JPS5829780A - 5-substituted alkyl-1,3,4-thiadiazole-thiol - Google Patents

Abstract

NEW MATERIAL:A 5-substituted alkyl-1,3,4-thiadiazol-thiol expressed by formulaI[R is di-substituted alkyl (the amino group may be protected) substituted by two amino groups or one amino group and carboxyl group respectively]. EXAMPLE:5-(1,5-Diaminopentayl)-1,3,4-thiadiazole-2-thiol. USE:An intermediate for medicines, e.g. an intermediate for cephalosporin antibiotic substances substituted at the 3- or 7-position. PROCESS:A compound expressed by formula II[R' is H2N(CH2)nC(NH2)H-, etc.]is esterified to give a compound expressed by formula III (R'' is methyl, ethyl or benzyl), which is then converted into a hydrazide to give a compound expressed by formula IV. The resultant hydrazide compound expressed by formula IV is then reacted with carbon bisulfide in the presence of a base, e.g. KOH, to afford a compound expressed by formula V, which is finally cyclized in the presence of a condensing agent to give the compound expressed by formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to iIT-based 5-monosubstituted-1s3+4-thiadiazole-A-2-thiols.

More specifically, R in general formula 1 shown in the figure below is . 5-monosubstituted - represented by two amino groups each having one amino group and a two I1-substituted alkyl group (the amino group may be protected) as a carboxyl & t-functional group
It relates to 1r3+4-theadiazole-2-thiols. These compounds #'i, pharmaceutical intermediates,
For example, it becomes an Ichikawa chemical compound as an intermediate for substitution at the 3rd or 7th position of cephalosporin antibiotics.

The raw materials used in the present invention are basic or acidic amino acids, and as such, h. Examples include lysine, ornithine, asparagine, or glutamic acid.

Drain these raw materials into the desired 51@conversion-1ri3ν4-
The method for synthesizing thiacyazole-2-thiols is shown in the reaction formula shown below.

(Reaction formula) Methyl, ethyl, and benzyl are added to the alcohol used in the esterification of reaction (1) above, and the usual esterification method, even I! yk drying using the above alcohol as a solvent
O/gas, 800/2, H, 80, etc. are used as dehydrating agents.

Furthermore, the hydrazidation of (2) can be easily achieved by reacting hydrazine with an ester.

The bahate used in this reaction is water, alcohol, or a mixture thereof, and the objective is to precipitate it in the form of crystals or oil, which can be removed by filtration or decantation.

Next to (2), dithiocarbazine oxidation can be carried out by treating hydrazide with carbon disulfide in the presence of a base. The solvent used in this reaction is alcohol, such as methanol or ethanol. Further, as the base, potassium hydroxide, sodium hydroxide, etc. are used.

Afterwards, the cyclization of (1) is carried out by reacting the dithiocarbazic acid salt with a condensing agent. The solvent II'i for this reaction is a condensing agent. Examples of condensing agents used for this purpose include strong acids such as Fisulfur #11 and phosphoric acid.

In this reaction, any group used as a retaining group for the amino group may be used as long as it is not eliminated during the reaction and does not particularly affect the reaction, but examples of such groups include acetyl group, benzyloxycarbonyl group.

Specific examples of target compounds obtained by the method of the present invention are shown below.

-N RJ8JJ-8H (OR=HtN(CHt)*OH: 5 (+ +
5-diaminoNH.

pentyl)-1-3-4-thiadiazole-2-/' Thiol.

(Phantom Lu H, N(OH,), (jH-: s-(l
ν4-diami/NH.

butyl) -1+ 394-theadiazole-2-thiol.

I) Lou HOOO((JH,), OH-: 5- (
1-Amino-3-NH.

carboxy) 10biru-1*3y4-thiadiazole-
2-thiol.

) R=HOOOOH,OH-: 5- (1-amino-2-kaban NH.

ruboxy)ethyl-1s3*4-nadiazole=2-
Thiol.

(V) R=HOOOUH[)H,), -: 5-(
3-7mi/-3-NH.

carboxypropyl) 1s3t4-thiadiazole-2-thiol.

(Tsukasa R=HOOOOOHO)1. - : 5- (2-
Amino-2-kaNH.

lupoxyenal), 1t3t4-thiadiazole-
2-thiol.

Next, an example of the method for producing the compound of the present invention will be explained.

Cool ME! ? 'jl 5 (1t5-diaminopentyl)193t4-thiadiazole-2-thiA-l.

