HK1095065B - Capsaicin derivates and the production and use thereof - Google Patents

Description

Capsaicin derivative and its production process and application

The present invention relates to a novel compound, namely a capsaicin derivative, a novel method for the production thereof and the use thereof as a microbioprotective agent in paints and coatings, especially for marine installations and ships, and for land-based equipment and materials.

When the hull is clean and smooth and free of marine growth, the ship will travel faster through the water while burning less fuel.

Tributyltin (TBT) is nowadays used to prevent the growth of algae and marine plants, mussels, marine tulips and the like on ships. This growth generates friction, which entails a sudden increase in fuel costs. TBT is therefore added to marine paints in order to produce so-called "antifouling" paints. The TBT poisons marine organisms in contact with it and thus keeps the sides of the vessel free of marine growth.

Unfortunately TBT has a number of environmental side effects. TBT not only affects marine organisms that attempt to cling to the side of a vessel, but also poisons other marine organisms. In addition, TBT has been shown to accumulate in the marine food chain and cause abnormal development of various organisms. In addition, TBT has been shown to cause malformation of the oyster shell structure, sexual reversal of snails, and immune disorders and neurotoxicity and genetic alterations of other marine species.

These findings have led the UN International Maritime Organization (IMO) to decide to ban all applications of TBT in marine paints. Once the treaty is approved by all flag states carrying at least 25% of the world's total tonnage or constituting 25% of the IMO member states, the ban will take effect. Regardless of whether the minimum requirements described above are met, the treaty will take effect at the latest on 1/2008.

Thus, after 2008 for 1 month there will be an absolute ban on the use of TBT in such paints. Furthermore, this lacquer must be physically removed or coated with a protective layer lacquer that prevents TBT from coming into contact with water.

Therefore, there is a need for additional non-toxic microbial protectants that can replace TBT in marine paints.

According to the invention, a novel class of compounds can replace TBT as a microbial protectant. Such novel compounds are novel derivatives of the naturally occurring substance capsaicin that is extracted from red pepper (Capsicum annum) and other pepper fruits (Capsicum fruits).

Capsaicin ((E) -8-methyl-N-vanillyl-6-nonenamide) is extracted from red pepper as described above. It is well known that such extracts have been used as microbial protectants in marine paints. Other useful pharmacological properties have also been described in Dray, n.s. biochemical Pharmacology, 44, (1992), 611.

However, capsaicin extract has the following disadvantages, making it unsuitable as an ingredient in "anti-marine antifouling paints".

First, because such extracts are based on natural sources, the possibility of generating sufficient quantities due to natural fluctuations in the supply of the source material will also fluctuate, and the supply of the source material will also depend on the size, quality, price, etc. of the crop. This large supply of raw materials is nowadays very unreliable.

Second, the standardized capsaicin extract contains at least 3 isomers, has different chemical properties and is difficult to distinguish. It may be difficult to obtain a capsaicin extract with sufficiently uniform purity and composition for the intended application.

Third, modern marine paints are based on chemical bonding of the repellent to the polymer substrate to prevent the repellent from being immediately washed into the seawater. The polymer-based protectant is released in synchronization with the reaction of seawater and the polymer substrate. The less hydrophilic the repellent, the longer the service life of the marine paint will be. Natural capsaicin extracts are composed of several isomers of different chemical nature whose aqueous solubility varies with the pH of the water. This would cause undesirable and uncontrollable changes in the solubility of the protectant product based on natural capsaicin extracts.

From us patent 5,143,545, an anti-marine antifouling paint containing antibiotic-type active agents like e.g. chloramphenicol is recognized. The risk of antibiotic resistance through the transmission of such antibiotics for combating infectious human diseases shows that the use of such active ingredients in marine paints should be avoided.

From us patent 5,226,380, an anti-marine antifouling paint is recognized which contains particles of red pepper or pepper oleoresin derivatives as active agents. These capsaicin or red pepper based active agents suffer from the same limitations in raw material supply as described above. This also applies to the marine antifouling paint of us patent 5,397,385. Which comprises as an active ingredient capsaicin in the form of a fine powder, a liquid solution of capsicum oleoresin or crystalline capsaicin. U.S. patent 5,629,045 also describes an anti-boat-fouling paint containing capsaicin and vanillylamide derivatives having alkyl derivatives as active ingredients. Vanillylamide derivatives are produced based on extracts of capsaicin. The lacquer of us patent 5,698,191 also comprises capsicum oleoresin combined with a saponin compound.

