GB2220415A - Process for producing a sulphamide - Google Patents

Process for producing a sulphamide Download PDF

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Publication number
GB2220415A
GB2220415A GB8820830A GB8820830A GB2220415A GB 2220415 A GB2220415 A GB 2220415A GB 8820830 A GB8820830 A GB 8820830A GB 8820830 A GB8820830 A GB 8820830A GB 2220415 A GB2220415 A GB 2220415A
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GB
United Kingdom
Prior art keywords
formula
compound
methyl
amino
diaminomethylene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB8820830A
Other versions
GB2220415B (en
GB8820830D0 (en
Inventor
Moon Gyu Koh
Jai Moo Shin
Dong Soo Kim
Choon Seok Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HANIL PHARMA IND
Hanil Pharmaceutical Ind Co Ltd
Original Assignee
HANIL PHARMA IND
Hanil Pharmaceutical Ind Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by HANIL PHARMA IND, Hanil Pharmaceutical Ind Co Ltd filed Critical HANIL PHARMA IND
Publication of GB8820830D0 publication Critical patent/GB8820830D0/en
Publication of GB2220415A publication Critical patent/GB2220415A/en
Application granted granted Critical
Publication of GB2220415B publication Critical patent/GB2220415B/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

1 CHEMICAL PROCESS The present invention relates to a novel process f or
preparing 3-[ [ [2- (diminomethylene) amino] -4-thiazolyl] inethyl]thio-Nsulphamoylpropionamidine of formula (I):
H 2N > = HN 2 N NSO 2NH2 / _r S NH 2 -\/ S 'I (I) various processes for the preparation of the compound of f ormula (I) are known in the art and are disclosed in European Patents Nos. 87,274 and 128,736; Japanese Patent Applications Nos. 80-118476 and 81-05469 and US Patent No. 4,496,737. However, all of the prior art processes described above disclose various complicated purification steps for obtaining the pure compound of formula (I) and do not disclose an improved process for producing the compound of formula (I) with excellent yields.
Accordingly, it is an object of the present invention to provide an improved process for the production of the compound of formula (I) with little or no byproduct and in relatively high yeild.
This invention provides a novel process for preparing the compound of formula (I) by reacting a monoprotected sulphamide of formula (II) with an imidate compound of formula (III) and subsequently deprotecting. In addition, the present invention has the advantage that the compound of formula (I) can be 2 obtained in relatively high yield and substantially without any by- products, and is easy to isolate and purify.
Formulae (I), (II) and (III), the latter two of which are general formulae, may be set out as follows:
NSO NH H 2 N > = N - N S "^ N112 H 2 N S (I) H2NS02NHR, NH H 2 N > = N -/< N S 11-1.1k H 2 N S 11 n OR2 (III) wherein, in formulae (II) and (III), R, is a trialkylsilyl radical and R2 is a lower alkyl group.
In this specification the terms "alkyl" and "lower alkyll' include alkyl chains having from 1 to 4, 6 or even 8 carbon atoms. Preferred R, radicals include trimethylsilyl and t-butyldimethylsilyl. Preferred R2 radicals include methyl, ethyl and propyl. The formulae (I), (II) and (III) encompass acid addition salts where appropriate.
Thus, the compound of formula (I) by this invention can be produced by the following process:
H2NSO 2M1R1 + (II) 1 3 H 2 N > = H 2 N NH N-( N rl S OR 2 S, (III) NS02NIIR 1 N S WL 2 > = N-< 2 (IV) H2N S t NSO 2UH2 H 2 N > =N-< N S H2N S wherein R, and R2 are the same as defined above.
(I) A compound of formula (IV) is prepared by the reaction 20 of a compound of formula (II) with a compound of formula (III) in generally high yield.
A compound of formula (II) is conveniently reacted with a compound of formula (III) at a temperature of from 300C to 700C, preferably at 500C. The reaction may take place in an aprotic solvent such as acetonitrile, tetrahydrofuran, dioxane, sulpholane or N,Ndimethy1formamide. The duration of the reaction may he from 8 hours to 12 hours.
