JPS61249973A - Novel pyrimidine derivative - Google Patents

Abstract

NEW MATERIAL:A pyrimidine derivative expressed by formula I [n is 0 or 1; R<1> is H or CH3; R<2> is H, 1-3C alkoxy or SCH3; R<3> is H (R<2> is not H in this case) or 1-3C alkoxy; R<4> is OH, 1-3C alkoxy or amino acid residue linked to CO in formula I through NH, and the terminal COOH may be esterified or converted into CH2OH]. EXAMPLE:5-Carboxy-2,4-dimethoxy-6-methylpyrimidine. USE:A medicine, e.g. carcinostatic agent or intermediate therefor. PREPARATION:A solution of the corresponding 5-halopyrimidine derivative in ether is cooled to -70 deg.C, and a solution of a lithium agent, e.g. butyl lithium, is dropped thereto. The resultant mixture is stirred for several minutes - several tens of minutes and treated with gaseous carbon dioxide to afford the aimed compound expressed by formula II (R<4> is OH) in formula I.

Description

[Detailed description of the invention] : Industrial application field) The present invention relates to novel pyrimidine derivatives.

More specifically, the present invention provides general formula (1) (in which n
is an integer of 0 or 1, R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom, a cl-5-alkoxy group, or a methylthio group, and R3 represents a hydrogen atom or a C1
~3-alkoxy group, R2 and R3 are not both hydrogen atoms, and R4 is a hydroxyl group or cl-3-alkoxy group, or is bonded to CO in the formula with an amine group. The terminal carboxyl group in this amino acid residue may be ecterized, or the carboxyl group may be converted to a hydroxymethyl group). The present invention provides pyrimidine compounds. The novel pyrimidine compound according to the present invention is a substance that is useful as a pharmaceutical product such as an anticancer agent or as an intermediate for manufacturing a pharmaceutical product.

(Prior art) Streptomyces subvarsogenes (Stre-pt.
Sparsomycin is an antibiotic produced by S. omyces sparsogenes [see formula (n) below]
Since its isolation in 1962, various biological activities have been investigated, and this
Showing antibacterial activity against a wide variety of bacteria and fungi;
It has been recognized that it exhibits considerably high antitumor activity against Walker's sarcoma and Sarcoma 180 solid tumor in vivo. However, as a result of clinical trials, it has been found that sparsomycin exhibits severe ocular effects, and the development of this substance as an antitumor agent has had to be discontinued.

On the other hand, research on the synthesis of sparsomycin congeners began around 1977, and in 1983, 8. Kanatomo
have synthesized 5-carboxy-6-methyluracil derivatives as sparsomycin analogues, but it has been reported that none of these had antibacterial or anticancer properties ( Chem, Pharm, Bul
l,, 31 (1), 135-143.1983
).

(Means for Solving the Problem) The present inventors focused on the basic skeleton of sparsomycin (formula ① above) and conducted repeated research to synthesize a new sparsomycin homolog. The inventors succeeded in synthesizing a novel pyrimidine derivative represented by formula (1) and completed the present invention.

When n in the formula is 0, the pyrimidine derivative represented by the general formula (1) according to the present invention has the following general formula (DI
) (In the formula, R1, R2, R3 and R' are the same as above.) Typical examples thereof include 5-
Carboxy-2,4-dimethoxy-6-methylpyrimidine, N-(2,4-dimethoxy-6-methyl-5-pyrimidinylcarbonyl)methionine, N-(2,4-:
) methoxy-6-methyl-5-hyIJ:/, N-
(2,4-dimethoxy-6-methyl-5-pyrimidinylcarbonyl)methionine-8-oxide and their methyl esters, N-(2,4-dimethoxy-6-methyl-5-pyrimidinylcarbonyl)methioninol,
N-(2,4-:)methoxy-6-methyl-5-pyrimidinylcarbonyl)noserinol, further 5-carboxy-2,4-jethoxy-6-methylpyrimidine, 5-
Carboxy-2,4-dipropoxy-6-methylpyrimidine, 5-carboxy-2-methoxy-6-methylpyrimidine, 5-carboxy-4-methoxy6-methylpyrimidine, 5-carboxy-2-methylthio-4-methoxy- 6-methylpyrimidine, 5-carboxy-2,4
-dimethoxypyrimidine, 5-carboxy-2-methoxypyrimidine, 5-carboxy-4-methoxypyrimidine, and lower alkyl esters and amino acid conjugates thereof. In this case, the amino acid part is L
It may be either type or D type.

When n in the formula is 1, it is a substance represented by the following general formula (IV) (in the formula, R1, R2, R3 and R4 are the same as above), and a typical example thereof is β −(2,
4-dimethoxy-6-methyl-5-pyrimidinyl)acrylic acid, β-(2,4-jethoxy-6-methyl-5-
pyrimidinyl)acrylic acid, β-(2,4-dipropoxy-6-methyl-5-pyrimidinyl)acrylic acid and their lower alkyl esters, N-[β-(2,4-
dimethoxy-6-methyl-5-pyrimidinyl)acryloyl]methionine, N-[β-(2,4-dimethoxy-
6-Methyl-5-pyrimidinyl)acryalyl]alanine, N-[β-(2,4-dimethoxy-6-methyl-5
-pyrimidinyl)acryloylcobalin, N-(β-(
2,4-dimethoxy-6-methyl-5-pyrimidinyl)
Acryloyl]methionine-8-oxide, N-[β
-(2,4-jethoxy-6-methyl-5-pyrimidinyl)acryloyl]methionine, N-[β-(2,4-
Jetoxy-6-methyl-5-pyrimidinyl)acryloyl]alanine, N-[β-(2,4-jethoxy-6
-methyl-5-pyrimidinyl)acryloylcobalin,
N-[β-(2,4-:)ethoxy-6-methyl-5-
pyrimidinyl)acryloyl]methionine-8-oxide, N-(β-(2,4-dipropoxy-6-methyl-5-pyrimidinyl)acryloyl]methionine, N-
(β-(2,4-dipropoxy-6-methyl-5-pyrimidinyl)acryloyl]alanine, N-[”β-(2
,4-dipropoxy-6-methyl-5-pyrimidinyl)
Acryloylcobalin, N-(β-(2,4-dipropoxy-6-methyl-5-pyrimidinyl)acryloyl)
Methionine-8-oxide and its methyl ester, N-[β-(2,4-dimethoxy-6-methyl-
5-pyrimidinyl)acryloyl]methioninol, N
-[β-(2゜4-dimethoxy-6-methyl-5-pyrimidinyl)acryloyl]parinol, N-(β-(2
゜4-Jethoxy-6-methyl-5-pyrimidinyl)acryloyl]methioninol, N-(β-(2,4-jethoxy-6-methyl-5-pyrimidinyl)acryloyl]parinol, N-(β-(2,4 -Dipropoxy-
6-Methyl-5-pyrimidinyl)acryloyl]methioninol, N-(β-(2,4-:)propoxy-6-
Methyl-5-pyrimidinyl)acryloyl]parinol, further β-(2-methoxy-6-methyl-5-pyrimidinyl)acrylic acid, β-(4-methoxy-6-methyl-5-pyrimidinyl)acrylic acid, β-( 2-Methylthio-4-methoxy-6-methyl-5-pyrimidinyl)acrylic acid, β-(2,4-dimethoxy-5-pyrimidinyl)acrylic acid, β-(2-methoxy-5-pyrimidinyl)acrylic acid, β -(4-methoxy-5-pyrimidinyl)acrylic acid and lower alkyl esters and amino acid conjugates thereof. The amino acid moiety in this case may be either L-type or D-type.

A novel pi IJ represented by the above general formula (I) according to the present invention
Midine derivatives are produced by the following method.

1, 5-Halopyrimidine derivative 1) Uracil or 6-methyluracil is heated under reflux for several hours in the presence of phosphorus oxychloride and N,N-dimethylaniline to form the product (2,4-dichloro-6-methylpyrimidine). Alternatively, 2,4-dialkoxy-6-methylpyrimidine or 2.4-:)alkoxypyrimidine is obtained by reacting alcohol and metallic sodium with 2.4-:,'chloropyrimidine), and this dialkoxypyrimidine and acetic acid is added to N-iodosuccinimide, which is a reaction product of N-chlorosuccinimide and sodium iodide,
Heating for several hours yields 5-iodo-2,4-dialkoxypyrimidines.

Alternatively, in place of the above N-iodosuccinimide, N
- 5 as above using promosuccinimide;
-Bromo-2,4-dialkoxypyrimidines are obtained.

