WO2001057229A1

WO2001057229A1 - Process for producing optically active 4-benzyloxy-3-hydroxybutyric acid esters

Info

Publication number: WO2001057229A1
Application number: PCT/JP2001/000735
Authority: WO
Inventors: Yoshihiko Yasohara; Junzo Hasegawa
Original assignee: Kaneka Corporation
Priority date: 2000-02-02
Filing date: 2001-02-02
Publication date: 2001-08-09
Also published as: AU2001230568A1

Abstract

A convenient and effective process for industrially producing optically active 4-benzyloxy-3-hydroxybutyric acid esters which are useful as intermediates of drugs, etc. A 4-benzyloxyacetoacetic acid ester is treated with a culture of a microorganism capable of asymmetrically reducing 4-benzyloxyacetoacetic acid esters or microbial cells separated from this culture, which have been optionally treated, and the thus formed optically active 4-benzyloxy-3-hydroxybutyric acid ester is collected.

Description

Specification

Method for producing optically active 4-benzyloxy-3-hydroxybutyrate

The present invention relates to a method for producing optically active 4-benzyloxy-3-hydroxybutyrate. Optically active 4-benzyloxy-3-hydroxybutyrate is used as a raw material for the synthesis of various pharmaceuticals. Background art

Conventionally, as a method for producing optically active 4-benzyloxy-3-hydroxybutyrate ester, a production method by asymmetric aldol condensation using a copper complex as a chiral Lewis acid (J. Am. Chem. Soc. Vol. 121, pp. 669, 1989 and pp. 118, 518, pp. 199, a process based on asymmetric hydrogenation using a ruthenium complex (S Synthesis, pp. 110, 199, J. Am. Chem. Soc. 110, Vol. 6, pp. 198, 1988, JP-A-6-87851, and JP-A-6-62522), a production method utilizing a reduction reaction with baker's yeast (Tetrahedron Letters, Vol. 39, p. 67, p. 1989, and Synthesis, p. 37, p. 1986) ) It has been known. Of these, the former two use an expensive asymmetric catalyst requiring a complicated preparation process and require a special reaction apparatus. According to the third method, the obtained 4-benzyloxy-3-hydroxybutyrate has a low optical purity and a low raw material concentration, which is not a practical method. Summary of the Invention

An object of the present invention is to provide an efficient method for producing optically active 4-^-hydroxyl-3-hydroxybutyrate, which is a useful synthetic intermediate for various pharmaceuticals. Detailed Disclosure of the Invention

The present inventors have developed a simple and efficient optically active 4- (1-benzyloxy) -3-hydroxy compound. As a result of intensive studies on the industrial production method of cybutyric acid esters, a microorganism having the ability to asymmetrically reduce the 3-position propyl group of the 4-benzyloxyacetoacetate ester to a hydroxyl group was found and completed the present invention. Reached.