A mono-protected sulphamide of formula (II) can easily be prepared from the reaction of sulphamide with hexamethyl disilazane or tbutyldimethylsilyl chloride 4 and used in situ. It is not necessary to isolate a compound of f ormula (IV). Without isolation, the compound of f ormula (IV) prepared as described above can be deprotected in situ with the removal of the R, group, particularly in the presence of an appropriate catalyst such as acetic acid, an alcohol, water, a tetraalkyl ammonium fluoride, a lithium halide or a caesium halide; deprotection may take place in a protic solvent such as methanol or ethanol to give the compound of formula (I) with high yields.
A process in accordance with this invention may provide the desired product in high yield without significant by-products, whereas known processes provide the product in relatively poor yield with some byproducts, one of which is a dimer-type sulphamoylamidine compound (I. Yanagisawa, et al., J. Med. Chem., 1987, 30, 1987).
Preferred embodiments of the present invention will now be described in more detail in connection with the following examples which should be considered as being exemplary and not limiting the present invention.
Example 1
2-5 N-trimethylsilvisullDhonamide To a suspension of sulphonamide (9.8g) in acetonitrile (100m1) a solution of hexamethyldisilazane (12m1) in acetonitrile (10m1) was added and the mixture refluxed for 4 hours to give clear solution.
The solvent was removed in vacuo, to give a crystalline solid, which was N-trimethylsilysulphamide (16.8g).
m. p. 57-580C (uncorrected) 1H NMR(WC13): delta 0.3(s,9H, -SiCMe3) 1 D Example 2 3-[[[2-(diaminomethylene)amino]-4-thiazolyl] methylithio-NsulphamovlproDionamidine To a solution of N-trimethylsilylsulphamide (26.7g) in an acetonitrile (150m1) was added methyl 3-[[[2(diaminomethylene) amino] -4- thiazolyl]methyl] thiopropionimidate (24.6g), and stirred at 500C for 12 hours. The solvent was removed in vacuo to give a syrupy solid, which wa! a mixture of N-silyl product, N-silysulphamide and a little desilylated sulphamide. The mixture was dissolved in methanol (150m1), and a solution of tetrabutylammonium fluoride trihydrate (5g) in water (15m1) was added with stirring at room temperature for 3h. Some solids were precipitated after standing overnight and kept at 40C for a few 20 hours.
The solids were collected by filtration, and recrystallized from DMF-H20 to give the title compound (24.2g).
m. p. 163-1640C 1H NMR(MSO-d6): delta 6.45(s, 1H), 3.60(s, 2H), 2.65(m, 2H), 2.50(m, 2H).
0 Example 3
To a solution of N-(t-butyldimethylsilyl)sulphamide (3.5g) in acetonitrile (15m1) was added solid methyl 3- 6 [ [ [2- (diaminomethylene) amino] -4-thiazolyl] methyl] thiopropionimidate (2.5g); the mixture was stirred at 600C for 12 hours. The solvent was removed by distillation in vacuo to give a syrupy residue, which was dissolved in methanol and a solution of tetrabutylammonium fluoride trihydrate (2g) in water (5m1) was added dropwise. The reaction mixture was stirred overnight to give a crystalline solid, 3[[[2(diaminomethylene)amino]-4-thiazolyl]methyl]thio-Nsulphamoylpropionamidine (2.1g).
Example 4
To a suspension of sulphamide (14.8g) in acetonitrile (70ml) was added hexamethy1disilazane (16ml); the mixture was refluxed for 5 hours. The clear solution was concentrated under reduced pressure and dissolved in anhydrous acetonitrile (80ml). To the solution as described above was added methyl 3-[[(2-amidino-4- thiazolyl)methyl]thio]propionimidate (27.3g); the mixture was stirred at 40-500C for 12 hours. The reaction mixture was concentrated to give a syrupy solid, which was dissolved in methanol (150ml). The solution was stirred at room temperature while a solution of tetrabutylammonium fluoride trihydrate (5g) in water (15ml) was added. Crystalline solids were separated and the suspension was cooled at 40C and left to stand overnight. The solids were collected, washed with a little cold methanol, and recrystallized from DMF-H20 to yield the desired N-sulphamoylamidine product (24.6g).
7

Claims (10)