(11 ester 1ζ and acetylated-lysine hydrochloride 18.25? (0.1 mol) 2
The suspension was suspended in 00-methanol, and dry hydrogen chloride gas was introduced therein until it was completely saturated. After 7 hours, the mixture was heated under reflux on an oil bath for 2 hours, and then 50 g of benzene was added thereto, and the bath was distilled off under reduced pressure. The obtained crystals were suspended in Methychloro 200ml, triethylamine 2BWIt was added thereto, anhydrous vinegar #30 was added to the solution excluding the precipitated crystals, and the mixture was reacted at room temperature for 4 hours. After the reaction, the reaction solution was washed several times with cold water 11005I, the solvent was removed under reduced pressure, and a syrup-like α
C-bisacetyllysine methyl ester IOf'i was obtained. Yield 41% I) L, 1733 country-1 (also Scholl)
1649 cm-' (2J hydrazidation f E (Z + t-bis-acetyllysine methylendel 9.769 (0.04 mol) i methanol 100
- dissolved in t~, where hydrazine dihydrate 4.4 v
After adding (o, osμ) and stirring at room temperature for one day, the precipitated crystals were mixed and washed with methanol to obtain the desired αt6-
Pisacetyllysine hydrazide 7tf samurai. Yield about 71
,7% L, 1647G! +' (KBr)J550a
*-” (3J dithiocarbazine oxidation tW (ate-bisacetyllysine hydrazide 4.8
8 r (0.02% & ) i 2.24 f O
The mixture was added to 30 ml of 1K solution of tJlium hydroxide and ethanol under cooling with water. To this, 2.28 f (0.03 mol) of carbon dioxide was added to the mixture under PjL##L, and the reaction was allowed to proceed overnight at room temperature. The precipitated crystals were removed and washed with cold ethanol to obtain the desired 3-(αIC-bisacetyl lysyl dithiocarbamono-compensated potassium salt 5.42).

Yield: 75.4% 10H2Om-' (KBr) 164] Preparation-1 (4) 3-(ate- and suaceterlysyl) ditheocarbazine potassium salt that was present in the cyclization reaction (6) 5.37 ? (0,015
mol) water-cooled l1w & acid 255drC 30 minutes E-f
I added fte little by little. This was further stirred for 2 hours at fC, and the Tomoyo reaction solution 1 was poured into 300 g of crushed ice while stirring.

The precipitated viscous crystals were collected and 5-(1?5-diacenalamitopentel)' 1+3+4-thiadiazole-2
-Chale 3. (I got 13ft.

Yield 66.95+! (4) 5-(lt 5-diacenalamidebentyl)-1r 3 + 4-thiadiazole-2-
Thiol 3y (9.9 mmol) was dissolved in 6N-hydrochloric acid 15
- It was dissolved in a bath and heated for 3 hours. This bath liquid was linearly dried under reduced pressure, and the residue was washed several times with ether to obtain the desired 5-
(1ν5-cyanobe/chill) l+3+4-theazole-2-thiol salt #salt 1.2 f sound thing.

Yield 56% I kL 3352cR1-” KBrl-2~z,
o(m) (OH@)* NMR (ppo>)1.8-2.2(m) 0H2-
0-N*ktllllI25 (+*4-diaminobutyl)-1v394-thiadiazole-2-thiol.

Synthesis of Yama dithiocarbazic acid L-1k2f:7m Salt 16,62 W (++, 1 mol) was used in the same manner as in Example 1 (11t (1) + <3) to prepare 3- (aν6 6.5 y of potassium salt of ditheocarbazate (bisacel orniter) was obtained. Yield: 18
．． 9% IR1683cm'1639m'' (21 cyclization reaction 113-(α2d-bisaceteloroninal) ditheocarbazic acid 6.5 r (18.9 mmol) was used,
Closing the ring using the same operation as in (41) of 5 (++
4-bisacetamidophthyl) 1 +394-thiadiazole-2-thiol 4.22. Yield 74.
6% IR33510m-' + 1633m-' (K
Br) NMFL (ppm)1. s ~z, z(m)oH
,ts! , (1-:s,3(m)OH,N on Nc5-(
Using 4v (13,4-' IJ mol) of 4-thiadiazole-2-thiol (atO-bisacetamidophthyl), the desired 5
-(ate-diaminobutyl)-1*3+4-thia7azole-2-thiol acid salt 2.3v.