2) (6-methyl)hydroxypyrimidines or (
6-methyl)thiouracil prepared in the same manner as above.
Add a suspension of iodosuccinimide in chloroform and heat under reflux for several hours to obtain 5-iodo(-6-methyl)hydroxypyrimidines or 5-iodo(-6-methyl)-
After obtaining 4-hydroxy, -2-methylthiopyrimidine and chlorinating them according to a conventional method, a methoxy group is introduced to form 5-iodo(-6-methyl)methoxypyrimidines or 5-iodo(-6-methyl )-4-methoxy-2-methylthiopyrimidine is obtained.

3) Bromine is added dropwise to an acetic acid suspension of hydroxygyrimidines and heated for several hours to obtain 5-bromohydroxypyrimidines, which are chlorinated according to a conventional method, and then a methoxy group is introduced to form 5-bromohydroxypyrimidines. Bromomethoxypyrimidines are obtained.

(2) A 5-carboxypyrimidine derivative in which R4 in the general formula (m) corresponds to a hydroxyl group can be obtained by combining each 5-carbohydrate obtained by the above method.

Furthermore, by processing triethylamine, methyl acrylate, acetic acid/Q radium, and triphenylphosphine into a 5-halopyrimidine derivative and heating it at about 140°C for several hours in a sealed tube, R' of the general formula (IV) can be prepared. A β-(5-pyrimidinyl)methyl acrylate derivative corresponding to a methoxy group is obtained, which is hydroxylated).By deesterification using IJ and methanol, R4 of the general formula (IV) is converted to a hydroxyl group. β-(5-
(pyrimidinyl)acrylic acid derivatives can be obtained.

Into the obtained dimethylformamide solution of the carboxylic acid, while stirring under water cooling, add isobutyl chloroformate and N-methylmorpholine paste methylformamide solution in sequence, then add dimethylformamide solution of amino acid methyl ester and leave overnight. A compound in which R4 of the general formula (1) is a methyl ester of an amino acid residue is obtained,
When R6 in the general formula (I) is deesterified using IJium (hydroxylated), a compound in which R6 of the general formula (I) is an amino acid residue is obtained, and lithium borohydride (LiBH , ) and stirring for several hours, a compound of general formula (I) in which R' is an amino acid alcohol can be obtained.

The cancer cell growth suppressive effect of the novel pyrimidine derivative according to the present invention using nucleic acid synthesis inhibition as an indicator will be described below.

The results obtained in this study are in good agreement with the results of antitumor studies using experimental animals.

(Test method) The target cells for determining the effect of the test compound are:
L 5178 Ylin tumor cells derived from DAB/2 mice were used. As a medium, RPM Knee 16 manufactured by Hinaga Pharmaceutical Co., Ltd.
40 medium to give a final concentration of 10%.
Add fetal bovine serum and further increase the final concentration of antibiotics between μ?
Kanamycin sulfate was added to a concentration of /ml. At this antibiotic concentration, there was no effect on cell proliferation ability. 20 on a Falcon U-shaped micro test plate
0 pL of L 5178 Y cell suspension (5 cells/5 g of 1xlO) was added, and 2 μt of the test compound dissolved in dimethyl sulfoxide was added thereto (final sample concentration of 200 t).
tf/me) after 40 h of culture at 37 °C, 1
0 μt of 3H-thymidine solution (O02 μCi) was added and cultured for an additional 6 hours. 3H into the cell at this time
The uptake (S) of 3H was measured using a liquid scintillation counter, and from the uptake of 3H (0) in the control group to which only dimethyl sulfoxide was added, the following equation was used:
The cancer cell growth inhibition rate was determined.

Cell growth inhibition rate (chi) = (i--)xlo.

Results> The test results are shown in Table 1. In the table, test compounds are indicated by each symbol in general formula (I).

Table 1 As is clear from the above test results, the pyrimidine derivative according to the present invention was found to have a remarkable cancer cell growth suppressive effect, that is, a high antitumor effect, and is expected to be developed as a pharmaceutical product. .

The novel compound according to the present invention can be expected to have higher activity by further chemical modification, and is therefore also useful as an intermediate for pharmaceutical production.

Production examples of the compounds and intermediates thereof according to the present invention will be shown below, along with physical property values of these substances.

Reference Example 1 Preparation of 2,4-dimethoxy-6-methylpyrimidine 6-methyluracil (50 mmot) was mixed with phosphorus oxychloride (20 mg, excess) and N,N-dimethylanili:/
(12f, 100 mm0t) and heated under reflux for 2 to 3 hours. From now on, excess phosphorus oxychloride will be distilled off under reduced pressure.
Ice water (1ooml) was added to the residue, and ether (80d
Extracted with X3). The extract was washed with a saturated chloride solution, dried (Na2so4), and the solvent was distilled off, made into a methyl alcohol (50 tttl) solution, and this was dissolved in methyl alcohol (50 tttl) containing an equimolar amount of metallic Na.
80 mg) solution was added dropwise to the solution under water cooling. After stirring for an additional hour under the same conditions, the mixture was heated to reflux for 1 to 2 hours. From now on, the methyl alcohol will be distilled off under reduced pressure, and the residue will be mixed with water (50 m
) and extracted with ether (50dX3). The extract was washed with a saturated IJ chloride solution and dried. After distilling off the solvent, the residue was subjected to silica gel column chromatography (chloroform: n-hexane = 4:1),
The title compound was obtained (yield 76%).

Reference Example 2 Production of 2,4-jethoxy-6-methylpyrimidine The title compound was obtained in the same manner as in Reference Example 1 except that methyl alcohol in Reference Example 1 was replaced with ethyl alcohol (yield: 40 cm).

Reference Example 32. Production of 4-dipropoxy-6-methylpyrimidine The title compound was obtained in the same manner as in Reference Example 1 except that methyl alcohol in Reference Example 1 was replaced with propyl alcohol (yield: 45
%).

Reference Example 4 Production of 2,4-dimethoxypyrimidine Reference Example 1
The title compound was obtained in the same manner as in Reference Example 1 except that 6-methyluracil was replaced with uracil (yield: 58 cm).

Reference Example 5 Preparation of 5-iodo-2,4-:)methoxy-6-methylpyrimidine N-rioo succinimide (2,Of, 15 mm
A solution of sodium iodide (2,3 t, ts mmol) in acetone (20 at#) was added dropwise to a suspension of sodium iodide (2,3 t, ts mmol) in acetone (20 ml) at room temperature over 5 minutes.

After further stirring for 10 minutes, the mixture was filtered and the acetate was distilled off under reduced pressure.

The residue contains 2.4-:)methoxy-6-methylpyrimidine 7
(13 mmot) and acetic acid (30 d),
The mixture was heated at c for several hours. Thereafter, the reaction mixture was poured into an ice-water layer and extracted with chloroform (60mJX3).

The extract is water (70x3), hypo (70ml),
It was washed with saturated sodium hydrogen carbonate (7 om) and saturated sodium chloride (70 at) in that order and dried. After distilling off the solvent, the residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (yield: 80 cm).

mps82-84°C (petroleum ether) CHCL3-1
.

Engineering Rν11az cm, 156O NMRδ (CDCA3): 4.17 (3H, s, O
Me), 4.13 (3H.

s e OMe) + 2-68 (3H+ ' +
Me) Reference example 65-iodo-2,4-jethoxy-6-
Production of methylpyrimidine 2,4-dimethoxy-6-methylpyrimidine in Reference Example 5 was changed to 2,4-jethoxy-6-methylpyrimyline,
The title compound was obtained in the same manner as in Reference Example 5 (yield 74%)
.

Reference Example 7 Production of 5-iodo-2,4-dipropoxy-6-methylpyrimidine 2,4-dimethoxy-6-methylpyrimidine in Reference Example 5 was replaced with 2,4-dipropoxy-6-methylpyrimidine, and The title compound was obtained in the same manner (yield 74%)
).

Reference Example 8 Production of 5-iodo-2,4-dimethoxypyrimidine The title compound was obtained in the same manner as in Reference Example 5 except that 2,4-dimethoxy-6-methylpyrimidine in Reference Example 5 was replaced with 2,4-dimethoxypyrimidine. (Yield: 15 cm).

ml): 63-64"C (petroleum ether)CuOmu -1゜engineeringRνy1az cm, 1550MMRδ(CD
CL3): 8.57 (IJs, ArH),
4.09 (3H, 8, OMe), 4.02 (3H, 8
10Me) Reference example 95-bromo-2,4-dimethoxy-
Preparation of 6-methylpyrimidine The title compound was obtained in the same manner as in Reference Example 5 using N-promosuccinimide (yield 1(1)).