That is, the present invention relates to the genera Arturoascus, Brettanomyces, Candida, Taliptococcus, Cisteromyces, Debaryomyces, Dipodascus, Genus Geotricum, Hormoascus, Isakenkia, Kluyveromyces, Komagataera , Rhodamyces, Mesienicobia, Ogataea, Pazosolen, Pichia, Rhodosporidium, Rhodotorula, Saccharomyces, Saccharomycopsis, Schizosaccharomyces, Sporoboromyces, Sizoblastosporion , Stefanoascus, Pseudomyces, Torulaspora, Trichosporon, Willioptis, Yamadaji genus, Chigosaccharomyces, Alcaligenes, Arthrobacter Genus, Genus Cyrus, Genus Brevibacterium, Genus Butyiaxella, Genus Sercoum, Genus Corynebacterium, Genus Comamonas, Genus Enterobacter, Genus Erwinia, Genus Escherichia, Klebsiella, Genus Micrococcus, Nocardia, Proteus Genus, Pseudomonas, Providencia, Rhodococcus, Serratia, Staphylococcus, Absizia, Acremo-Pum, Afanoascus, Aspergillus, Nosocraimis, Thyaetmidiz, Coprinus , Cubralaria, Dendrifiera, Emerycela, Eudisinium, Gibberella, Gromerella, Macroforma, Melanospora, Monascus, Morterella, Mucor, Neocosmospo Belonging to the genus selected from the group consisting of the genera, Penicillium, Proutus, Pycnopora, Rhizopus, Schleotuna, Schizophyllum, Sporomyela, Sporotrichum and Streptomyces; 4-benzyl A culture of a microorganism having the ability to asymmetrically reduce oxyacetoacetate, a microbial cell isolated from the culture or a processed product of the microbial cell is converted to 4-benzyloxyacetate. This is a method for producing optically active 4-benzyloxy-13-hydroxybutyrate, which comprises collecting optically active 4-benzyloxy-3-hydroxybutyrate produced by acting. The 4-benzyloxyacetoacetate ester used as a substrate in the present invention can be synthesized by a known method (see JP-A-6-87851 or Synthesis, page 104, 1995). . The ester chain of 4-benzyloxyacetate used in the present invention includes, for example, a saturated or unsaturated alkyl group such as a methyl group, an ethyl group, an isopropyl group, an n-butyl group, an isobutyl group and a tert-butyl group; An aryl group such as a phenyl group and a naphthyl group, and an aralkyl group such as a benzyl group can be used.

The microorganism used in the present invention for reducing 4-benzyloxyacetoacetate to 4-benzyloxy-3-hydroxybutyrate can be found, for example, by the method described below. In the case of yeast, for example, Darcos 3%, Peptone 0.5%, Potassium dihydrogen phosphate 0.2%, Nyanmonium phosphate 0.65%, Dipotassium hydrogen phosphate 0 1%, magnesium sulfate heptahydrate 0.006%, iron sulfate dehydrate 0.009%, copper sulfate pentahydrate 0.0005 ° /. , Manganese sulfate tetrahydrate 0.001%, sodium chloride 0.01%, yeast extract 0.3% A medium 5m1 (pH6.8) was put into a large test tube and sterilized. Inoculate the yeast and incubate at 30 ° C with shaking for 2-3 days. Thereafter, the cells were collected by centrifugation, and 4-benzyloxyacetoacetate was suspended in 2.5 ml of a phosphate buffer solution containing 0.1% to 0.1% and 2% darcos. In a large test tube for 2-3 days 3 (shake at TC.

The objective reduction ability was determined by adding 2.5 ml of methanol to the reaction solution after shaking culture, mixing well, and then forming 4-ethylbenzyl-3-hydroxybutyrate ethyl by high performance liquid chromatography. Column: YMC I-Pack ODS-A (4.6 mm x 250 mm), eluent: water Zacetonitrile = 55/45, flow rate: 0.8 ml / in, detection: 225 nm, column temperature : 30. C, elution time: 4-benzyloxy-3-ethylbutyrate; 8.4 minutes, 4-benzyloxyacetoacetate; 12.8 minutes. Note that this condition is merely an example].

The optical purity of the produced 4-benzyloxy-3-ethylbutyrate was determined by high performance liquid chromatography [column: Chira 1 ce 1 ~ OD (4.6 mm x 250 mm), eluent: hexane Z ethanol: 95 Z5, flow rate: 0.8 ml Zmin, detection: 225 nm, column temperature: room temperature, elution time: (S) 1-4 1-benzyloxyethyl 3-ethylbutyrate; 12 min, (R) -4 ethylbenzyloxyacetoacetate; 13.5 min. This condition is merely an example].

