobayashi, M Obayashi, Tea 7 Kug, Nis Shinawa and Ohnijimura Chemical 7 Armaseutical Bulletin, Vol. 22, +8570.1974 ) reacts slowly, probably due to steric reasons. The N-benzoyloxycarbonyl protecting group is removed by hydrogenolysis and the imbutyryl group is removed by ammonolysis as described above.

The pterin compound according to the present invention is used as various intermediates for pterin-related compounds. In particular, from the standpoint of crystallinity and stability, they offer a variety of options as intermediates in reaction steps.

The pterin compounds according to the invention also have the potential to increase their absorption into cells.

Next, the present invention will be explained in more detail based on Examples, but the present invention is not limited to these.

Example 1 N2-imbutyryl-5,6,7,8-tetrahydro-
Production of 6f7-nomethyl-5-succinylpterin N2
-imbutyryl-5,6,7,8-tetrahydro-6,
3.00° (9.39 mol) of monohydrate of 7-nomethylpterin mo7 hydrochloride was mixed with 40 zl of birinone! The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours.

Next, 4 zl of methanol was added, and the mixture was further stirred for 15 minutes. After removing the solvent under reduced pressure, the oily residue was extracted with hot ether until a solid formed. The obtained solid was crushed in ice water with a PTL of 1, the insoluble solid was collected,
Wash with water and dry to obtain N2-imbutyryl-5,6,7
, 280 g of 8-tetrahydro-6,7-nomethyl-5-succinylpterin (melting point 163-164°C) was obtained (
Yield: 86%). This was recrystallized from methanol/water to give the monohydrate.

Example 2 N-14-(N''-isobutyryl-5,6,7,8-tetrahydro-6t7-nomethylbuterin-5-I)
Preparation of bennorester of -1,4-dioxobutyl)-glutamic acid N2-imbutyryl-5,6,7,8-tetrahydro-
6,7-nomethyl-5-succinylpterin 1.10g
(3,0 mmol), 1.486 g (3,31 mmol) of glutamic acid nobennorester mo7tosylate) and 589xl of N-hydroxy-5-norbornene-2,3-nocarboximide? (3.31 mmol) was suspended in 30 ml of nochloromethane and the mixture was cooled to 0°C. Triethylamine 334B (3.31 mmol) was then added and stirring continued for an additional 15 minutes. Socyclohexylcarbonimide 682jl? (3°31 mmol) was added and stirring was continued for 2 hours at 0°C and 21 hours at room temperature. The precipitated nontalohexyl urea was filtered off and washed with nochloromethane (2×10zN). The filtrate was dried to dryness and the residue was taken up with dityl acetate 200+1. This solution was dissolved in 4% NaHCOi (2X 25z1
), 0.2H 110^C aqueous solution (2x50ml), 4
% NaHCO3 aqueous solution (2x 25v1) and water (2
x 25z1). After drying over Na25O, the solvent was removed and the residue was chromatographed on silica sol, eluting with chloroform/methanol (9:1). When the solvent is removed, a colorless solid foam (melting point = 1
84-185°C) 1,624g was returned (Yield: 8
0%). These were further recrystallized from ethyl acetate/ether to give a colorless solid.

Example 3 N-(4-(N”-isobutyryl-5,6,7,8-tetrahydro-6,7-)]methylpterin-5-yl-
of 1,4-dioxobutyl)-glutamic acid! ! ! N-14-(N2-isobutyryl-
1.119 (2.24 mmol) of bennorester of 5,6,7,8-tetrahydro-6,7-dimethylbuterin-5-yl)-1,4-dioxobutyl)-glutamic acid was added to palladium at room temperature and pressure. Hydrocracking was carried out using 100 mg of catalyst (5% in carbon) in methanol 50M1 for 5 hours. The catalyst was filtered off and the filtrate was dried.

The residue was redissolved in 10xl of methanol and the resulting solution was dropped into 100ml of ether to form a precipitate. The precipitate was collected, washed with ether and dried. Yield: 770zg, yield: 95%, melting point: 220~
Recrystallization from a small amount of an aqueous solution of 0.18 IIcZ at 221°C (decomposition) gave colorless crystals.

Example 4 N-+4-(5,6,7,8-tetrahydro-6,7-
N-14-(N2-inbutyryl-5-yl)-1,4-dioxobutyl)-glutamic acid prepared in Example 3
700zy (1,42 mmol) of 5,6,7,8-tetrahydro-6,7-nomethylbuterin-5-yl)-1,4-nooxobutyl l-glutamic acid was dissolved in meta/-3
It was dissolved in I11 and 3z1 of concentrated aqueous ammonia was added. The diluted solution was stirred at room temperature for 8 hours under a vacuum atmosphere, and then dried. The residue was dissolved in methanol 20ii' and acetone was added to form a precipitate. The precipitate was collected, washed with acetone and dried. The yield was 600 ml, the yield was 92%, and the melting point was 261-262°C (decomposition). 0
．． Recrystallization from a small amount of HCI aqueous solution of 1i4 gave colorless crystals.