NMRδ(CDCt3)=4.03(3H9elOMe
), 3.99 (3H,s, OMe), 2.48 (3H
, s, Me) Reference Example 10 Production of 5-bromo-2,4-dimethoxypyrimidine The title compound was obtained in the same manner as in Reference Example 9 using 2,4-dimethoxypyrimidine (yield: 84%).

ffp: 58-59°C (petroleum ether) NMRδ (
CDC: 8.31 (IH, e, ArH)
, 4.03 (3H,8,OMe), 3.9g (
3H,8,OMe) Reference Example 11 Production of 5-iodo-2-methoxypyrimidine 2-hydroxypyrimidine (10mmot) was mixed with N-chlorosuccinimide (1,6t, 12mmoA) and sodium iodide (1,8t, 12mm0L) ) yoυ
Prepared N-iodosuccinimide in chloroform (3
0 ml) of the suspension and heated under reflux for several hours.

Thereafter, the solvent was distilled off, water (30 ml) was added, and the mixture was filtered with suction. The obtained crystals were washed with ethanol and then dried to obtain 5-iodo-2-hydroxypyrimidine.

This product was chlorinated according to a conventional method and then a methoxy group was introduced to obtain the title compound (yield 10%).

mp: 57-57.5'C (petroleum ether) CH=C
Mu-1 Engineering RνmaX cm: 1560.154ONM
Rδ (CDC): 8.49 (2H,s, Ar
H)t 3.96 (3H, s, OMe) Reference Example 12 Production of 5-iodo-4-methoxypyrimidine The title compound was obtained in the same manner as in Reference Example 11 using 4-hydroxypyrimidine (yield u% ).

mp: 141-142°C (petroleum ether) CHCL
S −1 1Rνrnaxcrn=154O NMRδ (CDC23): 8.64 (2H, s,
ArH), 3.89 (3H,8,OMe) Reference Example 13 Production of 5-iodo-4-methoxy-6-methylpyrimidine The title compound was prepared in the same manner as in Reference Example 11 using 4-hydroxy-6-methylpyrimidine. (yield: 53 cm).

ml): 102-103°C (petroleum ether) CH
CLS-1.

Engineering Rv, aXcrn, 1560 mass m/z: 250 ('') NMRδ (CD
Cl3): 8.44 (IH, s, ArH), 4.01
(3H, El, OMe), 2.54 (3H, 13, M
e) Elemental analysis value Theoretical value as C, H7 and N20: C, 28,80i H, 2,80i N,
11.20 Actual value: C, 28,81i H, 2,77
i N, 11.16 Reference Example 14 Production of 5-iodo-4-methoxy-6-methyl-2-methylthiopyrimidine The title compound was obtained in the same manner as in Reference Example 11 using 6-methylthiouracil (yield 67%). ).

mpnia 2-73°C (petroleum ether) CHC mu -l IRνmax Cr1l :154QNMRδ(C
DCl3): 4.01 (3H,e, OMe
), 2.58 (3Hm e+Me), 2.53
(3H, s, 8Me) Reference example 15 5-bromo-2
-Production of methoxypyrimidine 2-hydroxypyrimidine (lQmmot) acetic acid (3
0 ml) After dropping Br2 (6 ml) into the suspension, 7
It was heated at 0''C for several hours. From now on, the precipitated crystals were separated, washed with ethanol, dried, and 5-bromo-2-
Hydroxypyrimidine was obtained.

This product was chlorinated according to a conventional method, and then a methoxy group was introduced to obtain the title compound (yield: low).

mp: 52-53°C (oil x-f le) CHCLS
-1.

EngineeringRvInlLXcm, 1570', 154
5NMRδ (CDC23): 8.56 (2H,s
, ArH)t 4.00 (3H,s, OMe) Reference Example 16 Production of 5-bromo-4-methoxypyrimidine The title compound was obtained in the same manner as in Reference Example 15 using 4-hydroxypyrimidine (yield: 42%). ).

lnp: 66-68°C (petroleum ether) CHCL3
-1.

Engineering RI/maxcrIT, 157O NMRδ (CDCl3): 8.44 (IH,
s, ArH), 8.39(lH,8,ArH), 4
．． Q3(3H,8,OMe) Example 15-carboxy-
Preparation of 2,4-dimethoxy-6-methylpyrimidine Ether (120txl) of 5-bromo 2,4-dimethoxy-6-methylpyrimidine (1?, 43 mmot)
) A solution of n-butyllithium in hexane (1.5 μ, 3.2 ttl, 4.3 mmot) was cooled to -70°C.
) was added dropwise and stirred for -15 minutes. The reaction solution was added to an ether (150x/) solution to which excess dry ice was added and allowed to stand at room temperature. After adding water (100 atl), separate the ether layer. The aqueous layer was acidified to 10% gcm, extracted with ACOEt (100 ml x 3), and dried. After evaporation of the solvent, the residue was recrystallized from CH3CN to give 5-carboxy-2,4-dimethoxy-6-methylpyrimi')7
(0.72t, 90chi) was obtained.

mp: 141-144℃ Nujol -1, Engineering Rνmaxcm, 1690.1575.155
ONMRδ (DMSO-d6): 1σ, 59 (
IH, 8, C0OH).

4.08(3H,8,OMe), 4.04(348)O
M'3) t2.63 (3H, s, Me) Example 2 N-(2,4-dimethoxy-6-methyh
Preparation of 5-carboxy-2,4-dimethoxy-6-methylpyrimidine (10 mmot) in dimethylformamide (20 mmot)
Inbutyl chloroformate (llmmot) and N-methylmorpholine (
After sequentially adding dimethylformamide (2 m/) solutions of llmmot), the mixture was left to stand for 15 minutes.

To this, L-alanine methyl ester hydrochloride (1
0mmot) and N-methylmorpholine (llmmot)
A dimethylformamide (20 ac/) solution of L-alanine methyl ester prepared above was added thereto, and the mixture was left to stand overnight.

After evaporating the solvent, water (40-) was added to the residue, acidified with 10% hydrochloric acid, and extracted with chloroform (50steX3). The extract was washed with 10 tons of sodium carbonate (50tttl) and saturated sodium chloride (50xg) and dried. After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (yield: 10 cm).

mass mHz: 283 (M)NMRδ(c
Dcz3) Near, 04 (IH, d, J=81'lZ+
NH).

4.9-4.5 (IH, m, CH), 4.02 (3H,
s, OMe).

3-993-99 (3H18tO3,78(3)1.8
．． OMe).

2.53 (3H,s, Me), 1.50 (3
H, eL, J=7Hy,.

Me) [α]D: -10,4' Elemental analysis value C□2H1'Theoretical value as FNI05:
C, 50,88; H, 6,05; N, 14.83
Actual measurements: C, 51,22; H, 6,08; N,
14.69 Example 3 N-(2,4-dimethoxy-
6-methy/I/-5-hirimi9ylcarbonyl)-L-
Preparation of methionine methyl ester Example 2 using L-methionine methyl ester hydrochloride
The title compound was obtained in the same manner as (yield: 26).

mp: 81-82℃ (petroleum ether-methanol) IR
V, 1Qit3crn-1: 3400.1740.1
660.1585mass mHz: 343 (M
+)NMRδ(CDCZa)' 6-92 (I J
d, J = 7 Hz + NH).

4.9-4.6 (IH, m, cH), 3.96 (3H
, s, 0ne).

3.92 (3H18#OMe) 13.72 (3H, 8,
OMe).

2.7-2.4 (2Ht ml CH2) 12.49
(3H,s,Me).

2.3-2.0 (2H, m, CHg), 2.10 (3H
,s,sMe)MeOH.

[α], -24,3° Elemental analysis value Theoretical value as C14H21N305S:
C, 48,97; H, 6,17; N, 12.24
Actual measurement: C, 48,87; H, 6,44; N,
11.96 Example 4 N-(2,4-dimethoxy-
Preparation of L-methionine-8-oxide methyl ester (6-methyl-5-hydinylcarbonyl)-L-methionine methyl ester obtained in Example 3 103.
Orq (0,3 mmot)- in MeOHCH2C4 solution cooled to 0 °C NaIO4 (67', 4 Q, 0.
315 mmot)/1 mt Hg0 was added dropwise with stirring, and the mixture was stirred at 0°C for 5 hours. After the reaction was completed, the reaction mixture was filtered, the solids were washed with CH2C22 and combined with P solution, MeOH in the solution was distilled off under reduced pressure, and then CH2C1
2, dried over Na25O, and the solvent was distilled off.

97.9 square meters (yield: 91 square meters) of an oily product were obtained.

NMR (CDC2,) δ (ppm): 2.33 (
m, 2H), 2.44 (Ill.

3H), 2.52 (8,3H), 2.62-3.
04 (m, 2H).

3.71 (8,3H), 3.90 ('8.3H)
, 3.95 (B, 3H).

4.74(m, IH), 7.55(1)r, IH) MS
mHz: 359 (M+') (crn-"): 3400.3240.17
40.1650゜Example 5 Production of N-(2,4-dimethoxy-6-methyl-S-<rimidinylcarbonyl)-L-valine methyl ester Same as Example 2 using L-valine methyl ester hydrochloride The title compound was obtained (yield 44%).