It is an object of the present invention to provide an alternative to TBT that is not toxic and does not accumulate in the marine food chain.

It is another object of the present invention to provide an alternative to previously known capsaicin products, thereby avoiding the problems of unreliable supply of raw materials and price and quality fluctuations.

It is another object of the present invention to provide alternatives to known capsaicin products that can be produced with defined composition and high product purity.

It is another object of the present invention to provide alternatives to known capsaicin products with defined and/or reduced hydrophilicity.

It is another object to provide products with a broad spectrum of biological activity.

It is a further object to provide a protectant product with an acceptable ecological profile.

These objects are achieved by the features defined in the claims that follow.

In accordance with the present invention, there are provided novel compounds, namely novel capsaicin alkyne analogs referred to as phenyl capsaicin. The novel compounds of the present invention are characterized by the compounds of the following formula (1),

wherein R is a substituent selected from alkyl, trifluoromethylcycloalkyl, phenyl or halogen; when the substituent R comprises a carbon chain, it may be straight or branched chain, and may be further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, amino, alkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, oxygen, nitro, trifluoromethyl.

When R comprises a carbon chain, the carbon chain has from 1 to 8 carbon atoms, more preferably from 2 to 6 carbon atoms. Another group of preferred compounds of formula (1) are those wherein R has a carbon chain length of from 1 to 4 carbon atoms.

A particularly preferred group of compounds is that in which R is an alkyl group having 1 to 4 carbon atoms, and most preferred compounds are those in which R is isopropyl or propyl.

The compounds of formula (1) can be produced from carboxylic acid derivatives (3) wherein Z is HO or from conversion of carboxylic acids with vanillyl amino to produce capsaicin derivatives of formula (1), as shown generally in scheme A below:

Z＝Cl，OH，R¹O，NR¹ ₂

R¹alkyl radical

R is a substituent selected from alkyl, trifluoromethyl, cycloalkyl, phenyl or halogen; when the substituent R contains a carbon chain, it may be straight-chain or branched, and may be further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, amino, alkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, oxygen, nitro, trifluoromethyl.

Carboxylic acid derivative (3) is meant to include any of the reactants used in the reaction shown in scheme a, and may most preferably be an ester, amide or acid chloride. In the present specification, the term "carboxylic acid derivative (3)" also includes the carboxylic acid (4) itself.

Vanillylamino compounds (2) from vanillin can be produced as described by Kaga, h., Miura, m, and Kazuhiko, o., j.org.chem.54(1989) 3477. A yield of 42% was obtained.

The other reactant, compound (3) or (4), may be produced by the following steps:

converting the acetylenic compound (8) with protected 5-chloro-1-pentanol (7) to produce a protected acetylenic alcohol compound (6);

decomposing the protecting group from compound (6) to produce a free acetylenic alcohol compound (5);

oxidizing the compound (5) to produce a carboxylic acid (4); and

or converting the acid (4) to the carboxylic acid chloride (3).

The reaction sequence is illustrated in the following reaction scheme B:

r is a substituent selected from alkyl, trifluoromethyl, cycloalkyl, phenyl or halogen; when the substituent R comprises a carbon chain, it may be straight or branched chain, and may be further substituted with alkyl, alkenyl, alkynyl, allyl, aryl, alkoxy, aryloxy, alkanoyl, aroyl, amino, alkylthio, arylthio, cyano, cycloalkyl, cycloalkenyl, halogen, hydroxy, oxygen, nitro, trifluoromethyl.

In one embodiment of the present invention, novel capsaicin alkyne analogs having formula (1) are useful as microbial protectants. The microbe-protecting agent may be included in the paint or coating, either alone or as an ingredient in a mixture of microbe-protecting agents, to produce a finished product that prevents the growth of microbes and other living organisms on the surface to which the product is applied.

The agent or mixture can be added to the lacquer or coating in such a way that the active compound of the formula (1) is present in a concentration of 0.1 to 50% by weight, in particular in a concentration of 0.2 to 10% by weight. The most preferred concentration of the addition of the compounds of the formula (1) to the lacquer or coating is a concentration of 0.5 to 5% by weight, in particular 0.3 to 1% by weight.

One embodiment of the present invention is a microbial protectant comprising a combination of two or more compounds of formula (1).

