JPH0386867A - Nitrogen-containing heterocyclic compound - Google Patents

Abstract

NEW MATERIAL:The nitrogen-containing heterocyclic compound of formula I or formula II (R<1> is B, 1-18C alkyl, aryl, aralkyl or heterocyclic group; R<2> is H or 1-6C alkyl; (n) is 0-3; when (n) is 1 and R<1> is H or methyl, R<2> is 1-6C alkyl) or its salt. EXAMPLE:2-Ethyl-1,4,5,6-tetrahydro-4-pyrimidinecarboxylic acid. USE:Useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals or organic electronic material such as liquid crystal. PREPARATION:The compound of formula I or formula II can be produced by reacting a compound of formula III (X is CidenticalN, group of formula IV or formula V; R<9> and R<11> are 1-6C alkyl; R<10> and R<12> are H or 1-8C alkyl) with a compound of formula VI (R<16> is H or 1-6C alkyl) (e.g. 2,3-diaminopropionic acid) in a solvent such as water or methanol.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel nitrogen-containing heterocyclic compound useful as a synthetic intermediate for medicines, agricultural chemicals, organic electronic materials such as liquid crystals, and an optically active form of the compound.

<Prior art> Ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid or 3.4°5.6-
It has been reported by TRU
PBR) [European Journal of Biochemistry (Eur, J.

Bioches, ), 149.135 (1985) Ko or Takano [Japanese Society for Fermentation Technology Conference Program, PI93
(1988)], but the synthesis method has not yet been reported. On the other hand, 1°4.5.6
-Tetrahydro-4-pyrimidinecarboxylic acid is synthesized by reacting formamidine acetate and DL-2,4-diaminobutyric acid in dilute ethanol, as described in BROWN [Journal of Chemical Society] (J.

Chem, Soc, ), 19 B 2.4039.

However, the above-mentioned document does not include the compound of the present invention. Furthermore, knowledge regarding the synthesis of optically active substances is still unknown.

<Problems to be Solved by the Invention> The present invention provides a novel nitrogen-containing heterocyclic compound that is closely related to ectoine and is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, or organic electronic materials such as liquid crystals, and an optically active form of the compound. It is to provide.

<Means for Solving the Problems> The present invention provides - formula I [1-] (Ib) (wherein R
' represents hydrogen, a C8-, 8-alkyl group, aryl group, aralkyl group, or heterocyclic group, R11 polyhydrogen or 01-. represents an alkyl group, and n represents an integer of 0 to 3. When n is 1 and R1 is hydrogen or methyl, R' represents an alkyl group of 01-8. ) or a salt thereof. - The compound of formula I has a resonance structure and can be represented by the structural formula Ia or Ib. In this specification, the structural formula of 1a will be used hereinafter for convenience, but the structure of 1b will of course also be included.

01-. represented by R1 in compound I. The alkyl group may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ea-butyl, tert-butyl, pentyl,
Mention may be made of isopentyl, neopentyl hexyl, octyl, decyl, dodecyl, octadecyl, which may optionally be substituted with halogen or hydroxy (eg halomethyl, hydroxymethyl). Also,
Examples of the aryl group include C, ~, aryl groups, such as phenyl, naphthyl, biphenyl, which optionally have %C1-6 alkyl groups (e.g., methyl, ethyl, propyl, butyl, hexyl), C5- .

alkoxy groups (e.g., methoxy, ethoxy, propoxy, propargyloxy), halogen, hydroxy, mercapto, cyano, nitro, NR'R' (R3 and R4
may be the same or different and may be substituted with one or more groups (representing hydrogen or a C+-6 alkyl group). Examples of the aralkyl group include those in which the aryl portion is as described above, and those in which the alkyl portion is C3-6.