Inp: 45-46”C (petroleum ether-/ evening/-
) CHCL3-1 XRνmaxcm: 3400.1740.166
0.1580mass mHz: 311 (M”
) NMRδ (CDC45): 6.84 (IH,a
, J==8tlz, NI().

4.8-4.6 (IH, m, CH), 4.01 (
3H,8,OMe).

3.98 (3H,s, OMe), 3.75 (3H
, s, oMe).

2.52 (3H, a, Me), 2.3-2.0 (IH,
m, cH).

1.01 (3H, d, J=7Hz, Me), 0.97
(3H, d.

J=7H29Me) [α North eOH, +, σ Example 6 N-(2,4-dimethoxy-6-methyl-
Preparation of D-methionine methyl ester (5-pyrimidinylcarbonyl) Example 2 using D-methionine methyl ester hydrochloride
The title compound was obtained in the same manner as (yield: 40 cm).

mp: 81-82°C (petroleum ether-methanol) I
Rv magazine 'it3cm-': 3400.1745.1
670.1695mass mHz: 343 (M
”) NMRδ (CDCl2) near, 02 (IH, d,
J=8Hz, NH).

5.0-4.6 (LH, m, CI, 4.02 (
3H, B, OMe).

3.98 (3HT' toMe) s 3.79
(3H*s + OMe).

""J (2H, ml "H2) + 2-53 (
3H, s, Me).

2.3-2.0 (2H, m, CH2), 2.11
(3H, 8, SMe) [α] Lips 80H: + 24.
σ Elemental analysis value Theoretical value as Cx4H2xNs06B:
C, 48,97; H, 6,17; N, 12.24
Actual value: C, 49,05; H, 5,92; N,
11.98 Example 7 N-(2,4-dimethoxy-6
-methyh-s-pyrimidinylcarbonyl) -Production of -D-valine methyl ester The title compound was obtained in the same manner as in Example 2 using -valine methyl ester (yield '5').

ml): 42-43°C (petroleum ether-methanol) I
Rvg device "5cm-': 3400.1735.16
60.1580mass mHz: 311 (M”
) NMRδ (CDC13): 6.87 (IH,
d, :r=8,,NH)t4.8-4.5(IJ
m, CH), 4.02 (3H, s, OMe).

3.98 (3H, a, oMe), 3.78 (3H, e
, one).

2.55 (3H, B, Me)t 2.4-2.0
(IH, m, CH).

1.03 (3J d, J=7Hz, Me), 0
．． 98 (3H, a.

, T=7Bzy Me) [α) MeOH, 5, Da elemental analysis value Theoretical value as Cx4H2xN305: C
,54,01i H,6,80i N, 13.50 Actual value: C,54,49i H,6,,96i Nl
12.92 Example 8 N-(2,4-:)methoxy-6-
Methyl-5-hy-17midinylcarbonyl)-L-methionine methyl ester obtained in Example 3 (3 mmol of IN
20 ml of sodium hydroxide C was added and stirred at room temperature for 1 hour. Chloroform (20 ml) was added to separate the aqueous layer, acidified with 10% hydrochloric acid, and ethyl acetate (40 mA' x 3
) After extraction, it was dried. After distilling off the solvent, the residue was recrystallized to obtain the title compound (yield: 83%).

mp: 142.5-143.5℃ (hexane-M1
9ON) IRI/Nuji 1-1 max “-”: 3400.1720.1655
．． 1580mass mHz: 329 (M”)
NMRδ(DMSO)' 8-38 (IH,s
r C0OH), 7-24 (IH, d, J=7H2,
NH), 4.8-4.5 (IH,, m.

CH), 3, 91 (3H+s+OMe)
y 3-88 (3H, s.

oMe), 2.7-2.4 (2)1. m, C
H2), 2.42 (3H.

s, Me)t 2.3-1.9 (2H1m, C
H2) t 2.05 (311B, SMe) [α] 〢00H knee 23.2 @ Elemental analysis value C13H engineering 9 Theoretical value as N305S:
C, 47,41; H, 5,82; N, 12.7
6 Actual measurements: C, 46,99; H, 5,85; N,
12.46 Example 9 N-(2,4-:)methoxy-6
-MethylA, 5-HlJmidinylcarbonyl)-Production of mono-ζphosphorus Using the methyl ester obtained in Example 5, the title compound was obtained in the same manner as in Example 8 (yield: 77%). %).

mp: 148-149°C (hexay-MeCN) IR
Bow R-"crrt-": 3420p 1720y
1655,1580@ass mHz: 297
(M10) NMRδ (DMSO): 9.70 (I
H,8,C0OH), 6.98(I H,d, J
=7FIz, NH), 4.8-4.5 (IH,
m.

cH), 4.01 (3H,s, OMe), 3
．． 99 (3H, s.

OMe), 2.50 (3H,s,Me), 2
．． 4-2.1 (IH.

m, CH), 1.02 (3H, d, J=7Hz
, Me), 0.98 (3H,a, J=7112
．． M19) [α), +14. Elemental analysis value Theoretical value as C13H engineering 9N305: C
,5'2.51;H,6,44; N, 14.1
3 actual measurements: C, 52,70; H, 6,58; N,
14.12 Example 1 ON-(2,4-dimethoxy-6
-Methyl-5-pyrimidinylcarbonyl) -Production of L-methioninol Lithium borohydride (2 mmot) was added to a solution of the methyl ester compound (1 mmot) obtained in Example 3 in tetrahydrofuran (20d), and the mixture was stirred for 5 hours. Excess lithium borohydride was decomposed by adding 10 HCt under water cooling, and extracted with cHc13 (30 txl x 3).

The extract was washed with water and then dried. After distilling off the solvent, the residue was purified by silica gel column chromatography (Ac0ICt) to obtain the title alcohol (yield: 84 cm).

ml): 103-105°C (yeOH-AcO!
! :t)IRvg'::'Scm-": 3420
．． 1650.1580mass m/z: 315
('M'')NMRδ(CDCts): 6-70
(IH, d, , T, = 8flz, NH) + 4.3
-3.6 (4H, m, CH, CH2 and OH),
3.99 (6H, 8, OMe!2), 2.59 (2
H, t, J=7H2ICH2)s2.11(3Ht's
Me)t C91 (2Htt+, T near H2, CHg
) [α]H: -25,4°Example 11 Production of N-(2,4-:)methoxy-6-methyl-5-midinylcarbonyl)-L-parinol Obtained in Example 5 The title compound was obtained in the same manner as in Example 10 using the methyl ester obtained (yield 411 ml): 148-149°C (hexane-MeOH)C
HCL3-1- Engineering RymaXcm, 3400.1650.158
0mass m/z: 283 (M+)NMRδ
(CDCl2): 6.75 (IH, d, J=8H
2,NH)t4.1-3.6 (4H,m, CH,0
M2 and on), 4.00(6Hy θt oyt
ex2) @ 2-47 (a H, 8t Me),
2-1-1.8 (IH, m, CH), 0.98 (3
H, d, J = 8Hz.

Me )t O,91(3H,d, J=8Hz, M
e) [α end 00H=+9. Elemental analysis value Theoretical value as C13H2□N304: C
, 55, 11; H, 7, 47; N, 14.83 Actual value: C, 55, 22; H, 7, 59; N, 1
4.49 Example 12 β-(2,4-dimethoxy-6
-Methyl-5-pyrimidinyl) Preparation of methyl acrylate 5-bromo-2,4-dimethoxy-6-methylpyrimidine (2mmot),)ethylamine (4mmot)
, methyl acrylate (20 mmO4), palladium acetate (3011 Ig), and triphenylphosphine (60
(2) was heated at 140° C. for 14 hours in a sealed tube.

From now on, excess methyl acrylate will be distilled off, and the residue will be subjected to silica gel column chromatography (CHCL3: Ac0Et=
9:1) to obtain the title compound (yield lO
%).

ml): 117-118°C (hexane-MeOH)
CHCL3-1.

Engineering Rvm, Xcm, 1705.1620.157
0mass m/z: 238 (M)NMRδ(
CDCts)' 7-79 (I H, d, J
==16Hz + =”CH).

6.65 (I H, d, J=16flz, =CH)
, 4.09 (3H, s.

OMe), 4.02 (3H,s, OMe),
3.82 (3H, s.

OMe), 2.57 (3H, s, Me) elemental analysis value C
Theoretical value as 11H14N204: C, 55, 45;
H, 5,92; N, 11.76 Actual value: C, 5
5,40; H, 5,93; N, 11.77 Example 13 β-(2,4-dimethoxy-6-methyl-5-
Example 12, except that 5-iodo-2,4-dimethoxy-6-methylpyrimidine was used and the heating time was changed to 7 hours.
The title compound was obtained in the same manner as (yield 91%).