Another embodiment of the present invention is a microbe-protecting agent comprising a combination of a compound of formula (1) and another microbe-protecting agent.

Another embodiment of the invention is a microbioprotectant mixture, wherein a compound of formula (1) is admixed with one or more inert additives, such as solvents, viscosity modifiers, i.e. diluents or thickeners; and/or a preservative is included in the mixture.

Another embodiment of the present invention is a paint or coating to which the microbial protectant or mixture of the present invention is added to prevent the growth of microorganisms or other small organisms such as seashells, algae, marine tulips, marine plants, and fungi. Such paints, known as "antifouling" paints, are mainly used on ships, in particular on ship hulls, or on marine installations, such as the hulls of solution environments, port structures and wharfs. The microbial protectant or mixture of the invention may also be applied in a coating that may be applied, for example, over a painted layer to form a watertight surface or a surface with other desirable characteristics.

Another embodiment of the invention is a paint or coating corresponding to that described above for land-based installations and structures, especially based on wood such as timber, wood panels and the like.

Biological assay

To elucidate the biological activity of capsaicin, the following biological assay was performed. This experiment shows that capsaicin has the biological activity and effect of the present invention. In other boat bottoms or paints, other activities may be obtained with capsaicin and/or other compounds of formula (1) at the concentrations used in this experiment.

Experimental procedure

Capsaicin was mixed into a commercially available boat primer that has been claimed to be free of biocide. The trade name of the lacquer is Fabio Eco^TMAnd produced by International Paint, Akzo-Nobel. 0g, 1g and 5g capsaicin per kg of lacquer produced 3 capsulesThe same concentration. Capsaicin was first dissolved in 10ml of diluent (International No.3) and then mixed into the paint. Only a mixture of the Fabio Eco and 10ml of diluent was used as a control. The paint mixture was allowed to stand for 1 hour prior to application. The lacquer was applied to a large number of plexiglass plates (11X 0.2 cm).

A total of 15 panels were painted.

5 plates were painted with control paint (0g/kg capsaicin)

5g/kg capsaicin on the surface of the fast board

5g/kg capsaicin on the surface of the fast board

The panels were left to dry at 21 ℃ for 24 hours according to the manufacturer's instructions. The panels were mounted on an aluminum frame and extended on a test raft 0.5-1m below the sea surface. The test raft is placed outside a ship biological laboratory with the water depth of 10 m. The painted panels were left for a period of time from 7/4/2001 to 8/31/2001. This time period is the period on the hull where marine life is first the most intense growth of the marine tulip (balanus provisus). The paint plate was then retrieved for immediate analysis.

Analysis of growth

The following paint plate analysis was performed:

and taking a picture of the paint plate.

The coverage of marine tulip (Balanus improvisus) was evaluated. The coverage of Mytilus edulis (Mytilus edulis) was evaluated. All growth on the paint plate was scraped off and the wet weight determined.

Drawings

The experimental results illustrated in fig. 1-6 show that significantly lower growth is obtained by treatment with a capsaicin concentration of 5g per kg of paint than the control treatment.

Figure 1 shows in bar graph the coverage of marine tulip (balanus provisus) with 3 different surface treatments. The bar graph represents the mean and standard deviation of 5 replicates.

From this graph it can be seen that the 5g capsaicin-treated surface per kg lacquer had significantly lower coverage than the other 2 treatments (1-factor analysis of difference, F)_2，1240.5; p < 0.0001). The reduction in growth was 74% as measured by marine tulip coverage.

FIG. 2 shows the coverage of Mytilus edulis (Mytilus edulis) determined by the same method as described in FIG. 1. The bar graph represents the mean and standard deviation of 5 replicates.

From this bar graph, it can be seen that there were no statistically significant differences between the 3 treatments (1-factor analysis of differences, F)_2，12＝3.0；p＞0.05)。

Fig. 3 shows the wet weight of the total growth on the 3 differently treated paint plates. The bar graph represents the mean and standard deviation of 5 replicates.

From this table it can be seen that 5g of capsaicin per kg of lacquer is significantly lower in growth than the two other treatments (1-factor analysis of difference, F_2，1212.6; p < 0.001). The reduction in growth was 64% as determined by the reduction in wet weight of the total growth.

FIG. 4 shows a plot (0g/kg) of 5 surfaces treated with control paint.

FIG. 5 shows a graph of 5 surfaces treated with the lowest concentration of 1 g/kg.