The heterocyclic group represented by R1 is a 5- or 6-membered saturated or unsaturated heterocyclic group having one or two heteroatoms selected from nitrogen, oxygen, and sulfur, such as pyrrole, furan, thiophene, Examples include heterocyclic groups selected from pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyran, pyrimidine, pyridazine, pyrazine, and hydrogen adducts thereof; Alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl), alkoxy groups of 01-6 (e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy), alkylthio groups of CI-8 (
Examples, methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio), 06~. aryl groups (e.g., phenyl, tolyl, xylyl, trimethylphenyl), hydroxy, nitro, cyano, mercapto,
Halogen (e.g. chlorine, bromine, iodine), GOOR'CR
” is water 1/U ItC, -@(D? alkyl group, NR@
R' (R@ and R7 are the same or different and each represents hydrogen or an alkyl group with CI-=6) may be substituted with one or more groups.

The C3-6 alkyl group represented by R1 may be either linear or branched, such as methyl,
Examples include ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and hexyl.

n is preferably 0-2.

Compound I has a basic nitrogen atom in its ring and forms salts with inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, methanesulfonic acid, and p-toluenesulfonic acid. Further, in Compound I, when R'' is hydrogen, it forms salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, ammonium salts, etc. These are also included in the present invention.

Further, Compound I has an asymmetric center at the 4-position of the ring and can exist as an optically active form. The present invention encompasses any optically active substance, including resolved optically active substances and mixtures thereof.

The compound (■) of the present invention has the formula ■R@X [■co (wherein, R8 represents the same meaning as R1 above, X represents CmiN1R''/, and rtll and R1 each represent a C3-8 alkyl group. and R'', R1'', R'', R'4 and RIS each represent S'', hydrogen or an alkyl group of C3~. )ncHcOOR"Ht [I[[] (wherein, R" represents hydrogen or an alkyl group of CI~, and n represents the same meaning as above) or a salt thereof is directly reacted or in a solvent. Alternatively, it can be produced by reacting in a solvent in the presence of a base.

Above 08~. Examples of the alkyl group include straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl.

Compounds represented by the formula ■ include nitriles such as propionitrile, butyronitrile, hexanenitrile, nonadecanenitrile, methylbrobionimidate,
Examples include imidic acid esters such as ethyl probionimidate, methyl hexaneamidine, methyl nonadecanamidate, and methyl pyridinecarboximidate, or amidines such as propionamidine, hexaneamidine, and nonadecanamidine, or salts thereof. . The above imidate esters and amidines can be easily derived from nitrile compounds, orthoester compounds, amide compounds, or imidate esters by known methods, and the derived compounds can also be used in reactions without isolation. can.

Compounds represented by general 2) include amino acids 1m such as 2.3-diaminopropionic acid, 2.4-diaminobutyric acid, ornithine, ethyl 2.3-diaminopropionate,
Amino acid esters such as methyl 2.4-diaminobutyrate, butyl 2.4-diaminobutyrate, ornithine methyl ester, ornithine ethyl ester, or salts thereof can be mentioned.

- As the salts of formulas (1) and (2), salts of inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, methanesulfonic acid, and p-toluenesulfonic acid can be used.

As the solvent, water, alcohols such as methanol and ethanol, and organic acids such as acetic acid and propionic acid can be used alone or in combination. In addition, as the base, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, sodium methoxide, and sodium ethoxide, and organic bases such as triethylamine can be used. The amount is sufficient to neutralize the salts of formulas (1) and (2). The reaction temperature is -50 to 250°C, preferably 0 to 15°C.
It is 0°C.

The optically active form of Compound I of the present invention can be produced by using an optically active form of the compound represented by the formula (2) or a salt thereof and reacting it at 0 to 100°C in the presence of a necessary amount of base. .

- The compound represented by the formula (2) or its salt is usually used in an amount of 1 to 100 equivalents relative to the compound represented by the formula (2) or its salt, but a large excess may also be used. The product can be separated and purified by conventional methods such as column chromatography.

