JPS62215597A - Beta-mercapto-alpha-aminoethylphosphonic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [n is 0, 1, 2; X is alkyl, formula II (R<3> is alkyl); Y is H, amino-protecting group; R<1>, R<2> are H, alkyl]. EXAMPLE:1-Carbobenzoxyamino-2-methylthioethylphosphonic acid S-oxide. USE:A synthetic intermediate of biosynthesis inhibitor of cell walls and of antibacterials. PREPARATION:For example, an aziridine derivative of formula IV is ring-opened with a mercaptan of formula: X-SH in the presence of an acid catalyst, to give beta mercapto-alpha-aminoethylphosphonic acid derivative of formula IV. When necessary, the product is oxidized with an oxidizing agent in a solvent to give a compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to β-mercap)-α-aminoethylphosphonic acid derivatives useful as synthetic intermediates for pharmaceutical agents.

(Structure of the Invention) The compound of the present invention is a β-
This invention relates to mercapto-α-aminoethylphosphonic acid derivatives.

HY [In general formula (1), n represents o, i or -, and X represents a
) l! does not include the case where is an alkyl group which may have a substituent (however, n is OC7'). ), or b) Hs (in the formula, Hs means a hydrogen atom or an alkyl group), or C) R4NH-〇- (in the formula, 2 is 0 or S, R4 is means a hydrogen atom, an alkyl group, or an aryl group (excluding cases where n is / and -).

Y is a hydrogen atom or a protecting group for an amino group, R1 and R2
means the same or different hydrogen atoms or alkyl groups. ] Among the β-wt stirred aminoaminoethylphosphonic acid derivatives of the present invention, compounds in which Y in the general formula (1) is a hydrogen atom are valuable as biosynthesis inhibitors of the slender V14 cell wall. is a 7-mino radical! ! ! With compounds that are ll groups, there is also a valence of 11I! When Y is a protective group of an amino group in the general formula (1), which is used as a synthetic intermediate for the production of an anti-inflammatory substance Jx, the protective group is a protective group commonly used in peptide chemistry, For example, carbobenzoxy, p-methoxybenzyloxycarbonyl, tart
Groups such as -butoxycarbonyl or trityl are preferably employed. Examples of the alkyl group for %R1 and R2 include straight-chain or branched alkyl having 1 to 2 carbon atoms.

When X is a), examples of the alkyl group which may have a substituent include straight-chain or branched alkyl having a carbon number of 1 to 2. Examples of substituents include aryl groups such as phenyl groups, hydroxy groups, lower alkoxy groups, lower alkanoyloxy groups such as acetoxy groups, benzoyloxy groups, amino groups, mono- or di-lower alkylamino groups, and acylamino groups. .

In the case of [ , the alkyl group for R3 includes a straight or branched alkyl having a carbon number of 1 to 2.

Where X is c) Z R4NkI-0-, the alkyl group of R' is a straight or branched alkyl having a carbon number of up to 1, and the aryl group is phenyl, naphthyl, biphenylyl and tetrahydronaphthyl. It will be done.

β-mercapto-α- represented by general formula (1) of the present invention
In the aminoethylphosphonic acid derivative, when Y, R1 and R2 are hydrogen atoms, these groups may be used as they are or may form a salt with another d6 or a base.

These strong salts include amine salts, salts with mineral acids such as fjiic acid, hydrogen oxide, and sulfuric acid, or salts with organic acids; salts of phosphonic acids include alkali salts such as sodium, potassium, calcium, or magnesium; The heptavalent A salts of alkaline earth metals, ammonibs, and amines are monovalent.

Specific examples of the β-mercapto-α-aminoethylphosphonic acid derivatives of the present invention include the following compounds.