Further, when the microorganism used is a bacterium, for example, a B medium (pH 7.0) having a composition of 1% peptone, 1% meat extract, and 0.5% yeast extract is used. In the case of actinomycetes, a C medium (pH 6.0) consisting of 5% and 5% corn steep liquor, for example, a composition of 3% tryptic soybean soup made by Dico and 1% soluble starch Microorganisms are cultured using each of the D media (ρΗ7.2) consisting of the following, and microorganisms having the intended ability can be found by the same operation as described above.

Microorganisms that can be used in the present invention include those that give the (S) form of 4-benzyloxy-3-hydroxybutyrate, including those belonging to the genera Arthroascus, Brettanomyces, Candida, Cryptococcus, Devaliomyces, and Dipodascus. Genus, Geotricum, Hormoascus, Isakenkia, Komagataera, Kluyveromyces, Pichia, Williopsis, Rhodalomyces, Mesienicobia, Ogatata, Pasisolen, Rhodospolidium, Mouth Saxonorella Saccharomycopsis, Sporobochus myces, Schizoblast sporon, Stefanoascus, Schwanyomyces, Torrasbora, Trichosporon, Willioptis, Yamadajima , S. saccharomyces, Alcaligenes, Arthrobacter, Brevipacterium, Butyiaxella, Serum monas, Corynebacterium, Comamonas, Enterobacter, Ervinia, Escherichia, Micrococcas, Providencia Genus Proteus, Serratia, Staphylococcus, Abscissia, Acremonium, Afanoascus, Vasoclimis, Chiyaetmidium, Coprinas, Corinascus, Cubularia, Dendrifiera, Jemelera, Giberella , Macroforma, Melanospora, Morterella, Mucor, Proutus, Pycnopora, Microorganisms belonging to a genus selected from the group consisting of the genus Rhizopus, Sporotrichum and Streptomyces, and the like. More specifically, for example, microorganisms shown in Tables 1, 2, and 3 can be used.

Table 2

Minoo evening variety

Ogataea ^"inu! ^{A var} FO Nonfu Amen chest of drawers nonf rnentans

Ogataea pol niorpha j IFO 0799 Ogataea henr icii iFO 1477 Ogataea wi ckerhami i iFO 1706 Ogataea angusta JF0 1475

Pachysol en tannophi tus iFO 1007 Bikia 1 Bmundaris Ptchia binundai ts IFO 1366 Bikia Cana "ncis Pi chia canadensis iFO 0976 Bikia trehalofira Pichia trehafophi la iFO 12S2 Bikia triangularis Pichia triangularis IFO 08i iki Bika Anorama Pi chia janonal a IFO 0707 Bikia Anorama Variety Miso Pi chia anonal a var. Mi so: IFO 0144 Rhodesporidium toruloides IFO 0559 Road torula Aarrow carry Rhodotorula araucariado |

□ — κ Glutinis Variety

Lula glut inis var.

Rhodotorula IFO 0415 dairenensis

Rhodetorula graninis IFO 0190 Rhodotorula minute IFO 0387 Saccharonyces cerevis iae Hansen HUT 7017 Saccharomyces セス balam Sacctiaronyces uverun ATCC9080 Repolity power Saccharonycop5 is lipolytica ilFO 1209 Saccharomycopsis malanga 'Saccharomycops is malanga IFO 1710 Schizosaccharomyces ponbe IFO 0347 Step anoascus ci ferr ii IFO 1854 occidental is var.

Schwannionyces IFO 0371 Occidental is

Toru iaspora de Ibruecki i IFO 0381 Toru faspora globosa IFO 0016 Tori faspora globosa IFO 0016

IFO 0895 Muraki fliraki i

Saturnas variety saturnus vs factory.

Wili top wisdom Wi 11 tops is IFO 0809 suaveotens

Saturnas variety saturnus var.