<Example> Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 2-Ethyl-1,4,5,6-tetrahydro-4-pyrimidinecarboxylic acid 2.47 g of methyl propionimidate hydrochloride and 1 of 2,4-diaminobutyric acid dihydrochloride in methanol 30-
．． 91 g was added thereto, and 40 mQ of IN-sodium methoxide/methanol solution was added at room temperature while stirring, and the mixture was heated under reflux for 8 hours. After concentrating the reaction solution, it was dissolved in a small amount of water and subjected to silica gel chromatography (Merck's Silica Gel Nr, 7735 60 g, 95% aqueous acetone solvent).
500ml of 95% aqueous acetone 12.80%
Hydrous acetone 500ml 12.75% Hydrous acetone 500
Elution was performed using mQ and 70% aqueous acetone 500-. After concentrating the relevant fraction under reduced pressure, add 150ml of acetone.
2 was added, powdered, and filtered. After washing with ether and drying, 1.41 g of the title compound was obtained as a colorless powder. Yield 90
%.

Elemental analysis value: CqH1*N*Ot'' Calculated value (%) assuming 0.4HtO: C, 53,58, H, 8,22.

N, 17.85 Actual value (%): C, 53,42, H, 8,16°N, 1
7.70 IR spectrum (KBr) am-': 1650.16
00.

1460.1440,1395,1305,1200°1135.1010 55N spectrum CD! O, internal standard 3-(trimethylsilyl)propionic acid-2,2,3,3-d.

Sodium salt (TMSPA)) δ: 1.25 (3H, t
.

J = 7Hz), 2.13 (2H, q, J = 6Hz), 2
．． 55 (2H, Q, J=7Hz), 3.07-3.67
(2H, m).

4.08 (IH, t, J = 6 Hz) Example 2 1.4.5.6-Tetrahydro-2-octyl-4-pyrimidinecarboxylic acid methanol 30-, 4.15 g of methyl nonylimidate hydrochloride and 2 .4-Diaminobutyric acid dihydrochloride 3.8
2 g was added thereto, and 60 ml of IN-sodium methoxide/methanol solution was added at room temperature while stirring, and the mixture was heated under reflux for 16 hours. After concentrating the reaction solution, it was dissolved in a small amount of water and subjected to silica gel chromatography (Silica gel Nr manufactured by Merck & Co.).

7735 120g, 95% hydrated acetone (solvent)), then 1000ml of 95% hydrated acetone12.90% hydrated acetone 500ml12.85% hydrated acetone 500a+
12, and 500ml of 80% aqueous acetone. After concentrating the relevant fractions under reduced pressure, acetone 100%
mQ was added to powder, the upper layer was discarded, 100 d of acetone was added again, filtered and dried, and the title compound 2.59 was obtained as a colorless powder.
I got g. Yield 53%.

Elemental analysis value: C+5HtaNtO Calculated value (%) as 10,4HtO: C, 64,77; H, 10,37; N
, 11.62 Actual value (%): C, 64, 5σ; H, 10, 25: N,
11.39 IR spectrum (KBr) am-': 1640,161
0°1460.1440, 1395.1305 NMR spectrum (D!O, TMSPA) δ: 0.96 (3H,
t, J=6Hz), 1.2-2.1 (12H.

m), 2.34 (2H, q, J = 6Hz), 2.77 (
2H,t.

J=7Hz), 3.6-4.0 (2H, m), 4.47
(IH.

t, J=6Hz) Example 3 1.4.5.6-tetrahydro-2-octadecyl-4
-pyrimidinecarboxylic acid methanol 30-, methyl nonadecylimidate hydrochloride 3.48 g and 2,4-diaminobutyric acid dihydrochloride 1
．． 91 g was added thereto, and 30 mQ of IN-sodium methoxide/methanol solution was added at room temperature while stirring, and the mixture was heated under reflux for 16 hours. After concentrating the reaction solution, it was dissolved in a mixed solvent (methanol: methylene chloride = 1:1), and subjected to silica gel chromatography (Silica gel Nr, 77 manufactured by Merck & Co., Ltd.).
35 120g.

methanol: methylene chloride = l:3 mixed solvent), then methanol: methylene chloride = l:3 mixed solvent 1
0100O, then methanol:methylene chloride = 1:1
Elution was performed using 1000ml of a mixed solvent of After concentrating the relevant fraction under reduced pressure, 100 ml of acetone was added to powder, and the mixture was filtered. After washing with acetone, methanol and water, the mixture was dried to obtain 2.12 g of the title compound as a colorless powder. Yield 5G%.