7! /-carbobenzoxyamino-comethylthioethylphosphone 111B-oxide 2 /-amino-comethylthioethylphosphonic acid S-oxide 3 /-carbobenzoxyamino-2-ethylthioethylphosphone Yabu S-oxidope /-amino- -Ethylthioethylphosphonic acid S-
Oxide /-amino-comethylthioethylphosphone rIR
B-dioxide K /-amino-ethylthioethylphosphonic acid S-
Dioxide Z /-carpopenzoxyamino--methylthioethyl monoethyl ester /-amino-comethylthioethylphosphonic acid monoethyl ester 9 /-carpopenzoxyamino-coethylthioethylphosphonate monoethyl ester Ester 10 /-amino-
2-Ethylthioethylphosphonic acid monoethyl ester///-amino--methylthioethylphosphonic acid monoethyl ester/dioxide/2/-amino-λ-
Ethylthioethylphosphonic acid monoethyl ester S-dioxide 73 /-amino-λ-(/'-methyltetrazol-!'-yl)thioethylphosphonic acid diethyl ester/-amino-cor(/'-methyltetrazol-!'-yl)
'-yl)thioethylphosphonic acid/yo/-carbobenzoxyamino-2-(/'-methyltetrazole-5'-
yl)thioethylphosphonic acid/h/-carbobenzoxyaminocor(//-methyltetrazol-t'-yl)thioethylphosphonic acid monoethyl ester/7/-amino-(/'-methyltetrazole-!
'-yl)thioethylphosphonic acid monoethyl ester /-amino-cocarbamoylthioethylphosphonic acid 79 /-amino-co-phenylated rubbermoyl-thioethyl phosphonic acid salt starch salt 2θ /-amino-λ-phenylthio Carbamoylthioethylphosphone 21 /-carpobenzoxyamino (-l.

3'-dihydroxyglobil)thioethylphosphonic acid diethyl ester 22/-amino-(λ',3'-dihydroxypropyl)thioethylphosphonic acid Next, a representative method for preparing the compounds of the present invention will be described. The present invention will be explained in more detail, but this is only a typical manufacturing method and is not limited thereto.

The following methods A to E are listed as typical methods for producing the β-mercapto-α-aminoethylphosphonic acid derivative of the present invention.

Method A (I) (Ill) (IV) (where K, Y, R' Oyo U R2+! General formula (1
) f) have the same meaning. However, R1 and R2
does not include the case where is a hydrogen atom and X is d). ) That is, an aziridine derivative represented by the general formula (I[) is subjected to a ring-opening reaction with a mercaptan represented by the general formula (1) in a suitable solvent in the presence of an acid catalyst to form a ring-opening reaction represented by the general formula (IV). This is a method for producing the desired β-mercagto α-aminoethylphosphonic acid derivative.

The ring-opening reaction of 2-acylidinephosphonic acids is usually carried out using hydrochloric acid or sulfuric acid as an acid catalyst [J, Zygm
unt, P, Mastalerz, Polish
J.

Ohem 12 2λ7/(/97/), 66 'I
BP as a catalyst,
An example of a method using a diethyl ether complex and BIF as a catalyst in a non-water bath is to use, for example, chloroform or dichloromethane as a bath medium, and to perform the process smoothly at room temperature.
The reaction is carried out easily and in high yield. This reaction is usually carried out with Y in general formula (11) in the form of a protecting group, but if the nucleophilicity of X-8R shown in general formula (1) is large, even when Y is a hydrogen atom, conveniently carried out.

Method B O HY (V) C'v1) (■) (In the formula, Y, 2% part, R1 and R4 have the same meanings as in general formula (1).) That is, represented by general formula (V) The compound and general formula (Vl
) is a method for producing the target compound represented by the general formula (■) by carrying out an addition reaction of β-mercapto-α-7minoethylphosphonic acids represented by the following in an appropriate IV medium.

This reaction is carried out by applying a known method, for example, the addition reaction of cysteines.

[L, 0.8m1th, J, S, Humphre
ys, O, G.

akinner, W, 8hive, Teras R
epts, Biol, Med.

2/ (2) - Taro (/ri63), D, L, R
a5s, C, G.

□　　　.

akinner, W, 5hive, J6Med, and
Pharm.

Chem, j! /9 (/Thailand/), JoM, Ra
ven, T.J.

McOord O, G 8 to 4nner, W, 8hiv
e, T, Biol.