Wili opsis is IFO 0992 Saturnas saturnus

Yanadazyma far inosa IFO 0534 Yanadazyna far inosa IFO 0193 Chigosaccharomyces barry Zygosaccharowyces bai 1 ij IFO 04B8 chigosaccharomyces i Mouth squid Icer alkaline zeogosaccharices 0 zygosacal genus zygosacxies ge genus zygosacxies ge. tr if icans ATCC 15173 Earthlobacta globi formis ATCC 8010 Earthlobacta pirotoformier 1 \ rthrobacter Drotophorrniae IFO 12128 Table 3

Microorganisms that give (R) -form 4-benzyloxy-13-hydroxybutyrate esters include Candida spp., Cisteromyces spp., Kluyveromyces spp. Genus Magataera, Genus Pichia, Genus Yamada, Genus Arthrobacter, Genus Bacillus, Genus Sermouth, Genus Enterobacter, Klebsiella, Nocardia, Proteus, Pseudomonas, Rhodococcus, Abscissia, Acremonium , Aspergillus, Emelysacea, Eudisinium, Monascus, Moretera, Neocosmosbora, Penicillium, Rhizopus, Shreoch-na, Schizophyllam, Sporomyela or Streptomyces Microorganisms to which they belong. More specifically, for example, microorganisms shown in Table 4 can be used.

Table 4

These microorganisms can generally be obtained from stocks that are easily available or purchased. It can also be separated from nature. In addition, by mutating these microorganisms, strains having more advantageous properties for this reaction can be obtained.

For cultivation of these microorganisms, any nutrient sources that these microorganisms can usually utilize Anything can be used. For example, sugars such as glucose, sucrose and maltose, organic acids such as lactic acid, acetic acid, cunic acid, and propionic acid, alcohols such as ethanol and glycerin, hydrocarbons such as paraffin, soybean oil, rapeseed oil, etc. Carbon sources such as oils and fats or a mixture thereof, and nitrogen sources such as ammonium sulfate, ammonium phosphate, urea, yeast extract, meat extract, peptone, corn steep liquor and the like can also be mixed. Further, other nutrients such as inorganic salts and vitamins may be appropriately mixed.

The cultivation of microorganisms can be carried out under general conditions, for example, pH 4.0 to 9.5, temperature range 20 to 45 ° C, aerobically 10 to 96. Incubate for hours. 4 When a microorganism is reacted with 1-benzyloxyacetoacetate, a culture solution of the microorganism can usually be used for the reaction as it is, but a concentrate of the culture solution can also be used. In addition, when components in the culture solution adversely affect the reaction, it is preferable to use cells obtained by treating the culture solution by centrifugation or the like, or processed cells.

The treated cells of the microorganisms are not particularly limited, and include, for example, dried cells obtained by dehydration with acetone or diphosphorus pentoxide or drying using a desiccator or a fan, treated with surfactants, Examples thereof include a lysate-treated product, immobilized cells or a cell-free extract prepared by crushing cells. Furthermore, an enzyme that catalyzes an asymmetric reduction reaction may be purified from a culture, and may be used without immobilization or immobilization.

In the case of the reduction reaction, the substrate 4 ^ -dioxy xyacetoacetate may be added all at once at the beginning of the reaction, or may be added in portions as the reaction progresses.

The temperature during the reaction is usually from 10 to 60 ° C, preferably from 20 to 40 ° C. The pH at the time of the reaction is 2.5-9, preferably 5-9.

The concentration of the microorganism in the reaction solution may be appropriately determined according to the ability to reduce these substrates. The substrate concentration in the reaction solution is preferably from 0.01 to 50% (W / V), and more preferably from 0.1 to 30%.

The reaction is usually carried out with shaking or aeration and stirring. Reaction time depends on substrate concentration, fine It is appropriately determined depending on the concentration of the organism and other reaction conditions. Usually, it is preferable to set each condition so that the reaction is completed in 2 to 168 hours.

When microbial cells are used to promote the reduction reaction, it is preferable to add an energy source such as dalcos or ethanol at a ratio of 1 to 30% to the reaction solution, since excellent results can be obtained.