Elemental analysis value: CzsH-NtOt” Calculated value (%): C, 71,57, H, 11,64°N
, 7.26 Actual value (%): C, 71, 44, H, + 1.91°N
, 7.12 IR spectrum (KBr) am-': 1655, 1
620.

1465.1375.1295 NMR spectrum (CDCI2s:CD5OD=1:
1.

TMS) δ: 0.89 (3H, t, J=6Hz), 1.
1-1.9 (32H, +++), 2.12 (2H, q,
J=6Hz).

2.45 (2H, t, J=7Hz), 3. '2-3.6
(2H.

m), 3.92 (IH, t, J = 6 Hz) Example 4 Methyl 1.4,5.6-tetrahydro-2-phenyl-4-pyrimidinecarboxylate benzimidate hydrochloride, 2.4-diaminobutyric acid The title compound was obtained in the same manner as in Example 2 using the dihydrochloride and IN-sodium methoxide/methanol solution. Yield 99%.

Elemental analysis value: Cr + Hr t N t Ot'
Calculated value (%) as 0,4 HtO: C,66
,46;H,6,30;N,13゜66 Actual value (%):C,66,21,H,6,45゜N,1
3.39 IR spectrum (KBr) cm-': 1630,160
5゜+490.1440.1395,1305,120
5NMR spectrum (D, O, TMSPA) δ: 2.2
6 (2H, Q, J = 6H2), 3.25-3.80 (2
H, i), 4.28 (IH, t, J=6Hz), 7.4
-7.9 (5H, m) Example 5 Methyl 2-benzyl-1,4,5,6-tetrahydro-4-pyrimidinecarboxylate phenylacetimidate hydrochloride, 2゜4-diaminobutyric acid dihydrochloride and IN -Sodium methoxide/
The title compound was obtained as colorless crystals in the same manner as in Example 2 using a methanol solution.

Yield 82%. Melting point 300℃ or higher.

Elemental analysis value: C+! H+4N*Ot” Calculated value (%) as 0.4HtO: C, 63,92: H, 6,62; N
, 12.42 Actual value (%): C, 64, 18, H, 6, 4o; N, 1
2.33 IR spectrum (KBr) am-': 1650,182
5゜1495.1435.13B0,1310,129
5゜11B0,1135.1010 65N spectrum (D*O, TMSPA) δ: 2.34
(2H, q, J=6Hz), 3.4-4.0 (2H.

m), 4.31 (2H, s), 4.49 (IH, t, J
=6Hz).

8.17(5H,s) Example 6 1.4.5.6-titrahydro-2-(2-pyridyl)
2.72 g of methyl 2-pyridinecarboximida-) and 3.82 g of 2,4-diaminobutyric acid dihydrochloride were added to 30-4-pyrimidinecarboxylic acid methanol, and while stirring at room temperature, IN-sodium methoxide/methanol was added. Solution 40- was added and stirred at room temperature for 48 hours.

After concentrating the reaction solution, it was dissolved in a small amount of water and subjected to silica gel chromatography (Silica gel Nr, 773 manufactured by Merck & Co., Ltd.).
5 120g, 95% aqueous acetone solvent),
Elution was performed using 500% of each of 95%, 90%, 85%, 80%, 75% and 70% aqueous acetone. After concentrating the relevant fraction under reduced pressure, acetone 100a+Q was added to powder it, the upper layer was discarded, and 100 ml of acetone was added again, filtered and dried to obtain 3.15 g of the title compound as a colorless powder. Yield 84%. Melting point: 262-264°C.