Ohem,, 2J, 2 /69 (/ri!/)].

c method N)i Y kNI Y(IV)
(■) (In the formula, K, Y, R1 and it" have the same meanings as in general formula (1)) That is, β-mercapto-α represented by general formula (1v)
This is a method for producing the desired sulfoxide compound represented by the general formula (m) by oxidizing -7 minoethylphosphone uR derivative with an oxidizing agent in a suitable solvent.

This reaction is carried out by applying a known method for producing a sulfoxide compound by oxidizing a sulfide compound. A typical manufacturing method uses sodium periodate as an oxidizing agent and is carried out in an aqueous solvent [0. R, Johnson, J.
, Ilf, Keiser, OrganicEly
nthesia OoloMol v, P lid/
John Wiley & 5ons, New York
(/ri74t)).

D method (b) (■) (in the formula, X,
Y, R' and R'' have the same meaning as general formula (1) +7).) That is, β-turcapto- represented by general formula (IV)
This is a method for producing the desired sulfone compound represented by the general formula (V) by oxidizing an α-7 minoethylphosphonic acid fatty conductor with an oxidizing agent in a suitable solvent.

This reaction is carried out by applying a known method for producing a sulfone compound by oxidizing a sulfide compound.

A typical production method is to use 30% hydrogen peroxide as an oxidizing agent and conduct the process in water, N-hydrochloric acid, or acetic acid [L, Goodman, L, O, Rose.

B, R, Baker, J, Org, Chew 2
3 /λJ-/ (/汀?)〕Enpo (X) (M) (XI) (wherein, X
%Y and R/ have the same meaning as in general formula (1). (However, this includes the case where R' is a hydrogen atom) In other words, β-mercaptoaminoethylphosphone I! represented by the general formula (X)! ! ! In this method, a derivative is subjected to a condensation reaction with an alcohol represented by general formula (XI) to produce a target ester represented by general formula (M).

A typical example of this reaction is the known esterification method that uses trichloroacetonitrile as a condensing agent (
J, Szewczyk, O, Wasia4-ewa
ki, Po1ioh J, Ohem! ! /ri/1
(/917)).

The condensation reaction is conveniently carried out by heating in the presence of pyridine using trichloroacetonitrile as the condensing agent.

F method (deprotection reaction) (where n, X, Y, R' and R2 are represented by the above general formula (I
) has the same meaning as However, this method does not include the case where Y1 moiety and R2 are hydrogen atoms), that is, it is a method of deprotecting the β-mercapto-α-aminoethylphosphonic acid derivative represented by the general formula (1).

The deprotection reaction is performed by applying a known method to 5A. Methods for removing the reserved groups used in the conventional fields of peptide chemistry and phosphonate chemistry are selected and carried out as appropriate depending on the purpose.

Typical examples of deprotection reactions are a) In the case of reaction, heating with LlBr and pyridine [
, T. Eigewczyk, a. Wasiele
waki.

Po1iah, ,T, Ohem, ! z/
11' (/9t/)) or hydroxide)
Examples of methods include treatment with IJum.

In the case of b) reaction, methods include heating with trifluoroacetic acid, or short-time treatment with saturated beautified hydrochloric acid-acetic acid at 7-trap temperature.

In the case of C) and d) reactions, methods include heating with saturated hydrobromic acid and acetic acid, or heating with concentrated hydrochloric acid for a long time.

When the desired compound to be obtained is a mineral acid or organic acid salt of an amine, it is converted into an inner salt, if desired. As a representative example, when the amine is a hydrochloride or hydrobromide salt, treatment with propylene oxide conveniently leads to the inner salt.

There is no need to use any special method for separating and purifying the target products produced in the implementation of Methods A to F, and well-known means commonly used for such purposes, such as solvent extraction, washing, crystallization, and ion exchange, can be used. The objective can be easily achieved using resin, normal phase and reverse phase column chromatography.

(Example) The present invention will be explained in more detail by showing examples below.
The present invention is not limited to the following examples unless it exceeds the gist thereof.