Yield 59.7% IR3120cm' (KBr) NMR (ppm) 1.5-2.2 (m) OH2 to IMA 35-(2-amino-2-calphokidiethyl)
]]t3t4-thiadiazole-2-thioll) acetylated asparaquine-β-benzyl ester 22.3 f(
The product was dissolved in 0.1 mol of t-50% acetonitrile (100%) and added with 30% of acetic anhydride to carry out monocenarization reaction. During this reaction, a 5% Na 800 s bath solution
I lowered KM by 1 town and adjusted 9H to 7-9. After the reaction, half of the solvent was removed under reduced pressure, then 2 to 3 VL of PU was extracted, the first layer was extracted with ethyl acetate (10), and the first layer was dried with nitric oxide and dried to a fine oil. This oil was washed with hexane and left to cool overnight to obtain N-acetyl anuparagic acid β-benzyl ester 229'.

Yield: 83% IR1734 (Il+'1651m' (2) Synthesis of hydrazide The above N-acetylaspartic acid-β-benzyl ester 22r (0,083 mol) was dissolved in 100% ethanol and hydrazine dihydrate 7. 889 (0.15 mol) was added and stirred at room temperature for 2 days to obtain an oily precipitate.The supernatant was removed by decantation, washed several times with ethanol, and N-acetylasparagine-β-hydrazide 11 .5f1ki.

Yield 72.16
1.52 & (0,t16 mol) was added to a bath solution of 6.729 potassium hydroxide and 70% ethanol in ice-cold F.
In addition, it was dissolved in bath. After this, disulfide coal car 6.84t (0,0
4 mol) and stirred at room temperature overnight to obtain an oily precipitate. The upper layer was removed by decantation, washed several times with ethanol, and dried to obtain 3-(3-acetamide-3
-carboxypropionyl)-diteocarbazate potassium salt 12.8 vtl was obtained.

Yield 69.7'X Upper Me3-(3-acetamido-3-carboxypropionyl)-dithiocarbazate potassium salt 9.18 f
(0,03mo, a, ) e Ice-cooled L7'j #Sulfur 1!1
30 mK was added in small portions over 30 minutes. This was further left in the dark for 2 hours, and then the reaction solution was poured into crushed ice with stirring. Take the precipitated crystals and give 5-(
2-acetamido-2-calphokidiethyl)-1g3*
5.4 ft of 4-thiadiazole-2-thiol was obtained.
Yield: 72.0 volumes IR334951't629m' (KBr
) NMR (ppm) 2.0 (8) OH3 above 5-(2-acetamido-2-carboxyethyl)
It3*4-thiadiazole-2-thiol5. Of
(0.02 mol) was dissolved in 30-6N hydrochloric acid and heated for 3 hours. This bath solution was concentrated and dried under reduced pressure, and the residue was washed with ethanol to obtain the desired 5-(2-amino-2
-carboxyethyl)-1-3-4-thiadiazole-
2-thiol hydrochloride 3.2tk'+1j'IC, yield 5
8.3
1+324-Thiadiazole-2-thiol・Glutamic acid-T-benzyl ester 23.79 (0,
(1 mol) of Example 3, (1)*(2J s
By the same operation as (3), 3-(4-acetamide-
12.6 ft'' of potassium salt of ditheocarbazate (4-carboxybutyroyl) was obtained. Yield: $39.4%I
R1682cIn-'1638011-' 3 (4-acetamido-4-carboxybutyroyl)-diteocarbazate potassium salt 11.16f (
(1,035 mol) using i, refreshing Ml? 113 (4), 5-(3-acetamido-3-carboxyproyl) 1w3t4-thiadiazole-2
- Thiol 5.9f was obtained. Yield 63.8% IR335
30gI' t 1630611-' (KB
r) NMFL (ppm) 2. u(s)OH.

Above 1c: 5-(3-acetamido-3-carboxyproyl) 1y394-thiadiazole-2-thiol 5,24 t (0,02 mol) (5 of Example 3 using gold)
), p, the desired 5-(3-amino-3-
3.7v of 3v4-thiadiazole-2-thiol hydrochloride was obtained.

Yield 64.85J6 1R3130a*-” (KBr) NMR (ppm
) 1.7~2.2 (m) OH2*hA155-(
1-amino-2-carboxyethyl) I*3t4-
Thiadiazole-2-thiol. .