Example 14 Production of β-(2,4-dimethoxy-6-methyl-5-pyrimidinyl)acrylic acid The methyl ester obtained in Example 12.13 (10 mrn
ol) with MeOH (20 ml) and INNaOH (
2 Dyttl ) mixture and stirred at room temperature for 2 hours.

After distilling off the residue, add 40 ml of water (40 ml) and CH (
J3 (50 l) was added and separated.

The aqueous layer was acidified with 10% HC1 and ACOFFft (1
00m/X3) Oil field and drying. After distilling off the solvent, the residue was recrystallized to obtain the title compound (yield 90%).

ml): 208.5-209°(:, (MecN)
Nujol -1゜Work Pνmax cm, 1705. i635ma
ss mHz: 224 (M”)NMRδ(DM
SO): 10.82 (IH, B, C00H)t 7
．． 88 (IH, d, , r=16Hz, =CH), 6.
68 (IH, d, J=16tlz, =CH), 4.
10 (3H,8,OMe), 4.03 (3H.

a t OMe) p 2-60 (3Hp 8z M
e) Elemental analysis value Theoretical value as Cl0H12N204:
C, 53,57; H, 5,39; N, 12.5
0 actual measurement value: C, 53,54; H, 5,39; N,
12.48 Example 15 Preparation of N-(β-(2,4-dimethoxy-6-methyl-5-pyrimidinyl)acryloyl]-L-alanine methyl ester β-(2,4-dimethoxy-6-methyl-5- The title compound was obtained in the same manner as in Example 2 using (pyrimidinyl)acrylic acid (10 mmoz) (yield: 6 mm).

CHCL3 −1°rRνmax cm, 3400.1730.1
660.1595NMRδ (CDC2a): 7.
69 (I H, d, J=16 Hz, =CH)+
6.68 (IH, (1,, T=16H2,=CH),
6.40 (IH.

d, I=8Hz, NH), 4.06 (3H,s
, oyte), 4.00 (3H#8tOMe)t
3.78 (3H,8,OMe), 2.54 (3Hv
s+ Me) + 1-48 (3Hp dg J=7
Hz lyte ) Example 16N-[β-(2,4-
Preparation of dimethoxy-6-methyl-5-pyrimidinyl)acryloyl]--methionine methyl ester Example 1 using L-methionine methyl ester hydrochloride
The title compound was obtained in the same manner as in 5 (yield: 59 yen).

mp: 152.5-153°C (Hexy-MeoH)
CHCL3-1゜engineering Rνmax crn, 3390, 1730.165
5.1590mass mlz: 36g (M+
) NMRδ (CDC25): 7.69 (IH, d
, J=16Hz, =CH).

6.42 (IH, d, :J=7Hz, NH), 6
', 73 (IH, d.

J=16■Zy=CH)15-0 4-8 (I H
, m, CH)t4.03 (3H,8,OMe),
3.99 (3Hpa as OMe)13.78
(3H,s, aye), 2.60 (2H,t,
J=7[z.

CH2) 12.51 (3H, B, Me), 2.
11 (2H, t, J==7HzHCH2) + 2
−10 (3Hp ”+ SMe) [α]ぢeOH,−
36, Go elemental analysis value Theoretical value as C16H23N305E':
C, 52,02; H, 6,28; N, 11.3
8 actual measurements: C, 52,03; H, 6,08; N,
11.18 Example 17 Preparation of N-(β-(2,4-:)methoxy-6-methyl-5-pyrimidinyl)acryloyl]-L-valine methyl ester Example 15 using L-valine methyl ester hydrochloride The title compound was obtained in the same manner as (yield 69%).

mp: 158-160°C (Heki'Fj7-MeOH
) CHCL3-z Engineering Rνmax crn: 3450 + 173
0t 1670.1615mass mHz: 3
37 (M+)NMRδ (CDC43): 7.73
(IH, d, J=16Hz, =CH).

6.73 (IH, eL, J=16Hz, =cH),
6.59 (IH.

de J = 8 Hz + NH) p 4-9-4
-6 (I H+ m y CH) s4.07 (3H
, s, OMe), 4.00 (3H, s, OMe).

3.76 (3H, s, OMe), 2.54 (3H, s,
Me).

2.4-2.2 (IH, m, CH)s O,98(
6H, d, , r=6.5Hzm Me2) [α]Yu”H: + 5.1' Elemental analysis value Theoretical value as C16H23N3015:
C, 56,96; H, 6,87: N, 12.46
Actual value: C, 57,13; H, 6,88; N,
12.46 Example 18 Preparation of N-(β-(2,4-dimethoxy-6-methyl-5-pyrimidinyl)acryloyl)-D-methionine methyl ester Example 1 using D-methionine methyl ester hydrochloride
The title compound was obtained in the same manner as in Example 5 (yield 59).
) CHCL3-z ENGRvrnaxcm: 3400.1735.17
60.1590mass mHz: 369 (M+
) NMRδ(CDCZ3)' 7-69 (IH
-d+ J=16 fiz,=CH) e6.69(
IH, d, J=16Hz, =CH), 6.45(IH
.

d, J=7tlz, NH), 5.0-4.8 (
I H, m, CH).

4.04 (3H,s, oMe), 3.98 (3H,s
,oMe).

3.77 (3H,s, oMe), 2.56 (
2H,t, J=7H2゜ca2), 2.52 (3
H, B, Me), 2.14 (2H, t, J=
7 H2+ CH2) t 2.10 (3Hr'
+ SMe ) [αchi00H: + 32.6' Elemental analysis value Theoretical value as C16H23N305S:
C, 52,02; H, 6,28; N, 11.38
Actual value: C, 52°55; H, 6,31; N,
11.40 Example 19 Preparation of N-(:β-(2,4-:)methoxy-6-methyl-5-pyrimidinyl)acryloyl]-D-methionine-S- oxide methyl ester D- obtained in Example 18 Methionine methyl ester form 18
M+30H-CH of 4.7 my (0.5 mmot)
2C22 solution was cooled to 0°C.
3mli, 0.525mmot)/1tttl
Add dropwise to H2O with stirring and stir at 0°C for 5 hours.

After the reaction was completed, the reaction mixture was filtered and the solid was removed with CH2Cl.
After washing with 2 and combining with r solution, MeOH in the solution was distilled off under reduced pressure, extracted with CH2Cl2, dried with Na2SO, and the solvent was distilled off. 188.3 my of oily product (98% yield) was obtained.

NMR (CDC43) δ(T)pm): 2.33
(m, 2H), 2.46(8,3H), 2.5
6 (+111,3H), 2.69-3.03 (m.

2H), 3.68 (8,3H), 3.90 (B
, 3H), 3.95(θl 3H), 4.73(
m, IH), 6.62.7.49 (AB.

2H, J=15.2Hz), 7.35 (br, I
H) MEI mHz: 385 (M”)
Nuzi: I-le) (cm-'): 3425,325
0,1740,1655゜1620,1015゛Example 2 Preparation of ON-[β-(2,4-dimethoxy-6-methyl-5-pyrimidinyl)acryloyl]-D-valine methyl ester D-noζ phosphorus methyl ester hydrochloric acid Example 15 using salt
The title compound was obtained in the same manner as (yield).

mp: 154-156°C (hexane-MeOH)CH
CL3-1゜engineering RVmaXcln, 3445.1725.1665
．． 1610mass mHz: 337 (M”)
NMRδ (CDC13): 7.69 (IH, d,
, T=16Hz, =CH).

6.80 (IH, d, J=16Hz, =CH), 6.6
2 (IH.

d, J = 8Hz, NH), 4.8-4.6 (
I H, m, CH).

4.10 (3H,s, OMe), 4.02 (3H,s,
OMe).

3.75 (3H, s, oMe), 2.62 (3H, s,
Me).

2.4-2.2 (IH, m, CH), 0.99 (6
H, d,, T=7Hz I Me2 ) [α) MeOH, z, a.

Elemental analysis value Theoretical value as C16H23N305: C
, 56,96; H, 6,87; N, 12.46 Actual value: C, 56,74; H, 6,89: N, 1
2.55 Example 21N-(β-(2,4-dimethoxy-
Production of 6-methyl-5-pyrimidinyl)acryloyl]-L-methionine The title compound was obtained in the same manner as in Example 8 using the L-methionine methyl ester obtained in Example 16 (yield: 61 cm).

In1): 185-186°C (hexane-MeOH
) 工R'藤;jz'-/'Crn-": 3450.
1710.1640.1620.1560mass m
Hz: 355 (M)NMRδ (DMSO)
: 7.64 (I H, eL, J=15, =C
H).

7.50 (IH, d, J=3Hz, NH), 6.81 (
LH, d.

J=15FIz, =CH), 4.9-4.6 (I
H, m, CH).

4.05 (3H,s,oMe), 3.92 (3H
,s,oMe).