Example / l-carbobenzoxyamino-twomethylthioethylphosphonic acid S-oxide a)/-aminotwomethylthioethylphosphonic acid,
ooy (j, 6 mmol) in sodium bicarbonate -/
, I Jl (240 mmol) in water (ioo*)
0.9 m (J♂yield mmol) of carbopenzoxychloride in ether solution (/J-tld) was added dropwise over 30 minutes with stirring under water cooling, and the mixture was further cooled for 3 hours under water cooling. Stir. After the reaction, remove the ether layer, wash with aqueous ether, make acidic by adding 41JHOJ- under ice cooling, extract with ethyl acetate, wash with saturated brine, dry over magnesium sulfate, and remove the solvent under reduced pressure. . The residue was crystallized from ether and converted into methylthioethylphosphonic acid.
Add IO (1,00 mmol) and stir for 1 hour.

The precipitated crystals are removed from P#, and P# is distilled off under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography ('lio developing solvent θ to 10 timetanol-containing water) to obtain the indicated compounds /, //I (yield: 6%).

NMR (CD, OD, δ)-06θ, 2.70 (3
H, 5xJCB, 130-), j, / ~j, 7 (
2H, m, 80H, -), u, 0~Q, 7 (/
H, m, 80H20H-), j, 06 (2, B
, -OH, Ph).

70.26 (jH, B, Ph-) Example λ /-amino-λ-methylthioethylphosphonic acid S-oxyze/-carpobenzoxyamino-1-methylthioethylphospho/acid 8-oxide/, //11 ( J, 4t! mmol) dissolved in trifluoroic acid 1111//ld, 4to
After stirring at °C for an hour, ether/10y11 was added and the precipitated crystals were collected. This was dissolved in j% hydrochloric acid and azeotroped several times, and the residue (1-[02 salt) was dissolved in ethanol.
Add propylene oxide and remove the crystals that precipitate.
After removing the substances insoluble in ethanol, liquid F is distilled off under reduced pressure. When the residue is powdered with ether, the indicated compound 3J is obtained.
jW (yield: 1) is obtained as a mixture of diastereomers. Melting point/3θ~/Jr"CC decomposition) Engineering R (KBr, cm-') /l/J', /
630, 10100ON (D, O, Na0Dδ)2
．． 7θ, 2.76 (3H, BX2 Cq, 80-
), J, 7~! ,! (jJ m, EIOH, OH
-) Example 3 /-carbobenzoxyamino-λ-ethylthioethylphosphone #S-oxide a)/-amino-λ-ethylthioethylphosphonic acid λ,
From j09 (/3.j mmol), /-carbobenzoxyamino-coethyltheoethylphosphone #J, -2gF (yield 7!%) is obtained in the same manner as in *Example/a).

b) From /-carbopenzoxyamino-ethylthioethylphosphonic acid 4/6~(/, 23 mmol), the title compound 200<i>I is quantitatively obtained in the same manner as in Example/b).

Example Hiroshi/-Amino-λ-ethylthioethylphosphonic acid B-oxide/-carbobenzoxyamino-coethylthioethylphosphone! 2 days - 700 capes of oxide (i, ?3 mmol)
In the same manner as in Example λ, the indicated compound rjMf (yield λ2%) is obtained as a mixture of /2/ diastereomers. Melting point/go! ~770°C (decomposition) Engineering R (KBr, cm-') 1531. /14
40. 101O101ON, O, δ)/, 2J, /,
30 (JH, tXJ, J=+7, jHz, OH, O
R, 80-) 2. λ~a,z (tll, m.

sashi0)I-,-(!horse5O-) Example! /-amino-λ-methylthioethylphosphonic acid S-dioxide/-amino-comethylthioethylphosphonic acid 9.00
mg (r, 2r mmol) dissolved in vinegar rIk30-,
30-Hydrogen peroxide solution at 10℃ for 7 hours by μ-6-
Add. After standing overnight at room temperature, the solvent was distilled off under reduced pressure, and the residue was recrystallized from water to obtain the indicated compound. '13■ (yield/
r%). Melting point - Hiro♂~2yo/"C (decomposition) Engineering R (KBr, cM-'), At♂z, /!2
0. /300゜//3j NMR (D, O, Na0D, δ) 3.26 (j
JB, Cdan, 5o-).