FIG. 6 shows a plot of 5 surfaces treated with the highest concentration of 5 g/kg. The surface in fig. 6 is clearly seen by visual comparison to be significantly lower in growth than the control surface.

Synthetic strategies and assays for the Synthesis of phenyl capsaicin

A detailed description of the synthesis of the novel compounds is given below. Reference is made to some documents collected in the list of documents listed at the end. Several syntheses of capsaicin and other capsaicinoids are known. 5-9 in the context of the present invention, the biological activity of capsaicin on marine microorganisms is of particular importance. To produce more potent capsaicinoids, synthetic strategies for capsaicin derivatives have been developed in which the carbon-carbon double bond has been replaced by a carbon-carbon triple bond. A general synthetic strategy is shown in table 1.

FIG. 1. retrosynthetic analysis of capsaicin alkyne analogs.

The synthetic strategy for capsaicin alkyne analogs is generally directed to the alkynyl material 8(R ═ aryl, alkyl, and the like). By varying the R-group, different capsaicin alkyne analogs can be synthesized and can thus be evaluated for biological activity. The first target molecule 1(R ═ Ph) yields alkynylbenzyne (8: R ═ Ph) and 4-hydroxy-3-methoxybenzaldehyde (vanillin) (4) and 5-chloro-1-pentanol (11) as substrates. 4-aminomethyl-2-methoxyphenol (vanillylamino) (2) was synthesized from vanillin (4) as described in the literature.⁶5-chloro-1-pentanol (11) is first protected as THP ether by using standard reaction conditions.^10，11The yield of the corresponding THP ether (10) was 95%. Substitution reaction with lithium phenylalkynide in THF (S)_N2) The desired product (7) was not produced, since elimination of lithium phenylalkynide and HCl (E) reacted as substrate from 10 was observed₂) The result of (a) is that the corresponding alkene is the only product formed. Sodium phenyl alkynide gave the same result. This problem is solved by 10 conversion to the corresponding iodine analogue 9 in the fenkelstein reaction (Frinkelstein reaction).^11-13The current substitution reaction proceeds well and alkyne 7 is formed in 85% yield. Acid catalyzed removal of THP protection in 7¹⁰An almost quantitative yield (97%) of alcohol 6 was produced. Modified Brown's chromic acid oxidation¹⁴Carboxylic acid 5 was produced in 90% yield. The 5 is then reacted with thionyl chloride to form the corresponding acid chloride 3 in 85% yield. Coupling reactions with acid chloride (3) and vanillylamino (2) produced 86% yield of the target molecule 7-phenylhex-6-yne-acid-4-hydroxy-3-methoxyThe benzyl amides (1) have not been synthesized to the best of the inventors' knowledge. The inventors propose phenyl capsaicin as the trivial name for 1.

Chart 2. experiment

Summary:

nuclear magnetic resonance spectra were obtained on a Varian 300MHz spectrometer, NRM 300MHz¹H-NMR spectrum and 75MHz¹³C-NMR spectrum. Tetramethylsilane (TMS) was used as an internal standard.¹Chemical shifts of the H-NMR spectrum are shown in ppm relative to TMS.¹³The C-NMR spectrum showed ppm (. delta.76.9 ppm) relative to deuterated chloroform. Thin layer chromatography was performed on Fluka silica gel plates (silica gel with fluorescent indicator/DC-Alufolien silica gel, product No. 60778). UV (. lamda. 254nm) or with MOP reagent (molyb-dato-phosphoric acid (14g) in ethanol (125mL) or CER-MOP reagent (molybdato-phosphoric acid (5g), cerium (IV) sulfate (2g) and 98W H₂SO₄(16mL) in water (mL)) and detection spotting was developed by heating a silica gel plate with a heat gun. Chemical reagents were supplied by Fluka, Sigma Aldrich, Acros, Merck and Lancaster. Standard drying methods were used as needed. Dry tetrahydrofuran was generated from sodium benzophenone ketyl under argon.

Reacting 2- (5-chloropentyloxy) tetrahydro-2H-pyran (10):

5-chloro-1-pentanol (12.26g, 0.1mol) is dissolved in dry dichloromethane (400 mL). Then 3, 4-dihydro-2H-pyran (12.62g, 0.15mol) and pyridyltoluene-4-sulfonate (1.26g, 5mmol) were added and the reaction mixture was magnetically stirred at room temperature overnight under nitrogen. A saturated solution of sodium bicarbonate (150mL) was added and the phases were separated. The aqueous phase was then extracted with dichloromethane (4X 5 mL). The combined dichloromethane phases were washed with water (2X 20mL) and then dried (MgSO₄). The dichloromethane was then distilled on a rotary evaporator and yielded 19. 6g (95%) of a pale yellow oil. Nuclear magnetic resonance showed pure product.