Elemental analysis value: C1゜HI+N30*'0,
Calculated value (%) as 2 Ht O: C, 57, 52:
H, 5,50; N, 20.12 Actual value (%) 2C, 57,37; H15,62; N, 1
9.85 IR spectrum (KBr) cm-': 1660,162
0°1590.1460,1430,1380,131
0° 20O NMR spectrum (DtO, TMSPA) δ: 2.31
(2H, q, J=6Hz), 3.35-3.95 (2H
, n+), 4.38 (IH, t, J=6Hz), 7.6
4-8.84(4H,++) Example 7 (+)-4,5,6,7-tetrahydro-2-methyl-
IH-1,3-diazepine-4-carboxylic acid methanol 60-, methyl acetimidate hydrochloride 4.38g
and 3.37 g of L-ornithine hydrochloride were added, and IN-sodium methoxide/methanol solution 60I1112 was added dropwise while stirring vigorously with water cooling. The mixture was stirred with water cooling for 10 minutes and then at room temperature for 48 hours. After concentrating the reaction solution,
Dissolved in a small amount of water and subjected to silica gel chromatography (Merck Silica Gel Nr, 7735'120g195
% aqueous acetone solvent), 95%, 85%, 8
0% and 75% acetone each 500m2 and 70%
Elution was performed using aqueous acetone +000-. After concentrating the relevant fraction under reduced pressure, it was purified again using the same silica gel chromatography.

The relevant fractions were concentrated under reduced pressure, pulverized by adding 100 ml of acetone, the upper layer was discarded, and 12 ml of acetone was added again, filtered and dried to obtain 0.46 g of the title compound as a colorless powder. Yield 15%.

Elemental analysis value: C1H+*NtOt" Calculated value (%) assuming 0.2HtO: C, 52, 61, H, 7, 82°N
, 17.52 Actual value (%): C, 52,33, H, 8,06.

N, 17.50 IR spectrum (KBr) cm-': 1620.146
0°1425.13B0,1345.1325,126
0°12O NMR spectrum (D, O, TMSPA) δ: 1.32
．． 6 (4H, m), 2.25 (3H, s), 3.20-
3.85 (2H, o+), 4.39 (IH, t, J=6
Hz) Specific optical rotation: [α ko I) 3・'=84.7 (C=1
．． 0. Methanol) Example 8 2-chloromethyl-1,4,5,6-tetrahydro-4
- Mix ethyl 2-chloroacetimidate hydrochloride 1.909 and 2,4-diaminobutyric acid dihydrochloride 1.919 in pyrimidinecarboxylic acid methanol 30H, and stir at room temperature for 2N-
11 mQ of sodium methoxide/methanol solution was added and stirred at room temperature for 24 hours. Insoluble materials were removed by filtration and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with 80% acetone. The eluate was concentrated under reduced pressure and then lyophilized. Ethanol 2011 in the residue
12 was added and the mixture was heated under reflux for 1 hour and then diluted with acetone 80112. The precipitate was collected by filtration and recrystallized from methanol-ether to obtain colorless powder 1.0259. Yield 58%.

Elemental analysis value: C* Hs C (l N t O*, calculated value (%): C, 40, 8!, H, 5, 14°N
, 15.86 Actual value (%): C, 40, 94, H, 5, 19°N, 1
5.62 NMR spectrum (DtO, TMSPA) δ: 2.16
(2H, Q, J=6H2), 3.15-3.74 (2H
, m), 4, 12 (l H, t, J = 5 Hz)
, 4.48 (2H,s) Example 9 Ethyl 2-hydroxymethyl-1,4,5,6-tetrahydro-4-pyrimidinecarboxylate 2-chloroacetimidate hydrochloride 3, I6y
, 2.4-diaminobutyric acid dihydrochloride 1.912, anhydrous sodium acetate 4.19 and acetic acid 50i12 were mixed, 1
The mixture was stirred at 20°C for 20 hours. Insoluble materials were removed by filtration and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with acetone-methanol. The eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized from 90% ethanol-ether to give 0.759 g of colorless needles. Yield 47%.