LJ ~4t, 0 (JH, m, 8(3H, (4-
) Example 6 Example from /-amino-coethylthioethylphosphonic acid S-dioxide/-amino-coethylthioethylphosphonic acid Z♂/ki (2,64t mmol)! In the same manner as above, the indicated compound 3/Misaki (yield: 6♂) was obtained. Melting point 2-〇～22Jr″C(min's)WorkR(KBr, cm-'
) /6/r, /j30. /,! 00-//3
O NMR (D20.Na0D δ)j, j ~j, Ta
(j kia mlSC!!, Odan-), 3.4
tO(,2kI,q,J-7,tHz.

-so, -ap, aa, ), 7.4tθ(jH,t
, 1w7. jHz.

-802-0) 1.0 days,] Example 2 /-carpobenzoxyamino-2-methylthioethylhonufonic acid monoethyl ester/-carpobenzoxyamino-11-methylthioethylhonufonic acid, ? 71(ri,
72 mmol) Kmm bipyridine 3θ Hatrichloroacetonitrile! , /d (30 mmol) and absolute ethanol 87d (j O mmol) are added and stirred at 100° C. for 3 hours.

Distill the solvent under reduced pressure, dissolve the residue in saturated aqueous sodium bicarbonate solution, and wash with ethyl acetate. Cool the aqueous layer, make it acidic by adding hydrochloric acid, extract with ethyl acetate, wash with saturated brine, and wash with sulfuric acid). Dry with IJum and evaporate the solvent.

The residue was recrystallized from ethyl acetate to give the indicated compound, t3p.
(yield 71%). Melting point 107J ~ 107. j℃
N M R (CD, OD, δ) 82j (3H, q, ,
T-7,OH2゜aH,cdan3),2,0j(3■,
a, O! ! 3B-), 2i~! ,0(2L m,
5OH2-), a, r N4t, j (3) 1. m,
80H, Odan-1-〇jiah, )es, or (
,2)1. s, c complaint Ph), ? ,,l (z
H.

s, Ph-) Example? /-Amino-co-methylthioethylphosphonic acid monoethyl ester/-600 μl (/, rO millisol) of Rubopenzoxyamino-co-methylthioethylphosphonic acid monoethyl ester in 1 t* of hydrogen bromide saturated acetic acid solution After 2 minutes, add ether and let it precipitate. The obtained crystals (HBr'r4) were crushed in ethanol,
Add glolene oxide. The solvent was distilled off, and the residue was subjected to reverse phase silica gel column chromatography (C1, developing solvent 0 to
Purify with 70% methanol-containing water) and recrystallize from ethanol and ethyl acetate.Then, the indicated compound, 2/7tII
f (yield 67%). Melting point/9ri! ~200J”
C (decomposition) Engineering R (KBr, yB-”) /64tO, /j%J
N MR (CD, OD, δ) i,, 2z (3H, t,
! -7Hz.

-a) I, a! ! , ), 2. / 0 (jJ 8.
O above, S-), 2. J~j,! (3H, m, 8
0H,OR-), j, 7~4<0.2(2kl, m
.

-0H20H,) Example /-Carbobenzoxiamino-Ethylthioethylphosphonic acid monoethyl ester/-Carbopenzoxia ξ
Norcoethylthioethylphosphonic acid J, 2e # (
10,/mmol) to obtain the indicated compound λ, jOI (yield 2/%) in the same manner as in Example 2. Melting point 10/~1
0λ℃NMR (OD, OD, δ) /, 20 (J'Ji
, t, :J-7,jHz80H,0dan3), /
, Jj (jH,t, J m7H2,OCR,OB,
).

, 2. jj(,2H,q, J-7,!Kg, BOshi0-)ko, 7~j, /(,2H,m, 80H,-),
! , /~4 transfer (JH, m.

BOHloH, -tunoajiOH,) J-0/0 (
λH,s, -0R1Ph).

2.30 (jH, s, Ph-) Example IO /-amino-coethylthioethylhonufonic acid monoethyl ester/-carbobenzoxyamino-ethylthioethylphosphonic acid monoethyl ester/0.20p (i3 (mmol) to the indicated compound 60- in the same manner as in Example ♂.
A cape (yield r-1) is obtained.