2- (5-iodopentyloxy) tetrahydro-2H-pyran (9):

a solution of 2- (5-chloropentyloxy) tetrahydro-2H-pyran (10) (20.67g, 0.1mol) in dry acetone (50mL) was added dropwise to a magnetically stirred solution of sodium iodide (16.49g, 0.11mol) in dry acetone (150 mL). The reaction mixture was refluxed under nitrogen overnight. After cooling, the precipitated sodium chloride is filtered off and the acetone is distilled off on a rotary evaporator. The residue, which still contained some sodium chloride, was dissolved in dry pentane (200 mL). The sodium chloride was filtered off and the pentane was distilled off on a rotary evaporator, yielding 26.2g (88%) of a yellow-brown oil. NMR showed pure product.

2- (7-phenylhex-6-ynyloxy) tetrahydro-2H-pyran (7):

BuLi (33.3mL, 50mmol, 1.5M) was added dropwise to a magnetically stirred solution of phenylacetylene (5.11g, 50mmol) in dry tetrahydrofuran (200mL) at 0 ℃ under nitrogen. After all the BuLi was added, the reaction mixture was stirred at 0 ℃ for 30 minutes. A solution of 2- (5-iodopentyloxy) tetrahydro-2H-pyran (9) (14.91g, 50mmol) in dry tetrahydrofuran (100mL) was added dropwise at 0 ℃. After the addition was complete, the reaction mixture was brought to room temperature in sequence and then refluxed overnight. The reaction was monitored by Thin Layer Chromatography (TLC). When all the substrate had been converted, water (300mL) was added and the aqueous phase was extracted with petroleum ether (bp 40-60 ℃ C.) (6X 50 mL). The combined organic phases were washed with water (4X 25mL) and then dried (MgSO)₄). Petroleum ether was distilled off on a rotary evaporator to yield 11.6g (85%). NMR showed pure product, therefore no further purification was required.

7-Phenylhex-6-yn-1-ol (6):

pyridinotoluene-4-sulfonate (0.75g, 3mmol) was added to a magnetically stirred solution of 2- (7-phenylhex-6-ynyloxy) -tetrahydro-2H-pyran (7) (13.62g, 50mmol) in dry methanol (300 mL). The reaction mixture was stirred at 55 ℃ and monitored by TLC. When all substrates were converted, methanol was distilled off on a rotary evaporator and water (200mL) was added to the residue. With petroleum ether(boiling point 40-60 ℃ C.)/Et₂O1: 1 (5X 50mL) extract the aqueous phase. The combined organic phases were washed with water (2X 20mL) and then dried (MgSO₄). Distillation on a rotary evaporator gave 9.1g (97%) of a yellow viscous oil. TLC and NMR showed pure product.

7-Phenylhex-6-ynoic acid (5):

brown's chromic acid reagent (133mL, 88mmol, 0,66M) was slowly added dropwise to a magnetically stirred solution of 7-phenylhex-6-yn-1-ol (6) (7.53g, 40mmol) in acetone (400mL) at 0 ℃. After chromic acid had been added, the reaction mixture was stirred at 0 ℃ and then at room temperature for 1 hour until TLC showed that all substrates had been converted. Water (300mL) and Petroleum Ether (bp 40-60 ℃ C.)/Et₂O1: 1 (6X 50mL) extract the aqueous phase. The combined organic phases were washed with water (2X 25mL) and then dried (MgSO)₄). Distillation on a rotary evaporator gave 7.3g (90%) of a pale yellow viscous oil which crystallized on standing. TLC and NMR showed pure product.

7-Phenylhex-6-ynoyl chloride (3):

a magnetically stirred mixture of 7-phenylhex-6-ynoic acid (5) (4.05g, 20mmol) and thionyl chloride (7.14g, 60mmol) was refluxed (100 ℃ C.) for 2 hours. Excess thionyl chloride was removed on a rotary evaporator to yield 3.7g (85%) of a brown oil. TLC and NMR showed pure product.