Elemental analysis value: as Ca H+ o N t Os,
Calculated value (%): C, 45, 57; H, 6° 37: N, 1
7.71 Actual value (%): C, 45, 42, H, 6, 4s; N, 1
7.54 NMR spectrum (D*O, TMSPA) δ: 2.17
(2H, q, J=6Hz), 3.10-3.70 (2H
, m), 4, 12 (I H, t, J = 5 Hz)
, 4.47 (2H,s) Example 10 Ethyl 2-(4-chlorophenyl)-1,4,5,6-tetrahydro-4-pyrimidinecarboxylate 4-chlorobenzimidate hydrochloride 1.109.2. 4-Diaminobutyric acid dihydrochloride 0.9559.2N-sodium methoxide/methanol solution 7, 5 *Q and methanol 3
0xQ was treated in the same manner as in Example 8 and subjected to column chromatography. The obtained eluate was concentrated and adsorbed on a column of Amber Ray) IR-120B (H") and washed with water. Elution was carried out with IN ammonia water and concentrated under reduced pressure. The remaining liquid was lyophilized and the obtained The resulting powder was recrystallized from methanol-ether to obtain a colorless powder of 0.6019. Yield: 47%.

Elemental analysis value: C+ 1Hl+ CQ N t Ot・
Calculated value (%) as H, O: C, 51, 47, H, 5
, 1o; N, 10.91 Actual value (%): C, 51,26, H, 4,76; N, 1
0.61 NMR spectrum ((CD3), SO, TMS) δ:1
．． 83-2.16 (2H, br m), 3.25-3.
50 (2H, br m), 3.79 (I H, t, J=
5Hz).

7.62 (2H, d, J=9Hz), 7.79 (2H,
d, J=9Hz) 7 Example 11 2-(4-hydroxyphenyl)-1,4,5,6-tetrahydro-4-pyrimidinecarboxylic acid l)ethyl 4
-Hydroxybenzimidate hydrochloride 1. o Iy, 2
．． Mix 0.9559 of 4-diaminobutyric acid dihydrochloride and 30xQ of methanol, and add 2N-sodium methoxide/
A methanol solution of 7°5JIQ was added and stirred at room temperature for 15 hours. After concentrating to dryness under reduced pressure, the residue was dissolved in water and adsorbed on an Amberlite IR-120B (H"") column. After washing with water, it was eluted with IN aqueous ammonia and concentrated under reduced pressure. The residual liquid was freeze-dried, and the resulting powder was recrystallized from methanol-ether to obtain colorless powder 0.2739. Yield 25%.

Elemental analysis value: CIIH+tNtOs'0. Calculated value (%) as JHtO: C, 59,51, H, 5,54; N
, 12.62 Actual value (%): C, 59,54, H, 5,40; N, 1
2.62 NMR spectrum (CD, OD, TMS) δ: 2.23
(2H, q-1ike), 3.53 (2H, t-1ike
e).

4.10 (IH, t, J=5Hz), 6.93 (2H,
d, J=9Hz), 7.62 (2H, d, J=9Hz)
2) Ethyl 4-hydroxybenzimidate hydrochloride 1
．． 01g, 2.4-diaminobutyric acid 0.9552, anhydrous sodium acetate 1.239, and acetic acid 50y, Q were mixed and stirred at 120°C for 20 hours. The mixture was concentrated under reduced pressure, methanol was added, and insoluble matter was filtered off. It was concentrated under reduced pressure and subjected to silica gel column chromatography. Elution was performed with acetone-methanol, and the eluate was concentrated to dryness under reduced pressure. Recrystallized from methanol-ether to give colorless powder 0.1
I got 329. Yield 12%.

Example 12 2-(4-propargyloxyphenyl)-1°4.5
．． 3.357 of 4-propargyloxybenzonitrile 6-tetrahydro-4-pyrimidinecarboxylate was dissolved in 5xQ ethanol and 200xQ ether, and hydrogen chloride gas was passed through the solution under water cooling. After leaving it at room temperature for 3 days,
The mixture was stirred under heating under reflux for 7 hours. Concentrate under reduced pressure and recrystallize from ethanol-ether to give colorless crystals of ethyl 4-propargyloxybenzimidate hydrochloride, 3.739 g.
I got it.

NMR spectrum C (CDs) tsO, TMS)61.
48 (3H, t, J=7Hz), 3.66 (I H, t
, J=2Hz), 4.63 (2H,q, J=7Hz)
, 4.98 (2H, d, J=2Hz), 7.22 (2'
H, d, J = 9Hr).