Melting point / 0 ~ / 2℃ R (KBr, cm-') /43θ, /J'
4tONMR (CD, OD, δ) /, 21 (JH,
t, Jl+lI7. JH2゜80H,OH,), 7
．． 30 (jH,t, ;J-7, OEM.

ooa, o peng)t 2,4tj (Jl(,q,,7m
7. jug.

Day Op, OH,), ,2. ♂～ jo, t (J
R, m, SO horse C! ! -).

J, l ~ g, j (λH, m, 0OHffiOH8)
Example // /-Amino-co-methylthioethylphosphonic acid monoethyl ester S-dioxide/-Amino-co-methylthioethylphosphonic acid monoethyl ester 4tr21tq (λ, 1 mmol of 4) Example! After reacting in the same manner as above and distilling off the solvent, it was purified by reverse-phase silica gel column chromatography ('11; developing solvent, water), and recrystallized from methanol to obtain the indicated compound j3.2.
A cape (yield 1%) is obtained. Melting point co/r-co/ri℃ (decomposition) Engineering R (KBr, cIn-') /62j, /j
41θ, /300°/ /4tO NMR (D, O, a) /, 2J-(JH, t, J
sw7Hz.

OH,0H8), 3.20 (,?H,51,OH,
SO, -), j, 4-1.7 (J-H, m, B-0
1j, OH-), -OH,CH,) Example/2 1-amino-coethylthioethylphosphonic acid monoethyl ester -dioxide/-amino-coethylthioethylphosphonic acid monoethyl ester 4tOO Misaki (i, tr mmol) to the compound λ θ1q (yield 3
%). Melting point KO♂~, 2//'C (decomposition) Engineering R (KBr, z-'-) /620. /141
0. /301°//4tO MMR (D, O, δ) /, Jj (jilt, t,
J shoes 4.1HIM.

00H! Odan, ), /, Jj (Jll, t,
J-7, 1Hz.

-so, -on,○L's )e '-J j ("e
qe J-7,! Hg.

80, OH, OR,), LJ ~41.3 (jll
, m, Bog, (4-.

oa4. am, ) Example/jj /-amino-λ-(/'-methyltetrazole-!'-
yl) Thioethylphosphonic acid diethyl ester - aziridinylphosphonic acid diethyl ester ≦4t0
119 (3,j♂mmol) and/-methyl-! -Mercaptotetrazole 730 mmol (7.7 mmol) was dissolved in chloroform/3 tnl and boron trifufluoride diethyl ether m form 0. /d and stir at room temperature for 3 days. After the reaction, a saturated aqueous sodium bicarbonate solution was added and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent 1.3 % methanol in chloroform) to give the title compound 710 (yield 4≦7%).

Engineering R (neat, am-ri /42j NMR (CD0I,, δ) /, J7 (4H, t,
J+m7Hz.

OH2(Ii,),/,71 (2H,s,-NH,)
, J, Oj~j, Ri! (j ji# m# day on
,c! ! -), 3. RiJ (jH, s, No! 3)
.

+1. JO (uki, q, tl J-7Hz,
7Hz, -0! ! tOH,) Example/4t l-amine-(/'-methyltetrazole-114
) thioethylphosphonic acid/-amino-! -(/'-methyltetrazole + j'
-yl)thioethylphosphonic acid diethyl ester 710
119 (4 t/mmol) was dissolved in a 20 M1 hydrogen bromide saturated vinegar solution and stirred at room temperature for 3 hours and at J-1°C for 30 minutes. The reaction solution was cooled to room temperature, ether 200°C was added, and the precipitate formed was cooled (0°C), filtered, and washed with ether.

The resulting precipitate (HBr salt) was dissolved in 21 d of ethanol, 7 d of propylene oxide was added, and the mixture was stirred at room temperature for 7 hours and cooled to 0°C. When the precipitated crystals were collected with VS and washed with ethanol and ether, the indicated compound was obtained (yield: 7
．． tl) is obtained. Melting point 203~-oa"cc decomposition) Engineering R (KBr, eM-") /6. lr, /j1
0. /jJjHMR(DtO,Na0D) 3.3
0-44.10 (jH, m, α.