Vanillylamino (2):

vanillylamino acid was synthesized as described in the literature in 100mmol quantities.⁶

7-phenylhex-6-yne-acid-4-hydroxy-3-methoxybenzyl amide (phenyl capsaicin) (1):

7-Phenylhex-6-ynylchloride (3) (10mmol, 2.21g) as dried Et was added dropwise under argon₂O (25mL) solution was added to vanillylamino (2) (3.06g, 20mmol) in dry Et₂O (75 mL). The reaction mixture was refluxed until TLC showed that the substrate had converted. Diethyl ether was removed on a rotary evaporator to give 2.9g (86%) of a yellow viscous oil which crystallized on standing.TLC and NMR showed pure product.

Reference to the literature

[1]A.Dray，Biochem.Pharmacol.1992，44，611.

[2]M.J.Caterina，M.A.Schumacher，M.Tominaga，T.A.

Rosen，J.D.Levine.D.Julius，Nature 1997，389，816.

[3]P.Holzer，Pharmacol.Rev.1991，43，143.

[4]T.R.LaHahn，R.W.Farmer，Proc.West.Pharmacol Soc.1983，26，145

[5]P.M.Gannett，D.L.Nagel，P.J.Reilly，T.Lawson，J.Sharpe，B.Toth，J.Org.Chem.1988，53，1064.

[6]Kaga，H.，Miura，M.and Kazuhiko，O.J.Org.Chem.1989，54，3477.

[7]K.Kobata，K.Yoshikawa，M.Kohashi，T.Watanabe，TetrahedronLett.1996，37，2789.

[8]H.Kaga，K.Goto，T.Takahashi，M.Hino，T.Tokuhashi，K.Orito，Tetrahedron 1996，52，8451.

[9]O.Dasse，A.Mahadevan，L.Han，B.R.Martin，V.Di Marzo，R.K.Razdan，Tetrahedron 2000，569195.

[10]M.Miyashita，A.Yoshikoshi，P.A.Grieco，J.Org.Chem.

1977，42，3772.

[11]K.J.Shea，L.D.Burke，J.Org.Chem.1988，53，318.

[11]H.Finkelstein，Chem.Ber.1910，43，1528

[12]G.D.Branum，Tetrahedron Lett.1981，22，2055.

[13]M.F.Sartori，Chem.Rev.1951，48，237.

[14]H.C.Brown，C.P.Garg，K.T.Liu，J.Org.Chem.1971，63，387

Claims (13)

1. A compound characterized by having the general formula (1),

wherein R is alkyl, trifluoromethyl, cycloalkyl, phenyl or halogen.

2. A compound according to claim 1, wherein R is C₁-C₈An alkyl group.

3. A compound according to claim 1, wherein R is C₁-C₄An alkyl group.

4. The compound according to claim 2, wherein R is isopropyl.

5. A compound according to claim 2, wherein R is C₄An alkyl group.

6. The compound according to claim 1, wherein R is phenyl.

7. A process for producing a compound of the following formula (1),

comprises reacting a carboxylic acid or carboxylic acid derivative of the following formula (2) with vanillylamino of the formula (3) to produce a capsaicin derivative of the formula (1), wherein Z in the formula (2) is Cl, OH, R¹O, or NR¹ ₂，R¹Is alkyl, R is alkyl, trifluoromethyl, cycloalkyl, phenyl or halogen, and

8. the method of claim 7, wherein the compound of formula (2) is produced by the steps of:

reacting an acetylenic compound of the formula with protected 5-chloro-1-pentanol of the formula, wherein M is Li, Na, K, or EtMgBr:

to produce protected acetylenic alcohol compounds of the formula:

removal of the protecting group from this compound yields a free acetylenic alcohol compound of the formula:

oxidizing the compound to produce an acetylenic carboxylic acid of the formula:

optionally converting the carboxylic acid to a carboxylic acid derivative of formula (2)

Wherein Z is as defined in claim 7, except that it is OH.

9. The method of claim 8, wherein the carboxylic acid derivative of formula (2) is an acid chloride of the formula:

10. use of a compound of formula (1) according to any one of claims 1 to 6 for the preparation of a microbiocide composition.

11. Use of a compound of formula (1) according to any one of claims 1 to 6 for the production of a lacquer or coating.

12. A lacquer or coating comprising a compound of formula (1).

13. Use of the paint or coating of claim 12 in ships, marine installations, wood or land installations.