2.58 (2H, t, J=7H2, CH2), 2.5
3 (3H,8゜Me)t 2.18 (2H,t,
J=7112. CH2), 2.09(3H,s,
SMe) Example 22 Production of N-(β-(2,4-:)methoxy-6-methyl-5-pyrimidinyl)acryloyl)-L-methioninol Using the L-methionine methyl ester obtained in Example 16, The title compound was obtained in the same manner as in Example 10 (yield: 4
4%).

mp: 142-143℃ (Hexane-MeOH) Engineering R
vg': cm-': 3460.1660.16
05.1580mass mHz: 341 (M”
) NMRδ (CDCl2) = 7.66 (IHld, J
=16H2, =CH).

6.64(IH, d, , T=16H2,=C),
6.41 (IH.

d, J=8Hz, NH), 4.2-3.6 (4
H, m, CH, CH2 and Q: OH), 4.02(
3H,s, OMe), 3.98 (3H.

θr OMe ), 2-60 (2H, t, J
=7 Hz l CH2) + 2-52(3H,s,
Me), 2. tl (3H, s, sMe), t, s6 (2
H, t, J=7H2,CH2) [α]:e0H+-30.8' Example 23 N-[β-(2,4-dimethoxy-6-
Production of methyl-5-pyrimidinyl)acryloyl]-L-parinol Using the L-valine methyl ester obtained in Example 17,
The title compound was obtained in the same manner as in Example 10 (yield: 56).

mp: 158-159℃ (h*fn-acomt)
Engineering RV'i:i"crn-': 3400.1665
．． 1610.1580mass m/z: 309
(M+)NMRδ (CDC23): 7.68 (L
H, d, J=1611z, =CH).

6.69 (IH, d, , T=16Hz, =CH), 6.
32 (IH.

d, J=8Hz, NH), 4.02 (3H, a
, OMe), 3.99 (3H,8,0M13)
t 4.0-2-6 (3)! , m, ca and CH
2), 3.02 (IH, brs, OH), 2.5
2 (3H,B.

Me), 1.99 (6H, d, J=7Hz,
Me2 ) [α] Di00H: -12,4° Example 24 Production of N-(β-(2,4-dimethoxy-6-methyl-5-pyrimidinyl)acryloyl)-D-methioninol D obtained in Example 18 - Using the methionine methyl ester, the title compound was obtained in the same manner as in Example 10 (yield: 5
9chi).

mT): 148-149℃ (hex y-acomt
) IR si: vessel '3m-': 3450.1650.1
605.1575mass m/z: 341 (M
+)NMRδ(CDCZs)” 7-69 (I
H, d, J = 16Hz + =CH).

6.67 (I L d, , T=16Hz, =CH)
, 6.33 (IH.

d, J=8Hz, CH), 4.2-3.5 (4
H, m, CH, CH2 and OH>s 4.04 (3
H,8,oMe), 4.00 (3H.

8, OMe), 2.60 (2H, t, J near 112. CH2), 2.54 (3H, B, Me
), 2.12(3H,B,SMe)s 1a90
(2H, t, J=7 ■zp CHa ) [α] ぢ”
H: +34.0° Elemental analysis value C15H23N3 o, S as theoretical value:
C, 52,77; H, 6,79; N, 12.3
1 actual measurement value: C, 52,40; H, 6,75; N,
12.35 Example 5 Production of β-(2,4-'7ethoxy-6-methyl-5-pyrimidinyl)acrylic acid ethyl ester 5-iodo-2,4-jethoxy-6- obtained in Reference Example 6
Example 1 using methylpyrimicin and ethyl acrylate
The title compound was obtained in the same manner as in 3.

mpnia 5-76°C (petroleum ether-methanol) engineering R4 pig t3cm-': 1700.1630+15
75mass m/z: 280 (M+)NMRδ
(CDCl2) near, 76 (IH, d,, T=16) 1
2. =CH).

6.66 (I H, d, J = 16 Hz + =
CH) ,4.6 4.0(6H,m, CH2X3
), 2.54 (3H+ '+Me)+C6-1
,2(3H,m, MeX3) Elemental analysis value Theoretical value as C1 H2ON2O4: C
, 59,98; H, 7, 19: N, 9.99 Actual value: C, 59, 88; H, 7, 22; N, 10
．． 00 Example is the production of β-(2,4-:)ethoxy-6-methyl-5-pyrimidinyl)acrylic acid.The ethyl ester obtained in Example 5 was used, and the reaction time was 1.
The title compound was obtained in the same manner as in Example 14 (
Yield: 86 cm).

mp: 132.5-133° (:, (MeCIJ) Nujol -1°IRvmaXcm, 1690.1620mass
m/z: 252 (M+)NMRδ (DMSO)
: 10.60 (lH,C0OH), 7.84
(IH.

d, , T=16IIZ, =CH), 6.66 (
I H,d, ,T=16■Z.

=cH), 4.7-4.3 (4H,m, CH2X
2) t 2.54 (3HM 8t Me), 2.6
-2.3 (6H, m, MeX2) Example 27N-(β
-(2,4-:)ethoxy-6-methyl-5-pyrimidinyl)acrylic acid) -L-methionine methyl ester production example using the acrylic acid body obtained in Example 3. The title compound was obtained (yield 74%).

mp: 136-137°C (petroleum ether-methanol) cHo"'-': 3450.1730
．． 1660.1605■R″maxcrrL mass m/z: 369 (M)NMRδ
(CDCJ3): 7.70 (I H, d, J
=16H2, =CH).

6.65 (I H, d, J=:16Hz,=:CH
), 6.63 (IH.

d, J, = 8Hz, NH), 5.0-4.7 (IH,
m, CF().

4.5:3 (2H, t, J=7Hz, CH2), 4
．． 38 (2H, t.

J = 7 fiz -CH2) * 3-76 (3H
, S-OMe) #2-56 (2H,t, J=
7Hz, CH2), 2.49 (3H,s, Me
).

2.19 (2H, t, J=7Hz, CH2), 2
．． 09 (3H, s.

SMe), 1.41 (3H,t, J=7[1z
, Me ), 1.35 (3H,t, J=7flz
, Me) [α3\jeOH, -31,5' Elemental analysis value C engineering. Theoretical value as N27N305S:
C, 54,40; H, 6,85; N, 10.57
Actual measurements: C, 54, 20; E(, 6, 81; N,
10.51 Example 28 Preparation of N-(β-('2,4-jethoxy-6-methyl-5-pyrimidinyl)acryloyl)-D-methionine methyl ester Proceed in the same manner as in each Example using D-methionine methyl ester hydrochloride. The title compound was obtained (yield: 88%).

mp: 133-134°C (petroleum ether-methanol) IRy0H0t3tMr”: 3450.1735
．． 1655.1610ax mass mHz: 369 (M”)NMRδ(
CDCl2): 7.74 (I H, d, J=
16H7,=CH).

6.69 (1)1. d, J=16Hz, =CH
)t 6°60 (I H.

d, J=8Hz, NH), 5.0-4.7 (I
H, m, CH).

4.51 (2H, t, J=7 Hz, CH2)
p 4.40 (2H, t+1=71'lZI ”N2
)y 3-78 (3H,s, OMe),
2-58 (2H, t, :J=7Fly,, CH2)
, 2.50 (3H,s, Me).

2.20 (2Ht ty J=71[IZ r CH
a) *2-10 (3HT8*SMe),
1.43 (3H,t, J=71[1z, Me
), 1.36 (3H, t, J=7Hz, yte
) eOH [α]: + 32.9° Elemental analysis value Theoretical value as C□eHzvN306s:
C, 54,40; H, 6,85; N, 10.57
Actual measurements: C, 54,22; H, 6,91; N,
10.70 Example 4 β-(2,4-dipropoxy-6
-Production of methyl-5-pyrimidinyl) acrylic acid propyl ester 5-iodo-2,4-dipropoxy-6 obtained in Reference Example 7
The title compound was obtained in the same manner as in Example 13 using -methylpyrimidine and propyl acrylate.

bp: 140-145℃/4 mmHgCHCl3
-1.

IRνmax crn, 1700, 1625.157
0mass mHz: 322 (M+)NMRδ(
CDC4s): 7.84 (IH, d,, T=161
12. =CH().

6-67 (I H9d, J = 16tlZ, 2CH
) + 4-6 4-0 (6H+ m+ CH2X3
)+2.58 (3H,s,Me), 2.1-1
．． 6 (6H, m, CH2X3), 1.3-0.
8 (9H, m.