β-CdanCcy), 4t, 02 (j[, 8, N-0
)13) Example/! /-carbobenzoxyamino-λ-(7/-methyltetrazole-61, (l)thioethylphosphonic acid/-amino-λ-(/'-methyltetrazole-!'-
il) thioethylphosphophone j! Iλ/θ■ (/, /7 mmol) was bathed in an aqueous solution (/j@/) of sodium carbonate 34401q (da,/mmol), and ether of carbobenzoxy chloride-4o IIF (hej2 mmol) was added. Add solution (10 gd) dropwise and stir at room temperature for 1 hour. Thereafter, the process was carried out in the same manner as in Example/a) except that the crystallization from ether was omitted. )) The indicated compound ♂Oq
(Yield, (4t) is obtained.

Example 7g /-carbobenzoxyamino-2-(//-methyltetrazol-!'-yl)thioethylphosphonic acid monoethyl ester/-carbobenzoxyamino-2-(//-methyltetrazol-!'-yl) -yl)thioethylphosphophone #! 2♂
0q (0,7! mmol), anhydrous pyridine jm,)lichloroa heptonitrile 32! Using Misaki (J, 27 mmol) and 70 mol of absolute ethanol (,2, Jj j 17 mol), the described compound Misaki (Yield: 0 Chi) is obtained in the same manner as in Example 7.

N MR(CDO4,,δ)/,/l (jH,t,
J-7Hz.

OH, 043), J', /J' ~4t, 7. ．． 2
(jH,m, -8OW,OH-.

-O horse OH,), 3.73 (jH, +1. NO!
3), r, 06 (JH.

s, -OH, PI), lh, jJ (jH, d,
ImrHz, 0OH3).

7. 2J'(jH,s, Ph), 9. jO(/k
l, s, 0IL) Example/7 /-amino-(/'-methylteto2zole+j/
-yl)thioethylphosphonic acid monoethyl ester/-carbopenzoxyamino-2-(7/-methyltet2zol-!'-yl)thioethylphosphonic acid monoethyl ester (o, 62 mmol) Hydrogen bromide saturated vinegar is added to solution 3d and stirred for t minutes at room temperature. Add ether io to the reaction solution.

- is added, and the precipitated wrinkles are cooled (0°C) and washed with ether. The resulting precipitate (HBr salt) is dissolved in ethanol/J- and propylene oxide J- is added. The solvent is distilled off under reduced pressure and the residue is washed with ether to obtain the title compound i 4to trq (yield: 2r). Melting point 77
~//! °C Engineering R (KBr, cm-')/710. /4koj
, /3IItONMR(D,O,Na0D, δ
)/, 20 (JH,t, J-7Hz.

OH, OH3), ! ,,2j ~4t, Jj (jH
,m, -8CH,OR-.

-OH, 0H3), 4t, θj (jH, B, NO
H,) Example/l l-amino-carpamoylthioethylphosphonic acid phosphocystine was concentrated with water [1! ! (/2/v/v) of θdK# oak and palladium black 20019 were added to the mixture and hydrogenated at room temperature and normal pressure. io waiting time post-medium is removed,
The p solution was dried under reduced pressure to quantitatively extract phosphocystine hydrochloride (
790~).

To this, water 7.1- and acetic acid θ, λ, 2 fRt (L/
Add diluted sodium chloride (mirisol) and add θ■ (
A water bath solution (jrnl> of 7,4jjHJ mol) is added dropwise.The reaction solution is allowed to stand for a day at room temperature, and when the crystalline Pi precipitates, the indicated compound/joyq (yield 20%) is obtained.Melting point: 24tr - 26J℃ (Disassembly) Engineering R (KBr, cIn
-' )/710. 11m 0. /jri0゜/!
36゜Example/9 /-Amino-λ-phenylcarbamoylthioethylphosphonate hydrochloride Phosphocystine trr2q (co, /4t mmol) was hydrogenated in the same manner as in Example // and quantitatively obtained phosphocystine Dimethylformamide hydrochloride! -, phenyl isocyanate 0.24tlR/(≦,/-
mmol] and leave to stand at room temperature for 2 days. After the reaction, the solvent was distilled off under reduced pressure! ! The 4 residue is crystallized from 90% ethanol to obtain the title compound ♂20■ (yield: 4tt%). Melting point/? ! ~200℃ (decomposition) Engineering R (KBr, tB-') /700. /61
0. /6θQ.