In addition, coenzymes such as reduced nicotine amide 'adenine dinucleotide (NADH) and reduced nicotinamide-adenedin dinucleotide phosphate (NADPH), which are generally required for reduction by biological methods, are added. Thereby, the reaction can be promoted. Specifically, these may be added directly to the reaction solution, or the reaction system for producing NADH and NADPH may be added to the reaction solution together with the oxidized coenzyme. For example, a reaction system in which formate dehydrogenase reduces NAD to NADH when producing carbon dioxide and water from formic acid, or a reaction system in which glucose dehydrogenase produces dalconolactone from dalcose converts NAD or NADP to NADH. Or NA

A reaction system for reducing each to DPH can be used.

It is also effective to add a surfactant such as Triton (trade name, manufactured by Nakarai Tesque), Span (trade name, manufactured by Kanto Kagaku), Tween (trade name, manufactured by Nakarai Testa) to the reaction solution. It is. In addition, water-insoluble organic solvents such as ethyl acetate, butyl acetate, isopropyl ether, and toluene are added to the reaction solution to avoid inhibition of the reaction by the substrate and Z or the alcohol product that is the product of the reduction reaction. You may do it. Further, for the purpose of increasing the solubility of the substrate, a water-soluble organic solvent such as methanol, ethanol, acetone, tetrahydrofuran or dimethyl sulfoxide can be added.

The optically active ^4- benzyloxy-3-hydroxybutyrate produced by the reduction reaction can be collected directly from the reaction solution, or after separating cells by centrifugation, etc., extracting with a solvent such as ethyl acetate, toluene, etc. This is performed by dissolving the solvent. Furthermore, high-purity optically active 4-benzyloxy-3-hydroxybutyrate can be obtained by purification by distillation, silica gel column chromatography, or the like.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. In the following description, “%” means “weight./.” Unless otherwise specified.

(Example 1)

5 ml of the above-mentioned A medium was placed in a large test tube, sterilized, and then inoculated with the microorganisms shown in Tables 5, 6, and 7, respectively. Aerobic shaking culture was performed at 30 ° C for 2 to 3 days. The cells were collected from 1 ml of this culture by centrifugation, and 4% benzyloxyacetoethyl acetate 1% and glucose 2 were collected. /. Was suspended in 0.5 ml of 100 mM phosphate buffer (pH 6.5), and placed in a test tube with a screw stopper, followed by shaking at 30 ° C. for 20 hours. After the reaction, the same volume of methanol was added to the reaction solution, mixed well, and the supernatant from which the cells were removed by centrifugation was analyzed by high performance liquid chromatography to determine the reaction rate and the amount of 4-benzyloxy 3- The optical purity of the ethyl butyrate was measured. The results are shown in Tables 5, 6 and 7. Racemic 4-benzyloxyethyl 3-hydroxybutyrate was synthesized by reducing 4-benzyloxyethyl acetate with sodium borohydride. The determination of the absolute configuration of the configuration was performed with reference to Synthesis, p.

n o

Microbial Yield (X) i it Chemical Purity (Xee) Configuration Debaraisces roberts'iae IFO 1277 92.7 49.4 S Dipodascus armt 1 lariae IFO 0102 100 64.6 S Geotric uin candldun CBS 187.67 99.6 55.4 s Geotr ichunt fernentans IFO 1199 66.3 S2.6 s Holmoreskas bratipodis Honoo3scus platypod'is IFO 1471 99.6 7ft. Orientalis 1 ssatchenkta or ientaf is IFO Ϊ279 90.8 86.6 s Isagenkia terricola 1 ssatchenkia terricola IFO 0933 98.2 87.0 s Kluyveromyces marcianus Kluyveronyces narxianus IFO 0277 98.1 40.0 s sloga 10 s sloga 10 s sloga o porus IFO 1676 94.4Β2 s Nonfernentans IFO 1473 79.8 24.8 s years old Bolimorpha Ogataea pol norpha IFO 0799 99.4 50.6 s years old Ogataea aneusta IFO 1475 96.6 92, 4 s Pachysolen tannophi lus IFO 1007 72.2 46.8 s Pichia binundal is IFO 1366 84.4 53.0 s Pichia trehalo phi la IFO 1282 89.0 83.1 s Vichia triangularis IFO 0836 51.3 71.6 s Vikia Zika-Hamiichi Pichia jwicker ami i IFO 1278 99.0 62.8 s Vikia anorama Pichia ianonala IFO 0707 79.9 58.0 s Bikivara an IFO 0144 96.9 21.8 s Rhodsporid'iun toruloides IFO 0559 97.0 62.6 s Rhodesporid'iun toruloides Rhodotorula araucariae IFO 10053 88.2 74, 2 s Rhodes gurutinis Rhodotorula elutini s IFO 0395 93,7 17.1 Variety dairenensis Rhodotorula iluttnis var.