8.18 (2H, d, J=9Hz), 11.2-12.
1(2H,br) Ethyl 4-propargyloxybenzimidate hydrochloride 2.409.2,4-diaminobutyric acid dihydrochloride 1.91
9.2N-sodium methoxide/methanol solution a15
xQ and 50 d of methanol were mixed and stirred at 50° C. for 20 hours. The residue was concentrated to dryness under reduced pressure, dissolved in water, and adsorbed on a column of Amberlite IR-120B (H"). After washing with water, it was eluted with IN aqueous ammonia, and concentrated under reduced pressure.

The residual liquid was freeze-dried, and the resulting powder was dissolved in methanol and then subjected to silica gel column chromatography. It was eluted with acetone-methanol and concentrated to dryness under reduced pressure. Recrystallization from methanol-ether gave 0.979 colorless powder. Yield 38%.

Elemental analysis value: Cl4H1hN*OsJ, Calculated value (%) as 3HtO: C, 63,62; H, 5,59; N,
10.60 Actual value (%): C, 63,91, H, 5,83°N, 1
0.24 NMR spectrum ((CDs)ysO,TMs) δ:1
．． 80-2.20 (2H, br), 3.20-3.50
(2H9br), 3.62 (I H, t, J = 2Hz
), 3.76 (IH, t, J=5Hz), 4.91 (2
H, d, J = 2Hz).

7.14 (2H, d, J=9Hz), 7.75 (2H,
d, J=9Hz), 9.2-I Q, 4(IH, br
) Example 13 1.4.5.6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid ethyl ester hydrochloride 1.4.5.6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid 0.71y The suspension was suspended in 50 liters of ethanol, and hydrogen chloride gas was passed through it until dissolved. The mixture was sealed tightly and allowed to stand for 2 days, then concentrated to dryness under reduced pressure. Chloroform was added, and insoluble materials were filtered off.

Concentration to dryness under reduced pressure gave a brown viscous substance (quantitative).

NMR spectrum (D!O, TMSPA) δ: 1.30
(3H, t, J=7Hz), 2.24 (2H, q, J=
16 Hz), 2.27 (3H, s), 3.13-3.
74 (2H, a+), 4.29 (2H, q, J=7'H
z), 4.44 (I H, t-1ike) Example I4 2-chloromethyl-1,4,5,6-tetrahydro-4
-pyrimidinecarboxylic acid ethyl ester hydrochloride 2-chloromethyl-1,4,5,6-tetrahydro-4
- 1.236 g of pyrimidine carboxylic acid in 50 g of ethanol
The mixture was suspended in a glass tube and hydrogen chloride gas was passed through the mixture until dissolved. After sealing the cap and leaving it for 2 days, it was concentrated to dryness under reduced pressure to obtain a brown powder.
5859 was obtained. Yield 94%.

Elemental analysis value: C* Ht s C(l N t O1
As HCQ・0.25H,O, calculated value (%): C, 39, 12, H, 5, 95°N, 1
1.41 Actual value (%): C, 39, 21:H, 5, 93°N, 1
1.3O NMR spectrum ((CD 3)! SO, T M
S) δ: 1.24 (3H, t, J=7Hz), 1.9
0-2.20 (2H, br m), 2.98-3.77
(2H, br m).

4.20 (2H, q, J=7Hz), 4.40-4.6
5 (I H, br a+), 4.60 (2H, s),
I O, 62 (I H.

br s), I 1.03 (I H, br s) Example 15! , 4.5.6-titrahydro-2-octadecyl-4
-pyrimidinecarboxylic acid methyl ester hydrochloride 1.4,5.6-tetrahydro-2-octadecyl-4
-pyrimidinecarboxylic acid 0.76 If methanol 2
The suspension was suspended in 0R12, and hydrogen chloride gas was passed through it for 15 minutes while cooling with water. The mixture was sealed tightly and allowed to stand for 2 days, and then stirred under heating and reflux for 5 hours. Insoluble materials were removed by filtration and concentrated to dryness under reduced pressure. It was dissolved in chloroform and subjected to silica gel column chromatography.