/ to 13;, /j0O N M R (CI+!, Co, D, δ) j, 7~4t
J (j)1. m.

5O40dan-), 7.0~7. j (J-H, m,
Ph) Example-〇/-amino-phenylthio-rupamoylthioethylphosphonic acid phosphocystine J/, lq (/, 00 mmol) was hydrogenated in the same manner as in Example/r and obtained quantitatively. Phosphocystine hydrochloride dimethylformamide 7, tNtl
ll: dissolved, phenyl isothiocyanate 0.2, Z
(2.4t mmol) t' added at room temperature/j waiting time then at 60℃! Heat for an hour.

After the reaction, the solvent is distilled off under reduced pressure, the residue (HCl salt) is dissolved in methanol, propylene oxide is added, and the solvent is distilled off. The residue was subjected to reverse phase silica gel column chromatography (018
; developing solution ts, 10~-θ timethanol-containing water) and recrystallized from water, the indicated compound/? 0 cape (yield 6
2%). Melting point -4t, <~7°C (decomposition) Engineering R (KBr, an-') /1.00. /jko! ,/! θQ.

NMR (OF, CtO□D, δ) El ~g, r (
jH, m.

7.31 (jH, a, Ph) Example 2/ /-Carbobenzoxyamino-,2-(2',3'-dihydroxyglobil)thioetherphosphonic acid diethyl ester N- Carbobenzoxy-coaziridinylphosphonic acid ethyl ester 609 (3,07 mmol) and α
-Thioglycerin tata (0, -0 mmol) is dissolved in chloroform Jr*, boron trifufluoride diethyl ether complex 0,/J-61 is added, and the mixture is stirred at room temperature for y days. Thereafter, the treatment was carried out in the same manner as in Example 3 (however, the developing solvent for silica gel column chromatography: 4t Timetanoe R)
(neat, 5F+-') /720. /Ot
! , /141ONMR(CD0J,, ,δ) /
, J4t(jH,t, Jm7k.

OH*O:, ) /, 30 (jH,t, J=7f
lffi, OH, O! ! ,).

2.16~ujj (/44 H, m, -0R20H
(4, Son, 0ff-.

0! , 0H3X, OHx, z), ! , /J (2
H, a, -0 equivalent Ph).

z, 70 (iH, a, J-i2kLz, 0ONK
-), y, jO (sJs, Ph) Example 2λ /-Aminocor(J/, 31-dihydroxyglobil)thioethylphosphonic acid/-Carpobenzoxyamino-(21,j/-dihydroxyglobil) Thioethylphosphonic acid diethyl ester J-jOq (/, 3/mi IJ mol) is mixed with mold salt i! i
Dissolved at 7 mK and heated under reflux for 77 hours. The solvent was distilled off under reduced pressure. Ethanol was added to the residue to remove insoluble substances, and F
Propylene oxide in liquid! Add -. θ'CK was cooled, the precipitated crystals were washed with ethanol and ether, and subjected to reverse phase silica gel column chromatography (O12;
When purified with developing solvent water-methanol), the indicated compound 9 is obtained.
owq (yield 30%) is obtained. Melting point /70~/7.2.
j℃(decomposition) , R(KBr, cm-' ) /j/J, /6
11N MR (DtO, Na0D, δ), 70-
u,jO(cl'H,m.

-ckl, adanCumaSCdan, Cdan-) Sender Sanshi Kasei Kogyo Co., Ltd. Representative Patent Attorney Hase - Others/names

Claims (1)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In general formula (I), n means 0, 1 or 2, and X has a) substituent. It means a good alkyl group (however, this does not include the case where n is 0), or b) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 means a hydrogen atom or an alkyl group. ) or c) ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Z means 0 or S, and R^4 means a hydrogen atom, an alkyl group, or an aryl group.However, when n is 1 or 2) does not include the case of ). Y is a hydrogen atom or a protecting group for an amino group, and R^1 and R^2 are the same or different hydrogen atoms or alkyl groups] A β-mercapto-α-aminoethylphosphonic acid derivative.