(Example 2)

The microorganisms shown in Table 8 were cultured in the same manner as in Example 1 using 5 ml of the B medium. Thereafter, the same reaction was performed, and the results are shown in Table 8.

1 ¹

o an

oo

The microorganisms shown in Tables 9 and 10 were used as in Example 1 using 5 ml of the C medium described above.

Fifteen

(J

Table 1 o

(Example 4)

Using 5 ml of the D medium described in Table 1 above, the microorganisms shown in the table were the same as in Example 1! Table 11

(Example 5)

A 50 Om 1 Sakaguchi flask containing 5 Om 1 of the B medium was inoculated with Brevibateterium 'Stationis (FOV 1244), and cultured with shaking at 30 ° C for 24 hours. After completion of the culture, the cells were collected by centrifugation and suspended in 25 ml of lOOmM phosphate buffer (pH 6.5). This The mixture was transferred to a Mitsuro flask, to which 0.5 g of glucose and ethyl 4-pentinoleoxyacetate were added, and reacted at 30 ° C. for 24 hours with stirring. During this time, the pH of the reaction solution was maintained at 6.5 with a 5N aqueous sodium hydroxide solution. After completion of the reaction, 50 ml of ethyl acetate was added to the reaction solution for extraction. The organic phase was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was purified by silica gel column chromatography to obtain 820 mg of (S) -ethyl 4-benzyloxy-13-hydroxybutyrate (yield 82%, optical purity 95% ee). The specific rotation and the ¹ H—NMR spectrum were as follows.

[a] D ²⁰ = -8.9 (C = 1.0, ethanol), 'H-NMR (40 OM Hz, CDC 13): ό = 1.24 (t, 3Η), 2. 52 (d, 2H), 3.

00 (d, 1H), 3.50 (m, 2H), 4.15 (q, 2H), 4.23 (m, 1H), 4.57 (s, 2H)

(Example 6)

Ogata angsta (Og a t a e a a n g u st a) using medium A

1 FO1475 was cultured in the same manner as in Example 6. Using the obtained cells, 4-ethylbenzyloxyacetoacetate was reduced in the same manner as in Example 6 to obtain 50 Omg of (S) -4-ethylbenzyloxy-3-ethylbutyrate. Rate 50%, optical purity 92% ee).

(Example 7)

Using medium C, Penicillium etaspansum (Penilicliumumexpansum) IFO 5854 was cultured in the same manner as in Example 6. Using the obtained cells, ethyl 4-benzyloxyacetoacetate was reduced in the same manner as in Example 6 to obtain 230 mg of ethyl (R) -4-benzyloxy-3-hydroxybutyrate (23% yield). , Optical purity 91% ee). Industrial applicability

According to the method of the present invention, 4- (1-benzyloxy) -3-hydroxybutyrate having high optical purity The acid ester can be conveniently obtained in high yield:

Claims

The scope of the claims

1. Genus Arturoascus, Brettanomyces, Candida, Cryptococcus, Cisteromyces, Debaryomyces, Divodascus, Genus Geotomicum, Holmoreskas, Isakenkia, Kluyveromyces, Komaga-taera, Rodaromyces Genus, Ogatata, Pasisolen, Pichia, Rhodosporidium, Rhodotorula, Saccharomyces, Saccharomycopsis, Schizosaccharomyces, Sporoboromyces, Schizoblastosporion, Stefanoa Genus Scas, genus Schneyomyces, genus Torula spora, genus Trichosporon, genus Williopsis, genus Yamadazyma, genus Chigosaccharomyces, genus Alcaligenes, genus Arthrobacter, Bacillus, Reviva bacterium, Butyiaxella, Serum monas, Corynebacterium, Comamonas, Enterobacter, Ervinia, Escherichia, Klebsiella, Micrococcus, Nocardia, Proteus, Pseudomonas, Providencia , Rhodococcus, Serratia, Staphylococcus, Absisidia, Acremonium, Afanoascus, Aspergillus, Basocoraimis, Tyaetmidimidium, Coprinas, Corinascus, Cubularia, Dendreriela , Eudinicillium, Gibberella, Gromerella, Macroforma, Melanospora, Monascus, Morterella, Mucor, Neocosmospora, Penicillium Belongs to the genus selected from the group consisting of Proutus, Pycnopora, Rhizopus, Shreotuna, Schizophyllum, Sporomyela, Sporotricum and Streptomyces, and comprises 4-benzyloxyacetoacetate. Culture activity of microorganisms capable of asymmetric reduction, microbial cells isolated from the cultures, or treated products of the microbial cells are allowed to act on 4-benzyloxyacetoacetate to produce optical activity A process for producing optically active 4-benzyloxy-3-hydroxybutyrate, comprising collecting a suitable 4-benzyloxy-3-hydroxybutyrate ester.

2. The microorganism is of the genus Arturoascus, Brettanomyces, Candida Genus, Cryptococcus, Debaryomyces, Divodacus, Genus Geotricum, Hormoascus, Isakenkia, Komagataera, Kluyveromyces, Pichia, Willioptis, Rhodamyces, Messienicobia, Rhodes sp. Polydium, Rhodotorula, Saccharomyces, Saccharomycopsis, Sporoboromyces, Schizoblast sporon, Stefanoascus, Schinyomyces, Torrasbora, Trichosporon, Williopsis, Yamadajima Genus, genus Chigosaccharomyces, genus Alcaligenes, genus Arthrobacter, brevibacterium, genus Butyia xella, genus Serum Monas, genus Corynebacterium, genus Comamonas, Genus Nterobacter, Erwinia, Escherichia, Micrococcus, Providencia, Proteus, Serratia, Staphylococcus, Abscissia, Acremonidum, Afanoascus, Bathocrymis, Tyaetkominas genus , Cubaria, Dendrifuiera, Emmericella, Gibberella, Gromerella, Macrophorma, Melanosbora, Mortellera, Muconore, Proutus, Pycnopora, Rhizopus, Sporoto 2. The process according to claim 1, wherein the process belongs to a genus selected from the group consisting of the genus Ricum and the genus Streptomyces and has the ability to produce (S) 141-benzyloxy-3-hydroxybutyrate. .

3. The microorganism is Candida, Cisteromyces, Kluyveromyces, Komagataera, Pichia, Yamadazyma, Arthrobacter, Bacillus, Cellu Monas, Enterobacter, Klebsiella, Nocardia, Proteus, Pseudomonas, Rhodococcus, Abscissia, Acremonium, Aspergillus, Emelisea, Eudisinirium, Monascus, Morterella, Neocosmosbora, Penicillium, Rhizopus, Shreochinina The genus selected from the group consisting of the genus Schizophyllum, the genus Sporomiera and the genus Streptomyces, which has the ability to produce (R) -4-benzyloxy-13-hydroxybutyrate. Manufacturing method.