Mexs) Elemental analysis value C□ヮTheoretical value as H26N204: C
,63,33; H,8,13; ! 11.8.69 Actual measurement: C, 62,95; H, 8,18; =, (
1, os Example addition β-(2,4-dipropoxy-6-
Preparation of methyl-5-pyrimidinyl)acrylic acid Using the ester obtained in Example 4, the title compound was obtained in the same manner as in Example 4 (yield: 85 cm).

mp: 133.5-140℃ (yiecN) Nujol -1゜engineering RvmaXcm, 1790.1620mass
mHz: 280 (M+)NMRδ (DMSO
): 10.49 (I H, 8, C0OH)) 7
．． 86 (IH, d, , T = 16Hz, =CH), 6.6
7(IH,d,,T=16H7,=CH), 4.41
(2H, t, J= 6.5H1, CH2).

4.28 (2H, t, J = 6.5Hz, CH2), 2
．． 54 (3H.

l1ls Me ) 12.1-1.6 (4H, m,
CH2X2 ), 1.04 (3H, t, J=6.5H
z, Me)t 1.01 (3H, t, y=6.5■
Z, Me) Elemental analysis value C14N20 N2 o, theoretical value:
C, 59,98; H, 7,19; N, 9.99
Actual value: C, 59,49; H, 6,85; N,
10.37 Example 31 Production of N-(β-(2,4-dipropoxy-6-methyl-5-pyrimidinyl)acryloyl]-L-methionine methyl ester Using the acrylic acid form obtained in Example I, Example 3 The title compound was obtained in the same manner as (yield: 65).

mpnia 4-75°C (oil ether-) evening/-le) I
Rv"HC43cm-': 3400.1735.1
660.1620ax mass mlz + 425 (M)NMRδ(
CDC4'): 7.72 (I H, d, J=1
5FIz, =CH).

6.70 (IH, cl, , T=15Hz, =CH),
6.58 (IH.

d, , T=8Hz, NH), s, o-4,7(I
H, m, cH).

4.43 (2H, t, J=6.5117. CH2
), 4.28 (2H.

t, J=6.511z, CH2) 13.77 (3
Hz as OMe) I2-57 (24tr J”
7Hz #”N2) I 2-52 (3H+
asMθ), 2.21 (2H,t, J =7Hz
, CH2), 2.11(3H,s, sMe),
2.1-1.7 (4H,m, CH,I2)sl
,14 (6H,t, ,T=6.5h, MeX2
) [α) MeOH, 30.7° Elemental analysis value C20H31N3 Theoretical value as o5S:
C, 56,46; H, 7,34; N, 9.88
Actual measurement: C, 56,07; H, 7°35; N,
9.95 Example 32N-1: Preparation of β-(2,4-:)propoxy-6-methyl-5-pyrimidinyl)acryloyl)-D-methionine methyl ester Example 31 using D-methionine methyl ester hydrochloride
The title compound was obtained in the same manner as (yield: 68 cm).

mP: 73-74°C (petroleum ether-methanol), CHC cm-”: 3400.1730.
1665.1615ax mass mlz: 425 (M+)NMRδ(C
DCl2): 6.69 (IH, (1, J=15Hz, =
CH).

6.71 (IH, d, J=15Hz, =CH),
6.60 (IH.

d, J=811z, NH), 5.0-4.7(1, m
, CH).

4.41 (2H, t, J==7tlz, CH2)
, 4.26 (2H, t.

, T=711Z, CH,), 3.75 (3H,s
, oMe), 2-56 (2Ht t, J=7Hz
, CHz), 2.52 (3H,a,Me).

2-20 (2H-t, J = 7 Hz -CH2)
-2-10 (3J 8rsMe), 2.1-1.7
(4H, In, CH2X2), 1.13 (6H+t
s J= 6.5tlz, MeX2) [α] ■e
OIt, +31. Elemental analysis value C20N31 N3 Theoretical value as o5S: C, 56,46; H, 7,34i N, 9.8
8 actual measurements: C, 55,97i H, 7,33i N,
10.13 Example β-(2,4-dimethoxy-5
-pyrimidinyl) Production of methyl acrylate Using 5-iodo-2,4-dimethoxypyrimidine obtained in Reference Example 8, the title compound was obtained in the same manner as in Example 13 (yield: 87%).

ml): 107-109°C (Hex-MeOH
) CHCL3-1.

Engineering RVmaz cm, 1710.1635.1
590mass mlz: 224 (M”) NMR
δ(CDC15): 8.39 (I H,s, A
rH), 7.62 (IH, d, J = 16Hz,
=CH), 6.59(IH,d, J=16Hz,
=CH), 4.10 (3H,e, OMe),
4.03 (3H, s, OMe), 3.81 (3H,
s, OMe) Examples β-(2,4-dimethoxy-5
-pyrimidinyl) Production of methyl acrylate Using 5-bromo-2,4-dimethoxypyrimidine obtained in Reference Example 10, the title compound was obtained in the same manner as in Example 12 (yield: 39 cm).

Example A Production of β-(2,4-dimethoxy-5-pyrimidinyl)acrylic acid Example O: Using acrylic acid methyl ester obtained in A,
The title compound was obtained in the same manner as in Example 26 (yield: 84a
Ib).

ml): 198-199°(: (MeCN-M
eOH) Nujol -1° Engineering Rνmax cyt, 1690. 1615
mass mlz: 210 (M”)NMRδ(D
MSO) Near, 95 (IH, s, ArH), 7.1
0(IN2d-J=15flzl=CH), 6
-16 (I H, d, J = 15Hz, =CH
), 3.82 (3H,8,aMe), 3.75
(3H,8,OMe) Elemental analysis value Theoretical value as C9HION204: C,
51,42i H, 4,80i N, 13.33 Actual value: C, 51,29i H, 4,80i N, 13
．． 31 Example 36 N-(β-2,4-dimethoxy-
Production Example of 5-pyrimidinyl)acryloyl]-L-methionine methyl ester Using the acrylic acid obtained in the Example, the title compound was obtained in the same manner as in Example 3 (yield: 61%).

mp: 101 102°C (hexay-MeOH)
CHCL3-1.

Engineering RVmaz cm, 3450. 1735.
1665. 1620mass m/z: 355
('') NMRδ (CDCta): 8.31 (
IH, s, ArH), 7.49 (LH, d, J=16
Hz, =CH), 6.60(IH, (L,, T=16H
z, =CH), 6.4'0 (I H, d, J
= 9H2, NH).

5.0-4.7 (LH, m, CH), 4.05 (3H,
El.

OMe ), 3.98 (3H,s, OMe ), 2.
7-2.4 (2H.

m+ CH2) + 2.3 2-0 (2” e m
+ CH2) #2-06 (3H, s, SMe) Elemental analysis value C engineering. Theoretical value as H2□N30°S:
C, 50,70; H, 5,96i N, 11.83
Actual measurements: C, 50,63i H, 6,12i N,
11.65 Example 37 Preparation of N-[β-(2,4-dimethoxy-5-pyrimidinyl)acryloyl]-D-methionine methyl ester Using D-methionine methyl ester hydrochloride, the same procedure as in Example part was carried out. The title compound was obtained (yield: 46 cm).

mp: 100-103°C (hexane-MeOH)C
HCL3-1.

IRI/maXcm, 3400.1735.16
65.1625mass m/z: 355 (M”
) NMRδ (CDcts): 8.35 (IH,
a, ArH), 7.51 (I H, d, J=16Hz
, =CH), 6.62 (I H,d, J=161
1z, =CH)t 6.41 (I H,d, J=
811z, NH).

5.0-4.7 (IH, m, CH), 4.02 (3
H,s,OMe).

3.97 (3H,s, oMe), 2.7-2.4 (2
H, m.

CHa), 2.3-2.0 (2H,m, CH2
)t 2.05 (3H.

s, SMe) Elemental analysis value Theoretical value as C1elH21N306B:
C, 50,70; H, 5,96i N, 11.8
3 actual measurements: C, 50,62; H, 6,01; N,
11.74 Example A Production of methyl β-(4-methoxy-6-methyl-5-pyrimidinyl)acrylate Using 5-iodo-4-methoxy-6-methylpyrimidine obtained in Example 13, the heating time was The title compound was obtained in the same manner as in Example 12 except that the time was changed to 6 hours (yield: 90%).

mp: 78-80”C (MeOH) CHCL3-1.

Engineering RνmaX cm, 1710. 1560ma
ss m/z: 208 (M”) NMRδ (CDC
13): 8.55 (IH, Ill, ArH),
7.74 (IH, d, J-16Hz, =CH), 6.
70 (IH, d, J=16Hz, =CH), 4.0
6 (3H,8,OMe), 3.81 (3H,s,
OMe), 2.60 (3H, s, Me) elemental analysis value
Theoretical value as C10HI3 N2 o3:, c, 5
7.68 i H, 5,81; N, 13.46 Actual value: C, 57,49i H, 5,77i N, 13
．． 49 Example 39 Production of β-(4-methoxy-6-methyl-5-pyrimidinyl)acrylic acid The title compound was obtained in the same manner as in Example using the acrylic acid methyl ester obtained in the Example section ( Yield: 86 cm).

ml): 199-200°C (MeCN-MeO
H) Nuryol-l.