L-7 Sparagine ill-a-benzyl ester 22
．． 3 t (o, 1 mol) t-50% acetonitrile 1
00- dissolved in anhydrous 1jil: fil 30 m
f 5% NaHOOs was added dropwise while adjusting the pH to 8-9. After the reaction, remove the solvent under reduced pressure II! i+L40m
And so. Then adjust the pH to 2-3 and i! 1′! After extraction with 200% of ethyl acetate, the organic layer was dried with e(in) and concentrated to dryness to leave an oily residue.

The oil was washed several times with hexane and 21.6 tons of heacetelaspartic acid a-benzyl ester was added. Yield: 81.5% (2) Hydrazated N-acenal asparagine 1ll-a-benzyl ester 19. Dissolve t ((1,0736 mol) in ethanol 150s!, hydrazine 2 water tFu@
7.35 (0.14 mol) was added and stirred at room temperature for 2 days to obtain an oily precipitate. Top 1! After removing It by decantation and washing with ethanol several times, 1! ! :
After drying, 10.7 ft of N-acetylasparagia ell-a-hydrazide was obtained. Yield: 75.7 units IR165251-' The above N-acetylaspartic acid-a-hydrazide 10
．． 37 f (0,054 mol) t1 potassium hydroxide 5
6 was dissolved in 75% of ethanol under water cooling and dissolved therein. When this hydrogen disulfide and 7 V (0,075 mol) were added and stirred overnight at room temperature, an oily precipitate was formed. The upper layer was removed by dtv decantation, washed several times with ethanol, dried, and 3-(2-acetamide-j
-carboxypropionyl)-diteocarpara/111
Potassium salt was 11.9Wlf.

Yield 72. 3-(2-acetamido-3-carboxypropionyl)-diteocarbazate potassium salt 9.18 v
(0.03 mol) was added portionwise to the cooled condensed acid 25 over a period of 30 minutes. After stirring for another 3 hours, the reaction solution was poured into crushed ice without stirring.

The precipitated crystals were taken and mixed with 5.62 ml of 5-(1-aceto-1mido-2-carboxyethyl)-1+324-thiadiazole-2-thiol. Yield 74.7 units IR33513't1635bi-' (KBr)
NMR (p) 2.0 (S) OH.

The above 5-(1-acetamido-2-calphokidiethyl)
-1* 3 r 4-thiadiazole-2-thio-#
5.0f (0.02%) was dissolved in 30% of 6N hydrochloric acid and heated for 5 hours at 111fIIt. This solution 'f: Dry the mold surface under reduced pressure, wash with residual ether, and remove the desired 5
-(+-amino-2-carboxyethyl) I? 3t
4-thiadiazole-2-thiol hydrochloride 3.82%. Yield 69.2 units IR31283'' (KBr) NMR (ppm) 2.2-2.6 (m) OH2
(Dl*Ot N5OD) 4.1~4.5 (FM)
CHN Example 65-(1-amino-3-carboxypropyl) I*3ν4-thiadiazole-2-thiol (1) Synthesis of dithiocarbazic acid L-glutamic acid-α-benzyl ester 23+7f(
0.1 mol) and carried out? ! l 5 (11y L2
)? 3-(2-acetamido-4
-Carboxybutyroyl)-diteocarbazic acid-potassium salt 12,85f was obtained. Yield 40.16% Upper (2-acetamido-4-carboxybutyroyl)-
Dithiocarbazine potassium salt 12.8 t (0,0
Using 4 mol), 5-(
1-acetamido-3-carboxypropyl)-1*3
6.3 tons of t4-thiadiazole-2-thiol were obtained.

Yield 59.7% IR3347tx-'t 163
4z-' (KBr)NMR (ppm) 2.
0 (S) 0H31,9~2.3 (f?riOH.

D, 0 () 2.1~2.4 (ffl)OH, -0
=OaOD 3.8-4.2 (m)OH-N LJJ De-retention reaction [5-(+-acetamido-3-carboxypropyl)-1s3t4-thiadiazole-2-thiol 6.6
1 (0-025 mol) and the same procedure as in Example 5 (5J) to prepare 5-(1-amino-3-carboxypropyl).
-1t3t4-theadiazole-2-thiol 3J8f was served. Yield 55,76%IR3126m
-' (KBr) NMR (ppm) 1.8-2.3 (m) OH@
Applicant Applicant Seikou Kogyo Co., Ltd.

Claims (1)

[Claims] General formula (in the formula, R is substituted with two amino groups or one amino group and a carboxyl group each. 2111 alkyl group (amino group may be retained) -5-substituted alkyl-1v3t4-thiadiazole-2-thiols represented by