  1. A process for preparing 3-[[[2(diaminomethylene)amino]-4thiazolyl]methyl]thio-N sulphamoylpropionamidine of formula (I) NSO 2 NH 2 N r /^,k H 2 N N 1 S NH 2 H 2 N > = - 5 1 (1) which process comprises the steps of:
    (a) (I1) reacting a mono-protected sulphamide of formula H2NS02NHR, with an imidate compound of formula (III) NU 33 H2N > = N _ S H25 1 N S ^ OR 2 (111) to produce an N-protected sulphamoylamidine compound of formula (IV) NSO 2 NHR 1 H N: If S NH H 2 N ≥N _ S 2 (IV) 8 and (b) deprotecting the N-protected sulphamoylamidin compound of formula (IV):
    NSO 2 NHR 1 NH 2 (IV) H N -": If S R2N > = N 2 wherein, in each of formulae (II), (III) and (IV), R, represents a trialkylsilyl radical and R2 represents a lower alkyl group.
  2. 2. A process as claimed in claim 1, wherein R, represents a trimethylsilyl or t-butyldimethylsilyl radical.
  3. 3. A process as claimed in claim 1 or 2, wherein R represents a methyl, ethyl or propyl group.
    2
  4. 4. A process as claimed in claim 1, 2 or 3, wherein reaction step (a) is conducted at a temperture of about 25 500C.
  5. 5. A process as claimed in any one of claims 1 to 4, wherein reaction step (a) is conducted in an aprotic solvent.
  6. 6. A process as claimed in any one of claims 1 to 5, wherein the compound of formula (IV) is deprotected in situ without isolation.
    9
  7. 7. A process as claimed in any one of claims 1 to 6, wherein reaction step (b) is catalysed.
  8. S. A process as claimed in claim 7, wherein the catalyst used comprises acetic acid, an alcohol, water, tetraalkyl ammonium fluoride, a lithium halide and/or caesium halide.
  9. 9. A process for the preparation of 3-[[[210 (diaminomethylene)amino]-4thiazolyl]methyl]thio-Nsulphamoylpropionamidine substantially as herein described with reference to the Examples.
  10. 10. 3- [ [ [2- (diaminomethylene) amino] -4 15 thiazolyl]methyl]thio-Nsulphamoylpropionamidine whenever prepared by a process as claimed in any one of claims 1 to 9.
    Published 1989 at The Patent Office. State House. 66,'71'High Holborn. London WCIR4TP. Further copies maybe obtained from The Patent Office. Sales Branch, St Mary Cray. Orpington, Kent BR5 3RD. Printed by Multiplex techniques itd, St Mary Cray, Kent, Con. 1/87
GB8820830A 1988-06-10 1988-09-05 Process for producing a sulphamide Expired - Lifetime GB2220415B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1019880006994A KR900004907B1 (en) 1988-06-10 1988-06-10 The preparation for n - sulfamoyl -3- ((2-guanidinothiazole -4- yl) methylthio) propion amidine derivatives

Publications (3)

Publication Number Publication Date
GB8820830D0 GB8820830D0 (en) 1988-10-05
GB2220415A true GB2220415A (en) 1990-01-10
GB2220415B GB2220415B (en) 1991-12-18

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GB8820830A Expired - Lifetime GB2220415B (en) 1988-06-10 1988-09-05 Process for producing a sulphamide

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KR (1) KR900004907B1 (en)
DE (1) DE3831162A1 (en)
GB (1) GB2220415B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731442A (en) * 1997-03-11 1998-03-24 Albemarle Corporation Synthesis of thiazole derivatives
US5856500A (en) * 1997-03-11 1999-01-05 Albemarle Corporation Synthesis of thiazole derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3644246A1 (en) * 1986-06-20 1987-12-23 Uriach & Cia Sa J Process for the preparation of 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulp honyl)propaneimideamide

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59227870A (en) * 1983-06-07 1984-12-21 Yamanouchi Pharmaceut Co Ltd Novel 2-guanidinothiazoline derivative and its preparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3644246A1 (en) * 1986-06-20 1987-12-23 Uriach & Cia Sa J Process for the preparation of 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulp honyl)propaneimideamide

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5731442A (en) * 1997-03-11 1998-03-24 Albemarle Corporation Synthesis of thiazole derivatives
US5856500A (en) * 1997-03-11 1999-01-05 Albemarle Corporation Synthesis of thiazole derivatives
US5856501A (en) * 1997-03-11 1999-01-05 Albemarle Corporation Synthesis of thiazole derivatives

Also Published As

Publication number Publication date
GB2220415B (en) 1991-12-18
GB8820830D0 (en) 1988-10-05
KR900004907B1 (en) 1990-07-09
KR900000346A (en) 1990-01-30
DE3831162A1 (en) 1989-12-14
JPH01313471A (en) 1989-12-18
DE3831162C2 (en) 1992-02-20

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