Engineering Rνm6z cm, 1700. 1625
mass m/z: 194 (M”)NMRδ(D
M80): 8.51 (IH, 8, ArH), 7.7
0 (IH.

d, J=16Hz, =, CH), 6.68 (I
H,d, ,T=16flz.

=CH), 4. Q4 (3H, 8, OMe), 2.5
8(3H, 8°Me) Example 4ON-(β-(4-methoxy-6-methyl-5
-pyrimidinyl)acryloyl]-L-methionine methyl ester Using the acrylic acid compound obtained in Example 39, the title compound was obtained in the same manner as in Example 3 (yield: 46 cm).

II): 120-121°C (petroleum ether-methanol) CHCL3-1 Engineering RVmaz cm: 3400.1735.1
670.1620mass m/z: 3Q7 (M+
) NMRδ (CDCAs): 8.40 (IH
, 8, ArH), 7.58 (la.

d, J=1611z, =CH), 6.68 (I
H, (1, J = 16Hz.

=CH), 6.40 (IH,d, ,T =8Hz
, NH), 5.0-4.5 (IH, m, CB)
, 3.99 (3)1.8. OMe) 13.72
(3H,8,OMe), 2.8-2.5 (2H,
m.

CH2), 2.55 (3H,8,Me), 2.
4-2.0 (2H.

m, CH2), 2.06 (3H,8,Me) Example 41N-[:β-(4-methoxy6-methyl-5
-pyrimidinyl) Acryloyl: Production of J-D-methionine methyl ester Using D-methionine methyl ester hydrochloride, Example 4
The title compound was obtained in the same manner as in Example 0 (yield 44%).

IQ: 120-121°C (petroleum ether-methanol): 3400.173
5.1670.1625mass m/z: 3Q7
(M”)NMRδ(CDCzs): 8.44(I
H,8,ArH), 7.59(IH,d, J=16
Hz, =CH), 6.71 (IH,d, J=16
11z, =CH), 6.41 (I H, d, J
=8Hz, NH).

4.9-4.6 (LH, m, CH), 4.01
(3H,s,OMe).

3.75 (3H,s, OMe), 2.8-2.
5 (2H, m.

CH2), 2.56 (3H, a, Me), 2.4-
2.0 (2H.

m+ CH2) + 2.05 (3H+ ' v M
e) Example 42 β-(4-methoxy-6-methyl-2-methylthio-5-pyrimidinyl) Production of methyl acrylate 5-iodo-4-methoxy-6-methyl-2-methylthio obtained in Reference Example 14 The title compound was obtained in the same manner as in Example 13 using pyrimidine (yield: 95 cm).

mp: 103-105°C (hexane) CHCL3-
1.

IRνmaz cm, 1700.162ONMR
δ (CDC): 7.47 (I H, d, , T
=16flZ, =CH).

6.44 (IH, d, J=16Hz, =CH),
3.93 (3H.

8, OMe), 3.67 (3H, e, 0118),
2.47 (3H.

'+'')+2.45 (3H, a, SMe)
Example 43 β-(4-methoxy-6-methyl-2-
(Methylthio-5-pyrimidinyl) Using the acrylic acid methyl ester obtained in Production Example 42 of acrylic acid,
The title compound was obtained in the same manner as in Example (Yield: 82ml): 205-205.5°C (MeCN) Nujol-l Engineering Rvmaz cm: 1695. 1615
ma88 m/z: 240 (M+)NMRδ(DM
SO): 7.73 (IH, (1, J=16) 1z, =
CH).

6.61 (I H, d, , T = 16H2, 2CH
), 4.03 (3H9S.

OMe), 2.55 (6H,s, SMe and M
e) Elemental analysis value Theoretical value as CION12 N203 S, C, 50,00; H, 5,04i N,
11.66 Actual value: C, 49,81; H, 5,00
i N, 11.65 Example 44 Production of N-[β-(4-methoxy-6-methyl-2-methylthio-5-pyrimidinyl)acryloyl]-L-methionine methyl ester Acrylic acid compound obtained in Example 43 The title compound was obtained in the same manner as in Example 3 (yield: 60%).

mI): 121-122°C (petroleum ether-methanol) IRv dedication "cm-': 3350.173
°0.1660.1615mass m/z: 3g
5 (M”)NMRδ(CDCM): 7.60 (
L H, (1, J=15Hz, =CH).

6.84 (lH, d, , T = f3Hz, NH)
, 6.72 (IH, (1°J=15tlz, =C
H), 4.9-4.6 (I H, m, CH).

3.99 (3H,s, OMe), 3.74 (3J8.
oMe).

2.7 2.4 (2H, m, CHz), 2.52 (3H
, 8, Me).

2.47 (3H,8,Me), 2.3-1.9
(2HI m, CH2).

2.08 (3H, s, Me) Elemental analysis value Theoretical value as C16H23N304S2:
C, 49,86; H, 6,02i N, 10.9
0 actual measurements: C, 49,85i H, 5,91i N,
10.94 Example 45N-[β-(4-methoxy-6
-Methyl-2-methylthio-5-pyrimidinyl)acryloyl]-D-methionine methyl ester Production Example 4 Using D-methionine methyl ester hydrochloride
The title compound was obtained in the same manner as in Example 4 (yield: 76 cm).

mp: 121-122°C (Hexane-MeOH)C
HCL, -1.

Engineering RVrnaz cm, 3350.1730.1
660.1610mass m/z: 385 (M
”) NMRδ (CDCts) Near, 72 (IH, d, J
=1511z, =CH).

6.84 (IH, (1, J=8+1z, Nu),
6.75 (I H, d.

J=15tlz, =CH), 4.9-4.6 (I
H, m, CH).

4.02 (3H, a, OMe), 3.78 (3H, s
, OMe).

2.6 2.4 (2H, m, CH2), 2.58 (3
H, s, Me).

2.49 (3H, 8, Me), 2.3 2.0 (2H,
m, CH2).

2.11 (3H, s, Me) Elemental analysis value C engineering. Theoretical value as H2S N30482: C, 49,86; H, 6,02i N, 10.
90 actual measurement value: C, 49,65, H, 6,01i N,
10.96 Example 46 β-(4-methoxy-5-
Production of methyl pyrimidinyl acrylate The title compound was obtained in the same manner as in Example 12, except that 1 5-bromo-4-methoxypyrimidine obtained in Reference Example 16 was added and the heating time was 16 hours. ).

Ip: 92-98°C (hexane) CHC Mu-l.

IRVmaz cm, 1710.1640.1
58ONMRδ (CDCLs): 8.85 (L
H,s, ArH), 3.6g (IH,s, ArH
), 7.73 (IH, d, J=16Hz, =CH).

6.80 (I H,d, , T =16Hz, =C
H), 4.16 (3H.

a, OMe ), 3.86 (3H,s, OMe
) Example 47 Production of methyl β-(2-methoxy-5-pyrimidinyl)acrylate The title compound was obtained in the same manner as in Example 12 using 5-bromo-2-methoxypyrimidine obtained in Reference Example 15 ( yield 51%).

m'9: 132-134°C (MeOH)CHCL
3-1.

IRVmaz cm -1710,1640,15
95NMRδ (CDCl2): 8.79 (2H,
s, ArH), 7.67 (I H, d, J = 1
7Hz, -〇H) + 6.53 (I H+ d
*J=17Hz, =CH), 4.09 (3H,s,
OMe), 3.85 (3H, s, OMe) Example 48 Production of methyl β-(2-methoxy-5-pyrimidinyl) acrylate Implemented using 5-iodo-2-methoxypyrimidine obtained in Reference Example 11. The title compound was obtained in the same manner as in the following examples (yield: 84 cm).

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, n is an integer of 0 or 1, R^1 represents a hydrogen atom or a methyl group, and R^2 represents hydrogen Atom, C_1_~
_3-Alkoxy group or methylthio group, R^3
represents a hydrogen atom or a C_1_~_3-alkoxy group, both R^2 and R^3 are not hydrogen atoms, and R^4 is a hydroxyl group or C_1_~
_ Indicates an amino acid residue that is a 3-alkoxy group or is bonded to CO in the formula with an amino group, and the terminal carboxyl group in this amino acid residue may be esterified, and the carboxyl group may be converted to a hydroxymethyl group). 2) The pyrimidine derivative according to claim 1, wherein the amino acid residue is selected from the group consisting of methionine residue, alanine residue, valine residue, and methionine-S-oxide residue. 3) The pyrimidine derivative according to claim 1 or 2, wherein when the terminal carboxyl group in the amino acid residue is esterified, the ester is a methyl ester. 4) The pyrimidine derivative according to claim 1, wherein when the carboxyl group in the amino acid residue is converted to a hydroxymethyl group, it is methioninol or valinol.