It was eluted with chloroform-methanol and concentrated to dryness under reduced pressure to obtain a colorless powder of 0.579. Yield 66%.

Elemental analysis value: C**H-*NtOt”HCQ・0.7H
Calculated values (%) as tO: C, 64,97, H, 10,99.

N, 6.31 Actual value (%): C, 65,02; H,! +, 12;N
, 6.35 NMR spectrum (CDC12, TMS) δ: 0.8
8 (31-1, t-1ike), 1.26 ((30-3
2)H.

5-1ike), 1.5-1.9((4-2)H, br
), 2.00-2.30 (2H, br), 2.60-2
．． 85 (2H, br).

3.78 (3H, s), 4.25-4.45 (IH, b
r).

10.9-11.1 (I H, br), 11.5-11
．． 8 (IH, br) Example 16 Methyl 2-methyl-4-imidacylinecarboxylate 1.1 g of acetimidate hydrochloride, 1.41 y of 2゜3-diaminopropionic hydrochloride and 60xQ of methanol were mixed, and 2N -Sodium methoxide/methanol solution 1
0xQ was added and stirred at room temperature for 20 hours.

Methyl acetimidate hydrochloride 1.19 and 2N-
Sodium methoxide/methanol solution 5FIQ was added and stirred at room temperature for 20 hours. Insoluble materials were filtered and concentrated under reduced pressure. Dissolved in water, Amberlite I R-1
It was adsorbed on a column of 20B()(''). After washing with water, IN
It was eluted with aqueous ammonia. The eluate was concentrated under reduced pressure, and the residue was lyophilized. The obtained powder was dissolved in methanol and subjected to silica gel column chromatography. Elution was performed with acetone-methanol, and the eluate was concentrated to dryness under reduced pressure. Recrystallized from methanol-acetone to give 0 colorless crystals.
．． 8419 was obtained. Yield 66%.

Elemental analysis value: Calculated value (%) as csHmNtOt:
C, 46,87; H, 6,29; N, 21.86 Actual value (%): C, 4e, s 4 , H, 6,44; N
, 21.77 NMR spectrum (D, O, TMSPA) δ 2.27 (
3H, s), 3.78-4.40 (2H, m).

4.55-4.77 (IH, m) Example 17 Ethyl 2-(4-chlorophenyl)-4-imidacylinecarboxylate 2.2 g of 4-chlorobenzimidate hydrochloride,
2,3-diaminopropionic hydrochloride and 60 g of methanol (!) were mixed, 10×Q of 2N sodium methoxide/methanol solution was added, and the mixture was stirred at room temperature for 20 hours. It was concentrated to dryness under reduced pressure, and water was added. Filter the precipitate,
After washing with water, recrystallize from methanol-ether and colorless crystals 1
．． 564g was obtained. Yield 70%.

Elemental analysis value: C,OH*CQNtOR-HlO,
Calculated value (%): C, 49,50; H, 4,57; N, 1
1.54 Actual value (%): C, 49,23; H, 3,99; N, 1
1.18 NMR spectrum (CDsOD, TMS
) δ: 3.99-4.41 (2H, m), 4.74 (I
H, dd, J-9Hz, 11Hz), 7.64 (2H,
d, J=9Hz).

7.89 (2H, d, J=9Hz) <Effects of the Invention> The compound (1) of the present invention is useful as a synthetic intermediate for medicines, agricultural chemicals, liquid crystals, etc.

Claims (4)

[Claims] (1) General formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I a ] or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I b] (In the formula, R^1 is hydrogen, alkyl of C_1 to_1_8 group, aryl group, aralkyl group or heterocyclic group,
R^2 represents hydrogen or an alkyl group of C_1 to_6, and n represents an integer of 0 to 3. However, when n is 1, R^1
When is hydrogen or methyl, R^2 represents an alkyl group of C_1 to_6. ) or a salt thereof. (2) The compound according to claim (1) or a salt thereof, which is an optically active substance. (3) The compound of claim (2) or a salt thereof, which is an S-active form. (4) The compound of claim (2) or a salt thereof, which is an R-active form.