Example 5 Preparation of 5-(Z'-N-bennoloxycarbonylaminoacetyl)-N2-imbutyryl-5,6,7,8-tetrahydro-6,fushimethylbuterin N2-imbutyryl-5,6,7 ,8-tetrahydro-
6,7-nomethylbuterine monohydrochloride monohydrate 1°O
Og (3.13 mmol) and N-hydroxy-containing cinimide ester of N-bennoloxycarbonylglycine 1.9h (6.27 mmol) were added to birinone ZOxl.
In addition to the mixture 1,000? 60'C'c in elementary atmosphere
Heated at 80° C. for 1 vI for 2 hours. Next, methanol 4a+1 was added and the mixture was stirred for an additional 15 minutes. After cooling to room temperature, the reaction mixture was dried and the residue was dissolved in toluene (3X
25z1). Dilute the residue with chloroform
00yN, and the solution was diluted with 4% NaHCOa aqueous solution.
(2X 25xf, 0.28 HO^C aqueous solution (2X
50zl), 4% NaHCO3 aqueous solution (2X 25x1
') and water (2 x 25d). Na
After drying over 2SO4, the solvent was removed and the residue was chromatographed on silica sol with methanol/chloroform (1:9) eluent. Removal of the solvent gave a foamy solid which was recrystallized from ethyl acetate/ether to yield a colorless solid. The yield was 1.149, 80%, and the melting point α was 152-154°C (decomposition).

Example 6 5-(2'-7mi7acetyl)-N2-imbutyryl-
Preparation of 5,6゜7.8-tetrahydro-6,7-methylpterin 5-(2'-N-bennoloxycarbonylami/acetyl)-2'-isobutyryl-5, obtained in Example 5
560 zg (1,23 mmol) of 6,7,8-tetrahydro-6,7-nomethylbuterine was dissolved in baraccum (5%, 50
zg) for 5 hours. The catalyst was filtered off and the filtrate was concentrated to a volume of Sal.

A precipitate was generated by dropping the resulting solution into 100 yl of ether. The precipitate was collected, washed with ether and dried. Yield: 360 mg, yield: 91%, melted,
Mine was 252-254°C (decomposed). Ethanol 1
0. The monohydrochloride salt was obtained by recrystallization from an aqueous solution of IN in lIC1/ether.

Example 7 Production of 5-(2'-aminoacetyl)-5,6,7,8-tetrahydro-6,7-nomethylpterin 5-(2'-7mi7acetyl) obtained in Example 6 -N
2-Inbutyryl-5,6,7,8-tetrahydro-6
, 200 ag (0.62 mmol) of 7-nomethylpterin in 1 x (l) of concentrated aqueous ammonia and 1 ml of methanol.
The mixture was stirred for 8 hours at room temperature under a nitrogen atmosphere. The solvent was then removed under reduced pressure, the residue was dissolved in methanol 10R1 and acetone was added to form a precipitate. The precipitate was collected, washed with 7 setsone, and dried. The yield was 144 mg, the yield was 92%, and the melting point and α were 290 to 291"C (decomposition).

Ethanol 10. The dihydrochloride salt was obtained by recrystallization from a mixture of IH lIc1 aqueous g/Et20.

Patent applicant Kanebuchi Chemical Industry Co., Ltd. +1.

Claims (1)

[Claims] 1 General formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, R^0 is -H or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^ 1 is -H, -CH_3, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or CH_2OR^1'(R^1' is an alkyl group of C_1 to C_1_0, a cycloalkyl group or represents an aralkyl group), R^2 is -H or -CH_3, R^3 is ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ or -CHR^5-
NHR^6 (R^4 is -H, -CH_3, -C_6H_
5CH_2, HOC_6H_4CH_2-, -CH_2
SH, -CH_2SCH_3, -CH_2CH_2SH
, -CH_2CH_2COOH or -CH_2CH_
2CH_2NH_2, R^5 is -H, -CH_3, C_
6H_5CH_2-, HOC_6H_4CH_2-, -
CH_2SCH_3, -CH_2SH, -CH_2CH
_2SH, -CH_2CH_2COOH or -CH_
2CH_2CH_2NH_2, R^6 is -H or C_
A 5N-acyltetrahydrobuterine compound represented by 6H_5CH_2COO-). 2 R^3 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼(R^
The compound according to claim 1, wherein 4 is the same as above. 3 R^1 is -CH_3, R^2 is -CH_3, R^4
3. The compound according to claim 2, wherein is -CH_3. 4 R^1 is -CH(OH)-CH(OH)-CH_3
, R^2 is -H, R^4 is -CH_2CH_2COOH
The compound according to claim 2, which is 5 R^1 is -CH(OH)-CH(OH)-CH_3
, R^2 is -H, and R^4 is ▲a numerical formula, a chemical formula, a table, etc.▼, the compound according to claim 2. 6. The compound according to claim 2, 3, 4 or 5, wherein R^0 is -H. 7 R^3 is -CH-NHR^6 (R^5 and R^6
is the same as above), the compound according to claim 1. 8 R^1, R^2 and R^5 are -CH_3, R^6
8. The compound according to claim 7, wherein is -H. 9 R^1 is -CH(OH)-CH(OH)-CH_3
, R^2 is -H, R^5 is -CH_2CH_2COOH
, R^6 is -H. 10. The compound according to claim 7, wherein R^1 and R^2 are -CH_3, and R^5 and R^6 are -H. 11 R^1 is -CH(OH)-CH(OH)-CH_
3. The compound according to claim 7, wherein R^2 and R^6 are -H, and R^5 is ▲a numerical formula, a chemical formula, a table, etc.▼. 12 Claims 7 and 8 in which R^0 is -H
A compound according to item 9, item 10 or item 11.